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Abstract The prevalence and progression of many illnesses, such as neurodegenerative and cardiovascular diseases, obesity, and cancer, vary between women and men, often in an age-dependent manner. A joint hallmark of these diseases is some type of mitochondrial dysfunction. While several mitochondrial proteins are known to be regulated by sex hormones, the levels of those proteins have not been systematically analyzed with regard to sex and age, and studies that consider sex and/or age differences in the protein expression are very rare. In this study, we compared the expression patterns of physiologically important mitochondrial proteins in female and male C57BL/6N mice of age cohorts frequently used in experiments. We found that sex-related differences in the expression of uncoupling proteins 1 and 3 (UCP1 and UCP3) occur in an age-dependent manner. The sex-specific expression of UCP1 and UCP3 in brown adipose tissue (BAT) was inversely correlated with differences in body weight. Expression of UCP4 in the brain, Complex I in the spleen, and Complex II in the brain and BAT was least affected by the sex of the mouse. We further demonstrated that there are serious limitations in using VDAC1 and actin as markers in western blot analyses, due to their sex- and age-specific fluctuations. Our results confirm that sex and age are important parameters and should be taken into account by researchers who examine the mechanistic aspects of diseases. Highlights I.The levels of UCP1 and UCP3 protein expression differ between females and males in an age-dependent manner.II.Pre-pubertal expression of almost all proteins tested in this study does not depend on the sex of the mouse.III.Expression of VDAC1 and actin, which are often used as loading control proteins in western blot analysis, is tissue-specifically influenced by sex and age.

It is challenging to characterize diverse transcript isoforms by short-read sequencing. Here the authors report full-length transcriptomes in rat hippocampus by hybrid-sequencing, predict isoform-specific translational status, and reconstruct open reading frames validated by mass spectrometry.

Abstract Background In recent years, the modified Dunn osteotomy has gained popularity to treat slipped capital femoral epiphysis (SCFE) with various complication rates. Most studies included patients with different severities. This study aimed to determine (1) the radiological and clinical outcome, (2) the health-related quality of life, and (3) the incidence of avascular necrosis of the femoral head (AVN) in patients with severe chronic or acute on chronic SCFE treated by the modified Dunn procedure. Methods Out of 150 patients with SCFE treated at our institution between 2001 and 2014, 15 patients (mean age 12.9 years (range 11.8–15)) were treated by the modified Dunn procedure. Eight SCFE were chronic and 7 acute on chronic. All slips were severe with a mean Southwick slip angle (SSA) of 67° (range 60–80). Radiographic and clinical outcomes were measured. Mean time of follow-up was 3.8 years (range 1–10). Results Anatomical reduction was achieved in all cases. Good radiological results according to the Stulberg Classification (grade 1 + 2) and the Sphericity Deviation Score ( 80). The quality of life measured by the Nottingham Health Profile (NHP) was described good in 10 out of 10 patients. Four out of 15 patients developed an AVN. Conclusions The modified Dunn procedure has a great potential to restore proximal femur geometry in severe chronic or acute on chronic SCFE. It should be considered only if there is no other possibility to restore proximal femur geometry, as is the case in severe slips, due to the risk of AVN.

Recently, a universal formula for the Nicolai map in terms of a coupling flow functional differential operator was found. We present the full perturbative expansion of this operator in Yang–Mills theories where supersymmetry is realized off-shell. Given this expansion, we develop a straightforward method to compute the explicit Nicolai map to any order in the gauge coupling. Our work extends the previously known construction method from the Landau gauge to arbitrary gauges and from the gauge hypersurface to the full gauge-field configuration space. As an example, we present the map in the axial gauge to the second order.

Introduction Women with gestational diabetes mellitus (GDM) have a higher risk of developing type 2 diabetes mellitus compared with women who never had GDM. Consequently, the question of structured aftercare for GDM has emerged. In all probability, many women do not receive care according to the guidelines. In particular, the process and interaction between obstetrical, diabetic, gynaecological, paediatric and general practitioner care lacks clear definitions. Thus, our first goal is to analyse the current aftercare situation for women with GDM in Germany, for example, the participation rate in aftercare diabetes screening, as well as reasons and attitudes stated by healthcare providers to offer these services and by patients to participate (or not). Second, we want to develop an appropriate, effective and patient-centred care model.Methods and analysis This is a population-based mixed methods study using both quantitative and qualitative research approaches. In various working packages, we evaluate data of the GestDiab register, of the Association of Statutory Health Insurance Physicians of North Rhine and the participating insurance companies (AOK Rheinland/Hamburg, BARMER, DAK Gesundheit, IKK classic, pronova BKK). In addition, quantitative (postal surveys) and qualitative (interviews) surveys will be conducted with randomly selected healthcare providers (diabetologists, gynaecologists, paediatricians and midwives) and affected women, to be subsequently analysed. All results will then be jointly examined and evaluated.Ethics and dissemination The study was approved by the ethics committee of the Faculty of Medicine, Heinrich-Heine-University Düsseldorf (Ethics Committee No.: 2019-738). Participants of the postal surveys and interviews will be informed in detail about the study and the use of data as well as the underlying data protection regulations before voluntarily participating. The study results will be disseminated through peer-reviewed journals, conferences and public information.Trial registration number DRKS00020283.

BackgroundHuman rabies remains a significant public health problem in Africa with outbreaks reported in most countries. In Nigeria-the most populous country in Africa-rabies causes a significant public health burden partly due to perennial obstacles to implementing a national prevention and control program.MethodsWe conducted a scoping review using standard Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to identify and select published articles from Nigeria during 1978-2020 reporting on rabies virus infections (human, canine, livestock, and wildlife), canine bites, knowledge, attitudes and practices (KAP) surveys on rabies and canine ecology studies. We extracted information on study location, year and additional details of each study such as rabies prevalence, general characteristics of offending dogs, dog vaccination status and health-seeking behaviours.FindingsBetween 1978 and 2020, 90 published articles met our inclusion criteria. The prevalence of rabies virus antigen detection varied between 3% and 28%, with more studies in the north. Most bites were unprovoked from dog bite studies (36.4%-97%), by dogs with low vaccination rates (12-38%). A more significant proportion of biting dogs were owned (31-90%). Laboratory confirmation for biting was available for only a small proportion of studies (6%; n = 2/32). Of the dogs surveyed during ecology studies, indigenous dogs accounted for the majority (62-98%), used mostly for security purposes (52-98%), with the vaccination rate between 15% and 38% in most states. Studies conducted in areas distant from rabies diagnostic facilities accounted for more human rabies cases and fewer dog rabies cases.ConclusionSignificant improvements are necessary to achieve the elimination of human rabies mediated via dogs by 2030.

The paleo-environmental setting of an organic-rich shale remains an essential controlling factor for shale reservoir distribution. The scarcity of generalised data on paleo-environment settings has been spurred using a simple investigative approach to decipher the provenance of organic-rich shale in various regions. This study investigates the organic-rich Madzaringwe shale of the Tuli Basin to reconstruct the provenance of the organic material for shale gas generation potential. Representative shale core samples were analysed for the stable isotopic fractions, functional groups, and major and trace compositions. The carbon isotopic composition, δ13C value, ranging from −21.01 to −24.0‰, averaging at −22.4‰. Inference from the stable isotopic compositions and functional group analysis indicate Type-III kerogen prone to gas generation in the studied Madzaringwe shale. The micro-Fourier transformed infrared (micro-FTIR) analysis reveals infrared absorption peaks between 2800 and 3300 cm−1 wavelengths corresponding to gaseous hydrocarbon. The x-ray fluorescence (XRF) result reveals major elements comprising Al2O3 (29.25–29.11%), CaO (0.29–0.28%), Fe2O3 (1.16–1.09%), K2O (0.97–0.98%), MgO (0.13–0.12%), Na2O (0.12–0.09%), P2O5 (0.22–0.21%), SiO2 (52.50–52.30%), and TiO2 (1.20–1.18%). The major element ratio of Al2O3/TiO2 values ≥ 25 indicates felsic and intermediate provenance from a terrigenous paleo-environment. In addition, laser ablation inductively coupled plasma mass spectrometry (LAICP-MS) reveals the trace elements in which elemental proxy of V/(V + Ni) with a value greater than 0.5 represent reducing environments. Furthermore, the geochemical proxies and isotopic compositions have revealed an anoxic paleo-environment for the non-marine-derived organic matter in the studied carbonaceous shale.

Dysfunctional cognitions are a crucial part of depression. Cognitive therapy aims to modify dysfunctional beliefs. Typically, dysfunctional beliefs are questioned, and patients are trained to think of alternative functional beliefs. We developed a computer-assisted, avatar-based adjunct for cognitive therapy that aims to reduce dysfunctional beliefs and symptom severity. Besides, it aims to promote alternative functional beliefs. In a randomized controlled trial with 34 patients diagnosed with major depression currently undergoing inpatient treatment at the university psychiatric hospital in Regensburg, Germany, participants were randomly assigned to receive either treatment as usual (TAU) or computer-assisted avatar-based treatment for dysfunctional beliefs (CAT-DB) in addition to TAU. In CAT-DB participants are faced with a virtual avatar expressing their personal dysfunctional beliefs. Participants are asked to contradict these and express alternative functional beliefs. Assessments of conviction of dysfunctional beliefs, functional beliefs and symptom severity were done shortly before the intervention (pre-treatment), right after the intervention (post-treatment) and 14 days later (follow-up). The reduction in conviction of dysfunctional beliefs and symptom severity, and the increase in conviction of alternative functional beliefs at post-treatment and follow-up were significantly greater for the group receiving CAT-DB. Our study provides an indication in favor of the effectiveness of CAT-DB for depressive patients. It is a simple tool that could support classical cognitive therapy. Further studies at different centres, with larger sample sizes and varying therapeutic contexts are required to prove the effectiveness of our intervention.

The electroencephalography (EEG) is a well-established non-invasive method in neuroscientific research and clinical diagnostics. It provides a high temporal but low spatial resolution of brain activity. To gain insight about the spatial dynamics of the EEG, one has to solve the inverse problem, i.e., finding the neural sources that give rise to the recorded EEG activity. The inverse problem is ill-posed, which means that more than one configuration of neural sources can evoke one and the same distribution of EEG activity on the scalp. Artificial neural networks have been previously used successfully to find either one or two dipole sources. These approaches, however, have never solved the inverse problem in a distributed dipole model with more than two dipole sources. We present ConvDip, a novel convolutional neural network (CNN) architecture, that solves the EEG inverse problem in a distributed dipole model based on simulated EEG data. We show that (1) ConvDip learned to produce inverse solutions from a single time point of EEG data and (2) outperforms state-of-the-art methods on all focused performance measures. (3) It is more flexible when dealing with varying number of sources, produces less ghost sources and misses less real sources than the comparison methods. It produces plausible inverse solutions for real EEG recordings from human participants. (4) The trained network needs

Objective: Audio-visual interventions have been used to provide relevant patient information to reduce pre-operative anxiety in children. The aim of the study was to investigate whether self-reported state anxiety in children could be reduced by presenting a child-friendly educational video on the day of surgery.Methods: A prospective, single-blinded, two-armed, randomized controlled study was designed with three measurement time points including 90 children (6–17 years) and their parents. In the intervention group (IG), the children and their parents were shown a child-friendly video explaining the perioperative procedures that would be applied during the hospital stay, in addition to receiving standard information. In the control group (CG), children and parents received standard information provided by the nursing staff. The primary outcome was any change in the children's pre-operative state anxiety levels, as measured by the State-Trait Operation Anxiety Inventory (STOA). A secondary outcome was patient satisfaction regarding the received information.Results: Anxiety was significantly reduced in both groups after receiving either the intervention plus standard information or the standard information only. No significant difference in anxiety reduction was observed between the IG and the CG. However, the children and parents in the IG reported fewer worries than those in the CG.Conclusion: A child-friendly, educational video can be an additional tool for providing patient information and reducing pre-operative anxiety in children and their parents. Further studies should focus on the timing of the intervention and on age- and developmentally appropriate information formats and contents to address children's pre-operative anxiety.Clinical Trial Registration: Patient Anxiety Reduction in Children by Using Simple Explanation Videos, ID: NCT0441377; www.clinicaltrials.gov, Data Sharing Statement: Deidentified individual participant data will not be made available.

Objective: Sleep-disordered breathing (SDB) is a widespread disease that is often associated with heart failure (HF) with preserved ejection fraction (HFpEF). HFpEF is more frequent in women than in men, but detailed pathomechanisms remain unclear. We investigated HFpEF in women and men in a high-risk cohort with SDB monitoring.Methods and Results: Three hundred twenty-seven patients (84.4% men) undergoing elective coronary artery bypass grafting were prospectively subjected to SDB monitoring, and an apnea–hypopnea index (AHI) ≥15/h defined SDB. HF was classified according to current guidelines. HFpEF was significantly more frequent in SDB patients compared to those without SDB (28 vs. 17%, P = 0.016). This distribution was driven by an increased frequency of HFpEF in female SDB patients (48% vs. only 25% in male, P = 0.022). In accordance, female patients with SDB exhibited significantly more impaired diastolic left ventricular filling compared to men (echocardiographic E/e′). In contrast to men, in women, minimum oxygen saturation (O2min, measured by polygraphy, R2 = 0.470, P < 0.001) and time of oxygen saturation

The long-term mitigation of human–domestic animal–wildlife conflicts is complex and difficult. Over the last 50 yr, the primary biomedical concepts and actualized collaborative global field applications of oral rabies vaccination to wildlife serve as one dramatic example that revolutionized the field of infectious disease management of free-ranging animals. Oral vaccination of wildlife occurred in diverse locales within Africa, Eurasia, the Middle East, and North America. Although rabies is not a candidate for eradication, over a billion doses of vaccine-laden baits distributed strategically by hand, at baiting stations, or via aircraft, resulted in widespread disease prevention, control, or local disease elimination among mesocarnivores. Pure, potent, safe, and efficacious vaccines consisted of either modified-live, highly attenuated, or recombinant viruses contained within attractive, edible baits. Since the late 1970s, major free-ranging target species have included coyotes (Canis latrans), foxes (Urocyon cinereoargenteus; Vulpes vulpes), jackals (Canis aureus; Lupulella mesomelas), raccoons (Procyon lotor), raccoon dogs (Nyctereutes procyonoides), and skunks (Mephitis mephitis). Operational progress has occurred in all but the latter species. Programmatic evaluations of oral rabies vaccination success have included: demonstration of biomarkers incorporated within vaccine-laden baits in target species as representative of bait contact; serological measurement of the induction of specific rabies virus neutralizing antibodies, indicative of an immune response to vaccine; and most importantly, the decreasing detection of rabies virus antigens in the brains of collected animals via enhanced laboratory-based surveillance, as evidence of management impact. Although often conceived mistakenly as a panacea, such cost-effective technology applied to free-ranging wildlife represents a real-world, One Health application benefiting agriculture, conservation biology, and public health. Based upon lessons learned with oral rabies vaccination of mesocarnivores, opportunities for future extension to other taxa and additional diseases will have far-reaching, transdisciplinary benefits. [ABSTRACT FROM AUTHOR]

Abstract Several studies emphasized the potential of single and multiple transcranial random noise stimulation (tRNS) sessions to interfere with auditory cortical activity and to reduce tinnitus loudness. It was the objective of the present study to evaluate the use of high-frequency (hf) tRNS in a one-arm pilot study in patients with chronic tinnitus. Therefore, 30 patients received 10 sessions of high frequency tRNS (100-640 Hz; 2 mA; 20 minutes) over the bilateral temporal cortex. All patients had received rTMS treatment for their tinnitus at least 3 months before tRNS. Primary outcome was treatment response (tinnitus questionnaire reduction of ≥5 points). The trial was registered at clinicaltrials.gov (NCT01965028). Eight patients (27%) responded to tRNS. Exactly the same number of patients had responded before to rTMS, but there were only two “double responders” for both treatments. None of the secondary outcomes (tinnitus numeric rating scales, depressivity, and quality of life) was significant when results were corrected for multiple comparisons. tRNS treatment was accompanied by tolerable side effects but resulted in temporal increases in tinnitus loudness in 20% of the cases (2 drop-outs). Our trial showed that hf-tRNS is feasible for daily treatment in chronic tinnitus. However, summarizing low treatment response, increase of tinnitus loudness in 20% of patients and missing of any significant secondary outcome, the use of hf-tRNS as a general treatment for chronic tinnitus cannot be recommended at this stage. Differences in treatment responders between tRNS and rTMS highlight the need for individualized treatment procedures.

Introduction: Rabies is a serious, neglected tropical disease. Zoonotic agents are RNA viruses (Genus Lyssavirus, Family Rhabdoviridae), global in distribution. As an acute, progressive, incurable encephalitis, rabies has the highest case fatality of any infectious disease. Warm-blooded vertebrates are susceptible hosts. Major mammalian reservoirs include mesocarnivores and bats. Given wildlife perpetuation, rabies is not eradicable, but is preventable and controllable, especially under newly available international guidelines. Areas covered: Literature review over the past 5 years reveals development of sensitive, specific diagnostic tests and safe and highly effective human and veterinary vaccines. Yet, tens of thousands of human fatalities occur annually, usually in Africa and Asia, primarily after canine exposure. Human and domestic animal vaccination, before or after exposure, is the single greatest preventative strategy following a rabid animal bite. Expert opinion: Significant progress occurred during the twenty-first century regarding vaccine development, doses, and schedules. Remaining barriers to widespread rabies vaccination include an inter-related set of economic, cultural, social, educational, ecological and technological factors. A basic understanding of local and regional root causes of cases historically allows for broader accessibility to vaccination in a trans-disciplinary fashion to meet the global elimination of human rabies caused via dogs (GEHRD) by 2030.

Emergency physicians in the field are sometimes confronted with cases wherein patients cannot be intubated and ventilated. In some cases, cricothyrotomy, the method of choice for securing an emergency airway, may not have a successful outcome. We report a rare case of a 35-yearold male patient with avulsion of the larynx and a comminuted fracture of the jawbone, due to entrapment in a dung excavator. Prehospital tracheotomy was successfully performed. In cases with crush injuries to the larynx, anatomic structures, including the ligamentum conicum, are destroyed. In addition, massive subcutaneous emphysema blurs the anatomical key structures; hence, only a tracheotomy can prevent a lethal outcome.

Abstract Background The incidence of perioperative myocardial infarction is reported to 2–8%. The aim of the study (retrospectively registered) was to evaluate whether control coronary angiography after surgery is useful in case of suspected postoperative myocardial ischemia. Methods All patients who demonstrated signs of myocardial ischemia post CABG and underwent coronary angiography from 6/2008 to 06/2015 were retrospectively analyzed. Myocardial ischemia post CABG was defined as an increase of CK/CK-MB, occasionally associated with arrhythmias or low output syndrome. Results Overall, 108 patients (age 66 ± 9 years) demonstrated signs of myocardial ischemia post CABG and underwent coronary angiography corresponding to an incidence of 2.2%. Of them, 70 patients (65%) demonstrated graft pathologies. A therapeutic consequence was drawn in 62 Patients (57%), which consisted of redo surgery in 10 patients (9%) and PCI with stent placement in 52 patients (48%). Of the remaining 46 patients, 29 patients showed intact bypass grafts (27%), whereas 17 patients had minor pathologies (16%). Demographic data including the extent of the coronary artery disease, urgency of operation, comorbidities, EuroScore, surgical technique, postoperative lab tests and transfusion requirements were comparable among the groups. Redo surgery patients had prior PCI in 33% of patients, which was much higher than in the other groups. Patients with reintervention had a 30d-mortality rate of 13%, conservatively treated patients only 2.2%. Mortality was highest after redo surgery with 25%. Conclusions Postoperative coronary angiography is a useful tool with a significant therapeutic value. Pathological findings mandate further revascularization therapy in roughly half of the patients. PCI is a safe choice in the majority of patients, redo surgery is much less indicated.

Abstract Background Ligand-driven modulation of the mitochondrial translocator protein 18 kDa (TSPO) was recently described to dampen the neuroinflammatory response of microglia in a retinal light damage model resulting in protective effects on photoreceptors. We characterized the effects of the TSPO ligand XBD173 in the postischemic retina focusing on changes in the response pattern of the major glial cell types of the retina—microglia and Müller cells. Methods Retinal ischemia was induced by increasing the intraocular pressure for 60 min followed by reperfusion of the tissue in mice. On retinal cell types enriched via immunomagnetic separation expression analysis of TSPO, its ligand diazepam-binding inhibitor (DBI) and markers of glial activation were performed at transcript and protein level using RNA sequencing, qRT-PCR, lipid chromatography-mass spectrometry, and immunofluorescent labeling. Data on cell morphology and numbers were assessed in retinal slice and flatmount preparations. The retinal functional integrity was determined by electroretinogram recordings. Results We demonstrate that TSPO is expressed by Müller cells, microglia, vascular cells, retinal pigment epithelium (RPE) of the healthy and postischemic retina, but only at low levels in retinal neurons. While an alleviated neurodegeneration upon XBD173 treatment was found in postischemic retinae as compared to vehicle controls, this neuroprotective effect of XBD173 is mediated putatively by its action on retinal glia. After transient ischemia, TSPO as a marker of activation was upregulated to similar levels in microglia as compared to their counterparts in healthy retinae irrespective of the treatment regimen. However, less microglia were found in XBD173-treated postischemic retinae at 3 days post-surgery (dps) which displayed a more ramified morphology than in retinae of vehicle-treated mice indicating a dampened microglia activation. Müller cells, the major retinal macroglia, show upregulation of the typical gliosis marker GFAP. Importantly, glutamine synthetase was more stably expressed in Müller glia of XBD173-treated postischemic retinae and homeostatic functions such as cellular volume regulation typically diminished in gliotic Müller cells remained functional. Conclusions In sum, our data imply that beneficial effects of XBD173 treatment on the postischemic survival of inner retinal neurons were primarily mediated by stabilizing neurosupportive functions of glial cells.

Rabies is a devastating disease and affects millions of people globally, yet it is preventable with appropriate and timely postexposure prophylaxis (PEP). The current WHO exposure categories (Categories I, II, and III) need revision, with a special Category IV for severe exposures. Rare cases of PEP failure have occurred in severe bites to the head and neck. Multiple factors, including route, wound severity, depth, contamination, viral dose, proximity to highly innervated areas and the CNS, and the number of lesions, remain unconsidered. Injuries in areas of high neural density are the most significant considering lyssavirus pathophysiology. Current recommendations do not account for these factors. A Category IV designation would acknowledge the severity and the increased risk of progression. Subsequently, patient management would be optimized with wound care and the appropriate administration of rabies-immune globulin/monoclonal antibodies (RIG/MAbs). All Category IV exposures would be infiltrated with the full dose of intact RIG (i.e., human RIG or MAbs) if the patient was previously unvaccinated. More concentrated RIG/MAb formulations would be preferred. As a world rabies community, we cannot tolerate PEP failures. A fourth WHO categorization will improve the care of these high-risk patients and highlight the global health urgency of this neglected disease.

Abstract Since both Edvard Grieg’s 175th birthday and Norwegian military music’s 200th anniversary are celebrated in 2018, a first look at compositions by Grieg for military music was in order. As one of Norway’s most popular and beloved composers, his works made it into the different repertoires, despite not being known for military compositions; instead his popular pieces were adapted. Military music bands in Halden, Oslo, Kristiansand, Bergen, Trondheim and Harstad played arrangements of his compositions. Today the archive inventory catalogues at the Forsvarsmuseum in Oslo present a wide range of Grieg arrangements from different decades and Norwegian military music bands. Arrangements of Grieg’s Landkjending, Sigurd Jorsalfar, Olav Trygvason, the F-dur Sonate or Bergliot are natural parts of the Norwegian military music’s repertoire. Several conductors, as for example Ole Olsen and Oscar Borg, promoted Norwegian compositions as a way to strengthen Norwegian national identity. The questions the archive catalogues are to provide information about are, which bands played what, what are the similarities or differences, and perhaps even when were the compositions included into the respective repertoires, and whether they have a national agenda.