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Jose Martinez-Raga,1,2 Carlos Knecht,3 Raquel de Alvaro4 1Teaching Unit of Psychiatry and Psychological Medicine, University Hospital Doctor Peset, University of Valencia, 2CEU Cardenal Herrera University, 3Área de Salud Mental, Hospital Padre Jofré, Valencia, 4Hospital General, Consorcio Hospitalario Provincial, Castellon, Spain Abstract: The α2-adrenergic receptor agonist guanfacine, in its extended-release formulation (GXR), is the most recent nonstimulant medication approved in several countries for the treatment of attention-deficit hyperactivity disorder (ADHD) as monotherapy and as adjunctive pharmacotherapy to stimulants in children and adolescents. The present paper aims to review comprehensively and critically the pharmacodynamic and pharmacokinetic characteristics and the published evidence on the efficacy and safety profile of GXR in the treatment of ADHD. A comprehensive search of relevant databases (PubMed, Embase, and PsycInfo) was conducted to identify studies published in peer-reviewed journals until January 15, 2015. Though the precise mechanism of action of guanfacine in the treatment of ADHD is not fully understood, it is thought to act directly by enhancing noradrenaline functioning via α2A-adrenoceptors in the prefrontal cortex. Weight-adjusted doses should be used, with a dosing regime on a milligram per kilogram basis, starting at doses in the range 0.05–0.08 mg/kg/day, up to 0.12 mg/kg/day. As evidenced in short-term randomized controlled trials and in long-term open-label extension studies, GXR has been shown to be effective as monotherapy in the treatment of ADHD. Furthermore, GXR has also been found to be effective as adjunctive therapy to stimulant medications in patients with suboptimal responses to stimulants. Many of the adverse reactions associated with GXR, particularly sedation-related effects, were dose-related, transient, mild to moderate in severity, and did not interfere with attention or overall efficacy. There are no reports of serious cardiovascular adverse events associated with GXR alone or in combination with psychostimulants. Keywords: guanfacine extended-release, attention-deficit hyperactivity disorder, ADHD, oppositional symptoms, adjunctive therapy, cardiovascular safety

Background: Distinguishing self-limiting ('trivial') from potentially consequential spinal pain in childhood and adolescence is crucial to prevent over- or under-medicalization. The aim of this study was to stratify participants for severity of spinal pain and to investigate associations of pain severity with potential consequences of pain and some psychophysical and clinical factors., Methods: In 2020 and 2021, children and adolescents took part in a voluntary population-based spine screening event across Switzerland organized by the Swiss Chiropractors Association. The screening consisted of a questionnaire (14 questions) based on the Young Spine Questionnaire and a clinical examination by a chiropractor. Three subgroups of pain severity [no pain (including mild, occasional pain), one-sited moderate pain, one-sited severe or moderate/severe pain at multiple sites of the spine] were formed by combining the self-reported measures for pain intensity and pain frequency for two recall periods (lifetime, last week) according to literature. Multivariable logistic regression analyses were conducted to determine the associations between pain severity and potential pain consequences (impact of spinal pain on health and seeking medical advice because of spinal pain), as well as between pain severity and some psychophysical factors (head and/or belly pain, sleep problems, daytime tiredness) and clinical measures [trunk symmetry (rib hump), trunk muscle endurance (plank position)]., Results: Of all participants (N = 457; 6-16 years; mean age = 10.9 ± 3.0 years; 220 boys), those with most severe spinal pain and with one-sited moderate pain in the last week had higher odds for reporting an impact of spinal pain on their health (OR = 13.5, 95%CI = 4.9-36.8; OR = 4.7, 95%CI = 1.5-14.4) and for searching medical advice because of spinal pain (OR = 11.6, 95%CI = 4.5-30.1; OR = 3.9, 95%CI = 1.6-9.2). Headache and/or belly pain (OR = 2.6, 95%CI = 1.2-5.5) and daytime tiredness (OR = 3.2, 95%CI = 1.3-7.9) increased the odds for having most severe pain compared to having no pain. The clinical measures were not associated with pain severity., Conclusion: Stratification by pain severity, particularly when asked for pain in the last week, might help to minimize over- and under-medicalization of spinal pain in childhood and adolescence. Prospective studies are needed to clarify the relevance of the investigated clinical tests in the context of adolescent spinal pain., Competing Interests: Declarations. Ethics approval and consent to participate: The questionnaire and the examination form used for this study were completely anonymous. An approval from the ethics review board of the Canton of Zurich was requested, but was by law not necessary (BASEC req-2020-00825 and req-2023-01333). Consent for publication: Not applicable (completely anonymous data). Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Aim: To investigate the professional dementia experts' understanding of a dementia-friendly hospital to identify its characteristics., Design: We used a qualitative design embedded in a case study. A total of 16 semi-structured expert interviews were conducted with 17 professional dementia experts. Using inductive content analysis, the interviews were analysed in a participatory manner involving a group of researchers and dementia experts., Results: We identified six characteristics of dementia-friendly hospitals: Proud to be dementia-friendly-That's what we want; Seeing the human being-Taking care of everyone; Having everyone on board-It's a collective task; Being professional-It takes more than being nice and kind; Rethinking the 'running' system-We have to change, not them; and Being part of the community-Thinking beyond the hospital., Conclusion: The concept of a dementia-friendly hospital seems complex and requires a rethinking of the traditional hospital. For a conceptualisation, the involvement of people with dementia and their relatives is important to gain a comprehensive understanding., Implications for the Profession and Patient Care: A dementia-friendly hospital is characterised by professional care that comprises a safe, familiar and supportive environment, is prepared but also flexible, has everyone on board, and sees the human being. To become dementia-friendly, individual interventions such as training courses can be a starting point. However, an overall concept is required that also includes components that contribute to successful implementation and a welcoming culture of people with dementia., Impact: Our findings on the perspective of professional dementia experts contribute to the conceptualisation of dementia-friendly hospitals., Reporting Method: We reported our study according to the COREQ checklist., Patient and Public Contribution: The investigation of the perspective of professional dementia experts is one part of a larger study. In this overall DEMfriendlyHospital study, we interviewed professional dementia experts, people with dementia and their relatives and also involved them in a participatory manner in various stages of the research process., (© 2024 The Author(s). Journal of Clinical Nursing published by John Wiley & Sons Ltd.)

Background: Older and very old persons have an increased risk of traumatic injuries as well as comorbidities and multimorbidities. The standardized workflow in hospitals can increase the occurrence of typical geriatric complications, such as challenging behavior and delirium, which can result in highly complex care situations. The application of advanced practice nurses (APN) is an international response to such challenges. In Germany, the scientifically based development of APN has so far lagged behind the international standard., Method: For this scoping review, a systematic search in the databases PubMed and CINAHL and a supplementary hand search was conducted for the period 2010-2022., Results: Tasks and role profiles for the scope of practice of APN in geriatrics and traumatology already exist in the literature. There is a lack of scientifically proven tasks and role profiles for APN in geriatric traumatology in the literature., Discussion: Based on the current state of research it is not yet possible to derive specific tasks and role profiles for APN in geriatric traumatology. The transferability of tasks and profiles from geriatrics and traumatology seem to be possible. The development of tasks and role profiles for geriatric traumatology APN requires further research, especially to identify the specific needs of geriatric traumatology patients., (© 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Vision provides animals with detailed information about their surroundings, conveying diverse features such as color, form, and movement across the visual scene. Computing these parallel spatial features requires a large and diverse network of neurons, such that in animals as distant as flies and humans, visual regions comprise half the brain's volume. These visual brain regions often reveal remarkable structure-function relationships, with neurons organized along spatial maps with shapes that directly relate to their roles in visual processing. To unravel the stunning diversity of a complex visual system, a careful mapping of the neural architecture matched to tools for targeted exploration of that circuitry is essential. Here, we report a new connectome of the right optic lobe from a male Drosophila central nervous system FIB-SEM volume and a comprehensive inventory of the fly's visual neurons. We developed a computational framework to quantify the anatomy of visual neurons, establishing a basis for interpreting how their shapes relate to spatial vision. By integrating this analysis with connectivity information, neurotransmitter identity, and expert curation, we classified the ~53,000 neurons into 727 types, about half of which are systematically described and named for the first time. Finally, we share an extensive collection of split-GAL4 lines matched to our neuron type catalog. Together, this comprehensive set of tools and data unlock new possibilities for systematic investigations of vision in Drosophila , a foundation for a deeper understanding of sensory processing.

Background: Infection with porcine reproductive and respiratory syndrome virus (PRRSV) leads to significant economic losses worldwide. One of the initial measures following an outbreak is to stabilise the herd and to prevent vertical transmission of PRRSV. The objective of this study was to detect PRRSV in different sampling material, both in an experimental model and on a commercial piglet producing farm, with a focus on evaluating the suitability of tongue fluid samples., Results: In the experimental model, PRRSV negative pregnant gilts were infected with PRRSV-1 AUT15-33 on gestation day 85 and necropsy of gilts and foetuses was performed three weeks later. 38.3% of individual foetal serum and 39.4% of individual foetal thymus samples were considered PRRSV RT-qPCR positive. Tongue fluids from individual foetuses showed a 33.0% positivity rate. PRRSV RNA was detected in all but one sample of litter-wise pooled processing fluids and tongue fluids. In the field study, the investigated farm remained PRRSV positive and unstable for five consecutive farrowing groups after the start of the sampling process. Tongue fluid samples pooled by litter in the first investigated farrowing group had a 54.5% positivity rate, with the overall highest viral load obtained in the field study. In this farrowing group, 33.3% of investigated litter-wise pooled processing fluid samples and all investigated serum samples (pools of 4-6 individuals, two piglets per litter) were considered positive. Across all investigated farrowing groups, tongue fluid samples consistently showed the highest viral load. Moreover, tongue fluid samples contained the virus in moderate amounts for the longest time compared to the other investigated sampling material., Conclusion: It can be concluded that the viral load in individual foetuses is higher in serum or thymus compared to tongue fluid samples. However, litter-wise pooled tongue fluid samples are well-suited for detecting vertical transmission within the herd, even when the suspected prevalence of vertical transmission events is low., (© 2024. The Author(s).)

Objectives: We conducted an implementation planning process during the pilot phase of a pragmatic trial, which tests an intervention guided by artificial intelligence (AI) analytics sourced from noninvasive monitoring data in heart failure patients (LINK-HF2)., Materials and Methods: A mixed-method analysis was conducted at 2 pilot sites. Interviews were conducted with 12 of 27 enrolled patients and with 13 participating clinicians. iPARIHS constructs were used for interview construction to identify workflow, communication patterns, and clinician's beliefs. Interviews were transcribed and analyzed using inductive coding protocols to identify key themes. Behavioral response data from the AI-generated notifications were collected., Results: Clinicians responded to notifications within 24 hours in 95% of instances, with 26.7% resulting in clinical action. Four implementation themes emerged: (1) High anticipatory expectations for reliable patient communications, reduced patient burden, and less proactive provider monitoring. (2) The AI notifications required a differential and tailored balance of trust and action advice related to role. (3) Clinic experience with other home-based programs influenced utilization. (4) Responding to notifications involved significant effort, including electronic health record (EHR) review, patient contact, and consultation with other clinicians., Discussion: Clinician's use of AI data is a function of beliefs regarding the trustworthiness and usefulness of the data, the degree of autonomy in professional roles, and the cognitive effort involved., Conclusion: The implementation planning analysis guided development of strategies that addressed communication technology, patient education, and EHR integration to reduce clinician and patient burden in the subsequent main randomized phase of the trial. Our results provide important insights into the unique implications of implementing AI analytics into clinical workflow., (Published by Oxford University Press on behalf of the American Medical Informatics Association 2024.)

Background: In January 2021, a female 1-year-old Kunekune was presented at the University Clinic for Swine with severe reduction of the field of vision resulting in prolonged reaction time when targeting barriers, due to moderate to severe thickening of the skin around both orbits also affecting the eyelids., Methods: Clinical examination revealed skin hyperplasia, nodular enlargement of the skin pores of the axillar and inguinal region. Ophthalmologists decided to remove parts of the thickened periocular skin, followed by histopathological examination., Results: Once large amounts of demodectic mites were detected by histopathology, demodicosis could be diagnosed and treatment of the pig was started using sarolaner. Morphological and molecular analyses were performed. Histopathological and parasitological exams led to the aetiological diagnosis of demodicosis in the affected Kunekune pig. Severe skin lesions were revealed to be the consequence of an infestation with Demodex sp. Morphological analyses confirmed the involvement of D. phylloides. Molecular characterization indicated a Demodex species closely related to mites documented in wild boar - most probably D. phylloides for which no explicit sequences are available in GenBank yet. Treatment with sarolaner (2.6 mg/kg) resulted in a substantial regression of skin lesions, already detectable 1 month after first treatment., Conclusions: Demodicosis is a very rare disease in pigs that is most probably related to an impaired immune response to the mites. Demodectic mange should be included in the list of differential diagnoses in cases of periocular alterations of the skin of pigs., (© 2024. The Author(s).)

Background: To become a dementia-friendly hospital (DFH) is increasingly being discussed in health care practice, research, politics and society. In our previous integrative review, we identified six characteristics of DFHs. To thoroughly discuss and contextualize these characteristics in relation to hospitals in Germany, we involved professional dementia experts in our review process., Methods: At the end of our review process, we involved professional dementia experts at the 'contributing' level of the ACTIVE framework to discuss and reflect on the six DFH characteristics we identified. We conducted a group process in the form of a one-day workshop. The workshop consisted of four steps: 1. presentation of review results (input), 2. modification of DFH characteristics and rating of their relevance in smaller working groups, 3. discussion of group results in plenary and 4. questionnaire for prioritization and rating of feasibility. The data were analyzed in MAXQDA using content analysis and descriptive statistics., Results: A total of 16 professional dementia experts working in hospitals participated in the workshop. All the previously identified characteristics of a DFH were rated as relevant or very relevant for patients with dementia, their relatives and health care professionals from the professional dementia experts' perspective. They made a few modifications of the six characteristics at the level of subcategories, aspects, and descriptions. The feasibility of the characteristics in hospitals was critically discussed regarding resources, hospital structures and processes, the role of nurses, and the current care situation of people with dementia in hospitals. More than half of the subcategories of the characteristics were considered very difficult or difficult to implement by most professional dementia experts., Conclusion: The involvement of professional dementia experts helped us contextualize our review findings within the German hospital setting. These results highlight the need to consider resources, funding options, influencing factors, and the current situation and culture of care provided by hospitals before implementing DFH characteristics. Beside the involvement of professional dementia experts and various health care professionals, the involvement of other stakeholders, such as people with dementia and their relatives, is necessary in future research for the development of a DFH., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Loss of elastin due to aging, disease, or injury can lead to impaired tissue function. In this study, de novo tropoelastin (TE) synthesis is investigated in vitro and in vivo using different TE-encoding synthetic mRNA variants after codon optimization and nucleotide modification. Codon optimization shows a strong effect on protein synthesis without affecting cell viability in vitro , whereas nucleotide modifications strongly modulate translation and reduce cell toxicity. Selected TE mRNA variants (3, 10, and 30 μg) are then analyzed in vivo in porcine skin after intradermal application. Administration of 30 μg of native TE mRNA with a me 1 Ψ modification or 10 and 30 μg of unmodified codon-optimized TE mRNA is required to increase TE protein expression in vivo . In contrast, just 3 μg of a codon-optimized TE mRNA variant with the me 1 Ψ modification is able to increase protein expression. Furthermore, skin toxicity is investigated in vitro by injecting 30 μg of mRNA of selected TE mRNA variants into a human full-thickness skin model, and no toxic effects are observed. Thereby, for the first time, an increased dermal TE synthesis by exogenous administration of synthetic mRNA is demonstrated in vivo . Codon optimization of a synthetic mRNA can significantly increase protein expression and therapeutic outcome., Competing Interests: The authors have no competing interests to declare., (© 2023 The Authors.)

Owing to their similarities, pigs are often used as experimental models for humans. In particular, the similarity of the skin allows them to be a good dermatological model. The aim of the study was to develop an animal model in conventional domestic pigs to evaluate skin lesions macroscopically and histologically after a continuous subcutaneous apomorphine application. A total of 16 pigs from two different age groups were injected with four different apomorphine formulations for 12 h daily over a period of 28 days into the subcutis, which was then evaluated macroscopically for nodules and erythema, as well as histologically. Differences in skin lesions between the formulations were found, with formulation 1 leading to the fewest nodules, least skin lesions, no lymph follicles, least necrosis, and best skin tolerance. Older pigs were easier to handle and, because of the thicker skin and subcutis of these animals, drug application with the appropriate needle length was safer. The experimental setup worked well and an animal model to assess skin lesions after a continuous subcutaneous application of drugs could be successfully established.

The impact of the Fusarium mycotoxin deoxynivalenol (DON) on the immune response against porcine reproductive and respiratory syndrome virus (PRRSV) vaccination and infection was investigated. Forty-two weaned piglets were separated into seven groups and received three different diets: Low DON (1.09 ppm), High DON (2.81 ppm) or No DON. These three treatments were split further into either vaccinated (Ingelvac PRRSFLEX EU) and challenged with PRRSV 28 days post-vaccination, or only infected at day 28. A seventh group received no DON, no vaccination, and no infection. Two weeks after challenge infection, when pigs were euthanized, the number of IFN-γ producing lymphocytes in the blood of vaccinated animals was lower in pigs on High DON compared to animals on Low DON or No DON. Intracellular cytokine staining showed that vaccinated animals fed with the Low DON diet had higher frequencies of TNF-α/IFN-γ co-producing CD4 + T cells than the other two vaccinated groups, particularly in lung tissue. Vaccinated animals on High DON had similar viral loads in the lung as the non-vaccinated groups, but several animals of the Low DON or No DON group receiving vaccination had reduced titers. In these two groups, there was a negative correlation between lung virus titers and vaccine-specific TNF-α/IFN-γ co-producing CD4 + T cells located either in lung tissue or blood. These results indicate that after PRRSV vaccination and infection, high levels of DON negatively influence immune parameters and clearance of the virus, whereas low DON concentrations have immunomodulatory effects., (© 2023. The Author(s).)

Background: The Veterans Health Administration (VHA) is one of the largest providers of telehealth in the United States and continues to lead the way in transforming healthcare services. VHA has been implementing its Whole Health (WH) initiative since 2018, a proactive practice empowering patients to take charge of their health and well-being. A key facilitator of the WH initiative is the WH coach who partners with Veterans to achieve their health-related goals. A gap exists in the literature regarding the understanding of WH coaches' use of telehealth to engage rural-residing Veterans. COVID-19 unexpectedly interrupted in-person VHA delivery of care, including WH coaching which primarily relied on in-person delivery and focused less on telehealth. During the pandemic, WH coaches had to adapt and integrate different modalities to engage their Veteran patients. We examined WH coaches' approaches to extending coaching to rural Veterans via technology, emphasizing the advantages of telehealth, existing gaps in telehealth delivery, and opportunities for telehealth as a coaching modality., Methods: This project was implemented as part of a larger mixed methods evaluation regarding WH coaching for rural Veterans; this manuscript presents the findings from the qualitative data from the larger study. The qualitative dataset is comprised of data collected using three different qualitative methods: four focus groups ( n  = 11; 3-4 participants per group), in-depth individual interviews ( n  = 9), and open-ended responses from a national web-based survey ( n  = 140). Focus group, in-depth interview, and open-ended survey data were collected sequentially and separately analyzed following each wave of data collection. Findings from the three analyses were then collaboratively merged, compared, reorganized, and refined by the evaluation team to create final themes., Results: Three final themes that emerged from the merged data were: (1) Advantages of Telehealth; (2) Telehealth Gaps for Rural Veterans, and (3) Strategies for Bridging Telehealth Gaps. Themes explicate telehealth advantages, gaps, and opportunities for rural Veteran WH coaching., Conclusion: Findings highlight that video telehealth alone is not sufficient for meeting the needs of rural Veterans. Digital technologies hold promise for equalizing health access gaps; however, both human factors and broadband infrastructure constraints continue to require WH coaches to use a mix of modalities in working with rural Veterans. To overcome challenges and bridge gaps, WH coaches should be ready to adopt a blended approach that integrates virtual, in-person, and lower-tech options., 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 LeBeau, Varma, Kreider, Castañeda, Knecht, Cowper Ripley, Jia and Hale-Gallardo.)

Metal-on-metal (MoM) bearing hip arthroplasty saw increasing utilization and peaked in the 1990s and early 2000s. Although the linear and volumetric wear rate for a MoM bearings was lower than its polyethylene counterpart, metal ion particles were found to be approximately 10 × smaller and 500 × higher in quantity compared to polyethylene wear debris. Research into these articulations have demonstrated their relationship to the formation of lymphocyte-mediated adverse local tissue reactions. The work-up for metal particle-associated conditions (metallosis) includes a thorough patient history and physical examination, blood laboratory studies for metal ion concentrations, and advanced imaging studies including magnetic resonance imaging (MRI). The treatment of metallosis and adverse local tissue reactions ranges from close serial observation to extensive debridement and full revision of arthroplasty components, when indicated., (© 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Objectives: The worldwide dissemination of carbapenemase-producing Escherichia coli lineages belonging to high-risk clones poses a challenging public health menace. The aim of this work was to investigate genomic features of a colonizing multidrug-resistant strain of Klebsiella pneumoniae carbapenemase (KPC)-producing E. coli from our institution., Methods: Whole-genome sequencing was done by Illumina MiSeq-I, and de novo assembly was achieved using SPAdes. Resistome, mobilome, plasmids, virulome, and integrons were analysed using ResFinder, AMRFinder, ISFinder, PlasmidFinder, MOB-suite, VirulenceFinder, and IntegronFinder. Sequence types (STs) were identified with pubMLST and BIGSdb databases. Conjugation assays were also performed., Results: Escherichia coli HA25pEc was isolated from a rectal swab sample taken within the framework of the hospital epidemiological surveillance protocol for detection of carbapenemase-producing Enterobacterales. Escherichia coli HA25pEc corresponded to the first report of ST648 co-harbouring bla KPC-2 and bla CTX-M-15 in Latin America from a colonized patient. It had 19 antibiotic resistance genes (ARGs), including bla KPC-2 , located on a Tn4401a isoform. Conjugation assays revealed that bla KPC-2 was not transferred by conjugation to E. coli J53 under our experimental conditions., Conclusion: Escherichia coli ST648 has been detected previously in companion and farm animals as well as in hospital- and community-acquired infections worldwide. Although scarcely reported as KPC-producers, our finding in a culture surveillance with several acquired ARGs, including bla CTX-M-15 , alerts the potential of this clone for worldwide unnoticed spreading of extreme drug resistance to β-lactams. These data reinforce the importance of carrying out molecular surveillance to identify reservoirs and warn about the dissemination of new international clones in carbapenemase-bearing patients., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Reproductive disorders caused by porcine reproductive and respiratory syndrome virus-1 are not yet fully characterized. We report QuPath-based digital image analysis to count inflammatory cells in 141 routinely, and 35 CD163 immunohistochemically stained endometrial slides of vaccinated or unvaccinated pregnant gilts inoculated with a high or low virulent PRRSV-1 strain. To illustrate the superior statistical feasibility of the numerical data determined by digital cell counting, we defined the association between the number of these cells and endometrial, placental, and fetal features. There was strong concordance between the two manual scorers. Distributions of total cell counts and endometrial and placental qPCR results differed significantly between examiner1's endometritis grades. Total counts' distribution differed significantly between groups, except for the two unvaccinated. Higher vasculitis scores were associated with higher endometritis scores, and higher total cell counts were expected with high vasculitis/endometritis scores. Cell number thresholds of endometritis grades were determined. A significant correlation between fetal weights and total counts was shown in unvaccinated groups, and a significant positive correlation was found between these counts and endometrial qPCR results. We revealed significant negative correlations between CD163+ counts and qPCR results of the unvaccinated group infected with the highly virulent strain. Digital image analysis was efficiently applied to assess endometrial inflammation objectively.