Premature morbidity and mortality associated with potentially undiagnosed familial hypercholesterolemia in the general population.

Background: Familial hypercholesterolemia (FH) is common, but underdiagnosed, and few systematic early screening programs exist. Objective: To assess health outcomes among those with a recorded diagnosis of FH and potential cases of FH with no recorded diagnosis. Methods: Retrospective cohort study using the UK Clinical Practice Research Datalink. Records of adults were classified as diagnosed FH (FHCoded), or via accepted algorithms using LDL-C and clinical characteristics as potential FH (FHPotential) or unlikely FH (FHUnlikely) using the DLCN or EUROASPIRE criteria (but no record of FH). Outcomes assessed were premature cardiovascular (CV) events, premature deaths and life expectancy. Results: Among 1,729,046 individuals free from CV events, a record of FHCoded before the age of 40 was 0.3/1000 (IQR 0.3-0.4) and increased with age. Where LDL-C levels were available, 1.8/1000 (IQR 1.6-2.0) could be classified as FHPotential. LDL-C was higher for both FHCoded and FHPotential vs FHUnlikely (185.6 and 216.6 vs 116 mg/dL, respectively, p<0.001). Compared to FHUnlikely both FHCoded and FHPotential cohorts had a higher risk of premature cardiovascular events (both p<0.001) with highest rates among FHCoded. Risk of premature deaths did not differ between FHCoded and FHUnlikely, but was 1.88 (95% CI 1.27-2.78, p = 0.002) for FHPotential vs FHCoded and 2.40 (95% CI 1.57-3.67, p<0.001) for FHPotential vs FHUnlikely. At age 18, the FHPotential cohort had a life expectancy 16 years lower than the FHCoded cohort (p<0.001). Conclusions: Potential cases of FH had a doubling in risk of premature death and a large reduction in life expectancy compared to individuals with a recorded diagnosis of FH. These findings strengthen the critical importance of identifying potential cases of FH early and early treatment.

The Burden of Progressive Supranuclear Palsy on Patients, Caregivers, and Healthcare Systems by PSP Phenotype: A Cross-Sectional Study.

Progressive supranuclear palsy (PSP) is a rare, relentlessly progressive, ultimately fatal neurodegenerative brain disease. The objective of this study was to assess the burden of PSP on patients, caregivers, and healthcare systems by PSP phenotype. Data were drawn from the Adelphi PSP Disease Specific Programme™, a cross-sectional study of neurologists and people living with PSP in the United States of America, France, Germany, Italy, Spain, and the United Kingdom. All people living with PSP with a reported phenotype were included. PSP phenotype was reported for 242 patients (mean age: 70.2 years, 58% male): PSP-Richardson's syndrome, n = 96; PSP-predominant Parkinsonism, n = 88; PSP-predominant corticobasal syndrome, n = 28; PSP-predominant speech/language disorder, n = 12; PSP-progressive gait freezing, n = 9; PSP-predominant frontal presentation, n = 9. Most patients reported impaired cognitive, motor, behavioral and ocular functionality; 67-100% of patients (across phenotypes) had moderate-to-severe disease at the time of data collection. Post-diagnosis, the majority were provided with a visual and/or mobility aid (55-100%, across phenotypes), and/or required home modification to facilitate their needs (55-78%, across phenotypes). Patients required multiple types of healthcare professionals for disease management (mean 3.6-4.4, across phenotypes), and the majority reported receiving care from at least one caregiver (mean 1.3-1.8, across phenotypes). There is a high burden on patients, caregivers, and healthcare systems across all PSP phenotypes. Although phenotypes manifest different symptoms and are associated with different diagnostic pathways, once diagnosed with PSP, patients typically receive similar care.

Screening and treatment of familial hypercholesterolemia in a French sample of ambulatory care patients: A retrospective longitudinal cohort study.

BACKGROUND AND AIMS: Untreated Familial Hypercholesterolemia (FH) leads to premature morbidity and mortality. In France, its epidemiology and management are understudied in ambulatory care. We described the clinical profile, pharmacological management, and clinical outcomes in a French sample of FH patients. METHODS: This was a retrospective longitudinal study on patients from The Health Improvement Network (THIN®) database in France, between October 2016-June 2019. Patients ≥18 years, with probable/definite FH based on the Dutch Lipid Clinic Network (DLCN) criteria were included. Baseline characteristics, lipid profile, lipid-lowering therapy (LLT), low-density lipoprotein-cholesterol (LDL-C) goal achievement; and disease management at 6-month of follow-up were analyzed. RESULTS: 116 patients with probable (n = 70)/definite (n = 46) FH were included (mean age:57.8±14.0 years; 56.0% women; 9.5% with personal history of cardiovascular events); 90 patients had data available at follow-up. At baseline, 77.6% of patients had LDL-C>190 mg/dL, 27.6% were not receiving LLTs, 37.9% received statins alone, 20.7% statins with other LLTs, and 7.7% other LLTs. High-intensity statins were prescribed to 11.2% of patients, 30.2% received moderate-intensity statins, and 8.6% low-intensity statins. Only 6.0% of patients achieved LDL-C goal. At 6-month of follow-up, statins discontinuation and switching were 22.7% and 2.3%, respectively. None of the patients received proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors at baseline nor follow-up. CONCLUSIONS: Despite the existence of effective LLTs, FH patients are suboptimally-treated, do not achieve LDL-C goal, and exhibit worsened pharmacological management over time. Future studies with longer follow-up periods and assessment of factors affecting LDL-C management, including lifestyle and diet, are needed.

Stage-specific survival and recurrence in patients with cutaneous malignant melanoma in Europe - a systematic review of the literature.

BACKGROUND: Given the increasing incidence in cutaneous malignant melanoma (CMM) and the recent changes in the treatment landscape, it is important to understand stage-specific overall and recurrence-free survival patterns in Europe. Despite publications such as EUROCARE-5, there is limited information on stage-specific survival for CMM in Europe. METHOD: We carried out a systematic literature review to provide an up-to-date summary of stage-specific survival and recurrence-free survival patterns in patients with CMM in Europe. Studies were included if they were published in Medline during the past 12 years and included information on stage-specific survival and/or recurrence in CMM. RESULTS: Of the 8,749 studies identified, 26 studies were included, representing nine countries. Collectively, the studies covered a population of 152,422 patients and included data from 1978 to 2011. Randomized clinical trials and single-center observational studies comprised the most common study designs, including five large registry-based studies. Stage-specific information for survival and recurrence varied: 5-year overall survival: 95%-100% (stage I), 65%-92.8% (stage II), 41%-71% (stage III), and 9%-28% (stage IV); 5-year relapse-free survival was reported less frequently: 56% (stage II), and 28%-44% (stage III). Studies reporting survival by sentinel node (SN) status reported 5-year overall survival as 80%-95% for negative SN (stage I/II) and 35%-75% for positive SN (stage III) status; recurrence-free survival at 5 years: 76%-90% for negative and 35%-58% for positive SN status. Some studies included comparisons of survival by key patient sociodemographic characteristics, suggesting that these have a substantial influence on survival and recurrence estimates. CONCLUSION: The studies identified in this review show large variations in stage-specific overall and recurrence-free survival by study type and by country. Owing to differing study designs and populations, it is difficult to make detailed comparisons. Large population-based studies that include stage-specific survival and recurrence in Europe are therefore important.

Parenting style in childhood and mortality risk at older ages: a longitudinal cohort study.

BACKGROUND: Parenting style is associated with offspring health, but whether it is associated with offspring mortality at older ages remains unknown. AIMS: We examined whether childhood experiences of suboptimal parenting style are associated with increased risk of death at older ages. METHOD: Longitudinal cohort study of 1964 community-dwelling adults aged 65-79 years. RESULTS: The association between parenting style and mortality was inverse and graded. Participants in the poorest parenting style score quartile had increased risk of death (hazard ratio (HR) = 1.72, 95% CI 1.20-2.48) compared with those in the optimal parenting style score quartile after adjustment for age and gender. Full adjustment for covariates partially explained this association (HR = 1.49, 95% CI 1.02-2.18). Parenting style was inversely associated with cancer and other mortality, but not cardiovascular mortality. Maternal and paternal parenting styles were individually associated with mortality. CONCLUSIONS: Experiences of suboptimal parenting in childhood are associated with increased risk of death at older ages.

Cross-sectional study on comorbidities and adverse events in patients with advanced and recurrent ovarian cancer in France.

PURPOSE: The purpose of this study was to evaluate the prevalence of comorbidities and adverse events (AEs), and determine the treatment patterns according to platinum-sensitivity status in patients with advanced (stage IIIB-IV) or recurrent epithelial ovarian cancer (EOC). METHODS: A cross-sectional study was carried out in France with patients over 18 years, diagnosed with advanced (stage IIIB-IV) or recurrent EOC between 2009 and 2012. A total of 23 physicians (oncologists and gynecologists) participated, contributing 127 patients. Data were abstracted by participating physicians into a case report form. RESULTS: Of the 127 patients included, 92 (72.4%) had advanced EOC and 35 (27.6%) had recurrent EOC. A total of 73 comorbidities were reported in 44 patients (34.6%). Vascular (10.2%), metabolic (7.1%), respiratory (5.5%), and psychiatric disorders (5.5%) were the most common types of comorbidities reported. Prevalence of AEs was 74.8%, of which 12.6% were classified as serious. The most common AEs were anemia (16.5%), hematologic events (12.6%), taste change (11.8%), and headache (7.1%). Throughout the follow-up period, twelve patient deaths were reported (six due to disease progression). Of 35 patients with recurrent disease, 16 were highly platinum sensitive (recurrence >12 months after stopping platinum-based therapy), eleven were partially platinum sensitive (recurrence 6-12 months after stopping platinum-based therapy), seven were platinum resistant (recurrence within 6 months of stopping platinum-based therapy or progression while receiving second- or later-line platinum-based therapy), and one was platinum refractory (recurrence within 6 months from the start of first-line platinum-based therapy). CONCLUSION: In this cross-sectional study of advanced and metastatic ovarian cancer patients, approximately one-third of patients were diagnosed with comorbidities, and approximately three-quarters were diagnosed with AEs (12.6% with severe AEs).

Early Childhood Development and Schooling Attainment: Longitudinal Evidence from British, Finnish and Philippine Birth Cohorts.

BACKGROUND: While recent literature has highlighted the importance of early childhood development for later life outcomes, comparatively little is known regarding the relative importance of early physical and cognitive development in predicting educational attainment cross-culturally. METHODS: We used prospective data from three birth cohorts: the Northern Finland Birth Cohort of 1986 (NFBC1986), the 1970 British Cohort Study (BCS1970), and the Cebu Longitudinal Health and Nutrition Survey of 1983 (CLHNS) to assess the association of height-for-age z-score (HAZ) and cognitive development measured prior to age 8 with schooling attainment. Multivariate linear regression models were used to estimate baseline and adjusted associations. RESULTS: Both physical and cognitive development were highly predictive of adult educational attainment conditional on parental characteristics. The largest positive associations between physical development and schooling were found in the CLHNS (ß = 0.53, 95%-CI: [0.32, 0.74]) with substantially smaller associations in the BCS1970 (ß = 0.10, 95% CI [0.04, 0.16]) and the NFBC1986 (ß = 0.06, 95% CI [-0.05, 0.16]). Strong associations between cognitive development and educational attainment were found for all three cohorts (NFBC1986: ß = 0.22, 95%-CI: [0.12, 0.31], BCS1970: ß = 0.58, 95%-CI: [0.52, 0.64], CLHNS: ß = 1.08, 95%-CI: [0.88, 1.27]). Models jointly estimating educational associations of physical and cognitive development demonstrated weaker associations for physical development and minimal changes for cognitive development. CONCLUSION: The results indicate that although physical and cognitive early development are both important predictors of educational attainment, cognitive development appears to play a particularly important role. The large degree of heterogeneity in the observed effect sizes suggest that the importance of early life physical growth and cognitive development is highly dependent on socioeconomic and institutional contexts.

Common variation near ROBO2 is associated with expressive vocabulary in infancy.

Twin studies suggest that expressive vocabulary at ~24 months is modestly heritable. However, the genes influencing this early linguistic phenotype are unknown. Here we conduct a genome-wide screen and follow-up study of expressive vocabulary in toddlers of European descent from up to four studies of the EArly Genetics and Lifecourse Epidemiology consortium, analysing an early (15-18 months, 'one-word stage', N(Total) = 8,889) and a later (24-30 months, 'two-word stage', N(Total)=10,819) phase of language acquisition. For the early phase, one single-nucleotide polymorphism (rs7642482) at 3p12.3 near ROBO2, encoding a conserved axon-binding receptor, reaches the genome-wide significance level (P=1.3 × 10(-8)) in the combined sample. This association links language-related common genetic variation in the general population to a potential autism susceptibility locus and a linkage region for dyslexia, speech-sound disorder and reading. The contribution of common genetic influences is, although modest, supported by genome-wide complex trait analysis (meta-GCTA h(2)(15-18-months) = 0.13, meta-GCTA h(2)(24-30-months) = 0.14) and in concordance with additional twin analysis (5,733 pairs of European descent, h(2)(24-months) = 0.20).

Social inequalities in early childhood health and development: a European-wide systematic review.

The evidence examining the relationship between specific social factors and early childhood health and developmental outcomes has never been systematically collated or synthesized. This review aims to identify the key social factors operating at the household, neighborhood, and country levels that drive inequalities in child health and development. Medline and CHICOS (a European child-cohort inventory) were systematically searched to identify all European studies published within the past 10 y. 13,270 Medline articles and 77 European child cohorts were searched, identifying 201 studies from 32 European countries. Neighborhood deprivation, lower parental income/wealth, educational attainment, and occupational social class, higher parental job strain, parental unemployment, lack of housing tenure, and household material deprivation were identified as the key social factors associated with a wide range of adverse child health and developmental outcomes. Similar association trends were observed across most European countries, with only minor country-level differences. Multiple adverse social factors operating at both the household and neighborhood levels are independently associated with a range of adverse health and developmental outcomes throughout early childhood. The social gradient in health and developmental outcomes observed throughout the remaining life course may be partly explained by gradients initiated in early childhood.

Infant locomotive development and its association with adult blood pressure.

UNLABELLED: Evidence from animal models suggests that locomotion and blood pressure share common neurophysiological regulatory systems. As a result of this common regulation, we hypothesized that the development of locomotion in human infants would be associated with blood pressure levels in adulthood. The study sample comprised 4,347 individuals with measures of locomotive and non-locomotive neuromotor development in infancy and adult blood pressure levels within a longitudinal birth cohort study, the Northern Finland Birth Cohort 1966. Later development in all three stages of locomotive development during infancy was associated with higher systolic and diastolic blood pressure levels at age 31. For age of walking without support, 0.34 (95 % CI 0.07 to 0.60)-mm Hg higher SBP and 0.38 (95 % CI 0.15 to 0.62)-mm Hg higher DBP were estimated for each month of later achievement (P = 0.012 for SBP; P = 0.001 for DBP). No association was identified for non-locomotive neuromotor development. CONCLUSION: These results highlight the positive sequelae of advanced locomotive development during infancy, suggesting that the common regulatory systems between locomotion and blood pressure may influence the development of raised blood pressure over time.

Suicide, fatal injuries, and other causes of premature mortality in patients with traumatic brain injury: a 41-year Swedish population study.

UNLABELLED: : IMPORTANCE: Longer-term mortality in individuals who have survived a traumatic brain injury (TBI) is not known. OBJECTIVES: To examine the relationship between TBI and premature mortality, particularly by external causes, and determine the role of psychiatric comorbidity. DESIGN, SETTING, AND PATIENTS: We studied all persons born in 1954 or later in Sweden who received inpatient and outpatient International Classification of Diseases-based diagnoses of TBI from 1969 to 2009 (n = 218,300). We compared mortality rates 6 months or more after TBI to general population controls matched on age and sex (n = 2,163,190) and to unaffected siblings of patients with TBI (n = 150,513). Furthermore, we specifically examined external causes of death (suicide, injury, or assault). We conducted sensitivity analyses to investigate whether mortality rates differed by sex, age at death, severity (including concussion), and different follow-up times after diagnosis. MAIN OUTCOMES AND MEASURES: Adjusted odds ratios (AORs) of premature death by external causes in patients with TBI compared with general population controls. RESULTS: Among those who survived 6 months after TBI, we found a 3-fold increased odds of mortality (AOR, 3.2; 95% CI, 3.0-3.4) compared with general population controls and an adjusted increased odds of mortality of 2.6 (95% CI, 2.3-2.8) compared with unaffected siblings. Risks of mortality from external causes were elevated, including for suicide (AOR, 3.3; 95% CI, 2.9-3.7), injuries (AOR, 4.3; 95% CI, 3.8-4.8), and assault (AOR, 3.9; 95% CI, 2.7-5.7). Among those with TBI, absolute rates of death were high in those with any psychiatric or substance abuse comorbidity (3.8% died prematurely) and those with solely substance abuse (6.2%) compared with those without comorbidity (0.5%). CONCLUSIONS AND RELEVANCE: Traumatic brain injury is associated with substantially elevated risks of premature mortality, particularly for suicide, injuries, and assaults, even after adjustment for sociodemographic and familial factors. Current clinical guidelines may need revision to reduce mortality risks beyond the first few months after injury and address high rates of psychiatric comorbidity and substance abuse.

Genome-wide association study of primary tooth eruption identifies pleiotropic loci associated with height and craniofacial distances.

Twin and family studies indicate that the timing of primary tooth eruption is highly heritable, with estimates typically exceeding 80%. To identify variants involved in primary tooth eruption, we performed a population-based genome-wide association study of 'age at first tooth' and 'number of teeth' using 5998 and 6609 individuals, respectively, from the Avon Longitudinal Study of Parents and Children (ALSPAC) and 5403 individuals from the 1966 Northern Finland Birth Cohort (NFBC1966). We tested 2 446 724 SNPs imputed in both studies. Analyses were controlled for the effect of gestational age, sex and age of measurement. Results from the two studies were combined using fixed effects inverse variance meta-analysis. We identified a total of 15 independent loci, with 10 loci reaching genome-wide significance (P < 5 × 10(-8)) for 'age at first tooth' and 11 loci for 'number of teeth'. Together, these associations explain 6.06% of the variation in 'age of first tooth' and 4.76% of the variation in 'number of teeth'. The identified loci included eight previously unidentified loci, some containing genes known to play a role in tooth and other developmental pathways, including an SNP in the protein-coding region of BMP4 (rs17563, P = 9.080 × 10(-17)). Three of these loci, containing the genes HMGA2, AJUBA and ADK, also showed evidence of association with craniofacial distances, particularly those indexing facial width. Our results suggest that the genome-wide association approach is a powerful strategy for detecting variants involved in tooth eruption, and potentially craniofacial growth and more generally organ development.

Relation of immediate postnatal growth with obesity and related metabolic risk factors in adulthood: the northern Finland birth cohort 1966 study.

The authors examined associations between postnatal growth velocity through age 2 years and metabolic outcomes at age 31 years in a population-based birth-cohort study of 3,778 Finns (1966-1998). Approximately 8 height measurements and 9 weight measurements were obtained from birth to age 2 years. Peak height velocity (PHV) and peak weight velocity (PWV) in infancy were derived from parametric growth curves fitted to longitudinal height and weight growth data. Body mass index (BMI), waist circumference (WC), high density lipoprotein (HDL) cholesterol, triglycerides, glucose, systolic and diastolic blood pressure (BP), and the metabolic syndrome were measured at age 31 years. PHV was significantly positively associated with systolic and diastolic BP and WC in adulthood. For each 8-cm/year (2-standard-deviation) increase in PHV, WC increased by 1.60 cm (95% confidence interval: 0.73, 2.46), after adjustment for potential confounders, including birth weight. PWV was significantly associated with adulthood systolic BP, WC, and BMI. A 4-kg/year higher PWV was associated with a 1.87-cm (95% confidence interval: 1.08, 2.65) larger WC in adulthood, after adjustment for potential confounders. HDL cholesterol (direct), triglycerides (inverse), and metabolic syndrome (inverse) displayed associations with PWV only after BMI was accounted for. These results showed that growth during the immediate postnatal period is associated with adulthood obesity and BP. Lifestyle changes from early life might be important in reducing adulthood obesity and high-BP risk.

Genome-wide association study reveals multiple loci associated with primary tooth development during infancy.

Tooth development is a highly heritable process which relates to other growth and developmental processes, and which interacts with the development of the entire craniofacial complex. Abnormalities of tooth development are common, with tooth agenesis being the most common developmental anomaly in humans. We performed a genome-wide association study of time to first tooth eruption and number of teeth at one year in 4,564 individuals from the 1966 Northern Finland Birth Cohort (NFBC1966) and 1,518 individuals from the Avon Longitudinal Study of Parents and Children (ALSPAC). We identified 5 loci at P<5x10(-8), and 5 with suggestive association (P<5x10(-6)). The loci included several genes with links to tooth and other organ development (KCNJ2, EDA, HOXB2, RAD51L1, IGF2BP1, HMGA2, MSRB3). Genes at four of the identified loci are implicated in the development of cancer. A variant within the HOXB gene cluster associated with occlusion defects requiring orthodontic treatment by age 31 years.

Genetic determinants of height growth assessed longitudinally from infancy to adulthood in the northern Finland birth cohort 1966.

Recent genome-wide association (GWA) studies have identified dozens of common variants associated with adult height. However, it is unknown how these variants influence height growth during childhood. We derived peak height velocity in infancy (PHV1) and puberty (PHV2) and timing of pubertal height growth spurt from parametric growth curves fitted to longitudinal height growth data to test their association with known height variants. The study consisted of N = 3,538 singletons from the prospective Northern Finland Birth Cohort 1966 with genotype data and frequent height measurements (on average 20 measurements per person) from 0-20 years. Twenty-six of the 48 variants tested associated with adult height (p<0.05, adjusted for sex and principal components) in this sample, all in the same direction as in previous GWA scans. Seven SNPs in or near the genes HHIP, DLEU7, UQCC, SF3B4/SV2A, LCORL, and HIST1H1D associated with PHV1 and five SNPs in or near SOCS2, SF3B4/SV2A, C17orf67, CABLES1, and DOT1L with PHV2 (p<0.05). We formally tested variants for interaction with age (infancy versus puberty) and found biologically meaningful evidence for an age-dependent effect for the SNP in SOCS2 (p = 0.0030) and for the SNP in HHIP (p = 0.045). We did not have similar prior evidence for the association between height variants and timing of pubertal height growth spurt as we had for PHVs, and none of the associations were statistically significant after correction for multiple testing. The fact that in this sample, less than half of the variants associated with adult height had a measurable effect on PHV1 or PHV2 is likely to reflect limited power to detect these associations in this dataset. Our study is the first genetic association analysis on longitudinal height growth in a prospective cohort from birth to adulthood and gives grounding for future research on the genetic regulation of human height during different periods of growth.

Economic aspects of epilepsy and antiepileptic treatment: a review of the literature.

The recent literature on the economic aspects of epilepsy and antiepileptic treatment are systematically reviewed. Studies for this literature review were selected by conducting a Medline literature search from January 1998 to October 2004. Studies reviewed had to follow one of the standard methods of health economics evaluation (cost of illness, cost-minimization analysis, cost-effectiveness analysis, cost-benefit analysis and cost-utility analysis). A total of 31 epilepsy cost studies were reviewed. Cost-of-illness studies showed a marked difference in cost between countries and healthcare systems. Cost-minimization analysis evaluations of four drugs with equivalent clinical efficacy found lamotrigine to be the most costly and carbamazepine the most economic. Cost-effectiveness analysis studies found topiramate to be more cost effective than lamotrigine, and surgical lobectomy to be a very cost-effective treatment in the long term. Cost-benefit analysis studies generally focused on vagal nerve stimulation and epilepsy surgery, and found both treatment modalities to be significantly cost beneficial. Only two cost-utility analysis studies were performed and found long-term lamotrigine treatment to be less economically effective than most other pharmacologic treatments of serious disorders. Vagal nerve stimulation was found to be of questionable economic value and further research is necessary for clarification. The methodologic heterogeneity observed in the studies reviewed makes comparisons between them difficult. Nevertheless, many interesting interpretations arise from the results. Cost-effectiveness analysis studies were found to be much more credible than cost-minimization or cost-benefit analysis evaluations since they avoid efficacy of drugs being reduced to clinical efficacy parameters alone. Cost-utility analysis studies were found to be the most promising type of economic analysis since they are the only type of analysis that incorporates the patients' point of view. In conclusion, comparison across studies can only be achieved if future studies follow a common set of methods and similar economic-evaluation models. A collaborative effort of all experts involved is necessary if this is to be achieved.