Hepatitis B Virus Reactivation after Switch to Cabotegravir/Rilpivirine in Patient with Low Hepatitis B Surface Antibody.

A patient in Japan with HIV began antiretroviral therapy because of acute hepatitis B virus (HBV) 15 years ago, with low hepatitis B surface antibody, and experienced breakthrough HBV reactivation 4 months after switching from bictegravir/emtricitabine/tenofovir alafenamide to cabotegravir/rilpivirine. An immune escape mutation, E164V, was identified in the isolated HBV DNA.

Vaginal Transmission of Cancer from Mothers with Cervical Cancer to Infants.

Two cases of pediatric lung cancer (in 23-month-old and 6-year-old boys) resulting from mother-to-infant transmission of uterine cervical tumors were incidentally detected during routine next-generation sequencing of paired samples of tumor and normal tissue. Spontaneous regression of some lesions in the first child and slow growth of the tumor mass in the second child suggested the existence of alloimmune responses against the transmitted tumors. Immune checkpoint inhibitor therapy with nivolumab led to a strong regression of all remaining tumors in the first child. (Funded by the Japan Agency for Medical Research and Development and others; TOP-GEAR UMIN Clinical Trials Registry number, UMIN000011141.).

Development of a unit conversion tool for five quantitative anti-spike assays and agreement analysis of three qualitative anti-nucleocapsid assays for SARS-CoV-2.

Commercially available assays for measuring severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) anti-spike (S) or anti-nucleocapsid (N) antibodies differ in units, making results comparisons challenging. This study aimed to develop conversion equations between five quantitative anti-S antibody tests and to assess the agreement over time between three qualitative anti-N antibody tests. Blood samples from 24 216 vaccinated healthcare workers in Hiroshima Prefecture, Japan, were analyzed for anti-S antibodies using five quantitative tests (Abbott, Fujirebio, Ortho, Sysmex, Roche) and for anti-N antibodies using three qualitative tests (Abbott, Sysmex, Roche). Geometric mean regression was performed to establish equations for converting measured values between the five quantitative tests. Fleiss κ statistic was used to assess the agreement between the three qualitative tests. A strong correlation (Pearson's coefficient r > 0.9) was found for each pair of the five quantitative tests measuring anti-S antibodies, enabling the development of equations to convert values between each pair. Using these equations, which are based on the original output unit of each test, values obtained from one test can be transformed to be equivalent to the corresponding values in another test. For the three tests for anti-N antibodies, the agreement was substantial in the total sample (Fleiss' κ, 0.74) and moderate among those with self-reported past coronavirus disease 2019 (COVID-19) infection (Fleiss' κ, 0.39). The agreement decreased with time after infection. Reduced agreement between anti-N antibodies tests over time suggests caution in comparing seroepidemiological studies of COVID-19 exposure based on anti-N antibodies measurement. The findings could help improve antibody measurement systems and inform public health decision-makers.

Characterization of mutations in hepatitis B virus DNA isolated from Japanese HBsAg-positive blood donors in 2021 and 2022.

Missense mutations in certain small envelope proteins diminish the efficacy of antibodies. Consequently, tracking the incidence and types of vaccine-escape mutations (VEMs) was crucial both before and after the introduction of universal hepatitis B vaccination in Japan in 2016. In this study, we isolated hepatitis B virus (HBV) DNA from 58 of 169 hepatitis B surface antigen (HBsAg)-positive blood samples from Japanese blood donors and determined the nucleotide sequence encoding the small envelope protein. DNA from six (10%) of the samples had VEMs, but no missense mutations, such as G145R, were detected. Complete HBV genome sequences were obtained from 29 of the 58 samples; the viral genotype was A1 in one (3%), A2 in three (10%), B1 in nine (31%), B2 in five (17%), B4 in one (3%), and C2 in 10 (34%) samples. Tenofovir-resistance mutations were detected in two (7%) samples. In addition, several core promoter mutations, such as 1762A>T and 1764G>A, and a precore nonsense mutation, 1986G>A, which are risk factors for HBV-related chronic liver disease, were detected. These findings provide a baseline for future research and highlight the importance of ongoing monitoring of VEMs and drug resistance mutations in HBV DNA from HBsAg-positive blood donors without HBV antibodies.

Epidemiological assessment of hepatitis E virus infection among 1565 pregnant women in Siem Reap, Cambodia using an in-house double antigen sandwich ELISA.

AIM: This study investigated hepatitis E virus (HEV) prevalence among pregnant women in Siem Reap, Cambodia, by developing a cost-effective, user-friendly in-house enzyme-linked immunosorbent assay (ELISA) for detecting total anti-HEV immunoglobulins (Ig). METHODS: The in-house ELISA was designed for large-scale screening in resource-limited settings. Its performance was benchmarked against two commercial tests: the Anti-HEV IgG EIA (Institute of Immunology, Co. Ltd) and the Anti-HEV IgG RecomLine LIA (Mikrogen). The in-house ELISA demonstrated a sensitivity of 76% and 71.4%, and a specificity of 94.1% and 98.6%, against the two commercial tests, respectively, with overall agreement rates of 92.4% and 94.3%. RESULTS: Among 1565 tested pregnant women, 11.6% were anti-HEV positive. Prevalence increased with age, particularly in women aged 35-40 years and over 40 years. No significant associations were found with education, number of children, family size, or history of blood transfusion and surgery, except for the occupation of the family head as a public officer. Of the total anti-HEV positive women, 22.7% had anti-HEV IgM, indicating recent or ongoing infection. CONCLUSION: The study concluded that the in-house ELISA is a viable option for HEV screening in regions with limited resources due to its high accuracy and cost-effectiveness. It is particularly suitable for large-scale studies and public health interventions in areas where HEV is endemic and poses a significant risk to pregnant women.

Attenuation of hepatitis A antibody after immunization with hepatitis A vaccine (Aimmugen) in people living with HIV.

AIM: Hepatitis A (HA) is a vaccine-preventable disease. In regions with good sanitation, men who have sex with men (MSM) are the key affected populations. During the 2018-2019 HA outbreak among MSM in Japan, we actively vaccinated MSM living with HIV (MSM-LWHIV) with Aimmugen. As previously reported, their antibody seroconversion rate due to vaccination was lower than that of healthy individuals. However, the durability of Aimmugen in people living with HIV has not yet been reported. We evaluated attenuation after the one-series vaccination (comprising three inoculations) and the factors associated with attenuation. METHODS: We retrospectively examined anti-HA immunoglobulin G (anti-HA-IgG) titers and other clinical data from our hospital's medical records. Patients with no history of vaccination or HA infection (i.e., negative HA-IgG titers) who received one series of Aimmugen, achieved seropositivity, and anti-HA-IgG antibodies were tested ≥2 years after three doses were included. Fisher's exact test and the Mann-Whitney U-test were performed. p < 0.05 was considered statistically significant. RESULTS: Fifty-one MSM-LWHIV were included. All were seropositive after the third dose with a median HA-IgG titer of 10.1 (interquartile range, 7.2-12.2) (sample/cut-off values [s/co]). In 45 (40-49) months, seropositivity decreased to 90% (46/51) and was attenuated to a median of 4.4 (2.3-6.5) s/co. Lower baseline B cell counts (p = 0.049), lower anti-HA-IgG levels after the second dose (p = 0.002), and lower anti-HA-IgG levels after the third dose (p = 0.003) were associated with seronegativity. CONCLUSIONS: Anti-HA-IgG titers of vaccinated MSM-LWHIV may be attenuated; thus, additional immunizations should be considered.

Diagnostic accuracy of hepatitis E virus antibody tests: A comprehensive meta-analysis.

AIM: Hepatitis E virus (HEV) is a major global health issue, with an estimated 20 million infections annually. Although polymerase chain reaction (PCR) is the diagnostic gold standard due to its precision, it is expensive and technically demanding. Antibody tests offer a more practical and cost-effective alternative, although their accuracy can vary due to factors, such as test manufacturer, antigen composition, HEV genotype, and host immune status. METHODS: A comprehensive search was conducted in PubMed, Cochrane, Scopus, and Web of Science databases. Studies included comparing the sensitivity and specificity of immunoglobulin M or immunoglobulin G antibody tests to PCR. Exclusion criteria were non-PCR comparisons, sample sizes under 10, IgA or antigen tests, non-human samples, or missing sensitivity and specificity data. Only English-language full-texts or abstracts were considered. Data analysis was performed using Meta-DTA v2.1.1 and Stata 16.0. RESULTS: The meta-analysis evaluated 8054 blood samples from 21 studies. Immunoglobulin M antibody tests demonstrated an overall sensitivity of 83% (95% CI 76-88) and specificity of 98% (95% CI 97-99). Immunoglobulin G tests showed a sensitivity of 74% (95% CI 62-82) and specificity of 89% (95% CI 84-93). Among manufacturers, Wantai was the most accurate for immunoglobulin M detection, whereas MP led for immunoglobulin G. Notably, test sensitivity improved when the test protein genotype aligned with the HEV genotype. CONCLUSION: This meta-analysis confirmed that antibody assays have a good sensitivity and high specificity to detect HEV infection in situations where PCR is not feasible, highlighting their potential as a practical diagnostic tool.

Unveiling the dynamics of hepatitis C virus transmission among injection drug users and men who have sex with men: A comprehensive study in Japan.

AIM: In Japan, despite low nationwide hepatitis C (HCV) incidence, new infections among people who inject drugs (PWID) and men who have sex with men (MSM) hinder HCV elimination. We explored HCV transmission dynamics and screened HCV recombination within these populations. METHODS: This cross-sectional study recruited HCV-infected patients from Osaka National Hospital, Osaka, Japan, from January 2010 to September 2023. Data from questionnaires and medical records were analyzed. Serum samples collected before anti-HCV treatment underwent HCV RNA extraction, and sequencing of full core (576 bp) and NS5B (267 bp) regions using the Sanger method. Genotype distribution was determined by phylogenetic analysis, and recombinant screening was conducted. RESULTS: A total of 115 patients were categorized into non-MSM PWID (31), MSM PWID (15), MSM non-PWID (25), and non-MSM non-PWID (44). Positive amplification rates were 99.1% (114/115) for the full-core region, and 96.5% (111/115) for NS5B. No intergenotypic recombination was detected. The predominant genotype in non-MSM PWID was 2a (58%), whereas genotype 1b was most common in MSM PWID, MSM non-PWID, and non-MSM non-PWID groups (79%, 64%, and 68%, respectively). Nucleotide sequence similarity of 94.75%-100% was found in HCV strains from MSM PWID and MSM non-PWID in both full-core and NS5B regions, whereas strains from non-MSM PWID and non-MSM non-PWID were distinct. CONCLUSION: The findings suggest that the transmission route in PWID is determined by MSM status, whereas MSM groups showed the same transmission route regardless of PWID. HCV control measures should be focused not only on PWID, but also on MSM to achieve HCV elimination in Japan.

Numerical evidence for the existence of three different stable liquid water structures as indicated by local order parameter.

Structures of liquid water are controversial not only in supercooled polyamorphism but also in stable bulk liquids in the high temperature and pressure range. Several experimental studies in bulk liquid have assumed the existence of three different liquid water structures. If indeed the three liquid water structures are different, they should be clearly distinguished by some measure other than density that characterizes the difference in structural order. In this study, whether the three different bulk liquid water structures are real or not is numerically verified based on molecular simulations using a reliable water molecular model. Since these liquid water structures have been suggested to be related to three different crystal structures (i.e., ice Ih, III, and V), liquid structures are sampled from the vicinity of the ice Ih-liquid coexistence point, the ice III-V-liquid triple point, and the ice V-VI-liquid triple point, respectively. An attempt is made to introduce local order parameters (LOPs) as an indicator to distinguish these structures. A fast and exhaustive LOP search is performed by the molecular assembly structure learning package for Identifying order parameters. The selected LOP distinguishes the molecular structures of three different stable liquid waters with high accuracy, providing numerical evidence that these structural orders differ from each other. Furthermore, regions of the liquid water structures are drawn on a phase diagram using the LOP, demonstrating their consistency with experimental studies.

Prognostic significance of adjuvant chemotherapy in stage I-II endometrial carcinoma patients who underwent lymphadenectomy.

BACKGROUND: Endometrial carcinoma, the most common gynecologic carcinoma, has an excellent prognosis post-surgery when diagnosed early. The role of postoperative adjuvant chemotherapy in stages I-II endometrial carcinoma remains controversial. This study assesses the efficacy of adjuvant chemotherapy in improving prognosis for these patients. METHODS: A retrospective analysis was conducted on 1223 stage I-II endometrial carcinoma patients who underwent surgical treatment including total hysterectomy, bilateral salpingo-oophorectomy, and lymph-node biopsy or dissection across four Jikei University School of Medicine-affiliated facilities between 2001 and 2018. Patients were divided into low intermediate risk (LIR) and high intermediate risk (HIR) groups based on recurrence risk. Propensity score matching adjusted for various covariates was used to compare progression-free survival (PFS) and overall survival (OS) between patients who received adjuvant chemotherapy and those who did not. RESULTS: The study included 443 eligible patients, with 288 in the LIR group and 155 in the HIR group. Post propensity score matching, no significant difference in PFS or OS was observed between the observation and adjuvant chemotherapy groups within both risk categories. Notably, the 5-year OS for LIR was 97.6% in the observation group and 96.7% in the chemotherapy group; for HIR, the 5-year OS was similarly high with no significant difference. CONCLUSIONS: The findings suggest that postoperative adjuvant chemotherapy does not significantly contribute to the improvement of recurrence or prognosis in patients with stage I-II endometrial carcinoma who are categorized outside the low-risk group and have no lymph-node metastasis.

Impact of microsampling on toxicological evaluation in rodent safety studies.

Recently, animal welfare has been attracting worldwide attention, and implementation of 3Rs (replacement, reduction, and refinement) is prioritized in every way possible in the drug development. Microsampling, in which small amounts of blood are collected, is attracting attention in this context. ICH S3A Q&A focused on microsampling was published in November 2017 to help accelerate the application of microsampling for toxicokinetic assessment. The increased sensitivity of drug measurement apparatuses such as mass spectrometers has made it possible to measure drug concentrations with small amounts of blood samples. In this review, we summarized the reports on toxicological influence of microsampling in rodents (rats and mice) with or without drug administration or recovery period after blood collection and influences that may arise from differences in the blood sampling site or blood sampling volume. We also summarized some perspectives on further implementation of microsampling in toxicology studies. The use of microsampling in regulatory toxicology studies has gradually increased, although at a lower rate than in discovery studies. Since more animals are used in GLP toxicology studies than in discovery studies, the effect of reducing the number of animals by microsampling is expected to be greater in the toxicology studies. This report aims to promote the application of microsampling to nonclinical studies, as it is beneficial for improving animal welfare and can contribute to the 3Rs.

Residual risk of mother-to-child transmission of HBV despite timely Hepatitis B vaccination: a major challenge to eliminate hepatitis B infection in Cambodia.

BACKGROUND: In countries with intermediate or high hepatitis B virus (HBV) endemicity, mother-to-child transmission (MTCT) represents the main route of chronic HBV infection. There is a paucity of information on HBV MTCT in Cambodia. This study aimed to investigate the prevalence of HBV infection among pregnant women and its MTCT rate in Siem Reap, Cambodia. METHODS: This longitudinal study included two parts, study-1 to screen HBsAg among pregnant women and study-2 to follow up babies of all HBsAg-positive and one-fourth of HBsAg-negative mothers at their delivery and six-month post-partum. Serum or dried blood spot (DBS) samples were collected to examine HBV sero-markers by chemiluminescent enzyme immunoassay (CLEIA), and molecular analyses were performed on HBsAg-positive samples. Structured questionnaires and medical records were used to examine the risk factors for HBV infection. MTCT rate was calculated by HBsAg positivity of 6-month-old babies born to HBsAg-positive mothers and ascertained by the homology of HBV genomes in mother-child pair at 6-month-old. RESULTS: A total of 1,565 pregnant women were screened, and HBsAg prevalence was 4.28% (67/1565). HBeAg positivity was 41.8% and was significantly associated with high viral load (p < 0.0001). Excluding subjects who dropped out due to restrictions during COVID-19, one out of 35 babies born to HBsAg-positive mothers tested positive for HBsAg at 6 months of age, despite receiving timely HepB birth dose and HBIG, followed by 3 doses of HepB vaccine. Hence the MTCT rate was 2.86%. The mother of the infected baby was positive for HBeAg and had a high HBV viral load (1.2 × 109 copies/mL). HBV genome analysis showed 100% homology between the mother and the child. CONCLUSIONS: Our findings illustrate the intermediate endemicity of HBV infection among pregnant women in Siem Reap, Cambodia. Despite full HepB vaccination, a residual risk of HBV MTCT was observed. This finding supports the recently updated guidelines for the prevention of HBV MTCT in 2021, which integrated screening and antiviral prophylaxis for pregnant women at risk of HBV MTCT. Furthermore, we strongly recommend the urgent implementation of these guidelines nationwide to effectively combat HBV in Cambodia.

Correction: Molecular cluster analysis using local order parameters selected by machine learning.

Correction for 'Molecular cluster analysis using local order parameters selected by machine learning' by Kazuaki Z. Takahashi et al., Phys. Chem. Chem. Phys., 2023, https://doi.org/10.1039/d2cp03696g.

Variant-specific symptoms after COVID-19: a hospital-based study in Hiroshima.

BackgroundSymptoms after COVID-19 recovery by SARS-CoV-2 strains are unspecified.MethodsThis self-administered questionnaire-based study was conducted to investigate symptoms after COVID-19 recovery at one of the main hospitals for COVID-19 treatment in Hiroshima, Japan, from September 2020 to March 2022 for patients who visited follow-up consultations after COVID-19. Study subjects were divided into four groups (Wild-type, Alpha, Delta, and Omicron periods) according to COVID-19 onset date. Hierarchical cluster analysis was performed to determine symptom clusters and investigate risk factors for each symptom cluster using multivariate analysis.ResultsAmong 385 patients who enrolled in this study, 249 patients had any persistent symptoms at a median of 23.5 [IQR, 20-31] days after COVID-19 onset. Among patients with any persistent symptoms, symptom clusters including olfactory or taste disorders, respiratory symptoms, and cardiac symptoms were found. Respiratory symptoms were more frequent among patients infected in the Omicron period compared to the Wild-type period (AOR, 3.13; 95% CI, 1.31-7.48; p=0.0101). Compared to patients who recovered from mild COVID-19, patients who needed for oxygen or ventilation support suffered fewer post-COVID-19 respiratory symptoms (AOR, 0.46; 95% CI, 0.22-0.97; p=0.0415) but more post-COID-19 cardiac symptoms among them (AOR, 2.67; 95% CI, 1.26-5.65; p=0.0103). Olfactory or taste disorders were fewer among patients infected in the Omicron period compared to the Wild-type period (AOR, 0.14; 95% CI, 0.04-0.46; p=0.0011).ConclusionThis study revealed that symptoms after COVID-19 may vary depending on the infected strain.

Mapping positron annihilation lifetime spectroscopy data of a polymer to classical molecular dynamics simulations without shifting the glass transition temperature.

Positron annihilation lifetime spectroscopy (PALS) enables the nondestructive measurement of nanoscale cavities in materials. In this study, a strategy was proposed for mapping PALS measurement data of isotactic polypropylene to classical molecular dynamics (CMD) simulations. The discrepancy between simulated and experimental glass transition temperatures was resolved by shortening the polymer chains, rather than adjusting for the temperature, using the Williams-Landel-Ferry (WLF) equation. The effective probe radii of ortho-positronium (o-Ps), determined by comparing PALS data with CMD simulations, were ∼0.8 nm, which was consistent with the o-Ps size given by the solution of the Schrödinger equation. The free-volume fraction corresponding to the effective probe radius was 12.3% at the glass transition temperature, close to the value estimated using Simha-Boyer theory. The cavity number density was proportional to the effective probe radius and decreased with temperature. The o-Ps effective probe radius was proportional to both the critical probe radius and the -1/3 power of the monomer number density, and increased with increasing temperature. These findings suggest that combining PALS measurements with CMD simulations may provide insight into cavities in polymeric materials without relying on the WLF equation.

Sequential dynamics of virological and serological changes in the serum of SARS-CoV-2 infected patients.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load dynamics in respiratory samples have been studied, but knowledge about changes in serial serum samples of infected patients in relation to their immunological response is lacking. We investigated the dynamics of SARS-CoV-2 viral load and antibody response in sequential serum of coronavirus disease 2019 (COVID-19) patients and attempted to culture the virus in the serum. A total of 81 sequential serum samples from 10 confirmed COVID-19 patients (5 with mild and 5 with moderate symptoms) were analyzed. Samples were collected during hospitalization and after discharge (median follow-up of 35 days). SARS-CoV-2 ribonucleic acid in the serum was detected by real-time polymerase chain reaction. Total antibody and IgG to SARS-CoV-2 Spike protein were analyzed by Chemiluminescent Immunoassays, and neutralizing antibodies were detected using a Surrogate Virus Neutralization Test. Viremia was observed in all cases at admission, and viral copy gradually dropped to undetectable levels in patients with mild symptoms but fluctuated and remained persistent in moderate cases. The viral culture of samples with the highest viral load for each patient did not show any cytopathic change. The antibody response was faster and higher in moderate cases. This study provides a basic clue for infectious severity-dependent immune response, viremia, and antibody acquisition pattern.

Molecular cluster analysis using local order parameters selected by machine learning.

Accurately extracting local molecular structures is essential for understanding the mechanisms of phase and structural transitions. A promising method to characterize the local molecular structure is defining the value of the local order parameter (LOP) for each particle. This work develops the Molecular Assembly structure Learning package for Identifying Order parameters (MALIO), a machine learning package that can propose an optimal (set of) LOP(s) quickly and automatically for a huge number of LOP species and various methods of selecting neighboring particles for the calculation. We applied this package to distinguish between the nematic and smectic phases of uniaxial liquid crystal molecules, and selected candidate LOPs that could be used to precisely observe the nematic-smectic phase transition. The LOP candidates were used to observe the nucleation and subsequent percolation transition, and the effect of the choice of LOP species and neighboring particles on the statistics of local molecular structures (clusters) was examined. The procedure revealed the time evolution of the number of clusters and the dependence of the percolation curve on the number of neighboring particles for each LOP species. The LOP species with the lowest dependence on the number of neighboring particles was the best-performing LOP species in the MALIO screening strategy. These results not only show that machine learning can powerfully screen a huge number of LOP species and suggest only a few promising candidates, but also indicate that MALIO can select the best LOP species.

Searching for local order parameters to classify water structures at triple points.

The diversity of ice polymorphs is of interest in condensed-matter physics, engineering, astronomy, and biosphere and climate studies. In particular, their triple points are critical to elucidate the formation of each phase and transitions among phases. However, an approach to distinguish their molecular structures is lacking. When precise molecular geometries are given, order parameters are often computed to quantify the degree of structural ordering and to classify the structures. Many order parameters have been developed for specific or multiple purposes, but their capabilities have not been exhaustively investigated for distinguishing ice polymorphs. Here, 493 order parameters and their combinations are considered for two triple points involving the ice polymorphs ice III-V-liquid and ice V-VI-liquid. Supervised machine learning helps automatic and systematic searching of the parameters. For each triple point, the best set of two order parameters was found that distinguishes three structures with high accuracy. A set of three order parameters is also suggested for better accuracy.

Re-thinking the prognostic significance of positive peritoneal cytology in endometrial cancer.

BACKGROUND: Whether abnormal peritoneal cytology (PC) is an independent prognostic factor in endometrial cancer (EC) remains controversial. This study aimed to re-think the prognostic significance of PC in not only all EC patients but also in various subgroups with similar clinicopathological and biological characteristics. METHODS: EC patients who underwent primary surgery of at least a hysterectomy and were pathologically diagnosed with EC in four hospitals affiliated with the Jikei University School of Medicine were retrospectively reviewed. The prognostic significance of PC was evaluated with univariate and multivariate analyses in the entire cohort and subgroups stratified by surgical stages (early/advanced stages), tumor types (types 1/2), and risk classifications (low/intermediate/high). RESULTS: Of 1963 EC cases, 1616 met the inclusion criteria. Positive PC was identified as an adverse prognostic factor in analyses of all EC cases and in all subgroup analyses stratified by surgical stages and tumor types. In survival curve comparisons, the progression-free survival (PFS) and disease-specific survival in early-stage patients with positive PC were clearly located between those of stage II patients with negative PC and stage III patients. In the subgroup analyses stratified by risk classification in early-stage EC, positive PC was related to poorer PFS in the intermediate- and high-risk groups but not in the low-risk group. CONCLUSION: PC status was an independent prognostic factor of EC in all stages and tumor types. Early PC-positive cases, except for the low-risk group, may be recommended for upstaging and should be carefully managed compared with PC-negative cases.

Mining of Effective Local Order Parameters to Classify Ice Polymorphs.

Order parameters make it possible to quantify the degree of structural ordering in a material and thus to apply as the reaction coordinates during the free-energy analysis of phase or structure transitions. Furthermore, order parameters are useful in determining the local structures of molecular groups during transition stages. However, identifying or developing local order parameters (LOPs) that are sensitive for specific materials and phases is a non-trivial task. In this study, the ability of LOPs to classify the solid and liquid structures of water at coexistence or triple points is investigated with the aid of supervised machine learning. The classification accuracy of a total of 179,738,433 combinations of 493 LOPs is automatically and systematically compared for water structures at the ice Ih-Ic-liquid coexistence point and the ice III-V-liquid and ice V-VI-liquid triple points. The optimal sets of two LOPs are found for each point, and sets of three LOPs are suggested for better accuracy.