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Background Anaesthetists need evidence-based clinical guidelines, also in obstetric anaesthesia. We compared the Danish, English, American, and German national guidelines for anaesthesia for Caesarean section. We focused on assessing the quality of guideline development and evaluation of the guidelines' content. Methods We compared the four countries' guideline developmental quality by using the Appraisal of Guidelines for Research and Evaluation ( AGREE) instrument, an international tool for development and assessment of guidelines. The clinically important content of these countries' guidelines was compared. Results We found differences in the quality of guideline development in the four countries. The German guidelines scored very low in the AGREE analysis, and the Danish national guideline scored low in the AGREE analysis. The American and British guideline both achieved high scores in the AGREE analysis. We found differences in the content of the four countries' guidelines. The Danish, American, and British guidelines were comprehensive but with some variation in the content. Conclusion Development of national guidelines might benefit from following standardised regulations, such as those used in the AGREE tool. Content of guidelines is not standardised. Recommendations for the content of guidelines might contribute to standardising clinical guidelines. [ABSTRACT FROM AUTHOR]

We evaluated the effects of acute pretreatment with lamotrigine, a putative glutamate release inhibitor, on the physiological and behavioral responses to intranasal cocaine in cocaine-dependent volunteers (N = 8). The study employed a double-blind, placebo-controlled, within-subject design. Subjects participated in six experimental sessions. On each study day, placebo, lamotrigine 125 mg, or lamotrigine 250 mg was administered orally in the morning, followed 2 hours later by intranasal cocaine 120 mg/70 kg or placebo. Measurements of heart rate and blood pressure were acquired, and subjects responded to mood state questionnaires at predetermined time intervals. Cocaine alone produced increases in heart rate, blood pressure, and several measures of pleasurable mood and drug effects. Lamotrigine alone produced a mild relaxing effect. Lamotrigine pretreatment altered neither the physiological responses nor the subjective ratings of cocaine's pleasurable or aversive mood effects. [ABSTRACT FROM AUTHOR]

Introduction: Preclinical studies suggest that cannabinoid receptor type 2 (CB2R) activation has a therapeutic effect in animal models on chronic inflammation and vascular permeability, which are key pathological features of diabetic retinopathy (DR). A novel CB2R agonist, triazolopyrimidine RG7774, was generated through lead optimization of a high-throughput screening hit. The aim of this study was to characterize the pharmacology, absorption, distribution, metabolism, elimination, and toxicity (ADMET) profile of RG7774, and to explore its potential for managing the key pathological features associated with retinal disease in rodents., Methods: The in vitro pharmacology of RG7774 was investigated for CB2R binding and receptor activation using recombinant human and mouse CB2R expression in Chinese hamster ovary cells, and endogenous CB2R expression in human Jurkat cells, and rat and mouse spleen cells. The ADMET profile was evaluated and the effects of RG7774 on retinal permeability, leukocyte adhesion, and choroidal neovascularization (CNV) were investigated in rodent models of retinal disease. Pharmacokinetic (PK) parameters and the exposure-response relationship were characterized in healthy animals and in animals with laser-induced CNV., Results: RG7774 was found to be a potent (EC 50 : 2.8 nM and K i : 51.3 nM), selective, and full CB2R agonist with no signs of cannabinoid receptor type 1 (CB1R) binding or activation. The ligand showed a favorable ADMET profile and exhibited systemic and ocular exposure after oral delivery. Functional potency in vitro translated from recombinant to endogenous expression systems. In vivo , orally administered RG7774 reduced retinal permeability and leukocyte adhesion in rodents with lipopolysaccharide (LPS)-induced uveitis and streptozotocin (STZ)-induced DR, and reduced lesion areas in rats with laser-induced CNV with an ED 50 of 0.32 mg/kg. Anatomically, RG7774 reduced the migration of retinal microglia to retinal lesions., Discussion: RG7774 is a novel, highly selective, and orally bioavailable CB2R agonist, with an acceptable systemic and ocular PK profile, and beneficial effects on retinal vascular permeability, leukocyte adhesion, and ocular inflammation in rodent animal models. Results support the development of RG7774 as a potential treatment for retinal diseases with similar pathophysiologies as addressed by the animal models., Competing Interests: UG, RF, SG, CK, AO, EZ, SU, MN, RM, CB, WG, AA, FR, AP, CP, AC, SF, CU: Employee: F. Hoffmann-La Roche Ltd. AK: Employee: Chugai Pharmaceuticals Co. Ltd. JT, NC, MR-E, SR, J-MA, JF: Employee: F. Hoffmann-La Roche Ltd., at the time of writing. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Grether, Foxton, Gruener, Korn, Kimbara, Osterwald, Zirwes, Uhles, Thoele, Colé, Rogers-Evans, Röver, Nettekoven, Martin, Adam, Fingerle, Bissantz, Guba, Alker, Szczesniak, Porter, Toguri, Revelant, Poirier, Perret, Winther, Caruso, Fezza, Maccarrone, Kelly, Fauser and Ullmer.)

Antibiotic development traditionally involved large Phase 3 programs, preceded by Phase 2 studies. Recognizing the high unmet medical need for new antibiotics and, in some cases, challenges to conducting large clinical trials, regulators created a streamlined clinical development pathway in which a lean clinical efficacy dataset is complemented by nonclinical data as supportive evidence of efficacy. In this context, translational Pharmacokinetic/Pharmacodynamic (PK/PD) plays a key role and is a major contributor to a "robust" nonclinical package. The classical PK/PD index approach, proven successful for established classes of antibiotics, is at the core of recent antibiotic approvals and the current antibacterial PK/PD guidelines by regulators. Nevertheless, in the case of novel antibiotics with a novel Mechanism of Action (MoA), there is no prior experience with the PK/PD index approach as the basis for translating nonclinical efficacy to clinical outcome, and additional nonclinical studies and PK/PD analyses might be considered to increase confidence. In this review, we discuss the value and limitations of the classical PK/PD approach and present potential risk mitigation activities, including the introduction of a semi-mechanism-based PK/PD modeling approach. We propose a general nonclinical PK/PD package from which drug developers might choose the studies most relevant for each individual candidate in order to build up a "robust" nonclinical PK/PD understanding.

Carbapenem-resistant Acinetobacter baumannii (CRAB) has emerged as a major global pathogen with limited treatment options 1 . No new antibiotic chemical class with activity against A. baumannii has reached patients in over 50 years 1 . Here we report the identification and optimization of tethered macrocyclic peptide (MCP) antibiotics with potent antibacterial activity against CRAB. The mechanism of action of this molecule class involves blocking the transport of bacterial lipopolysaccharide from the inner membrane to its destination on the outer membrane, through inhibition of the LptB 2 FGC complex. A clinical candidate derived from the MCP class, zosurabalpin (RG6006), effectively treats highly drug-resistant contemporary isolates of CRAB both in vitro and in mouse models of infection, overcoming existing antibiotic resistance mechanisms. This chemical class represents a promising treatment paradigm for patients with invasive infections due to CRAB, for whom current treatment options are inadequate, and additionally identifies LptB 2 FGC as a tractable target for antimicrobial drug development., (© 2024. The Author(s).)

The study aims to assess the concurrent validity of the SENS motion ® accelerometer system for device-based measurement of physical activity and sedentary behavior in healthy children and adolescents. Thirty-six healthy children and adolescents (mean ± standard deviation (SD) age, 10.2 ± 2.3 years) were fitted with three SENS sensors while performing standardized activities including walking, fast walking, sitting/lying, and arm movements. Data from the sensors were compared with video observations (reference criteria). The agreement between SENS motion ® and observation was analyzed using Student's t-test and illustrated in Bland-Altman plots. The concurrent validity was further evaluated using intraclass correlation coefficient (ICC) and was expressed as standard error of measurement (SEM) and minimal detectable change (MDC). Strong agreement was found between SENS and observation for walking time, sedentary time, and lying time. In contrast, moderate agreement was observed for number of steps, sitting time, and time with and without arm movement. ICC 2.1 values were overall moderate to excellent (0.5-0.94), with correspondingly low SEM% for walking time, sedentary time, lying time, and time with arm movement (2-9%). An acceptable SEM% level was reached for both steps and sitting time (11% and 12%). For fast walking time, the results showed a weak agreement between the measurement methods, and the ICC value was poor., Conclusion: SENS motion ® seems valid for detecting physical activity and sedentary behavior in healthy children and adolescents with strong agreement and moderate to excellent ICC values. Furthermore, the explorative results on arm movements seem promising., What Is Known: • Inactivity and sedentary behavior follow an increasing trend among children and adolescents. • SENS motion ® seems to be valid for measuring physical activity and sedentary behavior in adults and elderly patients., What Is New: • SENS motion ® seems valid with strong agreement between video observations and SENS measurement, and ICC values are moderate to excellent when measuring physical activity and sedentary behavior in healthy children and adolescents. • SENS motion ® seems promising for detection of arm movements., (© 2023. The Author(s).)

Many in vitro and in vivo models are used in pharmacological research to evaluate the role of targeted proteins in a disease. Understanding the translational relevance and limitation of these models for analyzing a drug's disposition, pharmacokinetic/pharmacodynamic (PK/PD) profile, mechanism, and efficacy, is essential when selecting the most appropriate model of the disease of interest and predicting clinically efficacious doses of the investigational drug. Selected animal models used in ophthalmology, infectious diseases, oncology, autoimmune diseases, and neuroscience are reviewed here. Each area has specific challenges around translatability and determination of an efficacious dose: new patient-specific dosing methods may help overcome these limitations., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Despite positive public attitudes toward solid organ donation in the United States, some of the lowest rates of donor designation persist among older adults and Latinx populations., Aims: To identify barriers and facilitators to organ donation and donor designation among lay health educators ( promotoras ) and mature Latina (50+ years)., Methods: An explanatory sequential mixed-method design was employed, with telephone surveys followed by focus group interviews, to assess and understand the nuances of organ donation and donor designation knowledge, attitudes, and practices among promotoras and mature Latinas in Chicago (IL), Philadelphia (PA), and San Antonio (TX). Descriptive statistics summarized quantitative survey data; thematic content analysis was performed on qualitative data., Results: Twenty-nine promotoras and 45 mature Latina participated in both the surveys and focus groups ( N = 74). Most participants (90%) had limited knowledge of organ donation but reported being "somewhat" or "strongly" in favor of donation (70%); 40.5% were registered donors. Participants lacked knowledge about the registration process and its legal standing and upheld concerns that registered donors would be vulnerable to organ traffickers or targets for murder. Themes emerging from the group interviews revealed additional barriers to designation including distrust of the medical establishment, perceptions of inequities in organ allocation, and family resistance to discussing death., Discussion: Low donor designation rates are primarily driven by concerns about organ trafficking and the fairness of the allocation system, particularly for undocumented immigrants., Conclusions: The results informed development of a culturally targeted educational and communication skills intervention to increase donor designation in Latinx communities., Trial Registration: ClinicalTrials.gov NCT04007419.

Objective: Exercise can improve treatment-related side effects, quality of life, and function in patients with various types of cancer; however, more evidence is needed for patients with advanced inoperable lung cancer., Material and Methods: We randomized 218 patients with advanced inoperable lung cancer to a 12-week supervised, structured exercise training program (aerobic, strength, and relaxation training) twice weekly versus usual care. Primary outcome was change in maximal oxygen uptake (VO 2 peak). Secondary outcomes were muscle strength, functional capacity, forced expiratory volume in 1 s, health-related quality of life, anxiety, and depression., Results: There was no significant difference between the intervention and control groups in VO 2 peak. There was a significant improvement in muscle strength. There was also a significant difference between the two for social well-being (Functional Assessment of Cancer Therapy-Lung, FACT-L), anxiety, and depression., Conclusion: There was a significant reduction in the level of anxiety and depression and a significant increase in all muscle strength outcomes in the intervention group compared to patients randomized to usual care. There was a significant difference between the groups for social well-being. The primary outcome did not show a significant improvement in VO 2 peak. Based on our results, future patients with advanced inoperable lung cancer should be considered for supervised exercise during the course of their disease., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: The SQ tree sublingual immunotherapy (SLIT)-tablet (ALK-Abelló, Hørsholm, Denmark) is developed for treatment of tree pollen-induced allergic rhinoconjunctivitis (ARC)., Objective: The aim of this pivotal phase III trial was to demonstrate the efficacy and safety of the SQ tree SLIT-tablet., Methods: This was a randomized, double-blind, placebo-controlled trial with 634 subjects (12-65 years) with moderate-to-severe ARC despite use of symptom-relieving medication. Eligible subjects were randomized 1:1 to active or placebo treatment. The primary end point was the average daily ARC total combined score (TCS) during the birch pollen season (BPS) analyzed for subjects with diary data during the BPS. Secondary end points included average daily symptom scores (DSS) during the BPS, average TCS and DSS during the tree pollen season (TPS), and average daily medication scores (DMS) in the BPS and TPS., Results: The primary and key secondary end points demonstrated statistically significant and clinically relevant effects of the SQ tree SLIT-tablet compared with placebo. For the BPS, absolute (relative) differences from placebo were 3.02 (40%) for TCS, 1.32 (37%) for DSS, and 1.58 (49%) for DMS (all P < .0001). For the TPS, absolute (relative) differences from placebo were 2.27 (37%) for TCS, 0.99 (33%) for DSS, and 1.20 (47%) for DMS (all P < .0001). Treatment was well tolerated. The most frequently reported treatment-related adverse events were mild or moderate local reactions related to sublingual administration., Conclusion: The trial demonstrated the efficacy and safety of the SQ tree SLIT-tablet compared with placebo during the BPS and TPS in adolescents and adults with birch pollen-induced ARC (EudraCT 2015-004821-15)., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: The SQ tree sublingual immunotherapy (SLIT)-tablet containing allergen extracts with the major allergen Bet v 1 from birch pollen is currently being developed for the treatment of tree pollen-induced allergic rhinitis/conjunctivitis with or without asthma. The aim of this Phase II trial was to investigate the dose-related efficacy and safety of the SQ tree SLIT-tablet., Methods: This study was a randomized, parallel-group, double-blind, placebo-controlled, multi-national trial conducted in Europe. A total of 637 participants were randomized equally to receive placebo or treatment with the SQ tree SLIT-tablet in doses of 0.5, 1, 2, 4, 7, or 12 development units (DU). Treatment was initiated ~16 weeks before onset of the 2013 birch pollen season (BPS) and was continued throughout the BPS with a total duration of at least 6 months. During the BPS and tree pollen season (TPS), subjects assessed rhinoconjunctivitis symptoms and medication use on a daily basis in an electronic diary; weekly assessments of rhinoconjunctivitis quality of life were also made., Findings: Analysis of the average daily symptom score during the BPS and the TPS showed that the difference between active treatment and placebo was statistically significant for the 7 DU group (BPS, P = 0.02; TPS, P = 0.03), with no clear dose-response relationship. All doses of the SQ tree SLIT-tablet induced changes from baseline in birch-specific IgE and IgG 4 that were statistically significant compared with placebo at all time points assessed (P < 0.0001) with a clear dose-response relationship for birch specific IgG 4 . In general, the SQ tree SLIT-tablet was well tolerated, with the majority of treatment-related adverse events (≥95%) being mild or moderate in severity. The most frequently reported treatment-related adverse events were generally related to the sublingual administration of the tablet (ie, they occurred in the oral cavity)., Implications: The results from this trial suggest that the SQ tree SLIT-tablet in doses up to 12 DU has a tolerability profile suitable for at-home administration. The immunomodulatory changes indicate a dose-response relationship, but clinical efficacy parameters were inconclusive, probably due to low pollen counts, emphasizing the importance of pollen exposure for the outcome of a pollen allergy immunotherapy trial. EudraCT no: 2012-000031-59., (Copyright © 2018 Elsevier HS Journals, Inc. All rights reserved.)

Background: Hairdressing is one of the professions with the highest risk of occupational skin and respiratory diseases. The incidence of these diseases in hairdressing apprentices has been studied only sparsely., Objective: To determine the incidence of skin and respiratory diseases in hairdressing apprentices, and to explore whether hairdressing apprentices leave the trade during training because of these diseases., Methods: A 3-year follow-up questionnaire study was conducted among 248 hairdressing apprentices and a control group comprising 816 young adults from the general population., Results: The incidence rate ratios (IRRs) for contact urticaria (IRR 4.7, 95%CI: 2.6-8.6), hand eczema (IRR 1.7, 95%CI: 1.1-2.6) and rhinitis symptoms (IRR 1.6, 95%CI: 1.2-2.2) were significantly increased in the hairdressing apprentices, whereas wheezing was similar between groups. During the follow-up period, 21.8% of the hairdressing apprentices had left the trade, and 70.3% of these had left because of health complaints. The most frequently reported reasons for leaving were musculoskeletal pain (47.4%) and skin diseases (47.4%), followed by respiratory symptoms (23.7%)., Conclusions: Hairdressing apprentices are at increased risk for contact urticaria, hand eczema and rhinitis symptoms compared with the general population, and a substantial proportion leave the trade because of these diseases, causing a 'healthy worker survivor effect.', (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Intranasal corticosteroids (INS) (corticosteroid nasal sprays) and oral antihistamines (OA) are two of the most common treatments for patients with allergic rhinitis (AR). To our knowledge, there are no systematic reviews on this topic including trials published after 2007., Objective: To compare INS with nonsedating OAs as treatments for AR., Methods: The systematic review and meta-analysis were based on the Grades of Recommendation, Assessment, Development, and Evaluation principles and the Patient, Intervention, Comparison, and Outcome approach. Primary literature was searched up to January 22, 2015. Criteria for eligibility were randomized controlled trials that compared the efficacy and/or adverse effects of INS and OA in patients with AR. Continuous outcome data were analyzed by using standardized mean differences (SMD) for multiple outcome measures, and mean differences in the case of a single study or outcome. Pooled estimates of effects, 95% confidence interval (CI), were calculated by using random-effects models., Results: The meta-analysis included five randomized controlled trials with a total of 990 patients. INS were superior to OAs in improving total nasal symptoms score (SMD -0.70 [95% CI, -0.93 to -0.47]) and in relieving the following: nasal obstruction (SMD -0.56 [95% CI, -0.82 to -0.29]), rhinorrhea (SMD -0.47 [95% CI, -1.00 to 0.05]), nasal itching (SMD -0.42 [95% CI, -0.65 to -0.18]), sneezing (SMD -0.52 [95% CI, -0.73 to -0.32]), and quality of life mean difference -0.90 [95% CI, -1.18 to -0.62]). There was no difference in relief of ocular symptoms (SMD -0.08 [95% CI, -0.23 to 0.08]). In addition, four randomized controlled trials were included in a narrative analysis. The results in the narrative analysis were comparable with those found in the meta-analysis., Conclusion: INS were superior to OAs in improving nasal symptoms and quality of life in patients with AR.

Background: Little is known about the occurrence of respiratory symptoms among hairdressing apprentices during their training. Therefore, in this study, we examined whether hairdressing apprentices are at increased risk of rhinitis and asthma symptoms when compared with other young adults from the general population., Methods: A questionnaire was completed by 504 hairdressing apprentices and 1400 control participants from the general population with a similar age, gender, and geographic distribution., Results: The 1-year prevalence of rhinitis symptoms was higher in hairdressing apprentices than in controls (58.1% vs 46.6%; odds ratio, 1.59; 95% confidence interval, 1.30-1.98), and the prevalence was higher among hairdressing apprentices in the last years of training compared with apprentices in the first year of training (62.4% vs 41.8%, p = 0.003). Current smoking was more common in hairdressing apprentices (28.4% vs 17.2%, p < 0.001). Asthma symptoms were equally common in the 2 groups; however, hairdressing apprentices had a later age of onset of wheezing than did the controls (18 years vs 14 years, p < 0.00001) and a decreased risk of wheezing (odds ratio, 0.72; 95% confidence interval, 0.54 to 0.95) after adjusting for smoking, education level, and degree of rurality. Bleaching products were the most frequently reported cause of rhinitis and asthma symptoms in hairdressing apprentices., Conclusions: Hairdressing apprentices seem to have an increased risk of occupational rhinitis, and bleaching products are the main cause of respiratory symptoms. In addition, our findings suggest that a healthy worker effect exists in relation to asthma among hairdressing apprentices., (© 2016 ARS-AAOA, LLC.)

Objective: The aim was to examine associations of age and gender with ADHD subtypes and subsequently to examine associations of age, gender, and subtypes with comorbid psychiatric disorders., Method: Odds ratios were calculated and logistic regression performed using information from a clinical sample of 155 ADHD adults referred to a Danish specialized ADHD unit from 2010 to 2011., Results: A majority of men (65%) was found in the sample. Most patients were subtyped ADHD combined (78%), followed by ADHD inattentive (18%), and ADHD hyperactive-impulsive (4%). No significant differences were found in gender and age across subtypes. Current comorbid disorders were found in 57% of the ADHD patients. Significantly more comorbidity was found in the ADHD combined type and in patients ≥25 years. Significantly more men had substance use disorders and significantly more women had personality disorders., Conclusion: When assessing adult ADHD patients' age, gender, subtype, and related comorbid symptom profiles should be taken into account., (© The Author(s) 2014.)

Objective: Knowledge of factors associated with treatment dropout and missed appointments in adults with attention-deficit/hyperactivity disorder (ADHD) is very limited. On the basis of proposed hypotheses that past behavior patterns are more predictive of current behaviors of treatment dropout and missed appointments than are sociodemographic and clinical characteristics, we examined the associations of sociodemographic variables, clinical variables, risk-taking behavior, educational and occupational instability, and behaviors during mandatory schooling with the primary outcome measures of treatment dropout and missed appointments., Method: In a naturalistic cohort study of 151 adult outpatients with ADHD initiating assessment in a Danish ADHD unit from September 1, 2010, to September 1, 2011, the Adult ADHD Self-Report Scale v1.1 symptom checklist (ASRS) and a thorough clinical interview were used to assess ADHD according to DSM-IV-TR criteria. Stepwise logistic regression analysis was used to estimate reported associations., Results: A total of 27% of patients dropped out of treatment and a total of 42% had ≥ 3 missed appointments during treatment. Mood and anxiety disorders significantly lowered the odds of treatment dropout (odds ratio [OR] = 0.18; 95% confidence interval [CI], 0.05-0.65), whereas having started but not completed 2 or more educational programs apart from mandatory schooling significantly increased the odds of dropout (OR = 3.01; 95% CI, 1.32-6.89). Variables significantly associated with most missed appointments were low educational level (OR = 2.19; 95% CI, 1.12-4.31), 3 or more employments of less than 3 months' duration (OR = 2.86; 95% CI, 1.30-6.28), and having skipped class often/very often during mandatory schooling (OR = 2.65; 95% CI, 1.29-5.43). Additionally, the predominantly inattentive ADHD (ADHD-I) subtype lowered the odds of missed appointments (OR = 0.17; 95% CI, 0.05-0.62)., Conclusion: Our results suggest that past behavior in terms of highest dropout rates in the educational and occupational systems and highest rates of skipping class during mandatory schooling is equally associated with current behavior of treatment dropout and missed appointments as are sociodemographic and clinical factors., Trial Registration: ClinicalTrials.gov identifier: NCT02226445., (© Copyright 2015 Physicians Postgraduate Press, Inc.)