Risk factors for relapse of immune-related pneumonitis after 6-week oral prednisolone therapy: a follow-up analysis of a phase II study.

BACKGROUND: Immune-related pneumonitis (irP) is one of the most important immune-related adverse events caused by immune checkpoint inhibitors (ICIs). After corticosteroid therapy irP frequently relapses, which can interfere with cancer therapy. However, risk factors for irP relapse are unknown. METHODS: This study was a follow-up analysis of a phase II study that evaluated 56 patients with grade ≥ 2 irP treated with oral prednisolone, 1 mg/kg/day, tapered over 6 weeks. Clinical factors including patient characteristics, blood test findings, and response to prednisolone therapy were assessed to identify risk factors for irP relapse using the Fine-Gray test. RESULTS: Among 56 patients with irP, 22 (39.3%) experienced irP relapse after 6 weeks of prednisolone therapy during the follow-up observation period. Radiographic organising pneumonia (OP) pattern and duration to irP onset ≥ 100 days from ICI initiation were determined to be significant risk factors for irP relapse in a multivariate Fine-Gray test (hazard ratio [HR] = 3.17, 95% CI 1.37-7.32, p = 0.007, and HR = 2.61, 95% CI 1.01-6.74, p = 0.048, respectively). Other patient characteristics, blood test findings, irP severity, and response to prednisolone therapy were not associated with irP relapse. CONCLUSIONS: In irP patients treated with 6-week prednisolone tapering therapy, OP pattern and duration to irP onset ≥ 100 days were associated with relapse risk. Assessment of the risk factors for irP relapse will be helpful for irP management.

COMMD5 counteracts cisplatin-induced nephrotoxicity by maintaining tubular epithelial integrity and autophagy flux.

Oxidative stress mediated by reactive oxygen species (ROS) contributes to apoptosis of tubular epithelial cells (TECs) and renal inflammation during acute kidney injury (AKI). Copper metabolism MURR1 domain-containing 5 [COMMD5/hypertension-related, calcium-regulated gene (HCaRG)] shows strong cytoprotective properties. COMMD5 is highly expressed in proximal tubules (PTs), where it controls cell differentiation. We assessed its role in cisplatin-induced AKI using transgenic mice in which COMMD5 is overexpressed in the PTs. Cisplatin caused the accumulation of damaged mitochondria and cellular waste in PTs, thus increasing the apoptosis of TECs. COMMD5 overexpression effectively protected TECs from cisplatin nephrotoxicity by decreasing intracellular ROS levels, mitochondrial dysfunction, and apoptosis through the preservation of tubular epithelial integrity, thus alleviating morphological and functional kidney damage. Excessive ROS production by hydrogen peroxide led to long-term autophagy activation through an increased burden on the autophagy/lysosome degradation system in TECs, and autophagic elimination of damaged mitochondria and cellular waste was compromised. COMMD5 attenuated oxidative injury by increasing autophagy flux, possibly due to a reduction of intracellular ROS levels through maintained tubular epithelial integrity, which decreased JNK/caspase-3-dependent apoptosis. Meanwhile, COMMD5 inhibition by siRNA reduced the resistance of TECs to cisplatin cytotoxicity, as shown by disrupted tubular epithelial integrity and cell viability. These data indicated that COMMD5 protects TECs from drug-induced oxidative stress and toxicity by maintaining tubular epithelial integrity and autophagy flux and ultimately decreases mitochondrial dysfunction and apoptosis. Increasing COMMD5 content in PTs is proposed as a new protective and therapeutic strategy against AKI.NEW & NOTEWORTHY Oxidative stress overload by drug treatment causes the accumulation of damaged mitochondria that could contribute to tubulopathy. However, effective preventive treatment for drug-induced acute kidney injury remains incompletely understood. Our study showed that copper metabolism MURR1 domain-containing 5 (COMMD5) reduced mitochondrial dysfunction and increased autophagy flux by alleviating reactive oxygen species production through maintaining tubular epithelial integrity when tubular epithelial cells were under oxidative stress, thus ameliorating renal function in cisplatin-treated mice. These results uncover a novel renoprotective mechanism underlying tubular epithelial integrity and autophagy flux.

CXCL10 predicts autoimmune features and a favorable clinical course in patients with IIP: post hoc analysis of a prospective and multicenter cohort study.

BACKGROUND: Interstitial pneumonia with autoimmune features (IPAF), which does not meet any of the criteria for connective tissue diseases (CTD), has been attracting an attention in patients with idiopathic interstitial pneumonia (IIP). However, the biomarkers that reflect the clinical course of these patients have not been fully elucidated. OBJECTIVE: To identify useful serum biomarkers reflecting CTD-related features and favorable prognoses in patients with IIP. METHODS: This was a post hoc analysis of a prospective and multicenter cohort study between 2015 and 2020. Newly diagnosed patients with IIP were consecutively enrolled, and 74 autoimmune features and autoantibodies were comprehensively checked during IIP diagnosis. Serum levels of CXCL10, CXCL1, CCL2, BAFF, angiopoietin-2, and leptin were evaluated at the time of IIP diagnosis. RESULTS: Two hundred twenty-two patients (159 men and 63 women) with IIP were enrolled. The median observation duration was 36 months. The median age was 71 years old, and median %forced vital capacity (FVC) was 84.1% at the time of IIP diagnosis. The proportion of patients who met the classification criteria for IPAF was 11.7%. In patients with high serum CXCL10, changes in both %FVC and %diffusion lung capacity for carbon monoxide at one year were significantly higher than those in patients with low CXCL10 (p = 0.014 and p = 0.009, respectively), whereas these changes were not significant for other chemokines and cytokines. High CXCL10 levels were associated with acute/subacute onset (p < 0.001) and the diagnosis of nonspecific interstitial pneumonia with organizing pneumonia overlap (p = 0.003). High CXCL10 levels were related to a higher classification of IPAF (relative risk for IPAF was 3.320, 95%CI: 1.571-7.019, p = 0.003) and lower classification of progressive pulmonary fibrosis (PPF; relative risk for PPF was 0.309, 95%CI: 0.100-0.953, p = 0.027) compared to those with low CXCL10. Finally, survival was higher in patients with IPF and high CXCL10 (p = 0.044), and high CXCL10 was a significant prognostic factor in multivariate Cox proportional hazards models (hazard ratio 0.368, p = 0.005). CONCLUSIONS: High serum levels of CXCL10 are associated with CTD-related features, the favorable clinical course, and survival in patients with IIP, especially IPF. CLINICAL TRIAL NUMBER: Not applicable.

Clinical Efficacy and Safety of Anti-Obesity Medications Among Adult East Asian People with Obesity: A Systematic Literature Review and Indirect Treatment Comparison.

INTRODUCTION: The prevalence of obesity has increased worldwide over the past decades. Regional variations exist in the relationship between body mass index (BMI), body fat, and health risks: Asians typically have a lower BMI than people of European descent, but a higher risk of obesity-related comorbidities. However, there is a paucity of evidence for anti-obesity medications (AOMs) in East Asian populations. In this study, we aimed to systematically review evidence regarding the safety and efficacy of AOMs among adults with obesity disease in East Asia, and to assess the feasibility of conducting an indirect treatment comparison (ITC) between the semaglutide and mazindol trials. METHODS: The Embase, MEDLINE, and ICHUSHI databases were searched via the Ovid SP platform for randomized controlled trials, in English or Japanese, reporting data on semaglutide or mazindol therapy with placebo or diet and exercise as comparators. The potential risks of bias in conducting a population-adjusted ITC were determined based on the heterogeneity of potential effect modifiers and variations in study design. RESULTS: Of 21 publications, 2 were included in this study based on the eligibility criteria. The STEP 6 study established the clinical efficacy of subcutaneous semaglutide compared with placebo in the reduction of body weight and cardiometabolic risk factors [glycated hemoglobin (HbA1c), total cholesterol, and systolic blood pressure] among Japanese and South Korean people with obesity disease. Mazindol also proved beneficial in reducing body weight and total cholesterol compared with placebo in Japan. Both semaglutide and mazindol were associated with higher rates of adverse events and treatment discontinuation than placebo. An ITC between the two studies was not deemed feasible based on the potential risks of bias. CONCLUSIONS: Semaglutide and mazindol are associated with significant body weight reduction among people with obesity in East Asia. Further research based on label indications and up-to-date real-world data among East Asian people with obesity would help determine additional clinical benefits.

Cost-utility analysis of second-line axicabtagene ciloleucel versus standard of care in Japan based on the ZUMA-7 trial.

Aim: To perform a cost-effectiveness analysis comparing axicabtagene ciloleucel (axi-cel) with standard of care (SoC; salvage chemoimmunotherapy, followed by high-dose therapy with autologous stem cell rescue for responders) for second-line (2L) treatment of adults with relapsed or refractory large B-cell lymphoma (r/r LBCL) in the pivotal ZUMA-7 trial data from a Japanese payer perspective.Materials & methods: A three-state partitioned survival model was utilized using population and clinical inputs from the ZUMA-7 trial data over a lifetime horizon.Results: Axi-cel was associated with greater incremental quality-adjusted life-years (2.06) and higher incremental total costs ($48,685.59/¥6.9 million) leading to an incremental cost-effectiveness ratio of $23,590.34/¥3.3 million per quality-adjusted life-years compared with SoC.Conclusion: Axi-cel is a cost-effective treatment alternative to SoC for 2L treatment of adults with r/r LBCL.

[Box: see text].

Olanzapine Plus Triple Antiemetic Therapy for the Prevention of Carboplatin-Induced Nausea and Vomiting: A Randomized, Double-Blind, Placebo-Controlled Phase III Trial.

PURPOSE: We evaluated the efficacy and safety of antiemetic therapy with olanzapine, a neurokinin-1 receptor antagonist (RA), a 5-hydroxytryptamine-3 (5-HT3) RA, and dexamethasone for preventing chemotherapy-induced nausea and vomiting in patients receiving carboplatin-containing chemotherapy. PATIENTS AND METHODS: Chemotherapy-naïve patients scheduled to receive carboplatin (AUC ≥5) were randomly assigned to receive either olanzapine 5 mg once daily (olanzapine group) or placebo (placebo group) in combination with aprepitant, a 5-HT3 RA, and dexamethasone. The primary end point was the complete response (CR; no vomiting and no rescue therapy) rate in the overall phase (0-120 hours). Secondary end points included the proportion of patients free of nausea and safety. RESULTS: In total, 355 patients (78.6% male, median age 72 years, 100% thoracic cancer), including 175 and 180 patients in the olanzapine and placebo groups, respectively, were evaluated. The overall CR rate was 86.9% in the olanzapine group versus 80.6% in the placebo group. The intergroup difference in the overall CR rate was 6.3% (95% CI, -1.3 to 13.9). The proportions of patients free of chemotherapy-induced nausea in the overall (88.6% in the olanzapine group v 75.0% in the placebo group) and delayed (89.7% v 75.6%, respectively) phases were significantly higher in the olanzapine group than in the placebo group (both P < .001). Somnolence was observed in 43 (24.6%) and 41 (22.9%) patients in the olanzapine and placebo groups, respectively, and no events were grade ≥3 in severity. CONCLUSION: The addition of olanzapine was not associated with a significant increase in the overall CR rate. Regarding the prevention of nausea, adding olanzapine provided better control in patients receiving carboplatin-containing chemotherapy, which needs further exploration.

Burden of Antimicrobial Resistance in Japan: A Systematic Literature Review and Meta-Analysis.

INTRODUCTION: Antimicrobial resistance (AMR) is one of the most serious public health challenges worldwide, including in Japan. However, there is limited evidence assessing the AMR burden in Japan. Thus, this systematic literature review (SLR) and meta-analysis (MA) were conducted to assess the clinical and economic burden of AMR in Japan. METHODS: Comprehensive literature searches were performed on EMBASE, MEDLINE, the Cochrane Library, and ICHUSHI between 2012 and 2022 following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. MA estimated a pooled effect between the two comparative arms (AMR vs. non-AMR). The results were reported in measures of odds ratios (ORs) for in-hospital mortality and in standardized mean differences (SMDs) for length of stay (LOS) and direct medical costs. RESULTS: Literature searches identified 1256 de-duplicated records, of which 56 observational studies (English, n = 35; Japanese, n = 21) were included. Of note, twenty-two studies (39.3%) compared the AMR group with non-AMR group. In the SLR, in-hospital mortality, LOS, and direct medical costs were higher in the AMR group compared to the non-AMR group. Eight studies were selected for the MA. In the AMR group, the pooled estimate showed a statistically higher in-hospital mortality [random effect (RE)-OR 2.25, 95% CI 1.34-3.79; I2 = 89%; τ2 = 0.2257, p < 0.01], LOS (RE-SMD 0.37, 95% CI - 0.09-0.84; I2 = 99%; τ2 = 0.3600, p < 0.01), and direct medical cost (RE-SMD 0.53, 95% CI 0.43-0.62; I2 = 0.0%; τ2 = 0.0, p = 0.88) versus the non-AMR group. CONCLUSION: Our study presents an overview of the clinical and economic burden of AMR in Japan. Patients with AMR infections experience significantly higher in-hospital mortality, LOS, and direct medical costs compared with patients without AMR infections.

Cost-effectiveness analysis 3L of axicabtagene ciloleucel vs tisagenlecleucel and lisocabtagene maraleucel in Japan.

Aim: Cost-effectiveness analysis (CEA) was performed to compare axicabtagene ciloleucel (axi-cel) with tisagenlecleucel (tisa-cel) and lisocabtagene (liso-cel) for treatment of relapsed or refractory large B-cell lymphoma in adult patients after ≥2 lines of therapy in Japan. Materials & methods: Cost-effectiveness analysis was conducted using the partition survival mixture cure model based on the ZUMA-1 trial and adjusted to the JULIET and TRANSCEND trials using matching-adjusted indirect comparisons. Results & conclusion: Axi-cel was associated with greater incremental life years (3.13 and 2.85) and incremental quality-adjusted life-years (2.65 and 2.24), thus generated lower incremental direct medical costs (-$976.29 [-¥137,657] and -$242.00 [-¥34,122]), compared with tisa-cel and liso-cel. Axi-cel was cost-effective option compared with tisa-cel and liso-cel from a Japanese payer's perspective.

[Box: see text].

Radiological and histopathological features and treatment response by subtypes of interstitial pneumonia with autoimmune features: A prospective, multicentre cohort study.

BACKGROUND: Patients with idiopathic interstitial pneumonia (IIP) have a favourable prognosis when they have interstitial pneumonia with autoimmune features (IPAF). However, precise IPAF-related findings from high-resolution computed tomography (HRCT) and lung histopathological specimens and the treatment response have not been fully determined. Therefore, this study was conducted to evaluate the relationship between findings on HRCT or lung histopathological specimens and the progression of interstitial pneumonia in patients with IPAF. METHODS: This multicentre cohort study prospectively enrolled consecutive patients with IIP. At the diagnosis of IIP, we systematically evaluated 74 features suggestive of connective tissue diseases and followed them up. HRCT, lung specimens, serum antibodies, and the clinical course were also evaluated. RESULTS: Among 222 patients with IIP, 26 (11.7%) fulfilled the IPAF criteria. During a median observation period of 36 months, patients with IPAF showed better survival than those without IPAF (p = 0.034). While histopathological findings were not related to IPAF, nonspecific interstitial pneumonia (NSIP) with organizing pneumonia (OP) overlap was the most prevalent HRCT pattern (p < 0.001) and the consolidation opacity was the most common radiological finding in IPAF (p = 0.017). Furthermore, in patients with IPAF, the diagnosis of COP or NSIP with OP overlap was associated with a higher increase in %FVC in 1 year than in those with idiopathic pulmonary fibrosis, NSIP, or unclassifiable IIP (p = 0.002). CONCLUSIONS: This study shows the presence of consolidation opacity on HRCT and the diagnosis of COP or NSIP with OP overlap are associated with IPAF and its favourable treatment response in patients with IPAF.

Cost-effectiveness analysis of COVID-19 booster vaccination with BNT162b2 in Japan.

BACKGROUND: The aim of this study was to evaluate the public health and economic impact of the COVID-19 booster vaccination with BNT162b2 in Japan during an Omicron-dominant period from early 2022. RESEARCH DESIGN AND METHODS: A combined cohort Markov decision tree model estimated the cost-effectiveness of annual or biannual booster vaccination strategies compared to no booster vaccination for those aged 65 years and above, and those aged 60-64 years at high risk as the base case. The societal perspective was primarily considered. We also examined other target populations with different age and risk groups. Sensitivity and scenario analyses with alternative inputs were performed. RESULTS: Annual and biannual vaccination strategies were dominant from the societal perspective in the base case. Incremental Cost Effectiveness Ratios (ICERs) from the payer perspective were JPY 1,752,499/Quality Adjusted Life Year (QALY) for annual vaccination and JPY 2,831,878/QALY for biannual vaccination, both less than the threshold value in Japan (JPY 5 million/QALY). The results were consistent even when examining other target age and risk groups. All sensitivity and scenario analyses indicated that ICERs were below JPY 5 million/QALY. CONCLUSIONS: Booster vaccination with the COVID-19 vaccine BNT162b2 is a dominant strategy and beneficial to public health in Japan.

Prognostic Role of Interferon-λ3 in Anti-Melanoma Differentiation-Associated Gene 5-Positive Dermatomyositis-Associated Interstitial Lung Disease.

OBJECTIVE: Interferon-λ3 (IFNλ3) is a cytokine with antiviral functions on barrier surfaces, and it is associated with disease activity in autoimmune diseases. This study assessed the clinical significance of serum IFNλ3 levels in polymyositis/dermatomyositis (PM/DM)-associated interstitial lung disease (ILD). METHODS: We measured serum IFNλ3 levels in 221 patients with PM/DM-ILD (155 in the derivation cohort, 66 in the validation cohort) and 38 controls. We evaluated factors associated with mortality risk among 79 patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive DM-ILD. RESULTS: Serum IFNλ3 levels at diagnosis were significantly higher in patients with PM/DM-ILD than in healthy controls. Remarkably, serum IFNλ3 levels were specifically increased in patients with anti-MDA5 antibody-positive DM-ILD in both the derivation and validation cohorts. In anti-MDA5 antibody-positive DM-ILD, patients with high IFNλ3 levels (>120 pg/mL) had significantly lower survival rates than those with low IFNλ3 levels (≤120 pg/mL). A multivariate analysis revealed that high IFNλ3 levels, as well as old age and low Pao2, were significantly associated with poor prognoses in patients with anti-MDA5 antibody-positive DM-ILD. In a classification analysis of patients with anti-MDA5 antibody-positive DM-ILD based on age, IFNλ3 level, and Pao2, patients with old age (>53 years), high IFNλ3 levels (>120 pg/mL), and low Pao2 (<75 mm Hg) had the worst survival. In lung pathologic analyses, IFNλ3-positive staining was observed in macrophages, airway epithelial cells, the pleural region, and intrapulmonary veins in patients with anti-MDA5 antibody-positive DM-ILD. CONCLUSION: Serum IFNλ3 is a promising biomarker for identifying patients at high risk of poor outcomes in anti-MDA5 antibody-positive DM-ILD.

Soft x-ray photoelectron momentum microscope for multimodal valence band stereography.

The photoelectron momentum microscope (PMM) in operation at BL6U, an undulator-based soft x-ray beamline at the UVSOR Synchrotron Facility, offers a new approach for µm-scale momentum-resolved photoelectron spectroscopy (MRPES). A key feature of the PMM is that it can very effectively reduce radiation-induced damage by directly projecting a single photoelectron constant energy contour in reciprocal space with a radius of a few Å-1 or real space with a radius of a few 100 µm onto a two-dimensional detector. This approach was applied to three-dimensional valence band structure E(k) and E(r) measurements ("stereography") as functions of photon energy (hν), its polarization (e), detection position (r), and temperature (T). In this study, we described some examples of possible measurement techniques using a soft x-ray PMM. We successfully applied this stereography technique to µm-scale MRPES to selectively visualize the single-domain band structure of twinned face-centered-cubic Ir thin films grown on Al2O3(0001) substrates. The photon energy dependence of the photoelectron intensity on the Au(111) surface state was measured in detail within the bulk Fermi surface. By changing the temperature of 1T-TaS2, we clarified the variations in the valence band dispersion associated with chiral charge-density-wave phase transitions. Finally, PMMs for valence band stereography with various electron analyzers were compared, and the advantages of each were discussed.

Six-week oral prednisolone therapy for immune-related pneumonitis: a single-arm phase II study.

BACKGROUND: There has been no prospective trial for treatment of immune-related pneumonitis (irP) occurred after immune checkpoint inhibitors (ICIs). METHODS: In this single-arm phase II study, patients with cancer with grade ≥2 irP received oral prednisolone (1 mg/kg/day), tapered over 6 weeks. The primary endpoint was a pneumonitis control rate at 6 weeks from the start of the study treatment, defined as complete disappearance or partial improvement of irP in high-resolution CT of the chest. RESULTS: Among 57 patients enrolled, 56 were included in the final analysis. The most frequent cause of irP was single ICI therapy (51.8%), followed by combination with chemotherapy plus ICI (39.3%). Thirty-five (62.5%) patients had grade 2 irP and 21 (37.5%) had grade ≥3. Fifty-one (91.1%) patients completed the study treatment while 5 discontinued the study treatment because of relapse of irP (n=1), death from cancer (n=1), occurrence of immune-related hepatitis (n=1), extension of the treatment duration more than 6 weeks (n=1), and attending physician's decision (n=1). Six weeks after the start of the study treatment, 16 (28.5%) patients demonstrated complete recovery from irP, 35 (62.5%) had a partial improvement in irP, 1 (1.8%) had a relapse of irP, and 4 (7.1%) were not evaluable. The pneumonitis control rate at 6 weeks was 91.1% (95% CI, 80.7% to 96.1%). Twelve weeks after the start of the study treatment, 5 (8.9%), 27 (48.2%), and 15 (26.8%) patients demonstrated complete recovery, partial improvement, and relapse, respectively, and 9 (16.1%) were not evaluable. The pneumonitis control rate at 12 weeks was 57.1% (95% CI, 44.1% to 69.2%). During the observation period, 18 (32.1%) patients experienced a relapse of irP, and of those, 17 received re-treatment with corticosteroids. Grade ≥3 adverse events occurred in 10 (17.9%) patients, in which hyperglycemia was most frequent (n=6). There was no treatment-related death. CONCLUSIONS: In this first prospective study for irP, prednisolone at 1 mg/kg/day, tapered over 6 weeks, demonstrated a promising clinical benefit and manageable toxicity, suggesting a potential treatment option for irP. TRIAL REGISTRATION NUMBER: jRCT: 1041190029.

Frequency of screw-retained angulated screw channel single crown following immediate implant placement and provisionalization in the esthetic zone: A cone beam computed tomography study.

OBJECTIVE: The purpose of this cone beam computed tomography (CBCT) study was to determine the frequency percentage of screw-retained crown using angulated screw channel (ASC) abutment for single immediate implant placement and provisionalization (IIPP) in the esthetic zone. METHODS: The CBCT images of 200 patients without disease and without metal restorations in maxillary anterior teeth were evaluated. The mid-sagittal-sectional CBCT images of maxillary anterior teeth (#6-#11) were created in an implant planning software, screen-captured, and transferred to a presentation program. Template of tapered implants with diameter of 3.5 mm (for central and lateral incisors) and 4.3 mm (for central incisors and canines) and lengths of 13, 15, and 18 mm were applied to the sagittal images to identify the IIPP cases. To qualify for IIPP, the implant must engage >35% bone with at least 1 mm of surrounding bone and no perforations. The IIPP cases were further divided into straight screw channel (IIPPSSC) abutment or 25-degree angulated screw channel abutment (IIPPASC), based upon its restorability. The frequency percentages of possible IIPP, IIPPSSC, and IIPPASC were reported and compared among all maxillary anterior teeth. RESULTS: A total of 1200 maxillary anterior teeth sagittal images from 200 patients (88 male and 112 female) with a mean age of 51.3 years (range 20-83 years) were evaluated in this study. The overall frequency percentages of IIPP, IIPPSSC, and IIPPASC possibility were 84% (74%-92%), 14% (10%-24%), and 75% (66%-87%), respectively. CONCLUSION: Within the limitations of this CBCT study, 90% of single IIPP in the esthetic zone can be restored with screw-retained crown when utilizing ASC. In addition, the possibility of using a screw-retained restoration following IIPP increases about five times with ASC abutment compared to the SSC abutment.

Mapping potential conflicts between global agriculture and terrestrial conservation.

Demand for food products, often from international trade, has brought agricultural land use into direct competition with biodiversity. Where these potential conflicts occur and which consumers are responsible is poorly understood. By combining conservation priority (CP) maps with agricultural trade data, we estimate current potential conservation risk hotspots driven by 197 countries across 48 agricultural products. Globally, a third of agricultural production occurs in sites of high CP (CP > 0.75, max = 1.0). While cattle, maize, rice, and soybean pose the greatest threat to very high-CP sites, other low-conservation risk products (e.g., sugar beet, pearl millet, and sunflower) currently are less likely to be grown in sites of agriculture-conservation conflict. Our analysis suggests that a commodity can cause dissimilar conservation threats in different production regions. Accordingly, some of the conservation risks posed by different countries depend on their demand and sourcing patterns of agricultural commodities. Our spatial analyses identify potential hotspots of competition between agriculture and high-conservation value sites (i.e., 0.5° resolution, or ~367 to 3,077km2, grid cells containing both agriculture and high-biodiversity priority habitat), thereby providing additional information that could help prioritize conservation activities and safeguard biodiversity in individual countries and globally. A web-based GIS tool at https://agriculture.spatialfootprint.com/biodiversity/ systematically visualizes the results of our analyses.

Cost-Effectiveness Analysis of Tofacitinib Compared with Biologics in Biologic-Naïve Patients with Moderate-to-Severe Ulcerative Colitis in Japan.

OBJECTIVE: Tofacitinib is an oral Janus kinase inhibitor approved for the treatment of ulcerative colitis (UC). The objective of this study was to evaluate the long-term cost-effectiveness of tofacitinib versus current biologics, considering combinations of first-line (1L) and second-line (2L) therapies, from a Japanese payer's perspective in patients with moderate-to-severe active UC following an inadequate response to conventional therapy and in those who were naïve to biologics. METHODS: A cost-effectiveness analysis was conducted during the time horizon specified in the Markov model, which considers a patient's lifetime as 60 years and an annual discount rate of 2% on costs and effects. The model compared tofacitinib with vedolizumab, infliximab, adalimumab, golimumab, and ustekinumab. The time of active treatment was divided into induction and maintenance phases. Patients not responding to their biologic treatment after induction or during the maintenance phase were switched to a subsequent line of therapy. Treatment response and remission probabilities (for induction and maintenance phases) were obtained through a systematic literature review and a network meta-analysis that employed a multinomial analysis with fixed effects. Patient characteristics were sourced from the OCTAVE Induction trials. Mean utilities associated with UC health states and adverse events (AEs) were obtained from published sources. Direct medical costs related to drug acquisition, administration, surgery, patient management, and AEs were derived from the JMDC database analysis, which corresponded with the medical procedure fees from 2021. The drug prices were adjusted to April 2021. Further validation through all processes by clinical experts in Japan was conducted to fit the costs to real-world practices. Scenario and sensitivity analyses were also performed to confirm the accuracy and robustness of the base-case results. RESULTS: In the base-case, the treatment pattern including 1L tofacitinib was more cost-effective than vedolizumab, infliximab, golimumab, and ustekinumab for 1L therapies in terms of cost per quality-adjusted life year (QALY) gained (based on the Japanese threshold of 5,000,000 yen/QALY [38,023 United States dollars {USD}/QALY]). The base-case results demonstrated that the incremental costs would be reduced for all biologics, and decreases in incremental QALYs were observed for all biologics other than adalimumab. The incremental cost-effectiveness ratio (ICER) was found to be dominant for adalimumab; for the other biologics, it was found to be less costly and less efficacious. The efficiency frontier on the cost-effectiveness plane indicated that tofacitinib-infliximab and infliximab-tofacitinib were more cost-effective than the other treatment patterns. When infliximab-tofacitinib was compared with tofacitinib-infliximab, the ICER was 282,609,856 yen/QALY (2,149,157 USD/QALY) and the net monetary benefit (NMB) was -12,741,342 yen (-96,894 USD) with a threshold of 5,000,000 yen (38,023 USD) in Japan. Therefore, infliximab-tofacitinib was not acceptable by this threshold, and tofacitinib-infliximab was the cost-effective treatment pattern. CONCLUSION: The current analysis suggests that the treatment pattern including 1L tofacitinib is a cost-effective alternative to the biologics for patients with moderate-to-severe UC from a Japanese payer's perspective.

Budget impact analysis of next-generation sequencing versus sequential single-gene testing in Japanese patients with advanced non-small-cell lung cancer.

BACKGROUND: Identification of genomic alterations (e.g., EGFR, ALK, ROS1, BRAF, NTRK, and MET) is essential for initiating targeted therapy in patients with advanced non-small-cell lung cancer (aNSCLC). This study estimated the budget impact of using the sequential single-gene (SSG) test, which tests for each mutation one at a time, versus next-generation sequencing (NGS), which tests for all mutations at the same time, among newly diagnosed patients with aNSCLC from a Japanese healthcare payer's perspective. METHODS: A budget impact model (BIM) was used to determine the expected budget impact associated with NGS for newly diagnosed aNSCLC in Japan over a 3-year period. The BIM compared the total costs (biopsy, testing, and treatment) and average turnaround time of "future NGS" and "current NGS" versus SSG testing. RESULTS: The adoption of current NGS over SSG testing had a budget impact of -0.24%, but adoption of future NGS over SSG testing had a budget impact of +4.33% across a 3-year time horizon on the Japanese budget for aNSCLC treatment. The adoption of current or future NGS over SSG testing would shorten the average turnaround time for testing. CONCLUSIONS: The adoption of current NGS over SSG testing would slightly decrease the yearly costs. However, the adoption of future or current NGS over SSG testing would shorten the average turnaround time, enabling faster identification of genomic alterations and earlier initiation of treatment for aNSCLC patients in Japan.

Serum immune modulators associated with immune-related toxicities and efficacy of atezolizumab in patients with non-small cell lung cancer.

PURPOSE: Identifying patients at high risk of immune-related adverse events (irAEs) that impede the achievement of durable efficacy of programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) blockade therapy is important in improving their management. Identification of a novel predictive factor of therapeutic benefit is also important in improving patient selection for treatment with PD-1/PD-L1 inhibitors. Further determinants driving response and linking with irAEs are urgently required. METHODS: To address these unmet needs in the field, we explored whether 27 soluble checkpoint proteins and immunomodulatory proteins in serum at the therapy baseline and after week 3 were associated with irAE onset and therapeutic efficacy using MILLIPLEX Human Immuno-Oncology Checkpoint Protein Panel assays in a prospective, multicenter cohort of 81 patients with non-small cell lung cancer (NSCLC) receiving atezolizumab monotherapy. RESULTS: By competing-risks regression analysis, we identified that high levels of B cell-activating factor (BAFF) at baseline were a significant and strong risk factor of irAEs (hazard ratio, 5.61; 95% confidence interval, 2.43-12.96; P < 0.0001). We also identified that increased inducible T cell co-stimulator (ICOS) during the first therapeutic cycle was an independent factor associated with prolonged progression-free survival and overall survival. CONCLUSION: These findings are in keeping with the reported mechanistic basis of these molecules and may provide potential guidance for clinical decision-making to improve patient care. Further validation studies are warranted. Trial registration UMIN000035616 (January 28, 2019).

Effectiveness of feedback control and the trade-off between death by COVID-19 and costs of countermeasures.

We provided a framework of a mathematical epidemic modeling and a countermeasure against the novel coronavirus disease (COVID-19) under no vaccines and specific medicines. The fact that even asymptomatic cases are infectious plays an important role for disease transmission and control. Some patients recover without developing the disease; therefore, the actual number of infected persons is expected to be greater than the number of confirmed cases of infection. Our study distinguished between cases of confirmed infection and infected persons in public places to investigate the effect of isolation. An epidemic model was established by utilizing a modified extended Susceptible-Exposed-Infectious-Recovered model incorporating three types of infectious and isolated compartments, abbreviated as SEIIIHHHR. Assuming that the intensity of behavioral restrictions can be controlled and be divided into multiple levels, we proposed the feedback controller approach to implement behavioral restrictions based on the active number of hospitalized persons. Numerical simulations were conducted using different detection rates and symptomatic ratios of infected persons. We investigated the appropriate timing for changing the degree of behavioral restrictions and confirmed that early initiating behavioral restrictions is a reasonable measure to reduce the burden on the health care system. We also examined the trade-off between reducing the cumulative number of deaths by the COVID-19 and saving the cost to prevent the spread of the virus. We concluded that a bang-bang control of the behavioral restriction can reduce the socio-economic cost, while a control of the restrictions with multiple levels can reduce the cumulative number of deaths by infection.