Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra, leading to various motor and non-motor symptoms. Several cellular and molecular mechanisms such as alpha-synuclein (α-syn) accumulation, mitochondrial dysfunction, oxidative stress, and neuroinflammation are involved in the pathogenesis of this disease. MicroRNAs (miRNAs) play important roles in post-transcriptional gene regulation. They are typically about 21-25 nucleotides in length and are involved in the regulation of gene expression by binding to the messenger RNA (mRNA) molecules. miRNAs like miR-221 play important roles in various biological processes, including development, cell proliferation, differentiation, and apoptosis. miR-221 is also implicated in promoting neuronal survival against oxidative stress and in promoting neurite outgrowth and neuronal differentiation. Additionally, the role of miR-221 in PD has been investigated in several studies. According to the results of this study; 1) miR-221 protects against oxidative stress in 6-hydroxydopamine-induced PC12 cells; 2) miR-221 prevents Bax/caspase-3 signaling activation by stopping Bim; 3) miR-221 has moderate predictive power for PD; 4) miR-221 directly targets PTEN, and PTEN over-expression eliminates the protective action of miR-221 on p-AKT expression in PC12 cells; 5) miRNA-221, by manipulating the Akt signaling pathway, performs in controlling cell viability and apoptosis in PD. This review study suggests that miR-221 has the potential to be used as a clinical biomarker for PD diagnosis and stage assignment.
Introduction Survival is dismal for the 40-60% of children with MDS who relapse post allogeneic HCT1,2,3. Strategies to decrease relapse risk include use of cytoreduction prior to HCT or maintenance treatment after HCT, data on the utility of these approaches remains limited4-12. Rapid withdrawal of immune suppression or use of donor lymphocyte infusion (DLI) can enhance the graft versus leukemia effect and achieve disease control in some cases13,14. Addition of hypomethylating agents to DLI may provide additional benefit15 and second HCT should be considered16-21. While several novel therapies may alter the future landscape of MDS therapy22-28 (Table 1), the optimal approach to relapsed pediatric MDS remains unclear. We report the management of a child who relapsed less than 70 days after initial HCT. Our approach demonstrates that multimodal therapy may permit prolonged survival with excellent quality of life (QOL) despite lack of long-term cure.
Difficulty to extubate any patient is not a problem commonly thought of during general anaesthesia. This case report describes some of the factors that lead to this predicament and the successful surgical removal of the endotracheal tube via a tracheostomy. This case report also highlights some of the deficiencies in the clinical practice of veterinary anaesthesia. Further research is required for the selection size criteria of endotracheal tubes in all species and the monitoring of cuff pressures during general anaesthesia.
Computing protein structure from amino acid sequence information has been a long-standing grand challenge. CASP (Critical Assessment of Structure Prediction) conducts community experiments aimed at advancing solutions to this and related problems. Experiments are conducted every two years. The 2020 experiment (CASP14) saw major progress, with the second generation of deep learning methods delivering accuracy comparable with experiment for many single proteins. There is an expectation that these methods will have much wider application in computational structural biology. Here we summarize results from the most recent experiment, CASP15, in 2022, with an emphasis on new deep learning-driven progress. Other papers in this special issue of Proteins provide more detailed analysis. For single protein structures, the AlphaFold2 deep learning method is still superior to other approaches, but there are two points of note. First, although AlphaFold2 was the core of all the most successful methods, there was a wide variety of implementation and combination with other methods. Second, using the standard AlphaFold2 protocol and default parameters only produces the highest quality result for about two thirds of the targets, and more extensive sampling is required for the others. The major advance in this CASP is the enormous increase in the accuracy of computed protein complexes, achieved by the use of deep learning methods, although overall these do not fully match the performance for single proteins. Here too, AlphaFold2 based method perform best, and again more extensive sampling than the defaults is often required. Also of note are the encouraging early results on the use of deep learning to compute ensembles of macromolecular structures. Critically for the usability of computed structures, for both single proteins and protein complexes, deep learning derived estimates of both local and global accuracy are of high quality, however the estimates in interface regions are slightly less reliable. CASP15 also included computation of RNA structures for the first time. Here, the classical approaches produced better agreement with experiment than the new deep learning ones, and accuracy is limited. Also, for the first time, CASP included the computation of protein-ligand complexes, an area of special interest for drug design. Here too, classical methods were still superior to deep learning ones. Many new approaches were discussed at the CASP conference, and it is clear methods will continue to advance.
Background: There remains limited knowledge about the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-COV2) vaccination in pediatric oncology patients, which is essential to provide counseling and risk adaptation in this vulnerable population. The goal of this study was to understand immunogenicity after vaccination in pediatric oncology patients and determine if certain clinical factors impacted response. Methods: Patients 0-25 years of age with a diagnosis of cancer and actively receiving therapy were enrolled on study. We excluded patients who were completely vaccinated prior to their cancer diagnosis. Blood samples were collected pre-vaccination, as well as 2, 4-6, and 8-12 weeks after vaccination. Healthy children who were fully vaccinated enrolled as controls. Clinical data and complete blood counts around time of vaccination were collected. To study B and T cell immunity, we measured neutralizing antibodies by enzyme-linked immunoassay and interferon gamma secretion by enzyme-linked immunospot, respectively. Results: 26 patients enrolled on study, for which 11 were evaluable oncology patients and 7 were healthy controls. Adequate B cell response was seen in 36.4% of patients and adequate T cell response in 77.8% of patients. Numbers were too small to detect differences based on malignancy type. There was no differences in immunity based on absolute lymphocyte count (ALC) or intensity of therapy. Conclusion: Pediatric oncology patients have a suboptimal immune response to SARS-COV2 vaccination. Booster doses will be imperative to provide optimal protection against COVID-19, however blood counts may not be a useful guide to optimize the time of administration.
Gene function conservation is crucial in molecular ecology, especially for key traits like growth and maturation in teleost fish. The vgll3 and six6 genes are known to influence age-at-maturity in Atlantic salmon, but their impact on other fish species is poorly understood. Here, we investigated the association of vgll3 and six6 in the domestication of gilthead seabream and European seabass, both undergoing selective breeding for growth-related traits in the Mediterranean. We analysed two different sets of samples using two different genotyping approaches. The first dataset comprised farmed and wild populations from Greece, genotyped for SNPs within the genomic range of the two genes (“gene-level genotyping”). The second dataset examined 300k to 600k SNPs located in the chromosomes of the two genes, derived from a meta-analysis of a Pool-Seq experiment involving farmed and wild populations distributed widely across the Mediterranean (“chromosome-level genotyping”). The gene-level analysis revealed a significant effect of domestication on both genes in each species. This finding was partially supported by the chromosome-level analysis, identifying highly differentiated regions associated with domestication at varying distances from the candidate genes. Noteworthy genomic features were found, such as a CpG island in gilthead seabream and novel candidate genes in European seabream, warranting further investigation. These findings support a putative role of vgll3 and six6 in the maturation and growth of gilthead seabream and European seabass, emphasizing the need for further research on their conserved function.
Telehealth is an emerging approach that uses technology to provide healthcare remotely. Recent publications have outlined the importance of supporting the transition to self-management of adolescents with allergic conditions. However, no synthesis of the evidence base on the use and impact of telehealth interventions for this purpose has been conducted to date. This review achieves these aims, in addition to exploring the language use surrounding these interventions, and their implementation. Four databases were searched systematically. References were independently screened by two reviewers. Methodological quality was assessed using the Mixed Methods Appraisal Tool. A narrative synthesis was undertaken. Eighteen papers were included, reporting on fifteen telehealth interventions. 86% targeted adolescents with asthma. Mobile applications were the most common telehealth modality used, followed by video-conferencing, web-based, virtual reality and artificial intelligence Five intervention content categories were identified; educational, monitoring, behavioural, psychosocial and healthcare navigational. Peer and/or healthcare professional interaction, gamification and tailoring may increase engagement. The studies showed positive effects of the interventions or no difference from active controls, in self-management outcomes such as knowledge, health outcomes such as quality-of-life, and economic outcomes such as healthcare utilisation. The most common implementation outcomes reported were acceptability, appropriateness, feasibility and fidelity.
TITLE PAGEArticle TypeClinical pictureTitlePenile Injury Caused by Neodymium MagnetsAuthorsYuki Akiyama1, Ryo Ichibayashi2Affiliations1. Department of Orthopaedic Surgery, Toho University Medical Center, Sakura Hospital, Chiba, Japan2. Division of Emergency Medicine Department of Internal Medicine, Toho University Medical Center, Sakura Hospital, Chiba, JapanCorresponding AuthorRyo Ichibayashi, MD, PhDORCID iD https://orcid.org/0000-0002-1273-4875Division of Emergency Medicine Department of Internal MedicineToho University Medical Center, Sakura Hospital564-1 ShimosizuSakura-shi, Chiba 285-8741, JapanPhone: +81-43-462-8811Fax: +81-43-462-8835e-mail: [email protected] titleDamage caused by neodymium magnetsKeywordsNeodymium magnet, Penile foreign body, Emergency, TreatmentConflict of interestThe authors have no conflict of interest to disclose.Financial supportThe author(s) received no financial support for this article’s research, authorship, and publication.Patient consentWritten informed consent was obtained from the patient to publish this report by the journal’s patient consent policy.Author contributionYA wrote and drafted the manuscript. RI helped draft the manuscript. All authors read and approved the final manuscript.Data availability statementThe data presented in this study are available on request from the corresponding author. The data are not publicly available due to privacy and ethical considerations.AcknowledgmentsNone.Key clinical messageMultiple neodymium magnets can pinch tissue and cause barotrauma. Be careful if the tissue of the penis or foreskin is pinched, as this may cause foreskin necrosis or damage to the urethra.Clinical picture11-year-old boy. He has no history of developmental disabilities or mental illness. The boy played with a neodymium magnet attached to his penis in the bathroom out of curiosity. However, the neodymium magnet remained attached to his penis and could not be removed, and he was transported to our hospital by ambulance with the chief complaint of penile pain. Emergency crews tried to remove it, but it was impossible because it was painful, and there were concerns that it might damage the foreskin. Two hours had passed since he was transferred to our hospital because he was refused admission by multiple medical institutions. At the time of his visit, his penis had two circular neodymium magnets, each approximately 1 cm in diameter, placed against the foreskin of his penis (Figure 1A). Although it was difficult to remove it by pulling it in the opposite direction, it was possible to remove it by shifting the ground surface. After the foreskin was released, there was a crushed wound, so ointment was applied（Figure 1B）. After confirming that there was no problem with the color tone of his glasses, he returned home. The next day, he returned to the outpatient clinic and confirmed that the color of his glans was standard and that he could urinate. Neodymium magnets were developed in Japan in 1982 and have become famous worldwide due to their effectiveness. It is said to be the strongest magnet currently in use. Neodymium magnets are used in various fields and children’s toys . For this reason, accidents such as accidental ingestion by children and insertion into the urinary tract or anus due to sexual preference are problems in the medical field. Accidents caused by multiple neodymium magnets, especially when accidentally swallowed or inserted with a foreign object, are dangerous because they adhere to each other and pinch tissue, resulting in pressure necrosis . This case also had a crush injury to the foreskin. A month later, the scar remained on my foreskin. Barotrauma caused by neodymium magnets often involves damage to thin tissues, including the intestinal tract and mucous membranes. The structures of the corpus cavernosum and the corpus cavernosum of the urethra, which form the penis, are spongy and soft tissues. This tissue becomes rigid as it fills with blood. For this reason, if not only the foreskin but also the corpus cavernosum of the penis is pinched, there is a possibility that blood flow to the corpus cavernosum and damage to the urethra may occur. After removing the neodymium magnet, it is necessary to observe the color of the glans and foreskin and the state of urination.References1. Taylor MA, Spanos SP, Fenton SJ, Russell KW. Ball Magnets Clicked Together on the Epiglottis. Cureus . 2020. 12(5): e8181. doi: 10.7759/cureus.81812. Yuksel C, Ankarali S, Aslan Yuksel N. The use of neodymium magnets in healthcare and their effects on health. North Clin Istanb . 2018; 5(3): 268-273. doi:10.14744/nci.2017.00483Figure 1A Neodymium magnet that pinches the foreskin of the penisB Foreskin with a crush injury
Title: Determinants of school absences due to respiratory tract infections among children during COVID-19 pandemic: a cross-sectional study of the Sentinel Schools Network.Antoni Soriano-Arandes1,●,○, Andreu Colom-Cadena2,3,●, Anna Bordas2,3, Fabiana Ganem2,3,4, Lucia Alonso3,5, Marcos Montoro2,3, Mireia Gascon6,7,8, Maria Subirana6,7,8, Ariadna Mas9, Jordi Sunyer6,7,8, Pere Soler-Palacin1, Jordi Casabona2,3,4,8 ; on behalf of Sentinel School Network of Catalonia*Paediatric Infectious Diseases and Immunodeficiencies Unit. Children’s Hospital. Vall d’Hebron Barcelona Hospital Campus, Barcelona, Catalonia, Spain.Centre d’Estudis Epidemiològics sobre les ITS i Sida de Catalunya (CEEISCAT). Badalona, Spain.Institut d’Investigació Germans Trias i Pujol (IGTP), Badalona, Spain.Departament de Pediatria, d’Obstetrícia i Ginecologia i de Medicina Preventiva i de Salut Publica, Universitat Autònoma de Barcelona, Bellaterra, Spain.Fundació Lluita contra les infeccions, Badalona, Spain.ISGlobal, Barcelona. Spain.Universitat Pompeu Fabra (UPF), Barcelona, SpainCentro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP) Instituto de Salud Carlos III, Madrid, Spain.Direcció Assistencial d’Atenció Primària i Comunitària, Institut Català de la Salut, Barcelona, Catalonia, Spain● Contributed equally to this work with: Antoni Soriano-Arandes, Andreu Colom-Cadena○ Corresponding author: Antoni Soriano-Arandes,[email protected]. ORCID: 0000-0001-9613-7228Keywords: COVID-19, respiratory infections, ventilation, school, CO2, Indoor air qualityTo the editor:Different public health measures were implemented during the COVID-19 pandemic to maintain the schools open1,2. Regarding COVID-19 vaccination, at the beginning of this study, more than 92% and 40% of population older than 12 years and children aged 5-11 years in Spain was fully vaccinated against COVID-19, respectively3.Ventilation was proposed as one of the main strategies to reduce aerosol transmission for SARS-CoV-2 during the pandemic. A study from Germany assessed the efficiency of air purifiers in reducing aerosols in high-school classrooms4. However, no clinical endpoints were investigated and, therefore, a very low certainty of evidence was graded by a Cochrane review5. In an Italian study, the authors concluded that ventilation reduced the likelihood of SARS-CoV-2 infection in classrooms by 80%6. Moreover, a survey study from the US reported that elementary schools with face masks and ventilation strategies in place had lower SARS-CoV-2 incidence rates7. In a Lancet Task Force Commission review8, the authors concluded that improving building ventilation systems may carry benefits beyond protection from COVID-19. However, there is scarce evidence that demonstrate the association of epidemiological and environmental risk factors, including CO2 concentrations, with the incidence of respiratory tract infections (RTI) in children who are attending schools.The present study is part of COVID-19 Sentinel Schools Network of Catalonia (CSSNC), a project including 23 schools and 5687 students, teachers and other school staff with the aim to monitor SARS-CoV-2 and other respiratory viruses, their determinants and preventive measures in Catalonia9. The objectives of this study are to assess the potential association of demographic and epidemiological factors, including the indoor environmental conditions (CO2levels) in the classrooms, with students’ school absence due to RTI.We conducted a cross-sectional study in two different periods, the first from April 19 to June 21, 2022, and the second from November 8 to December 21, 2022. The main outcome of the study was the absence of the child from attending the school in person due to RTI or other non-respiratory medical causes. The study population was composed of 253 students (4-11 years) belonging to 20 classrooms, 11 in spring 2022 and 9 in autumn 2022, attending 4 and 16 classrooms of preschool (4 to 5 years-old) and primary school (6 to 11 years-old) stages, respectively. A written informed consent was previously obtained from parents or guardians of children.Absences from school attendance were notified by the tutor/teacher to the study researchers. We proceed to collect epidemiological and clinical/diagnostic data within the first 48 hours through a case report form deposited on the digital platform REDCap©. All the absences (cases) were followed-up through telephone calls made by health professionals until their return to the school. RTI was registered according to the symptoms described during the telephonic interview and confirmed through the computerised health record programme of the Health Ministry (eCAP).Sensors to monitor the CO2 concentrations (DIOXCARE DX700 PDF, Smartcare Services, Spain) were installed in classrooms, recording data every 10 minutes. For the analysis we only used the measurements taken during the time in which the students were in the classroom. We obtained a median [IQR] of CO2 levels which was used to conduct our analyses. All the participating schools received an operational protocol to install the sensor correctly and download data weekly.We calculated the RTI incidence per week and for the total study period. We performed a descriptive analysis of all survey variables, stratifying them by respiratory-related absence or absence due to other causes. Additionally, we ran a univariate logistic model to study the association between the type of absence and each described variable to obtain the corresponding odds ratios, 95% confidence intervals and p-values.Furthermore, we conducted a Latent Class Analysis (LCA) to explore potential groups of students with similar symptomatology. We started exploring the optimal number of latent classes, trying two to five classes, and we selected the best model using the entropy criterion, which indicates the accuracy of the latent classes, combined with other goodness of fit criteria such as BIC, cAIC and likelihood ratio. All these measures suggested that the optimal number of classes was two. However, we also examined the rest of number of classes to see if their classification had more clinical significance. All statistical analyses were performed in R (version 4.2.2).We registered one-hundred and five school absences during the study, 43 in the first study period (spring 2022), and 62 in the last one (autumn 2022) (Figure 1S ). Among these, we could obtain data related to the diagnosis in 98 (93%) cases, the rest of them were lost during the follow-up of the absence. Seventy-one absences were respiratory-related and 27 were due to other causes, mainly with gastrointestinal symptoms (66.7%). Among the absences due to RTI, the most were upper RTI (56/71, 78.9%), and only six (8.5%) were confirmed infections, 2 caused by influenza virus and 4 due to SARS-CoV-2 infection. These results represent a RTI incidence of 15.9 and 33.1 cases per 100 population in the first and second study period, respectively. The maximum weekly RTI incidence was of 10.2 cases per 100 population in December 12-18, 2022.The clinical, epidemiological and environmental characteristics of study sample are summarized in table 1 , categorized by type of absence (respiratory versus non-respiratory). We found a statistically significant association with absences due to RTI when someone else at home had respiratory symptoms (OR=9.12, CI 95%=2.54-33.39). We found a positive association between higher median levels of CO2at class and respiratory-related absences (OR=1.2, CI 95%=0.98-1.46). Moreover, there were more respiratory absences in autumn (OR=2.4, CI 95%=0.97-5.94). However, these last two associations did not reach statistical significance at a level of 0.05; although their p-values were lower than 0.1.No other epidemiological risk factors were associated with RTI incidence, such as household floor level, number of people living at home, living with smokers, having any comorbidity or being vaccinated against COVID-19.Finally, in Figure 1 , we present the symptomatology of absences belonging to each of the two latent classes. We can see that in the first cluster, the most frequent symptoms were cough, nasal congestion and fever, whereas in the second one, fever, gastrointestinal symptoms, and fatigue predominated.Our findings confirm that the RTI incidence during the study period was very high in children attending in the CNSSC schools, and the main medical cause of school absence. Although differences on school absence due to RTI were observed between spring and autumn, they were not statistically significant and in any case they may be due to the respiratory viruses’ seasonal pattern. In fact, the most important and significantly associated risk factor for RTI was the presence of someone else at home with respiratory symptoms, suggesting that households could be the main setting for initiating of the transmission of RTI.We observed a slightly association between RTI and median of CO2 levels in classrooms (p=0.07), which is an indicator of the degree of ventilation. However, we cannot exclude other potential factors such as rainfall, ambient temperature, or air pollutants (e.g. PM2.5, NO2, etc.) influencing on this outcome, as suggested by other authors10. To our knowledge, previous studies assessed the CO2concentration as a proxy of ventilation to evaluate the risk transmission of SARS-CoV-2 in schools11,12, but they did not analyse the association between CO2 median values and RTI incidence.Finally, we studied the symptomatology associated with the school absences through a LCA. The best approach to differentiate RTI from other causes was using two latent classes, and the most frequent symptoms were cough, nasal congestion and fever.The major strength of this study is our extensive data collection on clinical, epidemiological and environmental factors related to the school and also to the households of the participants. However, there were limitations such as possible incomplete reporting of RTI or insufficient sample size to determine small effect sizes. CO2 concentration was only measured in a selection of classrooms per school, so it may not be representative for the entire study period and school.In conclusion, RTI incidence was very high during the study period being the most important and significantly associated factor with RTI to have anyone else at home with respiratory symptoms. This suggests that households and not schools could be the key epidemiological factor for initiating the transmission of RTI to the children. Improving household preventive measures could reduce childhood RTI. In the LCA, the most frequent symptoms associated with RTI were cough, nasal congestion and fever. Although we found a slightly association between RTI and reduced ventilation we cannot exclude other potential factors influencing on this outcome. The study has been crucial to assess the feasibility and potential utility of collecting both school absence and morbidity data for further developing a systematic monitoring system.
The enemy release hypothesis (ERH) is the best-known hypothesis explaining high performance (e.g., rapid population growth) of exotic species. However, the current framing of the ERH does not explicitly link evidence of enemy release with exotic performance. This leads to uncertainty regarding the role of enemy release in biological invasions. Here we demonstrate that the effect of enemy release on exotic performance is the product of three factors: enemy impact, enemy diversity, and host adaptation. These factors are modulated by seven contexts: time since introduction, resource availability, phylogenetic relatedness of exotic and native species, host-enemy asynchronicity, number of introduction events, type of enemy, and strength of growth-defence trade-offs. ERH-focused studies frequently test different factors under different contexts, leading to inconsistent findings, which characterise current evidence for the ERH. For example, over 80% of meta-analyses fail to consider ecological contexts that can modulate study findings; we demonstrate this by re-analysing a recent ERH synthesis. Structuring the ERH around factors and contexts promotes generalisable predictions about when and where exotic species may benefit from enemy release, empowering effective management. Our mechanistic factor-context framework clearly lays out the evidence required to support the ERH, unifies many enemy-related invasion hypotheses and enhances predictive capacity.
Title : Synovial Sarcoma of the Maxilla: A Challenging Diagnostic Case Report and Literature ReviewAbstract : Synovial sarcoma, a malignant mesenchymal tumor, is primarily associated with the extremities. Nevertheless, its appearance within the head and neck region, particularly in the maxillary area, is remarkably rare. This rarity underscores the significance of each case in unraveling the complexities of its behavior and management strategies. The core focus of this research is a detailed case report involving a 6-year-old female patient who presented with a conspicuous swelling in the left posterior maxilla. Subsequent incisional biopsy led to microscopic identification of malignant spindle cell proliferation, marked by dysplastic changes and abundant mitoses. Immunohistochemical analysis demonstrated negative reactivity for neural and muscular markers, while positive expression of Vimentin, Bcl-2, and TLE1. These morphological and immunohistochemical findings coalesced to definitively diagnose synovial sarcoma, substantiated by a notable 40% Ki67 proliferative index. The chosen treatment strategy encompassed surgery and radiotherapy, which yielded successful outcomes, with no recurrence observed during the one-year follow-up period. Beyond the specific case, this article undertakes a review of existing literature, meticulously analyzing nine similar cases reported in scholarly sources.Keywords : Case report, Head and neck, Maxilla, Synovial sarcoma
By employing the asymmetric end-group engineering, an asymmetric nonfused-ring electron acceptors (NFREAs) was designed and synthesized. Compared with the symmetric analogs (NoCA-17 and NoCA-18), NoCA-19 possesses broader light absorption range, more coplanar π-conjugated backbone, and appropriate crystallinity according to the experimental and theoretical results. The organic solar cells based on J52:NoCA-19 exhibited a power conversion efficiency as high as 12.26%, which is much higher than those of J52:NoCA-17 (9.50%) and J52:NoCA-18 (11.77%), mainly due to more efficient exciton dissociation, better and balanced charge mobility, suppressed recombination loss, shorter charge extraction time, longer charge carrier lifetimes, and more favorable blend film morphology. These findings demonstrate the great potential of asymmetric end-group engineering in exploring low-cost and high-performance NFREAs.
A reexamination of clinical principles of long-term opioid therapy (LTOT) for chronic pain is long overdue amid the ongoing opioid crisis. Most patients on LTOT report ineffectiveness (poor pain control, function, and health), but still find deprescribing challenging. Although prescribed as analgesics, opioids more likely provide pain relief primarily through reward system actions (enhanced relief and motivation) and placebo effect and less through anti-nociceptive effects. The unavoidable physiologic LTOT dependence can automatically lead to a paradoxical worsening of pain, disability, and medical instability (maladaptive opioid dependence) without addiction due to allostatic opponent neuroadaptations involving reward/anti-reward and nociceptive/anti-nociceptive systems. This opioid induced chronic pain syndrome (OICP) can persist/progress whether LTOT dose is maintained at the same level, increased, decreased, or discontinued. Current conceptualization of LTOT as a straightforward long-term analgesic therapy appears incongruous in view of the complex mechanisms of opioid action, LTOT dependence and OICP. LTOT can be more appropriately conceptualized as therapeutic induction and maintenance of an adaptive LTOT dependence for functional improvement irrespective of analgesic benefits. Adaptive LTOT dependence should be ideally used for a limited time to achieve maximum functional recovery and deprescribed while maintaining functional gains. Patients on LTOT should be regularly reevaluated to identify if maladaptive LTOT dependence with OICP has diminished any functional gains or lead to ineffectiveness. Ineffective LTOT (with maladaptive LTOT dependence) should be modified to make it safer and more effective. An adequately functional life without opioids is the ideal healthy long-term goal for both LTOT initiation and LTOT modification.