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1.
BMJ ; 373: n1114, 2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-33952445

RESUMO

OBJECTIVE: To assess rates of cardiovascular and haemostatic events in the first 28 days after vaccination with the Oxford-AstraZeneca vaccine ChAdOx1-S in Denmark and Norway and to compare them with rates observed in the general populations. DESIGN: Population based cohort study. SETTING: Nationwide healthcare registers in Denmark and Norway. PARTICIPANTS: All people aged 18-65 years who received a first vaccination with ChAdOx1-S from 9 February 2021 to 11 March 2021. The general populations of Denmark (2016-18) and Norway (2018-19) served as comparator cohorts. MAIN OUTCOME MEASURES: Observed 28 day rates of hospital contacts for incident arterial events, venous thromboembolism, thrombocytopenia/coagulation disorders, and bleeding among vaccinated people compared with expected rates, based on national age and sex specific background rates from the general populations of the two countries. RESULTS: The vaccinated cohorts comprised 148 792 people in Denmark (median age 45 years, 80% women) and 132 472 in Norway (median age 44 years, 78% women), who received their first dose of ChAdOx1-S. Among 281 264 people who received ChAdOx1-S, the standardised morbidity ratio for arterial events was 0.97 (95% confidence interval 0.77 to 1.20). 59 venous thromboembolic events were observed in the vaccinated cohort compared with 30 expected based on the incidence rates in the general population, corresponding to a standardised morbidity ratio of 1.97 (1.50 to 2.54) and 11 (5.6 to 17.0) excess events per 100 000 vaccinations. A higher than expected rate of cerebral venous thrombosis was observed: standardised morbidity ratio 20.25 (8.14 to 41.73); an excess of 2.5 (0.9 to 5.2) events per 100 000 vaccinations. The standardised morbidity ratio for any thrombocytopenia/coagulation disorders was 1.52 (0.97 to 2.25) and for any bleeding was 1.23 (0.97 to 1.55). 15 deaths were observed in the vaccine cohort compared with 44 expected. CONCLUSIONS: Among recipients of ChAdOx1-S, increased rates of venous thromboembolic events, including cerebral venous thrombosis, were observed. For the remaining safety outcomes, results were largely reassuring, with slightly higher rates of thrombocytopenia/coagulation disorders and bleeding, which could be influenced by increased surveillance of vaccine recipients. The absolute risks of venous thromboembolic events were, however, small, and the findings should be interpreted in the light of the proven beneficial effects of the vaccine, the context of the given country, and the limitations to the generalisability of the study findings.

2.
Mayo Clin Proc ; 96(3): 550-562, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33673909

RESUMO

OBJECTIVE: To examine the association between body mass index (BMI) and mortality after hospitalization for infection because obesity is associated with increased energy reserves that may protect against death from severe infections. PATIENTS AND METHODS: Of 76,044 patients admitted with a primary infection diagnosis from January 1, 2011, to September 30, 2015, in Central Denmark, we examined a subgroup of 35,406 patients with a known BMI. We compared the 90-day death risk among patients with underweight, overweight, or obesity with a reference cohort of normal-weight patients. We also examined the impact of comorbid conditions, including cancer, tobacco smoking, and recent weight changes, on the associations and adjusted for other potential confounding factors. RESULTS: The 90-day mortality after hospital admission was 9.8% (3479 of 35,406) for any infection, 10.5% (466 of 4425) for urinary tract infection, 17.3% (1536 of 8855) for pneumonia, 24.9% (986 of 3964) for sepsis, and 6.2% (114 of 1831) for skin infection. The 90-day adjusted hazard ratio (aHR) for death was substantially increased in patients with underweight (aHR, 1.75; 95% CI, 1.58 to 1.94) compared with normal-weight patients. In contrast, mortality aHRs were decreased in patients with overweight (aHR, 0.64; 95% CI; 0.58 to 0.69) and obesity (aHR, 0.55; 95% CI; 0.49 to 0.62). Mortality reductions with overweight and obesity were consistent for all major infection types and remained robust independent of recent weight changes, smoking status, or comorbid conditions. Mortality was highest in patients without an apparent reason for their underweight (smoking/known disease), suggesting a role of undiagnosed comorbid conditions. CONCLUSION: We found evidence that higher BMI (overweight and obesity) is associated with improved survival following acute hospitalization for infection, whereas underweight increases the risk for death.


Assuntos
Infecções Bacterianas/mortalidade , Índice de Massa Corporal , Hospitalização/estatística & dados numéricos , Índice de Gravidade de Doença , Magreza/mortalidade , Adulto , Idoso , Bacteriemia/mortalidade , Causalidade , Comorbidade , Estado Terminal/mortalidade , Dinamarca , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medição de Risco , Fatores de Risco , Magreza/complicações
3.
Artigo em Inglês | MEDLINE | ID: mdl-33755191

RESUMO

INTRODUCTION: Immunosuppressant drugs are increasingly being used in the reproductive years. Theoretically, such medications could affect fetal health either through changes in the sperm DNA or through fetal exposure caused by a presence in the seminal fluid. This systematic overview summarizes existing literature on the spermatotoxic and genotoxic potentials of methotrexate (MTX), a drug widely used to treat rheumatic and dermatologic diseases, and mycophenolate mofetil (MMF), which alone or supplemented with ganciclovir (GCV) may be crucial for the survival of organ transplants. MATERIAL AND METHODS: The systematic overview was performed in accordance with the PRISMA guidelines: A systematic literature search of the MEDLINE and Embase databases was done using a combination of relevant terms to search for studies on spermatotoxic or genotoxic changes related to treatment with MTX, GCV or MMF. The search was restricted to English language literature, and to in vivo animal studies (mammalian species) and clinical human studies. RESULTS: A total of 102 studies were identified, hereof 25 human and 77 animal studies. For MTX, human studies of immunosuppressive dosages show transient effect on sperm quality parameters, which return to reference values within 3 months. No human studies have investigated the sperm DNA damaging effect of MTX, but in other organs the genotoxic effects of immunosuppressive doses of MTX are fluctuating. In animals, immunosuppressive and cytotoxic doses of MTX adversely affect sperm quality parameters and show widespread genotoxic damages in various organs. Cytotoxic doses transiently change the DNA material in all cell stages of spermatogenesis in rodents. For GCV and MMF, data are limited and the results are indeterminate, for which reason spermatotoxic and genotoxic potentials cannot be excluded. CONCLUSIONS: Data from human and animal studies indicate transient spermatotoxic and genotoxic potentials of immunosuppressive and cytotoxic doses of MTX. There are a limited number of studies investigating GCV and MMF.

4.
Proc Natl Acad Sci U S A ; 118(11)2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33688047

RESUMO

The mosquito protein AEG12 is up-regulated in response to blood meals and flavivirus infection though its function remained elusive. Here, we determine the three-dimensional structure of AEG12 and describe the binding specificity of acyl-chain ligands within its large central hydrophobic cavity. We show that AEG12 displays hemolytic and cytolytic activity by selectively delivering unsaturated fatty acid cargoes into phosphatidylcholine-rich lipid bilayers. This property of AEG12 also enables it to inhibit replication of enveloped viruses such as Dengue and Zika viruses at low micromolar concentrations. Weaker inhibition was observed against more distantly related coronaviruses and lentivirus, while no inhibition was observed against the nonenveloped virus adeno-associated virus. Together, our results uncover the mechanistic understanding of AEG12 function and provide the necessary implications for its use as a broad-spectrum therapeutic against cellular and viral targets.

5.
Cancer Epidemiol Biomarkers Prev ; 30(5): 886-894, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33627380

RESUMO

BACKGROUND: Inflammatory bowel disease (IBD) has been associated with hepatobiliary cancer, but existing evidence is poor. We evaluated risk of death from hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), and extrahepatic cholangiocarcinoma (ECC) among patients with IBD. METHODS: This Swedish/Danish population-based cohort study (1969-2017) followed patients with IBD and 1:10 matched population comparators from their diagnosis/match date until death, emigration, or end of follow-up. RESULTS: Among the 97,496 patients with ulcerative colitis/963,026 comparators, we found 66/390 HCC-deaths, 120/173 ICC-deaths, and 91/220 ECC-deaths (median follow-up 10 years); the 10-year-mortality was 0.5‰ (per mille) for HCC, 0.6‰ for ICC, and 0.4‰ for ECC, which decreased to 0.3‰, 0.4‰, and 0.2‰, respectively, in 2003-2017. Overall hazard ratios (HR) were 1.83 [95% confidence interval (CI), 1.41-2.38] for HCC-, 7.33 (95% CI, 5.81-9.25) for ICC-, and 4.46 (95% CI, 3.49-5.70) for ECC-deaths. A total of 22/66 HCC-deaths, 87/120 ICC-deaths, and 55/91 ECC-deaths occurred among patients with ulcerative colitis with primary sclerosing cholangitis (PSC), corresponding to 10-year-mortality of 6.7‰, 26.2‰, and 17.2‰, respectively. Among 47,399 patients with Crohn's disease (median follow-up 11 years), 10-year-mortality from HCC (n = 28), ICC (n = 28), and ECC (n = 24) were 0.3‰, 0.1‰, and 0.3‰, respectively, and corresponding HRs were 1.96 (95% CI, 1.31-2.93), 3.33 (95% CI, 2.19-5.09), and 3.10 (95% CI, 1.97-4.87). One of 28 HCC-deaths, 14/28 ICC-deaths (10-year-mortality 19‰), and 12/24 ECC-deaths (10-year-mortality 14‰) occurred after PSC. CONCLUSIONS: Risk of HCC-, ICC-, and ECC-deaths was low in patients with IBD and decreased over time. However, a large proportion of deaths occurred after PSC. IMPACT: Guidelines on specific surveillance strategies for patients with IBD with PSC, but not those without PSC, are needed.

6.
Pharmacoepidemiol Drug Saf ; 30(6): 770-778, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33583126

RESUMO

BACKGROUND: Statins exert pleiotropic anti-inflammatory effects and may prevent diverticular disease. However, the association remains poorly understood with previous studies obtaining conflicting results. AIMS: To examine the effect of statin on the subsequent risk of diverticular disease. METHODS: We conducted a nested case-control study in Denmark among respondents (>18 years) of the 2010 or the 2013 Danish National Health Survey. Among these, we identified 8809 cases of hospital-diagnosed diverticular disease and risk-set sampled population controls without diverticular disease. Using complete prescription and hospital records, we used conditional logistic regression to compute odds ratios (ORs) associating statin use with diverticular disease. In adjusted analyses, we controlled for hospital-based diagnoses, medication use other than statins, and lifestyle and socioeconomic factors. RESULTS: The fully adjusted OR for diverticular disease associated with ever use (≥1 statin prescription filling) was 1.19 (95% CI: 1.12-1.27) compared with never use. However, we observed no dose-response relation. For example, among short-term users (<5 years), the OR was 1.18 (95% CI: 1.04-1.35) for low intensity users and 1.13 (95% CI: 1.01-1.26) for high intensity users. Among long-term users (≥5 years), the respective ORs were 1.25 (95% CI: 1.13-1.38) and 1.11 (95% CI: 0.98-1.24). In analyses restricting to cases and controls with a previous colonoscopy, associations were null (OR: 1.01 [95% CI: 0.85-1.20]). CONCLUSIONS: The observed association of a higher risk of diverticular disease associated with statins could be explained by diagnostic bias. Our study did not support a protective nor harmful effect of statins on the risk of diverticular disease.

7.
Artigo em Inglês | MEDLINE | ID: mdl-33624151

RESUMO

BACKGROUND: Studies of patient-rated outcome in septoplasty and turbinoplasty most frequently involve several surgeons with varying surgical skills, techniques and experience. The aim of the present study was to evaluate outcome based on one experienced surgeon. METHODS: Three hundred and sixty-six consecutive patients referred for nasal obstruction were included. All the patients were examined with nasal endoscopy before and after decongestion, they filled out a nose VAS and rated their overall general health before and three to six months after surgery. The patients underwent septoplasty, septoplasty plus turbinoplasty or turbinoplasty. RESULTS: The mean nose VAS for nasal obstruction (0-100) preoperatively was 64.7 for all patients. Patients undergoing septoplasty (n = 159) were younger than patients undergoing septoplasty + turbinoplasty (n = 79) or patients undergoing turbinoplasty alone (n = 128). The nose VAS for nasal obstruction improved significantly in all three groups and 25% had a normal nose VAS after surgery in the septoplasty and septoplasty + turbinoplasty groups compared to only 8% in the turbinoplasty alone group. There was no significant difference in the improvement in nasal obstruction between septoplasty and septoplasty + turbinoplasty, but the septoplasty + turbinoplasty group experienced a significantly greater improvement in general health. CONCLUSIONS: In 366 patients operated on by one experienced surgeon, septoplasty and septoplasty + turbinoplasty were more effective at relieving nasal obstruction than turbinoplasty alone. Septoplasty + turbinoplasty resulted in a greater improvement in general health than septoplasty alone, despite the same improvement in nasal obstruction, indicating a beneficial effect of additional turbinoplasty in septoplasty.

8.
Arch Dis Child ; 2021 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-33563603

RESUMO

OBJECTIVE: To investigate whether antibiotic exposure during pregnancy was associated with childhood asthma and if this relationship was conditional on timing of exposure and mode of delivery. DESIGN: A cohort study using multivariable logistic regression models adjusting for a priori defined confounders. Pregnant women were recruited from 1996 to 2002. SETTING: The Danish National Birth Cohort. PATIENTS: Of the 96 832 children in the cohort, 32 651 children were included in the study population. MAIN OUTCOME MEASURE: Parent-reported childhood asthma at 11 years. RESULTS: A total of 5522 (17%) children were born to mothers exposed to antibiotics during pregnancy. In adjusted analyses, children born to exposed mothers had higher odds of asthma (OR 1.14, 95% CI 1.05 to 1.24). There was no association with antibiotic exposure in the first trimester (OR 1.02, 95% CI 0.83 to 1.26), but higher odds were observed for antibiotic exposure in the second to third trimester (OR 1.17, 95% CI 1.06 to 1.28), compared with unexposed children. The overall association between antibiotics during pregnancy and childhood asthma was only observed in vaginally born children (OR 1.17, 95% CI 1.07 to 1.28) but not in caesarean section born children (planned caesarean section: OR 0.95, 95% CI 0.66 to 1.37; caesarean emergency: OR 0.96, 95% CI 0.73 to 1.28). In exposed vaginally born children, the odds for childhood asthma requiring treatment during the preceding year were 34% higher (OR 1.34, 95% CI 1.21 to 1.49), compared with unexposed vaginally born children. CONCLUSIONS: Antibiotic exposure in mid-to-late pregnancy is associated with higher odds of childhood asthma in vaginally born children. Mode of delivery may modify the association.

9.
J Alzheimers Dis ; 79(4): 1601-1612, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33459639

RESUMO

BACKGROUND: It is controversial whether B12 deficiency causes dementia or B12 treatment can prevent dementia. OBJECTIVE: To assess associations between low plasma (P-)B12 levels, B12 treatment, and risk of Alzheimer's disease (AD; primary outcome) and all-cause or vascular dementia (secondary outcomes). METHODS: We conducted a population-based cohort study using Danish registry data to assess associations between low P-B12 levels, high-dose injection or oral B12 treatment, and risk of dementia (study period 2000-2013). The primary P-B12 cohort included patients with a first-time P-B12 measurement whose subsequent B12 treatment was recorded. The secondary B12 treatment cohort included patients with a first-time B12 prescription and P-B12 measurement within one year before this prescription. For both cohorts, patients with low P-B12 levels (<200 pmol/L) were propensity score-matched 1:1 with patients with normal levels (200-600 pmol/L). We used multivariable Cox regression to compute 0-15-year hazard ratios for dementia. RESULTS: For low P-B12 and normal P-B12 level groups, we included 53,089 patients in the primary P-B12 cohort and 13,656 patients in the secondary B12 treatment cohort. In the P-B12 cohort, hazard ratios for AD centered around one, regardless of follow-up period or treatment during follow-up. In the B12 treatment cohort, risk of AD was unaffected by low pre-treatment P-B12 levels, follow-up period and type of B12 treatment. Findings were similar for all-cause and vascular dementia. CONCLUSION: We found no associatio1n between low P-B12 levels and dementia. Associations were unaffected by B12 treatment. Results do not support routine screening for B12 deficiency in patients with suspected dementia.

10.
Br J Anaesth ; 126(4): 872-880, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33455802

RESUMO

BACKGROUND: Ropivacaine is commonly used in local infiltration anaesthesia (LIA) as pain management after total knee arthroplasty (TKA). Although considered safe, no studies evaluated the pharmacokinetics of high-dose ropivacaine infiltration in simultaneous bilateral TKA. METHODS: We studied 13 patients undergoing unilateral and 15 undergoing bilateral TKA. Standard LIA technique was used with ropivacaine 0.2%, 200 ml (400 mg) injected peri-articularly in each knee. Free and total plasma concentrations of ropivacaine were measured within 24 h using liquid chromatography-mass spectrometry. A population pharmacokinetic model was built using non-linear mixed-effects models. RESULTS: Peak free ropivacaine concentration was 0.030 (0.017-0.071) µg ml-1 (mean [99% confidence interval]) vs 0.095 (0.047-0.208) µg ml-1, and peak total ropivacaine concentration was 0.756 (0.065-1.222) µg ml-1vs 1.695 (0.077-3.005) µg ml-1 for unilateral and bilateral TKA, respectively. The pharmacokinetics was ascribed a one-compartment model with first-order absorption. The main identified covariates were protein binding, allometrically scaled body weight on clearance and volume, and unilateral or bilateral surgery on volume. CONCLUSIONS: This is the first study to investigate the pharmacokinetics of free and total ropivacaine after unilateral and bilateral TKA. A population model was successfully built and peak free ropivacaine concentration stayed below previously proposed toxic thresholds in patients undergoing unilateral and bilateral TKA receiving LIA with high-dose ropivacaine. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04702282.


Assuntos
Anestesia Local/métodos , Anestésicos Locais/farmacocinética , Artroplastia do Joelho/efeitos adversos , Dor Pós-Operatória/metabolismo , Dor Pós-Operatória/prevenção & controle , Ropivacaina/farmacocinética , Idoso , Anestésicos Locais/administração & dosagem , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Manejo da Dor/métodos , Estudos Prospectivos , Ropivacaina/administração & dosagem
11.
Scand J Med Sci Sports ; 31(4): 936-939, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33480037

RESUMO

As the SARS-CoV-2 infection rate decreased in spring 2020, phased reopening of Danish society began, including a reopening of elite football (soccer), adhering to a strict protocol. In this study, we report the consequences of resumption of competitive play in the two best football (soccer) leagues for men in Denmark measured by number of SARS-CoV-2 positive players. The players were tested weekly for SARS-CoV-2 for 11 consecutive weeks. The test protocol comprised 26 teams with 748 players. In total, 6511 tests were done with a positivity rate of 0.06%. The incidence rate of players testing positive for SARS-CoV-2 was 0.53% (4/748). There were no signs of a chain of infection. We found a low incidence rate of SARS-CoV-2, and based on this, a controlled reopening of professional football strictly following a detailed protocol appears safe for the players.


Assuntos
/epidemiologia , Pandemias , Volta ao Esporte/normas , Futebol , Atletas , Dinamarca , Humanos , Incidência , Masculino
12.
J Clin Psychiatry ; 82(1)2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-33406323

RESUMO

OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) medications are increasingly used in pregnancy. Studies on the pregnancy safety of these medications that are restricted to live births may underestimate severe teratogenic effects that cause fetal demise or termination of pregnancy. The present study addresses this limitation by including data from both prenatal and postnatal diagnoses of major malformations. METHODS: A nationwide registry-based study was conducted of 364,012 singleton pregnancies in Denmark from November 1, 2007, to February 1, 2014. Exposures to ADHD medication were obtained from redeemed prescriptions from the Danish Health Services Prescription Database. Outcome data included prenatally diagnosed malformations from the Danish Fetal Medicine Database and postnatally diagnosed malformations from the Danish National Patient Registry. The primary outcome was major malformations overall, and secondary outcomes were malformations of the central nervous system and cardiac malformations. The comparison group was pregnancies with no redeemed prescriptions for ADHD medication. We defined severe cardiac malformations (SCM) as concurrent diagnoses of a cardiac malformation with miscarriage, termination, stillbirth, postnatal death, or cardiac surgery within 1 year of birth. RESULTS: The prevalence of first-trimester exposure to ADHD medication increased during the study period from 0.05% in 2008 to 0.27% in 2013, with the majority (473/569) of the exposures being to methylphenidate. There were 5.1% malformations overall and 2.1% cardiac malformations among the exposed compared to 4.6% and 1.0%, respectively, among the unexposed. For methylphenidate, the adjusted prevalence ratios (PRs) were 1.04 (95% confidence interval [CI], 0.70-1.55) for malformations overall and 1.65 (95% CI, 0.89-3.05) for any cardiac malformations (number needed to harm [NNH] = 92), with septum defects in 10 out of 12 cases. The PR for ventricular septal defect was 2.74 (95% CI, 1.03-7.28) and for SCM, 2.59 (95% CI, 0.98-6.90). CONCLUSIONS: Exposure to methylphenidate was not associated with an increased risk of malformations overall in data that included information from both prenatal and postnatal diagnoses of major malformations. There was an increased risk of cardiac malformations with NNH of 92 based on 12 cases among the exposed. More data are needed on other types of ADHD medication.

13.
Endoscopy ; 2020 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-33241540

RESUMO

BACKGROUND AND STUDY AIMS: Post-colonoscopy colorectal cancers (PCCRCs) may account for up to 50% of all colorectal cancers (CRCs) diagnosed in patients with inflammatory bowel disease (IBD). This may reflect a high colonoscopy frequency; however evidence remains limited. PATIENT AND METHODS: We conducted a cohort study of IBD and non-IBD patients undergoing colonoscopy. We calculated 6-36 months CIPs of PCCRC after first-time and subsequent colonoscopies. We also computed crude and adjusted HRs of PCCRC, comparing IBD with non-IBD patients undergoing first-time and subsequent colonoscopies. Separate analyses were conducted for consecutive colonoscopies. We calculated PCCRC-3 year rates to estimate the proportion of IBD and non-IBD CRC patients experiencing PCCRC. RESULTS: We observed 138 and 1,909 PCCRCs among 34,688 IBD and 358,217 non-IBD patients who underwent colonoscopy. The CIP of PCCRC after first-time colonoscopy was 0.21%, 95% confidence interval (CI): [0.17-0.27] for IBD patients and 0.37%, 95% CI: [0.35-0.39] for non-IBD patients. The adjusted HR of PCCRC after a first-time colonoscopy was 0.96, 95% CI: [0.75-1.22] and the adjusted HRs after subsequent colonoscopies had point estimates around 1.0. The PCCRC-3 year rate was 24.3%, 95% CI: [20.4-28.7] for IBD and 7.5%, 95% CI [7.2-7.8] for non-IBD patients. CONCLUSIONS: Although PCCRCs accounted for a substantial proportion of all IBD-related CRCs, IBD patients had a low CIP of PCCRC after colonoscopy. The elevated PCCRC-3 year rates may among other factors stem from increased colonoscopy frequency in IBD patients.

14.
BMJ Open ; 10(11): e038753, 2020 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-33191253

RESUMO

OBJECTIVE: The objective of the study is to compare body mass index (BMI), systolic/diastolic blood pressure (SBP/DBP) and serum total cholesterol levels between dementia cases and controls at multiple time intervals prior to dementia onset, and to test time interval as a modifying factor for these associations. DESIGN: Case-control study. SETTING: Six European electronic health records databases. PARTICIPANTS: 291 780 cases at the date of first-recorded dementia diagnosis, compared with 29 170 549 controls randomly selected from the same databases, age matched and sex matched at this index date. EXPOSURE: The following measures were extracted whenever recorded within each dataset: BMI (kg/m2), SBP and DBP (mm Hg) and serum total cholesterol (mmol/L). Levels for each of these variables were defined within six 2-year time intervals over the 12 years prior to the index date. MAIN OUTCOMES: Case-control differences in exposures of interest were modelled for each time period and adjusted for demographic and clinical factors (ischaemic/unspecified stroke, type 2 diabetes mellitus, acute myocardial infarction, hypertension diagnosis, antihypertensive medication, cholesterol-lowering medication). Coefficients and interactions with time period were meta-analysed across the six databases. RESULTS: Mean BMI (coefficient -1.16 kg/m2; 95% CI -1.38 to 0.93) and SBP (-2.83 mm Hg; 95% CI -4.49 to -1.16) were lower in cases at diagnosis, and case-control differences were greater in more recent time periods, as indicated by significant case-x-time interaction and case-x-time-squared interaction terms. Time variations in coefficients for cholesterol levels were less consistent between databases and those for DBP were largely not significant. CONCLUSION: Routine clinical data show emerging divergence in levels of BMI and SBP prior to the diagnosis of dementia but less evidence for DBP or total cholesterol levels. These divergences should receive at least some consideration in routine dementia risk screening, although underlying mechanisms still require further investigation.

15.
JAMA Netw Open ; 3(11): e2025570, 2020 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-33170264

RESUMO

Importance: There is concern about neurodevelopmental outcomes associated with prenatal exposure to valproate and other antiepileptic drugs (AEDs) among children of mothers with or without epilepsy. Objective: To study the risk of intellectual disability and delayed development in childhood milestones among children of women who used valproate or other AEDs during pregnancy. Design, Setting, and Participants: This population-based cohort study analyzed information on use of AEDs from the Danish National Prescription Registry and register diagnoses from the Danish Psychiatric Central Research Register and Danish National Patient Registry. The study included all live-born singletons in Denmark from January 1, 1997, to December 31, 2011. Data were analyzed in April 2020. Exposures: Prenatal exposure to maternal valproate and other AEDs. Main Outcomes and Measures: The main measures were adjusted Cox regression estimates of hazard ratios (aHRs) for intellectual disability and a combined outcome of intellectual disability with delayed childhood milestones. Results: A total of 913 302 children (468 708 [51.3%] boys; mean [SD] age, 10.3 [4.4] years and median [interquartile range] age, 10.1 [6.5-14.0] years at final follow-up) were identified and contributed more than 10.2 million person-years of observation, including 580 children exposed to valproate (302 [51.3%] boys). At end of follow-up, 6958 children (0.8%) were identified as having intellectual disability and 14 967 children (1.6%) were identified as having intellectual disability with delayed childhood milestones. Compared with offspring not exposed to valproate prenatally, offspring of women who used valproate during pregnancy had increased risk of intellectual disability (aHR, 4.48; 95% CI, 2.97-6.76) and intellectual disability with delayed childhood milestones (aHR, 6.07; 95% CI, 4.67-7.89). Among mothers with epilepsy, offspring exposed prenatally to valproate had increased risk of intellectual disability (aHR, 1.95; 95% CI, 1.21-3.14) and intellectual disability with delayed childhood milestones (aHR, 3.07; 95% CI, 2.24-4.20) compared with offspring without prenatal exposure. Compared with offspring without prenatal exposure to AEDs, increased risk of intellectual disability was identified in children with prenatal exposure to maternal monotherapy use of carbamazepine (aHR, 3.84; 95% CI, 2.32-6.38), clonazepam (aHR, 2.41; 95% CI, 1.09-5.35), and oxcarbazepine (aHR, 3.70; 95% CI, 2.11-6.51) but not lamotrigine (aHR, 1.33; 95% CI, 0.71-2.48). Conclusions and Relevance: These findings suggest that prenatal exposure to valproate was associated with increased risk of intellectual disability and delayed childhood milestones. Statistically significant associations were also found for prenatal exposure to other AEDs. These findings suggest that women of childbearing potential may need to be counseled on use of AEDs.

16.
Blood ; 2020 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-33171494

RESUMO

The incidence of venous thromboembolism in cancer patients may have changed in the past decade, possibly due to novel cancer therapies, improved survival, and high-resolution imaging. Danish medical registries were used to identify 499,092 patients with a first-time cancer diagnosis between 1997 and 2017, who were matched to 1,497,276 comparison individuals without cancer from the general population. We computed cumulative incidences of venous thromboembolism 6 and 12 months after the diagnosis/index date. Hazard ratios (HRs) were calculated using Cox regression. Risk factors were examined by computing subdistribution hazard ratios (SHRs) in a competing risk analysis. Cumulative incidence of venous thromboembolism 12 months after the cancer diagnosis/index date was 2.3% (95% confidence interval (CI), 2.2%-2.3%) in the cancer cohort and 0.35% (95% CI, 0.34%-0.36%) in the comparison cohort (HR, 8.5; 95% CI, 8.2-8.8). Important risk factors for cancer patients were prior venous thromboembolism (SHR, 7.6; 95% CI, 7.2-8.0), distant metastasis (SHR, 3.2; 95% CI, 2.9-3.4), and use of chemotherapy (SHR, 3.4; 95% CI, 3.1-3.7), protein kinase inhibitors (SHR, 4.1; 95% CI 3.4-4.9), anti-angiogenic therapy (SHR, 4.4; 95% CI, 3.8-5.2), and immunotherapy (SHR, 3.6; 2.8-4.6). Twelve-month incidence in the cancer cohort increased from 1.0% (95% CI, 0.9%-1.2%) in 1997 to 3.4% (95% CI, 2.9%-4.0%) in 2017, which was paralleled by improved 12-month survival and increased use of computed tomography (CT) scans, chemotherapy, and targeted therapies. In conclusion, the risk of venous thromboembolism in cancer patients is increasing steadily and is 9-fold higher than in the general population.

17.
PLoS Med ; 17(11): e1003429, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33211696

RESUMO

BACKGROUND: The proportion of births via cesarean section (CS) varies worldwide and in many countries exceeds WHO-recommended rates. Long-term health outcomes for children born by CS are poorly understood, but limited data suggest that CS is associated with increased infection-related hospitalisation. We investigated the relationship between mode of birth and childhood infection-related hospitalisation in high-income countries with varying CS rates. METHODS AND FINDINGS: We conducted a multicountry population-based cohort study of all recorded singleton live births from January 1, 1996 to December 31, 2015 using record-linked birth and hospitalisation data from Denmark, Scotland, England, and Australia (New South Wales and Western Australia). Birth years within the date range varied by site, but data were available from at least 2001 to 2010 for each site. Mode of birth was categorised as vaginal or CS (emergency/elective). Infection-related hospitalisations (overall and by clinical type) occurring after the birth-related discharge date were identified in children until 5 years of age by primary/secondary International Classification of Diseases, 10th Revision (ICD-10) diagnosis codes. Analysis used Cox regression models, adjusting for maternal factors, birth parameters, and socioeconomic status, with results pooled using meta-analysis. In total, 7,174,787 live recorded births were included. Of these, 1,681,966 (23%, range by jurisdiction 17%-29%) were by CS, of which 727,755 (43%, range 38%-57%) were elective. A total of 1,502,537 offspring (21%) had at least 1 infection-related hospitalisation. Compared to vaginally born children, risk of infection was greater among CS-born children (hazard ratio (HR) from random effects model, HR 1.10, 95% confidence interval (CI) 1.09-1.12, p < 0.001). The risk was higher following both elective (HR 1.13, 95% CI 1.12-1.13, p < 0.001) and emergency CS (HR 1.09, 95% CI 1.06-1.12, p < 0.001). Increased risks persisted to 5 years and were highest for respiratory, gastrointestinal, and viral infections. Findings were comparable in prespecified subanalyses of children born to mothers at low obstetric risk and unchanged in sensitivity analyses. Limitations include site-specific and longitudinal variations in clinical practice and in the definition and availability of some data. Data on postnatal factors were not available. CONCLUSIONS: In this study, we observed a consistent association between birth by CS and infection-related hospitalisation in early childhood. Notwithstanding the limitations of observational data, the associations may reflect differences in early microbial exposure by mode of birth, which should be investigated by mechanistic studies. If our findings are confirmed, they could inform efforts to reduce elective CS rates that are not clinically indicated.

18.
Org Biomol Chem ; 18(40): 8094-8102, 2020 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-33026409

RESUMO

Heparan sulfate (HS) and heparin are sulfated polysaccharides exhibiting diverse physiological functions. HS 6-O-sulfotransferase (6-OST) is a HS biosynthetic enzyme that transfers a sulfo group to the 6-OH position of glucosamine to synthesize HS with desired biological activities. Chemoenzymatic synthesis is a widely adopted method to obtain HS oligosaccharides to support biological studies. However, this method is unable to synthesize all possible structures due to the specificity of natural enzymes. Here, we report the use of an engineered 6-OST to achieve fine control of the 6-O-sulfation. Unlike wild type enzyme, the engineered 6-OST only sulfates the non-reducing end glucosamine residue. Utilizing the engineered enzyme and wild type enzyme, we successfully completed the synthesis of five hexasaccharides and one octasaccharide differing in 6-O-sulfation patterns. We also identified a hexasaccharide construct as a new anticoagulant drug candidate. Our results demonstrate the feasibility of using an engineered HS biosynthetic enzyme to prepare HS-based therapeutics.

19.
DNA Repair (Amst) ; 93: 102932, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-33087269

RESUMO

DNA polymerase µ is a Family X member that participates in repair of DNA double strand breaks (DSBs) by non-homologous end joining. Its role is to fill short gaps arising as intermediates in the process of V(D)J recombination and during processing of accidental double strand breaks. Pol µ is the only known template-dependent polymerase that can repair non-complementary DSBs with unpaired 3´primer termini. Here we review the unique properties of Pol µ that allow it to productively engage such a highly unstable substrate to generate a nick that can be sealed by DNA Ligase IV.

20.
Aquat Toxicol ; 227: 105625, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32927179

RESUMO

Here we report the molecular networks associated with the mucosal and systemic responses to peracetic acid (PAA), a candidate oxidative chemotherapeutic in Atlantic salmon (Salmo salar). Smolts were exposed to different therapeutic doses (0, 0.6 and 2.4 mg/L) of PAA for 5 min, followed by a re-exposure to the same concentrations for 30 min 2 weeks later. PAA-exposed groups have higher external welfare score alterations, especially 2 weeks after the re-exposure. Cases of fin damage and scale loss were prevalent in the PAA-exposed groups. Transcriptomic profiling of mucosal tissues revealed that the skin had 12.5 % more differentially regulated genes (DEGs) than the gills following PAA exposure. The largest cluster of DEGs, both in the skin and gills, were involved in tissue extracellular matrix and metabolism. There were 22 DEGs common to both mucosal tissues, which were represented primarily by genes involved in the biophysical integrity of the mucosal barrier, including cadherin, collagen I α 2 chain, mucin-2 and spondin 1a. The absence of significant clustering in the plasma metabolomes amongst the three treatment groups indicates that PAA treatment did not induce any global metabolomic disturbances. Nonetheless, five metabolites with known functions during oxidative stress were remarkably affected by PAA treatments such as citrulline, histidine, tryptophan, methionine and trans-4-hydroxyproline. Collectively, these results indicate that salmon were able to mount mucosal and systemic adaptive responses to therapeutic doses of PAA and that the molecules identified are potential markers for assessing the health and welfare consequences of oxidant exposure.


Assuntos
Metaboloma , Transcriptoma , Poluentes Químicos da Água/toxicidade , Animais , Biomarcadores/metabolismo , Doenças dos Peixes/genética , Perfilação da Expressão Gênica , Brânquias/efeitos dos fármacos , Membrana Mucosa/metabolismo , Oxidantes/metabolismo , Estresse Oxidativo , Salmo salar/metabolismo
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