Rapidly star-forming galaxies adjacent to quasars at redshifts exceeding 6.

The existence of massive (1011 solar masses) elliptical galaxies by redshift z ≈ 4 (refs 1, 2, 3; when the Universe was 1.5 billion years old) necessitates the presence of galaxies with star-formation rates exceeding 100 solar masses per year at z > 6 (corresponding to an age of the Universe of less than 1 billion years). Surveys have discovered hundreds of galaxies at these early cosmic epochs, but their star-formation rates are more than an order of magnitude lower. The only known galaxies with very high star-formation rates at z > 6 are, with one exception, the host galaxies of quasars, but these galaxies also host accreting supermassive (more than 109 solar masses) black holes, which probably affect the properties of the galaxies. Here we report observations of an emission line of singly ionized carbon ([C ii] at a wavelength of 158 micrometres) in four galaxies at z > 6 that are companions of quasars, with velocity offsets of less than 600 kilometres per second and linear offsets of less than 100 kiloparsecs. The discovery of these four galaxies was serendipitous; they are close to their companion quasars and appear bright in the far-infrared. On the basis of the [C ii] measurements, we estimate star-formation rates in the companions of more than 100 solar masses per year. These sources are similar to the host galaxies of the quasars in [C ii] brightness, linewidth and implied dynamical mass, but do not show evidence for accreting supermassive black holes. Similar systems have previously been found at lower redshift. We find such close companions in four out of the twenty-five z > 6 quasars surveyed, a fraction that needs to be accounted for in simulations. If they are representative of the bright end of the [C ii] luminosity function, then they can account for the population of massive elliptical galaxies at z ≈ 4 in terms of the density of cosmic space.

Hypothalamus enlargement in mood disorders.

OBJECTIVE: The purpose of this study was to determine, in vivo, whether the hypothalamus volume is reduced in patients with mood disorders. METHODS: The cross-sectional study included 20 unmedicated (MDDu) and 20 medicated patients with major depressive disorder, 21 patients with bipolar disorder, and 23 controls. Twenty of the controls were matched to the MDDu. Seven Tesla, T1-weighted magnetic resonance images were acquired and processed using methods specifically developed for high-precision volumetry of the hypothalamus. RESULTS: An overall group difference was observed for the left hypothalamus volume corrected for intracranial volume. Planned contrasts identified that the left hypothalamus was approximately 5% larger in each patient group compared with the control group. A paired t-test with the 20 matched pairs of MDDu and controls and without correction for covariates confirmed the larger left hypothalamus volume in MDDu. CONCLUSIONS: Contrary to our expectations, the hypothalamus volume was increased in patients with uni- and bipolar affective disorders. The effect was left-sided and independent of medication status or statistical correction for covariates. Supported by emerging evidence that the stress response may be related to structural and functional asymmetry in the brain, our finding suggests a crucial role of the hypothalamus in mood disorders.

Adverse obstetric history is not a risk factor for poor outcome after ventral rectopexy for obstructive defaecation syndrome.

AIM: Ventral rectopexy (VR) has gained popularity in the management of obstructive defaecation syndrome (ODS) due to a symptomatic rectocele ± intussusception. Data on the efficacy and safety of VR are variable and there are few predictors of successful outcome. This study aimed to examine whether or not an adverse obstetric history influenced the functional outcome following VR for ODS. METHOD: This was a retrospective study of a cohort of 76 consecutive patients who had undergone VR for ODS at a tertiary referral centre between 2012 and 2015. Patients were followed up by telephone questionnaire. The obstetric history and pre- and postoperative symptoms of ODS and faecal incontinence (FI) were obtained from telephone interviews. RESULTS: In this cohort, symptoms of ODS were significantly improved by surgery, with 56% of patients showing a reduction of symptoms of 50% or more (P < 0.001). Subgroup analysis demonstrated that a lower body mass index (BMI; 24.4 vs 27.3 kg/m2 ; P < 0.05) and shorter duration of symptoms (7 vs 10 years; P < 0.05) led to a better outcome. VR had no effect on FI. Obstetric factors such as foetal weight, instrumental delivery, episiotomy, perineal tear and total number of deliveries did not influence outcomes. CONCLUSION: Patients with a less straightforward obstetric history can be reassured that this should not adversely influence the functional outcome after VR for ODS. Colorectal surgeons who offer this surgery should warn patients with an elevated BMI or with longstanding symptoms that the operation may be less successful than for those with a lower BMI or shorter duration of symptoms.

[Pacemaker and MRI in clinical practice]. / Herzschrittmacher und MRT im klinischen Alltag.

The number of cardiac pacemaker wearers is continuously increasing in Germany as well as worldwide. The probability of indications for a magnetic resonance imaging (MRI) examination during the lifetime is approximately 50-75% for every person. An MRI examination is nowadays possible for pacemaker wearers under certain conditions. Due to the technical developments during the last 10 years certain MRI-conditional pacemakers are available. The recommendations of the German and American medical specialist societies currently allow an MRI examination in patients with conventional pacemakers beyond the approval conditions (off-label use) under prespecified conditions, based on the study data. This article summarizes the information on conditions of use and reprogramming strategies as well as on the study situation for the clinical routine.

[Attention deficit-hyperactivity disorder (ADHD) and comorbid mental disorders : ADHD-specific self-rating scales in differential diagnostics]. / Aufmerksamkeitsdefizit­/Hyperaktivitätssyndrom (ADHS) und komorbide psychische Erkrankungen : ADHS-spezifische Selbstbeurteilungsskalen bei der Differenzialdiagnostik.

BACKGROUND: It is still unclear how well the established attention deficit-hyperactive disorder (ADHD)-specific rating scales can differentiate between ADHD symptoms and symptoms of other mental disorders. METHODS: A total of 274 patients with suspected adult ADHD were extensively examined clinically and guideline-conform in an ADHD outpatient clinic. In 190 patients the diagnosis of ADHD could be made with certainty. The patients were also subsequently assessed according to the DSM IV criteria by self-rating scales on current (ADHS-SB, ASRS, CAARS) and retrospective (WURS-K) complaints. A binary logistic regression analysis was performed in order to extract from the questionnaires, which could best distinguish the diagnosis of ADHD from other mental disorders. RESULTS: The results showed that two self-rating scales (WURS-K and ADHS-SB) were sufficient to correctly diagnose ADHD in 83% of the patients examined with a sensitivity of 94% and specificity of 56%. CONCLUSION: The ADHD-specific self-rating scales are additionally useful for the diagnostic differentiation between ADHD-specific and other psychiatric symptoms in the clinical practice and can improve the safety of the diagnosis.

Chimeric rabies SADB19-VSVg-pseudotyped lentiviral vectors mediate long-range retrograde transduction from the mouse spinal cord.

Lentiviral vectors have proved an effective method to deliver transgenes into the brain; however, they are often hampered by a lack of spread from the site of injection. Modifying the viral envelope with a portion of a rabies envelope glycoprotein can enhance spread in the brain by using long-range axon projections to facilitate retrograde transport. In this study, we generated two chimeric envelopes containing the extra-virion and transmembrane domain of rabies SADB19 or CVS-N2c with the intra-virion domain of vesicular stomatitis virus. Viral particles were packaged containing a green fluorescent protein reporter construct under the control of the phosphoglycerokinase promoter. Both vectors produced high-titer particles with successful integration of the glycoproteins into the particle envelope and significant transduction of neurons in vitro. Injection of the SADB19 chimeric viral vector into the lumbar spinal cord of adult mice mediated a strong preference for gene transfer to local neurons and axonal terminals, with retrograde transport to neurons in the brainstem, hypothalamus and cerebral cortex. Development of this vector provides a useful means to reliably target select populations of neurons by retrograde targeting.

Discontinuation of clozapine: a 15-year naturalistic retrospective study of 320 patients.

OBJECTIVE: Clozapine is underutilized in the management of treatment-resistant schizophrenia. To understand contributing factors, we analyzed the frequency and causes of clozapine discontinuations that occurred over a 15-year period in a clinical setting. METHOD: Data were extracted from computerized records and from mandatory termination reports for discontinuation events 1993-2007. The reasons for termination were analyzed. RESULTS: Over half of the patients (n = 183/320; 57%) had at least one discontinuation (median time 609 days). The two most common causes for discontinuation were non-adherence (35%) and side-effects (28%). Hematological side-effects accounted for 45% of all side-effect associated discontinuations; most such patients remained eligible for clozapine treatment, and a significant fraction remained on clozapine after rechallenge. Central nervous system side-effects accounted for 35% of side-effect induced discontinuations. General factors significantly associated with discontinuation were African American race, older age at initiation of clozapine and less improvement in psychiatric symptoms. CONCLUSION: In addition to anticipating and addressing causes of non-adherence, psychiatrists should consider clozapine rechallenge in eligible patients and implement measures to mitigate clozapine-associated sedation, seizures, and other side-effects. Future studies should particularly address why African American and older patients may be more likely to discontinue clozapine.

[Assertive community treatment in patients with severe obsessive-compulsive disorders]. / Aufsuchende gemeindepsychiatrische Behandlung bei Patienten mit schweren Zwangsstörungen.

For the use of psychosocial treatments for severe mental illness, there is a high evidence level. Obsessive-compulsive disorders are accompanied by severe disabilities in one third of the cases, however, there is little scientific research on the use of psychosocial therapies in patients with obsessive-compulsive disorders. In the following, the concept of an outreaching multi-professional treatment based on the assertive community treatment (ACT) method for severe compulsive illnesses is presented and discussed based on two case studies. There was an obvious reduction in clinically rated severity of obsessive-compulsive disorder symptoms, as measured by the Yale-Brown obsessive-compulsive scale (Y-BOCS), over the course of ACT. Comparison between pre- and post-treatment states demonstrated a reduction in the total Y-BOCS score after the treatment (case 1: total Y-BOCS score 37 versus 26; case 2: total Y-BOCS score 36 versus 16).

Cognition in schizophrenia and schizo-affective disorder: impairments that are more similar than different.

BACKGROUND: Cognition is increasingly being recognized as an important aspect of psychotic disorders and a key contributor to functional outcome. In the past, comparative studies have been performed in schizophrenia and schizo-affective disorder with regard to cognitive performance, but the results have been mixed and the cognitive measures used have not always assessed the cognitive deficits found to be specific to psychosis. A set of optimized cognitive paradigms designed by the Cognitive Neuroscience Test Reliability and Clinical Applications for Schizophrenia (CNTRACS) Consortium to assess deficits specific to schizophrenia was used to measure cognition in a large group of individuals with schizophrenia and schizo-affective disorder. METHOD: A total of 519 participants (188 with schizophrenia, 63 with schizo-affective disorder and 268 controls) were administered three cognitive paradigms assessing the domains of goal maintenance in working memory, relational encoding and retrieval in episodic memory and visual integration. RESULTS: Across the three domains, the results showed no major quantitative differences between patient groups, with both groups uniformly performing worse than healthy subjects. CONCLUSIONS: The findings of this study suggests that, with regard to deficits in cognition, considered a major aspect of psychotic disorder, schizophrenia and schizo-affective disorder do not demonstrate major significant distinctions. These results have important implications for our understanding of the nosological structure of major psychopathology, providing evidence consistent with the hypothesis that there is no natural distinction between cognitive functioning in schizophrenia and schizo-affective disorder.

TB preventive therapy preferences among children and adolescents.

BACKGROUND: TB preventive therapy (TPT) is critical for ending TB, yet implementation remains poor. With new global guidelines expanding TPT eligibility and regimens, we aimed to understand TPT preferences among children, adolescents and caregivers.METHODS: We undertook a discrete choice experiment among 131 children, 170 adolescents and 173 caregivers, and conducted 17 in-depth interviews in 25 clinics in Cape Town, South Africa. The design included attributes for location, waiting time, treatment duration, dosing frequency, formulation/size, side effects, packaging and taste. Mixed-effects logistic regression models were used for analysis.RESULTS: Among children and caregivers, the number and size of pills, taste and side effects were important drivers of preferences. Among adolescents and caregivers, clinic waiting times and side effects were significant drivers of preferences. Adolescents expressed concerns about being stigmatised, and preferred services from local clinics to services delivered in the community. Dosing frequency and treatment duration were only significant drivers of choice among adolescents, and only if linked to fewer clinic visits.CONCLUSIONS: Introducing shorter TPT regimens in isolation without consideration of preferences and health services may not have the desired effect on uptake and completion. Developing TPT delivery models and formulations that align with preferences must be prioritised.

[The first clinical use of an Dynamic Registration Tool for Navigation in FESS]. / Der erste klinische Einsatz einer dynamischen (Nach-) Registrierung für die Navigation in der FESS.

BACKGROUND: The effective register accuracy in an situs issues a challenge to the employment of instrument navigation in the ENT Surgery. The idea of the initially determined process Dynamic Registration Supply (DRS) is to improve the register accuracy by the automatic, and interoperability of the register. MATERIALS AND METHODS: The aim was to determine clinical use of DRS. Opto-electrical system Navigation Panel Unit, vs. 4.0.0 with the functionality DRS was used. Experiments were carried out on 95 patients who had so called FESS. The data of a control group were available to researchers. The measuring log includes among other things following parameters: retooling time, cutting-suture time, frequency of use of the navigated pointer, frequency of additional registration. RESULTS: At least once during the procedure DRS has been activated in 85 of 95 interventions (89.5). The time required increased by 15% accumulated 189 s per intervention. The most frequently used additional registration was in the region of sphenoid sinus. The surgeons underlined that out of 95 surveys in 75 cases the DRS rendered the instrument navigation more precise, while 1% of 93 cases considered this function as unwanted. CONCLUSION: The first clinical study for use of an automatic algorithm for recognition and reduction of faulty registration of a CT, navigation was successful. The findings suggest that by using automatic intraoperative registration DRS consisting inaccuracy can be reduced. In practice this means an efficient quality improvement of the Navigation.

[Adjustment disorders in internal medicine diseases]. / Anpassungsstörungen bei internistischen Erkrankungen.

It is only possible to diagnose an adjustment disorder if there is an explicit connection to a stressful life event. Clinically this disorder is marked by a wide variability of symptoms (e.g. depressive mood, anxiety). The prodromal symptoms have not been unequivocally differentiated from those of other mental disorders and normal adaptation processes. Nevertheless, the diagnosis is often made in clinical practice and, in particular, in primary care. Against this background, its significance is to be examined in association with internal medicine diseases.

Hierarchical autoclassification of cryo-EM samples and macromolecular energy landscape determination.

BACKGROUND AND OBJECTIVE: Cryo-electron microscopy using single particle analysis is a powerful technique for obtaining 3D reconstructions of macromolecules in near native conditions. One of its major advances is its capacity to reveal conformations of dynamic molecular complexes. Most popular and successful current approaches to analyzing heterogeneous complexes are founded on Bayesian inference. However, these 3D classification methods require the tuning of specific parameters by the user and the use of complicated 3D re-classification procedures for samples affected by extensive heterogeneity. Thus, the success of these approaches highly depends on the user experience. We introduce a robust approach to identify many different conformations presented in a cryo-EM dataset based on Bayesian inference through Relion classification methods that does not require tuning of parameters and reclassification strategies. METHODS: The algorithm allows both 2D and 3D classification and is based on a hierarchical clustering approach that runs automatically without requiring typical inputs, such as the number of conformations present in the dataset or the required classification iterations. This approach is applied to robustly determine the energy landscapes of macromolecules. RESULTS: We tested the performance of the methods proposed here using four different datasets, comprising structurally homogeneous and highly heterogeneous cases. In all cases, the approach provided excellent results. The routines are publicly available as part of the CryoMethods plugin included in the Scipion package. CONCLUSIONS: Our results show that the proposed method can be used to align and classify homogeneous and heterogeneous datasets without requiring previous alignment information or any prior knowledge about the number of co-existing conformations. The approach can be used for both 2D and 3D autoclassification and only requires an initial volume. In addition, the approach is robust to the "attractor" problem providing many different conformations/views for samples affected by extensive heterogeneity. The obtained 3D classes can render high resolution 3D structures, while the obtained energy landscapes can be used to determine structural trajectories.

[The hypertensive emergency situation : Recommendations for initial drug therapy management]. / Der hypertensive Notfall : Empfehlungen zum initialen medikamentösen Therapiemanagement.

The hypertensive emergency situation is characterized by an acute-mostly life-threatening-blood pressure derailment with the risk of acute end organ damage. It is an acute manifestation of arterial hypertension, which manifests in a variety of symptoms. The etiology is in most cases long-term (chronic) hypertension as a result of low compliance or inadequate antihypertensive therapy. It can also occur as a first manifestation of arterial hypertension. It requires timely antihypertensive drug therapy, which should be initiated in an intensive or intermediate care unit. The choice of antihypertensive therapy regimen should be based on the underlying end organ damage. Fast-acting, easily controllable and intravenously administered substances should be preferred. The most commonly used substances (groups) are urapidil, nitroglycerin, beta blockers and short-acting calcium channel blockers. With a few exceptions, a deliberate, rapid reduction in blood pressure of no more than 20-25% of the initial value is sufficient for extracerebral causes. A subsequent systolic blood pressure target of 160/100 mm Hg should be aimed for within the next 2-6 h. An overly rapid drop in blood pressure can lead to reduced blood flow to the central nervous system due to changes in autoregulation. Exceptions to this rule are acute aortic dissection and flash pulmonary edema-in these cases, prompt blood pressure normalization should be achieved. The initial acute therapy should be followed by a more detailed investigation of the cause and a long-term therapy setting based on this.

Mental health over nine months during the SARS-CoV2 pandemic: Representative cross-sectional survey in twelve waves between April and December 2020 in Austria.

BACKGROUND: There is accumulating evidence about detrimental impacts of the pandemic on population mental health, but knowledge on risk of groups specifically affected by the pandemic and variations across time is still limited. METHODS: We surveyed approximately n=1,000 Austrian residents in 12 waves between April and December 2020 (n=12,029). Outcomes were suicidal ideation (Beck Suicidal Ideation Scale), depressive symptoms (Patient Health Questionnaire-9), anxiety (Hospital Anxiety Depression Scale), and domestic violence. We also assessed the perceived burden from the pandemic. Demographic and Covid-19 specific occupational and morbidity-related variables were used to explain outcomes in multivariable regression analyses, controlling for well-established risk factors of mental ill-health, and variations over time were analyzed. RESULTS: Young age, working in healthcare or from home, and own Covid-19 illness were consistent risk factors controlling for a wide range of known mental health risk factors. Time patterns in the perceived burden from Covid-19-related measures were consistent with the time sequence of restrictions and relaxations of governmental measures. Depressive and anxiety symptoms were relatively stable over time, with some increase of depression during the second phase of lockdowns. Domestic violence increased immediately after both hard lockdowns. Suicidal ideation decreased slightly over time, with a low during the second hard lockdown. Mental health indicators for women and young people showed some deterioration over time, whereas those reporting own Covid-19 illness improved. LIMITATIONS: Data from before the pandemic were not available. CONCLUSIONS: Among mental health outcomes, increases in domestic violence and, to some smaller extent, depressive symptoms, appeared most closely related to the timing of hard lockdowns. Healthcare staff, individuals working from home, those with Covid-19, as well as young people and women are non-traditional risk groups who warrant heightened attention in prevention during and in the aftermath of the pandemic.

Up on the Jaynes-Cummings ladder of a quantum-dot/microcavity system.

In spite of their different natures, light and matter can be unified under the strong-coupling regime, yielding superpositions of the two, referred to as dressed states or polaritons. After initially being demonstrated in bulk semiconductors and atomic systems, strong-coupling phenomena have been recently realized in solid-state optical microcavities. Strong coupling is an essential ingredient in the physics spanning from many-body quantum coherence phenomena, such as Bose-Einstein condensation and superfluidity, to cavity quantum electrodynamics. Within cavity quantum electrodynamics, the Jaynes-Cummings model describes the interaction of a single fermionic two-level system with a single bosonic photon mode. For a photon number larger than one, known as quantum strong coupling, a significant anharmonicity is predicted for the ladder-like spectrum of dressed states. For optical transitions in semiconductor nanostructures, first signatures of the quantum strong coupling were recently reported. Here we use advanced coherent nonlinear spectroscopy to explore a strongly coupled exciton-cavity system. We measure and simulate its four-wave mixing response, granting direct access to the coherent dynamics of the first and second rungs of the Jaynes-Cummings ladder. The agreement of the rich experimental evidence with the predictions of the Jaynes-Cummings model is proof of the quantum strong-coupling regime in the investigated solid-state system.

Adenovirally transferred p16INK4/CDKN2 and p53 genes cooperate to induce apoptotic tumor cell death.

Repression of cell cycle progression by tumor suppressors might provide a means for tumor therapy. Here we demonstrate that ectopic overexpression of the p16INK4/CDKN2 tumor suppressor from an adenovirus vector in various cell lines results in block of cell division and, subsequently, in a gradual reduction of the levels of the product of retinoblastoma susceptibility gene, pRb. Overexpression of p53 and p16INK4/CDKN2, but not p53 on its own, induces apoptotic death only in tumor cells. Simultaneous adenoviral transfer of p16 and p53 genes leads to inhibition of tumor growth in nude mice. These results suggest that combined delivery of two cooperating genes like p16 and p53 could be the basis for the development of a new strategy for cancer gene therapy.

Off-label use in Germany - a current appraisal of gynaecologic university departments.

OBJECTIVE: The off-label use, referring to the applicability of pharmaceutical drugs beyond the submitted and from the Federal Institute for Drugs and Medical Devices (BfArM, Bundesamt für Arzneimittel und Medizinprodukte) certified and approved administration, is the subject of controversial discussions. The application can be considered in case of severe illness - if no therapeutic alternatives are available - or it exists as a founded perspective for achieving therapeutic success. METHODS: A latitudinal study for evaluating the application of off-label use supplements was performed at 43 German university and academic teaching hospitals. Five doctors at each hospital applied off-label pharmaceutical drugs and were called upon to share their personal experience to the application of those medications. RESULTS: 75 (35%) questionnaires were returned out of 22 (51%) medical centres with 215 contacted physicians. Off-label use was common for 65 (91%) of the physicians. Only 9% of them obviate the application of off-label drugs. About a half of the medication is related to application in obstetrics (54%) and in most cases on an every day basis. Uterotonics were the most commonly used off-label medications (34%). The main part of information about off-label use is obtained from personal information of colleagues (66%) and personal experience (58%). 34% of physicians think that off label use is risky. Interestingly, the view about off label use of medication varies considerably among physicians from various hospitals. CONCLUSIONS: The application of off-label pharmaceutical drugs in Germany seems to be a well established practice. More than 90% of participators of our trial use at least one medication outside the administration. This includes particularly prostaglandins, anti-hypertonic therapeutics and chemotherapeutics.

[Influence of an auto-motorised optical navigation camera to the surgical workflow in ENT surgery]. / Die Auswirkungen einer robotergeführten Navigationskamera in der HNO-Chirurgie.

BACKGROUND: With the application of optical navigation systems an interruption of the line of sight (LOS) between navigation camera and the patient/instrument can occur. The goal of this work is the clinical evaluation of a newly developed system for automatic adjusting of an optical navigation camera (Navigation Camera Assistant, NCA). NCA is a miniature robot, which is able to position the navigation camera autonomously in 2 levels. MATERIAL AND METHODS: The influence of the NCA was examined on 128 patients: 55 procedures at the paranasal sinuses and 9 procedures at the temporal bone with the NCA were evaluated and compared with available workflow data of adequate surgeries without NCA. An optical navigation system of the 3 (rd) generation was used. The following parameters were recorded: Preparation time of the system, time of using the system, LOS-interruptions. RESULTS: The LOS-interruption decreased in the group of FESS with application of the NCA by 92%, in the group tympanic cavity by 85%. The number of corrective motions of the navigation camera was increased with application of the NCA in the group FESS by 73%, in the group tympanic cavity by 89%. The usage time of navigation increased with the application of the NCA in the group of FESS by 36%, in the group tympanic cavity by 16%. CONCLUSIONS: With a motorized navigation camera can be the interruption rate of LOS significantly improved at frontal and lateral skull base. The technical expenditure for installation of the NCA robot is little even during, for this reason there is the potential that this module can be established for the clinical practice.