Anxiety and related disorders are a significant public-health burden with rising prevalence in the wake of the COVID-19 pandemic. As demand for effective anxiety treatment increases, so too does the ...need for strategies to bolster treatment outcomes. Research on the mechanisms of exposure therapy, the frontline behavioral treatment, will be critically important for optimizing clinical outcomes. We outline an initial agenda for future research on the mechanisms of change of exposure therapy, developed in collaboration with a large international team of researchers through the Exposure Therapy Consortium. Key questions and recommendations for future research focus on four priority areas: conceptualization, measurement, study design/analysis, and individual/contextual differences. Rising to the challenge of addressing these questions will require coordinated action and availability of centralized tools that can be used across trials, settings, and research groups.
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•First international survey on the patterns of care of re-irradiation.•Re-irradiation is predominantly employed in the brain, pelvis, and head and neck region.•Variable ...decision-making regarding minimum interval, contraindications and dose constraints.•Advanced radiation techniques and imaging are used, but dose accumulation methods diverge.•Prospective studies are needed to support evidence-based re-irradiation.
Re-irradiation is an increasingly utilized treatment for recurrent, metastatic or new malignancies after previous radiotherapy. It is unclear how re-irradiation is applied in clinical practice. We aimed to investigate the patterns of care of re-irradiation internationally.
A cross-sectional survey conducted between March and September 2022. The survey was structured into six sections, each corresponding to a specific anatomical region. Participants were instructed to complete the sections of their clinical expertise. A total of 15 multiple-choice questions were included in each section, addressing various aspects of the re-irradiation process. The online survey targeted radiation and clinical oncologists and was endorsed by the European Society for Radiotherapy and Oncology (ESTRO) and the European Organisation for Research and Treatment of Cancer (EORTC).
371 physicians from 55 countries across six continents participated. Participants had a median professional experience of 16 years, and the majority (60%) were affiliated with an academic hospital. The brain region was the most common site for re-irradiation (77%), followed by the pelvis (65%) and head and neck (63%). Prolonging local control was the most common goal (90–96% across anatomical regions). The most common minimum interval between previous radiotherapy and re-irradiation was 6–12 months (45–55%). Persistent grade 3 or greater radiation-induced toxicity (77–80%) was the leading contraindication. Variability in organs at risk dose constraints for re-irradiation was observed. Advanced imaging modalities and conformal radiotherapy techniques were predominantly used. A scarcity of institutional guidelines for re-irradiation was reported (16–19%). Participants from European centers more frequently applied thoracic and abdominal re-irradiation. Indications did not differ between academic and non-academic hospitals.
This study highlights the heterogeneity in re-irradiation practices across anatomical regions and emphasizes the need for high-quality evidence from prospective studies to guide treatment decisions and derive safe cumulative dose constraints.
Dual orexin receptor (OXR) antagonists (DORAs) such as almorexant, 1 (SB-649868), or suvorexant have shown promise for the treatment of insomnias and sleep disorders in several recent clinical trials ...in volunteers and primary insomnia patients. The relative contribution of antagonism of OX1R and OX2R for sleep induction is still a matter of debate. We therefore initiated a drug discovery project with the aim of creating both OX2R selective antagonists and DORAs. Here we report that the OX2R selective antagonist 26 induced sleep in mice primarily by increasing NREM sleep, whereas the DORA suvorexant induced sleep largely by increasing REM sleep. Thus, OX2R selective antagonists may also be beneficial for the treatment of insomnia.
Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection with a hospital mortality in excess of 40%. Along with insufficient and delayed empirical ...antimicrobial therapy, inappropriate antimicrobial exposure has been identified to negatively affect patient outcomes. Receipt of prolonged infusion (i.e. extended or continuous infusion) of piperacillin/tazobactam (TZP) improves antimicrobial exposure and is associated with reduced mortality in patients with sepsis. Using therapeutic drug monitoring (TDM) with dosing tailored to the altered pharmacokinetics of the individual patient to avoid under- and overdosing may be a further strategy to improve patient outcomes. This current trial will address the question whether a TDM-guided therapy with TZP administered by continuous infusion will result in a greater resolution of organ dysfunction and hence better clinical outcome compared to continuous infusion of the total daily dose of TZP without TDM.
The study is an investigator-initiated, multi-centre, parallel-group, single-blinded, randomised controlled trial. The trial will be conducted in several centres across Germany. Adult patients (aged ≥ 18 years) with severe sepsis or septic shock will be eligible for study participation. Participants will be randomly assigned to receive either TZP by continuous infusion guided by daily TDM of piperacillin (experimental group) or by continuous infusion without TDM guidance (total daily dose in normal renal function 13.5 g TZP) (control group). The pharmacokinetic (PK)/pharmacodynamic (PD) target will be 100% f T
(percentage of time during a dosing interval that the free f drug concentration exceeds 4 times the minimum inhibitory concentration). The primary efficacy endpoint is the change in mean total Sequential Organ Failure Assessment score from day 1 after randomisation until day 10 or discharge from the intensive care unit or death, whichever comes first. Secondary outcomes include mortality, clinical cure, microbiological cure, overall antibiotic use, individual components of the primary outcome, adverse events and analysis of PK and (PD) indices.
This trial will assess for the first time whether continuous infusion of TZP guided by daily TDM in patients with sepsis will result in a greater resolution of organ dysfunction and hence better clinical outcome compared to continuous infusion without TDM.
German Clinical Trials Register (GermanCTR), DRKS00011159 . Registered on 10 October 2016.
Critical care cardiology (CCC) in the modern era is shaped by a multitude of innovative treatment options and an increasingly complex, ageing patient population. Generating high-quality evidence for ...novel interventions and devices in an intensive care setting is exceptionally challenging. As a result, formulating the best possible therapeutic approach continues to rely predominantly on expert opinion and local standard operating procedures. Fostering the full potential of CCC and the maturation of the next generation of decision-makers in this field calls for an updated training concept, that encompasses the extensive knowledge and skills required to care for critically ill cardiac patients while remaining adaptable to the trainee's individual career planning and existing educational programs. In the present manuscript, we suggest a standardized training phase in preparation of the first ICU rotation, propose a modular CCC core curriculum, and outline how training components could be conceptualized within three sub-specialization tracks for aspiring cardiac intensivists.
Europa in der Krise Hoyer, Werner; Niepelt, Dirk
Ifo schnelldienst,
02/2015, Letnik:
68, Številka:
4
Journal Article
Odprti dostop
Was kann in Europa getan werden, damit Wachstumsprognosen der EU wieder nach oben korrigiert werden und die Wettbewerbsfähigkeit Europas wieder hergestellt wird? Nach Ansicht von Werner Hoyer, ...Präsident der Europäischen Investitionsbank, sollten die Schaffung günstiger Rahmenbedingungen sowie die Innovationsfähigkeit und ein ausreichendes Finanzierungsangebot für volkswirtschaftlich sinnvolle Investitionen im Fokus stehen. Das im November 2014 angekündigte Investitionspaket für Europa sei Teil einer Antwort auf diese Herausforderungen. Für Dirk Niepelt, Studienzentrum Gerzensee und Universität Bern, geht es auch um eine sinnvolle Zuordnung von Verantwortlichkeiten. Die Forderung nach »mehr Europa«, sei berechtigt, wenn es um die grenzüberschreitende Internalisierung wichtiger externer Effekte gehe, aber unberechtigt, wenn sie dem Subsidiaritätsprinzip zuwiderlaufe.
Europe in crisis Hoyer, Werner; Niepelt, Dirk
Ifo schnelldienst,
02/2015, Letnik:
68, Številka:
8-9
Journal Article
What can be done in Europe to achieve an upwards revision of EU growth forecasts and to restore Europe's competitiveness? According to Werner Hoyer, President of the European Investment Bank, the ...focus should be on the creation of favourable framework conditions, as well as the ability to innovate and an adequate financing offering for investments that make economic sense. The investment package for Europe announced in November 2014 is part of a response to these challenges. For Dirk Niepelt, Studienzentrum Gerzensee and University of Bern, this is also a question of sensibly assigning responsibility. Demands for 'more Europe', are justified in terms of a trans-border internalisation of important external effects, but unjustified if they contradict the subsidiarity principle.
Dual orexin receptor (OXR) antagonists (DORAs) such as almorexant, SB-649868, suvorexant (MK-4305), and filorexant (MK-6096), have shown promise for the treatment of insomnias and sleep disorders. ...Whether antagonism of both OX1R and OX2R is necessary for sleep induction has been a matter of some debate. Experiments using knockout mice suggest that it may be sufficient to antagonize only OX2R. The recent identification of an orally bioavailable, brain penetrant OX2R preferring antagonist 2-((1H-Indol-3-yl)methyl)-9-(4-methoxypyrimidin-2-yl)-2,9-diazaspiro5.5undecan-1-one (IPSU) has allowed us to test whether selective antagonism of OX2R may also be a viable strategy for induction of sleep. We previously demonstrated that IPSU and suvorexant increase sleep when dosed during the mouse active phase (lights off); IPSU inducing sleep primarily by increasing NREM sleep, suvorexant primarily by increasing REM sleep. Here, our goal was to determine whether suvorexant and IPSU affect sleep architecture independently of overall sleep induction. We therefore tested suvorexant (25 mg/kg) and IPSU (50 mg/kg) in mice during the inactive phase (lights on) when sleep is naturally more prevalent and when orexin levels are normally low. Whereas IPSU was devoid of effects on the time spent in NREM or REM, suvorexant substantially disturbed the sleep architecture by selectively increasing REM during the first 4 h after dosing. At the doses tested, suvorexant significantly decreased wake only during the first hour and IPSU did not affect wake time. These data suggest that OX2R preferring antagonists may have a reduced tendency for perturbing NREM/REM architecture in comparison with DORAs. Whether this effect will prove to be a general feature of OX2R antagonists vs. DORAs remains to be seen.
Orexin receptor antagonists represent attractive targets for the development of drugs for the treatment of insomnia. Both efficacy and safety are crucial in clinical settings and thorough ...investigations of pharmacokinetics and pharmacodynamics can predict contributing factors such as duration of action and undesirable effects. To this end, we studied the interactions between various "dual" orexin receptor antagonists and the orexin receptors, OX1R and OX2R, over time using saturation and competition radioligand binding with (3)H-BBAC ((S)-N-(1,1'-biphenyl-2-yl)-1-(2-((1-methyl-1H-benzodimidazol-2-yl)thio)acetyl)pyrrolidine-2-carboxamide). In addition, the kinetics of these compounds were investigated in cells expressing human, mouse and rat OX1R and OX2R using FLIPR® assays for calcium accumulation. We demonstrate that almorexant reaches equilibrium very slowly at OX2R, whereas SB-649868, suvorexant, and filorexant may take hours to reach steady state at both orexin receptors. By contrast, compounds such as BBAC or the selective OX2R antagonist IPSU ((2-((1H-Indol-3-yl)methyl)-9-(4-methoxypyrimidin-2-yl)-2,9-diazaspiro5.5undecan-1-one) bind rapidly and reach equilibrium very quickly in binding and/or functional assays. Overall, the "dual" antagonists tested here tend to be rather unselective under non-equilibrium conditions and reach equilibrium very slowly. Once equilibrium is reached, each ligand demonstrates a selectivity profile that is however, distinct from the non-equilibrium condition. The slow kinetics of the "dual" antagonists tested suggest that in vitro receptor occupancy may be longer lasting than would be predicted. This raises questions as to whether pharmacokinetic studies measuring plasma or brain levels of these antagonists are accurate reflections of receptor occupancy in vivo.
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