Chemotactic Micro/Nanomotors for Biomedical Applications.

In nature, many organisms respond chemotactically to external chemical stimuli in order to extract nutrients or avoid danger. Inspired by this natural chemotaxis, micro/nanomotors with chemotactic properties have been developed and applied to study a variety of disease models. This chemotactic strategy has shown promising results and has attracted the attention of an increasing number of researchers. This paper mainly reviews the construction methods of different types of chemotactic micro/nanomotors, the mechanism of chemotaxis, and the potential applications in biomedicine. First, based on the classification of materials, the construction methods and therapeutic effects of chemotactic micro/nanomotors based on natural cells and synthetic materials in cellular and animal experiments will be elaborated in detail. Second, the mechanism of chemotaxis of micro/nanomotors is elaborated in detail: chemical reaction induced chemotaxis and physical process driven chemotaxis. In particular, the main differences and significant advantages between chemotactic micro/nanomotors and magnetic, electrical and optical micro/nanomotors are described. The applications of chemotactic micro/nanomotors in the biomedical fields in recent years are then summarized, focusing on the mechanism of action and therapeutic effects in cancer and cardiovascular disease. Finally, the authors are looking forward to the future development of chemotactic micro/nanomotors in the biomedical fields.

Epigenome signature as an immunophenotype indicator prompts durable clinical immunotherapy benefits in lung adenocarcinoma.

Intertumoral immune heterogeneity is a critical reason for distinct clinical benefits of immunotherapy in lung adenocarcinoma (LUAD). Tumor immunophenotype (immune 'Hot' or 'Cold') suggests immunological individual differences and potential clinical treatment guidelines. However, employing epigenome signatures to determine tumor immunophenotypes and responsive treatment is not well understood. To delineate the tumor immunophenotype and immune heterogeneity, we first distinguished the immune 'Hot' and 'Cold' tumors of LUAD based on five immune expression signatures. In terms of clinical presentation, the immune 'Hot' tumors usually had higher immunoactivity, lower disease stages and better survival outcomes than 'Cold' tumors. At the epigenome levels, we observed that distinct DNA methylation patterns between immunophenotypes were closely associated with LUAD development. Hence, we identified a set of five CpG sites as the immunophenotype-related methylation signature (iPMS) for tumor immunophenotyping and further confirmed its efficiency based on a machine learning framework. Furthermore, we found iPMS and immunophenotype-related immune checkpoints (IPCPs) could contribute to the risk of tumor progression, implying IPCP has the potential to be a novel immunotherapy blockade target. After further parsing of the role of iPMS-predicted immunophenotypes, we found immune 'Hot' was a protective factor leading to better survival outcomes when patients received the anti-PD-1/PD-L1 immunotherapy. And iPMS was also a well-performed signature (AUC = 0.752) for predicting the durable/nondurable clinical benefits. In summary, our study explored the role of epigenome signature in clinical tumor immunophenotyping. Utilizing iPMS to characterize tumor immunophenotypes will facilitate developing personalized epigenetic anticancer approaches.

Unlocking the full potential of mesenchymal stromal cell therapy for osteoarthritis through machine learning-based in silico trials.

Despite the potential of mesenchymal stromal cells (MSCs) in osteoarthritis (OA) treatment, the challenge lies in addressing their therapeutic inconsistency. Clinical trials revealed significantly varied therapeutic outcomes among patients receiving the same allogenic MSCs but different treatment regimens. Therefore, optimizing personalized treatment strategies is crucial to fully unlock MSCs' potential and enhance therapeutic consistency. We employed the XGBoost algorithm to train a self-collected database comprising 37 published clinical reports to create a model capable of predicting the probability of effective pain relief and Western Ontario and McMaster Universities (WOMAC) index improvement in OA patients undergoing MSC therapy. Leveraging this model, extensive in silico simulations were conducted to identify optimal personalized treatment strategies and ideal patient profiles. Our in silico trials predicted that the individually optimized MSC treatment strategies would substantially increase patients' chances of recovery compared to the strategies used in reported clinical trials, thereby potentially benefiting 78.1%, 47.8%, 94.4% and 36.4% of the patients with ineffective short-term pain relief, short-term WOMAC index improvement, long-term pain relief and long-term WOMAC index improvement, respectively. We further recommended guidelines on MSC number, concentration, and the patients' appropriate physical (body mass index, age, etc.) and disease states (Kellgren-Lawrence grade, etc.) for OA treatment. Additionally, we revealed the superior efficacy of MSC in providing short-term pain relief compared to platelet-rich plasma therapy for most OA patients. This study represents the pioneering effort to enhance the efficacy and consistency of MSC therapy through machine learning applied to clinical data. The in silico trial approach holds immense potential for diverse clinical applications.

Tryptophan metabolism in digestive system tumors: unraveling the pathways and implications.

Tryptophan (Trp) metabolism plays a crucial role in influencing the development of digestive system tumors. Dysregulation of Trp and its metabolites has been identified in various digestive system cancers, including esophageal, gastric, liver, colorectal, and pancreatic cancers. Aberrantly expressed Trp metabolites are associated with diverse clinical features in digestive system tumors. Moreover, the levels of these metabolites can serve as prognostic indicators and predictors of recurrence risk in patients with digestive system tumors. Trp metabolites exert their influence on tumor growth and metastasis through multiple mechanisms, including immune evasion, angiogenesis promotion, and drug resistance enhancement. Suppressing the expression of key enzymes in Trp metabolism can reduce the accumulation of these metabolites, effectively impacting their role in the promotion of tumor progression and metastasis. Strategies targeting Trp metabolism through specific enzyme inhibitors or tailored drugs exhibit considerable promise in enhancing therapeutic outcomes for digestive system tumors. In addition, integrating these approaches with immunotherapy holds the potential to further enhance treatment efficacy.

Integrated molecular characterization of esophageal basaloid squamous cell carcinoma: a subtype with distinct RNA expression pattern and immune characteristics, but no specific genetic mutations.

Esophageal basaloid squamous cell carcinoma (bSCC) is a subtype of squamous cell carcinoma (SCC) with a different behavior and poor prognosis. Exploring bSCC's molecular characteristics and treatment strategies are of great clinical significance. We performed multi-omics analysis of paired bSCC and common SCC (cSCC) using whole exome sequencing and a NanoString nCounter gene expression panel. Immunohistochemistry was used for verification of candidate biomarkers. Different treatment response was analyzed on both patients receiving neoadjuvant treatment and late-stage patients. The common genetically-clonal origin of bSCC and cSCC was confirmed. No significant differences between their genetic alterations or mutation spectra were observed. Mutation signature 15 (associated with defective DNA damage repair) was less prominent, and tumor mutational burden (TMB) was lower in bSCC. bSCC with an RNA expression pattern resembling cSCC had a better survival than other bSCCs. Moreover, bSCC showed significant upregulation of expression of genes associated with angiogenesis response, basement membranes, and epithelial-mesenchymal transition, and downregulation of KRT14 (squamous differentiation) and CCL21 (associated with immune response). Immunohistochemistry for SFRP1 was shown to be highly sensitive and specific for bSCC diagnosis (p < 0.001). In addition, bSCC receiving neoadjuvant immuno-chemotherapy had a worse pathological response than bSCC receiving neoadjuvant chemotherapy (but without statistical significance), even in bSCC positive for PD-L1. Our results demonstrated the molecular characteristics of esophageal bSCC as a subtype with a distinct RNA expression pattern and immune characteristics, but no specific genetic mutations. We provided a useful biomarker, SFRP1, for diagnosis. After outcome analysis for six bSCCs with neoadjuvant immunotherapy treatment and four late-stage bSCCs with immunotherapy, we found that immunotherapy may not be an effective treatment option for most bSCCs. This may also provide a clue for the same subtypes of lung and head and neck cancer. Our study highlighted the heterogeneity among bSCC patients, and might explain the conflicting results of bSCC outcomes in existing studies. © 2022 The Pathological Society of Great Britain and Ireland.

Gastric cancer in pregnancy: a review.

Malignant tumors including gastric cancer (GC) are the leading cause of deaths among reproductive women. Physiological morning sickness can mask the clinical manifestations of GC, whereas the clinical presence of metastatic tumors in the abdominal cavity may be easily mistaken for abdominal swelling caused by fetal growth. Pregnancy and delivery processes in young females could accelerate the growth of GC, leading to its rapid development and grave prognosis. Therefore, early diagnosis is critical and gastrointestinal endoscopy is recommended for any suspected pregnant woman with long-term morning sickness. Treatment strategies, including chemotherapy, resection surgery and radiotherapy, will be determined based on a comprehensive consideration of the status of both the fetus and the mother. Rational management, especially clinical multidisciplinary collaboration may significantly benefit such patients.

[Box: see text].

Current Treatment Practices for Adult Patients with Constipation in Japan.

BACKGROUND: The prevalence of constipation in Japan is estimated to be 2-5%. Constipation is a disease found in older adults. In particular, Japan is an aging society, with 65% of men and 80.5% of women aged 65 years or older accounting for the majority of its population. Chronic constipation may be associated with survival, cardiovascular events, decreased quality of life, and death. This study summarizes the recent findings regarding constipation treatment practice in Japan. SUMMARY: Until recently, the diagnosis of constipation was mainly based on medical interviews; however, with the recent development of handheld ultrasound devices, both physicians and nurses can easily and objectively diagnose fecal retention. Magnesium oxide and stimulant laxatives have been the mainstay treatments; however, since 2012, more than five new drugs for treating constipation have become available in Japan. KEY MESSAGES: Magnesium oxide is less effective in patients who use acid-secretion inhibitors and patients who have undergone total gastrectomy and should be cared for hypermagnesemia. In addition, regular use of stimulant laxatives may lead to colonic inertia and decreased bowel movements; therefore, they should be used only occasionally. The following is an overview of the different uses of conventional and newer laxatives for treating constipation.

An 'Adaptive Treatment Strategy' for Oral Vancomycin in Patients with the Orphan Disease Primary Sclerosing Cholangitis.

Decision-making in clinical medicine ideally is based upon evidence from randomized, placebo-controlled trials (RCTs) and subsequent systematic reviews and meta-analyses. However, for orphan diseases, the expectation of having one or multiple RCTs that inform clinical guidelines or justify specific treatments can be unrealistic and subsequent therapeutic nihilism can be detrimental to patients. This article discusses the benefits of therapeutic decision-making in the context of orphan diseases, focusing on primary sclerosing cholangitis (PSC) as an example of an orphan disease with poor clinical outcomes. PSC is a rare disorder characterized by inflammation and progressive fibrosis of the bile ducts. It carries a high risk of liver failure, malignancies, and debilitating symptoms that impair quality of life. Liver transplantation is currently the only life-prolonging intervention for PSC, but it is not a curative option. The article highlights the potential benefits of treating PSC patients with oral vancomycin (OV), which has shown significant clinical responses and improved quality of life in some cases. However, access to OV therapy is limited due to the lack of RCTs supporting its use. The standard requirement of having evidence from RCTs may result in withholding potentially life-altering and/or life-saving treatments for patients with orphan diseases. Conducting RCTs is challenging in these patient populations due to difficulties in recruiting the required patient cohorts and limited commercial returns. A standardized 'adaptive treatment strategy' is proposed to address this. This approach leverages the best available evidence for specific treatments, considers individual clinical responses, and adjusts treatment over time.

Treatment strategies for patients with out-of-hospital cardiac arrest associated with traumatic brain injury: A case series.

INTRODUCTION: Collapse after out-of-hospital cardiac arrest (OHCA) can cause severe traumatic brain injury (TBI). We aimed to investigate the clinical characteristics and treatment strategies for patients with OHCA and TBI. METHODS: We analyzed a consecutive cohort of patients with intrinsic OHCA retrospectively treated between January 2011 and December 2021 at a single critical care center, and presented a case series of seven patients. Patients with collapse-related TBI were examined for the causes and situations of cardiac arrest, laboratory data, radiological images, targeted temperature management (TTM), coronary angiography (CAG), percutaneous coronary intervention (PCI), and extracorporeal cardiopulmonary resuscitation (ECPR). RESULTS: Of the 197 patients with intrinsic OHCA, 7 (3.6%) had TBI (age range: 49-70 years; 6 men). All seven patients presented with ventricular fibrillation in the initial electrocardiograms, with four refractory cases treated with ECPR. All patients underwent CAG under heparinization, and four underwent PCI with antiplatelet administration. Initial head computed tomography indicated an intracranial hemorrhage (ICH) in three patients. ICH appeared or was exacerbated in six patients after CAG with or without PCI, except in one who underwent delayed PCI. All patients displayed elevated plasma D-dimer levels, and four underwent neurosurgical procedures. Four patients survived (three with cerebral performance category [CPC] 2, one with CPC 3) and three died; two had hypoxic-ischemic brain injury and one had severe TBI. CONCLUSION: Delayed ICH occurred frequently. Individualized management is required based on the extent of brain and cardiac damage, including optimal TTM, PCI procedures, and antiplatelet medications. Early detection of ICH and emergency treatment are critical for multi-disciplinary collaboration.

Potential therapeutic effect of a ketogenic diet for the treatment of lymphoedema: Results of an exploratory study.

BACKGROUND: Lymphoedema is a chronic and progressive disease characterised by excessive accumulation of lymph in the interstitial compartment, leading to tissue swelling and fibroadipose deposition. Lymphangiogenesis is partly regulated by ketone body oxidation, and a ketogenic diet (KD) has shown therapeutic efficacy in a preclinical mouse tail lymphoedema model. Therefore, we aimed to investigate the potential therapeutic effect of a KD in patients with secondary lymphoedema. METHODS: Nine patients with unilateral stage 2 lymphoedema secondary to lymphadenectomy were included in this quasi-experimental exploratory study consisting of a short run-in phase to gradually induce ketosis, followed by a classic KD (CKD) and modified Atkins diet (MAD) phase during which patients consumed a CKD and MAD, respectively. Lymphatic function and oedema volume, the primary outcomes, were assessed at baseline and at the end of both the CKD and MAD phase. Secondary outcomes included health-related and lymphedema-specific quality of life (QoL). RESULTS: Seven out of nine patients completed the study protocol. Lymphatic function was improved upon consumption of both a CKD (dermal backflow score [mean ± SD]: 7.29 ± 2.98 vs. 10.86 ± 2.19 at baseline; p = 0.03) and MAD (6.71 ± 2.06; p = 0.02), whereas oedema volume did not decrease during the course of the study (excess limb volume [mean ± SD]: 20.13 ± 10.25% at end of CKD and 24.07 ± 17.77% at end of MAD vs. 20.79 ± 12.96% at baseline; p > 0.99 and p > 0.30, respectively). No changes were observed in health-related, nor lymphoedema-specific QoL at the end of CKD and MAD. CONCLUSIONS: The consumption of a KD improved lymphatic function and was associated with a clinically meaningful reduction in oedema volume in some patients (3/7 at end of CKD, 2/7 at end of MAD) with unilateral stage 2 secondary lymphoedema. These results highlight the potential of a KD to improve lymphatic function in patients with lymphoedema. However, further studies are required to substantiate our findings.

Quercetin increases the antidepressant-like effects of sclareol and antagonizes diazepam in thiopental sodium-induced sleeping mice: A possible GABAergic transmission intervention.

Quercetin is the most common polyphenolic flavonoid present in fruits and vegetables demonstrating versatile health-promoting effects. This study aimed to examine the effects of quercetin (QR) and sclareol (SCL) on the thiopental sodium (TS)-induced sleeping and forced swimming test (FST) mouse models. SCL (1, 5, and 10 mg/kg, p.o.) or QR (50 mg/kg, p.o.) and/or diazepam (DZP) (3 mg/kg, i.p.) were employed. After 30 min of TS induction, individual or combined effects on the animals were checked. In the FST test, the animals were subjected to forced swimming after 30 min of administration of the test and/or controls for 5 min. In this case, immobility time was measured. In silico studies were conducted to evaluate the involvement of GABA receptors. SCL (5 and 10 mg/kg) significantly increased the latency and decreased sleeping time compared to the control in the TS-induced sleeping time study. DZP (3 mg/kg) showed a sedative-like effect in animals in both sleeping and FST studies. QR (50 mg/kg) exhibited a similar pattern of activity as SCL. However, its effects were more prominent than those of SCL groups. SCL (10 mg/kg) altered the DZP-3-mediated effects. SCL-10 co-treated with QR-50 significantly (p < 0.05) increased the latency and decreased sleep time and immobility time, suggesting possible synergistic antidepressant-like effects. In silico studies revealed that SCL and QR demonstrated better binding affinities with GABAA receptor, especially α2, α3, and α5 subunits. Both compounds also exhibited good ADMET and drug-like properties. In animal studies, the both compounds worked synergistically to provide antidepressant-like effects in a slightly different fashion. As a conclusion, the combined administration of SCL and QR may be used in upcoming neurological clinical trials, according to in vivo and in silico findings. However, additional investigation is necessary to verify this behavior and clarify the potential mechanism of action.

Prognostic value and potential mechanism of cellular senescence and tumor microenvironment in hepatocellular carcinoma: Insights from bulk transcriptomics and single-cell sequencing analysis.

The high mortality rate and postoperative recurrence of hepatocellular carcinoma (HCC) contribute to the burden on society and healthcare. The prognostic value and underlying mechanisms of cellular senescence and tumor microenvironment (TME) in HCC remain unclear. Bulk transcriptomic data were obtained from 368 HCC samples in The Cancer Genome Atlas-liver hepatocellular carcinoma cohort and 64 samples from the GSE116174 dataset. Single-cell RNA sequencing (scRNA-seq) data of HCC were obtained from the GSE149614 dataset, including 18 tumor samples from 10 patients. Prognosis-related cellular senescence genes and immune cells were identified through univariate analysis. Least absolute shrinkage and selection operator regression analysis was performed to construct the CellAge score and TME score, both of which were identified as independent prognostic factors for HCC based on multivariate Cox analysis. The combined CellAge and TME scores showed improved prognostic stratification for HCC patients, as confirmed by multivariate Cox analysis (p < .001). The gene set enrichment analysis (GSEA) revealed enrichment of the extracellular matrix receptor interaction signaling pathway in the group with high CellAge scores and low TME scores, which exhibited a worse prognosis. Single-cell sequencing results revealed higher expression activity of the cAMP response element modulator (CREM) extended transcription factor in HCC cells and most immune cells, indicating its involvement in TME remodeling. Finally, the tumor immune dysfunction and exclusion (TIDE) analysis demonstrated that the combined scores could predict the outcomes of immune therapy in patients with HCC. In conclusion, cellular senescence contributes to TME remodeling in HCC, and the developed CellAge and TME scores serve as independent prognostic factors and predictors of immune therapy in HCC.

Risk factors, impact and treatment of postoperative lymphatic leakage in children with abdominal neuroblastoma operated on by laparotomy.

BACKGROUND: Lymphatic leakage is one of the postoperative complications of neuroblastoma. The purpose of this study is to summarize the clinical characteristics and risk factors of lymphatic leakage and try to find effective prevention and treatment measures. METHODS: A retrospective study included 186 children with abdominal neuroblastoma, including 32 children of lymphatic leakage and 154 children of non-lymphatic leakage. The clinical information, surgical data, postoperative abdominal drainage, treatment of lymphatic leakage and prognosis of the two groups were collected and analyzed. RESULTS: The incidence of lymphatic leakage in this cohort was 14% (32 children). Through univariate analysis of lymphatic leakage group and non-lymphatic leakage group, we found that lymphatic leakage increased the complications, prolonged the time of abdominal drainage and hospitalization, and delayed postoperative chemotherapy (p < 0.05). In this cohort, the median follow-up time was 46 (95% CI: 44-48) months. The follow-up data of 7 children were partially missing. 147 children survived, of which 23 had tumor recurrence (5 children recurred in the surgical area). 37 children died, of which 32 had tumor recurrence (9 children recurred in the operation area). In univariate analysis, there was no statistical difference in overall survival (p = 0.21) and event-free survival (p = 0.057) between lymphatic leakage group and non-lymphatic leakage group, while 3-year cumulative incidence of local progression was higher in lymphatic leakage group (p = 0.015). However, through multivariate analysis, we found that lymphatic leakage did not affect event-free survival, overall survival and cumulative incidence of local progression in children with neuroblastoma. Resection of 5 or more lymphatic regions was an independent risk factor for lymphatic leakage after neuroblastoma surgery. All 32 children with lymphatic leakage were cured by conservative treatment without surgery. Of these, 75% (24/32) children were cured by fat-free diet or observation, 25% (8/32) children were cured by total parenteral nutrition. The median drain output at diagnosis in total parenteral nutrition group was higher than that in non-total parenteral nutrition group (p < 0.001). The cut-off value was 17.2 ml/kg/day. CONCLUSIONS: Lymphatic leakage does not affect the prognosis of children with neuroblastoma, but long-term drain output caused by lymphatic leakage will still adversely affect postoperative complications and follow-up treatment, which requires attention and active treatment measures. More attention should be paid to the children with 5 or more lymphatic regions resection, and the injured lymphatic vessels should be actively found and ligated after tumor resection to reduce the postoperative lymphatic leakage. Early application of total parenteral nutrition is recommended for those who have drain output at diagnosis of greater than 17.2 ml/kg/day. LEVEL OF EVIDENCE: Level III, Treatment study (Retrospective comparative study).

Comparison of the Pre-Established and Finally Selected Treatment Strategies for Endovascular Treatment in Femoropopliteal Artery Lesions.

This study aimed to compare lower limb events associated with preplanned and finally selected treatment strategies-the validity and usefulness of the physician-chosen strategy were verified.We examined the data of 1003 patients in the registry of multicenter endovascular treatment for superficial femoral and popliteal artery disease study and prospectively enrolled patients who underwent endovascular treatment (EVT) of the femoropopliteal (FP) artery between February 2017 and June 2018 from 67 Japanese institutes. The outcome measures were major adverse limb events (MALE) and target vessel revascularization.The EVT strategies were classified into balloon angioplasty-alone (37.3%), primary stenting (26.7%), and provisional stenting (36.0%) groups. In the initial strategy analysis for the balloon angioplasty-alone, primary stenting, and provisional stenting groups, two-year rates of freedom from MALE (95% confidence interval) were 0.680 (0.620-0.732), 0.754 (0.688-0.808), and 0.798 (0.746-0.840), respectively. Additionally, the rate of MALE was significantly higher among patients in the balloon angioplasty-alone group than among those in the primary or provisional stenting groups in the initial strategy analysis (P = 0.007). Changes in treatment strategy were more frequent in the primary stenting group than in the other groups. Furthermore, the rate of MALE did not significantly differ among the three groups in the final strategy analysis (P = 0.56).Limb outcomes for the final applied strategy did not differ among the three strategies. Additionally, the physician's selection bias was mostly appropriate in the EVT of the FP artery.

Blast injuries with contrasting outcomes treated by military surgery strategies: A case report.

The treatment strategy for blast injuries is closely linked to the clinical outcome of blast injury casualties. However, the application of military surgery experience to blast injuries caused by production safety accidents is relatively uncommon. In this study, the authors present 2 cases of blast injuries caused by one gas explosion, both cases involved individuals of the same age and gender and experienced similar degree of injury. The authors highlight the importance of using a military surgery treatment strategy, specifically emphasizing the need to understand the concept of damage control and disposal. It is recommended that relevant training in this area should be strengthened to improve the clinical treatment of such injuries. This study provides a valuable reference for healthcare professionals dealing with blast injuries.

Proactive Therapeutic Drug Monitoring Versus Conventional Management for Inflammatory Bowel Diseases: A Systematic Review and Meta-Analysis.

BACKGROUND & AIMS: Proactive therapeutic drug monitoring (TDM) has been proposed to improve outcomes in patients with inflammatory bowel disease (IBD) treated with tumor necrosis factor (TNF)α antagonists. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing proactive TDM with conventional management in patients with IBD. METHODS: We identified RCTs in patients with IBD treated with TNFα antagonists comparing proactive TDM (routine assessments of trough concentration with dose adjustments to maintain predetermined trough concentration, regardless of disease activity) with conventional management (clinically driven dose adjustments). The primary outcome was failure to maintain clinical remission. Certainty of evidence was appraised using Grading of Recommendations, Assessment, Development and Evaluations. RESULTS: On meta-analysis of 9 RCTs (8 RCTs in adults, and focusing on maintenance phase), there was no significant difference in the risk of failing to maintain clinical remission in patients who underwent proactive TDM (267/709; 38%) vs conventional management (292/696; 42%) (relative risk [RR], 0.96; 95% confidence interval [CI], 0.81-1.13) with moderate heterogeneity (inconsistency index = 36%) (Grading of Recommendations, Assessment, Development and Evaluations; low certainty evidence), with no differences in patients with Crohn's disease (RR, 0.87 ; 95% CI, 0.66-1.15) and ulcerative colitis (RR, 0.88; 95% CI, 0.72-1.07). Disease duration, concomitant immunomodulators, disease activity at baseline, and optimization of therapy before randomization did not modify this association. No differences were observed in risk of developing antidrug antibodies or serious adverse events. Patients in the proactive TDM arm were more likely to undergo dose escalation (RR, 1.56; 95% CI, 1.25-1.94). CONCLUSIONS: Routine proactive TDM to target biologic concentration to specific thresholds, regardless of disease activity, did not offer clinical benefit in patients with IBD treated with TNFα antagonists in RCTs conducted to date. We cannot exclude the possibility of benefit in disease subtypes and phases of therapy (induction) not represented in these RCT populations.

Impact of initial therapy with upadacitinib or adalimumab on achievement of 48-week treatment goals in patients with rheumatoid arthritis: post hoc analysis of SELECT-COMPARE.

OBJECTIVES: Evaluate the importance of treatment sequencing in SELECT-COMPARE, assessing potential differences between starting upadacitinib or adalimumab therapy following inadequate MTX response. METHODS: Patients from SELECT-COMPARE were randomized to upadacitinib 15 mg once daily, placebo or adalimumab 40 mg. Per protocol, patients with <20% improvement in tender or swollen joint counts (weeks 14, 18, 22) or failure to achieve Clinical Disease Activity Index (CDAI) low disease activity (LDA) at week 26 were blindly switched from upadacitinib to adalimumab or vice versa. Treatment outcomes, including clinical remission/LDA, physical function, pain and a novel combined endpoint for deep response, were evaluated through 48 weeks and corresponding time-averaged response rates determined. Data were analysed by initial randomized group regardless of any subsequent switch in therapy. RESULTS: This post hoc analysis included 651 patients initially randomized to upadacitinib (of whom 252 switched to adalimumab) and 327 patients initially randomized to adalimumab (of whom 159 switched to upadacitinib). At week 48, patients randomized to either therapy demonstrated similar achievement of most treatment endpoints. Greater improvements in the total time spent in a lower disease state were observed for initial upadacitinib vs initial adalimumab therapy across most clinical and patient-reported outcomes through 48 weeks, and the median time to DAS28(CRP) <2.6/≤3.2 occurred 6-8 weeks earlier among those randomized to upadacitinib. CONCLUSION: Following a modified treat-to-target strategy, rates of CDAI remission/LDA and DAS28(CRP) <2.6/≤3.2 at 48 weeks were similar, regardless of starting therapy. However, patients initially receiving upadacitinib reached treatment targets more quickly and spent more time in clinical targets over the initial 48 weeks of treatment. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT02629159.

The Prognostic Value of Biomarkers in Non-ST-Elevation Acute Coronary Syndrome Patients that are Treated by an Early Invasive Strategy: Insights from the OPTIMA-2 Trial.

Background: Patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) consists of a heterogenic population and improvement in identification of a specific risk profile is needed. In this study we aimed to obtain better insight in the role of different biomarkers for patients undergoing a routine invasive diagnostic strategy within 24 hours after admission. Methods: An Immediate or Early Invasive Strategy in Non-ST-Elevation Acute Coronary Syndrome (OPTIMA-2) study was a randomized controlled prospective open-label multicentre trial, randomizing NSTE-ACS patients. An invasive strategy was either immediate ( < 3 hours) or early (12-24 hours). Peak high-sensitive TroponinT (hsTropT) value was determined within the first 48 hours of admission. N-terminal proB-type natriuretic peptide (NTpro-BNP) and high-sensitivity C-reactive protein (hsCRP) values were determined at admission and at discharge. These biomarkers were then divided into tertiles and related to clinical outcomes up to one year. The relation between these biomarkers and myocardial function recovery established by echocardiography was analyzed as a secondary endpoint. Results: The OPTIMA-2 study included 249 patients. Overall, there was no significant increase in the risk of developing an adverse cardiovascular event in the first year if biomarker tertiles at admission were compared. However, mean NT-proBNP levels at admission were higher for patients that experienced all-cause death withing the first year (1.93 ± 0.49 vs 1.42 ± 0.58, p = 0.05). Also, peak hs-cTnT (232.0 ± 2846.0 vs 71.5 ± 1152.0, p = 0.06) values at baseline were higher in patients experiencing a myocardial infarction within 1-year. NT-proBNP levels at admission and at discharge correlated with recovery of the left ventricular (LV) function at 30 days (coefficient 0.021 (95% CI = 0.009-0.033) and coefficient 0.016 (95% CI = 0.005-0.027)). Conclusions: In NSTE-ACS patients treated by an early invasive strategy and administration of modern anticoagulant and antiplatelet therapy, multiple biomarker measurements during admission could not predict the occurrence of recurrent cardiovascular events within the first year of follow-up.

Unraveling the prevalence of various signalling pathways in non-small-cell lung cancer: a review.

Cancer has become a huge public health issue all around the world. The focus of research is on innovative cancer therapy techniques that include the disease's unique targets. Among the cancer-related deaths that occur, lung cancer is considered to be one of the major, accounting for about 1.6 million fatalities globally in 2012, or nearly 20% of all cancer deaths. Non-small-cell lung cancer, a type of lung cancer comprises upto 84% of lung cancer cases, demonstrating the need for a more effective treatment. A novel category of cancer management, known as targeted cancer medicines, has risen to prominence in recent years. Targeted cancer treatments, like traditional chemotherapy, employ pharmacological drugs to slow cancer development, enhance cell death, and prevent it from spreading. Targeted treatments, as the name implies, work by interfering with particular proteins implicated in cancer. Numerous research conducted in the last several decades have led to the conclusion that signalling pathways are involved in the growth of lung cancer. All malignant tumours are produced, spread, invade, and behave in various abnormal ways due to abnormal pathways. Numerous significant signalling pathways, including the RTK/RAS/MAP-Kinase pathway (hence often referred to as RTK-RAS for simplicity), PI3K/Akt signalling, and others, have been discovered as commonly genetically changed. The current developments in research on various signalling pathways, as well as the underlying mechanisms of the molecules implicated in these pathways, are innovatively summarised in this review. To give a good sense of the study that has been done so far, many routes are placed together. Thus, this review includes the detailed description regarding each pathways, the mutations formed, and the present treatment strategy to overcome the resistance.

Interim monitoring in sequential multiple assignment randomized trials.

A sequential multiple assignment randomized trial (SMART) facilitates the comparison of multiple adaptive treatment strategies (ATSs) simultaneously. Previous studies have established a framework to test the homogeneity of multiple ATSs by a global Wald test through inverse probability weighting. SMARTs are generally lengthier than classical clinical trials due to the sequential nature of treatment randomization in multiple stages. Thus, it would be beneficial to add interim analyses allowing for an early stop if overwhelming efficacy is observed. We introduce group sequential methods to SMARTs to facilitate interim monitoring based on the multivariate chi-square distribution. Simulation studies demonstrate that the proposed interim monitoring in SMART (IM-SMART) maintains the desired type I error and power with reduced expected sample size compared to the classical SMART. Finally, we illustrate our method by reanalyzing a SMART assessing the effects of cognitive behavioral and physical therapies in patients with knee osteoarthritis and comorbid subsyndromal depressive symptoms.