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1.
J Glob Health ; 14: 04052, 2024 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-38454881

RESUMO

Background: Female sex workers (FSW) in low- and middle-income countries (LMIC) are disproportionately vulnerable to poor health, social, and economic outcomes. The children of female sex workers (CFSW) experience health risks based on these challenging circumstances and the unique conditions to which they are exposed. Although country child mortality data exist, little is known about the causes of death among CFSW specifically, thereby severely limiting an effective public health response to the needs of this high-risk group of children. Methods: The Community Knowledge Approach (CKA) was employed between January and October 2019 to survey a criterion sample of 1280 FSW participants across 24 cities in eight LMIC countries. Participants meeting pre-determined criteria provided detailed reports of deaths among the CFSW within their community of peers. Newborn deaths were gleaned from FSW maternal death reports where the infants also died following birth. Results: Of the 668 child deaths reported, 589 were included in the analysis. Nutritional deficiencies comprised the leading cause of mortality accounting for 20.7% of deaths, followed closely by accidents (20.0%), particularly house fires, overdoses (19.4%), communicable diseases (18.5%), and homicides (9.8%). Other reported causes of death included neonatal conditions, respiratory illnesses, and suicides. Conclusions: The causes of CFSW death in these eight countries are preventable with improved protections. Governments, intergovernmental organisations like the United Nations, nongovernmental stakeholder organisations (e.g. sex worker organisations), and funders can implement targeted policies and programmes to protect CFSW and assist vulnerable FSW who are pregnant and raising children. Further research is needed to identify effective child welfare safeguards for CFSW.


Assuntos
Profissionais do Sexo , Suicídio , Lactente , Criança , Recém-Nascido , Gravidez , Humanos , Feminino , Países em Desenvolvimento , Causas de Morte , Mães
2.
J Alzheimers Dis Rep ; 7(1): 1015-1024, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37849628

RESUMO

Background: Zagotenemab (LY3303560), a monoclonal antibody, preferentially binds to extracellular, misfolded, aggregated tau that has been implicated in Alzheimer's disease (AD). Objective: The goal of this study was to assess the safety and pharmacokinetics of multiple doses of zagotenemab in participants with AD. Methods: This was a Phase Ib, multi-site, participant- and investigator-blind, placebo-controlled, parallel-group study in participants with mild cognitive impairment due to AD or mild to moderate AD. After screening, participants were randomized to zagotenemab 70 mg, 210 mg, or placebo every 4 weeks for up to 49 weeks and were followed up for 16 weeks. Results: A total of 13 males and 9 females, aged 59 to 84 years, were dosed. No deaths occurred during this study. A total of 4 serious adverse events occurred in 2 participants who then discontinued the study. The most commonly reported (3 or more participants) treatment-emergent adverse events were sinus bradycardia, headache, fall, and bronchitis. The pharmacokinetics profile showed generally linear exposures across the dose range studied with a clearance of ~8 mL/h. The half-life of zagotenemab in serum was ~20 days. A dose-dependent increase in plasma tau was observed. No other significant pharmacodynamic differences were observed due to low dose levels and limited treatment duration. Conclusions: No dose-limiting adverse events were observed with zagotenemab treatment. Pharmacokinetics of zagotenemab were typical for a monoclonal antibody. Meaningful pharmacodynamic differences were not observed.Clinicaltrials.gov: NCT03019536.

3.
Sex Reprod Health Matters ; 31(1): 2250618, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37712508

RESUMO

Previous studies have found high levels of unintended pregnancy among female sex workers (FSW), but less attention has been paid to their abortion practices and outcomes. This study is the first to investigate abortion-related mortality among FSW across eight countries: Angola, Brazil, Democratic Republic of Congo (DRC), India, Indonesia, Kenya, Nigeria, and South Africa. The Community Knowledge Approach (CKA) was used to survey a convenience sample of FSW (n = 1280). Participants reported on the deaths of peer FSW in their social networks during group meetings convened by non-governmental organisations (n = 165 groups, conducted across 24 cities in 2019). Details on any peer FSW deaths in the preceding five years were recorded. The circumstances of abortion-related deaths are reported here. Of the 1320 maternal deaths reported, 750 (56.8%) were due to unsafe abortion. The number of abortion-related deaths reported was highest in DRC (304 deaths reported by 270 participants), Kenya (188 deaths reported by 175 participants), and Nigeria (216 deaths reported by 312 participants). Among the abortion-related deaths, mean gestational age was 4.6 months and 75% occurred outside hospital. Unsafe abortion methods varied by country, but consumption of traditional or unknown medicines was most common (37.9% and 29.9%, respectively). The 750 abortion-related deaths led to 1207 children being left motherless. The CKA successfully recorded a stigmatised practice among a marginalised population, identifying very high levels of abortion-related mortality. Urgent action is now needed to deliver comprehensive sexual and reproductive healthcare to this vulnerable population, including contraption, safe abortion, and post-abortion care.


Assuntos
Aborto Induzido , Profissionais do Sexo , Gravidez , Criança , Feminino , Humanos , Lactente , Grupo Associado , Brasil , Idade Gestacional
4.
Alzheimers Dement (N Y) ; 9(2): e12404, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37388759

RESUMO

INTRODUCTION: Donanemab is an amyloid-targeting therapy that specifically targets brain amyloid plaques. The objective of these analyses was to characterize the relationship of donanemab exposure with plasma biomarkers and clinical efficacy through modeling. METHODS: Data for the analyses were from participants with Alzheimer's disease from the phase 1 and TRAILBLAZER-ALZ studies. Indirect-response models were used to fit plasma phosphorylated tau 217 (p-tau217) and plasma glial fibrillated acidic protein (GFAP) data over time. Disease-progression models were developed using pharmacokinetic/pharmacodynamic modeling. RESULTS: The plasma p-tau217 and plasma GFAP models adequately predicted the change over time, with donanemab resulting in decreased plasma p-tau217 and plasma GFAP concentrations. The disease-progression models confirmed that donanemab significantly reduced the rate of clinical decline. Simulations revealed that donanemab slowed disease progression irrespective of baseline tau positron emission tomography (PET) level within the evaluated population. DISCUSSION: The disease-progression models show a clear treatment effect of donanemab on clinical efficacy regardless of baseline disease severity.

5.
Clin Pharmacol Ther ; 113(6): 1258-1267, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36805552

RESUMO

Donanemab is an amyloid-targeting therapy that resulted in robust amyloid plaque reduction and slowed Alzheimer's disease (AD) progression compared with placebo in the phase II TRAILBLAZER-ALZ study (NCT03367403). The objectives of the current analyses are to characterize (i) the population pharmacokinetics of donanemab, (ii) the relationship between donanemab exposure and amyloid plaque reduction (response), and (iii) the relationship between donanemab exposure and amyloid-related imaging abnormalities with edema or effusions (ARIA-E). Model development included data from participants with mild cognitive impairment or mild to moderate dementia due to AD from the phase Ib study on donanemab (NCT02624778) and participants with early symptomatic AD from the TRAILBLAZER-ALZ study. The analysis showed donanemab has a terminal elimination half-life of 11.8 days. Body weight and antidrug antibody titer impact donanemab exposure but not the pharmacodynamic response. Maintaining a donanemab serum concentration above 4.43 µg/mL (95% confidence interval: 0.956, 10.4) is associated with amyloid plaque reduction. The time to achieve amyloid plaque clearance (amyloid plaque level < 24.1 Centiloids) varied depending on the baseline amyloid level, where higher baseline levels were associated with fewer participants achieving amyloid clearance. The majority of participants achieved amyloid clearance by 52 weeks on treatment. Apolipoprotein ε4 carriers, irrespective of donanemab serum exposure, were 4 times more likely than noncarriers to have an ARIA-E event by 24 weeks.


Assuntos
Doença de Alzheimer , Humanos , Doença de Alzheimer/tratamento farmacológico , Placa Amiloide/tratamento farmacológico , Anticorpos Monoclonais Humanizados , Anticorpos Monoclonais/uso terapêutico , Heterozigoto , Peptídeos beta-Amiloides
6.
Alzheimers Dement ; 19(6): 2253-2264, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36450003

RESUMO

INTRODUCTION: An Alzheimer's disease (AD) dementia disease progression model was developed based on the integrated Alzheimer's Disease Rating Scale (iADRS). METHODS: Data from 3483 placebo participants in six AD trials were used to develop the disease progression model with NONMEM (version 7.4.2) and examined for mild cognitive impairment, and mild and moderate dementia due to AD. RESULTS: Baseline iADRS score was significantly influenced by AD symptomatic medication use, EXPEDITION2 enrollment (included moderate AD participants), age, and baseline Mini-Mental State Examination (MMSE) score. Rate of disease progression increased across disease stage and was significantly influenced by AD medication use, age, and baseline MMSE score. Apolipoprotein E ε4 carrier status did not influence baseline iADRS score or disease progression. DISCUSSION: These results demonstrate a disease progression model describing the time course of the iADRS across the AD severity spectrum. This model can assist future clinical trials in study design optimization and treatment effect interpretation. HIGHLIGHTS: A disease progression model described the integrated Alzheimer's Disease Rating Scale (iADRS) time course in mild cognitive impairment to moderate Alzheimer's disease. Using the linear regression model, iADRS scores can be calculated for Mini-Mental State Examination scores. Results can help optimize future clinical trial design and aid in understanding treatment effects.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Humanos , Doença de Alzheimer/tratamento farmacológico , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/psicologia , Progressão da Doença
7.
EClinicalMedicine ; 52: 101658, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36313149

RESUMO

Background: The vast majority of studies on female sex workers (FSW) focus on causes of morbidity while data on causes of mortality are scarce. In low- and middle-income countries, where civil registry and vital statistics data are often incomplete and FSW may not be identified as such in official registries, identifying causes of mortality among FSW has proven challenging. Methods: As part of a larger investigation on the maternal health of FSW, the current study used the Community Knowledge Approach (CKA) to identify causes of mortality among FSW in LMIC across three global regions in 2019. The CKA, validated to identify maternal, neonatal, and jaundice-associated deaths among women living in a community, was employed to identify deaths of any cause among communities of FSW. Study participants, recruited by in-country partner non-governmental organizations (NGOs) working with local FSW, provided detailed information about FSW deaths in their communities. Findings: 1280 FSW participated in 165 group meetings through which 2112 FSW deaths were identified. Of these reported deaths, 57·9% occurred in 2019 and 57·2% were among women aged 20-29. Causes of death included abortion (35·5%), other maternal causes (16·6%), suicide (13·6%), murder (12·5%), unclassified causes (11·6%), HIV/AIDS (7·9%), and accidents (3·2%). A total of 3659 children lost their mothers. Interpretation: Maternal death comprised the leading cause of FSW mortality in our sample. This methodology can be used by local governments and NGOs to identify unrecognized patterns and clusters of FSW deaths in near-real time and urgently steer targeted preventative strategies. Funding: New Venture Fund.

8.
JAMA Neurol ; 79(10): 1015-1024, 2022 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-36094645

RESUMO

Importance: ß-amyloid plaques and neurofibrillary tau deposits biologically define Alzheimer disease. Objective: To perform post hoc analyses of amyloid reduction after donanemab treatment and assess its association with tau pathology and clinical measures. Design, Setting, and Participants: The Study of LY3002813 in Participants With Early Symptomatic Alzheimer's Disease (TRAILBLAZER-ALZ) was a phase 2, placebo-controlled, randomized clinical trial conducted from December 18, 2017, to December 4, 2020, with a double-blind period of up to 76 weeks and a 48-week follow-up period. The study was conducted at 56 centers in the US and Canada. Enrolled were participants from 60 to 85 years of age with gradual and progressive change in memory function for 6 months or more, early symptomatic Alzheimer disease, elevated amyloid, and intermediate tau levels. Interventions: Donanemab (an antibody specific for the N-terminal pyroglutamate ß-amyloid epitope) dosing was every 4 weeks: 700 mg for the first 3 doses, then 1400 mg for up to 72 weeks. Blinded dose-reduction evaluations occurred at 24 and 52 weeks based on amyloid clearance. Main Outcomes and Measures: Change in amyloid, tau, and clinical decline after donanemab treatment. Results: The primary study randomized 272 participants (mean [SD] age, 75.2 [5.5] years; 145 female participants [53.3%]). The trial excluded 1683 of 1955 individuals screened. The rate of donanemab-induced amyloid reduction at 24 weeks was moderately correlated with the amount of baseline amyloid (Spearman correlation coefficient r, -0.54; 95% CI, -0.66 to -0.39; P < .001). Modeling provides a hypothesis that amyloid would not reaccumulate to the 24.1-centiloid threshold for 3.9 years (95% prediction interval, 1.9-8.3 years) after discontinuing donanemab treatment. Donanemab slowed tau accumulation in a region-dependent manner as measured using neocortical and regional standardized uptake value ratios with cerebellar gray reference region. A disease-progression model found a significant association between percentage amyloid reduction and change on the integrated Alzheimer Disease Rating Scale only in apolipoprotein E (APOE) ε4 carriers (95% CI, 24%-59%; P < .001). Conclusions and Relevance: Results of post hoc analyses for donanemab-treated participants suggest that baseline amyloid levels were directly associated with the magnitude of amyloid reduction and inversely associated with the probability of achieving complete amyloid clearance. The donanemab-induced slowing of tau was more pronounced in those with complete amyloid clearance and in brain regions identified later in the pathologic sequence. Data from other trials will be important to confirm aforementioned observations, particularly treatment response by APOE ε4 status. Trial Registration: ClinicalTrials.gov Identifier: NCT03367403.


Assuntos
Doença de Alzheimer , Amiloidose , Idoso , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Amiloide , Peptídeos beta-Amiloides , Apolipoproteína E4 , Epitopos/uso terapêutico , Feminino , Humanos , Lactente , Placa Amiloide/tratamento farmacológico , Placa Amiloide/patologia , Tomografia por Emissão de Pósitrons , Ácido Pirrolidonocarboxílico/uso terapêutico , Proteínas tau
9.
BMC Med Res Methodol ; 22(1): 236, 2022 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-36045347

RESUMO

OBJECTIVE: Previous research has demonstrated that individual risk of mental illness is associated with individual, co-resident, and household risk factors. However, modelling the overall effect of these risk factors presents several methodological challenges. In this study we apply a multilevel structural equation model (MSEM) to address some of these challenges and the impact of the different determinants when measuring mental health risk. STUDY DESIGN AND SETTING: Two thousand, one hundred forty-three individuals aged 16 and over from 888 households were analysed based on the Household Survey for England-2014 dataset. We applied MSEM to simultaneously measure and identify psychiatric morbidity determinants while accounting for the dependency among individuals within the same household and the measurement errors. RESULTS: Younger age, female gender, non-working status, headship of the household, having no close relationship with other people, having history of mental illness and obesity were all significant (p < 0.01) individual risk factors for psychiatric morbidity. A previous history of mental illness in the co-residents, living in a deprived household, and a lack of closeness in relationships among residents were also significant predictors. Model fit indices showed a very good model specification (CFI = 0.987, TLI = 0.980, RMSEA = 0.023, GFI = 0.992). CONCLUSION: Measuring and addressing mental health determinants should consider not only an individual's characteristics but also the co-residents and the households in which they live.


Assuntos
Transtornos Mentais , Saúde Mental , Inglaterra/epidemiologia , Características da Família , Feminino , Humanos , Transtornos Mentais/diagnóstico , Transtornos Mentais/epidemiologia , Fatores de Risco
10.
BMC Med Res Methodol ; 22(1): 192, 2022 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-35820893

RESUMO

BACKGROUND: Meta-analyses of test accuracy studies may provide estimates that are highly improbable in clinical practice. Tailored meta-analysis produces plausible estimates for the accuracy of a test within a specific setting by tailoring the selection of included studies compatible with a specific setting using information from the target setting. The aim of this study was to validate the tailored meta-analysis approach by comparing outcomes from tailored meta-analysis with outcomes from a setting specific test accuracy study. METHODS: A retrospective cohort study of primary care electronic health records provided setting-specific data on the test positive rate and disease prevalence. This was used to tailor the study selection from a review of faecal calprotectin testing for inflammatory bowel disease for meta-analysis using the binomial method and the Mahalanobis distance method. Tailored estimates were compared to estimates from a study of test accuracy in primary care using the same routine dataset. RESULTS: Tailoring resulted in the inclusion of 3/14 (binomial method) and 9/14 (Mahalanobis distance method) studies in meta-analysis. Sensitivity and specificity from tailored meta-analysis using the binomial method were 0.87 (95% CI 0.77 to 0.94) and 0.65 (95% CI 0.60 to 0.69) and 0.98 (95% CI 0.83 to 0.999) and 0.68 (95% CI 0.65 to 0.71), respectively using the Mahalanobis distance method. The corresponding estimates for the conventional meta-analysis were 0.94 (95% CI 0.90 to 0.97) and 0.67 (95% CI 0.57 to 0.76) and for the FC test accuracy study of primary care data 0.93 (95%CI 0.89 to 0.96) and 0.61 (95% CI 0.6 to 0.63) to detect IBD at a threshold of 50 µg/g. Although the binomial method produced a plausible estimate, the tailored estimates of sensitivity and specificity were not closer to the primary study estimates than the estimates from conventional meta-analysis including all 14 studies. CONCLUSIONS: Tailored meta-analysis does not always produce estimates of sensitivity and specificity that lie closer to the estimates derived from a primary study in the setting in question. Potentially, tailored meta-analysis may be improved using a constrained model approach and this requires further investigation.


Assuntos
Doenças Inflamatórias Intestinais , Complexo Antígeno L1 Leucocitário , Doença Crônica , Humanos , Doenças Inflamatórias Intestinais/diagnóstico , Doenças Inflamatórias Intestinais/epidemiologia , Estudos Retrospectivos , Sensibilidade e Especificidade
11.
Health Technol Assess ; 26(30): 1-160, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35781133

RESUMO

BACKGROUND: Since changes in the national guidance in 2011, prophylactic antibiotics for women undergoing caesarean section are recommended prior to skin incision, rather than after the baby's umbilical cord has been clamped. Evidence from randomised controlled trials conducted outside the UK has shown that this reduces maternal infectious morbidity; however, the prophylactic antibiotics also cross the placenta, meaning that babies are exposed to them around the time of birth. Antibiotics are known to affect the gut microbiota of the babies, but the long-term effects of exposure to high-dose broad-spectrum antibiotics around the time of birth on allergy and immune-related diseases are unknown. OBJECTIVES: We aimed to examine whether or not in-utero exposure to antibiotics immediately prior to birth compared with no pre-incisional antibiotic exposure increases the risk of (1) asthma and (2) eczema in children born by caesarean section. DESIGN: This was a controlled interrupted time series study. SETTING: The study took place in primary and secondary care. PARTICIPANTS: Children born in the UK during 2006-18 delivered by caesarean section were compared with a control cohort delivered vaginally. INTERVENTIONS: In-utero exposure to antibiotics immediately prior to birth. MAIN OUTCOME MEASURES: Asthma and eczema in children in the first 5 years of life. Additional secondary outcomes, including other allergy-related conditions, autoimmune diseases, infections, other immune system-related diseases and neurodevelopmental conditions, were also assessed. DATA SOURCES: The Health Improvement Network (THIN) and the Clinical Practice Research Datalink (CPRD) primary care databases and the Hospital Episode Statistics (HES) database. Previously published linkage strategies were adapted to link anonymised data on mothers and babies in these databases. Duplicate practices contributing to both THIN and the CPRD databases were removed to create a THIN-CPRD data set. RESULTS: In the THIN-CPRD and HES data sets, records of 515,945 and 3,945,351 mother-baby pairs were analysed, respectively. The risk of asthma was not significantly higher in children born by caesarean section exposed to pre-incision antibiotics than in children whose mothers received post-cord clamping antibiotics, with an incidence rate ratio of 0.91 (95% confidence interval 0.78 to 1.05) for diagnosis of asthma in primary care and an incidence rate ratio of 1.05 (95% confidence interval 0.99 to 1.11) for asthma resulting in a hospital admission. We also did not find an increased risk of eczema, with an incidence rate ratio of 0.98 (95% confidence interval 0.94 to1.03) and an incidence rate ratio of 0.96 (95% confidence interval 0.71 to 1.29) for diagnosis in primary care and hospital admissions, respectively. LIMITATIONS: It was not possible to ascertain the exposure to pre-incision antibiotics at an individual level. The maximum follow-up of children was 5 years. CONCLUSIONS: There was no evidence that the policy change from post-cord clamping to pre-incision prophylactic antibiotics for caesarean sections during 2006-18 had an impact on the incidence of asthma and eczema in early childhood in the UK. FUTURE WORK: There is a need for further research to investigate if pre-incision antibiotics have any impact on developing asthma and other allergy and immune-related conditions in older children. STUDY REGISTRATION: This study is registered as researchregistry3736. FUNDING: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 30. See the NIHR Journals Library website for further project information.


WHAT WAS THE QUESTION?: Women giving birth by caesarean section are at risk of developing infections (such as wound infections) and are offered antibiotics at the time of their operation to reduce this risk. In 2011, the national guidelines changed from recommending antibiotics after cord clamping to giving them before the operation to further reduce the risk of maternal infection. During birth, the newborn gut is colonised by microbes. Antibiotics given to the mother before caesarean section can reach the baby through the placenta and disrupt the normal microbes that colonise the gut. These microbes are believed to play a role in the development of the immune system and altering the normal development of these microbes has been linked to children developing allergic conditions, such as asthma and eczema. This study investigated whether or not giving antibiotics before the caesarean section had a longer-term impact on children's health. WHAT DID WE DO?: We used routine NHS information already collected by hospitals and general practitioners about women who gave birth in the UK between 2006 and 2018, and their children. We compared the risk of asthma, eczema and other health conditions in the first 5 years after birth in children born by caesarean section before and after the change in hospital policies. We also compared their health with children born vaginally. WHAT DID WE FIND?: We found that there was no increased risk of asthma or eczema for children born by caesarean section after the policy decision in 2011 to give the mother antibiotics before the operation. WHAT DOES THIS MEAN?: The study findings provide further evidence for the current recommendation to give preventative antibiotics to women shortly before the caesarean section to reduce the overall risk of infections after birth.


Assuntos
Antibacterianos , Antibioticoprofilaxia , Asma , Cesárea , Eczema , Hipersensibilidade , Antibacterianos/efeitos adversos , Asma/epidemiologia , Cesárea/efeitos adversos , Criança , Pré-Escolar , Eczema/epidemiologia , Registros Eletrônicos de Saúde , Feminino , Humanos , Hipersensibilidade/epidemiologia , Estudos Longitudinais , Gravidez , Reino Unido
12.
Br J Radiol ; 95(1137): 20220152, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-35819918

RESUMO

OBJECTIVE: To estimate the risk of malignancy in gallbladder polyps of incremental sizes detected during transabdominal ultrasound (TAUS). METHODS: We searched databases including MEDLINE, Embase, and Cochrane Library for eligible studies recording the polyp size from which gallbladder malignancy developed, confirmed following cholecystectomy, or by subsequent follow-up. Primary outcome was the risk of gallbladder cancer in patients with polyps. Secondary outcome was the effect of polyp size as a prognostic factor for cancer. Risk of bias was assessed using the Quality in Prognostic Factor Studies (QUIPS) tool. Bayesian meta-analysis estimated the median cancer risk according to polyp size. This study is registered with PROSPERO (CRD42020223629). RESULTS: 82 studies published since 1990 reported primary data for 67,837 patients. 67,774 gallbladder polyps and 889 cancers were reported. The cumulative median cancer risk of a polyp measuring 10 mm or less was 0.60% (99% credible range 0.30-1.16%). Substantial heterogeneity existed between studies (I2 = 99.95%, 95% credible interval 99.86-99.98%). Risk of bias was generally high and overall confidence in evidence was low. 13 studies (15.6%) were graded with very low certainty, 56 studies (68.3%) with low certainty, and 13 studies (15.6%) with moderate certainty. In studies considered moderate quality, TAUS monitoring detected 4.6 cancers per 10,000 patients with polyps less than 10 mm. CONCLUSION: Malignant risk in gallbladder polyps is low, particularly in polyps less than 10 mm, however the data are heterogenous and generally low quality. International guidelines, which have not previously modelled size data, should be informed by these findings. ADVANCES IN KNOWLEDGE: This large systematic review and meta-analysis has shown that the mean cumulative risk of small gallbladder polyps is low, but heterogeneity and missing data in larger polyp sizes (>10 mm) means the risk is uncertain and may be higher than estimated.Studies considered to have better methodological quality suggest that previous estimates of risk are likely to be inflated.


Assuntos
Doenças da Vesícula Biliar , Neoplasias da Vesícula Biliar , Neoplasias Gastrointestinais , Pólipos , Teorema de Bayes , Vesícula Biliar/diagnóstico por imagem , Vesícula Biliar/patologia , Doenças da Vesícula Biliar/diagnóstico por imagem , Neoplasias da Vesícula Biliar/diagnóstico por imagem , Neoplasias da Vesícula Biliar/patologia , Neoplasias Gastrointestinais/patologia , Humanos , Pólipos/diagnóstico por imagem , Pólipos/patologia
13.
BMJ ; 377: e069704, 2022 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-35580876

RESUMO

OBJECTIVE: To investigate the impact on child health up to age 5 years of a policy to use antibiotic prophylaxis for caesarean section before incision compared with after cord clamping. DESIGN: Observational controlled interrupted time series study. SETTING: UK primary and secondary care. PARTICIPANTS: 515 945 children born in 2006-18 with linked maternal records and registered with general practices contributing to two UK primary care databases (The Health Improvement Network and Clinical Practice Research Datalink), and 7 147 884 children with linked maternal records in the Hospital Episode Statistics database covering England, of which 3 945 351 were linked to hospitals that reported the year of policy change to administer prophylactic antibiotics for caesarean section before incision rather than after cord clamping. INTERVENTION: Fetal exposure to antibiotics shortly before birth (using pre-incision antibiotic policy as proxy) compared with no exposure. MAIN OUTCOME MEASURES: The primary outcomes were incidence rate ratios of asthma and eczema in children born by caesarean section when pre-incision prophylactic antibiotics were recommended compared with those born when antibiotics were administered post-cord clamping, adjusted for temporal changes in the incidence rates in children born vaginally. RESULTS: Prophylactic antibiotics administered before incision for caesarean section compared with after cord clamping were not associated with a significantly higher risk of asthma (incidence rate ratio 0.91, 95% confidence interval 0.78 to 1.05) or eczema (0.98, 0.94 to 1.03), including asthma and eczema resulting in hospital admission (1.05, 0.99 to 1.11 and 0.96, 0.71 to 1.29, respectively), up to age 5 years. CONCLUSIONS: This study found no evidence of an association between pre-incision prophylactic antibiotic use and risk of asthma and eczema in early childhood in children born by caesarean section.


Assuntos
Antibioticoprofilaxia , Cesárea , Antibacterianos/uso terapêutico , Antibioticoprofilaxia/efeitos adversos , Asma/epidemiologia , Cesárea/métodos , Pré-Escolar , Constrição , Eczema/epidemiologia , Registros Eletrônicos de Saúde , Feminino , Humanos , Estudos Longitudinais , Gravidez , Infecção da Ferida Cirúrgica/prevenção & controle , Reino Unido/epidemiologia
14.
J Alzheimers Dis Rep ; 6(1): 1-15, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35243208

RESUMO

BACKGROUND: The development of beta-site amyloid-beta precursor protein cleaving enzyme (BACE) 1 inhibitors for the treatment of Alzheimer's disease requires optimization of inhibitor potency, selectivity, and brain penetration. Moreover, there is a need for low-dose compounds since liver toxicity was found with some BACE inhibitors. OBJECTIVE: To determine whether the high in vitro potency and robust pharmacodynamic effect of the BACE inhibitor LY3202626 observed in nonclinical species translated to humans. METHODS: The effect of LY3202626 versus vehicle on amyloid-ß (Aß) levels was evaluated in a series of in vitro assays, as well as in in vivo and multi-part clinical pharmacology studies. Aß levels were measured using analytical biochemistry assays in brain, plasma, and cerebrospinal fluid (CSF) of mice, dogs and humans. Nonclinical data were analyzed using an ANOVA followed by Tukey's post hoc test and clinical data used summary statistics. RESULTS: LY3202626 exhibited significant human BACE1 inhibition, with an IC50 of 0.615±0.101 nM in a fluorescence resonance energy transfer assay and an EC50 of 0.275±0.176 nM for lowering Aß1-40 and 0.228±0.244 nM for Aß1-42 in PDAPP neuronal cultures. In dogs, CSF Aß1hboxx concentrations were significantly reduced by ∼80% at 9 hours following a 1.5 mg/kg dose. In humans, CSF Aß1-42 was reduced by 73.1±7.96 % following administration of 6 mg QD. LY3202626 was found to freely cross the blood-brain barrier in dogs and humans. CONCLUSION: LY3202626 is a potent BACE1 inhibitor with high blood-brain barrier permeability. The favorable safety and pharmacokinetic/pharmacodynamic profile of LY3202626 supports further clinical development.

15.
Stat Methods Med Res ; 31(2): 287-299, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34994667

RESUMO

Tailored meta-analysis uses setting-specific knowledge for the test positive rate and disease prevalence to constrain the possible values for a test's sensitivity and specificity. The constrained region is used to select those studies relevant to the setting for meta-analysis using an unconstrained bivariate random effects model (BRM). However, sometimes there may be no studies to aggregate, or the summary estimate may lie outside the plausible or "applicable" region. Potentially these shortcomings may be overcome by incorporating the constraints in the BRM to produce a constrained model. Using a penalised likelihood approach we developed an optimisation algorithm based on co-ordinate ascent and Newton-Raphson iteration to fit a constrained bivariate random effects model (CBRM) for meta-analysis. Using numerical examples based on simulation studies and real datasets we compared its performance with the BRM in terms of bias, mean squared error and coverage probability. We also determined the 'closeness' of the estimates to their true values using the Euclidian and Mahalanobis distances. The CBRM produced estimates which in the majority of cases had lower absolute mean bias and greater coverage probability than the BRM. The estimated sensitivities and specificity for the CBRM were, in general, closer to the true values than the BRM. For the two real datasets, the CBRM produced estimates which were in the applicable region in contrast to the BRM. When combining setting-specific data with test accuracy meta-analysis, a constrained model is more likely to yield a plausible estimate for the sensitivity and specificity in the practice setting than an unconstrained model.


Assuntos
Algoritmos , Viés , Simulação por Computador , Funções Verossimilhança , Sensibilidade e Especificidade
16.
Stat Methods Med Res ; 31(1): 47-61, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34756132

RESUMO

Cluster analysis of functional data is finding increasing application in the field of medical research and statistics. Here we introduce a functional version of the forward search methodology for the purpose of functional data clustering. The proposed forward search algorithm is based on the functional spatial ranks and is a data-driven non-parametric method. It does not require any preprocessing functional data steps, nor does it require any dimension reduction before clustering. The Forward Search Based on Functional Spatial Rank (FSFSR) algorithm identifies the number of clusters in the curves and provides the basis for the accurate assignment of each curve to its cluster. We apply it to three simulated datasets and two real medical datasets, and compare it with six other standard methods. Based on both simulated and real data, the FSFSR algorithm identifies the correct number of clusters. Furthermore, when compared with six standard methods used for clustering and classification, it records the lowest misclassification rate. We conclude that the FSFSR algorithm has the potential to cluster and classify functional data.


Assuntos
Algoritmos , Análise por Conglomerados
17.
Br J Gen Pract ; 71(712): e854-e861, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34607795

RESUMO

BACKGROUND: Faecal calprotectin (FC) testing to detect inflammatory bowel disease (IBD) was recommended for use in UK general practice in 2013. The actual use of FC testing following the national recommendations is unknown. AIM: To characterise the use of FC testing for IBD in UK general practice. DESIGN AND SETTING: A retrospective cohort study of routine electronic patient records from The Health Improvement Network database from UK general practice. METHOD: The study included 6 965 853 adult patients (aged ≥18 years), between 2006 and 2016. FC test uptake, the patients tested, and patient management following testing were characterised. RESULTS: A total of 17 027 patients had 19 840 FC tests recorded. The mean age of tested patients was 44.2 years. The first FC tests were documented in 2009. FC test use was still increasing in 2016. By 2016, 66.8% (n = 493/738) of practices had started FC testing. About one-fifth (20.7%, n = 1253/6051) of tests were carried out in patients aged ≥60 years. Only 7.8% (n = 473/6051) of the FC test records were preceded by symptoms eligible for FC testing. Only 3.1% (n = 1720/55 477) of patients with eligible symptoms have received FC testing since the national recommendations were published. There was only a small number of patients with symptoms, FC test, and a IBD diagnosis. In total, 71.3% (n = 1416/1987) of patients with a positive and 47.7% (n = 1337/2805) with a negative FC test were referred or further investigated. CONCLUSION: Uptake of FC testing in clinical practice has been slow and inconsistent. The indication of non-compliance with national recommendations may suggest that these recommendations lack applicability to the general practice context.


Assuntos
Medicina Geral , Doenças Inflamatórias Intestinais , Adolescente , Adulto , Biomarcadores , Fezes , Humanos , Doenças Inflamatórias Intestinais/diagnóstico , Complexo Antígeno L1 Leucocitário , Estudos Retrospectivos , Reino Unido
18.
J Alzheimers Dis Rep ; 5(1): 321-336, 2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-34113788

RESUMO

BACKGROUND: LY3202626 is a small molecule inhibitor of ß-site amyloid precursor protein cleaving enzyme (BACE)1 shown to reduce amyloid-ß (Aß)1-40 and Aß1-42 concentrations in plasma and cerebrospinal fluid developed for the treatment of Alzheimer's disease (AD). OBJECTIVE: To assess the change from baseline in flortaucipir positron emission tomography (PET) after treatment with LY3202626 compared with placebo in patients with mild AD dementia. METHODS: Patients received daily 3 mg or 12 mg doses of LY3202626 or placebo for 52 weeks. The primary outcome was assessment of cerebral neurofibrillary tangle load by flortaucipir PET. The study was terminated early following an interim analysis due to a low probability of identifying a statistically significant slowing of cognitive and/or functional decline. RESULTS: A total of 316 patients were randomized and 47 completed the study. There was no statistically significant difference between placebo and either dose of LY3202626 from baseline to 52 weeks, or in annualized change for flortaucipir PET. There was no clinically meaningful difference between placebo and LY3202626 doses on efficacy measures of cognition and function. No deaths or serious adverse events considered related to LY3202626 were reported. A statistically significant increase in treatment-emergent adverse events in the psychiatric disorders system organ class was reported for both LY3202626 doses compared to placebo. CONCLUSION: LY3202626 tested at doses generating 70-90% BACE inhibition was generally well tolerated in this study. LY3202626 treatment did not result in a clinically significant change in cerebral tau burden as measured by flortaucipir nor in change of functional or cognitive decline compared to placebo.

19.
J Med Chem ; 64(12): 8076-8100, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34081466

RESUMO

The beta-site APP cleaving enzyme 1, known as BACE1, has been a widely pursued Alzheimer's disease drug target owing to its critical role in the production of amyloid-beta. We have previously reported the clinical development of LY2811376 and LY2886721. LY2811376 advanced to Phase I before development was terminated due to nonclinical retinal toxicity. LY2886721 advanced to Phase II, but development was halted due to abnormally elevated liver enzymes. Herein, we report the discovery and clinical development of LY3202626, a highly potent, CNS-penetrant, and low-dose BACE inhibitor, which successfully addressed these key development challenges.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Compostos Heterocíclicos com 2 Anéis/farmacologia , Inibidores de Proteases/farmacologia , Pirazinas/farmacologia , Pirróis/farmacologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Ácido Aspártico Endopeptidases/metabolismo , Barreira Hematoencefálica/fisiologia , Encéfalo/metabolismo , Cristalografia por Raios X , Cães , Estabilidade de Medicamentos , Compostos Heterocíclicos com 2 Anéis/síntese química , Compostos Heterocíclicos com 2 Anéis/farmacocinética , Humanos , Células Madin Darby de Rim Canino , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Inibidores de Proteases/síntese química , Inibidores de Proteases/metabolismo , Inibidores de Proteases/farmacocinética , Ligação Proteica , Pirazinas/síntese química , Pirazinas/farmacocinética , Pirróis/síntese química , Pirróis/farmacocinética , Ratos , Relação Estrutura-Atividade
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