Clinical Impact of Polymerase Chain Reaction-Based Aspergillus and Azole Resistance Detection in Invasive Aspergillosis: A Prospective Multicenter Study.

BACKGROUND: Invasive aspergillosis (IA) by a triazole-resistant Aspergillus fumigatus is associated with high mortality. Real-time resistance detection will result in earlier initiation of appropriate therapy. METHODS: In a prospective study, we evaluated the clinical value of the AsperGenius polymerase chain reaction (PCR) assay in hematology patients from 12 centers. This PCR assay detects the most frequent cyp51A mutations in A. fumigatus conferring azole resistance. Patients were included when a computed tomography scan showed a pulmonary infiltrate and bronchoalveolar fluid (BALf) sampling was performed. The primary end point was antifungal treatment failure in patients with azole-resistant IA. RESULTS: Of 323 patients enrolled, complete mycological and radiological information was available for 276 (94%), and probable IA was diagnosed in 99/276 (36%). Sufficient BALf for PCR testing was available for 293/323 (91%). Aspergillus DNA was detected in 116/293 (40%) and A. fumigatus DNA in 89/293 (30%). The resistance PCR was conclusive in 58/89 (65%) and resistance detected in 8/58 (14%). Two had a mixed azole-susceptible/azole-resistant infection. In the 6 remaining patients, treatment failure was observed in 1. Galactomannan positivity was associated with mortality (P = .004) while an isolated positive Aspergillus PCR was not (P = .83). CONCLUSIONS: Real-time PCR-based resistance testing may help to limit the clinical impact of triazole resistance. In contrast, the clinical impact of an isolated positive Aspergillus PCR on BALf seems limited. The interpretation of the EORTC/MSGERC PCR criterion for BALf may need further specification (eg, minimum cycle threshold value and/or PCR positive on >1 BALf sample).

Retrospective Multicenter Evaluation of the VirClia Galactomannan Antigen Assay for the Diagnosis of Pulmonary Aspergillosis with Bronchoalveolar Lavage Fluid Samples from Patients with Hematological Disease.

Galactomannan (GM) testing of bronchoalveolar lavage (BAL) fluid samples has become an essential tool to diagnose invasive pulmonary aspergillosis (IPA) and is part of diagnostic guidelines. Enzyme-linked immunosorbent assays (ELISAs) (enzyme immunoassays [EIAs]) are commonly used, but they have a long turnaround time. In this study, we evaluated the performance of an automated chemiluminescence immunoassay (CLIA) with BAL fluid samples. This was a multicenter retrospective study in the Netherlands and Belgium. BAL fluid samples were collected from patients with underlying hematological diseases with a suspected invasive fungal infection. Diagnosis of IPA was based on the 2020 European Organisation for Research and Treatment of Cancer (EORTC)/Mycoses Study Group Education and Research Consortium (MSGERC) consensus definitions. GM results were reported as optical density index (ODI) values. ODI cutoff values for positive results that were evaluated were 0.5, 0.8, and 1.0 for the EIA and 0.16, 0.18, and 0.20 for the CLIA. Probable IPA cases were compared with two control groups, one with no evidence of IPA and another with no IPA or possible IPA. Qualitative agreement was analyzed using Cohen's κ, and quantitative agreement was analyzed by Spearman's correlation. We analyzed 141 BAL fluid samples from 141 patients; 66 patients (47%) had probable IPA, and 56 cases remained probable IPA when the EIA GM result was excluded as a criterion, because they also had positive culture and/or duplicate positive PCR results. Sixty-three patients (45%) had possible IPA and 12 (8%) had no IPA. The sensitivity and specificity of the two tests were quite comparable, and the overall qualitative agreement between EIA and CLIA results was 81 to 89%. The correlation of the actual CLIA and EIA values was strong at 0.72 (95% confidence interval, 0.63 to 0.80). CLIA has similar performance, compared to the gold-standard EIA, with the benefits of faster turnaround because batching is not required. Therefore, CLIA can be used as an alternative GM assay for BAL fluid samples.

Inflammatory Blood Biomarkers Are Associated with Long-Term Clinical Disease Severity in Parkinson's Disease.

An altered immune response has been identified as a pathophysiological factor in Parkinson's disease (PD). We aimed to identify blood immunity-associated proteins that discriminate PD from controls and that are associated with long-term disease severity in PD patients. Immune response-derived proteins in blood plasma were measured using Proximity Extension Technology by OLINK in a cohort of PD patients (N = 66) and age-matched healthy controls (N = 52). In a selection of 30 PD patients, we evaluated changes in protein levels 7-10 years after the baseline and assessed correlations with motor and cognitive assessments. Data from the Parkinson's Disease Biomarkers Program (PDBP) cohort and the Parkinson's Progression Markers Initiative (PPMI) cohort were used for independent validation. PD patients showed an altered immune response compared to controls based on a panel of four proteins (IL-12B, OPG, CXCL11, and CSF-1). The expression levels of five inflammation-associated proteins (CCL23, CCL25, TNFRSF9, TGF-alpha, and VEGFA) increased over time in PD and were partially associated with more severe motor and cognitive symptoms at follow-up. Increased CCL23 levels were associated with cognitive decline and the APOE4 genotype. Our findings provide further evidence for an altered immune response in PD that is associated with disease severity in PD over a long period of time.

Natural variation in root exudation of GABA and DIMBOA impacts the maize root endosphere and rhizosphere microbiomes.

Root exudates are important for shaping root-associated microbiomes. However, studies on a wider range of metabolites in exudates are required for a comprehensive understanding about their influence on microbial communities. We identified maize inbred lines that differ in exudate concentrations of 2,4-dihydroxy-7-methoxy-1,4-benzoxazin-3-one (DIMBOA) and γ-aminobutyric acid (GABA) using a semi-hydroponic system. These lines were grown in the field to determine the changes in microbial diversity and gene expression due to varying concentrations of DIMBOA and GABA in exudates using 16S rRNA amplicon sequencing and metatranscriptomics. Results showed individual and interaction effects of DIMBOA and GABA on the rhizosphere and root endosphere ß-diversity, most strongly at the V10 growth stage. The main bacterial families affected by both compounds were Ktedonobacteraceae and Xanthomonadaceae. Higher concentrations of DIMBOA in exudates affected the rhizosphere metatranscriptome, enriching for metabolic pathways associated with plant disease. This study validated the use of natural variation within plant species as a powerful approach for understanding the role of root exudates on microbiome selection. We also showed that a semi-hydroponic system can be used to identify maize genotypes that differ in GABA and DIMBOA exudate concentrations under field conditions. The impact of GABA exudation on root-associated microbiomes is shown for the first time.

Multinational Observational Cohort Study of COVID-19-Associated Pulmonary Aspergillosis1.

We performed an observational study to investigate intensive care unit incidence, risk factors, and outcomes of coronavirus disease-associated pulmonary aspergillosis (CAPA). We found 10%-15% CAPA incidence among 823 patients in 2 cohorts. Several factors were independently associated with CAPA in 1 cohort and mortality rates were 43%-52%.

Aspergillus Test Profiles and Mortality in Critically Ill COVID-19 Patients.

The literature regarding COVID-19-associated pulmonary aspergillosis (CAPA) has shown conflicting observations, including survival of CAPA patients not receiving antifungal therapy and discrepancy between CAPA diagnosis and autopsy findings. To gain insight into the pathophysiology of CAPA, we performed a case-control study in which we compared Aspergillus test profiles in CAPA patients and controls in relation to intensive care unit (ICU) mortality. This was a multinational case-control study in which Aspergillus test results, use of antifungal therapy, and mortality were collected from critically ill COVID-19 patients. Patients were classified using the 2020 European Confederation for Medical Mycology and the International Society for Human and Animal Mycology (ECMM/ISHAM) consensus case definitions. We analyzed 219 critically ill COVID-19 cases, including 1 proven, 38 probable, 19 possible CAPA cases, 21 Aspergillus-colonized patients, 7 patients only positive for serum (1,3)-ß-d-glucan (BDG), and 133 cases with no evidence of CAPA. Mortality was 53.8% in CAPA patients compared to 24.1% in patients without CAPA (P = 0.001). Positive serum galactomannan (GM) and BDG were associated with increased mortality compared to serum biomarker-negative CAPA patients (87.5% versus 41.7%, P = 0.046; 90.0% versus 42.1%, P = 0.029, respectively). For each point increase in GM or 10-point BDG serum concentration, the odds of death increased (GM, odds ratio [OR] 10.208, 95% confidence interval [CI], 1.621 to 64.291, P = 0.013; BDG, OR, 1.247, 95% CI, 1.029 to 1.511, P = 0.024). CAPA is a complex disease, probably involving a continuum of respiratory colonization, tissue invasion, and angioinvasion. Serum biomarkers are useful for staging CAPA disease progression and, if positive, indicate angioinvasion and a high probability of mortality. There is need for a biomarker that distinguishes between respiratory tract colonization and tissue-invasive CAPA disease.

Gastric acid suppression, lifestyle factors and intestinal carriage of ESBL and carbapenemase-producing Enterobacterales: a nationwide population-based study.

BACKGROUND: Gastric acid-suppressive therapy has been suggested to increase the risk for intestinal carriage of MDR Enterobacterales, but there is scarce community-based evidence substantiating this risk. OBJECTIVES: To investigate if acid-suppressant use is associated with a risk of intestinal carriage of ESBL and carbapenemase-producing Enterobacterales (ESBL-E) in the open population, and to assess possible modifying factors. METHODS: Within the framework of a nationwide seroprevalence study, we identified a population-based cross-sectional cohort comprising 2746 adults (≥18 years), who provided stool specimens between February 2016 and June 2017. Specimens were tested by phenotypic assays and confirmatory genotype analysis to detect carriage of ESBL-E. Covariate data were extracted from self-administered questionnaires. ORs and 95% CIs were estimated using multivariable multilevel logistic regression, controlling for confounders informed by directed acyclic graphs. RESULTS: Among 2746 participants, 316 (11.5%) used acid suppressants; the prevalence of ESBL-E carriage was 7.4% (95% CI, 6.1%-8.6%). Current use of acid suppressants was not associated with ESBL-E carriage (adjusted OR [aOR], 1.05; 95% CI, 0.64-1.74); lifestyle and comorbidity did not modify this association. A higher BMI (≥25 kg/m2) (aOR, 1.42 [95% CI, 1.02-1.98]), non-Western ethnic origin (aOR, 1.96 [95% CI, 1.34-2.87]), travel to Eastern-Mediterranean, Western-Pacific or South-East Asia regions (aOR, 3.16 [95% CI, 1.71-5.83]) were associated with ESBL-E carriage. Sensitivity analyses confirmed these results; spline analysis supported a BMI-associated risk. CONCLUSIONS: In this open population study, current use of acid suppressants was not associated with ESBL-E carriage. Travel to high-endemic regions and non-Western ethnicity were confirmed as risk factors, while a higher BMI emerged as a potential new risk for ESBL-E carriage.

Paradoxal Trends in Azole-Resistant Aspergillus fumigatus in a National Multicenter Surveillance Program, the Netherlands, 2013-2018.

We investigated the prevalence of azole resistance of Aspergillus fumigatus isolates in the Netherlands by screening clinical A. fumigatus isolates for azole resistance during 2013-2018. We analyzed azole-resistant isolates phenotypically by in vitro susceptibility testing and for the presence of resistance mutations in the Cyp51A gene. Over the 6-year period, 508 (11%) of 4,496 culture-positive patients harbored an azole-resistant isolate. Resistance frequency increased from 7.6% (95% CI 5.9%-9.8%) in 2013 (58/760 patients) to 14.7% (95% CI 12.3%-17.4%) in 2018 (112/764 patients) (p = 0.0001). TR34/L98H (69%) and TR46/Y121F/T289A (17%) accounted for 86% of Cyp51A mutations. However, the mean voriconazole MIC of TR34/L98H isolates decreased from 8 mg/L (2013) to 2 mg/L (2018), and the voriconazole-resistance frequency was 34% lower in 2018 than in 2013 (p = 0.0001). Our survey showed changing azole phenotypes in TR34/L98H isolates, which hampers the use of current PCR-based resistance tests.

Case report: Candida krusei spondylitis in an immunocompromised patient.

BACKGROUND: Invasive infections with Candida krusei are uncommon and rarely complicated by spondylitis. Previous described cases were solely treated with antimycotic therapy, despite guidelines recommending surgical interventions. CASE PRESENTATION: We describe a case of C. krusei spondylitis in a patient treated with chemotherapy for acute myeloid leukemia. After induction chemotherapy, the patient developed a candidemia, which was treated with micafungin. One month after the candidemia, the patient was admitted with severe lumbar pain. Spondylitis of the L4 and L5 vertebra was diagnosed on MR-imaging, with signs suggesting an atypical infection. The patient was treated with anidulafungin combined with voriconazole. Despite maximal conservative management symptoms gradually worsened eventually requiring surgical intervention. CONCLUSIONS: In contrast to previous case reports, antimycotic treatment alone could be insufficient in treating C. krusei spondylitis.

CSF Biomarkers Reflecting Protein Pathology and Axonal Degeneration Are Associated with Memory, Attentional, and Executive Functioning in Early-Stage Parkinson's Disease.

In early-stage Parkinson's disease (PD), cognitive impairment is common, and a variety of cognitive domains including memory, attention, and executive functioning may be affected. Cerebrospinal fluid (CSF) biomarkers are potential markers of cognitive functioning. We aimed to explore whether CSF α-synuclein species, neurofilament light chain, amyloid-ß42, and tau are associated with cognitive performance in early-stage PD patients. CSF levels of total-α-synuclein and phosphorylated-α-synuclein, neurofilament light chain, amyloid-ß42, and total-tau and phosphorylated-tau were measured in 26 PD patients (disease duration ≤5 years and Hoehn and Yahr stage 1-2.5). Multivariable linear regression models, adjusted for age, gender, and educational level, were used to assess the relationship between CSF biomarker levels and memory, attention, executive and visuospatial function, and language performance scores. In 26 early-stage PD patients, attention and memory were the most commonly affected domains. A higher CSF phosphorylated-α-synuclein/total-α-synuclein ratio was associated with better executive functioning (sß = 0.40). Higher CSF neurofilament light was associated with worse memory (sß = -0.59), attentional (sß = -0.32), and executive functioning (sß = -0.35). Reduced CSF amyloid-ß42 levels were associated with poorer attentional functioning (sß = 0.35). Higher CSF phosphorylated-tau was associated with worse language functioning (sß = -0.33). Thus, CSF biomarker levels, in particular neurofilament light, were related to the most commonly affected cognitive domains in early-stage PD. This indicates that CSF biomarker levels may identify early-stage PD patients who are at an increased risk of developing cognitive impairment.

Case report: chronic relapsing cryptococcal meningitis in a patient with low mannose-binding lectin and a low naïve CD4 cell count.

BACKGROUND: Cryptococcal meningitis is most commonly found in HIV-infected patients. In HIV-negative patients, its low incidence can lead to prolonged time to diagnosis. Detailed case reports of chronic cryptococcal meningitis are scarce, but could provide clues for earlier diagnosis in this patient category. CASE PRESENTATION: A 60-year old man presented June 2015 with intermittent headaches for several months without any fever. Initial work-up showed a leukocytosis, raised CSF opening pressure and raised leukocytes and protein in the CSF. An MRI revealed leptomeningeal contrast enhancement and cerebellar oedema. While malignancy and various infectious causes were excluded, the patient had a spontaneous clinical and radiological recovery. One year later, the patient returned with complaints of headaches. Also, cerebellar oedema and leptomeningeal contrast enhancement had recurred. Eventually in March 2017, the novel cryptococcal antigen lateral flow assay (CrAg LFA) was positive on CSF, and one colony of Cryptococcus neoformans was cultured from CSF. The patient was treated with the standard antifungal regimen which resulted in resolution of his headaches. In retrospect, the cryptococcal antigen test was already positive on a serum sample from June 2015. Interestingly, post-treatment immunological analysis revealed both a low mannose-binding lectin (MBL) concentration and low naïve CD4 counts. CONCLUSIONS: We present a patient with cryptococcal meningitis in an HIV-negative patient with low MBL and low naïve CD4 count suffering a chronic relapsing meningo-encephalitis with relatively mild symptoms for around 2 years. In patients with an unexplained meningo-encephalitis such as this case, early performance of CrAg LFA on serum and/or CSF is an inexpensive and rapid method to reduce time-to diagnosis.

Holder-Pasteurized Human Donor Milk: How Long Can It Be Preserved?

OBJECTIVE: When own mother's milk falls short, pasteurized human donor milk is recommended as alternative feeding for preterm infants. Donor milk has to meet the highest safety standards, but its processing and storage is expensive. The recommended storage time of pasteurized donor milk is 3 months. The objective of the present study was to determine whether the frozen storage time of pasteurized donor milk can be extended beyond 3 months without compromising its safety and quality. METHODS: For this prospective observational study breast milk samples of 34 unique women, collected between November 2014 and June 2015, were provided by the Dutch Human Milk Bank. Samples were Holder pasteurized within 3 months after expression and stored at -20°C. Analysis of both bacterial growth (by inoculation of milk on a blood and a cysteine-, lactose-, and electrolyte-deficient agar) and fat, crude protein, carbohydrate and energy content of milk (analyzed by infrared spectroscopy) was done monthly during the first 6 months and every 2 months thereafter, up to 1 year postpasteurization. RESULTS: Thirty of 306 (9.8%) follow-up samples showed bacterial growth when cultured. None of the samples showed sequential contamination with the same strain up to 8 months of frozen storage. No significant decreases in macronutrients and energy content were observed over 8 months. CONCLUSION: Pasteurized human donor milk can be stored safely for 8 months at -20°C, without compromising its macronutrient and energy content. This longer storage time will reduce disposal of expired donor milk and subsequently reduce costs.

The diagnosis and treatment of invasive aspergillosis in Dutch haematology units facing a rapidly increasing prevalence of azole-resistance. A nationwide survey and rationale for the DB-MSG 002 study protocol.

Patients with haematological malignancies are at risk for invasive fungal diseases (IFD). A survey was conducted in all Dutch academic haematology centres on their current diagnostic, prophylactic and therapeutic approach towards IFD in the context of azole-resistance. In all 8 centres, a haematologist and microbiologist filled in the questionnaire that focused on different subgroups of haematology patients. Fungal prophylaxis during neutropaenia was directed against Candida and consisted of fluconazole and/or amphotericin B suspension. Mould-active prophylaxis was given to acute myeloid leukaemia patients during chemotherapy in 2 of 8 centres. All centres used azole prophylaxis in a subset of patients with graft-versus-host disease. A uniform approach towards the diagnosis and treatment of IFD and in particular azole-resistant Aspergillus fumigatus was lacking. In 2017, all centres agreed to implement a uniform diagnostic and treatment algorithm regarding invasive aspergillosis with a central role for comprehensive diagnostics and PCR-based detection of azole-resistance. This study (DB-MSG 002) will re-evaluate this algorithm when 280 patients have been treated. A heterogeneous approach towards antifungal prophylaxis, diagnosis and treatment was apparent in the Netherlands. Facing triazole-resistance, consensus was reached on the implementation of a uniform diagnostic approach in all 8 centres.

Hepatosplenic Candidiasis Without Prior Documented Candidemia: An Underrecognized Diagnosis?

INTRODUCTION: Patients with a history of chemotherapy or stem cell transplantation (SCT) and prolonged neutropenia are at risk for hepatic and/or splenic seeding of Candida. In our experience, hepatosplenic candidiasis (HSC) without documented candidemia often remains unrecognized. CASE PRESENTATIONS: We describe three cases of HSC without documented candidemia and the challenges in establishing the diagnosis and adequately treating this condition. The first patient had a history of SCT for treatment of breast cancer and was scheduled for hemihepatectomy for suspected liver metastasis. A second opinion at our institute resulted in the diagnosis of hepatic candidiasis without prior documented candidemia, for which she was treated successfully with fluconazole. The second case demonstrates the limitations of (blood and tissue) cultures and the value of molecular methods to confirm the diagnosis. Case 3 illustrates treatment challenges, with ongoing dissemination and insufficient source control despite months of antifungal therapy, eventually resulting in a splenectomy. LITERATURE REVIEW: A structured literature search was performed for articles describing any patient with HSC and documented blood culture results. Thirty articles were available for extraction of data on candidemia and HSC. Seventy percent (131/187) of patients with HSC did not have documented candidemia. The majority of HSC events were described in hematologic patients, although some cases were described in patients with solid tumors treated with SCT (n = 1) or chemotherapy and a history of leukopenia (n = 2). Current guidelines and practices for diagnosis and treatment are described. CONCLUSION: Clinicians should be aware that HSC most often occurs without documented candidemia. In case of persistent or unexplained fever or lesions in the liver and/or spleen, a history of neutropenia should place disseminated candidiasis in the differential diagnosis. HSC is not limited to hematological patients and may occur in patients with solid tumors treated with bone marrow-suppressing chemotherapy or SCT. In the latter group, HSC as alternative diagnosis for hepatic metastasis should be considered when lesions are not typical for metastasis. This might prevent unnecessary surgery or inappropriate treatment. IMPLICATIONS FOR PRACTICE: Timely diagnosis of hepatosplenic candidiasis (HSC) is challenging, but can prevent further complications and dissemination, and may even prevent unnecessary invasive procedures. Clinicians should realize that HSC often occurs without documented candidemia and that sensitivity of blood cultures for candidemia is limited. HSC is not strictly limited to hematologic patients and might also occur in patients with solid tumors treated with intensive chemotherapy or stem cell transplantation. Increased awareness for HSC in patients with any history of neutropenia is of importance to increase detection and prevent serious sequelae.

Diagnosis and management of aspergillosis in the Netherlands: a national survey.

A survey of diagnosis and treatment of invasive aspergillosis was conducted in eight University Medical Centers (UMCs) and eight non-academic teaching hospitals in the Netherlands. Against a background of emerging azole resistance in Aspergillus fumigatus routine resistance screening of clinical isolates was performed primarily in the UMCs. Azole resistance rates at the hospital level varied between 5% and 10%, although rates up to 30% were reported in high-risk wards. Voriconazole remained first choice for invasive aspergillosis in 13 out of 16 hospitals. In documented azole resistance 14 out of 16 centres treated patients with liposomal amphotericin B.

Purification and photobiochemical profile of photosystem 1 from a high-salt tolerant, oleaginous Chlorella (Trebouxiophycaea, Chlorophyta).

The eukaryotic green alga Chlamydomonas reinhardtii has been studied extensively within the biofuel industry as a model organism, as researchers look towards algae to provide chemical feedstocks (i.e., lipids) for the production of liquid transportation fuels. C. reinhardtii, however, is unsuitable for high-level production of such precursors due to its relatively poor lipid accumulation and fresh-water demand. In this study we offer insight into the primary light harvesting and electron transfer reactions that occur during phototropic growth in a high-salt tolerant strain of Chlorella (a novel strain introduced here as NE1401), a single-celled eukaryotic algae also in the phylum Chlorophyta. Under nutrient starvation many eukaryotic algae increase dramatically the amount of lipids stored in lipid bodies within their cell interiors. Microscopy and lipid analyses indicate that Chlorella sp. NE1401 may become a superior candidate for algal biofuels production. We have purified highly active Photosystem 1 (PS1) complexes to study in vitro, so that we may understand further the photobiochemisty of this promising biofuel producer and how its characteristics compare and contrast with that of the better understood C. reinhardtii. Our findings suggest that the PS1 complex from Chlorella sp. NE1401 demonstrates similar characteristics to that of C. reinhardtii with respect to light-harvesting and electron transfer reactions. We also illustrate that the relative extent of the light state transition performed by Chlorella sp. NE1401 is smaller compared to C. reinhardtii, although they are triggered by the same dynamic light stresses.

Depressive symptoms in Parkinson's disease are related to reduced [123I]FP-CIT binding in the caudate nucleus.

BACKGROUND: Depression is a common neuropsychiatric symptom in Parkinson's disease (PD). In previous research, PD-related depression was associated with striatal dopaminergic deficits, presumably due to degeneration of brainstem dopaminergic projections. Segregated areas of the striatum are crucially involved in various parallelly arranged cortical-striatal-thalamocortical circuits and serve functions in, among others, motor control or emotion. This suggests regional specificity of dopaminergic deficits in the striatum in motor and depressive symptoms in PD. METHODS: In this cross-sectional retrospective study, we correlated severity scores of depressive and motor symptoms in 100 non-demented PD patients (median Hoehn & Yahr stage: 2) with dopamine loss in specific regions of the striatum as measured by [(123)I]FP-CIT SPECT tracer binding to the dopamine transporter (DaT). RESULTS: Depressive symptoms were related to lower DaT binding in the right caudate nucleus, while motor symptoms were associated with decreased DaT binding in the right putamen. This double dissociation was most pronounced in early-stage PD patients. CONCLUSIONS: These results suggest that depressive symptoms in PD are associated with dopamine loss in the caudate nucleus, possibly related to degeneration of dopaminergic projections from the ventral tegmental area, while motor symptoms are associated with low dopamine signalling to the putamen and loss of nigrostriatal projections. This is consistent with the neuroanatomy of partially segregated cortical-striatal-thalamocortical circuits and supports the role of dysfunctional associative and motivational circuits in PD-related depression.

Coccidioidomycosis presenting years after returning from travel.

After having traveled to California in 2017, a 26-year old Dutch man presented in 2020 with persisting cough and shortness of breath. Radiology showed cystic bronchiectasis with peri-bronchial consolidation in his right upper lobe. Laboratory studies in August 2021 showed an increased total IgE, specific Aspergillus IgE, eosinophilia and positive BAL culture for Coccidioides immitis/posadasii. After 6 weeks of itraconazole treatment for suspected allergic bronchopulmonary aspergillosis, symptoms persisted and respiratory cultures remained positive. The infection was cleared after a 6-month course of fluconazole. (max 75 words).

[Hitting and yelling during sleep: diagnosis and implications of REM sleep behavior disorder]. / Slaan en schreeuwen in de slaap.

Rapid eye movement (REM) sleep behavior disorder is characterized by dream enactment during REM sleep. Due to different treatment requirements, it is important to distinguish REM sleep behavior disorder from other causes of nocturnal restlessness, including sleep apnea, non-REM parasomnia and sleep-related hypermotor epilepsy. In addition, a diagnosis of isolated REM sleep behavior disorder is impactful, because it carries a greatly increased risk for the later development of Parkinson's disease and related synucleinopathies. In this clinical lesson we describe three patients with abnormal nocturnal movements and vocalizations. The history can provide important clues towards the diagnosis, but a video-polysomnography is required before REM sleep behavior disorder can be diagnosed.