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The number of new oncological treatments is increasing rapidly, even though many offer limited benefit to patients. In these cases, the scientific research leading to approvals is marred by shortcomings. Nonetheless, many drugs of limited value are approved by regulatory agencies. One of the factors contributing thereto is financial conflict of interest (FCI) with the pharmaceutical industry (Pharma). This occurs at different levels, including researchers, opinion leaders and editors of medical journals. FCI contributes to patient exposure to treatments that offer limited or no benefit and to unjust spending of valuable resources while providing large revenues for Pharma. The important step of the 'NederlandsTijdschriftvoorGeneeskunde' (NTVG) to omit all pharmaceutical advertisement as well as advertisement for pharmaceutical industry sponsored medical education sends an important signal and is a first step to revalue the important relationship with the pharmaceutical industry.

As we witness an alarming change in the delivery of healthcare worldwide, there is a need for transformational leadership that can inspire and empower healthcare professionals, and patients alike. Due to the lack of economic, infrastructural and human resources especially in developing countries, the organisation and delivery of healthcare services is even more challenging. Hence, the focus of leadership development in resource-limited environments should be to facilitate knowledge building, interprofessional collaboration, empowerment and inclusion.In this paper, we use two exemplary cases to illustrate the impact of, and the challenges facing leadership capacity building in non-Western contexts with special reference to India and Curaçao. These cases demonstrate that there is a place for validated medical leadership models in developing countries with promising outcomes for the collective health status of communities at large. Such models, however, need to be contextualised to fit the individual country's economic and sociopolitical context. Also, the stakeholders should be prepared to create healthy professional cultures that embrace respect (for self and others) and focus on effective communication practices within their local environments.

Introduction The healthcare system in Curacao is complex, fragmented, and poorly organized and typifies a system in a resource-limited environment. Deficits in competencies and local cultural barriers are factors that hinder sustainable healthcare in such settings and a failure to meet WHO sustainable development goals. This study reports the potential cost-effectiveness and improved health outcomes of the first stage of a healthcare improvement project. The intervention, which is a multidisciplinary team-based leadership training program (MLP), reflects a promising strategy to tackle local healthcare needs. Methods A Multidisciplinary group of healthcare professionals in St. Elisabeth hospital, Curacao, was selected to 1) participate in the MLP and 2) co-design a healthcare pathway on the management of decubitus ulcers. Using a qualitative research methodology, we conducted interviews to assess the perceived leadership growth, teamwork, and the barriers to the introduction of the new care pathway in their setting. Six themes were identified that explained the perceived leadership development and interprofessional collaboration. These included 1) Professional background, 2) Healthcare pathway design, 3) Resources, 4) Personal development, 5) Collaboration 6) Execution. Conclusion/implication The participants valued the interdisciplinary approach of this health improvement project and acknowledged the added value of a training program that also addressed personal growth. This study shows how MLPs for health professionals can also serve as catalysts for health improvement efforts in resource-limited environments.

Background Vector-borne diseases (VBDs) such as dengue, chikungunya, and Zika pose a significant challenge to health systems in countries they affect, especially countries with less developed healthcare systems. Therefore, countries are encouraged to work towards more resilient health systems. This qualitative study aims to examine the performance of the health system of the Dutch Caribbean island of Curaҫao regarding the prevention and control of VBDs in the last decade by using the WHO health system building blocks. Methods From November 2018 to December 2020, a multi-method qualitative study was performed in Curaçao, applying content analysis of documents (n = 50), five focus group discussions (n = 30), interviews with experts (n = 11) and 15 observation sessions. The study was designed based on the WHO framework: health system building blocks. Two cycles of inductive and deductive coding were employed, and Nvivo software was used to analyse the data. Results This study’s data highlighted the challenges (e.g. insufficient oversight, coordination, leadership skills, structure and communication) that the departments of the health system of Curaҫao faced during the last three epidemics of VBDs (2010–2020). Furthermore, low levels of collaboration between governmental and non-governmental organisations (e.g. semi-governmental and private laboratories) and insufficient capacity building to improve skills (e.g. entomological, surveillance skills) were also observed. Lastly, we observed how bottlenecks in one building block negatively influenced other building blocks (e.g. inadequate leadership/governance obstructed the workforce's performance). Conclusions This study uncovers potential organisational bottlenecks that have affected the performance of the health system of Curaҫao negatively. We recommend starting with the reinforcement of oversight of the integrated vector management programme to ensure the development, implementation and evaluation of related legislation, policies and interventions. Also, we recommend evaluating and reforming the existing administrative and organisational structure of the health system by considering the cultural style, challenges and barriers of the current health system. More efforts are needed to improve the documentation of agreements, recruitment and evaluation of the workforce's performance. Based on our findings, we conceptualised actions to strengthen the health system's building blocks to improve its performance for future outbreaks of infectious diseases. Graphical abstract

Important breakthroughs in medical treatments have improved outcomes for patients suffering from several types of cancer. However, many oncological treatments approved by regulatory agencies are of low value and do not contribute significantly to cancer mortality reduction, but lead to unrealistic patient expectations and push even affluent societies to unsustainable health care costs. Several factors that contribute to approvals of low-value oncology treatments are addressed, including issues with clinical trials, bias in reporting, regulatory agency shortcomings and drug pricing. With the COVID-19 pandemic enforcing the elimination of low-value interventions in all fields of medicine, efforts should urgently be made by all involved in cancer care to select only high-value and sustainable interventions. Transformation of medical education, improvement in clinical trial design, quality, conduct and reporting, strict adherence to scientific norms by regulatory agencies and use of value-based scales can all contribute to raising the bar for oncology drug approvals and influence drug pricing and availability.

Epidemics of dengue, chikungunya, and Zika have been threatening the Caribbean. Since risk communication (RC) plays a fundamental role in preventing and controlling diseases understanding how RC works is essential for enabling risk-reducing behavior. This multimethod qualitative study compares news reports with local’s and health professional’s perspectives, currently lacking in RC research. It was found that RC strategies were obstructed by a lack of governmental structure, organization, and communication. The content analysis showed that the majority of newspaper articles contained negative reporting on the government. Furthermore, this study shows how trust and heuristics attenuate or amplify people’s risk perceptions and possibly positively and negatively influence people’s risk-reducing behavior. A transcending approach (e.g., structural, cooperative, and multidisciplinary) of the prevention and control of vector-borne diseases and the corresponding RC is recommended.

Purpose In a continued effort to improve the health care services, a project was set up to develop and implement a care pathway for the effective management of pressure ulcers in the St Elisabeth Hospital in Curacao, the Dutch Caribbean. To ensure the effective implementation of our intervention, we decided to investigate what factors define the implementation climate of a health care institution within a resource-limited environment. Methods We used a participatory tool approach in this study, where a mixed team of health professionals worked on two parts of a health improvement project, namely: 1) workforce leadership development through a clinical leadership training program; and 2) health care quality improvement through the pressure ulcer care pathway development. In-depth interviews were held with ten participants to gain insight into their experiences of the implementation climate in the hospitals and inductive analysis was used to identify the (sub)themes. Results Identified themes that described the implementation climate included: 1) the attitude of staff toward policy changes; 2) vision of the organization; 3) collaboration; 4) transparency and communication; 5) personal development; and 6) resources. These factors were interrelated and associated with several potential consequences such as loss of motivation among staff, loss of creativity to solve issues, the emergence of the feeling "us" vs "them", short-term solutions to problems, and a sense of suspicion/frustration among staff members. Conclusion From this study, positive subconstructs for a favorable implementation climate in a hospital organization were lacking and those that were identified were suboptimal. The inability to satisfy all the subconstructs seemed to be the consequence of insufficient resources and infrastructure within the current health system. A favorable implementation climate in a resource-limited environment is closely tied to the availability of health care resources and infrastructure.

Background Perinatally chikungunya infected neonates have been reported to have high rates of post-infection neurologic sequelae, mainly cognitive problems. In older children and adults chikungunya does not appear to have sequelae, but data on postnatally infected infants are lacking. Methods We performed a prospective, non-controlled, observational study of infants infected before the age of 6 months with a severe chikungunya infection during the 2014–2015 epidemic in Curaçao, Dutch Antilles. Two years post-infection cognitive and motor - (BSID-III) and social emotional assessments (ITSEA) were performed. Results Of twenty-two infected infants, two died and two were lost to follow up. Eighteen children were seen at follow-up and included in the current study. Of these, 13 (72%) had abnormal scores on the BSID-III (cognitive/motor) or ITSEA. Conclusion In the first study aimed at postnatally infected infants, using an uncontrolled design, we observed a very high percentage of developmental problems. Further studies are needed to assess causality, however until these data are available preventive measure during outbreaks should also include young infants. Those that have been infected in early infancy should receive follow up.

We write to introduce our novel group formed to confront some of the issues raised by the COVID-19 pandemic. Information about the group, which we named "cure COVid for Ever and for All" (RxCOVEA), its dynamic membership (changing regularly), and some of its activities-described in more technical detail for expert perusal and commentary-are available upon request.

The globalization of healthcare has had a significant impact on healthcare delivery and human workforce development in many countries. Consequently, many educational institutions have had to revise the content of their medical curricula to focus on training and preparing future doctors to effectively cater to the needs of the “modern patient”. The focus covers broader aspects of medicine that include environmental and professional culture and the impact of socioeconomic inequalities on the delivery of healthcare. Therefore, in most global health (GH) education programs described, students undertake a specific part of their clinical rotation in a foreign (non-western) educational setting to facilitate authentic learning experiences within a resource-constrained environment. In this paper we present a unique Global Health program for medical interns between the University Medical Center Groningen, Netherlands and the Sint Elisabeth Hospital, Curaçao, Dutch Caribbean that has, for more than 50 years, been providing a one-year internship program as part of the formal Groningen curriculum. The program we describe, illustrates the essential requirements for best practice in GH education that fully complies with recently proposed GH program objectives and competencies. The characteristics of our long running program show the basic requirements necessary for sustainable and successful health education collaboration between institutions in high- and low/middle income countries. Finally, this program, which is part of a Dutch medical curriculum, not only provided unique global health learning experiences for the interns, but importantly also contributed to improving the general healthcare delivery services on the island of Curaçao as well.

Background Risk communication (RC) is an essential tool for the prevention and control of diseases as it impacts risk perception, increases awareness and might change behaviour. It is the interactive exchange of information about risks among experts and people. Effective RC can minimize the impact that diseases such as dengue, chikungunya and Zika have on populations. This study aimed to understand RC regarding vector-borne diseases in its social context and from the viewpoint of the audience to strengthen RC strategies in Curaçao. Methods In 2015, a cross-sectional mixed-method study applying focus group discussions (n = 7), in-depth interviews (n = 20) and a structured survey questionnaire (n = 339) was done in Curaçao. The study was designed based on the Health Belief Model and the Theory of Planned Behaviour. In addition, the Social Amplification of Risk Framework and the theory of cultural schemas were applied to understand RC in the social context. Results Television, radio and newspapers were the most important channels of information regarding dengue and chikungunya. Moreover, individuals also reported receiving information via social media, the internet and family/friends. Interestingly, the use of internet to obtain information diminished with age, while females were more likely to use internet compared to men. These key findings were statistically significant. An important outcome was that the risk perception towards chikungunya at the beginning of the outbreak was attenuated. This might be due to the (perceived) lack of RC before the epidemic. This same risk perception was amplified later during the outbreak by the increased exposure to information. Lastly, we show how cultural schemas influence people’s perception regarding preventive measures and treatment of chikungunya and dengue. Conclusions Data obtained emphasise the importance of understanding the user of media platforms and sharing information in a timely fashion through a transparent process with the content that convinces people of the seriousness of the matter., Author summary Vector-borne diseases (VBDs) such as dengue, chikungunya and Zika are an increasing public health concern worldwide. The mentioned VBDs are transmitted to humans through the bite of an infected mosquito from the Aedes species. Preventing or reducing VBDs continues to depend mainly on vector control and interrupting human-vector contact. Risk communication (RC) is the interactive exchange of information about hazards among experts and individuals. As it influences individuals’ behaviour, a better understanding of how it works is vital to improving RC strategies in the context of VBD prevention and control strategies. Our study highlighted the complexity of this matter as we found that there are multiple factors, including the volume of information, trust, experience with a similar disease and cultural schemas that determine how people cope with risk and information. We recommend broadening the use and scope of media platforms to share information and to customise the messages taking the cultural schemas of the community into account.

Background Several countries have implemented safety strategies to reduce the risk of Zika virus (ZIKV) transmission through blood transfusion. These strategies have included nucleic acid amplification testing (NAT) of blood donations. In this study, a new real-time polymerase chain reaction (PCR) assay including internal control for the detection of ZIKV on the cobas omni Utility Channel (UC) on the cobas 6800 system is presented. Study design and methods PCR conditions and primer/probe concentrations were optimized on the LightCycler 480 instrument. Optimized conditions were transferred to the cobas omni UC on the cobas 6800 system. Subsequently, the limit of detection (LOD) in plasma and urine, genotype inclusivity, specificity, cross-reactivity, and clinical sensitivity were determined. Results The 95% LOD of the ZIKV PCR assay on the cobas 6800 system was 23.0 IU/mL (95% confidence interval [CI], 16.5-37.5) in plasma and 24.5 IU/mL (95% CI, 13.4-92.9) in urine. The assay detected African and Asian lineages of ZIKV. The specificity was 100%. The clinical concordance between the newly developed ZIKV PCR assay and the investigational Roche cobas Zika NAT test was 83% (24/29). Conclusions We developed a sensitive ZIKV PCR assay on the cobas omni UC on the cobas 6800 system. The assay can be used for large-scale screening of blood donations for ZIKV or for testing of blood donors returning from areas with ZIKV to avoid temporal deferral. This study also demonstrates that the cobas omni UC on the cobas 6800 system can be used for in-house-developed PCR assays.

Jamiu O Busari,1,2 Franka M Moll,3 Ashley J Duits3-5 1Department of Educational Development and Research, Faculty of Health, Medicine and Life Sciences, University of Maastricht, Maastricht, the Netherlands; 2Department of Pediatrics, Zuyderland Medical Center, Heerlen, the Netherlands; 3Department of Medical Education, St. Elisabeth Hospital, Willemstad, Curaçao; 4Institute for Medical Education, University Medical Center Groningen, Groningen, the Netherlands; 5Red Cross Blood Bank Foundation, Willemstad, Curaçao Background: A critical assessment of current health care practices, as well as the training needs of various health care providers, is crucial for improving patient care. Several approaches have been proposed for defining these needs with attention on communication as a key competency for effective collaboration. Taking our cultural context, resource limitations, and small-scale ­setting into account, we researched the applicability of a mixed focus group approach for analysis of the communication between doctors and nurses, as well as the measures for improvement. Study objective: Assessment of nurse-physician communication perception in patient care in a Caribbean setting. Methods: Focus group sessions consisting of nurses, interns, and medical specialists were conducted using an ethnographic approach, paying attention to existing communication, risk evaluation, and recommendations for improvement. Data derived from the focus group sessions were analyzed by thematic synthesis method with descriptive themes and development of analytic themes. Results: The initial focus group sessions produced an extensive list of key recommendations which could be clustered into three domains (standardization, sustainment, and collaboration). Further discussion of these domains in focus groups showed nurses’ and physicians’ domain perspectives and effects on patient care to be broadly similar. Risks related to lack of information, knowledge sharing, and professional respect were clearly described by the participants. Conclusion: The described mixed focus group session approach for effectively determining current interprofessional communication and key improvement areas seems suitable for our small‑scale, limited resource setting. The impact of the cultural context should be further ­evaluated by a similar study in a different cultural context. Keywords: interprofessional communication, focus group sessions, nurses’ perspective, cultural context, quality of care

Macro- and microclimates may have variable impact on dengue incidence in different settings. We estimated the short-term impact and delayed effects of climate variables on dengue morbidity in Curacao. Monthly dengue incidence data from 1999 to 2009 were included to estimate the short-term influences of climate variables by employing wavelet analysis, generalized additive models (GAM) and distributed lag nonlinear models (DLNM) on rainfall, temperature and relative humidity in relation to dengue incidence. Dengue incidence showed a significant irregular 4-year multi-annual cycle associated with climate variables. Based on GAM, temperature showed a U-shape, while humidity and rainfall exhibited a dome-shaped association, suggesting that deviation from mean temperature increases and deviation from mean humidity and rainfall decreases dengue incidence, respectively. Rainfall was associated with an immediate increase in dengue incidence of 4.1% (95% CI: 2.2-8.1%) after a 10-mm increase, with a maximum increase of 6.5% (95% CI: 3.2-10.0%) after 1.5 month lag. A 1 °C decrease of mean temperature was associated with a RR of 17.4% (95% CI: 11.2-27.0%); the effect was inversed for a 1°C increase of mean temperature (RR= 0.457, 95% CI: 0.278-0.752). Climate variables are important determinants of dengue incidence and provide insight into its short-term effects. An increase in mean temperature was associated with lower dengue incidence, whereas lower temperatures were associated with higher dengue incidence.

As the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic progresses, countries are depending on one another to acquire knowledge regarding effective measures to contain the virus. Public health measures to suppress transmissions have proven successful in Singapore, Hong Kong and Taiwan. Implementing and adhering to these interventions is challenging, with governments struggling to find a balance between necessary mitigation and suppression strategies, and interruptions of social-economic activities. While large high-income countries are struggling to keep their health systems and economies moving forward, small island developing states are facing even more significant challenges. Many Caribbean islands, including the six islands within the Dutch Kingdom, have been quick to implement stringent public health measures, yet they are facing unique challenges.A medida que avanza la pandemia de síndrome respiratorio agudo severo por coronavirus 2 (SARS-CoV-2), los países dependen unos de otros para adquirir conocimientos sobre las medidas eficaces para contener el virus. Las medidas de salud pública dirigidas a suprimir la transmisión han demostrado su eficacia en Singapur, Hong Kong y Taiwán. La aplicación y la adhesión a esas intervenciones representa un desafío, ya que los gobiernos necesitan encontrar un equilibrio entre las estrategias de mitigación y supresión necesarias y la interrupción de las actividades socioeconómicas. Al tiempo que los países grandes y de altos ingresos luchan por mantener sus sistemas de salud y sus economías en funcionamiento, los pequeños estados insulares en desarrollo se enfrentan a retos aún más importantes. Muchas islas del Caribe, incluidas las seis islas del Reino de los Países Bajos, han aplicado medidas de salud pública estrictas de manera rápida, pero se enfrentan a desafíos singulares.

Several countries have implemented safety strategies to reduce the risk of Zika virus (ZIKV) transmission through blood transfusion. These strategies have included nucleic acid amplification testing (NAT) of blood donations. In this study, a new real-time polymerase chain reaction (PCR) assay including internal control for the detection of ZIKV on the cobas omni Utility Channel (UC) on the cobas 6800 system is presented.PCR conditions and primer/probe concentrations were optimized on the LightCycler 480 instrument. Optimized conditions were transferred to the cobas omni UC on the cobas 6800 system. Subsequently, the limit of detection (LOD) in plasma and urine, genotype inclusivity, specificity, cross-reactivity, and clinical sensitivity were determined.The 95% LOD of the ZIKV PCR assay on the cobas 6800 system was 23.0 IU/mL (95% confidence interval [CI], 16.5-37.5) in plasma and 24.5 IU/mL (95% CI, 13.4-92.9) in urine. The assay detected African and Asian lineages of ZIKV. The specificity was 100%. The clinical concordance between the newly developed ZIKV PCR assay and the investigational Roche cobas Zika NAT test was 83% (24/29).We developed a sensitive ZIKV PCR assay on the cobas omni UC on the cobas 6800 system. The assay can be used for large-scale screening of blood donations for ZIKV or for testing of blood donors returning from areas with ZIKV to avoid temporal deferral. This study also demonstrates that the cobas omni UC on the cobas 6800 system can be used for in-house-developed PCR assays.

Retention in care is one of the major challenges to scaling up and maximizing the effectiveness of combination antiretroviral therapy (cART). High attrition rates have been reported in the Caribbean region, varying from 6% to 23%. We studied the incidence of and risk factors for intermittent care in a cohort of adult HIV-1-positive patients, who entered into care in Curaçao between January 2005 and July 2009. A total of 214 therapy-naïve HIV-1-infected patients aged 15 years or older, entered HIV care between January 2005 and July 2009. Intermittent care was defined as at least one period of 365 days or longer in which there was no HIV care contact in Curaçao. Cox regression models were used to identify characteristics associated with time to intermittent care. In all, 203 (95%) patients could be classified as having intermittent or continuous care. The incidence of intermittent care before starting cART was 25.4 per 100 person years observation (PYO), whilst it was 6.1 per 100 PYO after starting cART. Being born outside Curaçao was associated with intermittent care before and after starting cART. Time from diagnosis to entry into care was an independent predictor for intermittent care before starting cART. Younger age was independently associated with intermittent care after starting cART. Half of the patients returned to care after intermitting care. Upon returning to care, median CD4 count was 264 cells/mm(3) (IQR, 189-401) for those who intermitted care before starting cART, and 146 cells/mm(3) (IQR, 73-436) in those who intermitted care after starting cART. In conclusion, the incidence of intermitting care is high in Curaçao, especially before starting cART, and intermitting care before starting cART is an independent predictor for starting cART late.

We compared the efficacy of combination antiretroviral therapy (cART) of Antillean HIV-1-infected patients treated on the Caribbean island of Curaçao (CUR-AN) with Antillean (NL-AN), Surinam (NL-SUR), and Dutch (NL-NL) patients treated in The Netherlands. In total 2118 therapy-naive patients who started cART between January 2005 and August 2008 were included in the comparison. The CUR-AN patients initiated cART at a median CD4 cell count of 141 cells/mm(3) and 63% had counts below 200 cells/mm(3). Within 12 months of the start of cART 76% of the CUR-AN patients achieved viral suppression, defined as HIV-1 RNA plasma levels below 80 copies/ml. The percentage achieving viral suppression was higher in patients treated in The Netherlands (NL-AN = 87%, NL-SUR = 93%, and NL-NL = 96%). Lost to follow-up after 30 months of cART was 10% among CUR-AN patients and was higher than observed among patients treated in The Netherlands (NL-AN = 8%, NL-SUR = 3%, and NL-NL = 2%). A similar pattern was found for progression to AIDS and death (10% of CUR-AN vs. 5%, 6%, and 7% of NL-AN, NL-SUR, and NL-NL patients, respectively). Late start of cART and limited viral suppression after the start of cART determine the higher rate of disease progression to AIDS and death among Antillean patients treated in Curaçao. The high percentage of lost to follow-up may result in an underestimation of AIDS and AIDS-related death among HIV-1-infected Antilleans treated in Curaçao.

We aimed to study patterns of HIV transmission among Suriname, The Netherlands Antilles, and The Netherlands. Fragments of env, gag, and pol genes of 55 HIV-infected Surinamese, Antillean, and Dutch heterosexuals living in The Netherlands and 72 HIV-infected heterosexuals living in Suriname and the Antilles were amplified and sequenced. We included 145 pol sequences of HIV-infected Surinamese, Antillean, and Dutch heterosexuals living in The Netherlands from an observational cohort. All sequences were phylogenetically analyzed by neighbor-joining. Additionally, HIV-1 mobility among ethnic groups was estimated. A phylogenetic tree of all pol sequences showed two Surinamese and three Antillean clusters of related strains, but no clustering between ethnic groups. Clusters included sequences of individuals living in Suriname and the Antilles as well as those who have migrated to The Netherlands. Similar clustering patterns were observed in env and gag. Analysis of HIV mobility among ethnic groups showed significantly lower migration between groups than expected under the hypothesis of panmixis, apart from higher HIV migration between Antilleans in The Netherlands and all other groups. Our study shows that HIV transmission mainly occurs within the ethnic group. This suggests that cultural factors could have a larger impact on HIV mobility than geographic distance.

Procalcitonin (PCT) has been shown to be of additional value in the work-up of a febrile patient. This study is the first to investigate the additional value of PCT in an Afro-Caribbean febrile population at the emergency department (ED) of a general hospital. Febrile patients were included at the ED. Prospective, blinded PCT measurements were performed in patients with a microbiologically or serologically confirmed diagnosis or a strongly suspected diagnosis on clinical grounds. PCT analysis was performed in 93 patients. PCT levels differentiated well between confirmed bacterial and confirmed viral infection (area under the curve [AUC] of 0.82, sensitivity 85%, specificity 69%, cut-off 0.24 ng/mL), between confirmed bacterial infection and non-infectious fever (AUC of 0.84, sensitivity 90%, specificity 71%, cut-off 0.21 ng/mL) and between all bacterial infections (confirmed and suspected) and non-infectious fever (AUC of 0.80, sensitivity 85%, specificity 71%, cut-off 0.21 ng/mL). C-reactive protein (CRP) levels were shown to be less accurate when comparing the same groups. This is the first study showing that, in a non-Caucasian febrile population at the ED, PCT is a more valuable marker of bacterial infection than CRP. These results may improve diagnostics and eventually decrease antibiotic prescriptions in resource-limited settings.

Inflammation and angiogenesis are of importance in the pathophysiology of sickle cell disease (SCD). Recently, the chemokine stromal-derived factor-1 (SDF-1) has been shown to be a key mediator of angiogenesis and inflammation. In this study we determined serum SDF-1 levels in consecutive adult sickle cell patients during the clinically asymptomatic state as well as during painful crisis. Serum SDF-1 levels were significantly elevated in HbSS/HbSβ⁰-thalassaemia patients [n = 42; 5,177 pg/ml (2,438–7,246)] compared to HbSC/HbSβ+-thalassaemia patients [n = 16; 2,405 pg/ml (1,365–3,047)] and healthy HbAA controls [n = 45; 2,894 pg/ml (2,577–3,334)] (p = 0.001). No significant increments were observed during painful crisis (n = 40). SDF-1 levels were significantly higher in SCD patients with pulmonary hypertension (PHT) compared to patients without PHT. Elevated circulating SDF-1 levels occur in patients with SCD and may play a role in the pathophysiology of SCD-related PHT.

Pulmonary hypertension (PHT) occurs in approximately 30% of adults with sickle cell disease (SCD) and is an independent risk factor for early death. In this study, we aimed to determine the value of general laboratory testing, plain chest radiography, electrocardiography (ECG), high-resolution computer tomography (HRCT) of the thorax, pulmonary function testing, and plasma N-terminal brain natriuretic peptide (NT-proBNP) and brain natriuretic peptide (BNP) in patients with SCD-related PHT. A cohort of 85 ambulatory sickle cell patients were prospectively screened for PHT with echocardiography (defined as a tricuspid regurgitation flow velocity of >= 2.5 ml All patients were systematically evaluated by the aforementioned diagnostic tests comparing patients with and without PHT. The prevalence of PHT was 41% in HbSS/HbS beta(0)-thalassemia patients and 13% in HbSC/HbS beta(+)-thalassemia patients. No statistically significant differences were detected in ECG, chest radiography, HRCT, and pulmonary function testing between patients with and without PHT. The degree of anemia and renal dysfunction, but not the presence of PHT, were the most important determinants of plasma (NT pro)BNP levels. The performed imaging and functional studies do not seem to be of value in identifying etiological conditions (such as airflow obstruction or parenchymal lung disease) nor do they offer clues to the presence of mild PHT in SCD. Am. J. Hematol. 83:850-854, 2008. (C) 2008 Wiley-Liss, Inc.

The anti-angiogenic factors soluble fms-like tyrosine kinase (sFlt)-1 and soluble endoglin (sEng) have been shown to be of importance in angiogenesis by sequestering and inhibiting vascular endothelial growth factor, placenta-like growth factor and transforming growth factor-β1 signaling. Given the potential role of angiogenesis in the pathophysiology of sickle cell disease (SCD)-related complications, serum levels of sFlt-1 and sEng were determined in SCD patients and controls. Both sFlt-1 (p = 0.002) and sEng (p = 0.004) were elevated in patients during clinically asymptomatic SCD with no further increment during painful crisis. These data suggest that sFlt-1 and sEng may be important in the regulation of angiogenesis in SCD.

Background: The introduction of competency-based curricula in institutions situated in resource-limited environments is likely to pose new challenges for the implementation process. The St. Elisabeth Hospital (SEHOS) in Curacao, Dutch Caribbean, is affiliated to university teaching hospitals in the Netherlands. It is a teaching hospital in a resource-limited environment. Aims: Following the revision of the curriculum of the Dutch paediatric residency training, the country's paediatric society mandated its implementation in all training institutions within Dutch sovereignty. We set out to implement the revised curriculum in SEHOS and highlight the benefits it may have in a setting like Curacao. Method: The intended learning outcomes for the 16-week project were (1) the implementation of the core changes in the curriculum and (2) conduct an assessment of the learning environment. The strategies used included informative meetings, workshop and lecture-based trainings, questionnaire surveys, and focus group interviews. Results: Registrars and staff were successfully trained in how to use brief clinical assessments and digital portfolios. 'Departmental portfolio' was introduced as an innovative method of evaluating and monitoring departmental educational activities. Conclusions: Competency-based curricula can be successfully implemented in resource-limited environments. Educational experts in the local setting are crucial for the success of the process.

Sickle red blood cell (SRBC)-endothelial adhesion plays a central role in sickle cell disease (SCD)-related vaso-occlusion. As unusually large von Willebrand factor (ULVWF) multimers mediate SRBC-endothelial adhesion, we investigated the activity of ADAMTS13, the metalloprotease responsible for cleaving ULVWF multimers, in SCD. ADAMTS13 activity was determined using a quantitative immunoblotting assay. VWF:Ag and VWF:RCo were determined using commercial assays. The high-molecular-weight VWF multimer percentage was determined by employing gel electrophoresis. ADAMTS13 activity was similar among asymptomatic patients (n = 8), patients at presentation with a painful crisis (n = 23), and healthy controls. ADAMTS13/VWF:Ag ratios were lower in patients compared to healthy HbAA controls, with the lowest values at presentation with a painful crisis (P = 0.02). Division of samples in those with VWF:RCo/VWF:Ag ratios0.70 and those with ratiosor= 0.70 revealed significantly more samples with ratiosor= 0.70 (P = 0.01) collected during painful crises. ULVWF multimers were detected in 6 patient samples and in 1 control sample. ADAMTS13/VWF:Ag ratios were inversely related to the duration of symptoms at presentation with an acute vaso-occlusive event (r(s)-0.67, P = 0.002). Although SCD is characterized by elevated VWF:Ag levels, no severe ADAMTS13 deficiency was detected in our patients.

In recent years an important role has been ascribed to a reduced nitric oxide (NO) availability in the pathophysiology of sickle cell disease (SCD). Endogenously produced inhibitors of NO synthase, in particular asymmetric dimethylarginine (ADMA), are currently considered of importance in various vascular disease states characterized by reduced NO availability. We determined ADMA levels in plasma of 12 adult sickle cell patients (eight HbSS and four HbSC), and compared these to plasma levels in race- and age-matched controls. Sickle cell patients were characterized by strongly elevated levels of ADMA [HbSS: median 0.63 mu mol/l (interquartile range 0.54-0.85), HbSC: 0.43 mu mol/l (0.40-0.46), HbAA: 0.33 mu mol/l (0.32-0.35) p

Over the last few years, a pivotal role has been ascribed to reduced nitric oxide (NO) availability as a contributing factor to the vaso-occlusive process of sickle cell disease. We investigated whether arginine metabolism in sickle cell patients is different from healthy controls. Blood samples were drawn by venipuncture in the fasting state from 8 clinically asymptomatic HbSS patients and 14 race-matched HbAA controls. HbSS patients had decreased plasma arginine (p=0.001) and increased proline (p=0.015) levels as compared to controls. Ratios of arginine to ornithine (p

Reduced activity of naturally occurring anticoagulants (NOAC) protein C and protein S may contribute to vaso-occlusion in sickle cell disease (SCD). We studied whether protein C and S are related to clinical vaso-occlusion, hematological markers of disease severity (hemoglobin levels, leukocyte counts, and percentage of fetal hemoglobin), and inflammation in SCID. Protein C activity, protein S (free and total) antigen, endothelial activation markers (soluble vascular cell adhesion molecule-1 [sVCAM-1], von Willebrand antigen [vWF]), and high sensitive C-reactive protein (hsCRP) levels were measured in 30 HbSS and 20 HbSC patients and in race-matched HbAA controls. NOAC levels were reduced in patients, and endothelial activation markers and hsCRP were elevated (except vWF in HbSC patients). Protein C activity and vWF levels were lower in HbSC patients who experienced painful crises compared to HbSC patients who were clinically asymptomatic. No other differences were observed between patients who did and did not experience vaso-occlusive events (painful crises, stroke, acute chest syndromes) or leg ulcers. A significant positive correlation between total protein S with hemoglobin levels and a significant negative correlation between total and free protein S and sVCAM-1 were detected in HbSS patients. Except perhaps for protein C in relation to painful crises in HbSC patients, these markers were not associated with the occurrence of clinical events. The protein S, hemoglobin, and sVCAM-1 associations may suggest decreased endothelial protein S production due to the more severe endothelial perturbation in HbSS patients with lower hemoglobin levels. (C) 2004 Wiley-Liss, Inc

Cytokines and adhesion molecules play an important role in the pathophysiology of vaso-occlusion in sickle cell disease (SCD), and their in vivo profiles are potential tools for assessing SCD severity. We compared steady-state soluble vascular cell adhesion molecule-1 (sVCAM-1) serum levels to clinical (painful crisis frequency, occurrence of acute chest syndrome, leg ulcers, and cerebrovascular disease) and related hematological parameters of SCD severity (such as HbF%, hemoglobin levels, and leukocyte counts) in 29 HbSS adults. Serum sVCAM-1 levels were not related to clinical severity, but an inverse correlation was demonstrated between sVCAM-1 and hemoglobin levels (r=-0.71, p

PROBLEM: Pre-eclampsia is characterized by neutrophil activation. Interleukin-8 (IL-8) is a strong neutrophil chemo-attractant and activator. METHOD OF STUDY: We measured serum IL-8 in 13 pre-eclamptic Afro-Caribbean women and 13 gestational age-, race- and parity-matched normotensive and non-proteinuric controls. We also determined serum tumor necrosis factor-alpha (TNF-alpha), the phenotypes of the IL-8 binding Duffy blood group antigen receptor and the von Willebrand factor (vWF) plasma levels. RESULTS: Serum IL-8, TNF-alpha, Duffy negative phenotype frequency and plasma vWF were higher in pre-eclamptic women compared with controls. IL-8 correlated positively with both TNF-alpha and vWF in the entire study group. CONCLUSIONS: Higher IL-8 levels in pre-eclampsia may result from increased production (secondary to increased TNF-alpha levels) and/or reduced clearance (related to a high frequency of Duffy negative phenotype).

Objective: Human immunodeficiency virus (HIV) infection has become a chronic disorder for which adaptation of current healthcare practices is needed. In Curacao, a new organization of chronic HIV care is being set up based on task shifting in which healthcare workers (HCWs) will deliver HIV care more prominently within the primary healthcare system. In preparation for implementation of the proposed task-shifting model, we investigated the perception of HCWs regarding existing HIV care in Curacao and the need for training in HIV/AIDS among HCWs. Subjects and Methods: An in-depth questionnaire based study was used. Nineteen HCWs of seven different cadres were interviewed. The questionnaire constituted four sections: quality of existing HIV care, respondents own knowledge and willingness to be trained, need for training in HIV/AIDS and preferred educational approaches. Results: Quality of existing HIV services in Curacao is considered acceptable but needs improvement mainly to facilitate integration of chronic HIV care. All respondents indicated that training in HIV/AIDS is needed among HCWs in Curacao, especially for nurses and general practitioners. All were willing to participate in training with varying amounts of time to be spent. Training should be tailored to the level of expertise of HCWs and to the role a HCW is expected to have in the new healthcare delivery framework Conclusion: There is need for training to ensure the effective integration of chronic HIV care into the existing healthcare delivery system in Curacao. There is a willingness and need in all cadres for training with e-learning as a preferred educational tool.

Vasoocclusion is a continuous process in sickle cell disease (SCD) and accumulates to significant end organ damage, mostly irrespective of the occurrence of manifest acute vasoocclusive events. As there are indications that reversing the hypercoagulable state may be of clinical benefit in sickle cell patients, we performed a randomized, double blind, placebo-controlled, cross-over pilot study to assess the efficacy and safety of low-adjusted dose acenocoumarol therapy (International Normalized Ratio: 1.6–2.0) in SCD. Treatment consisted of either acenocoumarol or placebo for 14 weeks, after which treatment was discontinued for a period of five weeks. Then, patients initially on acenocoumarol received placebo (and vice versa) for 14 weeks. Therapy efficacy was assessed by comparing the frequency of vasoocclusive complications, the occurrence of bleeding, and clotting activation between acenocoumarol and placebo treatment of each individual patient. Twenty-two patients (14 homozygous [HbSS] and 8 double heterozygous sickle-C [HbSC]; aged 20–59 years) completed the entire study. Acenocoumarol treatment did not result in a significant reduction of acute vasoocclusive events (three painful crises during acenocoumarol, five painful crises during placebo). There was a marked reduction of the hypercoagulable state (depicted by a decrease in plasma levels of prothrombin F1.2 fragments [P = 0.002], thrombin-antithrombin complexes [P = 0.003], and D-dimer fragments [P = 0.001]) without the occurrence of major bleeding. Even though no clinical benefit (pertaining to the frequency of painful crises) was detected in this pilot study, the value of low adjusted-dose acenocoumarol for preventing specific events (such as strokes) and as a long-term treatment of sickle cell patients should be subject of further study. Am. J. Hematol. 68:179–183, 2001. © 2001 Wiley-Liss, Inc.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant bleeding disorder characterized by localized angiodysplasia. Mutations in either of two genes, endoglin or ALK-1, can cause HHT. Both genes encode putative receptors for the transforming growth factor-beta superfamily of ligands. Many mutations in each gene have been identified in HHT kindreds from around the world, and with few exceptions mutations are unique and family specific. The prevalence of HHT in the Leeward Islands of the Netherlands Antilles is possibly the highest of any geographical location. We wished to establish whether this high prevalence is due to a genetic founder effect or to multiple mutational events. HHT kindreds from the Netherlands Antilles and The Netherlands were screened for mutations in the two genes associated with HHT. Haplotype analysis of a 5-cM region on chromosome 9 flanking the endoglin gene revealed three distinct disease haplotypes in the ten Antillean families studied. Seven of these families share a splice-site mutation in exon 1 of endoglin. Two other Antillean families share a missense mutation in exon 9a of endoglin. This mutation was also found in a Dutch family that shares the same disease haplotype as the Antillean families with this mutation. Thus it appears that HHT in the Netherlands Antilles is due to a limited number of ancestral mutations in the endoglin gene, and that one of these mutations was introduced into the African slave population by a Dutch colonist. The limited scope of mutations suggests that a presymptomatic screening program for HHT would be feasible in this population.

Vascular occlusion is the main cause of the morbidity and mortality observed in patients with sickle cell disease (SCD). Increasing evidence indicates that (activated) neutrophils could play an important role in the initiation and propagation of vaso-occlusive processes in SCD. In this study, the activation state of neutrophils in sickle cell patients was analyzed by determining the level of expression of neutrophil antigens such as CD62L, CD11b, CD66b, CD63, and Fcγ receptors. We also analyzed plasma levels of lactoferrin, elastase, soluble (s)CD16 (sFcγRIII), and serum levels of soluble (s)CD62L (sL-selectin) as neutrophil activation markers in these patients. Significant differences were observed in the activation state of neutrophils in non-symptomatic sickle cell patients compared to healthy HbAA controls as exemplified by significant decrease in L-selectin expression, enhanced expression of CD64, and increased levels of soluble markers like sL-selectin, elastase, and sCD16. During vaso-occlusive crisis the differences were even more pronounced. These results show neutrophils to be activated in sickle cell patients, suggesting a role of importance in the pathophysiology of sickle cell disease. J. Leukoc. Biol. 66: 411–415; 1999.

It has been shown that the clinical course of sickle cell (SS) patients can be ameliorated by administration of hydroxyurea (HU). Induction of hemoglobin F (HbF) is thought to be the mechanism responsible for clinical improvement in some patients. However, HU has a variable effect on HbF production and there exists no good correlation between the extent of HbF increase and clinical response. On the other hand, the degree of adherence of SS to vascular endothelium and neutrophil counts correlate well with clinical severity. Being a cytotoxic drug, used in myeloproliferative diseases, HU may alter proliferation among various cell lines. Moreover, HU has been reported to reduce red blood cell (RBC) adhesion receptor expression in young SS individuals and induces changes in endothelial cells in vitro. It should be conceived that in addition to its effects on HbF production, HU may change the clinical symptoms of SS patients by affecting the degree of adherence of different blood cells, by influencing the activity of endothelium as well as the activity of white blood cells (WBC) and platelets. To analyze whether several of the determinants of adhesion are modulated by HU treatment we studied the levels of endothelial activity (soluble vascular adhesion molecule-1, (sVCAM-1), interleukin-8 (IL-8), fibronectin, neutrophil activity (sL-selectin, sIL-6 receptor-α, myeloperoxidase) and platelet activity (von Willebrand factor) in relation to clinical symptoms, hematological data and HbF levels in 8 SS patients before and during 5 months of HU therapy. Steady state sVCAM-1 levels are increased compared to normal controls and a significant decrease is noted during HU treatment, suggesting a decrease in the interactions between RBC and vascular endothelium. The IL-8 levels are comparable to those in normal controls and remain unaffected by HU therapy. Intercurrent infection and crises reveal striking increases in IL-8 which are accompanied by leukocytosis, but otherwise the IL-8 levels do not correlate with hematological data. HU has no demonstrable effect on fibronectin or soluble neutrophil adhesion molecules, but the levels of myeloperoxidase decrease significantly while WBC counts do not, implying a reduction in neutrophil activity which may help attenuate the propagation phase of a vasoocclusive crisis.

Pulmonary hypertension (PHT) occurs in approximately 30% of adult sickle cell patients and is associated with a high risk of early death. Hemolysis driven reductions in nitric oxide (NO) bioavailability resulting from NO scavenging by cell free hemoglobin and increased arginase activity are of

We investigated whether pediatric patients with sickle cell disease (SCD) (9 +/- 4 years; 27 homozygous SCD [HbSS]; 19 sickle-C disease [HbSC]) have different folate status compared with age-, sex-, and race-matched normal hemoglobin (HbAA) controls (n = 20), and whether their folate status can be improved by folate supplementation. The patients were supplemented with vitamins B6 and B12 during one week and with folate during the following week. Circulating folate, homocysteine, vitamin B6 and vitamin B12 levels were measured at baseline (patients and controls), after one week and after two weeks (patients). The patients had similar folate, vitamin B6, and vitamin B12, but higher homocysteine levels compared with HbAA controls (12.7 +/- 4.5 vs. 10.9 +/- 3.5 micromol/l; P = 0.04). Vitamin B6 and B12 supplementation did not change their homocysteine levels, but folate supplementation caused a 53% reduction (to 5.7 +/- 1.6). We conclude that patients with SCD have adequate vitamin B6 and B12 status, but suboptimal folate status, leading to elevated plasma homocysteine levels. They may therefore benefit from folate supplementation to reduce their high risk for endothelial damage.

Vasoocclusion leads to pain, chronic organ damage, and a decreased life expectancy in patients with sickle cell disease. Therapeutic options for sickle cell disease have usually been evaluated according to their capacity for reducing the frequency of vasoocclusive crises requiring clinical attention. However, the frequency of vasoocclusive crises is not representative for the rate of accumulating organ damage in most sickle cell patients. This implies that the frequency of vasoocclusive crises needn't correlate with disease severity and, although being of importance, cannot solely serve as a parameter of treatment efficacy. Therefore, additional new objective parameters are needed to effectively study the vasoocclusive process in sickle cell disease. Several studies show that intricate adhesive interactions between (red) blood cells, plasma components, and endothelium play a crucial role in the pathophysiology of sickle cell vasoocclusion, offering new potential parameters to effectively assess disease severity as well as new therapeutical targets in the near future. Whether these adhesive mechanisms involve the causes or the effects of vasoocclusion will be determined if their inhibition, by interventive measures, results in therapeutic benefits.

Hydroxyurea (HU) induces HbF production and can reduce painful crises in some patients with sickle cell anemia (SS). However, HbF induction alone cannot explain the beneficial effect of HU treatment as some patients experience clinical improvement while showing only minor increases in HbF. Other actions of HU, in particular its effects on vascular endothelium, adhesion molecule expression and cytokine production may also play a role in the final therapeutic outcome. In order to analyze these effects we studied the levels of interleukin-3 (IL-3), interleukin-6, granulocyte-macrophage colony-stimulating factor, erythropoietin, stem cell factor, soluble vascular adhesion molecule-1, soluble intercellular adhesion molecule-1, soluble E-selectin and soluble P-selectin in 7 SS patients before and during 5 months of HU treatment. Use of HU seems to have no detectable effect on soluble adhesion molecules, but the steady state levels of soluble vascular adhesion molecule-1 are enhanced in SS patients compared to normal controls. Of the cytokines studied, only IL-3 showed an increase during therapy, suggesting HU may induce early erythroid progenitors capable of producing HbF by a direct or indirect effect on IL-3 production. Remarkably, the steady state stem cell factor levels in sickle cell patients seemed to be decreased compared to healthy controls.