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We conducted a randomized, controlled trial (RCT) to investigate our hypothesis that the interactive chatbot, Vitalk, is more effective in improving mental wellbeing and resilience outcomes of health workers in Malawi than the passive use of Internet resources. For our 2-arm, 8-week, parallel RCT (ISRCTN Registry: trial ID ISRCTN16378480), we recruited participants from 8 professional cadres from public and private healthcare facilities. The treatment arm used Vitalk; the control arm received links to Internet resources. The research team was blinded to the assignment. Of 1,584 participants randomly assigned to the treatment and control arms, 215 participants in the treatment and 296 in the control group completed baseline and endline anxiety assessments. Six assessments provided outcome measures for: anxiety (GAD-7); depression (PHQ-9); burnout (OLBI); loneliness (ULCA); resilience (RS-14); and resilience-building activities. We analyzed effectiveness using mixed-effects linear models, effect size estimates, and reliable change in risk levels. Results support our hypothesis. Difference-in-differences estimators showed that Vitalk reduced: depression (-0.68 [95% CI -1.15 to -0.21]); anxiety (-0.44 [95% CI -0.88 to 0.01]); and burnout (-0.58 [95% CI -1.32 to 0.15]). Changes in resilience (1.47 [95% CI 0.05 to 2.88]) and resilience-building activities (1.22 [95% CI 0.56 to 1.87]) were significantly greater in the treatment group. Our RCT produced a medium effect size for the treatment and a small effect size for the control group. This is the first RCT of a mental health app for healthcare workers during the COVID-19 pandemic in Southern Africa combining multiple mental wellbeing outcomes and measuring resilience and resilience-building activities. A substantial number of participants could have benefited from mental health support (1 in 8 reported anxiety and depression; 3 in 4 suffered burnout; and 1 in 4 had low resilience). Such help is not readily available in Malawi. Vitalk has the potential to fill this gap., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Kleinau et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Stress, burnout, and mental health problems such as depression and anxiety are common, and can significantly impact workplaces through absenteeism and reduced productivity. To address this issue, organizations must first understand the extent of the difficulties by mapping the mental health of their workforce. Online surveys are a cost-effective and scalable approach to achieve this but typically have low response rates, in part due to a lack of interactivity. Chatbots offer one potential solution, enhancing engagement through simulated natural human conversation and use of interactive features., Objective: The aim of this study was to explore if a text-based chatbot is a feasible approach to engage and motivate employees to complete a workplace mental health assessment. This paper describes the design process and results of a pilot implementation., Methods: A fully automated chatbot ("Viki") was developed to evaluate employee risks of suffering from depression, anxiety, stress, insomnia, burnout, and work-related stress. Viki uses a conversation style and gamification features to enhance engagement. A cross-sectional analysis was performed to gain first insights of a pilot implementation within a small to medium-sized enterprise (120 employees)., Results: The response rate was 64.2% (77/120). In total, 98 employees started the assessment, 77 of whom (79%) completed it. The majority of participants scored in the mild range for anxiety (20/40, 50%) and depression (16/28, 57%), in the moderate range for stress (10/22, 46%), and at the subthreshold level for insomnia (14/20, 70%) as defined by their questionnaire scores., Conclusions: A chatbot-based workplace mental health assessment seems to be a highly engaging and effective way to collect anonymized mental health data among employees with response rates comparable to those of face-to-face interviews., (©Ines Hungerbuehler, Kate Daley, Kate Cavanagh, Heloísa Garcia Claro, Michael Kapps. Originally published in JMIR Formative Research (https://formative.jmir.org), 21.04.2021.)

Background: Mental health difficulties are highly prevalent, yet access to support is limited by barriers of stigma, cost, and availability. These issues are even more prevalent in low- and middle-income countries, and digital technology is one potential way to overcome these barriers. Digital mental health interventions are effective but often struggle with low engagement rates, particularly in the absence of human support. Chatbots could offer a scalable solution, simulating human support at a lower cost. Objective: To complete a preliminary evaluation of engagement and effectiveness of Vitalk, a mental health chatbot, at reducing anxiety, depression and stress. Methods: Real world data was analyzed from 3,629 Vitalk users who had completed the first phase of a Vitalk program ("less anxiety," "less stress" or "better mood"). Programs were delivered through written conversation with a chatbot. Engagement was calculated from the number of responses sent to the chatbot divided by days in the program. Results: Users sent an average of 8.17 responses per day. For all three programs, target outcome scores reduced between baseline and follow up with large effect sizes for anxiety (Cohen's d = -0.85), depression (Cohen's d = -0.91) and stress (Cohen's d = -0.81). Increased engagement resulted in improved post-intervention values for anxiety and depression. Conclusion: This study highlights a chatbot's potential to reduce mental health symptoms in the general population within Brazil. While findings show promise, further research is required., Competing Interests: IH, KD, and MK are employees of TNH Health. TNH Health created the chatbot and paid for the cost of submitting the publication. 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 © 2020 Daley, Hungerbuehler, Cavanagh, Claro, Swinton and Kapps.)

Proton magnetic resonance spectroscopy ((1)H-magnetic resonance spectroscopy (MRS)) is a translational modality with great appeal for neuroscience since the two major excitatory and inhibitory neurotransmitters, glutamate, and GABA, can be noninvasively quantified in vivo and have served to explore disease state and effects of drug treatment. Yet, if (1)H-MRS shall serve for decision making in preclinical pharmaceutical drug discovery, it has to meet stringent requirements. In particular, (1)H-MRS needs to reliably report neurobiologically relevant but rather small changes in neurometabolite levels upon pharmacological interventions and to faithfully appraise target engagement in the associated molecular pathways at pharmacologically relevant doses. Here, we thoroughly addressed these matters with a three-pronged approach. Firstly, we determined the sensitivity and reproducibility of (1)H-MRS in rat at 9.4 Tesla for detecting changes in GABA and glutamate levels in the striatum and the prefrontal cortex, respectively. Secondly, we evaluated the neuropharmacological and neurobiological relevance of the MRS readouts by pharmacological interventions with five well-characterized drugs (vigabatrin, 3-mercaptopropionate, tiagabine, methionine sulfoximine, and riluzole), which target key nodes in GABAergic and glutamatergic neurotransmission. Finally, we corroborated the MRS findings with ex vivo biochemical analyses of drug exposure and neurometabolite concentrations. For all five interventions tested, (1)H-MRS provided distinct drug dose-effect relationships in GABA and glutamate over preclinically relevant dose ranges and changes as low as 6% in glutamate and 12% in GABA were reliably detected from 16 mm(3) volumes-of-interest. Taken together, these findings demonstrate the value and limitation of quantitative (1)H-MRS of glutamate and GABA for preclinical pharmaceutical research in mental disorders.

Glucagon, an essential regulator of glucose homeostasis, also modulates lipid metabolism and promotes weight loss, as reflected by the wasting observed in glucagonoma patients. Recently, coagonist peptides that include glucagon agonism have emerged as promising therapeutic candidates for the treatment of obesity and diabetes. We developed a novel stable and soluble glucagon receptor (GcgR) agonist, which allowed for in vivo dissection of glucagon action. As expected, chronic GcgR agonism in mice resulted in hyperglycemia and lower body fat and plasma cholesterol. Notably, GcgR activation also raised hepatic expression and circulating levels of fibroblast growth factor 21 (FGF21). This effect was retained in isolated primary hepatocytes from wild-type (WT) mice, but not GcgR knockout mice. We confirmed this link in healthy human volunteers, where injection of natural glucagon increased plasma FGF21 within hours. Functional relevance was evidenced in mice with genetic deletion of FGF21, where GcgR activation failed to induce the body weight loss and lipid metabolism changes observed in WT mice. Taken together, these data reveal for the first time that glucagon controls glucose, energy, and lipid metabolism at least in part via FGF21-dependent pathways.

Rationale: LY354740 is a recently developed metabotropic glutamatergic receptor 2 and 3 (mGluR2/3) agonist. A high density of mGluR2 has been reported in terminal fields of the perforant path in rodents and humans, suggesting its involvement in cognitive functions mediated by the temporal lobe, including memory. A small number of in vivo studies in rodents have assessed the effects of LY354740 on memory tasks, reporting the induction of impaired memory for spatial orientation in a water maze task and for delayed match and non-match to position in an operant version of these tasks., Objective: In the present primate study, we used radioautography to describe the distribution and intensity of (3)H-LY354740 binding in the hippocampal formation of the common marmoset monkey (Callithrix jacchus) relative to the rat. In the major, in vivo part of the study, the effects of systemic LY354740 on computerized tasks of attention and memory were investigated., Methods: Adult common marmosets were trained to perform a five-choice serial reaction time (5-CSRT) task and a concurrent delayed match-to-position (CDMP) task from the Cambridge Neuropsychological Automated test Battery (CANTAB). Filter tests of LY354740 effects on motor dexterity and motivation for reward revealed high inter-individual variation in sensitivity; therefore, on the 5-CSRT, subjects were tested at a dose range of 3--10 mg/kg, and on the CDMP, subjects were tested at 1--3 or 3--10 mg/kg., Results: Radioautography revealed a relatively low level of (3)H-LY354740 binding in the marmoset hippocampal formation compared to the rat. Despite low binding, LY354740 reduced sustained-attention accuracy in the 5-CSRT, and reduced accuracy in two stages of the CDMP., Conclusions: The current study provides novel evidence for the importance of mGluR2/3 in the regulation of primate cognitive functioning.

In the current investigation, the alkaloid colchicine was administered intravenously to male Wistar rats both as a solution in isotonic sodium chloride (NaCl 0.9%, control group) and in NaCl 0.9%:Solutol HS 15 (95:5) at 1.5 mg/kg. At predetermined time points, plasma and urine were collected from the animals and analysed for colchicine and its demethylated metabolites by LC/MS-MS. In the presence of Solutol HS 15, colchicine clearance (CI) was significantly decreased and its maximum plasma concentration (c(max)) was significantly increased as compared to the control group (CI: 15.6+/-7.0 ml/min/kg vs 34.3+/-2.3 ml/min/kg; c(max) 3055.1+/-587.4 h vs 1260.1+/-223.7 h; p<0.05). Moreover, the amount of parent colchicine excreted into urine was markedly increased in the Solutol HS 15 treated group (41.50+/-3.23 vs 1.17+/-0.41% of total dose; p<0.05). By contrast, there was no statistically significant difference but a trend to lower values only in the volume of distribution (V(d) 13.3+/-2.2 l/h vs 31.4+/-17.7 l/h, p=0.35). The half-lives for the first (t(1/2 1stphase). 0.21+/-0.02 h vs 0.20+/-0.03 h) and second phase (t(1/2 2ndphase). 18.5+/-6.9 h vs 18.3+/-7.7 h) did not differ significantly in dependence on the dosing vehicle. The free fraction in rat plasma (FF), the blood/plasma (lambda) and erythrocyte/plasma concentration ratios (K(e)) were not significantly changed in the presence of different concentrations of Solutol HS 15 compared with surfactant-free incubations (overall means: 72.25+/-0.50% for FF, 0.80+/-0.02 for lambda, 0.46+/-0.04 for K(e)). In vitro, in rat hepatocytes, the clearance of colchicine was significantly reduced at 0.003% Solutol HS 15 present in the incubation medium (0.86+/-0.15 microl/min/10(-6) cells vs 1.46+/-0.06 microl/min/10(-6) cells). As colchicine exhibits a comparatively high aqueous solubility, an impact of Solutol HS 15 on the solubility of the alkaloid is very unlikely to be a reason for the observed effect. Therefore, our results indicate that the most likely reasons for the changed pharmacokinetic behaviour of colchicine in the presence of Solutol HS 15 are alterations of metabolism and/or transport as well as distribution and elimination processes., (Copyright 2003 John Wiley & Sons, Ltd.)

A case of occupational asthma associated with rhinitis and conjunctivitis occurred in a patient working in a textile factory and exposed to different coloring reagents is reported. Symptoms appeared in phases correlated with changes in the use of the coloring reagents. Prick tests were carried out with the different coloring reagents and were positive for the yellow color. The test was followed by a clear increase in bronchial hyperreactivity to methacholine. Some individual preventive measures, such as wearing a face mask, led to reduction then disappearence of the symptoms.

1. In the present study, in vivo pharmacokinetic data in animals were combined with in vitro metabolic data from animal and human hepatocytes to predict the human systemic plasma clearance and the kinetic profile of tolcapone, a compound metabolized by phase II reactions. 2. The integration of in vitro metabolic data from hepatocytes into allometric scaling gave satisfactory predictions of metabolic clearance in humans for tolcapone (74.2 ml/min predicted versus 118 ml/min observed). 3. Using combined time transformations and in vitro metabolic rates, the range of values predicted from the various animal species (90.4 to 242 ml/min, 0.60 to 2.2 h and 7.3 to 121 for clearance, half-life and volume of distribution, respectively) were in good agreement with the observed values in humans (118 ml/min, 1.3 h and 8.6 h, respectively). 4. Compared to the conventional correction factors (e.g. maximum life span, brain weight), in vitro metabolic data provide a more rational basis for extrapolating the metabolic clearance in humans.

The role of fog in the symptomatology in asthmatic subjects has been assessed by a questionnaire concerning respiratory complaints linked to meteorological conditions and to non-specific irritant factors. In a population of 121 asthmatics (59 men and 62 women) 74.4% complained that fog was a factor aggravating their symptoms while only 3% of a group of 30 non-asthmatic subjects expressed discomfort during episodes of fog. The chemical analysis of fog during 32 episodes of local fog (pH, chloride, nitrate, sulphate, sodium, ammonia, potassium, magnesium, calcium) has shown a greater concentration of pollutants and greater acidity in the smaller particles (2-6 microns) which are able to penetrate the bronchial tree. This acidity could explain the role of fog in respiratory physiology. Certain authors have suggested that the aggravation of respiratory symptoms observed during peaks of pollution could be induced by aerosols containing sulphuric acid while others have described effects on respiratory function at the time of exposure to acid aerosols in asthmatic subjects but the results of the different studies have not all been concordant. Putting aside the role of the susceptible individual, other factors may intervene at the time inhalation of pollutants, notably the ambient humidity, the neutralising effect of endogenous ammonia and the synergystic effect between acid aerosols and atmospheric pollutants.

We report a case of isocyanate induced asthma in a patient who had been previously exposed to isocyanate and had become a porter in a factory producing polyurethene foam. The test for exposure to TDI was positive. The recognition of occupational asthma was nevertheless challenged and the patient was not considered to be carrying out work involving exposure to the inhalation of isocyanates. The effect of a change of job in the development of occupational asthma, and the risk of asthma induced by isocyanates despite inhaled concentrations inferior to the VME, the difficulty of obtaining a recognition of occupational asthma when the working conditions fulfilled do not exactly correspond to those labelled in the schedule for occupational diseases, are discussed in this paper.

The commercial availability of high-dose inhaled corticosteroid preparations for the treatment of asthma offers an occasion for reviewing the different mechanisms of action of glucocorticoids notably glucocorticoids, notably their interference with lipocortin protein synthesis and arachidonic acid metabolism. A favourable effect on bronchial hyper-reactivity and on delayed hypersensitivity reactions has also been observed. The problems raised by the various preparations responsible for varying degrees of systemic activity, the difficulties inherent in the use of inhalers and the side-effects of these products are discussed. The effectiveness and safety of the current high-dose inhaled preparations are emphasized.

Forty-five patients with severe, poorly controlled asthma, including 23 corticosteroid-dependent patients, were treated with a preparation of beclomethasone dipropionate aerosol delivering 250 mcg per puff. The daily dose ranged from 1000 to 2000 mcg. The mean follow-up period was 14 +/- 7 months, and 11 patients have now been followed up for more than 2 years. Forty-two patients were improved, and total withdrawal of continuous steroid therapy could be achieved in 13 cases. Treatment remained effective in long term use, provided a minimum of 1000 mcg/day was given. However, despite clinical improvement the obstructive syndrome persisted in 65% of the patients.