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The severity of the ongoing opioid crisis, recently exacerbated by the COVID-19 pandemic, emphasizes the importance for individuals suffering from opioid use disorder (OUD) to have access to and receive efficacious, evidence-based treatments. Optimal treatment of OUD should aim at blocking the effects of illicit opioids while controlling opioid craving and withdrawal to facilitate abstinence from opioid use and promote recovery. The present work analyses the relationship between buprenorphine plasma exposure and clinical efficacy in participants with moderate to severe OUD using data from two clinical studies (39 and 504 participants). Leveraging data from placebo-controlled measures assessing opioid blockade, craving, withdrawal and abstinence, we found that buprenorphine plasma concentrations sustained at 2–3 ng/ml (corresponding to ≥70% brain mu -opioid receptor occupancy) optimized treatment outcomes in the majority of participants, while some individuals (e.g., injecting opioid users) needed higher concentrations. Our work also included non-linear mixed effects modeling and survival analysis, which identified a number of demographic, genetic and social factors modulating treatment response and retention. Altogether, these findings provide key information on buprenorphine plasma levels that optimize clinical outcomes and increase the likelihood of individual treatment success. NLM identifiers: NCT02044094, NCT02357901.

Background Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide and has poor prognosis. Specially, patients with HCC usually have poor tolerance of systemic chemotherapy, because HCCs develop from chronically damaged tissue that contains considerable inflammation, fibrosis, and cirrhosis. Since HCC exhibits highly heterogeneous molecular characteristics, a proper in vitro system is required for the study of HCC pathogenesis. To this end, we have established two new hepatitis B virus (HBV) DNA-secreting HCC cell lines from infected patients. Methods Based on these two new HCC cell lines, we have developed chemosensitivity assays for patient-derived multicellular tumor spheroids (MCTSs) in order to select optimized anti-cancer drugs to provide more informative data for clinical drug application. To monitor the effect of the interaction of cancer cells and stromal cells in MCTS, we used a 3D co-culture model with patient-derived HCC cells and stromal cells from human hepatic stellate cells, human fibroblasts, and human umbilical vein endothelial cells to facilitate screening for optimized cancer therapy. Results To validate our system, we performed a comparison of chemosensitivity of the three culture systems, which are monolayer culture system, tumor spheroids, and MCTSs of patient-derived cells, to sorafenib, 5-fluorouracil, and cisplatin, as these compounds are typically standard therapy for advanced HCC in South Korea. Conclusion In summary, these findings suggest that the MCTS culture system is the best methodology for screening for optimized treatment for each patients with HCC, because tumor spheroids not only mirror the 3D cellular context of the tumors but also exhibit therapeutically relevant pathophysiological gradients and heterogeneity of in vivo tumors.

Spruce budworm (Choristoneura fumiferana Clem.; SBW) outbreaks are one of the dominant natural disturbances in North America, having killed balsam fir (Abies balsamea (L.) Mill.) and spruce (Picea sp.) trees over tens of millions of hectares. Responses to past SBW outbreaks have included the aerial application of insecticides to limit defoliation and keep trees alive, salvage harvesting of dead and dying trees, or doing nothing and accepting the resulting timber losses. We tested a new ‘early intervention strategy’ (EIS) focused on suppressing rising SBW populations before major defoliation occurs, from 2014 to 2018 in New Brunswick, Canada. The EIS approach included: (1) intensive monitoring of overwintering SBW to detect ‘hot spots’ of low but rising populations; (2) targeted insecticide treatment to prevent spread; and (3) proactive public communications and engagement on project activities and results. This is the first attempt of area-wide (all areas within the jurisdiction of the province of New Brunswick) management of a native forest insect population. The project was conducted by a consortium of government, forest industry, researchers, and other partners. We developed a treatment priority and blocking model to optimize planning and efficacy of EIS SBW insecticide treatment programs. Following 5 years of over 420,000 ha of EIS treatments of low but increasing SBW populations, second instar larvae (L2) SBW levels across northern New Brunswick were found to be considerably lower than populations in adjacent Québec. Treatments increased from 4500 ha in 2014, to 56,600 ha in 2016, and to 199,000 ha in 2018. SBW populations in blocks treated with Bacillus thuringiensis or tebufenozide insecticide were consistently reduced, and generally did not require treatment in the subsequent year. Areas requiring treatment increased up to 2018, but SBW L2 populations showed over 90% reductions in that year. Although this may be a temporary annual decline in SBW population increases, it is counter to continued increases in Québec. Following 5 years of tests, the EIS appears to be effective in reducing the SBW outbreak.

Abstract The molecular complexity of cancer presents significant challenges to traditional therapeutic approaches, necessitating the development of innovative treatment strategies capable of addressing the disease’s dynamic nature and resistance mechanisms. Data-driven methodologies, particularly those employing Artificial Intelligence (AI), hold substantial promise by advancing a comprehensive understanding of the intricate molecular and cellular mechanisms underlying cancer and supporting the development of adaptive, patient-specific therapeutic strategies. Initiated through the Mertelsmann Foundation, the Collaborative Research Institute Intelligent Oncology (CRIION) in Freiburg im Breisgau, Germany, aims to drive progress in AI-driven oncology. CRIION fosters global collaboration through initiatives like the Intelligent Oncology Symposium and supports multidisciplinary projects designed to integrate AI innovations into clinical workflows.

Zusammenfassung Das abrupte Einsetzen der Situation nach einer traumatischen Amputation und die vorbereitenden Gespräche nach frustranem Erhaltungsversuch bei Gliedmaßenverletzung mit notwendiger Amputation erfordern ein hohes Maß an Empathie, Zuwendung und fundierten Informationen, die individuell für die Betroffenen aufgearbeitet sein müssen. Eine Optimierung des Behandlungsablaufes kann nur unter Beachtung dieser Aspekte erreicht werden. Die eigene Motivation und Mitarbeit sollen bei den Patientinnen und Patienten gefördert werden. Um dieses Ziel zu erreichen, eignen sich für die Beratung aus Ermangelung eigener Erfahrung weniger die beteiligten Professionen als viel mehr sog.Peers, die als kundige und selbsterfahrene Berater fungieren können. Diese Erkenntnis lässt sich aus vorhandenen Studien ableiten. Die Peerberatung (das Peer Counseling) konnte in der Unfallchirurgie zunehmend und mit positiven Effekten als ein gesondertes Instrument in die alltägliche Behandlung nach Amputation integriert werden. Sie gilt als leitliniengerechtes Verfahren nicht nur in der Rehabilitation. Vor dem Hintergrund langjährig gültiger Gesetzgebungen, insbesondere der UN-Behindertenrechtskonvention, und den Forderungen der von Amputation Betroffenen werden im vorliegenden Beitrag die Instrumentalisierung und der Nutzen der Beratung in den Fokus genommen. Die Strukturen dieser besonderen Beratungsoption, auch mit regelmäßiger Schulung der Berater, sowie der etablierte Einsatz sind derzeit nicht selbstverständlich gegeben, werden aber stetig ausgebaut und den Bedürfnissen angepasst. Ausstehend sind konkrete wissenschaftliche Nachweise über messbare Effekte und positive Auswirkungen auf das Outcome, die in einem aktuellen Forschungsvorhaben dargestellt werden.

This study was conducted to evaluate the application value of optimized treatment with radiofrequency (RF) thermotherapy and immunotherapy combined with CyberKnife for advanced high-risk tumors. The database of 1,013 patients with 2,136 tumor lesions and 1,237 target areas who underwent treatment with CyberKnife between November, 2010 and November, 2012, was retrospectively reviewed. We randomly assigned 505 eligible patients (observation group) to RF thermotherapy and adoptive immunotherapy with cytokine-induced killer cells and the remaining 508 patients (control group) to no adjuvant treatment. The patients in the two groups were recorded on efficacy assessment according to imageological examination, World Health Organization criteria, Karnofsky performance status, or radioimmunoassay (RIA) detection. The effective rate of the observation group was 75.05%, whereas that of the control group was 58.06% (P<0.05). The results revealed that CyberKnife combined with hyperthermia and biological therapy are highly effective in improving the local tumor control rate. Further analysis of the Karnofsky score and RIA detection confirmed that this type of combination therapy significantly improved the quality of life. The optimized treatment of RF thermotherapy and immunotherapy combined with CyberKnife may act synergistically in eliminating tumor cells, confirming the efficacy of this type of treatment for patients with advanced malignant tumors.

Induction and maintenance of remission, mucosal healing, the avoidance of surgical intervention, and decreasing the likelihood of cancer developing are the primary therapeutic goals in ulcerative colitis (UC). For the traditional therapies, 5-aminosalicylic acid (including mesalamine), corticosteroids, and thiopurines (azathioprine and mercaptopurine), there are major changes evolving in terms of formulation, patterns of use, and appreciation of long-term benefits and toxicities. The calcineurin inhibitors cyclosporin and tacrolimus, and infliximab, have recently defined, well-established roles. Preliminary supportive evidence is emerging in relation to novel antiinflammatory molecules such as curcumin, manipulation of the bacterial flora, enhancement of the mucosal barrier, and direct epithelial restoration. For patients in whom the disease is resistant to standard simple therapies, strategies are required to integrate these developing and new therapies into clinical practice. This review aims to highlight the evidence supporting new patterns of use of existing therapies and new therapies, and to devise therapeutic pathways that incorporate these new treatments. We propose how treatment might be optimized to improve the outcome in patients with mild-to-moderately active UC, chronic active UC, resistant proctitis, and fulminant UC.

For the low efficiency and large loss of cascade pumping stations, aiming to maximize system efficiency, an optimized scheduling model of cascade pumping stations is established with consideration of multiple constraints, and the optimal scheduling method based on the improved sparrow search algorithm (BSSA) is proposed. The BSSA is initialized by the Bernoulli chaotic map to solve the insufficient initial diversity of the sparrow search algorithm (SSA). The random boundary strategy is introduced to avoid local optimum when dealing with the scheduling problem of pumping stations. The performance and improvement strategy of BSSA are verified by eight benchmark functions. Results show that BSSA has better convergence accuracy and faster speed. BSSA is applied to a three-stage pumping station considering three flow conditions, and compared with the current scheme, particle swarm optimization and genetic algorithm optimization schemes, the operation efficiency of SSA can be increased by 0.72–0.96%, and operation cost can be reduced by ¥263,000/a–¥363,300/a. On this basis, the improvement of 0.04–0.30% and ¥14,800/a–¥109,900/a can be further achieved by the BSSA, which confirms the feasibility and effectiveness of BSSA to solve the pumping station optimal scheduling problem. The findings present useful reference for the optimized scheduling of pumping station system.

Background. Evidence is sparse regarding the optimal construction of regimens to treat multidrug-resistant (MDR) tuberculosis disease due to strains of Mycobacterium tuberculosis resistant to at least both isoniazid and rifampin. Given the low potency of many second-line antituberculous drugs, we hypothesized that an aggressive regimen of at least 5 likely effective drugs during the intensive phase, including a fluoroquinolone and a parenteral agent, would be associated with a reduced risk of death or treatment failure. Methods. We conducted a retrospective cohort study of patients initiating MDR tuberculosis treatment between 2000 and 2004 in Tomsk, Russian Federation. We used a multivariate Cox proportional hazards model to assess whether monthly exposure to an aggressive regimen was associated with the risk of death or treatment failure. Results. Six hundred fourteen individuals with confirmed MDR tuberculosis were eligible for analysis. On multivariable analysis that adjusted for extensively drug-resistant (XDR) tuberculosis—MDR tuberculosis isolates resistant to fluoroquinolones and parenteral agents—we found that monthly exposure to an aggressive regimen was significantly associated with a lower risk of death or treatment failure (hazard ratio, 0.52 [95% confidence interval, .29–.94]; P = .030). Conclusions. Receipt of an aggressive treatment regimen was a robust predictor of decreased risk of death or failure during MDR tuberculosis treatment. These findings further support the use of this regimen definition as the benchmark for the standard of care of MDR tuberculosis patients and should be used as the basis for evaluating novel therapies.

The combination of folinic acid, 5-fluorouracil, oxaliplatin and/or irinotecan (FOLFOXIRI) is the standard of care for metastatic colorectal cancer (CRC). This strategy inhibits tumor growth but provokes drug resistance and serious side effects. We aimed to improve FOLFOXIRI by optimization of the dosing and the sequence of drug administration. We employed an orthogonal array composite design and linear regression analysis to obtain cell line-specific drug combinations for four CRC cell lines (DLD1, SW620, HCT116, LS174T). Our results confirmed the synergy between folinic acid and 5-fluorouracil and additivity, or even antagonism, between the other drugs of the combination. The drug combination administered at clinical doses resulted in significantly higher antagonistic interactions compared to the low-dose optimized drug combination (ODC). We found that the concomitant administration of the optimized drug combination (ODC) was comparatively active to sequential administration. However, the administration of oxaliplatin or the active metabolite of irinotecan seemed to sensitize the cells to the combination of folinic acid and 5-fluorouracil. ODCs were similarly active in non-cancerous cells as compared to the clinically used doses, indicating a lack of reduction of side effects. Interestingly, ODCs were inactive in CRC cells chronically pretreated with FOLFOXIRI, suggesting the occurrence of resistance. We were unable to improve FOLFOXIRI in terms of efficacy or specificity. Improvement of CRC treatment should come from the optimization of targeted drugs and immunotherapy strategies.