Non-responder Group Research Articles

Discovery biomarker to optimize obeticholic acid treatment for non-alcoholic fatty liver disease

The response rate to obeticholic acid (OCA), a potential therapeutic agent for non-alcoholic fatty liver disease, is limited. This study demonstrated that upregulation of the alternative bile acid synthesis pathway increases the OCA treatment response rate. The hepatic transcriptome and bile acid metabolite profile analyses revealed that the alternative bile acid synthesis pathway (Cyp7b1 and muricholic acid) in the OCA-responder group were upregulated compared with those in the OCA-non-responder group. Intestinal microbiome analysis also revealed that the abundances of Bacteroidaceae, Parabacteroides, and Bacteroides, which were positively correlated with the alternative bile acid synthesis pathway, were higher in the OCA-responder group than in the non-responder group. Pre-study hepatic mRNA levels of Cyp8b1 (classic pathway) were downregulated in the OCA-responder group. The OCA response rate increased up to 80% in cases with a hepatic Cyp7b1/Cyp8b1 ratio ≥ 5.0. Therefore, the OCA therapeutic response can be evaluated based on the Cyp7b1/Cyp8b1 ratio or the alternative/classic bile acid synthesis pathway activity.

Effect of CYP2C9 rs2860905 Polymorphism on the Efficacy of Losartan in Pakistani Hypertensive Patients

Hypertension is a multifactorial disease characterized by high blood pressure in blood vessels. It is caused by the dysregulation of renin angiotensin aldosterone system (RAAS). It is a major risk factor for other metabolic diseases including cardiovascular diseases, diabetes, and others. Various RAAS targeting drugs such as losartan are prescribed as the first line therapy to treat hypertension. However, their efficacy varies among individuals owing to genetic variations in drug binding substrates or drug metabolizing enzymes, which convert the prodrug to active drug. CYP2C9 gene encodes for an enzyme which metabolizes losartan. Various studies have concluded that genetic variations in CYP2C9 affect the response of losartan due to the variation in its metabolism. Thus, the current study aimed to check the effect of CYP2C9 rs2860905 G>A polymorphism on the efficacy of losartan. For this purpose, a total of 48 subjects were selected and genotyped for rs2860905 polymorphism using in-house developed tetra-ARMS-PCR. The subjects were divided into responding (n=34) and non-responding (n=14) groups on the basis of their blood pressure after treatment with losartan. Statistical analysis demonstrated that rs2860905 GG genotype was more prevalent in the responding group as compared to the non-responding group (50% vs. 36%). Multinomial regression analysis showed that the carriers of GA or AA genotype did not respond to losartan treatment efficiently as compared to those of GG genotype. However, these results could not achieve statistical significance. To conclude, CYP2C9 rs2860905 G>A polymorphism does not affect the efficacy of losartan in Pakistani hypertensive subjects.

Potential biomarkers for psoriasis topical treatment by in-depth serum proteomics

BackgroundPsoriasis is a chronic skin disease, and topical sequential therapy with a combination of calcipotriol and calcipotriol betamethasone is currently approved topical treatment. However, the exact mechanism by which this treatment regimen relieves psoriasis is unknown.MethodWe assembled a cohort of 65 psoriasis patients and divided post-treatment cohort into responder group and non-responder group according to the Psoriasis Area Severity Index (PASI) score after 12-week treatment. We measured the expression levels of proteins in collected 130 serum samples using our in-depth proteomics platform with a data-independent acquisition mass spectrometer and antibody microarray. We performed bioinformatics analyses of the biologic processes and signaling pathways that were changed in the responder group and constructed a proteomics landscape of psoriasis pathogenesis response to treatment. We then validated the biomarkers of disease severity in an independent cohort of 88 samples using an enzyme-linked immunosorbent assay.ResultsWe first identified 174 differentially expressed proteins (DEPs) for comparative analysis of proteins between responders and non-responders at baseline (p < 0.05). Then pathway analysis showed that the responders focused more on signaling molecules and interaction, complement and coagulation cascades, whereas the non-responders more on signal transduction and IL-17 signaling pathways. We further identified four candidate biomarkers (COLEC11, C1QA, BNC2, ITIH4) response to treatment. We also found 125 DEPs (p < 0.05) after treatment compared with before treatment in responder group. Pathway analysis showed an enrichment in pathways related to complement and coagulation cascades, phagosome, ECM-receptor interaction, cholesterol metabolism, vitamin digestion and absorption. CD14 was validated as potential biomarkers for the disease severity of psoriasis and treatment targets.ConclusionIn this work, we analyzed the response to topical sequential therapy and finally identified four biomarkers. Additionally, we found that topical sequential therapy may alleviate psoriasis by regulating lipid metabolism and modulating the immune response by affecting the complement activation process.

The impact of smoking status on clopidogrel responsiveness in patients with coronary artery disease who undergo percutaneous coronary intervention

Background: Previous studies have pointed out the disproportionate action of clopidogrel in inhibiting platelet aggregation due to smoking more than ten cigarettes per a day. This study was designed to examine whether smoking enhances clopidogrel responsiveness in patients who are clinically diagnosed with coronary artery disease (CAD), following percutaneous coronary intervention (PCI). Methods: A total of 324 IHD participants were enrolled in a case-control study. Platelet function test was performed to all participants two hours before PCI procedure to measure clopidogrel response. Participants were then categorized into a non-responder group (case group n = 111) and responder group (control group n = 213). Each group was subdivided into a smoker group and a non-smoker group. All participants received clopidogrel loading dose equivalent to 600 mg and scheduled for elective PCI. Participants’ age, gender, family history of chronic illnesses was recorded in this study. Results: Smoking participants displayed a significant higher level of hemoglobin as compared to the non-smoking participants among the responder and the non-responder study groups (14.6±0.55 vs. 13.12±0.38, P &lt; 0.029; 14.3±0.31 versus 12.96±0.39, P &lt; 0.033) but lower AUC level (17±9 vs. 45±6, P &lt; 0.005; 62±3 vs. 95±7, P &lt; 0.008). Additionally, smoking intensity enhanced clopidogrel responsiveness by odd’s ratio 0.4213 at 95% C.I. (0.259 - 0.684), P &lt; 0.0002. Conclusions: Current smokers had a good response to clopidogrel therapy which exerted a beneficial effect when undergoing PCI as compared to non-smokers. The marked difference in AUC between smokers and non-smokers could be related to the variance in hemoglobin level. The smokers’ paradox needs further justification to confirm this concept.

Effects of mandibular advancement devices on upper airway dimensions in obstructive sleep apnea: responders versus non-responders

Study objectivesTo compare the effects of mandibular advancement device (MAD) therapy on upper airway dimensions between responders and non-responders with mild to moderate obstructive sleep apnea (OSA).MethodsThirty-one participants (21 men and 10 women) with a mean ± SD apnea-hypopnea index (AHI) of 16.6 ± 6.7 events/h, and aged 48.5 ± 13.9 years, were included in this study. Polysomnographic recordings and cone beam computed tomography (CBCT) scans in supine position were performed for every participant at baseline and at 3-month follow-up with their MAD in situ. Responders were defined as having ≥ 50% reduction in baseline AHI with a residual AHI < 10 events/h. The primary outcome variable was the minimal cross-sectional area of the upper airway (CSAmin).ResultsNo significant differences were found between responders (n = 15) and non-responders (n = 16) in age, gender distribution, body mass index, and neck circumference (P = 0.06–0.93), nor in AHI and CSAmin (P = 0.40 and 0.65, respectively) at baseline. The changes of the CSAmin with MAD in situ in the responder group were not significantly different compared to those in the non-responder group (P = 0.06).ConclusionWithin the limitations of this study, we conclude that the changes of the upper airway dimensions induced by MADs are not significantly different between responders and non-responders with mild to moderate OSA.Trial registrationClinicalTrials.gov Identifier: NCT02724865. https://clinicaltrials.gov/ct2/show/NCT02724865

Delhi Model: A New Tool for Predicting Response to Terlipressin in Hepatorenal Syndrome—Acute Kidney Injury

International club of ascites (ICA) has introduced revised criteria for hepatorenal syndrome-acute kidney injury (HRS-AKI) with an aim to improve the response rate to treatment. We lack prospective trials to assess its positive impact on the response rate and factors influencing response rate. Thus, we conducted this study with the primary aim of identifying independent factors that predict treatment response to terlipressin. We prospectively included patients of HRS-AKI as per the revised ICA criteria. All were treated with terlipressin and albumin according to the defined protocol and were followed for 90 days, death or liver transplantation. Baseline parameters, as well as delta serum creatinine (sCr) at day 4 (DCD4), were investigated as predictive factors influencing response to terlipressin (primary endpoint). Secondary endpoints were the overall response rate to terlipressin, response in various subgroups of acute-on-chronic liver failure (ACLF) patients, need for readmission, and 90 days survival. The study included 114 patients with a median age of 52 years (83% males). 70 (61%) patients responded to terlipressin. Response rate among ACLF1, ACLF2, and ACLF3 were 62%, 48%, and 35%, respectively. On multivariate analysis, baseline creatinine (odds ratio [OR] 7.889, 95% confidence interval [CI] 3.335, 18.664), Child Turcotte Pugh (CTP) score (OR 1.470, 95% CI 1.026, 2.106), and the DCD4 (OR 0.048, 95% CI 0.015, 0.158) were independently predicting response. We also created a Delhi Model (DM) with an excellent predictive ability for response prediction at day 4 with an AUROC of 0.940 (95% CI 0.897, 0.982). Among responder group, 50% of patients required readmission within three months.The 90-days survival among responder and non-responder groups were 68.5% and 9% (Pvalue<0.01), respectively. Baseline creatinine, CTP score, and DCD4 independently predict response to terlipressin in HRS-AKI. The DM may guide terlipressin treatment in HRS-AKI but need further validation.

The relationship between inadequate response to physical therapy and central sensitization in patients with knee osteoarthritis: A prospective cohort study.

Objectives: This study aims to investigate the relationship between physical therapy response and the presence of central sensitization (CS) in patients with painful knee osteoarthritis (OA). Patients and methods: Between May 2019 and March 2020, a total of 84 patients with knee OA (12 males, 72 females; mean age: 60.7±7.7 years; range 50 to 74 years) and 30 age and sex-matched controls (6 males, 24 females; mean age: 59.2±8.9 years; range 50 to 75 years) were included in this study. Knee pain and functional status were evaluated by Visual Analog Scale (VAS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Structural damage was assessed by knee radiography. The Central Sensitization Inventory (CSI), Beck Depression Inventory (BDI), Insomnia Severity Index (ISI), Pain Catastrophizing Scale (PCS), and PainDETECT Questionnaire (PDQ) were applied at baseline. Pain pressure thresholds (PPTs) of the patients were measured and compared with the control group. All patients underwent a total of 15 sessions of physical therapy program for five sessions/weekly. After treatment, the patients were divided into two groups as responders and non-responders according to the Osteoarthritis Research Society International (OARSI) criteria. Results: The CSI score of the patients in non-responder group was significantly higher compared to the responder group (p=0.004). Using a cut-off value of ≥40, the proportion of patients with CSI scores of ≥40 was significantly lower in the responder group compared to non-responder group (p=0.021). The PPT measurement values were significantly lower in the non-responder group compared to the responder and control groups (p <0.01). There was a significant difference in the frequency of hyperalgesia between the groups (p=0.021). Central sensitization and depression were the most significant predictors of non-response to physical therapy (p=0.045 and p=0.024, respectively). Conclusion: Our study results suggest the presence of CS and depression may result in an inadequate response to physical therapy in patients with knee OA. Clinicians should consider the findings of CS and depression in treatment planning.

Clinical presentation and prognosis in children over 10-year-old with primary nephrotic syndrome

Objective: To summary the clinical presentation and prognosis of primary nephrotic syndrome (PNS) in teenagers. Methods: The clinical data, renal pathological types and prognosis of 118 children over 10-year-old with PNS treated in the Department of Nephrology of the Children's Hospital Affiliated to Capital Institute of Pediatrics from January 2010 to December 2020 were retrospectively analyzed, with 408 children ≤10-year-old as control group synchronously. Chi-square test was used to compare the difference of clinical types, pathologic types, response to steroids and tubulointerstitial changes between the groups. The teenagers with steroid resistant nephrotic syndrome (SRNS) were divided into initial non-responder group and late non-responder group. Kaplan-Meier method was used to compare the difference of persistent proteinuria, and Fisher's exact test for the histological types. Results: There were 118 children >10-year-old, including 74 males and 44 females, with the onset age of 12.1 (10.8, 13.4) years; and 408 children ≤10-year-old with the onset age of 4.5 (3.2, 6.8) years. The proportion of SRNS was significantly higher in patients >10-year-old than those ≤10-year-old (24.6% (29/118) vs. 15.9% (65/408), χ2=4.66, P=0.031). There was no statistical difference in the pathological types between >10-year-old and ≤10-year-old (P>0.05), with minimal change disease the most common type (56.0% (14/25) vs. 60.5% (26/43)). The percentage of cases with renal tubulointerstitial lesions was significantly higher in children >10-year-old compared to those ≤10-year-old (60.0% (15/25) vs. 23.3% (10/43), χ2=9.18, P=0.002). There were 29 cases presented with SRNS in PNS over 10-year-old, including 19 initial non-responders and 10 late non-responders. Analyzed by Kaplan-Meier curve, it was shown that the percentage of persistent proteinuria after 6 months of immunosuppressive treatments was significantly higher in initial non-responders than those of the late non-responders ((22±10)% vs. 0, χ2=14.68, P<0.001); the percentage of minimal change disease was significantly higher in patients of late non-responders than those of the initial non-responders (5/6 vs. 3/13, P=0.041). Of the 63 >10-year-old with steroid-sensitive nephrotic syndrome followed up more than one year, 38 cases (60.3%) had relapse, and 14 cases (22.2%) were frequent relapse nephrotic syndrome and steroid dependent nephrotic syndrome. Among the 45 patients followed up over 18-year-old, 22 cases (48.9%) had recurrent proteinuria continued to adulthood, 3 cases of SRNS progressed to kidney insufficiency, and one of them developed into end stage kidney disease and was administrated with hemodialysis. Conclusions: Cases over 10-year-old with PNS tend to present with SRNS and renal tubulointerstitial lesions. They have a favorable prognosis, but are liable to relapse in adulthood.

A hierarchical multi-level model for compromise allocation in multivariate stratified sample surveys with non-response problem

Stratified sampling, a widely-applicable probabilistic technique, is especially suited for large and heterogeneously distributed populations. This paper studies optimal allocation of sampling units to minimize variances and cost. Given that not all strata hold equal importance in survey projects, we propose a hierarchical multi-level programming model for compromise allocation in stratified sampling. The model considers multiple objectives across hierarchical levels and addresses the issue of non-response by dividing strata into respondent and non-respondent groups. The survey budget restriction is considered as a constraint in our model. We employ a fuzzy concept-based solution methodology to solve the multi-level allocation problem. A literature-based numerical example describes the model’s applicability and efficiency. Comparative analysis shows our model’s superior efficiency over existing models due to its optimization of allocation across varied strata, non-response consideration, and budget constraint integration. The proposed model promotes flexibility, enhancing representativeness and cost-effectiveness of large-scale surveys, thereby improving decision-making in research and industry settings.

Predicting response of gemcitabine plus cisplatin chemotherapy using RNA sequencing in patients with advanced urothelial carcinoma.

66 Background: Despite of advancement using new agents including ICIs in treatment of urothelial carcinoma (UC), cisplatin-based chemotherapy is still standard of care in both 1st line palliative setting and perioperative setting. Previous studies regarding response prediction of cisplatin-based chemotherapy are limited in selecting target molecule or gene, there have been no comprehensive study for whole genome information. This study aimed to identify key genes to predict response of gemcitabine plus cisplatin (GC) in advanced UC by mRNA sequencing (RNA-seq). Methods: Between JAN 2016 and DEC 2019, advanced UC patients treated with GC and underwent response evaluation were enrolled. Patients were divided into the responder group (CR or PR) and non-responder group (SD or PD). RNA was extracted from the formalin fixed embedded tissue (FFED) and RNA-seq was performed on the Illumina RNA-seq platform. Differentially expressed genes (DEGs) were identified between responder group and non-responder group. Marker selection was performed as following steps: (1) DESeq2 (Adjusted P-value &lt; 0.1) and Mann-Whitney U test (P-value &lt; 0.05), (2) random forest (RF) and logistic regression, and (3) assessments for relevant markers by analyzing RNA/Protein expression level, survival information, and antibody staining results using ProteinAtlas. Results: Twenty-nine patients received GC chemotherapy during study period. Among them, 10 patients who had available FFED specimens and clear response evaluation were enrolled and performed RNA-seq. Median age was 65.5 years (range, 62-76), and all were male. They were grouped of 7 patients in responder and 3 patients in non-responder. Among 13,773 genes based on RNAseq, we identified 37 DEGs candidate (Step 1), followed by 22 DEGs selected (Step 2), and finally 9 DEGs were identified (Step 3). Among the 9 DEGs, 3 genes (UPK2, PCGF3, and POFUT1) were consistently expressed with survival data of TCGA, the expression of 3 (ITGA3, HSPA1B, GSTM3) was the opposite of that of TCGA, and the remaining 3 genes (S100A2, TDRP, and RPS6KA2) were not relevant. Conclusions: We found 3 key genes (UPK2, PCGF3, and POFUT1) that related with favorable response of GC in our advanced UC cohort which were confirmed in TCGA data. Our study results should be further investigated in an expansion cohort using immunohistochemistry staining matched with key genes for convenient practical application.

Peripheral blood nutrient indices as biomarkers for anti‑PD‑1 therapy efficacy and prognosis in patients with advanced gastric cancer.

Immunotherapy offers survival benefits for patients with advanced gastric cancer, but not all populations can benefit from immunotherapy. Good nutritional status is fundamental to a patient's immune function and may have an impact on the efficacy of immunotherapy. The present study aimed to investigate changes in prognostic nutritional index (PNI), advanced lung cancer inflammation index (ALI) and albumin-globulin ratio (AGR) values before and after immunotherapy in patients with advanced gastric cancer. The study also aimed to determine the potential association of the aforementioned values with patient outcomes and prognosis. Body mass index (BMI), serum albumin, total protein, peripheral blood lymphocyte, neutrophil, carcinoembryonic antigen (CEA), carbohydrate antigen19-9 (CA19-9) and a-fetoprotein (AFP) data were collected from 195 patients with advanced gastric cancer who underwent immunotherapy from January 2020 to October 2021. In addition, PNI, ALI and AGR values were calculated based on variables in blood collected from the patients within 3 days prior to immunotherapy and 3 weeks after immunotherapy. The results demonstrated that low PNI was associated with elevated CEA levels. Moreover, low ALI levels were associated with reduced BMI levels, elevated AFP levels, PD-L1 negative and first-line treatment. Comparison of responding and non-responding groups revealed that patients who responded to immunotherapy had higher PNI and AGR values than patients who did not respond, both before and after treatment, but had lower CEA and CA19-9 levels after treatment. Furthermore, in the non-responding group, PNI and AGR values were decreased and CEA values were increased following treatment compared with those prior to treatment. The objective response and disease control rates were higher in the high PNI and AGR groups compared with the low PNI and AGR groups, respectively. Moreover, PNI and AGR were found to be independent predictors of the short-term efficacy of immunotherapy for advanced gastric cancer, with cut-off values of 47.18 and 1.29, respectively. Univariate analysis revealed that ALI was associated with the progression-free survival (PFS) of patients, while multivariate analysis demonstrated that baseline PNI and AGR were independent predictors of PFS. In conclusion, tumor progression leads to a decline in the nutritional level of patients, and the present study indicated that effective immunotherapy may alleviate this deterioration to a certain extent. Furthermore, PNI and AGR exhibit potential in predicting the efficacy of immunotherapy and the prognosis of patients with advanced gastric cancer, and may exhibit potential as biomarkers in clinical practice.

Clinical Outcomes of Condoliase Injection Therapy for Lateral Lumbar Disc Herniation.

This study aimed to evaluate the efficacy of condoliase injection therapy (CIT) for lateral lumbar disc herniation (LLDH). This retrospective study included 157 of 180 enrolled patients (70 males, 87 females; mean age: 52.6±16.9 years). These patients were divided into two groups (group L: LLDH, group M: medial LDH [subligamentous and transligamentous]). From baseline to 1 year after injection (final follow-up), leg pain was assessed using the visual analog scale (VAS) and the Japanese Orthopedic Association (JOA) scoring for CIT's clinical efficacy of CIT. Radiography and magnetic resonance imaging conducted before and 3 months after the injection were assessed. Patients with a VAS improvement of ≥50% at the final follow-up were defined as responders. The responder and nonresponder LLDH groups were also compared. Groups L and M showed comparable responder rates (75.0% and 77.4%, respectively) (P=0.80). VAS and JOA scores at 1 year showed no significant differences between the groups (P=0.82 and 0.80, respectively). VAS score at 1 month after injection reduced considerably in the responder group compared with that in the nonresponder group (19.7 vs. 66.0, P<0.01) and continued to decrease at the last follow-up (3.5 vs. 52.0, P<0.001). Nonresponders had significantly lower disc heights after 3 months. However, intervertebral instability, alignment, and disc degeneration did not differ between the responders and nonresponders. The response rate of CIT for LLDH was comparable to that for medial LDH. Therefore, CIT is an effective treatment for LLDH.

Renal arterial resistive index as a prognostic marker in lupus nephritis patients

IntroductionLupus nephritis (LN) is known to be one of the most serious complications of SLE and it is a major predictor of poor prognosis. Despite the improvement in understanding the pathophysiology of lupus nephritis and greater improvement in diagnostic approaches, lupus nephritis patients have poorer outcomes. ObjectivesStudy the relation between renal resistive index (RRI) and renal function and histopathological parameters in lupus nephritis (LN) patients. Also to investigate the usefulness of RRI in predicting response to treatment. Patients and methodsThis study included 126 patients who were split into two groups (group 1: 101 LN patients and group 2: 25 SLE patients without renal affection); and 100 healthy controls (group 3). The RRI was measured for all participants through a colored Doppler ultrasound examination. LN patients underwent renal biopsy and received their therapy and were followed up for 6 months. ResultsThe RRI was significantly greater in the LN group (mean±SD; 0.64±0.07) than in SLE patients without nephritis (0.5884±0.04) (P<0.0001). The RRI was greater in LN class IV (P<0.0001). RRI significantly correlated with the chronicity index (r=0.704, P<0.0001), activity index (r=0.310, P=0.002), and serum creatinine (r=0.607, P<0.0001) and negatively correlated with eGFR (r=−0.719, P<0.0001). Almost eighty-five percent (84.8%) of LN patients responded to induction therapy. RRI was significantly greater in the nonresponder group (mean±SD, 0.73±0.02) than that in the responder group (0.63±.07) (P<0.0001). All non-responders to induction therapy while only 29.8% of responders had an RRI of ˃0.7. RRI, according to regression analysis was a significant predictor of response to treatment in LN patients. ConclusionRRI was significantly greater in the LN group and significantly correlated with kidney function and histopathological parameters. RRI can predict response to induction therapy in LN patients.

Rectal Cancer Tissue Lipidome Differs According to Response to Neoadjuvant Therapy.

Rectal cancer (RC) is a gastrointestinal cancer with a poor prognosis. While some studies have shown metabolic reprogramming to be linked to RC development, it is difficult to define biomolecules, like lipids, that help to understand cancer progression and response to therapy. The present study investigated the relative lipid abundance in tumoral tissue associated with neoadjuvant therapy response using untargeted liquid chromatography-mass spectrometry lipidomics. Locally advanced rectal cancer (LARC) patients (n = 13), clinically staged as T3-4 were biopsied before neoadjuvant chemoradiotherapy (nCRT). Tissue samples collected before nCRT (staging) and afterwards (restaging) were analyzed to discover lipidomic differences in RC cancerous tissue from Responders (n = 7) and Non-responders (n = 6) to nCRT. The limma method was used to test differences between groups and to select relevant feature lipids from tissue samples. Simple glycosphingolipids and differences in some residues of glycerophospholipids were more abundant in the Non-responder group before and after nCRT. Oxidized glycerophospholipids were more abundant in samples of Non-responders, especially those collected after nCRT. This work identified potential lipids in tissue samples that take part in, or may explain, nCRT failure. These results could potentially provide a lipid-based explanation for nCRT response and also help in understanding the molecular basis of RC and nCRT effects on the tissue matrix.

The prospective study of 54 children with ESES: how to simplify the EEG diagnosis and guide the treatment.

To simplify the electroencephalogram (EEG) diagnosis and guide the treatment of electrical status epilepticus during sleep (ESES). We recruited 54 children with ESES from December 2019 to December 2020 and compared various spike-wave index (SWI) calculation methods. Time-frequency analysis assessed the correlation between high-frequency oscillations (HFOs) energy and the SWI. We divided 42 children into responder and non-responder treatment groups based on the observations made during a 12-month follow-up period and evaluate different treatment and the independent risk factors of refractory ESES. The SWI of five minutes before the second sleep cycle of non-rapid eye movement (NREM; long method II) and that of all NREM sleep (total method) were not significantly different (P = 0.06). The average energy of γ (r = 0.288, P = 0.002) and ripple (r = 0.203, P = 0.04) oscillations were correlated with the SWI. Encephalomalacia was an independent risk factor for refractory ESES (OR: 10.48, 95% CI: 1.62-67.63). The clinical seizure improvement rates of ASMs, ASMs with benzodiazepines, and ASMs with benzodiazepines and steroids after 12 months were 9.3%, 42.8%, and 53.8%, EEG improvement rate were 5.5%, 30.9% and 37%, respectively. The intelligence of the children in the responder treatment group has improved during the 1-year follow-up. These findings demonstrate EEG and clinical features of ESES and may provide basis for simplifying diagnosis and guiding the treatment of children with ESES.

Intact glycopeptides identified by LC-MS/MS as biomarkers for response to chemotherapy of locally advanced cervical cancer.

For locally advanced cervical cancer (LACC), patients who respond to chemotherapy have a potential survival advantage compared to nonresponsive patients. Thus, it is necessary to explore specific biological markers for the efficacy of chemotherapy, which is beneficial to personalized treatment. In the present study, we performed a comprehensive screening of site-specific N-glycopeptides in serum glycoproteins to identify glycopeptide markers for predicting the efficacy of chemotherapy, which is beneficial to personalized treatment. In total, 20 serum samples before and after neoadjuvant chemotherapy (NACT) from 10 LACC patients (NACT response, n=6) and NACT nonresponse, n=4) cases) were analyzed using LC-MS/MS, and 20 sets of mass spectrometry (MS) data were collected using liquid chromatography coupled with high-energy collisional dissociation tandem MS (LC-HCD-MS/MS) for quantitative analysis on the novel software platform, Byos. We also identified differential glycopeptides before and after chemotherapy in chemo-sensitive and chemo-resistant patients. In the present study, a total of 148 glycoproteins, 496 glycosylation sites and 2279 complete glycopeptides were identified in serum samples of LACC patients. Before and after chemotherapy, there were 13 differentially expressed glycoproteins, 654 differentially expressed glycopeptides and 93 differentially expressed glycosites in the NACT responsive group, whereas there were 18 differentially expressed glycoproteins, 569 differentially expressed glycopeptides and 99 differentially expressed glycosites in the NACT nonresponsive group. After quantitative analysis, 6 of 570 glycopeptides were identified as biomarkers for predicting the sensitivity of neoadjuvant chemotherapy in LACC. The corresponding glycopeptides included MASP1, LUM, ATRN, CO8A, CO8B and CO6. The relative abundances of the six glycopeptides, including MASP1, LUM, ATRN, CO8A, CO8B and CO6, were significantly higher in the NACT-responsive group and were significantly decreased after chemotherapy. High levels of these six glycopeptides may indicate that chemotherapy is effective. Thus, these glycopeptides are expected to serve as biomarkers for predicting the efficacy of neoadjuvant chemotherapy in locally advanced cervical cancer. The present study revealed that the N-glycopeptide of MASP1, LUM, ATRN, CO8A, CO8B and CO6 may be potential biomarkers for predicting the efficacy of chemotherapy for cervical cancer.

Predictive Factors Associated with Long-Term Response to Combination Immunotherapy in Patients with Untreated Advanced Non-Small-Cell Lung Cancer: A Multicenter Retrospective Study

Introduction: Combination immunotherapy is widely used in clinical practice as the first-line treatment for advanced non-small-cell lung cancer (NSCLC). However, predictive factors associated with long-term response to combination immunotherapy have not been well investigated. Herein, we compared the clinical findings, including systemic inflammatory nutritional biomarkers, between responders and nonresponders to combination immunotherapy. In addition, we investigated the predictive factors associated with long-term response to combination immunotherapy. Methods: This study included a total of 112 previously untreated advanced NSCLC patients who received combination immunotherapy at eight institutions in Nagano prefecture between December 2018 and April 2021. The responders were defined as those who achieved progression-free survival for 9 months or longer with combined immunotherapy. We evaluated predictive factors associated with long-term response, and the favorable prognostic predictors associated with overall survival (OS) using statistical analyses. Results: The responder and nonresponder groups included 54 and 58 patients, respectively. Compared with the nonresponder group, the responder group had significantly younger age (p = 0.046), higher prognostic nutritional index (44.8 vs. 40.7, p = 0.010), lower C-reactive protein/albumin ratio (CAR) (0.17 vs. 0.67, p = 0.001), and a higher rate of complete plus partial response (83.3% vs. 34.5%, p < 0.001). The area under the curve and optimal cut-off value for CAR were 0.691 and 0.215, respectively. The CAR and best objective response were identified as independent favorable prognostic predictors associated with OS in the multivariate analyses. Conclusion: The CAR and best objective response were suggested to be useful predictors of long-term response in NSCLC patients who received combination immunotherapy.

Predictors of complete remission of type 2 diabetes in patients over 65 years of age – a multicenter study

IntroductionThe type 2 diabetes (T2D) improvement rate in the elderly is high after bariatric and metabolic surgery, but not all patients achieve complete remission of disease. There are some predictors for T2D remission after bariatric surgery in patients of different ages, but there are few studies describing these factors in elderly patients. The study aimed to determine predictors for diabetes remission after bariatric surgery among patients over 65 years of age.Material and methodsA retrospective study analyzed patients over 65 years with T2D who underwent laparoscopic bariatric procedures in European country from 2008 to 2022. Multivariate logistic regression analysis was performed to obtain significant, independent risk factors.ResultsThe group consisted of 146 patients divided into two groups: responders (R) and nonresponders (NR). The complete remission of T2D was achieved in 51 (34.9%) patients. There were 95 (65.1%) patients in the NR group with partial remission, improvement, or no changes in T2D. The mean follow-up was 50.0 months. In a multivariate logistic regression analysis, a T2D duration of less than 5 years was found to be a predictor to T2D remission (OR = 5.5, p = 0.002), %EWL significantly corresponded to T2D remission (OR = 1.090, p = 0009).ConclusionBariatric and metabolic surgery appears to be a good option for T2D treatment in elderly patients. A shorter duration of T2D before surgery and higher %EWL after surgery were independent predictors of T2D remission in patients over 65 years of age.Graphical abstract

Increased absolute lymphocyte count, increased absolute neutrophil count and low platelet to lymphocyte ratio as predicting factors in the superior disease control of refractory/relapsing gynecologic malignancies with anti PD-1 therapy: 10 years of experience in a single institution

ObjectiveImmune checkpoint inhibitors are rapidly being used in solid and hematologic malignancies, including gynecologic cancers. The high mortality and relapsing rates of advanced gynecologic malignancies remain a challenging issue. This study aimed to identify the predicting factors associated with survival prognosis and disease control in patients with refractory/relapsing (R/R) gynecologic malignancies receiving anti PD-1 therapy. Materials and methodsWe retrospectively reviewed the medical records of 49 patients diagnosed with R/R gynecologic malignancies between July 2012 and June 2019 in Chang Gung Memorial Hospital, Taiwan. Among the 49 patients, 6 were excluded due to incomplete medical records or not receiving anti PD-1 therapy. The remaining 43 patients were further divided into responsive and non-responsive groups according to disease control for predicting prognostic factor analysis. ResultsFor the 43 cases, the median age at diagnosis and disease follow-up length were 54 years and 29 months, respectively. Among them, 23 (53%) were categorized into the responsive group, and the remaining 20 (47%) were categorized into the non-responsive group. The mortality rates were 17% and 25% in the responsive and non-responsive groups, respectively. The responsive group had significantly higher absolute lymphocyte count (ALC), higher absolute neutrophil count (ANC) and low platelet to lymphocyte ratio (PLR) than the non-responsive group. A superior long-term survival trend was also observed in the responsive group, but the difference was not statistically significant. ConclusionsThis study reinforced the hypothesis that high ALC, high ANC and low PLR are associated with superior disease control in patients with R/R gynecologic malignancies receiving anti PD-1 therapy.

The role of T1 mapping and Extracellular Volume (ECV) in predicting cardiac reverse remodelling and response to Heart Failure with reduced Ejection Fraction (HFrEF) therapy

Abstract Funding Acknowledgements Type of funding sources: None. Background Adverse cardiac remodelling results from an insult such as myocardial infarction, or as seen in Heart Failure (HF), maladaptive neurohormonal activation. Reverse remodelling describes improvement in cardiac geometry; the left ventricle (LV) recovers more normal structure with improved function and prognosis. Cardiovascular Magnetic Resonance imaging (CMR) allows gold standard assessment of LV volumes and function, diffuse and focal fibrosis and estimation of extracellular volume (ECV) by T1 mapping. Purpose Elevated T1 and ECV values are associated with worse outcome in many cardiac conditions. We conducted the first prospective study to investigate whether T1 mapping and ECV can predict cardiac reverse remodelling in response to treatment, in a cohort of patients hospitalised with a new HF diagnosis. Methods This was a single centre observational study. Inclusion criteria were admission with new HF, LVEF ≤50% or elevated NTproBNP and being treated with intravenous furosemide. Only patients with Heart Failure with reduced Ejection Fraction (HFrEF) and EF &amp;lt;40% on baseline echocardiography were included in this analysis. 36 consecutive eligible participants were included and had both echocardiogram and CMR studies to establish anatomy, function, and myocardial tissue characteristics at baseline. Participants were treated according to international HF guidelines and underwent reviews and repeat echocardiography at 6, 12–18 and 24–30 months. "Responders" to guideline directed HFrEF therapy were defined as those who had an increase in LVEF of ≥10% to a value of ≥40% between their baseline and latest follow-up echocardiogram. Baseline CMR volumes, function, presence of Late Gadolinium Enhancement (LGE), septal and whole heart T1 and ECV values were compared between responder and non-responder groups. Results Median follow-up was 26 months. 27 (75%) participants were responders to therapy. There were no differences in baseline characteristics between groups. There was high uptake of HFrEF medical therapy in both groups. (Table 1) There was no significant difference found between septal or whole heart T1 or ECV values between responder and non-responder groups. There was a trend towards lower whole heart ECV values (29% vs. 35%; p = 0.06) in the responder group but this did not reach statistical significance. (Figure 1) Overall, there was no difference in rates of LGE presence between groups but there was a significantly higher proportion of participants with non-ischaemic LGE pattern in the responder group compared to non-responder group (48% vs 11%; p = 0.05). Conclusions In this cohort of patients hospitalised with a new HFrEF diagnosis, the majority demonstrated reverse remodelling in response to therapy by 26 months. Whole heart ECV (%) as a surrogate marker for fibrosis calculated by whole heart T1 mapping may play a role in understanding which patients are likely to respond to HF therapy but further larger studies are required.