Beyond immune escape:a variant surface glycoprotein causes suramin resistance in Trypanosoma brucei

Suramin is one of the first drugs developed in a medicinal chemistry program (Bayer, 1916), and it is still the treatment of choice for the hemolymphatic stage of African sleeping sickness caused by Trypanosoma brucei rhodesiense. Cellular uptake of suramin occurs by endocytosis, and reverse genetic studies with T. b. brucei have linked downregulation of the endocytic pathway to suramin resistance. Here we show that forward selection for suramin resistance in T. brucei spp. cultures is fast, highly reproducible and linked to antigenic variation. Bloodstream-form trypanosomes are covered by a dense coat of variant surface glycoprotein (VSG), which protects them from their mammalian hosts' immune defenses. Each T. brucei genome contains over 2000 different VSG genes, but only one is expressed at a time. An expression switch to one particular VSG, termed VSGSur , correlated with suramin resistance. Reintroduction of the originally expressed VSG gene in resistant T. brucei restored suramin susceptibility. This is the first report of a link between antigenic variation and drug resistance in African trypanosomes

Ecophysiological properties of three biological soil crust types and their photoautotrophs from the Succulent Karoo, South Africa

Background and Aims Biological soil crusts cover about one third of the terrestrial soil surfaces in drylands, fulfilling highly important ecosystem services. Their relevance to global carbon cycling, however, is still under debate. Methods We utilized CO2 gas exchange measurements to investigate the net photosynthetic response of combined cyanobacteria/cyanolichen-, chlorolichen- and moss-dominated biocrusts and their isolated photoautotrophic components to light, temperature, and water. The results were compared with field studies to evaluate their compatibility. Results Different biocrust types responded similarly, being inhibited by limited and excess water, saturated by increasing light intensities, and having optimum temperatures. Cyanobacteria/cyanolichen-dominated biocrusts reached their water optimum at lowest contents (0.52–0.78 mm H2O), were saturated at highest light intensities, and had a comparably high temperature optimum at 37 °C. Chlorolichen-dominated crusts had a medium water optimum (0.75–1.15 mm H2O), medium saturating light intensities and a moderate temperature optimum of 22 °C. Moss-dominated biocrusts had the highest water optimum (1.76–2.38 mm H2O), lowest saturating light intensities, and a similar temperature optimum at 22 °C. Isolated photoautotrophs responded similar to complete crusts, only isolated moss stems revealed much lower respiration rates compared to complete crusts. Conclusions In addition to their overall functional similarities, cyanobacteria/cyanolichen-dominated biocrusts appeared to be best adapted to predicted climate change of increasing temperatures and smaller precipitation events, followed by chlorolichen-dominated biocrusts. Moss-dominated biocrusts needed by far the largest amounts of water, thus likely being prone to anticipated climate change

Disagreement in primary study selection between systematic reviews on negative pressure wound therapy

<p>Abstract</p> <p>Background</p> <p>Primary study selection between systematic reviews is inconsistent, and reviews on the same topic may reach different conclusions. Our main objective was to compare systematic reviews on negative pressure wound therapy (NPWT) regarding their agreement in primary study selection.</p> <p>Methods</p> <p>This retrospective analysis was conducted within the framework of a systematic review (a full review and a subsequent rapid report) on NPWT prepared by the Institute for Quality and Efficiency in Health Care (IQWiG).</p> <p>For the IQWiG review and rapid report, 4 bibliographic databases (MEDLINE, EMBASE, The Cochrane Library, and CINAHL) were searched to identify systematic reviews and primary studies on NPWT versus conventional wound therapy in patients with acute or chronic wounds. All databases were searched from inception to December 2006.</p> <p>For the present analysis, reviews on NPWT were classified as eligible systematic reviews if multiple sources were systematically searched and the search strategy was documented. To ensure comparability between reviews, only reviews published in or after December 2004 and only studies published before June 2004 were considered.</p> <p>Eligible reviews were compared in respect of the methodology applied and the selection of primary studies.</p> <p>Results</p> <p>A total of 5 systematic reviews (including the IQWiG review) and 16 primary studies were analysed. The reviews included between 4 and 13 primary studies published before June 2004. Two reviews considered only randomised controlled trials (RCTs). Three reviews considered both RCTs and non-RCTs. The overall agreement in study selection between reviews was 96% for RCTs (24 of 25 options) and 57% for non-RCTs (12 of 21 options). Due to considerable disagreement in the citation and selection of non-RCTs, we contacted the review authors for clarification (this was not initially planned); all authors or institutions responded. According to published information and the additional information provided, most differences between reviews arose from variations in inclusion criteria or inter-author study classification, as well as from different reporting styles (citation or non-citation) for excluded studies.</p> <p>Conclusion</p> <p>The citation and selection of primary studies differ between systematic reviews on NPWT, particularly with regard to non-RCTs. Uniform methodological and reporting standards need to be applied to ensure comparability between reviews as well as the validity of their conclusions.</p

Association between solar insolation and a history of suicide attempts in bipolar I disorder

In many international studies, rates of completed suicide and suicide attempts have a seasonal pattern that peaks in spring or summer. This exploratory study investigated the association between solar insolation and a history of suicide attempt in patients with bipolar I disorder. Solar insolation is the amount of electromagnetic energy from the Sun striking a surface area on Earth. Data were collected previously from 5536 patients with bipolar I disorder at 50 collection sites in 32 countries at a wide range of latitudes in both hemispheres. Suicide related data were available for 3365 patients from 310 onset locations in 51 countries. 1047 (31.1%) had a history of suicide attempt. There was a significant inverse association between a history of suicide attempt and the ratio of mean winter solar insolation/mean summer solar insolation. This ratio is smallest near the poles where the winter insolation is very small compared to the summer insolation. This ratio is largest near the equator where there is relatively little variation in the insolation over the year. Other variables in the model that were positively associated with suicide attempt were being female, a history of alcohol or substance abuse, and being in a younger birth cohort. Living in a country with a state-sponsored religion decreased the association. (All estimated coefficients p <0.01). In summary, living in locations with large changes in solar insolation between winter and summer may be associated with increased suicide attempts in patients with bipolar disorder. Further investigation of the impacts of solar insolation on the course of bipolar disorder is needed.Peer reviewe

Variations in seasonal solar insolation are associated with a history of suicide attempts in bipolar I disorder

Background: Bipolar disorder is associated with circadian disruption and a high risk of suicidal behavior. In a previous exploratory study of patients with bipolar I disorder, we found that a history of suicide attempts was associated with differences between winter and summer levels of solar insolation. The purpose of this study was to confirm this finding using international data from 42% more collection sites and 25% more countries. Methods: Data analyzed were from 71 prior and new collection sites in 40 countries at a wide range of latitudes. The analysis included 4876 patients with bipolar I disorder, 45% more data than previously analyzed. Of the patients, 1496 (30.7%) had a history of suicide attempt. Solar insolation data, the amount of the sun’s electromagnetic energy striking the surface of the earth, was obtained for each onset location (479 locations in 64 countries). Results: This analysis confirmed the results of the exploratory study with the same best model and slightly better statistical significance. There was a significant inverse association between a history of suicide attempts and the ratio of mean winter insolation to mean summer insolation (mean winter insolation/mean summer insolation). This ratio is largest near the equator which has little change in solar insolation over the year, and smallest near the poles where the winter insolation is very small compared to the summer insolation. Other variables in the model associated with an increased risk of suicide attempts were a history of alcohol or substance abuse, female gender, and younger birth cohort. The winter/summer insolation ratio was also replaced with the ratio of minimum mean monthly insolation to the maximum mean monthly insolation to accommodate insolation patterns in the tropics, and nearly identical results were found. All estimated coefficients were significant at p &lt; 0.01. Conclusion: A large change in solar insolation, both between winter and summer and between the minimum and maximum monthly values, may increase the risk of suicide attempts in bipolar I disorder. With frequent circadian rhythm dysfunction and suicidal behavior in bipolar disorder, greater understanding of the optimal roles of daylight and electric lighting in circadian entrainment is needed

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

a randomized controlled clinical trial

Hintergrund: Dauerhafte Schmerzen im Lendenwirbelsäulenbereich sind in Deutschland häufige Anlässe für Arztbesuche und können Arbeitsunfähigkeit und die Inanspruchnahme von Rehabilitationsleistungen verursachen. Therapeutisch werden neben konservativen Herangehensweisen (Analgetika, Physiotherapie) zunehmend Multimodale Therapiekonzepte mit Komponenten der Psycho- und Entspannungstherapie untersucht. Meditation, als Teil der Mind-Body-Medizin (MBM), ist in ihrer Einsatzmöglichkeit für chronische Rückenschmerzen derzeit noch nicht weitgehend erschlossen. In der vorliegenden Studie wurde Meditation bei chronischen unspezifischen Lendenwirbelsäulenschmerzen vergleichend gegenüber herkömmlichen leichten physiotherapeutischen Übungen getestet. Methodik: Das randomisierte Studienkollektiv bestand aus 68 Teilnehmern (18-75 Jahre) mit Rückenschmerzen. Die durchschnittliche Schmerzintensität betrug mindestens 40mm auf der Visuellen Analogskala (VAS), die Schmerzdauer mehr als 3 Monate. Die Interventionsgruppe erhielt über 8 Wochen Meditationsgruppentreffen mit einem Meditationslehrer (1/Woche). Die Kontrollgruppe erhielt zu informativen Zwecken ein sog. Self-care book mit dem derzeitigen Standard der konventionellen Rückenschule. Als Hauptzielparameter diente die Veränderung der Schmerzintensität als Durchschnittswert der letzten 7 Tage. Die Auswertung erfolgte nach Interventionsende (8 Wochen) anhand der VAS, gemessen an 2 Meßpunkten (Studienbeginn und Interventionsende). Die Prüfung des Hauptzielparameters erfolgte konfirmatorisch für das Intention-to- treat-Kollektiv (ITT), in einem zweiten Schritt für die Per-Protocol- Population (PP). Als sekundäre Zielparameter dienten u.a. Fragebögen zur Erfassung der Stresswahrnehmung, Lebensqualität und Gemütslage (CPSS, SF-36, POMS, HADS). Ergebnisse: Der Hauptzielparameter, die durchschnittliche Schmerzintensität, belief sich zu Beginn der Studie in der Meditationsgruppe auf einen Mittelwert von 59.3 ± 13.9 mm, in der Kontrollgruppe auf 52.9 ± 11.8 mm. Während des Interventionszeitraumes kam es in beiden Gruppen analog zu einem Rückgang der zu Beginn der Studie angegeben Schmerzintensität der Rückenschmerzen. Der adjustierte Mittelwert lag in der Meditationsgruppe nach 8 Wochen Meditation bei 40.8 ± 21.8 mm und in der Kontrollgruppe bei 37.3 ± 18.2 mm (95% KI -11.6; 8.8). Gegenüber der Kontrollgruppe zeigte sich somit kein statistischer Gruppenunterschied zugunsten der Meditationsgruppe (p= 0.758). Bezüglich der Nebenzielparameter zeigte sich für die Meditationsgruppe eine signifikante Verbesserung hinsichtlich des gesundheitsbezogenen Stressempfindens (CPSS) nach 4 und 8 Wochen des Interventionszeitraumes. Zusammenfassung: Anhand der untersuchten Ergebnisse konnte kein signifikanter Gruppenunterschied des Hauptzielparameters, durchschnittliche Schmerzintensität der letzten 7 Tage, gemessen werden. Meditation erwies sich bei der Behandlung von Patienten mit chronischen unspezifischen Rückenschmerzen im LWS-Bereich in der vorliegenden Studie als wirksam, wenn auch nicht überlegen gegenüber einer leichten konventionellen Rückenschule. Die Bedeutung von Meditation in Hinblick auf die Möglichkeiten eines therapeutischen Einsatzes von meditativen Techniken bei chronischen unspezifischen Rückenschmerzen benötigt weitere Forschung auf diesem Gebiet.Background: In Germany, chronic unspecific back pain is a frequent cause for patients to seek medical treatment and is thus a burden for social and healthcare services. Besides conservative therapy approaches (analgetics, physiotherapy) multimodal therapy-concepts are of growing interest which combine elements of psychotherapy and relaxation techniques. One approach is meditation, which has not yet been fully validated as a treatment for chronic unspecific back pain. This study evaluated the efficacy of meditation for patients with chronic unspecific back pain between meditation technique compared to conventional therapy. Methodology: In a randomized trial, 68 patients (18-75 years old) with chronic back pain were included. Inclusion criteria were: a) Average pain intensity over the last seven days above 40 mm (Visual analog scale=VAS), b) pain duration longer than 3 months. The intervention-group had group meetings over 8 weeks (1/week) with a meditation teacher. The control-group received a self-care book with light, conventional exercise for the spine. The primary outcome measure was average pain intensity over the last seven days on VAS after 8 weeks. Evaluation was performed on VAS at two time points (start of study, end of intervention). The primary outcome measure was tested in a confirmatory fashion in an intention-to-treat analysis (ITT), in a second analysis in the per-protocol-population (PP). Subjective stress perception, quality of live and emotional stability of the participants were evaluated as secondary outcome measures. Results: Average pain intensity at the start of the study was 59.3 mm (adjusted mean; sd ± 13.9 mm) in the meditation-group and 52.9 mm (sd: ± 11.8 mm) in the control-group. Both groups showed similar reduction of pain from the beginning until the end of the trial. The adjusted pain intensity in the meditation-group reduced to 40.8 mm (sd: ± 21.8 mm) and in the control-group to 37.3 mm (sd: ± 18.2 mm; 95% KI -11.6; 8.8). Compared to the control group no significant differences were found (p= 0.758). For the secondary outcomes, positive differences favoring the mediation-group were found in stress perception (CPSS), which showed significant differences after 4 and 8 weeks. Conclusion: Although meditation reduced pain intensity in patients with chronic unspecific low back pain, light conventional physical exercise in the control-group achieved very similar results. Further research is required on meditation techniques in terms of their medical impact, their application on back pain and how they could be applied most effectively

Corpora in Translator Training - A Program for an eLearning Course

none3siWithin recent years, corpora have gained considerable importance in Translation Studies, and a number of studies have also appeared which show their value for translator training (e.g. Zanettin et al. 2003). However, results from a recent survey reveal that current practising and trainee translators still have insufficient awareness of corpora and expertise in using them to help in their translation workflow. In addition, while corpus linguistics courses are offered at some universities, no materials for self-learning are available to our knowledge: such materials might not only complement traditional courses, but would also be of special interest for professional translators, who are often under serious time constraints. This paper presents a free eLearning course on “Corpora for Translators” which has been developed by the EU-funded MeLLANGE project in an attempt to fill this gap. It deals with the use of corpora for different translation-related activities (e.g. source text analysis, translation proper, revision, terminology extraction) and is tailored to the needs of professional and trainee translators alike.mixedK. Kunz; S. Castagnoli; N. KüblerK. Kunz; S. Castagnoli; N. Küble

Orangutan mothers adjust their behaviour during food solicitations in a way that likely facilitates feeding skill acquisition in their offspring

Immature orangutans acquire their feeding skills over several years, via social and independent learning. So far, it has remained uninvestigated to what extent orangutan mothers are actively involved in this learning process. From a fitness point of view, it may be adaptive for mothers to facilitate their offspring’s skill acquisition to make them reach nutritional independence faster. Food solicitations are potential means to social learning which, because of their interactive nature, allow to investigate the degree of active involvement of the mother. To investigate the role of food solicitation and the role of the mother in immatures’ foraging skill acquisition, we analysed 1390 food solicitation events between 21 immature Sumatran orangutans (Pongo abelii) and their mothers, collected over 13 years at the Suaq Balimbing orangutan population. We found that solicitation rates decreased with increasing age of the immatures and increased with increasing processing complexity of the food item. Mothers were more likely to share complex items and showed the highest likelihoods of sharing around the age at which immatures are learning most of their feeding skills. Our results indicate that immature Sumatran orangutans use food solicitation to acquire feeding skills. Furthermore, mothers flexibly adjust their behaviour in a way that likely facilitates their offspring’s skill acquisition. We conclude that orangutan mothers have a more active role in the skill acquisition of their offspring than previously thought