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Maren Leiz,1,* Nils Pfeuffer,1,* Laura Rehner,2 Ulrike Stentzel,1 Neeltje van den Berg1 1Institute for Community Medicine, University Medicine, Greifswald, Germany; 2Institute for Nursing Science and Interprofessional Learning, University Medicine, Greifswald, Germany*These authors contributed equally to this workCorrespondence: Nils Pfeuffer, Institute for Community Medicine, Ellernholzstr. 1– 2, Greifswald, 17487, Germany, Tel +49 3834 / 86 76 18, Email nils.pfeuffer@med.uni-greifswald.deAbstract: Affective disorders are a common psychological impairment. A major problem with respect to treatment is medication non-adherence. eHealth interventions are already widely used in the treatment of patients living with affective disorders. The aim of this systematic literature review is to obtain the current scientific evidence to eHealth as a tool to improve medication adherence in patients with affective disorders. A systematic search was performed across PubMed, Cochrane Library, Web of Science and PsycInfo. Studies in English and German published between 2007 and 2020 were included. The review followed the PRISMA guidelines and were performed with the CADIMA online tool. A total of 17 articles were included in this review. Eleven studies were randomized controlled trials, two were controlled clinical trials, and four had a pre-/post-design. Three different types of interventions could be identified: internet-based self-management programs (n=4), multi-faceted interventions addressing different dimensions of medication adherence (n=4), and single-faceted interventions (n=9) comprising four mobile interventions and five telehealth interventions. Eleven interventions addressed patients with (comorbid) depressions and six addressed patients with bipolar disorders. Six interventions showed a statistically significant positive effect on medication adherence. None of the studies showed a statistically significant negative effect. All interventions which had a statistically significant positive effect on medication adherence involved personal contacts between therapists and patients. All included eHealth interventions are at least as effective as control conditions and seems to be effective for patients with depression as well as with bipolar disorders. Personal contacts seem to improve the effectiveness of eHealth interventions. eHealth interventions are an effective way to improve medication adherence in patients with affective disorders. In rural or underserved regions, eHealth can supplement usual care interventions on medication adherence by expanding access. More analyses are needed in order to understand determinants for the effectiveness of eHealth interventions on medication adherence enhancement.Keywords: affective disorder, eHealth, medication adherence, medication nonadherence, compliance, noncompliance

Schistosomiasis is a disease caused by parasites of the genus Schistosoma, currently affecting more than 200 million people. Among the various species of this parasite that infect humans, S. mansoni is the most common. Pharmacological treatment is limited to the use of a single drug, praziquantel (PZQ), despite reports of parasite resistance and low efficacy. It is therefore necessary to investigate new potential schistosomicidal compounds. In this study, we tested the efficacy of epiisopilosine (EPIIS) in a murine model of schistosomiasis. A single dose of EPIIS (100 or 400 mg/kg) administered orally to mice infected with adult S. mansoni resulted in reduced worm burden and egg production. The treatment with the lower dose of EPIIS (100 mg/kg) significantly reduced total worm burden by 60.61% (P < 0.001), as well as decreasing hepatosplenomegaly and egg excretion. Scanning electron microscopy revealed morphological changes in the worm tegument after treatment. Despite good activity of EPIIS in adult S. mansoni, oral treatment with single dose of EPIIS 100 mg/kg had only moderate effects in mice infected with juvenile S. mansoni. In addition, we performed cytotoxicity and toxicological studies with EPIIS and found no in vitro cytotoxicity (in HaCaT, and NIH-3T3 cells) at a concentration of 512 μg/mL. We also performed in silico analysis of toxicological properties and showed that EPIIS had low predicted toxicity. To confirm this, we investigated systemic acute toxicity in vivo by orally administering a 2000 mg/kg dose to Swiss mice. Treated mice showed no significant changes in hematological, biochemical, or histological parameters compared to non-treated animals. Epiisopilosine showed potential as a schistosomicidal drug: it did not cause acute toxicity and it displayed an acceptable safety profile in the animal model.

Antimicrobial peptides (AMPs) from the dermaseptin and phylloseptin families were isolated from the skin secretion of Phyllomedusa nordestina, a recently described amphibian species from Northeastern Brazil. One dermaseptin and three phylloseptins were chosen for solid phase peptide synthesis. The antiprotozoal and antimicrobial activities of the synthetic peptides were determined, as well as their cytotoxicity in mouse peritoneal cells. AMPs are being considered as frameworks for the development of novel drugs inspired by their mechanism of action.

Background: Early diagnosis is mandatory for the medical care of children and adolescents with pediatric-onset inflammatory bowel disease (PIBD). International guidelines ('Porto criteria') of the European Society for Pediatric Gastroenterology, Hepatology and Nutrition recommend medical diagnostic procedures in PIBD. Since 2004, German and Austrian pediatric gastroenterologists document diagnostic and treatment data in the patient registry CEDATA-GPGE on a voluntary basis. The aim of this retrospective study was to analyze whether the registry CEDATA-GPGE reflects the Porto criteria and to what extent diagnostic measures of PIBD according to the Porto criteria are documented. Methods: Data of CEDATA-GPGE were analyzed for the period January 2014 to December 2018. Variables representing the Porto criteria for initial diagnostic were identified and categorized. The average of the number of measures documented in each category was calculated for the diagnoses CD, UC, and IBD-U. Differences between the diagnoses were tested by Chi-square test. Data on possible differences between data documented in the registry and diagnostic procedures that were actually performed were obtained via a sample survey. Results: There were 547 patients included in the analysis. The median age of patients with incident CD (n = 289) was 13.6 years (IQR: 11.2–15.2), of patients with UC (n = 212) 13.1 years (IQR: 10.4–14.8) and of patients with IBD-U (n = 46) 12.2 years (IQR: 8.6–14.7). The variables identified in the registry fully reflect the recommendations by the Porto criteria. Only the disease activity indices PUCAI and PCDAI were not directly provided by participants but calculated from obtained data. The category 'Case history' were documented for the largest part (78.0%), the category 'Imaging of the small bowel' were documented least frequently (39.1%). In patients with CD, the categories 'Imaging of the small bowel' (χ2 = 20.7, Cramer-V = 0.2, p < 0.001) and 'Puberty stage' (χ2 = 9.8, Cramer-V = 0.1, p < 0.05) were documented more often than in patients with UC and IBD-U. Conclusion: The registry fully reproduces the guideline's recommendations for the initial diagnosis of PIBD. The proportion of documented diagnostic examinations varied within the diagnostic categories and between the diagnoses. Despite technological innovations, time and personnel capacities at participating centers and study center are necessary to ensure reliable data entry and to enable researchers to derive important insights into guideline-based care. [ABSTRACT FROM AUTHOR]

Schistosomiasis is a serious disease currently estimated to affect more that 207 million people worldwide. Due to the intensive use of praziquantel, there is increasing concern about the development of drug-resistant strains. Therefore, it is necessary to search for and investigate new potential schistosomicidal compounds. This work reports the in vivo effect of the alkaloid epiisopiloturine (EPI) against adults and juvenile worms of Schistosoma mansoni. EPI was first purified its thermal behavior and theoretical solubility parameters charaterised. In the experiment, mice were treated with EPI over the 21 days post-infection with the doses of 40 and 200 mg/kg, and 45 days post-infection with single doses of 40, 100 and 300 mg/kg. The treatment with EPI at 40 mg/kg was more effective in adult worms when compared with doses of 100 and 300 mg/kg. The treatment with 40 mg/kg in adult worms reduced parasite burden significantly, lead to reduction in hepatosplenomegaly, reduced the egg burden in faeces, and decreased granuloma diameter. Scanning electron microscopy revealed morphological changes to the parasite tegument after treatment, including the loss of important features. Additionally, the in vivo treatment against juvenile with 40 mg/kg showed a reduction of the total worm burden of 50.2%. Histopathological studies were performed on liver, spleen, lung, kidney and brain and EPI was shown to have a DL50 of 8000 mg/kg. Therefore EPI shows potential to be used in schistosomiasis treatment. This is the first time that schistosomicidal in vivo activity of EPI has been reported.

This paper presents an industrial scale process for extraction, purification, and isolation of epiisopiloturine (EPI) (2(3H)-Furanone,dihydro-3-(hydroxyphenylmethyl)-4-[(1-methyl-1H-imidazol-4-yl)methyl]-, [3S-[3a(R*),4b]]), which is an alkaloid from jaborandi leaves (Pilocarpus microphyllus Stapf). Additionally for the first time a set of structural and spectroscopic techniques were used to characterize this alkaloid. EPI has shown schistomicidal activity against adults and young forms, as well as the reduction of the egg laying adult worms and low toxicity to mammalian cells (in vitro). At first, the extraction of EPI was done with toluene and methylene chloride to obtain a solution that was alkalinized with ammonium carbonate. The remaining solution was treated in sequence by acidification, filtration and alkalinization. These industrial procedures are necessary in order to remove impurities and subsequent application of the high performance liquid chromatography (HPLC). The HPLC was employed also to remove other alkaloids, to obtain EPI purity higher than 98%. The viability of the method was confirmed through HPLC and electrospray mass spectrometry, that yielded a pseudo molecular ion of m/z equal to 287.1 Da. EPI structure was characterized by single crystal X-ray diffraction (XRD), (1)H and (13)C nuclear magnetic resonance (NMR) in deuterated methanol/chloroform solution, vibrational spectroscopy and mass coupled thermal analyses. EPI molecule presents a parallel alignment of the benzene and the methyl imidazol ring separated by an interplanar spacing of 3.758 Å indicating a π-π bond interaction. The imidazole alkaloid melts at 225°C and decomposes above 230°C under air. EPI structure was used in theoretical Density Functional Theory calculations, considering the single crystal XRD data in order to simulate the NMR, infrared and Raman spectra of the molecule, and performs the signals attribution.

Antimicrobial peptides (AMPs) from the dermaseptin and phylloseptin families were isolated from the skin secretion of Phyllomedusa nordestina, a recently described amphibian species from Northeastern Brazil. One dermaseptin and three phylloseptins were chosen for solid phase peptide synthesis. The antiprotozoal and antimicrobial activities of the synthetic peptides were determined, as well as their cytotoxicity in mouse peritoneal cells. AMPs are being considered as frameworks for the development of novel drugs inspired by their mechanism of action. [ABSTRACT FROM AUTHOR]

This paper presents an industrial scale process for extraction, purification, and isolation of epiisopiloturine (EPI) (2(3H)-Furanone,dihydro-3-(hydroxyphenylmethyl)-4-[(1-methyl-1H-imidazol-4-yl)methyl]-, [3S-[3a(R*),4b]]), which is an alkaloid from jaborandi leaves (Pilocarpus microphyllus Stapf). Additionally for the first time a set of structural and spectroscopic techniques were used to characterize this alkaloid. EPI has shown schistomicidal activity against adults and young forms, as well as the reduction of the egg laying adult worms and low toxicity to mammalian cells (in vitro). At first, the extraction of EPI was done with toluene and methylene chloride to obtain a solution that was alkalinized with ammonium carbonate. The remaining solution was treated in sequence by acidification, filtration and alkalinization. These industrial procedures are necessary in order to remove impurities and subsequent application of the high performance liquid chromatography (HPLC). The HPLC was employed also to remove other alkaloids, to obtain EPI purity higher than 98%. The viability of the method was confirmed through HPLC and electrospray mass spectrometry, that yielded a pseudo molecular ion of m/z equal to 287.1 Da. EPI structure was characterized by single crystal X-ray diffraction (XRD), 1H and 13C nuclear magnetic resonance (NMR) in deuterated methanol/chloroform solution, vibrational spectroscopy and mass coupled thermal analyses. EPI molecule presents a parallel alignment of the benzene and the methyl imidazol ring separated by an interplanar spacing of 3.758 Å indicating a π-π bond interaction. The imidazole alkaloid melts at 225°C and decomposes above 230°C under air. EPI structure was used in theoretical Density Functional Theory calculations, considering the single crystal XRD data in order to simulate the NMR, infrared and Raman spectra of the molecule, and performs the signals attribution. [ABSTRACT FROM AUTHOR]

Background: Due to unidentified geriatric needs, elderly patients have a higher risk for developing chronic conditions and acute medical complications. Early geriatric screenings and assessments help to identify geriatric needs. Holistic and coordinated therapeutic approaches addressing those needs maintain the independence of elderly patients and avoid adverse effects. General practitioners are important for the timely identification of geriatric needs. The aims of this study are to examine the spatial distribution of the utilization of outpatient geriatric services in the very rural Federal State of Mecklenburg-Western Pomerania in the Northeast of Germany and to identify regional disparities., Methods: Geographical analysis and cartographic visualization of the spatial distribution of outpatient geriatric services of patients who are eligible to receive basic geriatric care (BGC) or specialized geriatric care (SGC) were carried out. Claims data of the Association of Statutory Health Insurance Physicians in Mecklenburg-Western Pomerania were analysed on the level of postcode areas for the quarter periods between 01/2014 and 04/2017. A Moran's I analysis was carried out to identify clusters of utilization rates., Results: Of all patients who were eligible for BGC in 2017, 58.3% (n = 129,283/221,654) received at least one BCG service. 77.2% (n = 73,442/95,171) of the patients who were eligible for SGC, received any geriatric service (BGC or SGC). 0.4% (n = 414/95,171) of the patients eligible for SGC, received SGC services. Among the postcode areas in the study region, the proportion of patients who received a basic geriatric assessment ranged from 3.4 to 86.7%. Several regions with statistically significant Clusters of utilization rates were identified., Conclusions: The widely varying utilization rates and the local segregation of high and low rates indicate that the provision of outpatient geriatric care may depend to a large extent on local structures (e.g., multiprofessional, integrated networks or innovative projects or initiatives). The great overall variation in the provision of BGC services implicates that the identification of geriatric needs in GPs' practices should be more standardized. In order to reduce regional disparities in the provision of BGC and SGC services, innovative solutions and a promotion of specialized geriatric networks or healthcare providers are necessary., (© 2024. The Author(s).)

Background: In Germany, patients under the age of 18 receive medical care from pediatricians. In sparsely populated regions, general practitioners often have to do the job of pediatricians and offer medical care to children, which in most cases is adequate. However, it does not meet the goal of demand planning namely, every patient should have equal access to care regardless of their place of residence. One option to help achieve this is the implementation of consultation hours with pediatricians in general practitioners' practices (tandem practices). The aim of this study was to investigate the feasibility and acceptance of this cooperation and whether this improved access to pediatric care., Methods: First, general practitioners willing to participate were identified, where the nearest pediatrician's practice was more than 20 kilometers away. The second step was to find suitable pediatricians willing to offer regular weekly pediatric consultations in the practice of a general practitioner. For the evaluation, various data collection methods were used: one-off parent questionnaires at the time of study inclusion, questionnaires filled out by the pediatricians for each consultation, and data from the practice information systems in the participating practices. The distance between the patients' place of residence and the next regular outpatient pediatrician's practice were calculated and compared to the distance to a tandem practice., Results: In April 2019, in two practices tandem consultation hours were implemented. During 12 months, 192 children and adolescents (50.2% female) were included. They attended the consultation hours a total of 387 times. Of 482 reasons given in the doctor's questionnaire, 36.9% were vaccinations (n=178), 14.9% were preventive examinations (n=72), the most frequently coded ICD-10 diagnostic groups were diseases of the respiratory system (J00-J99: 8.5%, n=41) and mental/behavioral disorders (F00-F99: 7.7%, n=37). Before the project, the patients had an average of 20.2 kilometers (min 0.3; max 34.8) to the next regular outpatient pediatrician's practice; within the project, the distance decreased to 5.1 kilometers (min 0.1; max 26.7)., Conclusion: All doctors involved wanted to continue the tandem consultations after the end of the test phase. The project results showed the feasibility and a high level of acceptance of tandem practices, both for the doctors involved and for the patients and their parents., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

In rural areas, healthcare providers, patients and relatives have to cover long distances. For specialised ambulatory palliative care (SAPV), a supply radius of max. 30 km is recommended. The aim of this study was to analyse whether there are regional disparities in the supply of SAPV and whether it is associated with the distance between the SAPV team's site and the patient's location. Therefore, anonymised data of the Association of Statutory Health Insurance Physicians of the Federal State of Mecklenburg-Western Pomerania (M-V) were retrospectively analysed for the period of 2014-2017. Identification as a palliative patient was based on palliative-specific items from the ambulatory reimbursement catalogue. In total, 6940 SAPV patients were identified; thereof, 48.9% female. The mean age was 73.3 years. For 28.3% of the identified SAPV patients ( n = 1961), the SAPV teams had a travel distance of >30 km. With increasing distance, the average number of treatment days per patient increased. It was found that there are regional disparities in the provision of SAPV services in M-V and that local structures have an important impact on regional supply patterns. The distance between the SAPV team's site and the patient's location is not the only determining factor; other causes must be considered.

The incidence and prevalence of pediatric-onset inflammatory bowel disease (PIBD) are on the rise worldwide. Initial symptoms are often recognized with a delay, which reduces the quality of life and may lead to an increased rate of complications. The aim of this study was to determine the diagnostic delay in PIBD and to identify potential influencing factors. Therefore, data from the German-Austrian patient registry CEDATA-GPGE for children and adolescents with PIBD were analyzed for the period January 2014 to December 2018. There were 456 children identified in the data, thereof 258 children (57%) with Crohn's disease (CD) and 198 children (43%) with Ulcerative colitis (UC). The median age was 13.3 years (interquartile range (IQR) = 10.9-15.0), and 44% were females. The median diagnostic delay was 4.1 months (IQR = 2.1-7.0) in CD and 2.4 months (IQR = 1.2-5.1) in UC (p = 0.01). UC was associated with earlier diagnosis than CD (p < 0.001). Only a few factors influencing the diagnostic delay have been verified, e.g., abdominal pain at night and if video capsule endoscopy was performed. Diagnostic delay improved over the years in participating centers, but the level of awareness needs to be high even in common symptoms like abdominal pain., (© 2022. The Author(s).)

Background: Patients of geriatrics are often treated by several health care providers at the same time. The spatial, informational, and organizational separation of these health care providers can hinder the effective treatment of these patients., Objective: This study aimed to develop a regional health information exchange (HIE) system to improve HIE in geriatric treatment. This study also evaluated the usability of the regional HIE system and sought to identify barriers to and facilitators of its implementation., Methods: The development of the regional HIE system followed the community-based participatory research approach. The primary outcomes were the usability of the regional HIE system, expected implementation barriers and facilitators, and the quality of the developmental process. Data were collected and analyzed using a mixed methods approach., Results: A total of 3 focus regions were identified, 22 geriatric health care providers participated in the development of the regional HIE system, and 11 workshops were conducted between October 2019 and September 2020. In total, 12 participants responded to a questionnaire. The main results were that the regional HIE system should support the exchange of assessments, diagnoses, medication, assistive device supply, and social information. The regional HIE system was expected to be able to improve the quality and continuity of care. In total, 5 adoption facilitators were identified. The main points were adaptability of the regional HIE system to local needs, availability to different patient groups and treatment documents, web-based design, trust among the users, and computer literacy. A total of 13 barriers to adoption were identified. The main expected barriers to implementation were lack of resources, interoperability issues, computer illiteracy, lack of trust, privacy concerns, and ease-of-use issues., Conclusions: Participating health care professionals shared similar motivations for developing the regional HIE system, including improved quality of care, reduction of unnecessary examinations, and more effective health care provision. An overly complicated registration process for health care professionals and the patients' free choice of their health care providers hinder the effectiveness of the regional HIE system, resulting in incomplete patient health information. However, the web-based design of the system bridges interoperability problems that exist owing to the different technical and organizational structures of the health care facilities involved. The regional HIE system is better accepted by health care professionals who are already engaged in an interdisciplinary, geriatric-focused network. This might indicate that pre-existing cross-organizational structures and processes are prerequisites for using HIE systems. The participatory design supports the development of technologies that are adaptable to regional needs. Health care providers are interested in participating in the development of an HIE system, but they often lack the required time, knowledge, and resources., (©Nils Pfeuffer, Angelika Beyer, Peter Penndorf, Maren Leiz, Franziska Radicke, Wolfgang Hoffmann, Neeltje van den Berg. Originally published in JMIR Human Factors (https://humanfactors.jmir.org), 15.09.2022.)

Pilocarpus microphyllus Stapf ex Wardlew (Rutaceae), popularly known as jaborandi, is a plant native to the northern and northeastern macroregions of Brazil. Several alkaloids from this species have been isolated. There are few reports of antibacterial and anthelmintic activities for these compounds. In this work, we report the antibacterial and anthelmintic activity of five alkaloids found in P. microphyllus leaves, namely, pilosine, epiisopilosine, isopilosine, epiisopiloturine and macaubine. Of these, only anthelmintic activity of one of the compounds has been previously reported. Nuclear magnetic resonance, HPLC and mass spectrometry were combined and used to identify and confirm the structure of the five compounds. As regards the anthelmintic activity, the alkaloids were studied using in vitro assays to evaluate survival time and damaged teguments for Schistosoma mansoni adult worms. We found epiisopilosine to have anthelmintic activity at very low concentrations (3.125 μg mL -1 ); at this concentration, it prevented mating, oviposition, reducing motor activity and altered the tegument of these worms. In contrast, none of the alkaloids showed antibacterial activity. Additionally, alkaloids displayed no cytotoxic effect on vero cells. The potent anthelmintic activity of epiisopilosine indicates the potential of this natural compound as an antiparasitic agent. Copyright © 2017 John Wiley & Sons, Ltd., (Copyright © 2017 John Wiley & Sons, Ltd.)

Objective: This study aimed to investigate the protective effect of epiisopiloturine hydrochloride (EPI), an imidazole alkaloid, on NAP-induced gastrointestinal damage in rats., Methods: Initially, rats were pretreated with 0.5% carboxymethylcellulose (vehicle) or EPI (3, 10 and 30mg/kg, p.o. or i.p., groups 3-5, respectively) twice daily, for 2days. After 1h, NAP (80mg/kg, p.o.) was given. The control group received only vehicle (group 1) or vehicle+naproxen (group 2). Rats were euthanized on 2nd day, 4h after NAP treatment. Stomachs lesions were measured. Samples were collected for histological evaluation and glutathione (GSH), malonyldialdehyde (MDA), myeloperoxidase (MPO), and cytokines levels. Moreover, gastric mucosal blood flow (GMBF) was evaluated., Results: EPI pretreatment prevented NAP-induced macro and microscopic gastric damage with a maximal effect at 10mg/kg. Histological analysis revealed that EPI decreased scores of damage caused by NAP. EPI reduced MPO (3.4±0.3U/mg of gastric tissue) and inhibited changes in MDA (70.4±8.3mg/g of gastric tissue) and GSH (246.2±26.4mg/g of gastric tissue). NAP increased TNF-α levels, and this effect was reduced by EPI pretreatment. Furthermore, EPI increased GMBF by 15% compared with the control group., Conclusion: Our data show that EPI protects against NAP-induced gastric and intestinal damage by reducing pro-inflammatory cytokines, reducing oxidative stress, and increasing GMBF., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Leishmaniasis is one of the most serious diseases in the world and can be lethal if untreated. This is especially the case for visceral leishmaniasis, which is commonly caused by Leishmania (L.) infantum and for which available medication is still inadequate. A recently described antimicrobial peptide DRS 01 has been reported to kill L. infantum promastigotes, but nothing is known about its mode of action or effect on the cell. In this paper we report the visualization of the interaction between DRS 01 and L. infantum promastigotes using two high resolution microscopic techniques: atomic force microscopy and scanning electron microscopy. The results show considerable morphological changes at and above the IC50 in the treated cells. Both membrane damage and flagella alterations were observed. The results strongly suggest a membrane-directed action for DRS 01 on the Leishmania species studied., From the Clinical Editor: In this paper, the effects of DRS 01, an antimicrobial peptide, is studied in Leishmania infantum using atomic force microscopy as well as standard scanning electron microscopy techniques, with the conclusion of a membrane-based effect by DRS 01 on the parasites., (© 2014.)