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1.
Lancet ; 2021 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-34774197

RESUMO

BACKGROUND: Concomitant administration of COVID-19 and influenza vaccines could reduce burden on health-care systems. We aimed to assess the safety of concomitant administration of ChAdOx1 or BNT162b2 plus an age-appropriate influenza vaccine. METHODS: In this multicentre, randomised, controlled, phase 4 trial, adults in receipt of a single dose of ChAdOx1 or BNT162b2 were enrolled at 12 UK sites and randomly assigned (1:1) to receive concomitant administration of either an age-appropriate influenza vaccine or placebo alongside their second dose of COVID-19 vaccine. 3 weeks later the group who received placebo received the influenza vaccine, and vice versa. Participants were followed up for 6 weeks. The influenza vaccines were three seasonal, inactivated vaccines (trivalent, MF59C adjuvanted or a cellular or recombinant quadrivalent vaccine). Participants and investigators were masked to the allocation. The primary endpoint was one or more participant-reported solicited systemic reactions in the 7 days after first trial vaccination(s), with a difference of less than 25% considered non-inferior. Analyses were done on an intention-to-treat basis. Local and unsolicited systemic reactions and humoral responses were also assessed. The trial is registered with ISRCTN, ISRCTN14391248. FINDINGS: Between April 1 and June 26, 2021, 679 participants were recruited to one of six cohorts, as follows: 129 ChAdOx1 plus cellular quadrivalent influenza vaccine, 139 BNT162b2 plus cellular quadrivalent influenza vaccine, 146 ChAdOx1 plus MF59C adjuvanted, trivalent influenza vaccine, 79 BNT162b2 plus MF59C adjuvanted, trivalent influenza vaccine, 128 ChAdOx1 plus recombinant quadrivalent influenza vaccine, and 58 BNT162b2 plus recombinant quadrivalent influenza vaccine. 340 participants were assigned to concomitant administration of influenza and a second dose of COVID-19 vaccine at day 0 followed by placebo at day 21, and 339 participants were randomly assigned to concomitant administration of placebo and a second dose of COVID-19 vaccine at day 0 followed by influenza vaccine at day 21. Non-inferiority was indicated in four cohorts, as follows: ChAdOx1 plus cellular quadrivalent influenza vaccine (risk difference for influenza vaccine minus placebos -1·29%, 95% CI -14·7 to 12·1), BNT162b2 plus cellular quadrivalent influenza vaccine (6·17%, -6·27 to 18·6), BNT162b2 plus MF59C adjuvanted, trivalent influenza vaccine (-12·9%, -34·2 to 8·37), and ChAdOx1 plus recombinant quadrivalent influenza vaccine (2·53%, -13·3 to 18·3). In the other two cohorts, the upper limit of the 95% CI exceeded the 0·25 non-inferiority margin (ChAdOx1 plus MF59C adjuvanted, trivalent influenza vaccine 10·3%, -5·44 to 26·0; BNT162b2 plus recombinant quadrivalent influenza vaccine 6·75%, -11·8 to 25·3). Most systemic reactions to vaccination were mild or moderate. Rates of local and unsolicited systemic reactions were similar between the randomly assigned groups. One serious adverse event, hospitalisation with severe headache, was considered related to the trial intervention. Immune responses were not adversely affected. INTERPRETATION: Concomitant vaccination with ChAdOx1 or BNT162b2 plus an age-appropriate influenza vaccine raises no safety concerns and preserves antibody responses to both vaccines. Concomitant vaccination with both COVID-19 and influenza vaccines over the next immunisation season should reduce the burden on health-care services for vaccine delivery, allowing for timely vaccine administration and protection from COVID-19 and influenza for those in need. FUNDING: National Institute for Health Research Policy Research Programme.

2.
Front Cardiovasc Med ; 8: 655463, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34336942

RESUMO

Rare pathogenic copy number variants (CNVs) are genetic rearrangements that have been associated with an increased risk for congenital heart disorders (CHDs). However, the association of CNVs with atypical brain development, leading to neurodevelopmental disorders (NDDs), in the presence of CHDs remains unclear. We attempted to explore this association by establishing the prevalence and burden of CNVs associated with CHD in a Welsh population and by studying the effect of rare CNVs associated with CHDs in mediating the risk of NDDs. Toward this goal, we analyzed data from the Congenital Anomaly Register for Wales (CARIS), referred from hospitals in Wales between 1998 and 2018, which included 1,113 subjects in total. Of these, 785 subjects were included in the study following application of the exclusion criteria, and a total of 28 rare CNVs associated with CHD were analyzed. The findings from this cohort study identified 22q11.2 deletion as the most prominent CNV across the cohort. Our data demonstrates that the survival rate of the cohort after 3 years was 99.9%, and mortality fell significantly between 1 and 2 years and between 2 and 3 years [F (1,27) = 10, p = 0.0027; F (1,27) = 5.8, p = 0.0222]. Importantly, the data set revealed a positive correlation between the incidence of congenital heart disease and the incidence of neurodevelopmental abnormalities in patients with CNVs across the whole cohort [95% CI (0.4062, 0.8449), p < 0.0001, r = 0.6829]. Additionally, we identified significant CNVs that result in the co-morbidity of CHD and NDD and show that septal defects and global developmental delay are major congenital defects. Further research should identify a common molecular mechanism leading to the phenotypic comorbidity of CHDs and NDDs, arising from a common CNV, which can have an implication for improving risk classification and for fetal neuroprotection strategies in the affected children and in precision medicine.

3.
Front Pediatr ; 9: 635776, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34295856

RESUMO

Background: Hypoplastic Left Heart Syndrome (HLHS) is a severe congenital heart defect (CHD) characterised by the underdevelopment of the left side of the heart with varying levels of hypoplasia of the left atrium, mitral valve, left ventricle, aortic valve and aortic arch. In the UK, age 12 survival for cases born between 1991 and 1993 was 21%. UK survival estimates corresponding to cases born between 2000 and 2015 were improved at 56%, but survival was examined up to age five only. Contemporary long-term survival estimates play a crucial role in counselling parents following diagnosis. The aim of this study was to report survival estimates up to age 15 for children born with HLHS or hypoplastic left ventricle with additional CHD in England and Wales between 1998 and 2012. Methods: Cases of HLHS notified to four congenital anomaly registers in England and Wales during 1998-2012, matched to Office for National Statistics mortality information, were included. Kaplan-Meier survival estimates to age 15 were reported. Cox regression models were fitted to examine risk factors for mortality. Results: There were 244 cases of HLHS and 99 cases of hypoplastic left ventricle co-occurring with other CHD, with traced survival status. Kaplan-Meier survival estimates for HLHS were 84.4% at age 1 week, 76.2% at 1 month, 63.5% at age 1 year, 58.6% at age 5 years, 54.6% at age 10 years, and 32.6% to age 15 years. The Kaplan-Meier survival estimates for cases of hypoplastic left ventricle co-occurring with additional CHD were 90.9% at age 1 week, 84.9% at 1 month, 73.7% at age 1 year, 67.7% to age 5 years, 59.2% to age 10 years, and 40.3% to age 15 years. Preterm birth (p = 0.007), low birth weight (p = 0.005), and female sex (p = 0.01) were associated with mortality. Conclusions: We have shown that prognosis associated with HLHS in the twenty first century exceeds that of many previous population-based studies, likely due to improvements in intensive care technologies and advances in surgical techniques over the last few decades.

4.
Front Pediatr ; 9: 647038, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34249803

RESUMO

Objective: Thirty years ago it was demonstrated that folic acid taken before pregnancy and in early pregnancy reduced the risk of a neural tube defect (NTD). Despite Public Health Initiatives across Europe recommending that women take 0.4 mg folic acid before becoming pregnant and during the first trimester, the prevalence of NTD pregnancies has not materially decreased in the EU since 1998, in contrast to the dramatic fall observed in the USA. This study aimed to estimate the number of NTD pregnancies that would have been prevented if flour had been fortified with folic acid in Europe from 1998 as it had been in the USA. Design and Setting: The number of NTD pregnancies from 1998 to 2017 that would have been prevented if folic acid fortification had been implemented in the 28 countries who were members of the European Union in 2019 was predicted was predicted using data on NTD prevalence from 35 EUROCAT congenital anomaly registries and literature searches for population serum folate levels and folic acid supplementation. Results: From 1998 to 2017 an estimated 95,213 NTD pregnancies occurred amongst 104 million births in the 28 countries in the EU, a prevalence of 0.92 per 1,000 births. The median serum folate level in Europe over this time period was estimated to be 14.1 µg/L. There is a lack of information about women taking folic acid supplements before becoming pregnant and during the first trimester of pregnancy, with one meta-analysis indicating that around 25% of women did so. An estimated 14,600 NTD pregnancies may have been prevented if the European countries had implemented fortification at the level adopted by the USA in 1998 and 25% of women took folic acid supplements. An estimated 19,500 NTD pregnancies would have been prevented if no women took folic acid supplements. Conclusions: This study suggests that failure to implement mandatory folic acid fortification in the 28 European countries has caused, and continues to cause, neural tube defects to occur in almost 1,000 pregnancies every year.

5.
Paediatr Perinat Epidemiol ; 35(5): 530-539, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34132407

RESUMO

BACKGROUND: Pierre Robin sequence (PRS) is a rare congenital anomaly. Respiratory disorders and feeding difficulties represent the main burden. OBJECTIVE: The aim of this study was to investigate the epidemiology of PRS using a cohort of cases from EUROCAT, the European network of population-based registries of congenital anomalies. METHODS: We analysed cases of PRS born in the period 1998-2017 collected by 29 population-based congenital anomaly registries in 17 different countries. We calculated prevalence estimates, prenatal detection rate, survival up to 1 week, and proportions of associated anomalies. The effect of maternal age was tested using a Poisson regression model. RESULTS: Out of 11 669 155 surveyed births, a total of 1294 cases of PRS were identified. The estimate of the overall prevalence was 12.0 per 100 000 births (95% CI 9.9, 14.5). There was a total of 882 (68.2%) isolated cases, and the prevalence was 7.8 per 100 000 births (95% CI 6.7, 9.2). A total of 250 cases (19.3%) were associated with other structural congenital anomalies, 77 cases (6.0%) were associated with chromosomal anomalies and 77 (6.0%) with genetic syndromes. The prenatal detection rate in isolated cases was 12.0% (95% CI 9.8, 14.5) and increased to 16.0% (95% CI 12.7, 19.7) in the sub-period 2008-2017. The prevalence rate ratio of non-chromosomal cases with maternal age ≥35 was higher than in cases with maternal age <25 for total (PRR 1.26, 95% CI 1.05, 1.51) and isolated cases (PRR 1.33, 95% CI 1.00, 1.64). Survival of chromosomal cases (94.2%) and multiple anomaly cases (95.3%) were lower than survival of isolated cases (99.4%). CONCLUSIONS: This epidemiological study using a large series of cases of PRS provides insights into the epidemiological profile of PRS in Europe. We observed an association with higher maternal age, but further investigations are needed to test potential risk factors for PRS.


Assuntos
Anormalidades Múltiplas , Síndrome de Pierre Robin , Europa (Continente)/epidemiologia , Feminino , Humanos , Idade Materna , Síndrome de Pierre Robin/epidemiologia , Gravidez , Prevalência , Sistema de Registros
6.
Br J Haematol ; 194(2): 365-377, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33959947

RESUMO

Mantle cell lymphoma (MCL) presenting in elderly, unfit patients represents a clinical challenge. Front-line 'attenuated' or low-intensity immunochemotherapy is often employed, although outcomes are relatively unexplored. We report outcomes of attenuated immunochemotherapy in 95 patients with MCL across 19 centres in the UK and Ireland considered unfit for full-dose rituximab-bendamustine or rituximab-cyclophosphamide, doxorubicin, vincristine, prednisolone (R-CHOP). Regimens examined were rituximab-cyclophosphamide, vincristine, prednisolone (R-CVP) (n = 19), dose-attenuated R-CHOP (n = 22), dose attenuated rituximab-bendamustine (n = 24) and rituximab-chlorambucil (n = 30). The primary outcome was progression-free survival (PFS). The secondary outcomes included overall response, overall survival (OS) and toxicity. The median (range) age was 79 (58-89) years and 50% were aged ≥80 years. The median (range) Cumulative Illness Rating Scale-Geriatric score was 6 (0-24). The median PFS for all patients was 15 months [95% confidence interval (CI) 8·7-21·2) and median OS was 31·4 months (95% CI 19·7-43·2). By multivariable analysis (MVA), the only clinical factor associated with an inferior PFS was blastoid morphology [hazard ratio (HR) 2·90, P = 0·01). Notably, higher treatment intensity (R-CHOP/R-bendamustine composite) provided an independently superior PFS compared with R-CVP/R-chlorambucil (MVA HR 0·49, P = 0·02). Factors associated with inferior OS by MVA were Eastern Cooperative Oncology Group Performance Status (HR 2·14, P = 0·04), blastoid morphology (HR 4·08, P = 0·001) and progression of disease at <24 months status (HR 5·68, P < 0·001). Overall, survival after front-line dose-attenuated immunochemotherapy is unsatisfactory. Clinical trials investigating novel agents such as Bruton tyrosine kinase and B-cell lymphoma 2 inhibitors in this specific clinical setting are warranted.

7.
Drug Saf ; 44(7): 765-785, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33966183

RESUMO

INTRODUCTION: Knowledge on the safety of medication use during pregnancy is often sparse. Pregnant women are generally excluded from clinical trials, and there is a dependence on post-marketing surveillance to identify teratogenic medications. AIMS: This study aimed to identify signals of potentially teratogenic medications using EUROmediCAT registry data on medication exposure in pregnancies with a congenital anomaly, and to investigate the use of VigiBase reports of adverse events of medications in the evaluation of these signals. METHODS: Signals of medication-congenital anomaly associations were identified in EUROmediCAT (21,636 congenital anomaly cases with 32,619 medication exposures), then investigated in a subset of VigiBase (45,749 cases and 165,121 exposures), by reviewing statistical reporting patterns and VigiBase case reports. Evidence from the literature and quantitative and qualitative aspects of both datasets were considered before recommending signals as warranting further independent investigation. RESULTS: EUROmediCAT analysis identified 49 signals of medication-congenital anomaly associations. Incorporating investigation in VigiBase and the literature, these were categorised as follows: four non-specific medications; 11 likely due to maternal disease; 11 well-established teratogens; two reviewed in previous EUROmediCAT studies with limited additional evidence; and 13 with insufficient basis for recommending follow-up. Independent investigations are recommended for eight signals: pregnen (4) derivatives with limb reduction; nitrofuran derivatives with cleft palate and patent ductus arteriosus; salicylic acid and derivatives with atresia or stenosis of other parts of the small intestine and tetralogy of Fallot; carbamazepine with atrioventricular septal defect and severe congenital heart defect; and selective beta-2-adrenoreceptor agonists with posterior urethral valve and/or prune belly. CONCLUSION: EUROmediCAT data should continue to be used for signal detection, accompanied by information from VigiBase and review of the existing literature to prioritise signals for further independent evaluation.

9.
Leuk Lymphoma ; 62(10): 2392-2399, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33896333

RESUMO

M7583 is a potent, highly selective, covalent BTK inhibitor in development. In this phase I, first-in-human, open label, multicenter dose-escalation trial, M7583 was given at 80 mg (three days)/160 mg (full 28-day cycle), then 300 mg/day, 600 mg/day, 900 mg/day, and 300 mg twice daily to 18 patients (median age 63 years) with refractory/resistant, stage III/IV B-cell malignancies who failed prior therapy (NCT02825836). No dose-limiting toxicities were reported. Treatment-emergent adverse events (AEs) occurred in 89% of patients, treatment-related AEs in 78%, and treatment-related grade ≥3 AEs in 17%. Common AEs were diarrhea (33%), fatigue (22%), and vomiting (17%). M7583 was rapidly absorbed and exposure was dose-proportional. BTK occupancy was >95% in the 300 mg twice daily and 900 mg/day cohorts. Objective response rate was 50% and disease control rate 78%, supporting a favorable benefit:risk profile. Fasted doses up to 900 mg once daily and 300 mg twice daily were well tolerated and may be tested in future clinical studies.


Assuntos
Neoplasias , Inibidores de Proteínas Quinases , Linfócitos B , Fadiga/induzido quimicamente , Humanos , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/efeitos adversos
10.
Reprod Toxicol ; 100: 101-108, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33454317

RESUMO

This study investigated the risk of congenital heart defects (CHD) and other congenital anomalies (CA) associated with first trimester use of macrolide antibiotics (mainly erythromycin, spiramycin, clarithromycin and azithromycin) and lincosamides (clindamycin) using a case-malformed control design. Data included 145,936 babies with a CA diagnosis (livebirths, stillbirths and terminations of pregnancy for CA) from 15 population-based EUROCAT registries in 13 European countries, covering 9 million births 1995-2012. Cases were babies with CHD, anencephaly, orofacial clefts, genital and limb reduction anomalies associated with antibiotic exposure in the literature. Controls were babies with other CA or genetic conditions. Main outcomes were odds ratios adjusted (AOR) for maternal age and registry, with 95 % Confidence Intervals (95 %CI). Macrolide and lincosamide exposure was recorded for 307 and 28 cases, 72 and 4 non-genetic controls, 57 and 7 genetic controls, respectively. AOR for CHD was not significantly raised (AOR 0.94, 95 %CI: 0.70-1.26 vs non-genetic controls; AOR 1.01, 95 %CI: 0.73-1.41 vs genetic controls), nor significantly raised for any specific macrolide. The risk of atrioventricular septal defect was significantly raised with exposure to any macrolide (AOR 2.98; 95 %CI: 1.48-6.01), erythromycin (AOR 3.68, 95 %CI: 1.28-10.61), and azithromycin (AOR 4.50, 95 %CI: 1.30-15.58). Erythromycin, clarithromycin, azithromycin, and clindamycin were associated with an increased risk of at least one other CA. Further research is needed on the risk of specific CA associated with macrolide and lincosamide use in the first trimester, particularly relevant for the potential use of azithromycin in the treatment of COVID-19.


Assuntos
Anormalidades Induzidas por Medicamentos/etiologia , Antibacterianos/efeitos adversos , Lincosamidas/efeitos adversos , Macrolídeos/efeitos adversos , COVID-19/tratamento farmacológico , Estudos de Casos e Controles , Feminino , Cardiopatias Congênitas/induzido quimicamente , Humanos , Gravidez , Primeiro Trimestre da Gravidez , SARS-CoV-2
12.
Br J Haematol ; 192(6): 1035-1038, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32445482

RESUMO

This is a 5-year real-world study of 65 patients treated with ibrutinib for relapsed/refractory mantle cell lymphoma across the UK and Ireland. Ibrutinib was well tolerated with no fatal adverse events. The median progression-free survival and overall survival (OS) was 12 and 18·5 months, respectively. Overall, 80% of patients discontinued treatment, predominantly for progressive disease. On discontinuation, 20% received alternative immunochemotherapy with a median OS of 24 months. Ibrutinib was used as a bridge to transplant in 8% (median OS not reached). These observations are comparable with trial outcomes with encouraging responses to immunochemotherapy at relapse.


Assuntos
Adenina/análogos & derivados , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/mortalidade , Piperidinas/administração & dosagem , Adenina/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Irlanda/epidemiologia , Masculino , Pessoa de Meia-Idade , Recidiva , Taxa de Sobrevida , Reino Unido/epidemiologia
13.
PLoS One ; 15(12): e0242489, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33296383

RESUMO

OBJECTIVES: To explore associations between exposures to medicines prescribed for asthma and their discontinuation in pregnancy and preterm birth [<37 or <32 weeks], SGA [<10th and <3rd centiles], and breastfeeding at 6-8 weeks. METHODS: Design. A population-based cohort study. Setting. The Secure Anonymised Information Linkage [SAIL] databank in Wales, linking maternal primary care data with infant outcomes. Population. 107,573, 105,331, and 38,725 infants born 2000-2010 with information on premature birth, SGA and breastfeeding respectively, after exclusions. Exposures. maternal prescriptions for asthma medicines or their discontinuation in pregnancy. Methods. Odds ratios for adverse pregnancy outcomes were calculated for the exposed versus the unexposed population, adjusted for smoking, parity, age and socio-economic status. RESULTS: Prescriptions for asthma, whether continued or discontinued during pregnancy, were associated with birth at<32 weeks' gestation, SGA <10th centile, and no breastfeeding (aOR 1.33 [1.10-1.61], 1.10 [1.03-1.18], 0.93 [0.87-1.01]). Discontinuation of asthma medicines in pregnancy was associated with birth at<37 weeks' and <32 weeks' gestation (aOR 1.22 [1.06-1.41], 1.53 [1.11-2.10]). All medicines examined, except ICS and SABA prescribed alone, were associated with SGA <10th centile. CONCLUSIONS: Prescription of asthma medicines before or during pregnancy was associated with higher prevalence of adverse perinatal outcomes, particularly if prescriptions were discontinued during pregnancy. Women discontinuing medicines during pregnancy could be identified from prescription records. The impact of targeting close monitoring and breastfeeding support warrants exploration.


Assuntos
Asma/tratamento farmacológico , Aleitamento Materno , Medicamentos sob Prescrição/uso terapêutico , Suspensão de Tratamento , Estudos de Coortes , Humanos , Recém-Nascido , Recém-Nascido Pequeno para a Idade Gestacional , Nascimento Prematuro/epidemiologia , Resultado do Tratamento
14.
J Anim Sci ; 98(10)2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32815548

RESUMO

Methane production from rumen methanogenesis contributes approximately 71% of greenhouse gas emissions from the agricultural sector. This study has performed genomic predictions for methane production from 99 sheep across 3 yr using a residual methane phenotype that is log methane yield corrected for live weight, rumen volume, and feed intake. Using genomic relationships, the prediction accuracies (as determined by the correlation between predicted and observed residual methane production) ranged from 0.058 to 0.220 depending on the time point being predicted. The best linear unbiased prediction algorithm was then applied to relationships between animals that were built on the rumen metabolome and microbiome. Prediction accuracies for the metabolome-based relationships for the two available time points were 0.254 and 0.132; the prediction accuracy for the first microbiome time point was 0.142. The second microbiome time point could not successfully predict residual methane production. When the metabolomic relationships were added to the genomic relationships, the accuracy of predictions increased to 0.274 (from 0.201 when only the genomic relationship was used) and 0.158 (from 0.081 when only the genomic relationship was used) for the two time points, respectively. When the microbiome relationships from the first time point were added to the genomic relationships, the maximum prediction accuracy increased to 0.247 (from 0.216 when only the genomic relationship was used), which was achieved by giving the genomic relationships 10 times more weighting than the microbiome relationships. These accuracies were higher than the genomic, metabolomic, and microbiome relationship matrixes achieved alone when identical sets of animals were used.


Assuntos
Genômica , Metaboloma , Metano/metabolismo , Microbiota , Ovinos/genética , Animais , Feminino , Fenótipo , Rúmen/metabolismo , Rúmen/microbiologia , Ovinos/metabolismo , Ovinos/microbiologia
15.
Birth Defects Res ; 112(9): 688-698, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32319733

RESUMO

BACKGROUND: The VACTERL association (VACTERL) is the nonrandom occurrence of at least three of these congenital anomalies: vertebral, anal, cardiac, tracheoesophageal, renal, and limb anomalies. Despite suggestions for involvement of several genes and nongenetic risk factors from small studies, the etiology of VACTERL remains largely unknown. OBJECTIVE: To identify maternal risk factors for VACTERL in offspring in a large European study. METHODS: A case-control study was performed using data from 28 EUROCAT registries over the period 1997-2015 with case and control ascertainment through hospital records, birth and death certificates, questionnaires, and/or postmortem examinations. Cases were diagnosed with VACTERL, while controls had a genetic syndrome and/or chromosomal abnormality. Data collected included type of birth defect and maternal characteristics, such as age, use of assisted reproductive techniques (ART), and chronic illnesses. Multivariable logistic regression analyses were performed to estimate confounder adjusted odds ratios (aOR) with 95% confidence intervals (95% CI). RESULTS: The study population consisted of 329 VACTERL cases and 49,724 controls with recognized syndromes or chromosomal abnormality. For couples who conceived through ART, we found an increased risk of VACTERL (aOR 2.3 [95% CI 1.3, 3.9]) in offspring. Pregestational diabetes (aOR 3.1 [95% CI 1.1, 8.6]) and chronic lower obstructive pulmonary diseases (aOR 3.9 [95% CI 2.2, 6.7]) also increased the risk of having a child with VACTERL. Twin pregnancies were not associated with VACTERL (aOR 0.6 [95% CI 0.3, 1.4]). CONCLUSION: We identified several maternal risk factors for VACTERL in offspring befitting a multifactorial etiology.


Assuntos
Cardiopatias Congênitas , Deformidades Congênitas dos Membros , Canal Anal/anormalidades , Estudos de Casos e Controles , Esôfago/anormalidades , Feminino , Cardiopatias Congênitas/etiologia , Cardiopatias Congênitas/genética , Humanos , Rim/anormalidades , Deformidades Congênitas dos Membros/etiologia , Deformidades Congênitas dos Membros/genética , Gravidez , Fatores de Risco , Coluna Vertebral/anormalidades , Traqueia/anormalidades
16.
Paediatr Perinat Epidemiol ; 34(2): 122-129, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32101337

RESUMO

BACKGROUND: Public health organisations use public health indicators to guide health policy. Joint analysis of multiple public health indicators can provide a more comprehensive understanding of what they are intended to evaluate. OBJECTIVE: To analyse variaitons in the prevalence of congenital anomaly-related perinatal mortality attributable to termination of pregnancy for foetal anomaly (TOPFA) and prenatal diagnosis of congenital anomaly prevalence. METHODS: We included 55 363 cases of congenital anomalies notified to 18 EUROCAT registers in 10 countries during 2008-12. Incidence rate ratios (IRR) representing the risk of congenital anomaly-related perinatal mortality according to TOPFA and prenatal diagnosis prevalence were estimated using multilevel Poisson regression with country as a random effect. Between-country variation in congenital anomaly-related perinatal mortality was measured using random effects and compared between the null and adjusted models to estimate the percentage of variation in congenital anomaly-related perinatal mortality accounted for by TOPFA and prenatal diagnosis. RESULTS: The risk of congenital anomaly-related perinatal mortality decreased as TOPFA and prenatal diagnosis prevalence increased (IRR 0.79, 95% confidence interval [CI] 0.72, 0.86; and IRR 0.88, 95% CI 0.79, 0.97). Modelling TOPFA and prenatal diagnosis together, the association between congenital anomaly-related perinatal mortality and TOPFA prevalence became stronger (RR 0.70, 95% CI 0.61, 0.81). The prevalence of TOPFA and prenatal diagnosis accounted for 75.5% and 37.7% of the between-country variation in perinatal mortality, respectively. CONCLUSION: We demonstrated an approach for analysing inter-linked public health indicators. In this example, as TOPFA and prenatal diagnosis of congenital anomaly prevalence decreased, the risk of congenital anomaly-related perinatal mortality increased. Much of the between-country variation in congenital anomaly-related perinatal mortality was accounted for by TOPFA, with a smaller proportion accounted for by prenatal diagnosis.


Assuntos
Aborto Eugênico/estatística & dados numéricos , Anormalidades Congênitas , Diagnóstico Pré-Natal , Adulto , Anormalidades Congênitas/diagnóstico , Anormalidades Congênitas/epidemiologia , Europa (Continente)/epidemiologia , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Análise Multinível , Mortalidade Perinatal , Gravidez , Diagnóstico Pré-Natal/métodos , Diagnóstico Pré-Natal/estatística & dados numéricos , Prevalência , Vigilância em Saúde Pública , Sistema de Registros/estatística & dados numéricos
17.
Br J Haematol ; 189(4): 684-688, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32011729

RESUMO

Patients with mantle cell lymphoma progressing on Bruton's tyrosine kinase inhibitor (BTKi) have very poor prognosis and there is currently no standard of care. In this retrospective cohort study, patients progressing on BTKi received R-BAC (rituximab, bendamustine, cytarabine). Overall response rate was 83% (complete response 60%) and 31% were bridged to allogeneic stem cell transplant (alloSCT). Median progression-free survival was 10.1 months (95% confidence interval (CI) 6·9-13·3) and median overall survival was 12·5 months (95% CI 11·0-14·0). In those consolidated with alloSCT only one patient relapsed. R-BAC demonstrates a high response rate in the post-BTKi setting and in transplant eligible patients is an effective bridge to alloSCT.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cloridrato de Bendamustina/uso terapêutico , Citarabina/uso terapêutico , Linfoma de Célula do Manto/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Rituximab/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Cloridrato de Bendamustina/farmacologia , Citarabina/farmacologia , Feminino , Humanos , Linfoma de Célula do Manto/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Rituximab/farmacologia
18.
Pediatr Res ; 87(3): 541-549, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31499513

RESUMO

BACKGROUND: The VACTERL (Vertebral anomalies, Anal atresia, Cardiac malformations, Tracheo-Esophageal fistula, Renal anomalies, Limb abnormalities) association is the non-random occurrence of at least three of these congenital anomalies: vertebral, anal, cardiac, tracheo-esophageal, renal, and limb anomalies. Diagnosing VACTERL patients is difficult, as many disorders have multiple features in common with VACTERL. The aims of this study were to clearly outline component features, describe the phenotypic spectrum among the largest group of VACTERL patients thus far reported, and to identify phenotypically similar subtypes. METHODS: A case-only study was performed assessing data on 501 cases recorded with VACTERL in the JRC-EUROCAT (Joint Research Centre-European Surveillance of Congenital Anomalies) central database (birth years: 1980-2015). We differentiated between major and minor VACTERL features and anomalies outside the VACTERL spectrum to create a clear definition of VACTERL. RESULTS: In total, 397 cases (79%) fulfilled our VACTERL diagnostic criteria. The most commonly observed major VACTERL features were anorectal malformations and esophageal atresia/tracheo-esophageal fistula (both occurring in 62% of VACTERL cases), followed by cardiac (57%), renal (51%), vertebral (33%), and limb anomalies (25%), in every possible combination. Three VACTERL subtypes were defined: STRICT-VACTERL, VACTERL-LIKE, and VACTERL-PLUS, based on severity and presence of additional congenital anomalies. CONCLUSION: The clearly defined VACTERL component features and the VACTERL subtypes introduced will improve both clinical practice and etiologic research.


Assuntos
Canal Anal/anormalidades , Esôfago/anormalidades , Cardiopatias Congênitas/diagnóstico , Rim/anormalidades , Deformidades Congênitas dos Membros/diagnóstico , Coluna Vertebral/anormalidades , Traqueia/anormalidades , Consenso , Bases de Dados Factuais , Europa (Continente)/epidemiologia , Predisposição Genética para Doença , Cardiopatias Congênitas/classificação , Cardiopatias Congênitas/epidemiologia , Cardiopatias Congênitas/genética , Humanos , Classificação Internacional de Doenças , Deformidades Congênitas dos Membros/classificação , Deformidades Congênitas dos Membros/epidemiologia , Deformidades Congênitas dos Membros/genética , Fenótipo , Valor Preditivo dos Testes , Prevalência , Terminologia como Assunto
19.
Arch Dis Child Fetal Neonatal Ed ; 105(2): 151-157, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31229957

RESUMO

OBJECTIVE: Methadone is a vital treatment for women with opioid use disorder in pregnancy. Previous reports suggested an association between methadone exposure and Pierre Robin sequence (PRS), a rare craniofacial anomaly. We assessed the association between gestational methadone exposure and PRS. DESIGN/SETTING: This case-malformed control study used European Surveillance of Congenital Anomalies population-based registries in Ireland, the Netherlands, Italy, Switzerland, Croatia, Malta, Portugal, Germany, Wales, Norway and Spain, 1995-2011. PATIENTS: Cases included PRS based on International Classification of Disease (ICD), Ninth Edition-British Paediatric Association (BPA) code 75 603 or ICD, Tenth Edition-BPA code Q8708. Malformed controls were all non-PRS anomalies, excluding genetic conditions, among live births, fetal deaths from 20 weeks' gestation and terminations of pregnancy for fetal anomalies. An exploratory analysis assessed the association between methadone exposure and other congenital anomalies (CAs) excluding PRS. Methadone exposure was ascertained from medical records and maternal interview. RESULTS: Among 87 979 CA registrations, there were 127 methadone-exposed pregnancies and 336 PRS cases. There was an association between methadone exposure and PRS (OR adjusted for registry 12.3, 95% CI 5.7 to 26.8). In absolute terms, this association reflects a risk increase from approximately 1-12 cases per 10 000 births. A raised OR was found for cleft palate (adjusted OR 5.0, 95% CI 2.7 to 9.2). CONCLUSIONS: These findings suggest that gestational methadone exposure is associated with PRS. The association may be explained by unmeasured confounding factors. The small increased risk of PRS in itself does not alter the risk-benefit balance for gestational methadone use. The association with cleft palate, a more common CA, should be assessed with independent data.


Assuntos
Fissura Palatina/epidemiologia , Metadona/administração & dosagem , Síndrome de Pierre Robin/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Adulto , Estudos de Casos e Controles , Comorbidade , Europa (Continente) , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Masculino , Metadona/uso terapêutico , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Gravidez , Medição de Risco
20.
PLoS One ; 14(11): e0225133, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31738813

RESUMO

OBJECTIVES: To explore associations between exposure to antidepressants, their discontinuation, depression [medicated or unmediated] and preterm birth [<37 and <32 weeks], small for gestational age (SGA) [<10th and <3rd centiles], breastfeeding [any] at 6-8 weeks. METHODS: Design: A population-based cohort study. Setting: The Secure Anonymised Information Linkage [SAIL] databank in Wales, linking maternal primary care data with infant outcomes. Participants: 107,573, 105,331, and 38,725 infants born 2000-2010 with information on prematurity, SGA and breastfeeding respectively, after exclusions. Exposures: Maternal antidepressant prescriptions in trimesters 2 or 3, discontinuation after trimester 1, recorded diagnosis of depression [medicated or unmediated] in pregnancy. Methods: Odds ratios for adverse pregnancy outcomes were calculated, adjusted for smoking, parity, socio-economic status, and depression. RESULTS: Exclusive formula feeding at 6-8 weeks was associated with prescriptions in trimesters 2 or 3 for any antidepressants (adjusted odds ratio [aOR] 0.81, 95% confidence intervals 0.67-0.98), SSRIs [aOR 0.77, 0.62-0.95], particularly higher doses [aOR 0.45, 0.23-0.86], discontinuation of antidepressants or SSRIs after trimester 1 (aOR 0.70, 0.57-0.83 and 0.66, 0.51-0.87), diagnosis of depression aOR 0.76 [0.70-0.82), particularly if medicated (aOR 0.70, 0.58-0.85), rather than unmedicated (aOR 0.87, 0.82-0.92). Preterm birth at <37 and <32 weeks' gestation was associated with diagnosis of depression (aOR 1.27, 1.17-1.38, and 1.33, 1.09-1.62), particularly if medicated (aOR 1.56, 1.23-1.96, and 1.63, 0.94-2.84); birth at <37 weeks was associated with antidepressants, (aOR 1.24, 1.04-1.49]. SGA <3rd centile was associated with antidepressants (aOR 1.43, 1.07-1.90), and SSRIs (aOR 1.46, 1.06-2.00], particularly higher doses [aOR 2.10, 1.32-3.34]. All adverse outcomes were associated with socio-economic status and smoking. IMPLICATIONS: Exposure to antidepressants or depression increased risks of exclusive formula feeding at 6-8 weeks, and prescription of antidepressants was associated with SGA <3rd centile. Prescription of antidepressants offers a useful marker to target additional support and additional care before and during pregnancy and lactation.


Assuntos
Antidepressivos , Aleitamento Materno , Depressão/epidemiologia , Depressão/etiologia , Prescrições de Medicamentos/estatística & dados numéricos , Antidepressivos/administração & dosagem , Peso ao Nascer , Estudos de Coortes , Depressão Pós-Parto/epidemiologia , Depressão Pós-Parto/etiologia , Feminino , Humanos , Lactente , Recém-Nascido , Razão de Chances , Vigilância da População , Gravidez , Nascimento Prematuro/epidemiologia
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