Exploring Indigenous and Local Knowledge and Practices (ILKPs) in Traditional Jhum Cultivation for Localizing Sustainable Development Goals (SDGs): A Case Study from Zunheboto District of Nagaland, India.

Globally, shifting cultivation is known to be an important driver of tropical deforestation. However, in this paper, we argue that it can be sustainably managed if the environmental boundary conditions, laid by the traditional customs and practices, are fully respected. We narrate an empirical study from the Zunheboto district of Nagaland, India, where we deployed a mixed research method to explore the Indigenous and Local Knowledge and Practices (ILKPs) associated with shifting cultivation (aka Jhum), particularly concerning farm-level practices, forest and biodiversity conservation, and disaster risk reduction measures. The research method included analysis of primary data obtained through Focus Group discussions (FGDs), key informant interviews (n = 21), and a questionnaire survey (n = 153) with Jhum farmers from two different age groups, i.e., below 50 years (middle-aged farmers) and above 50 years (older farmers). From the qualitative inquiry, we identified 15 ILKPs, which were then validated from survey responses. We used the Mann-Whitney U test to examine differences in agreement between two groups of framers. Based on this analysis, we conclude that upholding of the ILKPs holds strong potential for the local implementation of several Sustainable Development Goals (SDGs), particularly, SDG-1(No poverty), SDG-2 (Zero hunger), and SDG-15 (Life on land). However, eight of the identified ILKPs showed a statistically significant difference between older and middle-aged farmers, underlining a declining trend. Finally, we suggest suitable policy measures to mainstream ILKPs to balance the trade-offs in food production and biodiversity conservation, and to ensure the future sustainability of Jhum cultivation in the region and beyond.

Phase I Study of Tremelimumab Monotherapy or in Combination With Durvalumab in Japanese Patients With Advanced Solid Tumors or Malignant Mesothelioma.

BACKGROUND: The primary objective of this phase I, open-label trial was to assess safety and tolerability of tremelimumab monotherapy and combination therapy with durvalumab in Japanese patients with advanced cancer. Tremelimumab is a fully human monoclonal antibody against CTLA-4 in clinical trials; durvalumab is a monoclonal antibody against PD-L1 for the treatment of bladder and lung cancer. METHODS: In part 1, tremelimumab 3 or 10 mg/kg was given every 4 weeks (Q4W) for 6 doses, and thereafter every 12 weeks until discontinuation (n = 8); subsequently tremelimumab 10 mg/kg Q4W for 6 doses/Q12W and thereafter until discontinuation was administered in 41 patients with malignant pleural or peritoneal mesothelioma (MPM). In part 2, tremelimumab 10 mg/kg (Q4W for 6 doses followed by Q12W for 3 doses) was given in combination with durvalumab 15 mg/kg (Q4W for 13 doses) in cohort 1 (n = 4). In cohort 2 (n = 6), tremelimumab 1 mg/kg (Q4W for 4 doses) was given in combination with durvalumab 20 mg/kg (Q4W for 4 doses followed by 10 mg/kg Q2W for 22 doses), while in cohort 3 (n = 6), fixed-dose tremelimumab 75 mg Q4W for 4 doses plus durvalumab 1500 mg Q4W for 13 doses was given. RESULTS: In part 1, no dose-limiting toxicities (DLTs) for tremelimumab 3 or 10 mg/kg (Q4W for 6 doses/Q12W thereafter until discontinuation) were observed. Six (75%) patients reported treatment-related adverse events (trAEs). In the MPM dose-expansion cohort, 38 (92.7%) patients reported trAEs. In part 2, one DLT (Grade 4 myasthenia gravis) was reported for tremelimumab 10 mg/kg (Q4W for 6 doses/Q12W for 3 doses) plus durvalumab 15 mg/kg (Q4W for 13 doses). One DLT (Grade 4 hyperglycemia) was reported for tremelimumab 75 mg (Q4W for 4 doses) plus durvalumab 1500 mg (Q4W for 13 doses). Fourteen (87.5%) patients reported trAEs. Tremelimumab demonstrated low immunogenicity; 1 (16.7%) patient developed antidrug antibodies. CONCLUSION: Tremelimumab 10 mg/kg (Q4W/Q12W), tremelimumab 1 mg/kg (Q4W) plus durvalumab 20 mg/kg (Q4W/10 mg/kg Q2W), and fixed-dose tremelimumab 75 mg (Q4W) plus durvalumab 1500 mg (Q4W) were safe and tolerable.ClinicalTrials.gov Identifier: NCT02141347 (https://clinicaltrials.gov/ct2/show/NCT02141347).

Arginine is a disease modifier for polyQ disease models that stabilizes polyQ protein conformation.

The polyglutamine (polyQ) diseases are a group of inherited neurodegenerative diseases that include Huntington's disease, various spinocerebellar ataxias, spinal and bulbar muscular atrophy, and dentatorubral pallidoluysian atrophy. They are caused by the abnormal expansion of a CAG repeat coding for the polyQ stretch in the causative gene of each disease. The expanded polyQ stretches trigger abnormal ß-sheet conformational transition and oligomerization followed by aggregation of the polyQ proteins in the affected neurons, leading to neuronal toxicity and neurodegeneration. Disease-modifying therapies that attenuate both symptoms and molecular pathogenesis of polyQ diseases remain an unmet clinical need. Here we identified arginine, a chemical chaperone that facilitates proper protein folding, as a novel compound that targets the upstream processes of polyQ protein aggregation by stabilizing the polyQ protein conformation. We first screened representative chemical chaperones using an in vitro polyQ aggregation assay, and identified arginine as a potent polyQ aggregation inhibitor. Our in vitro and cellular assays revealed that arginine exerts its anti-aggregation property by inhibiting the toxic ß-sheet conformational transition and oligomerization of polyQ proteins before the formation of insoluble aggregates. Arginine exhibited therapeutic effects on neurological symptoms and protein aggregation pathology in Caenorhabditis elegans, Drosophila, and two different mouse models of polyQ diseases. Arginine was also effective in a polyQ mouse model when administered after symptom onset. As arginine has been safely used for urea cycle defects and for mitochondrial myopathy, encephalopathy, lactic acid and stroke syndrome patients, and efficiently crosses the blood-brain barrier, a drug-repositioning approach for arginine would enable prompt clinical application as a promising disease-modifier drug for the polyQ diseases.

Risk Factors for Delayed Bleeding after Therapeutic Gastrointestinal Endoscopy in Patients Receiving Oral Anticoagulants: A Multicenter Retrospective Study.

BACKGROUND/AIMS: Delayed bleeding is among the adverse events associated with therapeutic gastrointestinal endoscopy. The aim of this study was to evaluate risk factors for delayed bleeding after gastrointestinal endoscopic resection in patients receiving oral anticoagulants as well as to compare the rates of occurrence of delayed bleeding between the oral anticoagulants used. METHODS: We retrospectively analyzed a total of 772 patients receiving anticoagulants. Of these, 389 and 383 patients were receiving direct oral anticoagulants (DOACs) and warfarin, respectively. Therapeutic endoscopic procedures performed included endoscopic submucosal dissection (ESD), endoscopic mucosal resection, polypectomy, and cold polypectomy. RESULTS: Delayed bleeding occurred in 90 patients (11.7%) with no significant difference between the DOAC and warfarin groups (9.5 and 13.8%, respectively). Delayed bleeding occurred significantly more frequently with apixaban than with rivaroxaban (13.5 vs. 6.4%; p < 0.05). A multivariate analysis identified continued anticoagulant therapy (OR 2.29), anticoagulant withdrawal with heparin bridging therapy (HBT; OR 2.18), anticoagulant therapy combined with 1 antiplatelet drug (OR 1.72), and ESD (OR 3.87) as risk factors for delayed bleeding. CONCLUSION: This study identified continued anticoagulant therapy, anticoagulant withdrawal with HBT, anticoagulant therapy combined with 1 antiplatelet drug, and ESD as risk factors for delayed bleeding after therapeutic endoscopy in patients receiving oral anticoagulants. Delayed bleeding rates were not significantly different between those receiving DOACs and warfarin. It was also suggested that the occurrence of delayed bleeding may vary between different DOACs and that oral anticoagulant withdrawal should be minimized during therapeutic gastrointestinal endoscopy, given the thromboembolic risk involved.

Signal Detection of Potential Hepatotoxic Drugs: Case-Control Study Using Both a Spontaneous Reporting System and Electronic Medical Records.

Drug-induced liver injury (DILI) is a common adverse drug event. Spontaneous reporting systems such as the Japanese Adverse Event Report Database (JADER) have been used to evaluate the association between drugs and adverse drug events. However, the association of drugs with adverse drug events may be overestimated due to reporting biases. Therefore, it is important to objectively evaluate the association using liver function test values. The aim of the present study was to predict potential hepatotoxic drugs using real-world data including electronic medical records and the JADER database. A total of 70009 (2779 with DILI and 67230 without DILI) and 438515 (10235 with DILI and 428280 without DILI) Japanese adult patients were extracted from electronic medical records and the JADER database, respectively. Drugs with ≥100 DILI patients in both of the two databases were regarded as suspected drugs for DILI. We used multivariate logistic regression to evaluate the association between the suspected drugs and increased risk of DILI. Among the suspected drugs, broad-spectrum antibiotics such as meropenem, tazobactam/piperacillin and ceftriaxone were significantly associated with an increased risk of DILI, and meropenem had a greater risk of DILI in both of the two databases. Additionally, there were significant associations of mosapride and L-carbocisteine with increased risk of DILI. In addition to well-known associations between antibiotic drugs and DILI, mosapride and L-carbocisteine were found to be new potential signals of drugs causing hepatotoxicity. This study indicates potential hepatotoxic drugs that require further causality assessment.

[CapeOX Therapy as a Salvage Treatment for Advanced Gastric Cancer Refractory to S-1, Cisplatin, Irinotecan, and Taxanes].

AIM: This study aimed to retrospectively evaluate the efficacy and safety of capecitabine plus oxaliplatin(CapeOX)for heavily pretreated advanced gastric cancer(AGC)refractory to S-1, cisplatin, irinotecan, and taxanes. METHODS: Twelve patients with AGC refractory to S-1, cisplatin, irinotecan, and taxanes were enrolled in this study.Treatment comprised capecitabine(1,000mg/m / 2 twice a day on days 1-14)and oxaliplatin(130mg/m2 on day 1).Cycles were repeated at 3- week intervals. RESULTS: The overall response rate was 16.7%, and the disease control rate at 6 weeks was 75.0%. The progression free survival was 3.1 months, and the overall survival was 8.3 months after initiation of CapeOX therapy. The most common hematological toxicity was grade 3 neutropenia(50%).Peripheral neuropathy of Grade 1 or 2 was found in 50%of cases, but no Grade 3 or 4 neuropathy was found. CONCLUSIONS: CapeOX showed some activities as salvage therapy for heavily pretreated AGC patients.We suggest that CapeOX therapy should be considered a treatment option for pretreated AGC with good performance status.

Safety, tolerability and pharmacokinetics of the fibroblast growth factor receptor inhibitor AZD4547 in Japanese patients with advanced solid tumours: a Phase I study.

Background AZD4547 is a potent, oral, highly selective fibroblast growth factor receptor (FGFR) inhibitor in clinical development for treating tumours with a range of FGFR aberrations, including FGFR mutations, amplifications and fusions. Methods This open-label, Phase I, multicentre study (NCT01213160) evaluated the safety, pharmacokinetics, and preliminary antitumour efficacy (RECIST v1.1) of AZD4547 monotherapy in Japanese patients with advanced solid tumours. Part A was a dose-escalation part; Part B was a dose-expansion part in patients with FGFR-amplified tumours, confirmed by fluorescence in situ hybridization. Results Thirty patients enrolled in Part A (dose range: 40 mg twice daily [bid] to 120 mg bid; 160 mg once daily [qd]), four in Part B (80 mg bid). No dose-limiting toxicities were observed and maximum tolerated dose was not determined. Most common adverse events (AEs; any grade) were: dysgeusia (50% of patients); stomatitis (41%); diarrhoea (38%); hyperphosphataemia (38%); dry mouth (35%). Common grade ≥3 AEs were nausea (12% of patients) and neutropenia (9%). No complete or partial responses were observed: 21/30 patients had stable disease ≥4 weeks in Part A, and 1/4 patients had stable disease ≥10 weeks in Part B. Following single and multiple dosing, absorption rate appeared moderate; peak plasma concentrations generally occurred 3-4 h post-dose, then declined biphasically with terminal half-life ~30 h. Steady state was reached by day 8. Compared with single dosing, plasma concentrations were, on average, 2.4- and 3.3- to 5.4-fold higher after qd and bid dosing, respectively. Conclusions AZD4547 was well tolerated in Japanese patients, with best response of stable disease ≥4 weeks.

Conversion therapy for inoperable advanced gastric cancer patients by docetaxel, cisplatin, and S-1 (DCS) chemotherapy: a multi-institutional retrospective study.

BACKGROUND: Conversion therapy is an option for unresectable metastatic gastric cancer when distant metastases are controlled by chemotherapy; however, the feasibility and efficacy remain unclear. This study aimed to assess the feasibility and efficacy of conversion therapy in patients with initially unresectable gastric cancer treated with docetaxel, cisplatin, and S-1 (DCS) chemotherapy by evaluating clinical outcomes. METHODS: One hundred unresectable metastatic gastric cancer patients, enrolled in three DCS chemotherapy clinical trials, were retrospectively evaluated. The patients received oral S-1 (40 mg/m2 b.i.d.) on days 1-14 and intravenous cisplatin (60 mg/m2) and docetaxel (50-60 mg/m2) on day 8 every 3 weeks. Conversion therapy was defined when the patients could undergo R0 resection post-DCS chemotherapy and were able to tolerate curative surgery. RESULTS: Conversion therapy was achieved in 33/100 patients, with no perioperative mortality. Twenty-eight of the 33 patients (84.8 %) achieved R0 resection, and 78.8 % were defined as histological chemotherapeutic responders. The median overall survival (OS) of patients who underwent conversion therapy was 47.8 months (95 % CI 28.0-88.5 months). Patients who underwent R0 resection had significantly longer OS than those who underwent R1 and R2 resections (P = 0.0002). Of the patients with primarily unresectable metastases, 10 % lived >5 years. Among patients who underwent conversion therapy, multivariate analysis showed that the pathological response was a significant independent predictor for OS. CONCLUSIONS: DCS safely induced a high conversion rate, with very high R0 and pathological response rates, and was associated with a good prognosis; these findings warrant further prospective investigations.

Comparative effect of fixed-dose combination tablets of candesartan cilexetil/amlodipine versus olmesartan medoxomil/azelnidipine on laboratory parameters in patients with hypertension: a retrospective cohort study.

We conducted a retrospective cohort study to evaluate and compare the long-term effects of two single-pill fixed-dose combinations (FDCs), candesartan/amlodipine and olmesartan/azelnidipine, on laboratory parameters in patients in routine clinical practice. We identified an equal number of new users (n = 182) of a candesartan/amlodipine (8/5 mg/day) FDC tablet (CAN/AML users) and a propensity-score matched cohort (n = 182) receiving an olmesartan/azelnidipine (20/16 mg/day) FDC tablet (OLM/AZ users). Generalized estimating equations were used to estimate and compare the effects of the drugs on serum levels of creatinine, estimated glomerular filtration rate (eGFR), blood urea nitrogen (BUN), uric acid, sodium, potassium, aspartate aminotransferase, and alanine aminotransferase levels up to 12 months after the start of study drug administration. There was a significant increase of serum creatinine level and a significant decrease of eGFR from the baseline period to during the exposure period in both CAN/AML and OLM/AZ users, and a significant increase of BUN level in CAN/AML users. However, there were no significant differences in the mean changes of laboratory parameters between CAN/AML and OLM/AZ users. Our findings suggested that the effects of CAN/AML and OLM/AZ on laboratory parameters, including an unfavorable effect on renal function, were similar at least during 1 year of administration.

Open-label, randomized, comparative, phase III study on effects of reducing steroid use in combination with Palonosetron.

The purpose of this study is to compare the efficacy of a single administration of dexamethasone (DEX) on day 1 against DEX administration on days 1-3 in combination with palonosetron (PALO), a second-generation 5-HT3 receptor antagonist, for chemotherapy-induced nausea and vomiting (CINV) in non-anthracycline and cyclophosphamide (AC) moderately-emetogenic chemotherapy (MEC). This phase III trial was conducted with a multi-center, randomized, open-label, non-inferiority design. Patients who received non-AC MEC as an initial chemotherapy were randomly assigned to either a group administered PALO (0.75 mg, i.v.) and DEX (9.9 mg, i.v.) prior to chemotherapy (study treatment group), or a group administered additional DEX (8 mg, i.v. or p.o.) on days 2-3 (control group). The primary endpoint was complete response (CR) rate. The CR rate difference was estimated by logistic regression with allocation factors as covariates. The non-inferiority margin was set at -15% (study treatment group - control group). From April 2011 to March 2013, 305 patients who received non-AC MEC were randomly allocated to one of two study groups. Overall, the CR rate was 66.2% in the study treatment group (N = 151) and 63.6% in the control group (N = 154). PALO plus DEX day 1 was non-inferior to PALO plus DEX days 1-3 (difference, 2.5%; 95% confidence interval [CI]: -7.8%-12.8%; P-value for non-inferiority test = 0.0004). There were no differences between the two groups in terms of complete control rate (64.9 vs 61.7%) and total control rate (49.7% vs 47.4%). Anti-emetic DEX administration on days 2-3 may be eliminated when used in combination with PALO in patients receiving non-AC MEC.

Comparative effect of clopidogrel and aspirin versus aspirin alone on laboratory parameters: a retrospective, observational, cohort study.

BACKGROUND: Clopidogrel and aspirin are antiplatelet agents that are recommended to reduce the risk of recurrent stroke and other cardiovascular events. Combination therapy of clopidogrel and aspirin has been shown to increase the risk of hemorrhage, but the effects of the drugs on laboratory parameters have not been well studied in patients in routine clinical practice. Therefore, we evaluated and compared the effects of combination therapy with clopidogrel plus aspirin and aspirin monotherapy on laboratory parameters using a clinical database. METHODS: We used data from the Clinical Data Warehouse of Nihon University School of Medicine obtained between November 2004 and April 2011, to identify cohorts of new users (n = 159) of clopidogrel (75 mg/day) plus aspirin (100 mg/day) and new users (n = 834) of aspirin alone (100 mg/day). We used a multivariable regression model and regression adjustment with the propensity score to adjust for differences in baseline covariates between settings, and compare the mean changes in serum levels of creatinine, aspartate aminotransferase, alanine aminotransferase and hematological parameters, including hemoglobin level, hematocrit, and white blood cell (WBC), red blood cell and platelet counts up to two months after the start of study drug administration. RESULTS: After adjustment, the reduction of WBC count in clopidogrel plus aspirin users was significantly greater than that in aspirin alone users. All other tests showed no statistically significant difference in the mean change from baseline to during the exposure period between clopidogrel plus aspirin users and aspirin alone users. The combination of clopidogrel and aspirin increased the risk of gastrointestinal bleeding compared with aspirin alone, with a relative risk ranging from 2.06 (95% CI, 1.02 to 4.13; p = 0.043) for the multivariate model and 2.61 (95% CI, 1.18 to 5.80; p = 0.0184) for propensity adjustment. CONCLUSION: Our findings suggested that hematological adverse effects may be greater with combination therapy of clopidogrel plus aspirin than with aspirin monotherapy.

Comparative effect of angiotensin II type I receptor blockers on serum uric acid in hypertensive patients with type 2 diabetes mellitus: a retrospective observational study.

BACKGROUND: Angiotensin II type 1 receptor blockers (ARB) are a frequently used class of antihypertensive drug. The ARB losartan is known to decrease the serum uric acid (SUA) level. However, there are very few clinical data comparing the effects of other ARBs on SUA level under the conditions of clinical practice. This study evaluated and compared the long-term effects of monotherapy with five ARBs on SUA level in Japanese hypertensive patients with type 2 diabetes mellitus (DM). METHODS: We identified hypertensive patients with type 2 DM who had been treated with monotherapy with losartan (n = 214), valsartan (n = 266), telmisartan (n = 185), candesartan (n = 458), or olmesartan (n = 192), in whom laboratory data of SUA between November 1, 2004 and July 31, 2011 were available, from the Nihon University School of Medicine's Clinical Data Warehouse (NUSM's CDW). We used a propensity-score weighting method and a multivariate regression model to adjust for differences in the background among ARB users, and compared the SUA level. The mean exposure of losartan was 264.7 days, valsartan 245.3 days, telmisartan 235.9 days, candesartan 248.9 days, and olmesartan 234.5 days. RESULTS: In losartan users, mean SUA level was significantly decreased from baseline, while it was conversely increased in users of other ARBs; valsartan, telmisartan, candesartan, and olmesartan. The mean reduction of SUA level from baseline was significantly greater in losartan users compared with that in other ARB users. Comparison of ARBs other than losartan showed no significant difference in mean change in SUA level from baseline. CONCLUSIONS: Our study showed that losartan had the most beneficial effect on SUA level among five ARBs, and that there was no significant difference in the unfavorable effects on SUA level among four ARBs other than losartan, at least during one year. These findings provide evidence of an effect of ARBs on SUA level, and support the benefit of the use of losartan in hypertensive patients with type 2 DM.

Cytosolic chaperonin prevents polyglutamine toxicity with altering the aggregation state.

Polyglutamine (polyQ)-expansion proteins cause neurodegenerative disorders including Huntington's disease, Kennedy's disease and various ataxias. The cytotoxicity of these proteins is associated with the formation of aggregates or other conformationally toxic species. Here, we show that the cytosolic chaperonin CCT (also known as TRiC) can alter the course of aggregation and cytotoxicity of huntingtin (Htt)-polyQ proteins in mammalian cells. Disruption of the CCT complex by RNAi-mediated knockdown enhanced Htt-polyQ aggregate formation and cellular toxicity. Analysis of the aggregation states of the Htt-polyQ proteins by fluorescence correlation spectroscopy revealed that CCT depletion results in the appearance of soluble Htt-polyQ aggregates. Similarly, overexpression of all eight subunits of CCT suppressed Htt aggregation and neuronal cell death. These results indicate that CCT has an essential role in protecting against the cytotoxicity of polyQ proteins by affecting the course of aggregation.

A phase II clinical study of mFOLFOX6 plus bevacizumab as first-line therapy for Japanese advanced/recurrent colorectal cancer patients.

OBJECTIVE: In Japan, there had been no prospective clinical studies conducted in terms of modified FOLFOX6 + bevacizumab therapy. We performed a post-marketing Phase II multicenter clinical study to examine the efficacy and safety of this regimen as first-line therapy for Japanese patients with advanced/recurrent colorectal cancer. METHODS: Bevacizumab (5 mg/kg) was administered intravenously, and then oxaliplatin (85 mg/m(2)) and levofolinate calcium (200 mg/m(2)) were infused intravenously over 2 h. Subsequently, a bolus dose of 5-fluorouracil (400 mg/m(2)) was injected, followed by infusion of 5-fluorouracil (2400 mg/m(2)) for 46 h. This regimen was repeated every 2 weeks until 24 cycles unless there was disease progression, unacceptable toxicity or patient refusal. The primary end point was the response rate. RESULTS: Among the 70 patients enrolled, two patients withdrew the study before treatment, and 68 patients were eligible for analysis of efficacy and safety. The response rate was 51.5% (95% confidence interval: 39.0-63.8%). The median progression-free survival and median overall survival time were 12.6 months (95% confidence interval: 10.4-14.5 months) and 28.5 months [95% confidence interval: 23.1 months-(not applicable)], respectively. There were no treatment-related deaths observed. The most common Grade 3 and 4 adverse events included neutropenia in 35.3% of the patients, peripheral neuropathy in 16.2% and hypertension in 16.2%. All adverse events were manageable and tolerable. The exploratory analysis of polymorphisms of three genes, ERCC1, XPD and GSTP1, did not show any trends in terms of correlation with the efficacy or safety of modified FOLFOX6 + bevacizumab therapy. CONCLUSIONS: Modified FOLFOX6 + bevacizumab therapy was manageable and tolerable in Japanese patients, achieving a high response rate.

Detection of potential drug-drug interactions for risk of acute kidney injury: a population-based case-control study using interpretable machine-learning models.

Background: Acute kidney injury (AKI), with an increase in serum creatinine, is a common adverse drug event. Although various clinical studies have investigated whether a combination of two nephrotoxic drugs has an increased risk of AKI using traditional statistical models such as multivariable logistic regression (MLR), the evaluation metrics have not been evaluated despite the fact that traditional statistical models may over-fit the data. The aim of the present study was to detect drug-drug interactions with an increased risk of AKI by interpreting machine-learning models to avoid overfitting. Methods: We developed six machine-learning models trained using electronic medical records: MLR, logistic least absolute shrinkage and selection operator regression (LLR), random forest, extreme gradient boosting (XGB) tree, and two support vector machine models (kernel = linear function and radial basis function). In order to detect drug-drug interactions, the XGB and LLR models that showed good predictive performance were interpreted by SHapley Additive exPlanations (SHAP) and relative excess risk due to interaction (RERI), respectively. Results: Among approximately 2.5 million patients, 65,667 patients were extracted from the electronic medical records, and assigned to case (N = 5,319) and control (N = 60,348) groups. In the XGB model, a combination of loop diuretic and histamine H2 blocker [mean (|SHAP|) = 0.011] was identified as a relatively important risk factor for AKI. The combination of loop diuretic and H2 blocker showed a significant synergistic interaction on an additive scale (RERI 1.289, 95% confidence interval 0.226-5.591) also in the LLR model. Conclusion: The present population-based case-control study using interpretable machine-learning models suggested that although the relative importance of the individual and combined effects of loop diuretics and H2 blockers is lower than that of well-known risk factors such as older age and sex, concomitant use of a loop diuretic and histamine H2 blocker is associated with increased risk of AKI.

Direct Imaging of Ion Migration in Amorphous Oxide Electronic Synapses with Intrinsic Analog Switching Characteristics.

Amorphous metal oxides with analog resistive switching functions (i.e., continuous controllability of the electrical resistance) are gaining emerging interest due to their neuromorphic functionalities promising for energy efficient electronics. The mechanisms are currently attributed to field-driven migration of the constituent ions, but the applications are being hindered by the limited understanding of the physical mechanisms due to the difficulty in analyzing the causal ion migration, which occurs on a nanometer or even atomic scale. Here, the direct electrical transport measurement of analog resistive switching and ångström scale imaging of the causal ion migration is demonstrated in amorphous TaOx (a-TaOx) by conductive atomic force microscopy. Atomically flat thin films of a-TaOx, which is a practical material for commercial resistive random access memory, are fabricated in this study, and the mechanisms of the three known types of analog resistive switching phenomena (current-dependent set, voltage-dependent reset, and time-dependent switching) are directly visualized on the surfaces. The observations indicate that highly analog type of resistive switching can be induced in a-TaOx by inducing the continuous redox reactions for 2.0 < x < 2.5, which are characteristic of a-TaOx. The measurements also demonstrate drastic control of the switching stochasticity, which is attributable to controlled segregation of a metastable a-TaO2 phase. The findings provide direct clues for tuning the analog resistive switching characteristics of amorphous metal oxides and developing new functions for future neuromorphic computing.

Benzodiazepine-related dementia risks and protopathic biases revealed by multiple-kernel learning with electronic medical records.

Objectives: To simultaneously estimate how the risk of incident dementia nonlinearly varies with the administration period and cumulative dose of benzodiazepines, the duration of disorders with an indication for benzodiazepines, and other potential confounders, with the goal of settling the controversy over the role of benzodiazepines in the development of dementia. Methods: The classical hazard model was extended using the techniques of multiple-kernel learning. Regularised maximum-likelihood estimation, including determination of hyperparameter values with 10-fold cross-validation, bootstrap goodness-of-fit test, and bootstrap estimation of confidence intervals, was applied to cohorts retrospectively extracted from electronic medical records of our university hospitals between 1 November 2004 and 31 July 2020. The analysis was mainly focused on 8160 patients aged 40 or older with new onset of insomnia, affective disorders, or anxiety disorders, who were followed up for 4.10±3.47 years. Results: Besides previously reported risk associations, we detected significant nonlinear risk variations over 2-4 years attributable to the duration of insomnia and anxiety disorders, and to the administration period of short-acting benzodiazepines. After nonlinear adjustment for potential confounders, we observed no significant risk associations with long-term use of benzodiazepines. Conclusions: The pattern of the detected nonlinear risk variations suggested reverse causation and confounding. Their putative bias effects over 2-4 years suggested similar biases in previously reported results. These results, together with the lack of significant risk associations with long-term use of benzodiazepines, suggested the need to reconsider previous results and methods for future analysis.

Genome-wide Association Studies Categorized by Class of Antihypertensive Drugs Reveal Complex Pathogenesis of Hypertension with Drug Resistance.

Resistant hypertension is defined as uncontrolled blood pressure (BP) despite the use of three or more antihypertensive drugs of different classes. Although genetic factors may greatly contribute to hypertension with resistance to multiple drug classes, more than for general hypertension, its pathogenesis remains unknown. To reveal the genetic background of resistant hypertension, we categorized 32,239 patients whose data were obtained from the BioBank Japan Project, by prescription of 7 classes of antihypertensive drugs and performed genome-wide association studies (GWAS). Our GWAS identified four loci with significant association (P < 5 × 10-8 ): rs6445583 in CACNA1D and rs12308051 in the intergenic region on chromosome 12 for angiotensin II receptor blockers, rs35497065 in FOXA3 for calcium channel blockers, and rs11066280 in HECTD4 for αß-blockers. Because these loci are known to be susceptibility loci for hypertension and/or BP, our results indicate that resistant hypertension is caused by a combination of excessive BP and drug resistance to each antihypertensive pharmacological class. Furthermore, to investigate the genetic difference between BP traits and the treatment effectiveness of antihypertensive drugs, we performed gene-set analysis and calculated the genetic correlation continuously. Most of the genetic factors were in common between BP traits and antihypertensive effectiveness, but it seems that the genetic architecture of the drug response to antihypertensive treatment is more complicated than BP traits. This corresponds to the well-known mosaic theory of hypertension. Our findings reveal the complex pathogenesis of hypertension with resistance to multiple classes of antihypertensive drugs.

FIGHT-102: A phase 1 study of pemigatinib in Japanese patients with advanced malignancies.

BACKGROUND: FIGHT-102 was a phase 1, dose-escalation, dose-expansion study of pemigatinib in Japanese patients with advanced solid tumors. Here, we report safety, tolerability, and preliminary efficacy of pemigatinib from FIGHT-102. METHODS: Patients (≥20 years old) self-administered oral pemigatinib 9, 13.5, or 18 mg QD on intermittent dosing (Part 1) or 13.5 mg QD intermittent or continuous dosing (Part 2). A dosing cycle was 21 days (2 weeks on/1 week off or 21 continuous days). Primary endpoint was safety. Secondary endpoints were pharmacokinetics, pharmacodynamics, and preliminary efficacy. RESULTS: Forty-four patients (Part 1, n = 14; Part 2, n = 30) were enrolled; most common tumors, cholangiocarcinoma, n = 8; esophageal, n = 6; 26 patients had confirmed FGF/FGFR alterations (Part 1, n = 3; Part 2, n = 23); 70.5% had ≥3 prior systemic therapies. Maximum tolerated dose was not identified. The recommended phase 2 dosage was determined to be 13.5 mg QD. Most common treatment-emergent adverse events (TEAEs) were hyperphosphatemia (81.8%), dysgeusia (45.5%), stomatitis (43.2%), and alopecia (38.6%); most frequent Grade ≥3 TEAEs were anemia and decreased appetite (9.1% each). In Part 1, no patient achieved partial response (PR) or complete response, and 7 (50.0%) patients had stable disease (SD). In Part 2, 5 (16.7%) patients achieved PR (one each with cholangiocarcinoma, gall bladder cancer, breast cancer, urothelial tract/bladder cancer, and sweat gland carcinoma) and 6 (20%) had SD. Median duration of response was 9.56 months (95% CI: 4.17, 14.95). CONCLUSIONS: Pemigatinib demonstrated manageable adverse events, consistent pharmacokinetics and pharmacodynamics profiles, and preliminary efficacy in Japanese patients with advanced solid tumors.

Risk factors associated with relapse after methotrexate dose reduction in patients with rheumatoid arthritis receiving golimumab and methotrexate combination therapy.

AIM: To identify risk factors for relapse after methotrexate (MTX) dose reduction in rheumatoid arthritis (RA) patients receiving golimumab (GLM)/MTX combination therapy. METHOD: Data on RA patients ≥20 years old receiving GLM (50 mg) + MTX for ≥6 months were retrospectively collected. MTX dose reduction was defined as a reduction of ≥12 mg from the total dose within 12 weeks of the maximum dose (≥1 mg/wk average). Relapse was defined as Disease Activity Score in 28 joints using C-reactive protein level (DAS28-CRP) score ≥3.2 or sustained (≥ twice) increase of ≥0.6 from baseline. RESULTS: A total of 304 eligible patients were included. Among the MTX-reduction group (n = 125), 16.8% of patients relapsed. Age, duration from diagnosis to the initiation of GLM, baseline MTX dose, and DAS28-CRP were comparable between relapse and no-relapse groups. The adjusted odds ratio (aOR) of relapse after MTX reduction was 4.37 (95% CI 1.16-16.38, P = 0.03) for prior use of non-steroidal anti-inflammatory drugs (NSAIDs), and the aORs for cardiovascular disease (CVD), gastrointestinal disease and liver disease were 2.36, 2.28, and 3.03, respectively. Compared to the non-reduction group, the MTX-reduction group had a higher proportion of patients with CVD (17.6% vs 7.3%, P = 0.02) and a lower proportion of prior use of biologic disease-modifying antirheumatic drugs (11.2% vs. 24.0%, P = 0.0076). CONCLUSION: Attention should be given to RA patients with history of CVD, gastrointestinal disease, liver disease, or prior NSAIDs-use when considering MTX dose reduction to ensure benefits outweigh the risks of relapse.