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.

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].

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].

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 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.

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.

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.

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).

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.

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.

Trajectory to local extinction of an isolated dugong population near Okinawa Island, Japan.

A small animal population becomes extinct owing to demographic and environmental stochasticity after declining below the minimum viable population (MVP). However, the actual process of extinction derived by stochastic factors after crossing MVP has not been recorded for long-lived marine mammals. Here, we reconstructed the declining history of a small, isolated population of dugongs in Okinawa over 125 years. The initial population size of approximately 280-420 in the nineteenth century declined to approximately < 100 in 1917 because of overfishing, < 70 in 1979, 11 in 1997, 3 after 2006, and all known individuals disappeared or died by 2019. After 1979, a decline in the natural growth rate has led to extinction. Long-lived animals may persist for a few decades after the population falls below the MVP, at which time active conservation measures, such as captive breeding, should be implemented.

Antibiotics, antibiotic-resistant bacteria, and resistance genes in aquaculture: risks, current concern, and future thinking.

Aquaculture is remarkably one of the most promising industries among the food-producing industries in the world. Aquaculture production as well as fish consumption per capita have been dramatically increasing over the past two decades. Shifting of culture method from semi-intensive to intensive technique and applying of antibiotics to control the disease outbreak are the major factors for the increasing trend of aquaculture production. Antibiotics are usually present at subtherapeutic levels in the aquaculture environment, which increases the selective pressure to the resistant bacteria and stimulates resistant gene transfer in the aquatic environment. It is now widely documented that antibiotic resistance genes and resistant bacteria are transported from the aquatic environment to the terrestrial environment and may pose adverse effects on human and animal health. However, data related to antibiotic usage and bacterial resistance in aquaculture is very limited or even absent in major aquaculture-producing countries. In particular, residual levels of antibiotics in fish and shellfish are not well documented. Recently, some of the countries have already decided the maximum residue levels (MRLs) of antibiotics in fish muscle or skin; however, many antibiotics are yet not to be decided. Therefore, an urgent universal effort needs to be taken to monitor antibiotic concentration and resistant bacteria particularly multiple antibiotic-resistant bacteria and to assess the associated risks in aquaculture. Finally, we suggest to take an initiative to make a uniform antibiotic registration process, to establish the MRLs for fish/shrimp and to ensure the use of only aquaculture antibiotics in fish and shellfish farming globally.

Prognostic Impact of Lymphocyte-C-Reactive Protein Ratio in Patients Who Underwent Surgical Resection for Hepatocellular Carcinoma.

BACKGROUND: Systemic inflammation-related factors, either independently or in combination, are recognized as prognostic factors for various cancers. The ratio of lymphocyte count to C-reactive protein concentration (lymphocyte-CRP ratio; LCR) is a recently identified prognostic marker for several cancers. Here, we examined the prognostic value of the LCR in patients with hepatocellular carcinoma (HCC). METHODS: This was a single-center retrospective study of patients who underwent surgical resection for HCC between 2004 and 2017. Patients were divided into high- and low-LCR status groups, and the relationships between LCR status, prognosis, and other clinicopathological characteristics were analyzed. RESULTS: A total of 454 patients with HCC were enrolled and assigned to the high- (n=245) or low- (n=209) LCR groups. Compared with the high-LCR group, patients in the low-LCR group had a significantly lower serum albumin level (median 4.1 vs. 3.9 g/dL, P <0.0001), lower platelet count (median 14.0 vs. 12.0 ×104/µL, P=0.0468), lower prothrombin time (median 93.2 vs. 89.6 %, P=0.0006), and larger tumor size (median 2.3 vs. 2.5 cm, P=0.0056). Patients with low-LCR status had significantly worse outcomes of overall survival and disease-free survival than patients with high-LCR status (P=0.0003 and P=0.0069, respectively). Low-LCR status was significantly associated with worse overall survival in multivariate analysis (hazard ratio 1.57, 95% confidence interval 1.14-2.17, P=0.0058). CONCLUSIONS: Low-LCR status may predict worse outcomes in patients with HCC. Measurement of LCR is routine and can easily be applied for risk stratification in the assessment of patients with HCC.

Urinary biopyrrins and free immunoglobin light chains are biomarker candidates for screening at-risk mental state in adolescents.

BACKGROUND: Early diagnosis of individuals' at-risk mental state (ARMS) is important for preventing their pathogenesis or, at least, delaying onset of overt psychosis. Traditional diagnosis of ARMS subjects is mainly based on structured interviews, but future diagnosis would be carried out together with biomarkers. AIM: In this study, we report urinary biopyrrins and free immunoglobin light chains κ and λ (κFLC and λFLC) as novel diagnostic biomarker candidates for screening ARMS subjects. METHODS: Nineteen ARMS subjects and 21 age- and sex-matched healthy controls were enrolled in this study. Inclusion criteria of the ARMS subjects were based on a comprehensive assessment of Structured Interview for Prodromal Syndromes. We compared oxidative stress and immunological markers in the urine of ARMS subjects with those of healthy controls by ELISA protocol. RESULTS: Augmentation of biopyrrins and reduction of κFLC and λFLC were found in the ARMS samples, and their diagnostic performance was evaluated by receiver operating characteristic analysis, of which area under the curve was as large as 0.915 in combination. CONCLUSION: Our findings suggest that the ARMS subjects were under higher oxidative stress but lower in B cell activation, and that the combined assay of urinary biopyrrins and free immunoglobulin light chains would be useful for the early detection and screening of ARMS subjects among adolescents.