The TRACK-PD study: protocol of a longitudinal ultra-high field imaging study in Parkinson's disease.

BACKGROUND: The diagnosis of Parkinson's Disease (PD) remains a challenge and is currently based on the assessment of clinical symptoms. PD is also a heterogeneous disease with great variability in symptoms, disease course, and response to therapy. There is a general need for a better understanding of this heterogeneity and the interlinked long-term changes in brain function and structure in PD. Over the past years there is increasing interest in the value of new paradigms in Magnetic Resonance Imaging (MRI) and the potential of ultra-high field strength imaging in the diagnostic work-up of PD. With this multimodal 7 T MRI study, our objectives are: 1) To identify distinctive MRI characteristics in PD patients and to create a diagnostic tool based on these differences. 2) To correlate MRI characteristics to clinical phenotype, genetics and progression of symptoms. 3) To detect future imaging biomarkers for disease progression that could be valuable for the evaluation of new therapies. METHODS: The TRACK-PD study is a longitudinal observational study in a cohort of 130 recently diagnosed (≤ 3 years after diagnosis) PD patients and 60 age-matched healthy controls (HC). A 7 T MRI of the brain will be performed at baseline and repeated after 2 and 4 years. Complete assessment of motor, cognitive, neuropsychiatric and autonomic symptoms will be performed at baseline and follow-up visits with wearable sensors, validated questionnaires and rating scales. At baseline a blood DNA sample will also be collected. DISCUSSION: This is the first longitudinal, observational, 7 T MRI study in PD patients. With this study, an important contribution can be made to the improvement of the current diagnostic process in PD. Moreover, this study will be able to provide valuable information related to the different clinical phenotypes of PD and their correlating MRI characteristics. The long-term aim of this study is to better understand PD and develop new biomarkers for disease progression which may help new therapy development. Eventually, this may lead to predictive models for individual PD patients and towards personalized medicine in the future. TRIAL REGISTRATION: Dutch Trial Register, NL7558 . Registered March 11, 2019.

The role of the clinical laboratory in diagnosing acid-base disorders.

Acid-base homeostasis is fundamental for life. The body is exceptionally sensitive to changes in pH, and as a result, potent mechanisms exist to regulate the body's acid-base balance to maintain it in a very narrow range. Accurate and timely interpretation of an acid-base disorder can be lifesaving but establishing a correct diagnosis may be challenging. The underlying cause of the acid-base disorder is generally responsible for a patient's signs and symptoms, but laboratory results and their integration into the clinical picture is crucial. Important acid-base parameters are often available within minutes in the acute hospital care setting, and with basic knowledge it should be easy to establish the diagnosis with a stepwise approach. Unfortunately, many caveats exist, beginning in the pre-analytical phase. In the post-analytical phase, studies on the arterial reference pH are scarce and therefore many different reference values are used in the literature without any solid evidence. The prediction models that are currently used to assess the acid-base status are approximations that are mostly based on older studies with several limitations. The two most commonly used methods are the physiological method and the base excess method, both easy to use. The secondary response equations in the base excess method are the most convenient. Evaluation of acid-base disorders should always include the assessment of electrolytes and the anion gap. A major limitation of the current acid-base laboratory tests available is the lack of rapid point-of-care laboratory tests to diagnose intoxications with toxic alcohols. These intoxications can be fatal if not recognized and treated within minutes to hours. The surrogate use of the osmolal gap is often an inadequate substitute in this respect. This article reviews the role of the clinical laboratory to evaluate acid-base disorders.

Global health and transfusion medicine: education and training in developing countries.

Education and training in transfusion medicine have improved over the past decade in developing countries but are still generally deficient for the purpose of maintaining the safety of the global blood supply. In 2009, the World Health Organization global database on blood safety indicated that only 72% of countries in the world were able to meet their training needs necessary for maintaining the safety of their local blood supply. Educational approaches in transfusion medicine vary widely between continents and world regions. In this article, we summarize a session on global health education and training in developing countries that took place at the 2012 AABB conference. The panel consisted of transfusion representatives from South America (Brazil), Asia (China), Africa (South Africa), and the Caribbean (Curaçao), as well as a description of capacitation issues in postearthquake Haiti and the pivotal role of the US President's Emergency Plan for AIDS Relief (PEPFAR) in transfusion training and education in Africa. We present here summaries of each of these panel presentations.

Pharmaceutical Industry Payments to Medical Oncologists in the Netherlands: Trends and Patterns Provided by an Open-Access Transparency Data Set.

PURPOSE: Health care expenditure related to oncologic treatments is skyrocketing although many treatments offer marginal, if any, clinical benefit. Financial conflicts of interest (fCOI) resulting from pharmaceutical industry (pharma) payments to physicians is increasingly recognized as a predictive factor for regulatory board approval and guideline incorporation of low-value treatments. We sought to study the extent to which pharma payments to medical oncologists occur in the Netherlands, the amount of money involved, and whether these occur more frequently and are higher for key opinion leaders (KOLs). METHODS: In our cross-sectional retrospective database study, we used several Dutch open-access databases and extracted data registered between 2019 and 2021. RESULTS: A cumulative amount of €899,863 was paid to 48.8% of the 408 registered medical oncologists. Over time, there was a marked decline in both the proportion of medical oncologists receiving payments (from 40.4% in 2019 to 19.1% in 2021) and the mean annual value of payments (from €2,962 in 2019 to €2,188 in 2021) with the latter mainly resulting from a decline in hospitality-related transactions. KOLs were more likely to receive industry payments and received a higher median payment value. DISCUSSION: Our findings should contribute to the increasing awareness in the Netherlands of the potential effects of fCOI.

High incidence of intermittent care in HIV-1-infected patients in Curaçao before and after starting cART.

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.

Optimizing chronic HIV care in the Dutch Caribbean: a questionnaire based study on experience and perception of healthcare workers.

OBJECTIVE: Human immunodeficiency virus (HIV) infection has become a chronic disorder for which adaptation of current healthcare practices is needed. In Curaçao, 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 Curaçao 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 Curaçao 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 Curaçao, 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 Curaçao.There is a willingness and need in all cadres for training with e-learning as a preferred educational tool.

Fatigue and heat sensitivity in patients with multiple sclerosis.

OBJECTIVES: Fatigue is one of the most common and troubling symptoms of multiple sclerosis (MS), and heat is often reported as a trigger. Although it is assumed that this heat sensitivity is specific for MS, the evidence for disease specificity is limited. We studied the relationship between fatigue, heat sensitivity, and environmental temperature, and its specificity for MS. MATERIALS AND METHODS: We compared 88 MS patients with 76 patients with ulcerative colitis (UC), another chronic auto-immune disease. As most important outcome measures, heat sensitivity, physical fatigue, mental fatigue, environmental temperature, and ambient UV-light levels were determined. RESULTS: More patients with MS reported heat sensitivity for fatigue, compared to patients with UC (53.4% vs 35.5%, respectively, P = 0.016). However, heat-sensitive patients were equally fatigued as heat-insensitive patients. Climatological data, including day temperature and amount of ambient UV light, were not related to fatigue in both heat-sensitive and heat-insensitive patients with MS. CONCLUSIONS: Our findings support the assumption that heat sensitivity regarding fatigue has an MS-specific component. Although patients with MS experience a relationship between environmental temperature and fatigue, objective assessment by climatological data could not confirm this.

A case study of the implementation of a competency-based curriculum in a Caribbean teaching hospital.

OBJECTIVE: Several teaching hospitals are currently modifying their curriculum to comply with the changing demands in medical education. As a result, we decided to evaluate whether a competency-based curriculum implemented in a Caribbean teaching hospital fulfilled the requirements as defined by the CanMEDS framework. METHODS: We made use of a triangulation method in the survey to obtain information on the educational process. Two separate methods were used consisting of site visits by visiting professors and a medical educator. The focus was on the structure, content and assessments of the educational activities. RESULTS: Major recommendations included increased involvement of medical specialists in the educational activities in the clinical workplace. There was need for improvement of communication between medical specialists, patients, nurses, trainees and residents. Overall, improvements were observed in the structure of clinical rotations and content of the training programme. CONCLUSION: The implemented assessment programme provided necessary information for effective evaluation of the competency-based curriculum. We were able to identify new and feasible methods for improving the curriculum in our educational setting.

Epidemiology of febrile diseases in the emergency department of a Caribbean island: the Curaçao experience.

OBJECTIVE: The aetiology of febrile diseases in tropical countries often remains poorly characterized. We aim to describe the aetiology and outcome of febrile illnesses at the Emergency Department (ED) in Curaçao. METHODS: From April 2008 - April 2009, all adult febrile patients (T> 38.5 degrees C) at the ED of the St Elisabeth Hospital, Curaçao, Netherlands Antilles, were included. Clinical data were recorded, routine laboratory measurements and blood cultures were taken. Final diagnoses were made at discharge by an independent physician and in retrospect by the main investigator RESULTS: Four hundred and three patients were included: 223 patients (55.6%) were hospitalized, 32 patients (7.9%) died and 18 patients (4.5%) were admitted to the Intensive Care Unit. In 129 febrile patients (32.0%), infection was proven; 84.4% of patients had bacterial (29.0% urinary tract infection, 23.2% pneumonia infection), 5.6% viral and 10.0% parasitic or fungal infections. Twenty-one patients (5.2%) were discharged with a non-infectious diagnosis and 172 patients (42.7%) without a clear diagnosis. CONCLUSION: A high mortality rate of 7.9% was observed. We found a high prevalence of bacterial infections, with pneumonia and urinary tract infections as the most common causes of fever. One in 20 patients did not have an infectious disease.

Procalcitonin as a potent marker of bacterial infection in febrile Afro-Caribbean patients at the emergency department.

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.

Plasma asymmetric dimethylarginine concentrations in sickle cell disease are related to the hemolytic phenotype.

Asymmetric dimethylarginine (ADMA) is associated with pulmonary hypertension (PHT) in sickle cell disease (SCD). We studied the relationship of ADMA to other SCD-related complications. Plasma ADMA and associated parameters were determined in 52 HbSS/HbSbeta(0)-thalassemia and 24 HbSC/HbSbeta(+)-thalassemia patients. As expected ADMA levels were higher in HbSS/HbSbeta(0)-thalassemia patients with PHT (p=0.018), but also in those with other hemolysis-associated complications such as leg ulcers (p=0.012), cholelithiasis (p=0.008) and priapism (p=0.02) compared with counterparts without these complications. ADMA levels did not differ between patients with and without other disease related complications such as retinopathy and avascular osteonecrosis. Higher ADMA concentrations therefore seem to be associated to the hemolytic phenotype of SCD.

Plasma annexin A5 and microparticle phosphatidylserine levels are elevated in sickle cell disease and increase further during painful crisis.

Expression of phosphatidylserine (PS) on the membrane surface of red blood cells and circulating microparticles (MP) plays an important role in etiology of the hypercoagulable state of sickle cell disease (SCD), as well as in the reduced red cell life span and adhesive interactions between red cells and endothelium. Annexin A5, an intracellular protein abundantly present in endothelial cells and platelets, exhibits high affinity for PS and has been shown to inhibit several of these PS-mediated pathophysiological processes. We determined plasma annexin A5 levels and MP-associated procoagulant activity, a measure of MP-PS exposure, in 17 sickle cell patients (12 HbSS and 5 HbSC) in steady state and at presentation with a painful crisis. Twenty-five HbAA blood donors served as controls. Both annexin A5 and MP-PS were highest in HbSS patients (5.7 ng/mL, IQR 3.7-7.6 and 37.9 nM, IQR 31.9-69.8) as compared to HbSC patients (1.8 ng/mL, IQR 1.7-7.6 and 20.9 nM, IQR 10.9-29.6) and healthy controls (2.5 ng/mL, IQR 1.4-4.4 and 13.1 nM, IQR 9.5-18.5) (p=0.01 and p<0.001, respectively). At presentation with a painful crisis, annexin A5 and MP-PS had increased in 16 of 17 patients (p=0.001 and p<0.001, respectively). Most interestingly, in 7 HbSS patients the proportional increase in MP-PS exposure was higher than the proportional increase in plasma annexin A5 concentration, leading to lower annexin A5/MP-PS ratio of HbSS patients during crisis than HbAA controls (0.0027 (0.0017-0.0049) vs 0.0048 (0.0027-0.0085), p=0.05). In conclusion, patients with SCD have elevated plasma levels of annexin A5- and PS-exposing MP. During crisis both levels increase, but in most HbSS patients MP-PS exposure increases more than annexin A5. Future studies must address a potential role of annexin A5 in modulating PS-related pathophysiological processes in SCD.

Elevated circulating stromal-derived factor-1 levels in sickle cell disease.

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/HbSbeta(0)-thalassaemia patients [n = 42; 5,177 pg/ml (2,438-7,246)] compared to HbSC/HbSbeta(+)-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.

Cognitive complaints in the early phase after stroke are not indicative of cognitive impairment.

OBJECTIVE: The present study was designed to evaluate the diagnostic contribution of subjective information, obtained by a standardised checklist, to the identification of patients with cognitive impairment in the early phase after stroke. METHODS: The data were collected retrospectively by file analysis of both medical and psychological records of patients with a first-ever stroke who were discharged home from the stroke unit. All these patients underwent neuropsychological examination by protocol. Patients were included for data analyses if they completed the Checklist for Cognitive and Emotional consequences following stroke within 2 weeks after discharge. Data from a control group were used to classify patients into normal and cognitively impaired. RESULTS: A total of 61 patients was included in the study. Ninety percent reported at least one psychological problem hindering daily life and 74% of the total sample reported at least one hindering cognitive problem. The most reported cognitive complaints concerned attention (38%), mental speed (46%) and memory (38%). Cognitive impairment varied between 16 and 66% based on the specific neuropsychological task. Cognitive complaints appeared to be unrelated to cognitive impairment. Only the relationship between cognitive and emotional complaints was significant (p<0.01). CONCLUSIONS: Cognitive complaints hindering daily life are frequently reported in the early weeks after stroke but are no indication for impaired cognitive performance. To identify patients with cognitive impairment, neuropsychological assessment is essential.

Increased serum levels of anti-angiogenic factors soluble fms-like tyrosine kinase and soluble endoglin in sickle cell disease.

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-beta(1) 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.

Ethics of Deep Brain Stimulation in Adolescent Patients with Refractory Tourette Syndrome: a Systematic Review and Two Case Discussions.

INTRODUCTION: Tourette Syndrome (TS) is a childhood onset disorder characterized by vocal and motor tics and often remits spontaneously during adolescence. For treatment refractory patients, Deep Brain Stimulation (DBS) may be considered. METHODS AND RESULTS: We discuss ethical problems encountered in two adolescent TS patients treated with DBS and systematically review the literature on the topic. Following surgery one patient experienced side effects without sufficient therapeutic effects and the stimulator was turned off. After a second series of behavioural treatment, he experienced a tic reduction of more than 50%. The second patient went through a period of behavioural disturbances that interfered with optimal programming, but eventually experienced a 70% tic reduction. Sixteen DBS surgeries in adolescent TS patients have been reported, none of which pays attention to ethical aspects. DISCUSSION: Specific ethical issues arise in adolescent TS patients undergoing DBS relating both to clinical practice as well as to research. Attention should be paid to selecting patients fairly, thorough examination and weighing of risks and benefits, protecting the health of children and adolescents receiving DBS, special issues concerning patient's autonomy, and the normative impact of quality of life. In research, registration of all TS cases in a central database covering a range of standardized information will facilitate further development of DBS for this indication. CONCLUSION: Clinical practice should be accompanied by ongoing ethical reflection, preferably covering not only theoretical thought but providing also insights in the views and perspectives of those concerned, that is patients, family members and professionals.

Cognitive behavioural therapy for anxiety disorders in Parkinson's disease: Design of a randomised controlled trial to assess clinical effectiveness and changes in cerebral connectivity.

BACKGROUND: Anxiety disorders occur in up to 35% of patients with Parkinson's disease (PD) and have a negative effect on motor symptoms and quality of life. To date, no clinical trials specifically targeting anxiety in PD patients have been published. OBJECTIVE: To describe the rationale and methodology of a randomised controlled trial (RCT) that aims to study the clinical effectiveness, alterations in brain circuitry, and cost-effectiveness of cognitive behavioural therapy (CBT) for anxiety in PD. METHODS: This study is a prospective, two-centre RCT in which sixty PD patients with anxiety will be randomised to CBT treatment and clinical monitoring (intervention group) or to clinical monitoring only (control group). The CBT module used in this study was specifically developed to address symptoms of anxiety in PD patients. Participants will undergo standardised clinical, cognitive and behavioural assessment at baseline and at 2 follow-up measurements, as well as resting-state fMRI and DTI scanning before and after the intervention. The primary outcome measure is changes in severity of anxiety symptoms. Secondary outcome measures involve long-term changes in anxiety symptoms, changes in functional and structural connectivity between limbic and frontal cortices, and cost-effectiveness of the treatment. The study is registered at the ClinicalTrials.gov database under registration number NCT02648737. CONCLUSION: This study is the first that evaluates both the clinical effectiveness, cost-effectiveness, as well as the biological impact of CBT for anxiety in PD patients that, if proven effective, will hopefully contribute to a better and evidence-based approach for these non-motor symptoms.

Functional connectivity disruptions correlate with cognitive phenotypes in Parkinson's disease.

Cognitive deficits in Parkinson's disease are thought to be related to altered functional brain connectivity. To date, cognitive-related changes in Parkinson's disease have never been explored with dense-EEG with the aim of establishing a relationship between the degree of cognitive impairment, on the one hand, and alterations in the functional connectivity of brain networks, on the other hand. This study was aimed at identifying altered brain networks associated with cognitive phenotypes in Parkinson's disease using dense-EEG data recorded during rest with eyes closed. Three groups of Parkinson's disease patients (N = 124) with different cognitive phenotypes coming from a data-driven cluster analysis, were studied: G1) cognitively intact patients (63), G2) patients with mild cognitive deficits (46) and G3) patients with severe cognitive deficits (15). Functional brain networks were identified using a dense-EEG source connectivity method. Pairwise functional connectivity was computed for 68 brain regions in different EEG frequency bands. Network statistics were assessed at both global (network topology) and local (inter-regional connections) level. Results revealed progressive disruptions in functional connectivity between the three patient groups, typically in the alpha band. Differences between G1 and G2 (p < 0.001, corrected using permutation test) were mainly frontotemporal alterations. A statistically significant correlation (ρ = 0.49, p < 0.001) was also obtained between a proposed network-based index and the patients' cognitive score. Global properties of network topology in patients were relatively intact. These findings indicate that functional connectivity decreases with the worsening of cognitive performance and loss of frontotemporal connectivity may be a promising neuromarker of cognitive impairment in Parkinson's disease.

Differential expression of the gene encoding the novel pituitary polypeptide 7B2 in human lung cancer cells.

The protein designated 7B2 is a recently discovered pituitary polypeptide which is selectively expressed in cells containing secretory granules, such as neurons and endocrine cells. Northern blot analysis of 7B2 gene expression in small cell lung carcinoma (SCLC) cell lines revealed that 7B2 was expressed in all nine cell lines of the classic type tested, but in six of seven SCLC cell lines of the variant type, 7B2 expression could not be detected. In only one of four non-SCLC cell lines tested, 7B2 was expressed. Furthermore, in 16 primary human non-SCLCs, no or only very low expression of 7B2 was found. In the eight primary human SCLCs tested, expression of 7B2 appeared variable: three exhibited a high level of expression; three a low level; while in two cases, expression was very low or not detectable at all. Finally, the three carcinoid tumors tested expressed very high levels of 7B2 mRNA. These data indicate that the 7B2 gene is a useful marker not only to discriminate between classic and variant types of SCLC cell lines, but also in human lung cancer diagnosis.