Clinical and Immunological Phenotype of Patients With Primary Immunodeficiency Due to Damaging Mutations in NFKB2

Non-canonical NF-κB-pathway signaling is integral in immunoregulation. Heterozygous mutations in NFKB2 have recently been established as a molecular cause of common variable immunodeficiency (CVID) and DAVID-syndrome, a rare condition combining deficiency of anterior pituitary hormone with CVID. Here, we investigate 15 previously unreported patients with primary immunodeficiency (PID) from eleven unrelated families with heterozygous NFKB2-mutations including eight patients with the common p.Arg853* nonsense mutation and five patients harboring unique novel C-terminal truncating mutations. In addition, we describe the clinical phenotype of two patients with proximal truncating mutations. Cohort analysis extended to all 35 previously published NFKB2-cases revealed occurrence of early-onset PID in 46/50 patients (mean age of onset 5.9 years, median 4.0 years). ACTH-deficiency occurred in 44%. Three mutation carriers have deceased, four developed malignancies. Only two mutation carriers were clinically asymptomatic. In contrast to typical CVID, most patients suffered from early-onset and severe disease manifestations, including clinical signs of T cell dysfunction e.g., chronic-viral or opportunistic infections. In addition, 80% of patients suffered from (predominately T cell mediated) autoimmune (AI) phenomena (alopecia > various lymphocytic organ-infiltration > diarrhea > arthritis > AI-cytopenia). Unlike in other forms of CVID, auto-antibodies or lymphoproliferation were not common hallmarks of disease. Immunophenotyping showed largely normal or even increased quantities of naïve and memory CD4+ or CD8+ T-cells and normal T-cell proliferation. NK-cell number and function were also normal. In contrast, impaired B-cell differentiation and hypogammaglobinemia were consistent features of NFKB2-associated disease. In addition, an array of lymphocyte subpopulations, such as regulatory T cell, Th17-, cTFH-, NKT-, and MAIT-cell numbers were decreased. We conclude that heterozygous damaging mutations in NFKB2 represent a distinct PID entity exceeding the usual clinical spectrum of CVID. Impairment of the non-canonical NF-κB pathways affects function and differentiation of numerous lymphocyte-subpopulations and thus causes a heterogeneous, more severe form of PID phenotype with early-onset. Further characteristic features are multifaceted, primarily T cell-mediated autoimmunity, such as alopecia, lymphocytic organ infiltration, and in addition frequently ACTH-deficiency

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

The relationship of sleep with temperature and metabolic rate in a hibernating primate.

Study objectivesIt has long been suspected that sleep is important for regulating body temperature and metabolic-rate. Hibernation, a state of acute hypothermia and reduced metabolic-rate, offers a promising system for investigating those relationships. Prior studies in hibernating ground squirrels report that, although sleep occurs during hibernation, it manifests only as non-REM sleep, and only at relatively high temperatures. In our study, we report data on sleep during hibernation in a lemuriform primate, Cheirogaleus medius. As the only primate known to experience prolonged periods of hibernation and as an inhabitant of more temperate climates than ground squirrels, this animal serves as an alternative model for exploring sleep temperature/metabolism relationships that may be uniquely relevant to understanding human physiology.Measurements and resultsWe find that during hibernation, non-REM sleep is absent in Cheirogaleus. Rather, periods of REM sleep occur during periods of relatively high ambient temperature, a pattern opposite of that observed in ground squirrels. Like ground squirrels, however, EEG is marked by ultra-low voltage activity at relatively low metabolic-rates.ConclusionsThese findings confirm a sleep-temperature/metabolism link, though they also suggest that the relationship of sleep stage with temperature/metabolism is flexible and may differ across species or mammalian orders. The absence of non-REM sleep suggests that during hibernation in Cheirogaleus, like in the ground squirrel, the otherwise universal non-REM sleep homeostatic response is greatly curtailed or absent. Lastly, ultra-low voltage EEG appears to be a cross-species marker for extremely low metabolic-rate, and, as such, may be an attractive target for research on hibernation induction

Statistical Analysis of Relationships of EEG Activity to REMs, Metabolic Rate, and Temperature in 7 Animals Recorded During Torpor.

*<p>p<0.05;</p>**<p>p<0.01;</p>***<p>p<0.0001 For Difference between REM Epochs and Epochs Other Than REM; DLC = Duke Lemur Center;</p>‡<p>Only 2 REM epochs were included in these analyses.</p

Four 30 second segments of EEG Data.

<p>A. Two segments of data recorded in non-torpid sleep in Duke Lemur Center. The top segment displays EEG data during a period of REM sleep. The display scale is 250 µV from the top to the bottom. The bottom segment displays EEG data during a period of Non-REM sleep. The display scale is 150 µV from the top to the bottom. b. Two 30 second segments of EEG data recorded during torpor in the wild verified by decreased metabolic rate. The top segment includes REMs. The display scale is 250 µV from the top to the bottom. The bottom segment is typical monotonous very low-voltage activity seen through much of these recordings and the display scale is 75 µV from the top to the bottom.</p

REMs per 30 second epoch and Ambient Temperature vs Time of Day in Hours in 6 C. medius studied in the wild in Madagascar.

<p>The top panel of the figure represents data from the animal documented to be in torpor with metabolic measurement. Note: the periods where EEG data were available for each animal coincides with the time-points where Ambient Temperature data is included in the graphs. Graphs a-f depict these data for Lemurs 1–6 respectively as designated in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0069914#pone-0069914-t001" target="_blank">Table 1</a>. Note: Because we have plotted a data point for every 30 second period over the roughly 4 days of data depicted, data from adjacent 30 second epochs which have the same or nearly the same value will appear to be on top of each other.</p

Data from recordings carried out for a torpid C.

<p>medius studied in the Duke Lemur Center. Simultaneous EEG, Temperature and Metabolic Rate recordings were obtained. a. Ambient Temperature, Skin Temperature, and Metabolic Rate vs Time of Day in Hours. Arousal from torpor is evident at approximately 13.5 hours. b. State (derived from visual scoring of the data in 30 second epochs) and Metabolic Rate vs. Time of Day in Hours.</p

Assessing ecosystem services for informing land-use decisions: a problem-oriented approach

Assessments of ecosystem services (ES), that aim at informing decisions on land management, are increasing in number around the globe. Despite selected success stories, evidence for ES information being used in decision making is weak, partly because ES assessments are found to fall short in targeting information needs by decision makers. To improve their applicability in practice, we compared existing concepts of ES assessments with focus on informing land use decisions and identified opportunities for enhancing the relevance of ES assessments for decision making. In a process of codesign, building on experience of four projects in Brazil, China, Madagascar, and Vietnam, we developed a step-wise approach for better targeting ES assessments toward information needs in land use decisions. Our problem-oriented approach aims at (1) structuring ES information according to land use problems identified by stakeholders, (2) targeting context-specific ES information needs by decision makers, and (3) assessing relevant management options. We demonstrate how our approach contributes to making ES assessments more policy relevant and enhances the application of ES assessments as a tool for decision support

Rezidiv: Prävention und Behandlung, allogene Stammzelltransplantation

Die allogene hämatopoetische Stammzelltransplantation (allo-HSZT) ist ein effektives Therapieverfahren bei Patienten mit hämatologischen Neoplasien. Allerdings kommt es in Abhängigkeit von Art der Grunderkrankung und Stadium zum Transplantationszeitpunkt im weiteren Verlauf bei einem Teil der Patienten zu einem Rezidiv. Prophylaktische oder präemptive Maßnahmen betreffen die Intensität der Konditionierungstherapie, die Modulation der Immunsuppression und entitätsspezifische Erhaltungstherapien. Zur Therapie des Rezidivs stehen Chemotherapie, eine Modulation der Immunsuppression sowie neue zielgerichtete Therapien und immuntherapeutische Maßnahmen (Zytokine, Zelltherapeutika, Antikörper) zur Verfügung. Aufgrund des steten Fortschrittes des medizinischen Wissens und der spezifischen Gegebenheiten des einzelnen Patienten sollte das Vorgehen bei jedem Patienten individuell entschieden werden