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The mandibular second molars can become impacted beneath the crown of the first molars due to various causes and fail to erupt normally. Presented herewith is a case report of orthodontic uprighting of a mesioangular impacted mandibular right permanent second molar. Though various treatment options were available, an uprighting push spring appliance was used as it is easy to fabricate and produces distal tipping and uprighting of the impacted tooth without the necessity of surgical assistance, bone removal, or splinting. The uprighting of the mandibular second molar was achieved within two months. [ABSTRACT FROM AUTHOR]

The interplay between biomaterials and host immune responses critically determines outcomes in tissue restoration. Recent studies suggest that physicochemical properties of materials can dictate pro-regenerative versus pro-fibrotic responses and have begun to define the key immune cell types and signals governing these divergent effects. This emerging understanding enables the engineering of regenerative biomaterials capable of functional restoration in situ. An injectable nanofiber-hydrogel composite (NHC) microparticles are designed and constructed from cross-linked electrospun collagen nanofiber fragments surface-bonded to the hyaluronic acid hydrogel network via covalent conjugation during the cross-linking process. The collagen nanofiber fragments, acting as the structural reinforcement component, increased the overall storage modulus of the NHC to a level comparable to native soft tissues while maintaining a sufficiently high degree of porosity of the hydrogel phase to allow host cell infiltration following subcutaneous injection of the NHC microparticles. More importantly, the NHC promoted macrophage/monocyte infiltration, migration, and spreading, sustained cell recruitment over time, and enhanced the proangiogenic effect and recruitment of PDGFRα + perivascular progenitor cells, leading to extensive adipose tissue remodeling. This study demonstrates the regenerative potential of the injectable NHC microgels as an off-the-shelf solution for devastating soft tissue losses., (© 2024 The Author(s). Advanced Healthcare Materials published by Wiley‐VCH GmbH.)

Objective: To undertake a systematic review of the medical literature on telesurgery, with a key focus on identifying the key technical and non-technical themes searched in medical articles and to analyze gaps in the current knowledge base on telesurgery., Background: It has now been over two decades since the first successful case of telesurgery and since this time there have been significant technological and telecommunications advancements., Methods: A systematic review of the literature was completed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. Details of the protocol for this systematic review were registered on PROSPERO (CRD42024511530)., Results: In total, 102 unique references which were allocated into five categories; technical, cybersecurity, ethical, financial, regulatory considerations to discuss key themes. The vast majority of references were related to technical considerations which have demonstrated the feasibility of telesurgery. The non-technical considerations have a paucity of literature and a lack of guidance on telesurgery which appears to still be the major barriers to telesurgery., Conclusions: Telesurgery presents many interdisciplinary challenges, encompassing both important technical and non-technical (such as cybersecurity, ethical, financial, and regulatory) considerations. Further research, collaboration between stakeholders, collaborative community of experts, and the development of comprehensive consensus frameworks are essential steps toward the widespread adoption of telesurgery., Competing Interests: Conflict of interest statement: All authors declare that they have no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The cooperative mechanism is of paramount importance in the synthesis of supramolecular polymers with desired characteristics, including molecular mass, polydispersity, and morphology. It is primarily driven by the presence of intermolecular interactions, which encompass strong hydrogen bonding, metal-ligand interactions, and dipole-dipole interactions. In this study, we utilize density functional theory and energy decomposition analysis to investigate the cooperative behavior of perylene diimide (PDI) oligomers with alkyl chains at their imide positions, which lack the previously mentioned interactions. Our systematic examination reveals that dispersion interactions originating from the alkyl side-chain substituents play an important role in promoting cooperativity within these PDIs. This influence becomes even more pronounced for alkyl chain lengths beyond hexyl groups. The energy decomposition analysis reveals that the delicate balance between dispersion energy and Pauli repulsion energy is the key driver of cooperative behavior in PDIs. Additionally, we have developed a mathematical model capable of predicting the saturated binding energies for PDI oligomers of varying sizes and alkyl chain lengths. Overall, our findings emphasize the previously undervalued significance of dispersion forces in cooperative supramolecular polymerization, enhancing our overall understanding of the cooperative mechanism., (© 2024 Wiley-VCH GmbH.)

Size-dependent phagocytosis is a well-characterized phenomenon in monocytes and macrophages. However, this size effect for preferential gene delivery to these important cell targets has not been fully exploited because commonly adopted stabilization methods for electrostatically complexed nucleic acid nanoparticles, such as PEGylation and charge repulsion, typically arrest the vehicle size below 200 nm. Here, we bridge the technical gap in scalable synthesis of larger submicron gene delivery vehicles by electrostatic self-assembly of charged nanoparticles, facilitated by a polymer structurally designed to modulate internanoparticle Coulombic and van der Waals forces. Specifically, our strategy permits controlled assembly of small poly(β-amino ester)/messenger ribonucleic acid (mRNA) nanoparticles into particles with a size that is kinetically tunable between 200 and 1,000 nm with high colloidal stability in physiological media. We found that assembled particles with an average size of 400 nm safely and most efficiently transfect monocytes following intravenous administration and mediate their differentiation into macrophages in the periphery. When a CpG adjuvant is co-loaded into the particles with an antigen mRNA, the monocytes differentiate into inflammatory dendritic cells and prime adaptive anticancer immunity in the tumor-draining lymph node. This platform technology offers a unique ligand-independent, particle-size-mediated strategy for preferential mRNA delivery and enables therapeutic paradigms via monocyte programming., Competing Interests: Competing interests statement:S.K.R., J.J.G. and H.-Q.M. are cofounders of Wyverna Therapeutics Inc. Y.H. was a consultant for Wyverna Therapeutics Inc. Y.H., S.Y.T., L.C., J.J.G. and H.-Q.M. are inventors of a patent application covering the nanoparticle assembly technology described here; S.Y.T., D.R.W., Y.R. and J.J.G. are inventors of a patent application covering the PBAE structures described here.Both patents were filed through and are managed by Johns Hopkins Technology Ventures. The other authors declare no conflict of interest.

Human skin is the host to various commensal microbes that constitute a substantial microbial community. The reciprocal communication between these microbial inhabitants and host cells upholds both the morphological and functional attributes of the skin layers, contributing indispensably to microenvironmental and tissue homeostasis. Thus, disruption of the skin barrier or imbalances in the microbial communities can exert profound effects on the behavior of host cells. This influence, mediated by the microbes themselves or their metabolites, manifests in diverse outcomes. In this review, we examine existing knowledge to provide insight into the nuanced behavior exhibited by the microbiota on skin cells in health and disease states. These interactions provide insight into potential cellular targets for future microbiota-based therapies to prevent and treat skin disease., Competing Interests: Declaration of interests L.A.G. has received grant support paid to his institution, Johns Hopkins University, from Sun Pharma Advanced Research Company (SPARC). This grant is to investigate intellectual property of which Johns Hopkins University is the owner. L.A.G. is one of several inventors and is under a licensing agreement with SPARC; this intellectual property has resulted in royalty payments to inventors. This grant and the royalty payments are not related to the research presented in this manuscript., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background The body undergoes numerous metabolic changes during severe illness or physiological stress to protect itself by lowering metabolism and reducing overall demands. This evolutionary adaptation dates back to early human development, long before the advent of ICU facilities and advanced treatments. One such protective mechanism is Sick Euthyroid Syndrome (SES), also known as Non-thyroidal Illness Syndrome (NTIS). SES commonly occurs in critically ill patients and is frequently observed in conditions such as heart failure, chronic kidney disease, and severe sepsis. This syndrome is characterized by abnormal thyroid function tests in patients with acute or chronic systemic illnesses who do not have intrinsic thyroid disease. Typically, these patients exhibit low serum levels of triiodothyronine (T3), normal or low levels of thyroxine (T4), and normal or low thyroid-stimulating hormone (TSH) levels. SES is believed to be an adaptive response to illness, aimed at reducing the body's metabolic rate and conserving energy during severe physiological stress. This original article delves into SES's prevalence and clinical impact in these settings. Materials and methods The study aims to determine the prevalence of SES in patients with long-standing heart failure, elucidate the relationship between thyroid function and heart failure severity, and assess its impact on various hematological and clinical parameters. This observational, cross-sectional study was conducted at Dr. D. Y. Patil Medical College, Hospital and Research Centre, Pune, India, a 2011-bed hospital, over one and a half years. This study included 70 patients with chronic heart failure, aged 18 years and above, defined by a left ventricular ejection fraction of 40% or less and a Boston criteria score of 8 or more. Patients were excluded if they had a history of thyroid dysfunction, clinical sepsis, or were taking thyroid-affecting drugs.  Results The study provides important insights into the prevalence and impact of SES in long-standing heart failure patients. It found that a significant 44.29% of these patients exhibited low T3 levels, highlighting the substantial occurrence of SES in this population. Additionally, the study revealed a negative correlation between N-terminal pro-b-type natriuretic peptide (NT-proBNP) levels, Boston score, and total T3, suggesting that as indicators of heart failure severity worsen, total T3 levels may decrease further. Another key finding is the high prevalence of anemia among heart failure patients, with a notable gender disparity: 92.11% of male patients were affected compared to 50% of female patients.  Conclusion The study concluded that SES is significantly prevalent among long-standing heart failure patients, further indicating that thyroid suppression increases with the severity of heart failure. Recognizing SES can guide tailored treatments, prompting intensive monitoring and optimized heart failure management. Additionally, the study found a high prevalence of anemia, particularly among male patients, highlighting the need for gender-specific considerations in managing heart failure. These findings underscore the importance of routine thyroid function assessments and regular monitoring of anemia in heart failure patients. Future research should focus on improving clinical outcomes through comprehensive management of both thyroid function and anemia in these patients., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Institutional Ethics Sub-committee, Dr. D. Y. Patil Medical College, Hospital and Research Centre, Pune, India issued approval I.E.S.C/274/2022. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Mahashabde et al.)

Background: A substantial proportion of persons with psychosis (PWP) remain untreated in the community across the world. Factors that preclude them from accessing psychiatric treatment are poorly studied. In this study, we explored the factors that prevented persons with schizophrenia and their caregivers from accessing psychiatric treatment using an interview schedule specifically developed for this purpose., Methods: We identified individuals with schizophrenia and related disorders who had never accessed psychiatric treatment. We interviewed 67 such individuals and their family members using a validated tool, the Schedule of Factors Influencing Access to Treatment (SOFIAc) and analysed the data using descriptive statistics., Results: The M ( SD ) number of factors reported to preclude individuals with psychosis and families from seeking psychiatric treatment was 10 (3.32). No PWP/family reported any single factor as the sole reason for not accessing treatment. Distance to the nearest psychiatric centre (97%), PWP's/family members' knowledge and attitude towards symptoms of psychosis and treatment (92.5%), financial problems (91%), lack of insight and active resistance to efforts towards treatment (86.6%), lack of support from the family (83.6%) and family issues and dynamics (79.1%) were reported to be the commonest factors that precluded them from accessing psychiatric treatment., Conclusions: The reason for individuals with psychosis and their family members not accessing psychiatric treatment was invariably multifactorial, involving, on average, 10 factors. Programmes that target the reduction of the treatment gap should be cognizant of the multifactorial nature of the challenge of reaching psychiatric treatment for persons with psychoses.

Summary: Plastic surgery offices are subject to a wide variety of cybersecurity threats, including ransomware attacks that encrypt the plastic surgeon's information and make it unusable, as well as data theft and disclosure attacks that threaten to disclose confidential patient information. Cloud-based office systems increase the attack surface and do not mitigate the effects of breaches that can result in theft of credentials. Although employee education is often recommended to avoid the threats, a single error by a single employee has often led to security breaches, and it is unreasonable to expect that no employee will ever make an error. Recognition of the 2 most common vectors of these breaches-compromised email attachments and surfing to compromised websites-allows the use of technical networking tools to prevent both email attachments from being received and employee use of unsanctioned and potentially compromised websites. Furthermore, once compromised code has been allowed to run within the office network, that code must necessarily make outbound connections to exploit the breach. Preventing that outbound traffic can mitigate the effects of a breach. However, most small office network consultants design firewalls to only limit incoming network traffic and fail to implement technical measures to stop the unauthorized outbound traffic that is necessary for most network attacks. The authors provide detailed techniques that can be used to direct information technology consultants to properly limit outbound network traffic as well as incoming email attachments., (Copyright © 2023 by the American Society of Plastic Surgeons.)

Understanding solvent-solute interactions is essential to designing and synthesising soft materials with tailor-made functions. Although the interaction of the solute with the solvent mixture is more complex than the single solvent medium, solvent mixtures are exciting to unfold several unforeseen phenomena in supramolecular chemistry. Here, we report two unforeseen pathways observed during the hierarchical assembly of cationic perylene diimides (cPDIs) in water and amphiphilic organic solvent (AOS) mixtures. When the aqueous supramolecular polymers (SPs) of cPDIs are injected into AOS, initially kinetically trapped short SPs are formed, which gradually transform into thermodynamically stable high aspect ratio SP networks. Using various experimental and theoretical investigations, we found that this temporal evolution follows two distinct pathways depending on the nature of the water-AOS interactions. If the AOS is isopropanol (IPA), water is released from cPDIs into bulk IPA due to strong hydrogen bonding interactions, which further decreases the monomer concentration of cPDIs (Pathway-1). In the case of dioxane AOS, cPDI monomer concentration further increases as water is retained among cPDIs (Pathway-2) due to relatively weak interactions between dioxane and water. Interestingly, these two pathways are accelerated by external stimuli such as heat and mechanical agitation., (© 2024 Wiley-VCH GmbH.)

Diabetic retinopathy (DR) stands as a prevalent complication in the eye resulting from diabetes mellitus, predominantly associated with high blood sugar levels and hypertension as individuals age. DR is a severe microvascular complication of both type I and type II diabetes mellitus and the leading cause of vision impairment. The critical approach to combatting and halting the advancement of DR lies in effectively managing blood glucose and blood pressure levels in diabetic patients; however, this is seldom achieved. Both human and animal studies have revealed the intricate nature of this condition involving various cell types and molecules. Aside from photocoagulation, the sole therapy targeting VEGF molecules in the retina to prevent abnormal blood vessel growth is intravitreal anti-VEGF therapy. However, a substantial portion of cases, approximately 30-40%, do not respond to this treatment. This review explores distinctive pathophysiological phenomena of DR and identifiable cell types and molecules that could be targeted to mitigate the chronic changes occurring in the retina due to diabetes mellitus. Addressing the significant research gap in this domain is imperative to broaden the treatment options available for managing DR effectively., Competing Interests: RG is a co-founder and holds equity in Cell Care Therapeutics Inc., which is interested in using adipose-derived stromal cells in visual disorders. 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Reddy, Devi, Seetharaman, Shailaja, Bhat, Gangaraju and Upadhya.)

Lipid nanoparticles (LNPs) can be designed to potentiate cancer immunotherapy by promoting their uptake by antigen-presenting cells, stimulating the maturation of these cells and modulating the activity of adjuvants. Here we report an LNP-screening method for the optimization of the type of helper lipid and of lipid-component ratios to enhance the delivery of tumour-antigen-encoding mRNA to dendritic cells and their immune-activation profile towards enhanced antitumour activity. The method involves screening for LNPs that enhance the maturation of bone-marrow-derived dendritic cells and antigen presentation in vitro, followed by assessing immune activation and tumour-growth suppression in a mouse model of melanoma after subcutaneous or intramuscular delivery of the LNPs. We found that the most potent antitumour activity, especially when combined with immune checkpoint inhibitors, resulted from a coordinated attack by T cells and NK cells, triggered by LNPs that elicited strong immune activity in both type-1 and type-2 T helper cells. Our findings highlight the importance of optimizing the LNP composition of mRNA-based cancer vaccines to tailor antigen-specific immune-activation profiles., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

The synthesis of supramolecular polymers with controlled architecture is a grand challenge in supramolecular chemistry. Although living supramolecular polymerization via primary nucleation has been extensively studied for controlling the supramolecular polymerization of small molecules, the resulting supramolecular polymers have typically exhibited one-dimensional morphology. In this report, we present the synthesis of intriguing supramolecular polymer architectures through a secondary nucleation event, a mechanism well-established in protein aggregation and the crystallization of small molecules. To achieve this, we choose perylene diimide with 2-ethylhexyl chains at the imide position as they are capable of forming dormant monomers in solution. Activating these dormant monomers via mechanical stimuli and hetero-seeding using propoxyethyl perylene diimide seeds, secondary nucleation event takes over, leading to the formation of three-dimensional spherical spherulites and scarf-like supramolecular polymer heterostructures, respectively. Therefore, the results presented in this study propose a simple molecular design for synthesizing well-defined supramolecular polymer architectures via secondary nucleation., (© 2024. The Author(s).)

Objectives: Agriculture is associated with various physical and mental health risks. There has been growing concern about the psychological hazards associated with farming including high stress levels, depression, anxiety, and increasing rates of suicide. To bolster resilience and overall survival within the farmers, it is imperative to gain a comprehensive understanding of the protective factors that contribute to mental and psychological well-being., Materials and Methods: The study followed an explorative research design and used purposive sampling to select samples from Chikkaballapur District in Karnataka. Nine farmers were interviewed based on inclusion and exclusion criteria. The interview schedule was prepared based on the literature review. Experts in the field did content and face validation. The transcribed data were coded using the free version of QDA Miner. The thematic analysis approach was used for data analysis., Results: Three broader themes and 15 sub-themes emerged: (1) Personal protective factors: feeling of autonomy, purpose in life, passion for work, problem-solving skills, positive mindset and building resilience, learning new skills, and spiritual and religious beliefs; (2) social protective factors: friends and peer group, belongingness, family, and social engagements; and (3) environmental protective factors: lifestyle and being physically active, rural environment, government/institutional support, and recognition in the society., Conclusion: The study successfully emerged three overarching protective factors that farmers perceived as significant for their mental health and well-being, entitled personal, social, and environmental. The study findings provide valuable insights for social work practitioners, guiding them in developing interventions and strategies to support the mental health and well-being of the farming population., Competing Interests: There are no conflicts of interest., (© 2024 Published by Scientific Scholar on behalf of Journal of Neurosciences in Rural Practice.)

Background : Our aim was to examine the frequency and prescription pattern of breakthrough (BTO) and scheduled (SCH) opioids and their ratio (BTO/SCH ratio) of use, prior to and after referral to an inpatient supportive care consult (SCC) for cancer pain management (CPM). Methods and Materials : Patients admitted at the MD Anderson Cancer Center and referred to a SCC were retrospectively reviewed. Cancer patients receiving SCH and BTO opioids for ≥24 h were eligible for inclusion. Patient demographics and clinical characteristics, including the type and route of SCH and BTO opioids, daily opioid doses (MEDDs) of SCH and BTO, and BTO/SCH ratios were reviewed in patients seen prior to a SCC (pre-SCC) and during a SCC. A normal BTO ratio was defined as 0.5-0.2. Results : A total of 665/728 (91%) patients were evaluable. Median pain scores ( p < 0.001), BTO MEDDs ( p < 0.001), scheduled opioid MEDDs ( p < 0.0001), and total MEDDs ( p < 0.0001) were higher, but the median number of BTO doses was fewer (2 vs. 4, p < 0.001), among patients seen at SCC compared to pre-SCC. A BTO/SCH ratio over the recommended ratio (>0.2) was seen in 37.5% of patients. The BTO/SCH ratios in the pre-SCC and SCC groups were 0.10 (0.04, 0.21) and 0.17 (0.10, 0.30), respectively, p < 0.001. Hydromorphone and Morphine were the most common BTO and SCH opioids prescribed, respectively. Patients in the early supportive care group had higher pain scores and MEDDs. Conclusions : BTO/SCH ratios are frequently prescribed higher than the recommended dose. Daily pain scores, BTO MEDDs, scheduled opioid MEDDs, and total MEDDs were higher among the SCC group than the pre-SCC group, but the number of BTO doses/day was lower.

Introduction: In the phase 2/3 study QUILT-3.032 (NCT03022825), the ability of the IL-15RαFc superagonist N-803 (nogapendekin alfa inbakicept) plus bacillus Calmette-Guérin (BCG) to elicit durable complete responses in patients with BCG-unresponsive nonmuscle-invasive bladder cancer (NMIBC) was demonstrated. As a secondary end point, patient-reported outcomes (PROs) were assessed., Methods: Both cohort A patients with carcinoma in situ with or without Ta/T1 disease and cohort B patients with high-grade Ta/T1 papillary disease who received N-803 plus BCG therapy completed the EORTC (European Organization for Research and Treatment of Cancer) Core 30 and Quality of Life NMIBC-Specific 24 questionnaires at baseline and months 6, 12, 18, and 24 on study. Scores were analyzed using descriptive statistics, and multivariable analyses were performed to identify baseline variables associated with PROs., Results: On study, mean physical function (PF) and global health (GH) scores remained relatively stable from baseline for cohorts A (n = 86) and B (n = 78). At month 6, cohort A patients with a complete response reported higher PF scores than those without ( P = .0659); at month 12, > 3 as compared with ≤ 3 prior transurethral resections of bladder tumor was associated ( P = .0729) with lower GH scores. In cohort B, baseline disease type was associated ( P = .0738) with PF and race was significantly associated ( P = .0478) with GH at month 6. NMIBC-Specific 24 summary scores also remained stable on study for both cohorts., Conclusions: The overall stability of PROs scores, taken together with the efficacy findings, indicates a favorable risk-benefit ratio and quality of life following N-803 plus BCG.

Summary: Artificial intelligence (AI) has been a disruptive technology within health care, from the development of simple care algorithms to complex deep-learning models. AI has the potential to reduce the burden of administrative tasks, advance clinical decision-making, and improve patient outcomes. Unlocking the full potential of AI requires the analysis of vast quantities of clinical information. Although AI holds tremendous promise, widespread adoption within plastic surgery remains limited. Understanding the basics is essential for plastic surgeons to evaluate the potential uses of AI. This review provides an introduction of AI, including the history of AI, key concepts, applications of AI in plastic surgery, and future implications., (Copyright © 2023 by the American Society of Plastic Surgeons.)

Purpose: Few studies have examined the long-term impact of communication skills training for oncologists. We developed a year-long communication skills curriculum for medical oncology fellows with the primary goals of fostering life-long learning of patient-centered communication skills and internalization of associated attitudes and beliefs. We engaged learners through reflection, narrative methods, and action methods, thereby creating a non-threatening, team-based environment. The purpose of the current study was to determine whether learners perceived that they had acquired enduring skills, attitudes, and knowledge years after they participated., Methods: Former fellows completed an online cross-sectional survey from June to July 2019 that included demographic information, 21 items on a numerical scale, and 3 narrative prompts. Survey items pertained to 4 domains, including skills, attitudes, confidence with specific scenarios, and overall impressions. The numerical scale ranged from "strongly agree" = 1 to "strongly disagree" = 5., Results: A total of 114 fellows, including 27 teaching assistants, participated in the communication skills training over 8 years. The average time between the end of the training program and completion of the survey was 5.2 years. The response rate was 68/114 (64%). Forty-one (60%, 95% CI: 49.3-73.8) fellows agreed or strongly agreed that the curriculum profoundly impacted their practice of medicine. Forty-three (64%, 95% CI: 51.5-75.5) fellows strongly agreed or agreed that they often found themselves informally sharing lessons they learned during the series. Overall average domain scores were 1.89 (SD = 0.84) for skills, 2.16 (0.79) for attitudes, 2.05 (0.81) for confidence with specific challenges, and 2.38 (0.94) for lasting impressions. Results were significantly more favorable for teaching assistants than for others., Conclusion: Engaging, interactive, safe, and learner-centered communication skills training has an enduring and favorable impact on oncologists' self-perceived skills, confidence with specific challenges, and attitudes., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)