Exotic Dark Matter Search with the Majorana Demonstrator.

With excellent energy resolution and ultralow-level radiogenic backgrounds, the high-purity germanium detectors in the Majorana Demonstrator enable searches for several classes of exotic dark matter (DM) models. In this work, we report new experimental limits on keV-scale sterile neutrino DM via the transition magnetic moment from conversion to active neutrinos ν_{s}→ν_{a}. We report new limits on fermionic dark matter absorption (χ+A→ν+A) and sub-GeV DM-nucleus 3→2 scattering (χ+χ+A→ϕ+A), and new exclusion limits for bosonic dark matter (axionlike particles and dark photons). These searches utilize the (1-100)-keV low-energy region of a 37.5-kg y exposure collected by the Demonstrator between May 2016 and November 2019 using a set of ^{76}Ge-enriched detectors whose surface exposure time was carefully controlled, resulting in extremely low levels of cosmogenic activation.

Constraints on the Decay of

^{180m}Ta is a rare nuclear isomer whose decay has never been observed. Its remarkably long lifetime surpasses the half-lives of all other known ß and electron capture decays due to the large K-spin differences and small energy differences between the isomeric and lower-energy states. Detecting its decay presents a significant experimental challenge but could shed light on neutrino-induced nucleosynthesis mechanisms, the nature of dark matter, and K-spin violation. For this study, we repurposed the Majorana Demonstrator, an experimental search for the neutrinoless double-beta decay of ^{76}Ge using an array of high-purity germanium detectors, to search for the decay of ^{180m}Ta. More than 17 kg, the largest amount of tantalum metal ever used for such a search, was installed within the ultralow-background detector array. In this Letter, we present results from the first year of Ta data taking and provide an updated limit for the ^{180m}Ta half-life on the different decay channels. With new limits up to 1.5×10^{19} yr, we improved existing limits by 1-2 orders of magnitude which are the most sensitive searches for a single ß and electron capture decay ever achieved. Over all channels, the decay can be excluded for T_{1/2}<0.29×10^{18} yr.

Erratum: Search for Spontaneous Radiation from Wave Function Collapse in the Majorana Demonstrator [Phys. Rev. Lett. 129, 080401 (2022)].

This corrects the article DOI: 10.1103/PhysRevLett.129.080401.

Final Result of the Majorana Demonstrator's Search for Neutrinoless Double-ß Decay in

The Majorana Demonstrator searched for neutrinoless double-ß decay (0νßß) of ^{76}Ge using modular arrays of high-purity Ge detectors operated in vacuum cryostats in a low-background shield. The arrays operated with up to 40.4 kg of detectors (27.2 kg enriched to ∼88% in ^{76}Ge). From these measurements, the Demonstrator has accumulated 64.5 kg yr of enriched active exposure. With a world-leading energy resolution of 2.52 keV FWHM at the 2039 keV Q_{ßß} (0.12%), we set a half-life limit of 0νßß in ^{76}Ge at T_{1/2}>8.3×10^{25} yr (90% C.L.). This provides a range of upper limits on m_{ßß} of (113-269) meV (90% C.L.), depending on the choice of nuclear matrix elements.

[Refractory thrombotic thrombocytopenic purpura]. / Therapierefraktäre thrombotisch-thrombozytopenische Purpura.

Thrombotic thrombocytopenic purpura (TTP) remains a serious illness with potentially life-threatening complications. The following case of a TTP patient describes a serious relapse with exacerbation in spite of adequately initiated therapy and highlights the necessity of interdisciplinary expertise in the treatment of the disease.

Search for Spontaneous Radiation from Wave Function Collapse in the Majorana Demonstrator.

The Majorana Demonstrator neutrinoless double-beta decay experiment comprises a 44 kg (30 kg enriched in ^{76}Ge) array of p-type, point-contact germanium detectors. With its unprecedented energy resolution and ultralow backgrounds, Majorana also searches for rare event signatures from beyond standard model physics in the low energy region below 100 keV. In this Letter, we test the continuous spontaneous localization (CSL) model, one of the mathematically well-motivated wave function collapse models aimed at solving the long-standing unresolved quantum mechanical measurement problem. While the CSL predicts the existence of a detectable radiation signature in the x-ray domain, we find no evidence of such radiation in the 19-100 keV range in a 37.5 kg-y enriched germanium exposure collected between December 31, 2015, and November 27, 2019, with the Demonstrator. We explored both the non-mass-proportional (n-m-p) and the mass-proportional (m-p) versions of the CSL with two different assumptions: that only the quasifree electrons can emit the x-ray radiation and that the nucleus can coherently emit an amplified radiation. In all cases, we set the most stringent upper limit to date for the white CSL model on the collapse rate, λ, providing a factor of 40-100 improvement in sensitivity over comparable searches. Our limit is the most stringent for large parts of the allowed parameter space. If the result is interpreted in terms of the Diòsi-Penrose gravitational wave function collapse model, the lower bound with a 95% confidence level is almost an order of magnitude improvement over the previous best limit.

Search for Solar Axions via Axion-Photon Coupling with the Majorana Demonstrator.

Axions were originally proposed to explain the strong-CP problem in QCD. Through axion-photon coupling, the Sun could be a major source of axions, which could be measured in solid state detection experiments with enhancements due to coherent Primakoff-Bragg scattering. The Majorana Demonstrator experiment has searched for solar axions with a set of ^{76}Ge-enriched high purity germanium detectors using a 33 kg-yr exposure collected between January, 2017 and November, 2019. A temporal-energy analysis gives a new limit on the axion-photon coupling as g_{aγ}<1.45×10^{-9} GeV^{-1} (95% confidence level) for axions with mass up to 100 eV/c^{2}. This improves laboratory-based limits between about 1 eV/c^{2} and 100 eV/c^{2}.

α -event characterization and rejection in point-contact HPGe detectors.

P-type point contact (PPC) HPGe detectors are a leading technology for rare event searches due to their excellent energy resolution, low thresholds, and multi-site event rejection capabilities. We have characterized a PPC detector's response to α particles incident on the sensitive passivated and p + surfaces, a previously poorly-understood source of background. The detector studied is identical to those in the Majorana Demonstrator experiment, a search for neutrinoless double-beta decay ( 0 ν ß ß ) in 76 Ge. α decays on most of the passivated surface exhibit significant energy loss due to charge trapping, with waveforms exhibiting a delayed charge recovery (DCR) signature caused by the slow collection of a fraction of the trapped charge. The DCR is found to be complementary to existing methods of α identification, reliably identifying α background events on the passivated surface of the detector. We demonstrate effective rejection of all surface α events (to within statistical uncertainty) with a loss of only 0.2% of bulk events by combining the DCR discriminator with previously-used methods. The DCR discriminator has been used to reduce the background rate in the 0 ν ß ß region of interest window by an order of magnitude in the Majorana Demonstrator  and will be used in the upcoming LEGEND-200 experiment.

Lightweight, wireless LED implant for chronic manipulation in vivo of spontaneous activity in neonatal mice.

BACKGROUND: Long-term manipulation of activity in the neonatal rodent brain can help us understand healthy development, but also involves a set of challenges unique to the neonatal animal. As pups are small, cannot be separated from their mother for long periods of time, and must be housed in a nest, many traditional techniques are unusable during the first two postnatal weeks. NEW METHOD: Here, we describe the use of magnetic resonance induction to allow wireless and chronic optogenetic manipulation of spontaneous activity in mouse pups during the second postnatal week. RESULTS: Pups were implanted with a lightweight receiver coupled to an LED and successfully returned to the homecage. A transmitter coil surrounding the homecage drove the implanted LED and was regulated by a microcontroller to allow flexible, precisely-timed and wireless control over neuronal manipulation. In vivo patch-clamp recordings verified that activation of the LED triggered bursts of action potentials in layer 2/3 neurons that expressed channelrhodopsin-2 in the visual cortex without directly affecting neighboring, non-expressing neurons. The implants are stable and functional for at least 10 days and do not have an impact on the weight gain of pups. Implanted pups' behavior is mildly affected only briefly after surgery, while maternal behavior of dams remains unaffected. COMPARISON WITH EXISTING METHOD(S): In contrast to most other methods for wireless optogenetic stimulation, the small size and low weight of the receiver allow complete implantation in animals that are as small as a newborn mouse. CONCLUSIONS: This method is ideal for investigating the function and development of cortical circuits in small and developing animals. Furthermore, our method is economical and easy to adapt to diverse experimental designs.

[Sepsis with hemolysis due to a liver abscess in a 60-year-old male patient]. / Sepsis mit Hämolyse im Rahmen eines Leberabszesses bei einem 60-jährigen Patienten.

Many cases of Clostridium perfringens sepsis prove to be fatal. We present a case of C. perfringens sepsis with a liver abscess as the focus of infection, which was successfully treated by an interdisciplinary intensive medical care management. The sepsis with this rare pathogen was favored by the presence of a bilioenteric anastomosis and immunosuppressive treatment of a pre-existing Crohn's disease. Antibiotic treatment with clindamycin and penicillin G was initiated and the abscess was drained. Hemodialysis with high cut-off filters was started because of acute kidney failure in the Acute Kidney Injury Network (AKIN) stage III, hemolysis and rhabdomyolysis. Therapeutic plasma exchange was performed due to sepsis and acute liver failure.

Activity-dependent regulation of mitochondrial motility in developing cortical dendrites.

Developing neurons form synapses at a high rate. Synaptic transmission is very energy-demanding and likely requires ATP production by mitochondria nearby. Mitochondria might be targeted to active synapses in young dendrites, but whether such motility regulation mechanisms exist is unclear. We investigated the relationship between mitochondrial motility and neuronal activity in the primary visual cortex of young mice in vivo and in slice cultures. During the first 2 postnatal weeks, mitochondrial motility decreases while the frequency of neuronal activity increases. Global calcium transients do not affect mitochondrial motility. However, individual synaptic transmission events precede local mitochondrial arrest. Pharmacological stimulation of synaptic vesicle release, but not focal glutamate application alone, stops mitochondria, suggesting that an unidentified factor co-released with glutamate is required for mitochondrial arrest. A computational model of synaptic transmission-mediated mitochondrial arrest shows that the developmental increase in synapse number and transmission frequency can contribute substantially to the age-dependent decrease of mitochondrial motility.

[Treatment of severe COVID-19 courses in intensive care medicine]. / Therapie schwerer COVID-19-Verläufe in der Intensivmedizin.

The pandemic triggered by coronavirus disease 2019 (COVID-19) has put intensive care medicine into the focus of public attention. The mortality of patients with the disease escalates, particularly at the moment when the treatment possibilities of intensive medical care end. In the routine intensive medical care practice, the challenges due to the special features of infections with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its treatment become obvious. These occur in the development and treatment of respiratory and multiorgan failure as well as the severe inflammatory syndrome. For these severe courses there is still only little evidence available as to which interventions are the most effective. In addition to the knowledge that can be gained from the rapid performance of clinical trials, the treatment is therefore based on analogies to other syndromes, such as sepsis and macrophage activation syndrome.

[Acute liver failure-The importance of rapid diagnostics and early initiation of treatment]. / Akutes Leberversagen ­ die Bedeutung einer schnellen Diagnostik und frühen Therapieeinleitung.

Acute liver failure (ALF) is a rare disease with high mortality. It is defined as coagulopathy and encephalopathy in a person with a previously healthy liver. The etiology of ALF is a decisive prognostic factor and varies depending on the country of origin of the patient. Although in many countries the main triggers are hepatotropic viruses, in western industrial countries toxic medicinal causes and autoimmune phenomena predominate. The course of ALF runs through various phases. The complete picture of ALF can mostly no longer be casually treated but necessitates in particular timely contact with a transplantation center. If a causal treatment exists, the effectiveness is greatly dependent on the timing of initiation. In the best case scenario this can completely avoid liver damage. In the complete picture of ALF the main focus is on the intensive medical care of a threatening multiorgan failure. In this context new standards of treatment were established by studies on plasmapheresis.

Hyaluronic acid coating of gold nanoparticles for intraocular drug delivery: Evaluation of the surface properties and effect on their distribution.

Due to the unique anatomical structure of the eye, ocular drug delivery is a promising delivery route for the treatment of several ocular diseases, such as the ocular neovascularization that contributes to diabetic retinopathy. This disease is triggered by inflammation, retinal ischemia, and/or deposits of advanced-glycation end-products (AGEs), as well as increased levels of vascular endothelial growth factor (VEGF), interleukins, or reactive oxygen species (ROS). Gold has unique antioxidant and antiangiogenic properties and can inhibit angiogenic molecules. Furthermore, gold nanoparticles (GNPs) are not only biocompatible, they are easy to synthesize, they absorb and scatter visible light, and they can be made with precise control over size and shape. GNPs are an excellent candidate for ocular drug delivery because they can be conjugated to an extraordinarily diverse array of different biomolecules, and surface functionalization can improve the mobility of GNPs across the physiological barriers of the eye, such as the vitreous humour or the inner limiting membrane. For this purpose, we employed low molecular weight hyaluronan (HA) to increase the mobility of the nanoparticles as well as target them to HA receptors that are expressed in different cells of the eye. In this study, the combination of gold and HA enhanced the stability of the whole carrier and promoted their distribution across ocular tissues and barriers to reach the retina. Moreover, analysis in vitro, ex vivo, and in ovo revealed the protective and antiangiogenic effect of GNPs as inhibitors of AGEs-mediated- retinal pigment epithelial cell death and neovascularization. We demonstrated that conjugation with HA enhances GNP stability and distribution due to a specific CD44 receptor interaction. The capacity of HA-GNPs to distribute through the vitreous humour and their avidity for the deeper retinal layers ex vivo, suggest that HA-GNPs are a promising delivery system for the treatment of ocular neovascularization and related disorders.

[Treatment of severe COVID-19 courses in intensive care medicine]. / Therapie schwerer COVID-19-Verläufe in der Intensivmedizin.

The pandemic triggered by coronavirus disease 2019 (COVID-19) has put intensive care medicine into the focus of public attention. The mortality of patients with the disease escalates, particularly at the moment when the treatment possibilities of intensive medical care end. In the routine intensive medical care practice, the challenges due to the special features of infections with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its treatment become obvious. These occur in the development and treatment of respiratory and multiorgan failure as well as the severe inflammatory syndrome. For these severe courses there is still only little evidence available as to which interventions are the most effective. In addition to the knowledge that can be gained from the rapid performance of clinical trials, the treatment is therefore based on analogies to other syndromes, such as sepsis and macrophage activation syndrome.

Estimated dates of detectable infection (EDDIs) as an improvement upon Fiebig staging for HIV infection dating.

Accurate methods for determining the duration of HIV infection at the individual level are valuable in many settings, including many critical research studies and in clinical practice (especially for acute infection). Since first published in 2003, the 'Fiebig staging system' has been used as the primary way of classifying early HIV infection into five sequential stages based on HIV test result patterns in newly diagnosed individuals. However, Fiebig stages can only be assigned to individuals who produce both a negative and a positive test result on the same day, on specific pairs of tests of varying 'sensitivity'. Further, in the past 16 years HIV-testing technology has evolved substantially, and three of the five key assays used to define Fiebig stages are no longer widely used. To address these limitations, we developed an improved and more general framework for estimating the duration of HIV infection by interpreting any combination of diagnostic test results, whether obtained on single or multiple days, into an estimated date of detectable infection, or EDDI. A key advantage of the EDDI method over Fiebig staging is that it allows for the generation of a point estimate, as well as an associated credibility interval for the date of first detectable infection, for any person who has at least one positive and one negative HIV test of any kind. The tests do not have to be run on the same day; they do not have to be run during the acute phase of infection and the method does not rely on any special pairing of tests to define 'stages' of infection. The size of the interval surrounding the EDDI (and therefore the precision of the estimate itself) depends largely on the length of time between negative and positive tests. The EDDI approach is also flexible, seamlessly incorporating any assay for which there is a reasonable diagnostic delay estimate. An open-source, free online tool includes a user-updatable curated database of published diagnostic delays. HIV diagnostics have evolved tremendously since that original publication more than 15 years ago, and it is time to similarly evolve the methods used to estimate timing of infection. The EDDI method is a flexible and rigorous way to estimate the timing of HIV infection in a continuously evolving diagnostic landscape.

GloPID-R report on Chikungunya, O'nyong-nyong and Mayaro virus, part I: Biological diagnostics.

The GloPID-R (Global Research Collaboration for Infectious Disease Preparedness) Chikungunya (CHIKV), O'nyong-nyong (ONNV) and Mayaro virus (MAYV) Working Group is investigating the natural history, epidemiology and medical management of infection by these viruses, to identify knowledge gaps and to propose recommendations for direct future investigations and rectification measures. Here, we present the first report dedicated to diagnostic aspects of CHIKV, ONNV and MAYV. Regarding diagnosis of the disease at the acute phase, molecular assays previously described for the three viruses require further evaluation, standardized protocols and the availability of international standards representing the genetic diversity of the viruses. Detection of specific IgM would benefit from further investigations to clarify the extent of cross-reactivity among the three viruses, the sensitivity of the assays, and the possible interfering role of cryoglobulinaemia. Implementation of reference panels and external quality assessments for both molecular and serological assays is necessary. Regarding sero-epidemiological studies, there is no reported high-throughput assay that can distinguish among these different viruses in areas of potential co-circulation. New specific tools and/or improved standardized protocols are needed to enable large-scale epidemiological studies of public health relevance to be performed. Considering the high risk of future CHIKV, MAYV and ONNV outbreaks, the Working Group recommends that a major investigation should be initiated to fill the existing diagnostic gaps.

Corrigendum: Limitations in activities of daily living in old age in Germany and the EU - Results from the European Health Interview Survey (EHIS) 2.

[This corrects the article on p. 48-56 in vol. 4.].