COVID-19 Stroke Apical Lung Examination Study 2: a national prospective CTA biomarker study of the lung apices, in patients presenting with suspected acute stroke (COVID SALES 2).

BACKGROUND: Apical ground-glass opacification (GGO) identified on CT angiography (CTA) performed for suspected acute stroke was developed in 2020 as a coronavirus-disease-2019 (COVID-19) diagnostic and prognostic biomarker in a retrospective study during the first wave of COVID-19. OBJECTIVE: To prospectively validate whether GGO on CTA performed for suspected acute stroke is a reliable COVID-19 diagnostic and prognostic biomarker and whether it is reliable for COVID-19 vaccinated patients. METHODS: In this prospective, pragmatic, national, multi-center validation study performed at 13 sites, we captured study data consecutively in patients undergoing CTA for suspected acute stroke from January-March 2021. Demographic and clinical features associated with stroke and COVID-19 were incorporated. The primary outcome was the likelihood of reverse-transcriptase-polymerase-chain-reaction swab-test-confirmed COVID-19 using the GGO biomarker. Secondary outcomes investigated were functional status at discharge and survival analyses at 30 and 90 days. Univariate and multivariable statistical analyses were employed. RESULTS: CTAs from 1,111 patients were analyzed, with apical GGO identified in 8.5 % during a period of high COVID-19 prevalence. GGO showed good inter-rater reliability (Fleiss κ = 0.77); and high COVID-19 specificity (93.7 %, 91.8-95.2) and negative predictive value (NPV; 97.8 %, 96.5-98.6). In subgroup analysis of vaccinated patients, GGO remained a good diagnostic biomarker (specificity 93.1 %, 89.8-95.5; NPV 99.7 %, 98.3-100.0). Patients with COVID-19 were more likely to have higher stroke score (NIHSS (mean +/- SD) 6.9 +/- 6.9, COVID-19 negative, 9.7 +/- 9.0, COVID-19 positive; p = 0.01), carotid occlusions (6.2 % negative, 14.9 % positive; p = 0.02), and larger infarcts on presentation CT (ASPECTS 9.4 +/- 1.5, COVID-19 negative, 8.6 +/- 2.4, COVID-19 positive; p = 0.00). After multivariable logistic regression, GGO (odds ratio 15.7, 6.2-40.1), myalgia (8.9, 2.1-38.2) and higher core body temperature (1.9, 1.1-3.2) were independent COVID-19 predictors. GGO was associated with worse functional outcome on discharge and worse survival after univariate analysis. However, after adjustment for factors including stroke severity, GGO was not independently predictive of functional outcome or mortality. CONCLUSION: Apical GGO on CTA performed for patients with suspected acute stroke is a reliable diagnostic biomarker for COVID-19, which in combination with clinical features may be useful in COVID-19 triage.

A COVID-19 vaccination program for high-risk children aged 12-17 years in Curacao.

Objective: This study aimed to describe and critically evaluate the COVID-19 vaccination program for high-risk children in Curacao and provide information about important factors such as parents' vaccination hesitancy and effective strategies for communicating and delivering information about vaccination. Methods: This was a cross-sectional study. It was important to identify children aged 12-17 years who were at high risk of severe COVID-19 infection because of the limited medical facilities on the island; children considered to be at high risk were those with diseases such as obesity, hypertension or diabetes mellitus type 2. These children or their caregivers were invited by their pediatricians to be vaccinated as part of a program run by the Public Health Department of Curacao. These high-risk patients were vaccinated between 30 May 2021 and 25 February 2022 in designated child-friendly spaces, with a pediatrician present for guidance and reassurance. Children received the Pfizer-BioNTech COVID-19 vaccine at the recommended dose for their age. The primary outcome was a description and evaluation of the attendance for vaccination. The secondary outcomes were side effects after vaccination for the age groups 12-15 years and 16-17 years. Reasons for refusal or nonadherence were also registered. Results: Altogether 51% (24/47) of those aged 16-17 years who were invited were vaccinated compared with 42% (26/69) of those aged 12-15 years who were invited. Altogether, 46% of these high-risk children were vaccinated compared with 48% of children aged 12-17 years without risk factors. In our population, most patients did not experience any side effects and if they did, the side effects were mild. No cases of myocarditis or pericarditis were observed. A lack of trust in the vaccine and a lack of prioritization of vaccination when scheduling daily activities were important factors in refusal and nonadherence. Conclusions: To organize a successful vaccination program in a small community with limited resources for treating high-risk children it is crucial for medical professionals to provide reliable information. Public health initiatives should focus on assuaging parents' fears about vaccines. In addition, ensuring there is good cooperation between doctors and the Public Health Department can help to make implementation successful. Finally, involving pediatricians and using dedicated areas for vaccinating children can help build trust with parents and caregivers.

COVID-19 vaccination program for high-risk children aged 12–17 years in Curacao

[ABSTRACT]. Objective. This study aimed to describe and critically evaluate the COVID-19 vaccination program for high-risk children in Curacao and provide information about important factors such as parents’ vaccination hesitancy and effective strategies for communicating and delivering information about vaccination. Methods. This was a cross-sectional study. It was important to identify children aged 12–17 years who were at high risk of severe COVID-19 infection because of the limited medical facilities on the island; children con- sidered to be at high risk were those with diseases such as obesity, hypertension or diabetes mellitus type 2. These children or their caregivers were invited by their pediatricians to be vaccinated as part of a program run by the Public Health Department of Curacao. These high-risk patients were vaccinated between 30 May 2021 and 25 February 2022 in designated child-friendly spaces, with a pediatrician present for guidance and reassurance. Children received the Pfizer-BioNTech COVID-19 vaccine at the recommended dose for their age. The primary outcome was a description and evaluation of the attendance for vaccination. The secondary outcomes were side effects after vaccination for the age groups 12–15 years and 16–17 years. Reasons for refusal or nonadherence were also registered. Results. Altogether 51% (24/47) of those aged 16–17 years who were invited were vaccinated compared with 42% (26/69) of those aged 12–15 years who were invited. Altogether, 46% of these high-risk children were vaccinated compared with 48% of children aged 12–17 years without risk factors. In our population, most patients did not experience any side effects and if they did, the side effects were mild. No cases of myocardi- tis or pericarditis were observed. A lack of trust in the vaccine and a lack of prioritization of vaccination when scheduling daily activities were important factors in refusal and nonadherence. Conclusions. To organize a successful vaccination program in a small community with limited resources for treating high-risk children it is crucial for medical professionals to provide reliable information. Public health initiatives should focus on assuaging parents’ fears about vaccines. In addition, ensuring there is good coop- eration between doctors and the Public Health Department can help to make implementation successful. Finally, involving pediatricians and using dedicated areas for vaccinating children can help build trust with parents and caregivers.

[RESUMEN]. Objetivo. El objetivo de este estudio consistió en describir y realizar una evaluación crítica del programa de vacunación contra la COVID-19 para adolescentes de alto riesgo en Curazao, así como proporcionar infor- mación sobre factores importantes, como el recelo de los progenitores con respecto a la vacunación y las estrategias eficaces para comunicar y ofrecer información sobre ella. Métodos. Se llevó a cabo un estudio transversal. Debido a las limitaciones de los centros médicos de la isla, era importante seleccionar a los adolescentes de entre 12 y 17 años con un riesgo alto de infección grave por COVID-19; se consideró que tenían un riesgo alto los miembros de este grupo poblacional que presentaban enfermedades como obesidad, hipertensión arterial o diabetes mellitus de tipo 2. Tanto estos adolescentes como sus cuidadores fueron invitados por sus pediatras a vacunarse dentro del marco de un programa impulsado por el Departamento de Salud Pública de Curazao. Estos pacientes de alto riesgo se vacunaron entre el 30 de mayo del 2021 y el 25 de febrero del 2022 en espacios adaptados a la población pediátrica, que contaban con la presencia de un especialista en pediatría para orientarles y tranquilizarles y donde se les administró la vacuna contra la COVID-19 de Pfizer-BioNTech en la dosis recomendada para su edad. El crite- rio de valoración principal fue la descripción y evaluación de la asistencia para recibir la vacuna. El criterio de valoración secundario fueron los efectos secundarios posteriores a la vacunación en los grupos de edad de 12 a 15 años y de 16 a 17 años. También se registraron los motivos para negarse a recibir la vacuna o para el incumplimiento del calendario de vacunación. Resultados. En total, se vacunó al 51% (24/47) de las personas de 16-17 años invitadas, en comparación con el 42% (26/69) de las de 12-15 años. Se vacunó al 46% de esta población de alto riesgo, en comparación con el 48% de la población de 12 a 17 años sin factores de riesgo. En nuestra población, la mayoría de los pacientes no presentaron ningún efecto secundario y cuando los hubo, estos fueron leves. No se observaron casos de miocarditis ni de pericarditis. La falta de confianza en la vacuna y la baja prioridad otorgada a la vacunación a la hora de programar las actividades diarias fueron factores importantes en la negativa a recibir la vacuna o el incumplimiento del calendario de vacunación. Conclusiones. Si se quiere organizar un programa de vacunación exitoso en una comunidad pequeña y con recursos limitados para tratar a la población adolescente de alto riesgo, es crucial que el personal médico proporcione una información fiable. Las iniciativas de salud pública deben centrarse en disipar los temores de los progenitores sobre las vacunas. Asimismo, el hecho de asegurar una buena cooperación entre el personal médico y el Departamento de Salud Pública puede contribuir al éxito de la iniciativa. Por último, la involucración de pediatras y el uso de espacios específicos para la vacunación de la población adolescente pueden ayudar a generar un clima de confianza en progenitores y cuidadores.

[RESUMO]. Objetivo. Este estudo teve como objetivo descrever e avaliar de maneira crítica o programa de vacinação contra a COVID-19 para adolescentes de alto risco em Curaçao e dar informações sobre fatores importantes, como a hesitação vacinal dos pais e estratégias efetivas para comunicar e fornecer informações sobre a vacinação. Métodos. Este foi um estudo transversal. Era importante identificar os adolescentes entre 12 e 17 anos que tinham alto risco de infecção grave por COVID-19 devido à escassez de estabelecimentos de saúde na ilha; os adolescentes considerados de alto risco tinham obesidade, hipertensão arterial ou diabetes mellitus tipo 2. Esses adolescentes e seus cuidadores foram convidados por seus pediatras a serem vacinados como parte de um programa do Departamento de Saúde Pública de Curaçao. Esses pacientes de alto risco foram vacina- dos entre 30 de maio de 2021 e 25 de fevereiro de 2022 em espaços adaptados para adolescentes e com a presença de um pediatra para orientação e segurança. Os adolescentes receberam a vacina Pfizer-BioNTech COVID-19 na dose recomendada para a idade. O desfecho primário foi a descrição e a avaliação do comparecimento à vacinação. Os desfechos secundários foram os efeitos colaterais após a vacinação nas faixas etárias de 12 a 15 anos e de 16 a 17 anos. Os motivos de recusa ou não adesão também foram registrados. Resultados. No total, 51% (24/47) dos adolescentes convidados de 16 a 17 anos de idade foram vacinados, em comparação com 42% (26/69) dos adolescentes convidados de 12 a 15 anos de idade. No total, 46% desses adolescentes de alto risco foram vacinados, em comparação com 48% dos adolescentes de 12 a 17 anos sem fatores de risco. Na população do estudo, a maioria dos pacientes não apresentou nenhum efeito colateral e, quando presentes, os efeitos colaterais foram leves. Não foram observados casos de miocardite ou pericardite. A falta de confiança na vacina e a falta de priorização da vacinação ao programar as ativi- dades diárias foram fatores importantes para recusa e não adesão. Conclusões. Para organizar um programa de vacinação bem-sucedido em uma pequena comunidade com recursos limitados para o tratamento de adolescentes de alto risco, é fundamental que os profissionais médi- cos apresentem informações confiáveis. As iniciativas de saúde pública devem se concentrar em aliviar o medo dos pais em relação às vacinas. Além disso, garantir que haja boa cooperação entre os médicos e o Departamento de Saúde Pública pode ajudar no sucesso da implementação. Por fim, o envolvimento de pediatras e o uso de áreas

Sialendoscopic removal of metastatic adenocarcinoma in a mucous plug from Stensen's duct.

Sialendoscopy is a minimally invasive technique used mainly in the diagnosis and treatment of obstructive salivary gland disorders. There has yet to be a report on its use in the diagnosis of metastatic disease. While metastatic cancer has been described in numerous head and neck anatomic subsites, it has not been reported to be found in a mucous plug in Stensen's duct. Sialendoscopy was performed in a 68-year-old female patient who presented with symptoms of ductal obstruction. Basket removal of a mucous plug was done and histopathological analysis of this specimen found adenocarcinoma. The overall clinical picture, imaging, and final histopathological results suggested that this patient had metastatic breast carcinoma to a mucous plug in Stensen's duct, the diagnosis of which was made with the aid of interventional sialendoscopy. This is the first report in which metastatic cancer was identified in a mucous plug in Stensen's duct. Sialendoscopy can be a useful tool to aid in the diagnosis of metastatic diseases in rare and unusual clinical situations.

Prevalence of congenital anomalies in the Dutch Caribbean islands of Aruba, Bonaire, and Curaçao.

BACKGROUND: Congenital anomalies represent an important global health issue. Data on the prevalence and pattern of congenital anomalies in the Caribbean region are scarce and lacking altogether in Aruba, Bonaire and Curaçao (ABC islands). METHODS: We performed a population-based surveillance study to determine the prevalence of structural congenital anomalies in the ABC islands, including all live births and stillbirths between January 1, 2008 and December 31, 2017 with major congenital anomalies according to EUROCAT guide 1.5. Terminations of pregnancy for fetal anomaly were included as well. Cases were identified by active case ascertainment, using multiple sources including pediatric patient files and discharge letters, delivery records, and clinical genetic patient files. Total and subgroup prevalence rates were compared between the three islands and to the French West Indies and Northern Netherlands. RESULTS: Total prevalence of congenital anomalies on the ABC islands was 242.97 per 10,000 births. Total prevalence of congenital anomalies in Bonaire (325.15 per 10,000 births) was higher compared to Aruba (233.29 per 10,000 births) and Curaçao (238.58 per 10,000 births), which was mainly attributable to a higher prevalence of limb anomalies, in particular polydactyly, in Bonaire. Total prevalence of congenital anomalies on the ABC islands was comparable to the French West Indies (248.69 per 10,000 births) but significantly lower compared to the Northern Netherlands (298.98 per 10,000 births). In the subgroup prevalence analysis, the prevalence of polydactyly and atrial septal defect on the ABC islands was significantly higher compared with the French West Indies and the Northern Netherlands, while the prevalence of congenital anomalies of the kidney and urinary tract and genetic disorders was significantly lower. CONCLUSIONS: This is the first study to establish the prevalence and pattern of congenital anomalies on the ABC islands, which is important to inform healthcare managers and policymakers and to provide a basis for continuous surveillance of congenital anomalies.

A COVID-19 vaccination program for high-risk children aged 12-17 years in Curacao / Programa de vacunación contra la COVID-19 para adolescentes de alto riesgo de 12 a 17 años en Curazao / Programa de vacinação contra a COVID-19 para adolescentes de alto risco com idades entre 12 e 17 anos em Curaçao

ABSTRACT Objective. This study aimed to describe and critically evaluate the COVID-19 vaccination program for high-risk children in Curacao and provide information about important factors such as parents' vaccination hesitancy and effective strategies for communicating and delivering information about vaccination. Methods. This was a cross-sectional study. It was important to identify children aged 12-17 years who were at high risk of severe COVID-19 infection because of the limited medical facilities on the island; children considered to be at high risk were those with diseases such as obesity, hypertension or diabetes mellitus type 2. These children or their caregivers were invited by their pediatricians to be vaccinated as part of a program run by the Public Health Department of Curacao. These high-risk patients were vaccinated between 30 May 2021 and 25 February 2022 in designated child-friendly spaces, with a pediatrician present for guidance and reassurance. Children received the Pfizer-BioNTech COVID-19 vaccine at the recommended dose for their age. The primary outcome was a description and evaluation of the attendance for vaccination. The secondary outcomes were side effects after vaccination for the age groups 12-15 years and 16-17 years. Reasons for refusal or nonadherence were also registered. Results. Altogether 51% (24/47) of those aged 16-17 years who were invited were vaccinated compared with 42% (26/69) of those aged 12-15 years who were invited. Altogether, 46% of these high-risk children were vaccinated compared with 48% of children aged 12-17 years without risk factors. In our population, most patients did not experience any side effects and if they did, the side effects were mild. No cases of myocarditis or pericarditis were observed. A lack of trust in the vaccine and a lack of prioritization of vaccination when scheduling daily activities were important factors in refusal and nonadherence. Conclusions. To organize a successful vaccination program in a small community with limited resources for treating high-risk children it is crucial for medical professionals to provide reliable information. Public health initiatives should focus on assuaging parents' fears about vaccines. In addition, ensuring there is good cooperation between doctors and the Public Health Department can help to make implementation successful. Finally, involving pediatricians and using dedicated areas for vaccinating children can help build trust with parents and caregivers.

resumen está disponible en el texto completo

RESUMO Objetivo. Este estudo teve como objetivo descrever e avaliar de maneira crítica o programa de vacinação contra a COVID-19 para adolescentes de alto risco em Curaçao e dar informações sobre fatores importantes, como a hesitação vacinal dos pais e estratégias efetivas para comunicar e fornecer informações sobre a vacinação. Métodos. Este foi um estudo transversal. Era importante identificar os adolescentes entre 12 e 17 anos que tinham alto risco de infecção grave por COVID-19 devido à escassez de estabelecimentos de saúde na ilha; os adolescentes considerados de alto risco tinham obesidade, hipertensão arterial ou diabetes mellitus tipo 2. Esses adolescentes e seus cuidadores foram convidados por seus pediatras a serem vacinados como parte de um programa do Departamento de Saúde Pública de Curaçao. Esses pacientes de alto risco foram vacinados entre 30 de maio de 2021 e 25 de fevereiro de 2022 em espaços adaptados para adolescentes e com a presença de um pediatra para orientação e segurança. Os adolescentes receberam a vacina Pfizer-BioNTech COVID-19 na dose recomendada para a idade. O desfecho primário foi a descrição e a avaliação do comparecimento à vacinação. Os desfechos secundários foram os efeitos colaterais após a vacinação nas faixas etárias de 12 a 15 anos e de 16 a 17 anos. Os motivos de recusa ou não adesão também foram registrados. Resultados. No total, 51% (24/47) dos adolescentes convidados de 16 a 17 anos de idade foram vacinados, em comparação com 42% (26/69) dos adolescentes convidados de 12 a 15 anos de idade. No total, 46% desses adolescentes de alto risco foram vacinados, em comparação com 48% dos adolescentes de 12 a 17 anos sem fatores de risco. Na população do estudo, a maioria dos pacientes não apresentou nenhum efeito colateral e, quando presentes, os efeitos colaterais foram leves. Não foram observados casos de miocardite ou pericardite. A falta de confiança na vacina e a falta de priorização da vacinação ao programar as atividades diárias foram fatores importantes para recusa e não adesão. Conclusões. Para organizar um programa de vacinação bem-sucedido em uma pequena comunidade com recursos limitados para o tratamento de adolescentes de alto risco, é fundamental que os profissionais médicos apresentem informações confiáveis. As iniciativas de saúde pública devem se concentrar em aliviar o medo dos pais em relação às vacinas. Além disso, garantir que haja boa cooperação entre os médicos e o Departamento de Saúde Pública pode ajudar no sucesso da implementação. Por fim, o envolvimento de pediatras e o uso de áreas exclusivas para a vacinação de adolescentes podem ajudar a criar confiança nos pais e cuidadores.

Physician-Targeted Interventions in Antibiotic Prescribing for Urinary Tract Infections in General Practice: A Systematic Review.

Urinary tract infections (UTIs) are the most common reason for women to consult a general practitioner (GP). While UTIs are self-limiting in half of cases, most women are prescribed antibiotics, often in discordance with established guidelines. Researchers have employed different interventions to improve GPs' prescribing behavior, especially for respiratory infections, but it is uncertain whether these are effective for UTI care. Therefore, we performed a systematic review, including (cluster) randomized clinical trials investigating the effect of interventions targeted at GPs to improve antibiotic prescriptions for UTI. From September to December 2021 we searched the Medline, Web of Science, and CENTRAL databases, ultimately including ten studies describing eleven trials. We determined the effect of the interventions on the decision to prescribe and on the choice of antibiotic. Results showed that most studies employed multifaceted interventions, most frequently including audit & feedback and/or educational meetings. Seven out of nine trials that recorded first-choice prescriptions saw an increased proportion of first-choice antibiotics in the intervention groups compared to control groups. The employed interventions also caused a decreased proportion of at least one broad-spectrum antibiotic in five out of six studies that measured broad-spectrum antibiotic prescriptions. However, the total number of antibiotic prescriptions for UTIs increased in four out of eight studies. Therefore, while effective at influencing GPs' prescribing behavior, future interventions should also focus on improving the decision to prescribe at all.

Cross-sectional internet survey exploring women's knowledge, attitudes and practice regarding urinary tract infection-related symptoms in the Netherlands.

OBJECTIVES: Urinary tract infections (UTIs) are the most prevalent cause for women to consult a general practitioner (GP) and are commonly treated with (broad-spectrum) empirical antibiotics, even though 50% of UTIs are self-limiting. In this study, we aim to explore women's attitudes and experiences regarding UTIs, in order to determine patients' willingness to accept delayed antibiotic prescriptions. DESIGN: An internet-based cross-sectional survey SETTING: We recruited participants during 2 weeks of March and April in 2020 through several social media platforms. PARTICIPANTS: We obtained 1476 responses, of which 975 were eligible for analysis. RESULTS: We asked women about their knowledge, attitudes and practice regarding UTI-related symptoms. Participants ranked 'confirmation of diagnosis' (43.8%) as the most important reason to consult a GP with urinary symptoms, followed by 'pain relief' (32%), and 'antibiotic prescription' (14.3%). For treatment, 71% of participants reported that their GP prescribed immediate antibiotics, while only 3% received a delayed antibiotic prescription and 1% was advised pain medication. Furthermore, 50% of respondents were aware of the possible self-limiting course of UTIs and 70% would be willing to accept delayed antibiotic treatment, even if a certain diagnosis of UTI was established. Willingness to delay was lower in experienced patients compared to inexperienced patients. CONCLUSIONS: Women are quite receptive to delayed antibiotics as an alternative to immediate antibiotics for UTIs or urinary symptoms. GPs should consider discussing delayed antibiotic treatment more often with women presenting with urinary symptoms.

Genetic care in geographically isolated small island communities: 8 years of experience in the Dutch Caribbean.

Worldwide, there are large inequalities in genetic service delivery. In 2011, we established a bi-annual joint pediatric-genetics clinic with a visiting clinical geneticist in the Dutch Caribbean. This retrospective study evaluates the yield of diagnostic testing and the clinical utility of a diagnosis for patients with rare diseases on these relatively isolated, resource-limited islands. A total of 331 patients that were referred to the clinical geneticist between November 2011 and November 2019 and had genetic testing were included in this study. A total of 508 genetic tests were performed on these patients. Microarray, next-generation sequencing gene panels, and single-gene analyses were the most frequently performed genetic tests. A molecularly confirmed diagnosis was established in 33% of patients (n = 108). Most diagnosed patients had single nucleotide variants or small insertions and/or deletions (48%) or copy number variants (34%). Molecular diagnostic yield was highest in patients referred for seizures and developmental delay/intellectual disability. The genetic diagnosis had an impact on clinical management in 52% of patients. Referrals to other health professionals and changes in therapy were the most frequently reported clinical consequences. In conclusion, despite limited financial resources, our genetics service resulted in a reasonably high molecular diagnostic yield. Even in this resource-limited setting, a genetic diagnosis had an impact on clinical management for the majority of patients. Our approach with a visiting clinical geneticist may be an example for others who are developing genetic services in similar settings.

Donanemab (LY3002813) Phase 1b Study in Alzheimer's Disease: Rapid and Sustained Reduction of Brain Amyloid Measured by Florbetapir F18 Imaging.

BACKGROUND: Donanemab (LY3002813) is an IgG1 antibody directed at an N­terminal pyroglutamate of amyloid beta epitope that is present only in brain amyloid plaques. OBJECTIVES: To assess effects of donanemab on brain amyloid plaque load after single and multiple intravenous doses, as well as pharmacokinetics, safety/tolerability, and immunogenicity. DESIGN: Phase 1b, investigator- and patient-blind, randomized, placebo-controlled study. SETTING: Patients recruited at clinical research sites in the United States and Japan. PARTICIPANTS: 61 amyloid plaque-positive patients with mild cognitive impairment due to Alzheimer's disease and mild-to-moderate Alzheimer's disease dementia. INTERVENTION: Six cohorts were dosed with donanemab: single dose 10-, 20- or 40- mg/kg (N = 18), multiple doses of 10-mg/kg every 2 weeks for 24 weeks (N = 10), and 10- or 20-mg/kg every 4 weeks for 72 weeks (N=18) or placebo (N = 15). MEASUREMENTS: Brain amyloid plaque load, using florbetapir positron emission tomography, was assessed up to 72 weeks. Safety was evaluated by occurrence of adverse events, magnetic resonance imaging, electrocardiogram, vital signs, laboratory testing, neurological monitoring, and immunogenicity. RESULTS: Treatment with donanemab resulted in rapid reduction of amyloid, even after a single dose. By 24 weeks, amyloid positron emission tomography mean changes from baseline for single donanemab doses in Centiloids were: -16.5 (standard error 11.22) 10-mg/kg intravenous; 40.0 (standard error 11.23) 20 mg/kg intravenous; and -49.6 (standard error 15.10) 40-mg/kg intravenous. Mean reduction of amyloid plaque in multiple dose cohorts by 24 weeks in Centiloids were: 55.8 (standard error 9.51) 10-mg/kg every 2 weeks; -50.2 (standard error 10.54) 10-mg/kg every 4 weeks; and -58.4 (standard error 9.66) 20-mg/kg every 4 weeks. Amyloid on average remained below baseline levels up to 72 weeks after a single dose of donanemab. Repeated dosing resulted in continued florbetapir positron emission tomography reductions over time compared to single dosing with 6 out of 28 patients attaining complete amyloid clearance within 24 weeks. Within these, 5 out of 10 patients in the 20 mg/kg every 4 weeks cohort attained complete amyloid clearance within 36 weeks. When dosing with donanemab was stopped after 24 weeks of repeat dosing in the 10 mg every 2 weeks cohort, florbetapir positron emission tomography reductions were sustained up to 72 weeks. For the single dose cohorts on day 1, dose proportional increases in donanemab pharmacokinetics were observed from 10 to 40 mg/kg. Dose proportional increases in pharmacokinetics were also observed at steady state with the multiple dose cohorts. Donanemab clearance was comparable across the dose levels. Mean donanemab elimination-half-life following 20 mg/kg single dose was 9.3 days with range of 5.6 to 16.2 days. Greater than 90% of patients had positive treatment-emergent antidrug antibodies with donanemab. However, overall, the treatment-emergent antidrug antibodies did not have a significant impact on pharmacokinetics. Donanemab was generally well tolerated. Amongst the 46 participants treated with donanemab, the following amyloid-related imaging abnormalities, common to the drug class, were observed: 12 vasogenic cerebral edema events (12 [19.7%] patients), 10 cerebral microhemorrhage events (6 [13.0%] patients), and 2 superficial siderosis events (2 [4.3%] patients). CONCLUSIONS: Single and multiple doses of donanemab demonstrated a rapid, robust, and sustained reduction up to 72 weeks in brain amyloid plaque despite treatment-emergent antidrug antibodies detected in most patients. Amyloid-related imaging abnormalities were the most common treatment-emergent event.

Clinical validation of 2D perfusion angiography using Syngo iFlow software during peripheral arterial interventions.

OBJECTIVE: Endovascular surgery is an important treatment modality in peripheral arterial disease. Digital subtraction angiography is the standard post revascularisation diagnostic tool to locate lesions and to evaluate the effect of an intervention. However, interpretation of digital subtraction angiography images is subjective and it is difficult to determine whether revascularisation has been sufficient for clinical improvement. A new technique is 2D perfusion angiography, which creates a 2D colour map and time density curve from the digital subtraction angiography scan for an objective evaluation of the results. However, its clinical relevance is unknown. The aim is to evaluate the association between 2D perfusion angiography parameters and clinical outcome after peripheral arterial interventions. METHODS: In this retrospective study, post revascularisation angiographic data and clinical data were reviewed of patients who underwent treatment of femoral-popliteal or femoral-tibial arteries. The outcome was assessed at three time points using three classification systems for peripheral arterial disease: Fontaine classification, American Medical Association whole person impairment classification (AMA) and average wound, ischemia, foot infection score. Post revascularisation angiographic data consisted of time density curves of the foot and lower leg which were extracted from the Syngo iFlow system (Siemens Healthineers). For each time density curve, five descriptive parameters were calculated: time of arrival, time to peak, mean transit time, wash-in rate and area under the curve. The association between the time density curve parameters and peripheral arterial disease classification systems was assessed using a regression analysis. RESULTS: Between July 2016 and December 2018, 103 patients underwent peripheral endovascular interventions in the hybrid operating room; 39 patients were suitable for analysis, of which 28 patients underwent digital subtraction angiography of the lower leg, 3 patients underwent digital subtraction angiography of the foot and 8 patients underwent digital subtraction angiography of both regions. Limited significant relations were found for time of arrival with Fontainde classification (B = 0.806, p = 0.043) and area under the curve with AMA classification (B = -0.027, p = 0.047). CONCLUSION: In this retrospective study, time density curve parameters (time of arrival and area under the curve), measured in the lower leg, showed a limited significant association with two classification systems for peripheral arterial disease. Future prospective studies to determine the clinical relevance of this 2D perfusion angiography method should focus on standardisation of angiography protocols and comparison of pre- and post-intervention parameters.

Oral Epstein-Barr virus-positive mucocutaneous ulcer: gingival presentation of a benign lymphoproliferative lesion.

Epstein-Barr virus-positive mucocutaneous ulcer (EBVMCU) is a benign lymphoproliferative lesion related to iatrogenic or age-related immunosuppression in patients with prior Epstein-Barr virus (EBV) infection. Although the clinical presentation may resemble malignant disease, the course of EBVMCU is indolent, and regression is expected when immunosuppression is reduced. We present a case of EBVMCU in the gingiva of a 59-year-old male patient with long-standing pemphigus vulgaris. The initial presentation was suspicious for oral cavity cancer, which was ruled out by biopsy. After reduction of immunosuppression, the ulceration regressed and an area of exposed necrotic bone remained. Complete healing was achieved after sequestrectomy and primary closure with a local gingival flap.

Tetrahydrobiopterin administration facilitates amphetamine-induced dopamine release and motivation in mice.

Dopamine (DA) is a critical neurotransmitter involved in motivational processes. Tetrahydrobiopterin (BH4) is an essential cofactor for tyrosine hydroxylase, the rate-limiting enzyme in DA synthesis. Decreases in BH4 levels are observed in several DA-related neuropsychiatric diseases involving impairment in motivation. Yet, whether BH4 could be used to treat motivational deficits has not been comprehensively investigated. To investigate the effects of exogenous BH4 administration on the dopaminergic system and related behaviors, we acutely injected mice with BH4 (50 mg/kg). Passage of BH4 through the blood brain barrier and accumulation in brain was measured using the in situ brain perfusion technique. DA release was then recorded using in-vivo micro-dialysis and motivation was evaluated through operant conditioning paradigms in basal condition and after an amphetamine (AMPH) injection. First, we showed that BH4 crosses the blood-brain barrier and that an acute peripheral injection of BH4 is sufficient to increase the concentrations of biopterins in the brain, without affecting BH4- and DA-related protein expression. Second, we report that this increase in BH4 enhanced AMPH-stimulated DA release in the nucleus accumbens. Finally, we found that BH4-induced DA release led to improved performance of a motivational task. Altogether, these findings suggest that BH4, through its action on the dopaminergic tone, could be used as a motivational enhancer.