Alteration of functional connectivity despite preserved cerebral oxygenation during acute hypoxia.

Resting state networks (RSN), which show the connectivity in the brain in the absence of any stimuli, are increasingly important to assess brain function. Here, we investigate the changes in RSN as well as the hemodynamic changes during acute, global hypoxia. Mice were imaged at different levels of oxygen (21, 12, 10 and 8%) over the course of 10 weeks, with hypoxia and normoxia acquisitions interspersed. Simultaneous GCaMP and intrinsic optical imaging allowed tracking of both neuronal and hemodynamic changes. During hypoxic conditions, we found a global increase of both HbO and HbR in the brain. The saturation levels of blood dropped after the onset of hypoxia, but surprisingly climbed back to levels similar to baseline within the 10-min hypoxia period. Neuronal activity also showed a peak at the onset of hypoxia, but dropped back to baseline as well. Despite regaining baseline sO2 levels, changes in neuronal RSN were observed. In particular, the connectivity as measured with GCaMP between anterior and posterior parts of the brain decreased. In contrast, when looking at these same connections with HbO measurements, an increase in connectivity in anterior-posterior brain areas was observed suggesting a potential neurovascular decoupling.

Antibodies Against Angiotensin II Receptor Type 1 and Endothelin A Receptor Are Associated With an Unfavorable COVID19 Disease Course.

Background: Lung histopathology demonstrates vasculopathy in a subset of deceased COVID19 patients, which resembles histopathology observed in antibody-mediated lung transplant rejection. Autoantibodies against angiotensin II type 1 receptor (AT1R) and Endothelin receptor Type A (ETAR) have been demonstrated in antibody-mediated rejection and may also be associated with severe COVID19 infection. Objective To assess AT1R and ETAR auto-antibodies in COVID19 patients and controls, and explore their association with disease course. Methods: 65 hospitalized patients with COVID19 infection were included. Clinical and laboratory findings were retrospectively assessed. Patients with unfavorable disease course, admitted at the intensive care unit and/or deceased during hospital admission (n=33) were compared to admitted COVID19 patients with favorable disease course (n=32). The presence of antinuclear antibodies (ANA) and auto-antibodies against AT1R or ETAR in peripheral blood were compared between COVID19 with unfavorable and favorable disease course and age matched controls (n=20). Results: The presence of ANA was not significantly different between COVID19 patients with unfavorable (n=7/33; 21%) and favorable disease course (n=6/32; 19%) (p= 0.804) and controls (n=3/20; 15%). Auto-antibodies against AT1R were significantly increased in unfavorable disease course (median 14.59 U/mL, IQR 11.28 - 19.89) compared to favorable disease course (median 10.67 U/mL, IQR 8.55 - 13.0, p< 0.01). ETAR antibody titers were also significantly increased in unfavorable disease course (median 7.21, IQR 5.0 - 10.45) as compared to favorable disease course (median 4.0, IQR 3.0 - 6.0, p <0.05). Conclusion: Auto-antibodies against AT1R and ETAR are significantly increased in COVID19 patients with an unfavorable disease course.

[Coercive measures for covid-19: application of which law?] / Dwangmaatregelen vanwege covid-19.

Since the end of January 2020, covid-19 is a group A infectious disease according to the Public Health Act (in Dutch: Wet publiekegezondheid or Wpg). To avert the risk of infection with covid-19, coercive measures can be imposed under this law. Almost at the same time, since January 1 2020, two new Dutch laws regulate the mandatory care for people with intellectual disability and dementia (the Care and Compulsion Act (in Dutch: Wet zorgendwang or Wzd) and for people with a mental disorder (the Mandatory Mental Health Care Act (in Dutch: Wet verplichte GGZ or Wvggz). Just like the Wpg, the Wzd and Wvggz allow coercion for the benefit of third parties. In this clinical lesson we describe the use of the Wpg, Wzd and Wvggz in order to avert covid-19 infection risk.

The tough process of unmasking the slow-growing mycobacterium: case report of Mycobacterium microti infection.

Mycobacterium microti belongs to the Mycobacterium tuberculosis complex (MTBC). It can cause pulmonary and extrapulmonary tuberculosis in humans. Compared to M. tuberculosis , which is the most prevalent subspecies of the MTBC, M. microti infection has a different etiology. Moreover, establishing the diagnosis with conventional bacteriology can be difficult. We will illustrate this with a case of an extrapulmonary tuberculosis of the hip caused by M .microti in an immunocompetent patient in The Netherlands.

[Our new donation law: more autonomy?] / Onze nieuwe donorwet ­ meer autonomie?

On 1 July 2020, the registration of organ and tissue donors in the Netherlands changed from an opt-in to an opt-out system. This means that everyone in the Netherlands will be registered as an organ and tissue donor unless they have registered a different choice in the donor register. The hope is that this new method for donor registration will lead to more donors. Only a small majority of members of the Senate and the House of Representatives in the Netherlands voted for the legislative amendment that enabled this new system to come into effect. In the Senate the amendment was defended on the grounds that it would do more justice to the autonomy of the deceased; the new law will, however, have to be defended from the principles of justice and solidarity by a government that feels responsibility towards those needing a donor organ.

[Ethical principles compromised during the COVID-19 pandemic?] / Ethische principes in het gedrang door COVID-19?

In the late 1970s, the American bioethicists Tom Beauchamp and James Childress described the four ethical principles that should guide a physician's actions in individual patient care. These principles are: (a) respect for autonomy; (b) doing well (beneficence); (c) not harming (non-maleficence); and (d) justice. In many countries, the global outbreak of SARS-CoV-2 has led to overloaded healthcare systems due to large numbers of COVID-19 patients. In order to provide care to this high volume of patients, far-reaching measures are taken that affect everyone. These measures are not taken from an individual patient's perspective but in the interest of public health; nonetheless, they can directly affect the individual patient's interests. This article examines the extent to which Beauchamp and Childress' ethical principles may be compromised during the COVID-19 pandemic.

Prevalence of Positive QuantiFERON-TB Gold In-Tube Test in Uveitis and its Clinical Implications in a Country Nonendemic for Tuberculosis.

PURPOSE: To report on the prevalence and clinical implications of positive QuantiFERON-Gold (QFT-G) test results in the diagnostic evaluation of a large cohort of consecutive patients with uveitis in the Netherlands. DESIGN: Retrospective cross-sectional study. METHODS: This study included 710 consecutive patients who all underwent evaluation for uveitis including QFT-G testing. The ocular features, comorbidity, and abnormalities in diagnostic imaging and laboratory tests were registered for QFT-G-positive patients with uveitis. RESULTS: Of all patients, 13% (92/710) were positive for QFT-G. Previously treated tuberculosis (TB) was documented in 2 patients. Of all 92 QFT-G-positive patients, culture-proven active TB was observed in 1 case. The proportion of patients with uveitis of unknown etiology was higher in QFT-G-positive than in the QFT-G-negative patients (54/92, 59% vs 238/618, 39%; P = .0004). The uveitis features of QFT-G-positive patients were mainly nonspecific. Of all QFT-G-positive patients with uveitis, 17 patients had chest imaging changes suggesting either TB or sarcoidosis. Twenty-nine QFT-G-positive patients with otherwise unexplained uveitis completed antituberculous therapy (29/710; 4% of all included patients) with beneficial effect in most cases. CONCLUSION: The QFT-G tested positive in 13% of patients with uveitis in the Netherlands, whereas only sporadic patients had a documented previous or active TB infection. The proportion of patients with unexplained uveitis was higher in QFT-G-positive patients. Though the association between uveitis and a positive QFT-G test might be coincidental, the majority of treated QFT-G-positive patients with otherwise unexplained severe uveitis cause had a beneficial response to antituberculous therapy.

Rectal Organoids Enable Personalized Treatment of Cystic Fibrosis.

In vitro drug tests using patient-derived stem cell cultures offer opportunities to individually select efficacious treatments. Here, we provide a study that demonstrates that in vitro drug responses in rectal organoids from individual patients with cystic fibrosis (CF) correlate with changes in two in vivo therapeutic endpoints. We measured individual in vitro efficaciousness using a functional assay in rectum-derived organoids based on forskolin-induced swelling and studied the correlation with in vivo effects. The in vitro organoid responses correlated with both change in pulmonary response and change in sweat chloride concentration. Receiver operating characteristic curves indicated good-to-excellent accuracy of the organoid-based test for defining clinical responses. This study indicates that an in vitro assay using stem cell cultures can prospectively select efficacious treatments for patients and suggests that biobanked stem cell resources can be used to tailor individual treatments in a cost-effective and patient-friendly manner.

Type 1 interferon-inducible gene expression in QuantiFERON Gold TB-positive uveitis: A tool to stratify a high versus low risk of active tuberculosis?

QuantiFERON-Gold TB (QFT)-positive patients with undetermined cause of uveitis are problematic in terms of whether to diagnose and treat them for tuberculosis (TB). Here, we investigated whether peripheral blood expression of type 1 interferon (IFN)-inducible genes may be of use to stratify QFT-positive patients with uveitis into groups of high versus low risk of having active TB-associated uveitis. We recruited all new uveitis patients in Cipto Mangunkusumo Hospital, Jakarta, Indonesia for one year. We included 12 patients with uveitis and clinically diagnosed active pulmonary TB, 58 QFT-positive patients with uveitis of unknown cause, 10 newly diagnosed sputum-positive active pulmonary TB patients without uveitis and 23 QFT-negative healthy controls. Expression of 35 type 1 IFN-inducible genes was measured in peripheral blood cells from active pulmonary TB patients without uveitis and healthy controls. Differentially expressed genes were identified and used for further clustering analyses of the uveitis groups. A type-1 IFN gene signature score was calculated and the optimal cut-off value for this score to differentiate active pulmonary TB from healthy controls was determined and applied to QFT-positive patients with uveitis of unknown cause. Ten type 1 IFN-inducible genes were differentially expressed between active pulmonary TB and healthy controls. Expression of these 10 genes in QFT-positive patients with uveitis of unknown cause revealed three groups: 1); patients resembling active pulmonary TB, 2); patients resembling healthy controls, and 3); patients displaying an in-between gene expression pattern. A type 1 IFN gene signature score ≥5.61 displayed high sensitivity (100%) and specificity (91%) for identification of active TB. Application of this score to QFT-positive patients with uveitis of unknown cause yielded two groups with expected different likelihood (high vs. low) of having active-TB uveitis, and therefore may be useful in clinical management decisions.

[Within the limits of the law? Compulsory isolation and compulsory treatment for tuberculosis]. / Binnen de grenzen van de wet?

We discuss two patients with infectious tuberculosis who underwent compulsory isolation and treatment without their consent. We describe the threat to the patient's rights, i.e. the right of freedom, the right of autonomy and the right of protection of the integrity of the body. We describe the application of the relevant laws and of the differing safeguards, and discuss the unlimited length of the Dutch Public Health Act orders. We refer to a Dutch statement and the WHO ethics guidelines on the implementation of their End TB Strategy. Forced isolation may be the last resort to protect society from patients with infectious diseases who do not comply with isolation measures, but compulsory treatment for tuberculosis patients is considered unacceptable. We suggest an amendment of the Dutch Public Health Act to enable better protection of the rights of tuberculosis patients.

Policy and practice of programmatic management of latent tuberculosis infection in The Netherlands.

Latent tuberculosis infection (LTBI) screening and preventive treatment is one of the components of the World Health Organization (WHO) End TB strategy, and particularly relevant for low tuberculosis (TB) incidence countries, i.e. less than 100 TB cases per million population. The Netherlands is such a low-incidence country with traditionally a strong emphasis on programmatic management of LTBI, e.g. examining contacts of infectious TB patients by the public health services. Increasingly, curative services are involved in LTBI management of clinical risk groups. The country recently adopted a five-year strategic national plan recommending LTBI screening of high-risk migrants populations. A monitoring and evaluation system is already in place to measure programme performance and guide policy. Research on LTBI screening of migrants is on-going and results should inform future decisions in scaling-up this intervention. Several challenges remain for programmatic LTBI management, such as securing financial resources and the right professional cadre for implementation; availability of screening tests and drugs; collecting additional data for monitoring and evaluation, in line with the WHO indicators for LTBI programmatic management; developing cultural-sensitive and client-centred education for migrants; reducing patient costs for LTBI screening and preventive treatment; and assessing cost-effectiveness and impact on TB epidemiology.

Clinical manifestations of patients with intraocular inflammation and positive QuantiFERON-TB gold in-tube test in a country nonendemic for tuberculosis.

PURPOSE: To evaluate clinical manifestations of patients with uveitis and scleritis of unknown origin and positive QuantiFERON-TB Gold In-Tube test (quantiferon) in a country not endemic for tuberculosis. DESIGN: Multicenter retrospective cohort study. METHODS: Retrospective review of the clinical, laboratory, and imaging data of 77 patients. Main outcome measures consisted of ocular and systemic features as well as results of laboratory examinations. RESULTS: Out of all, 60 of 71 (85%) were living for at least 6 months in tuberculosis-endemic regions. Location of uveitis was variable; posterior uveitis (29/77; 38%) was the most frequent. Two clinical entities were commonly noted: retinal occlusive vasculitis (21/77; 27%) and serpiginoid choroiditis (11/77; 14%). Antituberculosis treatment was completed in 32 patients; 29 of them (91%) achieved complete remission. Mean quantiferon level was 7.5 U/mL; 71% had values above 2 U/mL and 41% above 10 U/mL. We observed no associations between quantiferon levels and clinical and/or imaging features. Previous tuberculosis infection was diagnosed in 5 of 77 patients (6.5%), while hilar/mediastinal lymphadenopathy was found in 25 of 76 patients (33%). Of these, 12 were consistent with the diagnosis of sarcoidosis, 9 were typical for (prior) tuberculosis, and 4 were compatible with both diagnoses. CONCLUSIONS: Ocular features of patients with idiopathic uveitis and positive quantiferon were diverse, but retinal occlusive vasculitis and serpiginoid choroiditis were common. The quantiferon levels were usually highly elevated and 33% of patients exhibited lymphadenopathy, suggesting frequently the diagnosis of sarcoidosis. Ocular inflammation reacted favorably to antituberculosis treatment, although only a small minority had documented (prior) tuberculosis.

Cytokines in nasal lavages and plasma and their correlation with clinical parameters in cystic fibrosis.

BACKGROUND: Because persistent inflammation plays a dominant role in cystic fibrosis (CF), we assessed systemic and local upper airway responses during and after pulmonary exacerbation. METHODS: We followed a cohort of Pseudomonas aeruginosa-infected adult CF patients (n=16) over time in pulmonary exacerbation and in stable disease. Interleukin (IL)-1ß, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-17A, IL-22, interferon-γ and TNFα levels were measured in sputum, nasal lavages and plasma. RESULTS: In CF patients IL-6 and IL-10 levels in nasal lavages were significantly increased in exacerbation compared with stable disease. Systemic IL-6 significantly correlated with CRP levels and FEV1 (%predicted), independently of disease status. Systemic IL-10 also correlated significantly with CRP and FEV1 (%predicted), but only in exacerbation. Other cytokines tested did not discriminate between exacerbation and stable disease. CONCLUSIONS: Determination of IL-6 and IL-10 in nasal lavages may provide a minimally invasive tool in the assessment of an exacerbation in CF.

Incidence of viral respiratory pathogens causing exacerbations in adult cystic fibrosis patients.

Respiratory infections caused by respiratory viruses are common in paediatric cystic fibrosis (CF) patients and are associated with increased morbidity. There is only little data on the incidence of viral respiratory pathogens causing exacerbations in the adult CF patient population. In this observational pilot study we show, by using molecular as well as conventional techniques for viral isolation, that during 1 y a viral pathogen could be isolated in 8/24 (33%) adult CF patients who presented with a pulmonary exacerbation. This result shows that there is a considerable incidence of viral pathogens in pulmonary exacerbations in adult CF patients. Newly identified viruses such as pandemic influenza A/H1N1, human metapneumovirus, human bocavirus, and human coronavirus NL63 were not detected in our population, except for 1 human coronavirus NL63.

History of tuberculosis as an independent prognostic factor for lung cancer survival.

INTRODUCTION: It is well known that pulmonary tuberculosis is associated with an increased risk of lung cancer. We investigated whether a history of pulmonary tuberculosis is an independent risk factor for lung cancer survival in Caucasian patients. METHODS: The data of the prospective population-based cohort of The Rotterdam Study were used. During a mean follow-up time of 18 years, there were 214 incident cases of pathology-proven lung cancer in a source population of 7983 study participants. History of tuberculosis was assessed at baseline by interviewers using standardized questionnaires. Associations of lung cancer survival with the occurrence of pulmonary tuberculosis were assessed using Cox's proportional hazard regression analysis adjusted for age, gender, pack-years, educational level and tumor stage. RESULTS: A history of tuberculosis was reported in 13 of the 214 subjects with lung cancer. The survival of patients with lung cancer was significantly shorter in subjects with a history of pulmonary tuberculosis (HR=2.36, CI95%: 1.1-4.9), than in subjects without a history of pulmonary tuberculosis with a mean difference of 311 days. CONCLUSION: The presence of a history of pulmonary tuberculosis may be an important prognostic factor in the survival of lung cancer.