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Climate impact of anthropogenic activities is more and more of public concern. But while CO2 emissions are accounted in emissions trading and mitigation plans, emissions of non-CO2 components contributing to climate change receive much less attention. One of the anthropogenic emission sectors, where non-CO2 effects play an important part, is aviation. Hence, for a quantitative estimate of total aviation climate impact, assessments need to comprise both CO2 and non-CO2 effects (e.g., water vapor, nitrogen dioxide, and contrails), instead of calculating and providing only CO2 impacts. However, while a calculation of CO2 effects relies directly on fuel consumption, for non-CO2 effects detailed information on aircraft trajectory, engine emissions, and ambient atmospheric conditions are required. As often such comprehensive information is not available for all aircraft movements, a simplified calculation method is required to calculate non-CO2 impacts. In our study, we introduce a simple calculation method which allows quantifying climate assessment relying on mission parameters, involving distance and geographic flight region. We present a systematic analysis of simulated climate impact from more than 1000 city pairs with an Airbus A330-200 aircraft depending on the flight distance and flight region to derive simplified but still realistic representation of the non-CO2 climate effects. These new formulas much better represent the climate impact of non-CO2 effects compared to a constant CO2 multiplier. The mean square error decrease from 1.18 for a constant factor down to 0.24 for distance dependent factors and can be reduced even further to 0.19 for a distance and latitude dependent factor. [ABSTRACT FROM AUTHOR]

Background: The "Baveno classification" replaced the apnoea hypopnoea index (AHI) with symptoms and comorbidities for treatment indication in obstructive sleep apnoea (OSA). This study evaluates a modified Baveno classification which adds a validated cardiovascular disease (CVD) risk score and acknowledges severe breathing disturbances., Method: OSA patients from the European Sleep Apnoea Data Base (ESADA) were retrospectively allocated into CVD risk groups 1-3 based on SCORE-2 and the ESC guidelines. AHI ≥30 /h conferred strong treatment indication. When AHI was <30/h, symptoms and CVD risk dictated allocation to weak, intermediate or strong treatment indication group. Change in Epworth Sleepiness Scale (ESS) and office systolic blood pressure (SBP) at follow-up (12-24 months) under positive airway pressure (PAP) were assessed., Results: 8625 patients were analysed (29% female, age 56 [49;64] years, BMI 31.9 [28.4;36.3] kg·m -2 ). Treatment indication was weak in 501 (6%), intermediate in 2085 (24%) and strong in 6039 (70%). There was a continuous increase in age, SBP, C-reactive protein and glycosylated haemoglobin from weak to strong (p<0.001). PAP prescription increased from 52% to 64% to 93% (weak to strong, p<0.001). The change in ESS score was -2, -4 and -5, respectively (p<0.001). Reductions of ≥3 mmHg of median SBP occurred when AHI was ≥30/h and in symptomatic patients with CVD risk levels>1 when AHI was <30/h., Conclusion: This analysis provides supporting evidence for the key role of CVD risk assessment and severe breathing disturbances in the identification of OSA patients most likely to benefit from treatment., (Copyright ©The authors 2024. For reproduction rights and permissions contact permissions@ersnet.org.)

Background: Our centre followed a stepwise approach in the nonpharmacological treatment of respiratory failure in COVID-19 in accordance with German national guidelines, escalating non-invasive measures before invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO). The aim of this study was to analyse this individualized approach to non-pharmacologic therapy in terms of patient characteristics and clinical features that may help predict more severe disease, particularly the need for intensive care., Method: This retrospective single-centre study of COVID-19 inpatients between March 2020 and December 2021 analysed anthropometric data, non-pharmacological maximum therapy and survival status via a manual medical file review., Results: Of 1052 COVID-19-related admissions, 835 patients were included in the analysis cohort (54% male, median 58 years); 34% (n=284) received no therapy, 40% (n=337) conventional oxygen therapy (COT), 3% (n=22) high flow nasal cannula (NHFC), 9% (n=73) continuous positive airway pressure (CPAP), 7% (n=56) non-invasive ventilation (NIV), 4% (n=34) intermittent mandatory ventilation (IMV), and 3% (n=29) extracorporeal membrane oxygenation (ECMO). Of 551 patients treated with at least COT, 12.3% required intubation. A total of 183 patients required ICU treatment, and 106 (13%) died. 25 (74%) IMV patients and 23 (79%) ECMO patients died. Arterial hypertension, diabetes and dyslipidemia was more prevalent in non-survivors. Binary logistic analysis revealed the following risk factors for increased mortality: an oxygen supplementation of ≥2 L/min at baseline (OR 6.96 [4.01-12.08]), age (OR 1.09 [1.05-1.14]), and male sex (OR 2.23 [0.79-6.31])., Conclusion: The physician's immediate clinical decision to provide oxygen therapy, along with other recognized risk factors, plays an important role in predicting the severity of the disease course and thus aiding in the management of COVID-19., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

The serotonin pathway has long been proposed as a promising target for pulmonary arterial hypertension (PAH)-a progressive and uncurable disease. We developed a highly specific inhibitor of the serotonin synthesizing enzyme tryptophan hydroxylase 1 (TPH1), TPT-001 (TPHi). In this study, the authors sought to treat severe PAH in the Sugen/hypoxia (SuHx) rat model with the oral TPHi TPT-001. Male Sprague Dawley rats were divided into 3 groups: 1) ConNx, control animals; 2) SuHx, injected subcutaneously with SU5416 and exposed to chronic hypoxia for 3 weeks, followed by 6 weeks in room air; and 3) SuHx+TPHi, SuHx animals treated orally with TPHi for 5 weeks. Closed-chest right- and left heart catheterization and echocardiography were performed. Lungs were subject to histologic and mRNA sequencing analyses. Compared with SuHx-exposed rats, which developed severe PAH and right ventricular (RV) dysfunction, TPHi-treated SuHx rats had greatly lowered RV systolic (mean ± SEM: 41 ± 2.3 mm Hg vs 86 ± 6.5 mm Hg; P  < 0.001) and end-diastolic (mean ± SEM: 4 ± 0.7 mm Hg vs 14 ± 1.7 mm Hg; P  < 0.001) pressures, decreased RV hypertrophy and dilation (all not significantly different from control rats), and reversed pulmonary vascular remodeling. We identified perivascular infiltration of CD3 + T cells and proinflammatory F4/80 + and CD68 + macrophages and proliferating cell nuclear antigen-positive alveolar epithelial cells all suppressed by TPHi treatment. Whole-lung mRNA sequencing in SuHx rats showed distinct gene expression patterns related to pulmonary arterial smooth muscle cell proliferation (Rpph1, Lgals3, Gata4), reactive oxygen species, inflammation (Tnfsrf17, iNOS), and vasodilation (Pde1b, Kng1), which reversed expression with TPHi treatment. Inhibition of TPH1 with a new class of drugs (here, TPT-001) has the potential to attenuate or even reverse severe PAH and associated RV dysfunction in vivo by blocking the serotonin pathway., Competing Interests: This study was funded by the Federal Ministry of Education and Research (01KC2001B and 03VP08053 to Dr Hansmann; 01KC2001A, 03VP08051, and 16GW0298 to Dr Bader). Dr Hansmann also receives funding from the German Research Foundation (DFG KFO311 grant HA4348/6-2) and the European Pediatric Pulmonary Vascular Disease Network. Dr Nazaré has received funding from the Federal Ministry of Economic Affairs (ZIM grant 16KN073251). Drs Specker, Nazaré, Matthes, and Bader hold patents on the novel class of TPHi. Drs Specker, Wesolowski, and Bader are founders of Trypto Therapeutics GmbH. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Introduction: Advanced chronic obstructive pulmonary disease (COPD) is associated with chronic hypercapnic failure. The present work aimed to comprehensively investigate inspiratory muscle function as a potential key determinant of hypercapnic respiratory failure in patients with COPD., Methods: Prospective patient recruitment encompassed 61 stable subjects with COPD across different stages of respiratory failure, ranging from normocapnia to isolated nighttime hypercapnia and daytime hypercapnia. Arterialized blood gas analyses and overnight transcutaneous capnometry were used for patient stratification. Assessment of respiratory muscle function encompassed body plethysmography, maximum inspiratory pressure (MIP), diaphragm ultrasound, and transdiaphragmatic pressure recordings following cervical magnetic stimulation of the phrenic nerves (twPdi) and a maximum sniff manoeuvre (Sniff Pdi)., Results: Twenty patients showed no hypercapnia, 10 had isolated nocturnal hypercapnia, and 31 had daytime hypercapnia. Body plethysmography clearly distinguished patients with and without hypercapnia but did not discriminate patients with isolated nocturnal hypercapnia from those with daytime hypercapnia. In contrast to ultrasound parameters and transdiaphragmatic pressures, only MIP reflected the extent of hypercapnia across all three stages. MIP values below -48 cmH2O predicted nocturnal hypercapnia (area under the curve = 0.733, p = 0.052)., Conclusion: In COPD, inspiratory muscle dysfunction contributes to progressive hypercapnic failure. In contrast to invasive tests of diaphragm strength only MIP fully reflects the pathophysiological continuum of hypercapnic failure and predicts isolated nocturnal hypercapnia., (© 2024 S. Karger AG, Basel.)

Tryptophan hydroxylases catalyze the first and rate-limiting step in the biosynthesis of serotonin, a well-known neurotransmitter that plays an important role in multiple physiological functions. A reduction of serotonin levels, especially in the brain, can cause dysregulation leading to depression or insomnia. In contrast, overproduction of peripheral serotonin is associated with symptoms like carcinoid syndrome and pulmonary arterial hypertension. Recently, we developed a class of TPH inhibitors based on xanthine-benzimidazoles, characterized by a tripartite-binding mode spanning the binding sites of the cosubstrate pterin and the substrate tryptophan and by chelation of the catalytic iron ion. Herein, we describe the structure-based development of a second generation of xanthine-imidiazopyridines and -imidazothiazoles designed to inhibit TPH1 in the periphery while preventing the interaction with TPH2 in the brain. Lead compound 32 (TPT-004) shows superior pharmacokinetic and pharmacodynamic properties as well as efficacy in preclinical models of peripheral serotonin attenuation and colorectal tumor growth.

Inhalation therapy represents the standard of care in children, adolescents as well as in young, middle-aged and geriatric adults with asthma or chronic obstructive pulmonary disease. However, there are only few recommendations for the choice of inhalation devices, which consider both, age-specific limitations in young and geriatric patients. Transition concepts are lacking. In this narrative review, the available device technologies and the evidence for age-specific problems are discussed. Pressurized metered-dose inhalers may be favoured in patients who fulfill all cognitive, coordinative and manual power requirements. Breath-actuated metered-dose inhalers, soft-mist inhalers or the use of add-on devices such as spacers, face masks and valved holding chambers may be suitable for patients with mild to moderate impairments of these variables. In these cases, available resources of personal assistance by educated family members or caregivers should be used to allow metered-dose inhaler therapy. Dry powder inhalers may be reserved for patients with a sufficient peak inspiratory flow and good cognitive and manual abilities. Nebulizers may be indicated in persons who are either unwilling or unable to use handheld inhaler devices. After initiation of a specific inhalation therapy, close monitoring is essential to reduce handling mistakes. An algorithm is developed that considers age and relevant comorbidities to support the decision-making process for the choice of an inhaler device., (© 2023 The Authors. The Clinical Respiratory Journal published by John Wiley & Sons Ltd.)

Objective: The classification of anorexia nervosa (AN) into subtypes is relevant due to their different symptomatology. However, subtypes (restricting type: AN-R; purging type: AN-P) differ also in terms of their personality functioning. Knowledge about these differences would allow for better treatment stratification. A pilot study indicated differences in structural abilities that can be assessed by the operationalized psychodynamic diagnosis (OPD) system. The aim of this study was therefore to systematically explore differences in personality functioning and personality between the two AN subtypes and bulimia nervosa (BN) using three personality (functioning) constructs., Methods: A total of N = 110 inpatients with AN-R ( n = 28), AN-P ( n = 40), or BN ( n = 42) were recruited in three clinics for psychosomatic medicine. Assignment to the three groups was performed using a comprehensive questionnaire validated for diagnostic purposes (Munich-ED-Quest). Personality functioning was examined using OPD Structure Questionnaire (OPD-SQ), personality by using the Personality Inventory for DSM-5-Brief Form and Big Five Inventory-10. (M)ANOVAs were used to examine differences across eating disorder groups. In addition, correlation and regression analyses were conducted., Results: We observed differences on several sub- and main scales of the OPD-SQ. Whereas patients with BN showed the lowest levels, AN-R patients displayed the highest levels of personality functioning. On some sub- and main scales, such as "affect tolerance," the subtypes of AN differed from BN, whereas on the scale "affect differentiation," AN-R, differed from the other two groups. The total eating disorder pathology score of the Munich-ED-Quest best predicted overall personality structure [stand. β = 0.650; t (104) = 6.666; p < 0.001] and self-regulation [stand. β = 0.449; t (104) = 3.628; p < 0.001]., Discussion: Our findings confirm most of the results of the pilot study. These findings can facilitate the development of stratified treatment approaches for eating disorders., Competing Interests: The 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 © 2023 Rohde, Obbarius, Voigt, Sarrar, Biesenthal-Matthes, Kind, Rose and Hofmann.)

Background: Early intubation versus use of conventional or high-flow nasal cannula oxygen therapy (COT/HFNC), continuous positive airway pressure (CPAP), and non-invasive ventilation (NIV) has been debated throughout the COVID-19 pandemic. Our centre followed a stepwise approach, in concordance with German national guidelines, escalating non-invasive modalities prior to invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO), rather than early or late intubation., Objectives: The aims of the study were to investigate the real-life usage of these modalities and analyse patient characteristics and survival., Method: A retrospective monocentric observation was conducted of all consecutive COVID-19 hospital admissions between March 2020 and December 2021 at a university-affiliated pulmonary centre in Germany. Anthropometric data, therapy, and survival status were descriptively analysed., Results: From 1,052 COVID-19-related admissions, 835 patients were included (54% male, median 58 years). Maximum therapy was as follows: 34% (n = 284) no therapy, 40% (n = 337) COT, 3% (n = 22) HFNC, 9% (n = 73) CPAP, 7% (n = 56) NIV, 4% (n = 34) IMV, and 3% (n = 29) ECMO. Of 551 patients treated with at least COT, 12.3% required intubation. Overall, 183 patients required intensive unit care, and 106 (13%) died. Of the 68 patients who received IMV/ECMO, 48 died (74%). The strategy for non-pharmacological therapy was individual but remained consistent throughout the studied period., Conclusions: This study provides valuable insight into COVID-19 care in Germany and shows how the majority of patients could be treated with the maximum treatment required according to disease severity following the national algorithm. Escalation of therapy modality is interlinked with disease severity and thus associated with mortality., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Arbutin, the glucoside of hydroquinone, exists in two isomers, α-arbutin and β-arbutin. The synthetic α isomer is mainly used as a skin brightening agent, while β-arbutin occurs naturally, for instance in bearberry, and is used in drugs for treatment of lower urinary tract infections and as a food supplement. Since both isomers can be harmful at high concentrations, methods for their quantification are required. Classically they have been determined by reversed-phase chromatography, but separation of both isomers is often unsatisfactory. Here we present a simple and reliable method for quantification of α- and β-arbutin based on hydrophilic-interaction chromatography. Prior to analysis, interfering compounds that would frequently be present in cosmetics and drugs, particularly biopolymers, were efficiently removed by precipitation with acetonitrile. In this paper, for separation, a Cyclobond I 2000 5 µm 250 × 4.6 mm column was employed as stationary phase and acetonitrile/water 92/8 (v/v) was used as an eluent at a flow rate of 0.8 mL min−1. For quantification, a UV detector operating at 284 nm was applied. Although analysis took less than 10 min, baseline separation of α- and β-arbutin was achieved. The response was highly linear (r > 0.999) and the method had, for both α- and β-arbutin, a LOD of 0.003% (w/w) and a LOQ of 0.009% (w/w). Moreover, the method showed excellent intra-day and inter-day repeatability with relative standard deviations in the range of 0.5% to 2.3% and 1.0% to 2.2%, respectively, with cosmetics, drugs and food supplements as samples., Competing Interests: The authors declare no conflict of interest.

When to look for sleep disturbances in heart failure patients and how best to treat them: a practical and evidence-based expert opinion https://bit.ly/3LpCnNP., Competing Interests: Conflict of interest: S. Matthes has nothing to disclose. Conflict of interest: W. Randerath reports the following relationships outside the submitted work: consulting fees received from Jazz Pharmaceuticals (ongoing), Bioprojet (ongoing) and Philips (until 2021); payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing or educational events received from Jazz Pharmaceuticals, Bioprojet, Philips Respironics and Desitin (in 2020); and support for attending meetings and/or travel from Jazz Pharmaceuticals, Bioprojet and Philips Respironics., (Copyright ©ERS 2022.)

Tryptophan hydroxylases catalyze the first and rate-limiting step in the synthesis of serotonin. Serotonin is a key neurotransmitter in the central nervous system and, in the periphery, functions as a local hormone with multiple physiological functions. Studies in genetically altered mouse models have shown that dysregulation of peripheral serotonin levels leads to metabolic, inflammatory, and fibrotic diseases. Overproduction of serotonin by tumor cells causes severe symptoms typical for the carcinoid syndrome, and tryptophan hydroxylase inhibitors are already in clinical use for patients suffering from this disease. Here, we describe a novel class of potent tryptophan hydroxylase inhibitors, characterized by spanning all active binding sites important for catalysis, specifically those of the cosubstrate pterin, the substrate tryptophan as well as directly chelating the catalytic iron ion. The inhibitors were designed to efficiently reduce serotonin in the periphery while not passing the blood-brain barrier, thus preserving serotonin levels in the brain.

Human papillomavirus (HPV) causes 99% of cervical cancers. In the USA, HPV testing has recently been recommended as a stand-alone option for cervical cancer screening in women over 30 years of age. Yet, studies have shown low awareness of HPV testing. This study examines awareness and knowledge that US women possess regarding HPV testing using the social determinants of health (SDOH) framework. Women aged 30 to 65 years, without hysterectomy, completed an online survey (N = 812). The outcome variables included HPV testing awareness and HPV testing knowledge, a six-item validated scale. Predictor variables included three domains of the Healthy People 2020 SDOH framework: economic stability, education, and health and healthcare. Other important sociodemographic predictors were also included. Multiple logistic and linear regression identified variables associated with HPV testing awareness and knowledge, respectively. 62.4% of the women were aware of HPV testing, and the mean knowledge score was 2.8 (out of 6). Lower awareness and knowledge were observed in older women compared with younger women and among women who had either not received HPV vaccination or were unsure of their vaccination status. Higher education attainment was associated with greater awareness and knowledge. Also, women who had a well-woman visit in the last year had better knowledge. Findings from the study can be used to develop targeted prevention strategies and initiatives to improve HPV testing awareness and knowledge to help women make more informed health decisions and promote uptake of this screening tool., (© 2020. American Association for Cancer Education.)

Introduction: There is a general underappreciation of the spectrum of obesity-related breathing disorders and their consequences. We therefore compared characteristics of obese patients with eucapnic obstructive sleep apnea (OSA), OSA with obesity-related sleep hypoventilation (ORSH) or obesity hypoventilation syndrome (OHS) to identify the major determinants of hypoventilation., Patients and Methods: In this prospective, diagnostic study (NCT04570540), obese patients with OSA, ORSH or OHS were characterized applying polysomnography with transcutaneous capnometry, blood gas analyses, bodyplethysmography and measurement of hypercapnic ventilatory response (HCVR). Pathophysiological variables known to contribute to hypoventilation and differing significantly between the groups were specified as potential independent variables in a multivariable logistic regression to identify major determinants of hypoventilation., Results: Twenty, 43 and 19 patients were in the OSA, ORSH and OHS group, respectively. BMI was significantly lower in OSA as compared to OHS. The extent of SRBD was significantly higher in OHS as compared to OSA or ORSH. Patients with ORSH or OHS showed a significantly decreased forced expiratory volume in 1 s and forced vital capacity compared to OSA. HCVR was significantly lower in OHS and identified as the major determinant of hypoventilation in a multivariable logistic regression (Nagelkerke R 2  = 0.346, p = 0.050, odds ratio (95%-confidence interval) 0.129 (0.017-1.004))., Conclusion: Although there were differences in BMI, respiratory mechanics and severity of upper airway obstruction between groups, our data support HCVR as the major determinant of obesity-associated hypoventilation., (Copyright © 2022 Elsevier B.V. All rights reserved.)

A two-dimensional numerical model for self-propagating reactions in Al/Ni multilayer foils was developed. It was used to study thermal properties, convective heat loss, and the effect of initial temperature on the self-propagating reaction in Al/Ni multilayer foils. For model adjustments by experimental results, these Al/Ni multilayer foils were fabricated by the magnetron sputtering technique with a 1:1 atomic ratio. Heat of reaction of the fabricated foils was determined employing Differential Scanning Calorimetry (DSC). Self-propagating reaction was initiated by an electrical spark on the surface of the foils. The movement of the reaction front was recorded with a high-speed camera. Activation energy is fitted with these velocity data from the high-speed camera to adjust the numerical model. Calculated reaction front temperature of the self-propagating reaction was compared with the temperature obtained by time-resolved pyrometer measurements. X-ray diffraction results confirmed that all reactants reacted and formed a B2 NiAl phase. Finally, it is predicted that (1) increasing thermal conductivity of the final product increases the reaction front velocity; (2) effect of heat convection losses on reaction characteristics is insignificant, e.g., the foils can maintain their characteristics in water; and (3) with increasing initial temperature of the foils, the reaction front velocity and the reaction temperature increased.

Serotonin (5-hydroxytryptamine, 5-HT) is a crucial signal in the neurogenic niche of the hippocampus, where it is involved in antidepressant action. Here, we utilized a new transgenic rat model (TetO-shTPH2), where brain 5-HT levels can be acutely altered based on doxycycline (Dox)-inducible shRNA-expression. On/off stimulations of 5-HT concentrations might uniquely mirror the clinical course of major depression (e.g., relapse after discontinuation of antidepressants) in humans. Specifically, we measured 5-HT levels, and 5-HT metabolite 5-HIAA, in various brain areas following acute tryptophan hydroxylase 2 ( Tph2 ) knockdown, and replenishment, and examined behavior and proliferation and survival of newly generated cells in the dentate gyrus. We found that decreased 5-HT levels in the prefrontal cortex and raphe nuclei, but not in the hippocampus of TetO-shTPH2 rats, lead to an enduring anxious phenotype. Surprisingly, the reduction in 5-HT synthesis is associated with increased numbers of BrdU-labeled cells in the dentate gyrus. At 3 weeks of Tph2 replenishment, 5-HT levels return to baseline and survival of newly generated cells is unaffected. We speculate that the acutely induced decrease in 5-HT concentrations and increased neurogenesis might represent a compensatory mechanism.