Inter-reporter differences in symptom burdens in Japanese children with cancer.

BACKGROUND: Recent studies about inter-reporter differences and patient-reported outcomes (PROs) in childhood cancer from Western countries showed that caregiver proxy reports tend to overestimate symptom burdens in comparison with children's self-reports. However, the results from Western countries may not be generalizable to Asian countries. METHODS: This paper is a secondary analysis of a validation study of the Japanese pediatric version of the Memorial Symptom Assessment Scale including 88 dyads of children aged 7-12 years and 74 dyads of children aged 13-18 years and their caregivers. The study assessed the inter-reporter differences of eight and 31 symptom burdens calculated as symptom scores in children aged 7-12 years and 13-18 years, respectively, and the association between inter-reporter differences and the characteristics of children and caregivers. RESULTS: The majority of children and caregivers scored equally at the dyadic level for almost all symptoms. However, 37.5% of symptoms in children aged 7-12 years and 10.0% of symptoms in children aged 13-18 years showed significant inter-reporter differences, suggesting a general tendency of caregivers to underestimate their children's symptom burden. The caregiver's age was the characteristic most frequently associated with magnitude of inter-reporter differences. CONCLUSIONS: Caregiver proxy reports may be a reliable source of PROs in Japanese children with cancer, as self-reported and caregiver proxy-reported symptom burdens were generally concordant. However, as some significant inter-reporter differences were observed, an effort should be made within the medical community to evaluate the parent-child relationship to minimize inter-reporter differences and achieve better symptom management.

Current methods of preventing infectious disease and managing febrile neutropenia in childhood cancer patients: a nationwide survey in Japan.

BACKGROUND: Preventing infection and managing febrile neutropenia (FN) is mandatory for children with cancer undergoing chemotherapy. However, the current situation in Japan is unknown. METHODS: We conducted a nationwide web-based questionnaire survey in 153 institutions treating childhood cancer in Japan. We asked about the type prophylaxis used to prevent infectious disease and manage FN. If patients with childhood cancer were managed by both pediatricians and surgeons at the same institution, we asked both to reply. RESULTS: We received replies from 117 departments at 111 centers: of these, 108 were from pediatricians. Laminar air flow for neutropenic patients, and frequent hand sanitization with ethanol, were widespread. Twenty-eight percent and forty percent of departments performed active surveillance by taking cultures from patients and the environment, respectively, before initiation of chemotherapy. Forty-four percent of departments administered prophylactic intravenous antibiotics according to patient status. Many departments measured serum (1,3)-ß-D glucan, procalcitonin, and aspergillus galactomannan at the onset of FN. Twenty-eight percent of departments used carbapenem as empirical therapy for FN. Some departments used prophylactic granulocyte-colony stimulating factor for acute leukemia. Seventy-two percent of departments used prophylactic immunoglobulin for hypogammaglobinemia caused by chemotherapy. Palivizumab was administered widely for respiratory syncytial virus prophylaxis in immunocompromised infants. CONCLUSION: As a whole, intensive care for infectious prophylaxis or FN is applied in Japan; however, the methods vary among centers, and some are excessive or inadequate. Therefore, it is desirable to conduct clinical trials and establish adequate care protocols for infection in children with cancer in Japan.

Direct and indirect effects of amphidromous shrimps on nutrient mineralization in streams in Japan.

Animals affect element cycling in ecosystems by consumption and excretion. Amphidromous shrimps frequently dominate low-mid altitude streams, where downstream connectivity to oceans is sustained. Although shrimps' direct influence on benthic communities has been studied, little is known about their influences on nutrient cycling. Here, we hypothesized that the dominance of shrimps alters nutrient mineralization by benthic macroinvertebrates in streams due to the difference in the quality and quantity of excretion between shrimps and aquatic insects. We tested this hypothesis through a field manipulative experiment, excretion measurements of animals, and field surveys. In the field manipulative experiment, the presence of shrimps slightly decreased the biomass of aquatic insects but tripled total benthic macroinvertebrate biomass directly through their own biomass. The mass-specific NH4+ excretion rate by shrimps was similar to aquatic insects, and the areal NH4+ excretion by benthic macroinvertebrates was increased by 2.5 times in the presence of shrimps. In contrast, shrimps excreted significantly less soluble reactive phosphorus (SRP) than aquatic insects, and the presence of shrimps did not affect areal SRP excretion by benthic macroinvertebrates. The field survey showed a positive correlation of NO3- concentration with the shrimp density, inferring the excess NH4+ was nitrified. Although the nutrient concentration of stream water is frequently attributed to watershed conditions, the results of this study indicate that downstream connectivity to oceans may also influence nutrient dynamics of the stream through the density of amphidromous shrimps.

Difference of compliance rates for the recommendations in Japanese Guideline on Febrile Neutropenia according to respondents' attributes: the second report on a questionnaire survey among hematology-oncology physicians and surgeons.

PURPOSE: The Japanese Society of Medical Oncology (JSMO) published a guideline (GL) on febrile neutropenia (FN) in 2017. This study aims to identify promoting factors and disincentives for complying with GL recommendations according to attributes of doctors providing chemotherapy. METHODS: A questionnaire survey was conducted with SurveyMonkey™ for physician members of the Japanese Association of Supportive Care in Cancer and relevant academic organizations. Each question had four options (always do, do in more than half of patients, do in less than half, do not at all) and a free description form. Responses were analyzed according to the respondents' attributes. RESULT: Seven hundred eighty-eight out of retrieved 801 responses were available for analysis. Multivariable analysis demonstrated that the percentage of GL users was higher among women and Japanese Society of Clinical Oncology members. The overall compliance rate was higher among women, JSMO members, and board-certified medical oncologists. Internists emphasized the significance of collecting blood cultures at FN onset, and surgeons stressed the importance of G-CSF prophylaxis. Hematologists were less likely to adhere to recommendations on risk assessment of FN by the Multinational Association of Supportive Care in Cancer score and administration of gammaglobulin products. However, those are acceptable due to the characteristics of their practice. Eight recommendations had no difference in compliance rates between users and non-users, some of whose statements were ambiguous and discretionary. CONCLUSION: Women were more likely to use and adhere to GL. The recommendations should be developed considering the characteristics of specialty and subspecialty and avoiding ambiguity and discretionary statements.

Influence of δ18 O of water on measurements of δ18 O of nitrite and nitrate.

RATIONALE: Oxygen isotope ratio measurements of NO2 - and NO3 - by the azide method and denitrifier method are sensitive to the δ18 O value of the sample water. However, the influence of δ18 OH2O on those measurements has not been quantitatively evaluated and documented so far. Therefore, we investigated the influence of δ18 OH2O of a sample on the δ18 O analysis of NO2 - and NO3 - . METHODS: We prepared NO2 - and NO3 - standards (with known δ18 ONO2- and δ18 ONO3- values) dissolved in waters having different δ18 OH2O values (δ18 OH2O = -12.6, 25.9, 56.7, and 110.1‰). Nitrite and nitrate were converted into N2 O using the azide method and the denitrifier method, respectively. The isotope ratios of the generated N2 O were measured with a Sercon purge-and-trap gas chromatography/isotope ratio mass spectrometry (PT-GC/IRMS) system. The measured δ18 O values of the produced N2 O were plotted against known δ18 ONO2- and δ18 ONO3- values to evaluate the influence of exchange of an oxygen atom with H2 O during the conversion of NO2 - into N2 O and NO3 - into N2 O, respectively. RESULTS: The degree of oxygen isotope exchange was 10.8 ± 0.3% in the azide method and 5.5 ± 1.0% in the denitrifier method, indicating that the azide method is more susceptible to artifacts arising from differences in the δ18 OH2O value of water than the denitrifier method. Thus, the intercept of the standard calibration curve must be corrected to account for differences in δ18 OH2O . Abiotic NO2 -H2 O equilibrium isotope effect experiments yielded a rate constant of (1.13 ± 007) × 10-2 (h-1 ) and an equilibrium isotope effect of 11.9 ± 0.1‰ under the condition of pH = 7.5, 30°C, and 2.5% salinity. CONCLUSIONS: Oxygen isotope ratio measurements of NO2 - by the azide method are highly sensitive to δ18 OH2O as a result of significant oxygen isotope exchange between NO2 - and H2 O. Therefore, to obtain the most accurate measurements water with the same δ18 OH2O value as that of the sample must be used to make the NO2 - and NO3 - standards.

A questionnaire survey on evaluation for penetration and compliance of the Japanese Guideline on Febrile Neutropenia among hematology-oncology physicians and surgeons.

PURPOSE: The Japanese Society of Medical Oncology published a guideline (GL) on febrile neutropenia (FN) in 2017. The study's purpose is to reveal how widely GL penetrated among physicians and surgeons providing chemotherapy. METHODS: A questionnaire survey was conducted with SurveyMonkey™ for members of the Japanese Association of Supportive Care in Cancer and relevant academic organizations. Each question had four options (always do, do in more than half of patients, do in less than half, do not at all) and a free description form. Responses were analyzed with statistical text-analytics. RESULT: A total of 800 responses were retrieved. Major respondents were experts with more than 10-year experience, physicians 54%, and surgeons 46%. Eighty-seven percent of respondents knew and used GL. Forty-eight percent assessed FN with Multinational Association of Supportive Care in Cancer (MASCC) score "always" or "more than half." Eighty-one percent chose beta-lactam monotherapy as primary treatment in high-risk patients. Seventy-seven percent did oral antibacterial therapy in low-risk patients ambulatorily. Seventy-eight percent administered primary prophylactic G-CSF (ppG-CSF) in FN frequency ≥ 20% regimen. Fifty-nine percent did ppG-CSF for high-risk patients in FN frequency 10-20% regimen. Ninety-seven percent did not use ppG-CSF in FN frequency < 10% regimen. The medians of complete and complete plus partial compliance rates were 46.4% (range 7.0-92.8) and 77.8% (range 35.4-98.7). The complete compliance rates were less than 30% in seven recommendations, including the MASCC score assessment. CONCLUSION: GL is estimated to be widely utilized, but some recommendations were not followed, presumably due to a mismatch with actual clinical practices in Japan.

Genetic consequences of plant edaphic specialization to solfatara fields: Phylogenetic and population genetic analysis of Carex angustisquama (Cyperaceae).

Edaphic specialization is one of the main drivers of plant diversification and has multifaceted effects on population dynamics. Carex angustisquama is a sedge plant growing only on heavily acidified soil in solfatara fields, where only extremophytes can survive. Because of the lack of closely related species in similar habitats and its disjunct distribution, the species offers ideal settings to investigate the effects of adaptation to solfatara fields and of historical biogeography on the genetic consequences of plant edaphic specialization to solfatara fields. Here, genome-wide single nucleotide polymorphisms were used to reveal the phylogenetic origin of C. angustisquama, and 16 expressed sequence tag-simple sequence repeat markers were employed to infer population demography of C angustisquama. Molecular phylogenetic analysis strongly indicated that C. angustisquama formed a monophyletic clade with Carex doenitzii, a species growing on nonacidified soil in the sympatric subalpine zone. The result of population genetic analysis showed that C. angustisquama has much lower genetic diversity than the sister species, and notably, all 16 loci were completely homozygous in most individuals of C. angustisquama. Approximate Bayesian computation analysis supported the model that assumed hierarchical declines of population size through its evolutionary sequence. We propose that the edaphic specialist in solfatara fields has newly attained the adaptation to solfatara fields in the process of speciation. Furthermore, we found evidence of a drastic reduction in genetic diversity in C. angustisquama, suggesting that the repeated founder effects associated with edaphic specialization and subsequent population demography lead to the loss of genetic diversity of this extremophyte in solfatara fields.

Clinical and molecular characteristics of MEF2D fusion-positive B-cell precursor acute lymphoblastic leukemia in childhood, including a novel translocation resulting in MEF2D-HNRNPH1 gene fusion.

Fusion genes involving MEF2D have recently been identified in precursor B-cell acute lymphoblastic leukemia, mutually exclusive of the common risk stratifying genetic abnormalities, although their true incidence and associated clinical characteristics remain unknown. We identified 16 cases of acute lymphoblastic leukemia and 1 of lymphoma harboring MEF2D fusions, including MEF2D-BCL9 (n=10), MEF2D-HNRNPUL1 (n=6), and one novel MEF2D-HNRNPH1 fusion. The incidence of MEF2D fusions overall was 2.4% among consecutive precursor B-cell acute lymphoblastic leukemia patients enrolled onto a single clinical trial. They frequently showed a cytoplasmic µ chain-positive pre-B immunophenotype, and often expressed an aberrant CD5 antigen. Besides up- and down-regulation of HDAC9 and MEF2C, elevated GATA3 expression was also a characteristic feature of MEF2D fusion-positive patients. Mutations of PHF6, recurrent in T-cell acute lymphoblastic leukemia, also showed an unexpectedly high frequency (50%) in these patients. MEF2D fusion-positive patients were older (median age 9 years) with elevated WBC counts (median: 27,300/ml) at presentation and, as a result, were mostly classified as NCI high risk. Although they responded well to steroid treatment, MEF2D fusion-positive patients showed a significantly worse outcome, with 53.3% relapse and subsequent death. Stem cell transplantation was ineffective as salvage therapy. Interestingly, relapse was frequently associated with the presence of CDKN2A/CDKN2B gene deletions. Our observations indicate that MEF2D fusions comprise a distinct subgroup of precursor B-cell acute lymphoblastic leukemia with a characteristic immunophenotype and gene expression signature, associated with distinct clinical features.

Necrotizing Ulcer After BCG Vaccination in a Girl With Leukocyte-adhesion Deficiency Type 1.

Leukocyte-adhesion deficiency-1 is a recessively inherited disorder associated with recurrent bacterial infections, severe periodontitis, peripheral leukocytosis, and impaired wound healing. We diagnosed moderate-type leukocyte-adhesion deficiency-1 in a 7-year-old girl who developed a necrotizing ulcer after Bacillus Calmette-Guerin vaccination. The patient showed moderate expression of CD18 in neutrophils with a homozygous splice mutation with c.41_c.58+2dup20 of ITGB2 and experienced recurrent severe infections complicated with systemic lupus erythematosus. She received hematopoietic stem cell transplantation from a matched elder brother with heterozygous mutation of ITGB2, and has since remained free of infection and systemic lupus erythematosus symptoms without immunosuppression therapy.

Predominance of a single clone of the most widely distributed bamboo species Phyllostachys edulis in East Asia.

Phyllostachys edulis, one of the most dominant bamboo species with the leptomorph rhizome system, has been asexually expanding its range into adjacent natural forest sites by shooting new culms. The resulting ecological problems include simplification of stand structure and decline in the species diversity of local flora. In this study, the genetic diversity of P. edulis for the entire distribution range from Japan to China was analyzed using 16 microsatellite markers. Among these, 12 loci were fixed by a single allele, whereas only two alleles were detected for each of the remaining 4 loci; all adult samples shared the same genotype at all loci including the four heterozygous loci. These observations indicate that all current samples from Japan and China comprise an identical clone. The clone is distributed over more than 2,800 km with an estimated biomass of approximately 6.6 × 10(11) kg, which is exceptionally large. Among seedlings from flowering events in 2005 and 2006, 20 different genets were generated by recombination through selfing of a single flowering genet. Predominance of a single clone in the wild and a diverse composition of genets among seedlings suggest that the intermittent flowering of P. edulis in the wild has produced a variety of clones through recombination. However, the resulting seedlings cannot compete with other tree species or adult P. edulis, and almost all adult P. edulis growing in Japan and China likely propagated through vegetative reproduction of a single clone by human transplantation, and subsequently expanded into adjacent forest sites by shooting young sprouts. The relatively small size of the flowering area and rapid culm reproduction has led to the stability of P. edulis communities. However, the low genetic diversity is an important consideration for the long-term management of this prevailing bamboo species.

Pharmacokinetics and safety of voriconazole intravenous-to-oral switch regimens in immunocompromised Japanese pediatric patients.

The aim of this study was to investigate the pharmacokinetics, safety, and tolerability of voriconazole following intravenous-to-oral switch regimens used with immunocompromised Japanese pediatric subjects (age 2 to <15 years) at high risk for systemic fungal infection. Twenty-one patients received intravenous-to-oral switch regimens based on a recent population pharmacokinetic modeling; they were given 9 mg/kg of body weight followed by 8 mg/kg of intravenous (i.v.) voriconazole every 12 h (q12h), and 9 mg/kg (maximum, 350 mg) of oral voriconazole q12h (for patients age 2 to <12 or 12 to <15 years and <50 kg) or 6 mg/kg followed by 4 mg/kg of i.v. voriconazole q12h and 200 mg of oral voriconazole q12h (for patients age 12 to <15 years and ≥50 kg). The steady-state area under the curve over the 12-h dosing interval (AUC0-12,ss) was calculated using the noncompartmental method and compared with the predicted exposures in Western pediatric subjects based on the abovementioned modeling. The geometric mean (coefficient of variation) AUC0-12,ss values for the intravenous and oral regimens were 51.1 µg · h/ml (68%) and 45.8 µg·h/ml (90%), respectively; there was a high correlation between AUC0-12,ss and trough concentration. Although the average exposures were higher in the Japanese patients than those in the Western pediatric subjects, the overall voriconazole exposures were comparable between these two groups due to large interindividual variability. The exposures in the 2 cytochrome P450 2C19 poor metabolizers were among the highest. Voriconazole was well tolerated. The most common treatment-related adverse events were photophobia and abnormal hepatic function. These recommended doses derived from the modeling appear to be appropriate for Japanese pediatric patients, showing no additional safety risks compared to those with adult patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT01383993.).

Necessary stem cell transplantation using myeloablative therapy for myelodysplastic syndrome with progression of genotypic abnormalities and TP53 dysfunction in a young adult.

A 14-yr-old male was admitted to our hospital with MDS and the chromosomal abnormality 45,XY,der(5;17)(p10;q10). He rapidly developed karyotype abnormalities, accompanied by the loss of tumor suppressor gene TP53 function. He suffered an early relapse after reduced-intensity-conditioning SCT and ultimately required myeloablative therapy before a second SCT. We consider that the analysis of TP53 mutations is essential when planning the treatment of patients with MDS.

Analysis of overweight/obese pediatric patients with acute myeloid leukemia: a report from the Japanese Pediatric Leukemia/Lymphoma Study Group AML-05 study.

The dosage of chemotherapy drugs for overweight/obese children with acute myeloid leukemia (AML) has been empirically reduced based on ideal body weight (BW) in Japan to reduce the risk of adverse events. We investigated the associations between pre-therapeutic body mass index (BMI) and clinical outcomes among children with AML. A total of 280 children were divided into two groups based on the World Health Organization Child Growth Standards: a healthy-weight group (n = 254), and an overweight/obese group (n = 26). If BW exceeded 1.2 times the standard BW of Japanese children, the dosage of chemotherapy drugs was calculated using 1.2 times the standard BW. The dosage of chemotherapy drugs was reduced during at least one chemotherapy cycle in 24 of 26 patients (92.3%) in the overweight/obese group, compared with zero patients in the healthy-weight group. Overall/event-free survival, cumulative incidence of relapse, and treatment-related mortality (TRM) did not differ between the overweight/obese and healthy weight groups. However, the frequency of bacteremia was higher in the overweight/obese group (80.8 vs. 52.4%, P = 0.006). This indicates that TRM may increase when chemotherapy drug dosage is not corrected in overweight/obese patients. Drug reduction is a potential treatment strategy.

A retrospective analysis of voriconazole pharmacokinetics in Japanese pediatric and adolescent patients.

Voriconazole (VFEND(®)) is a triazole antifungal agent which inhibits the biosynthesis of ergosterol, a fungal cell membrane component. In Japan, voriconazole has become a commonly used antimicrobial in off-label use for pediatric patients. The aims of this report were to provide information about voriconazole pharmacokinetics (PK) in Japanese pediatric and adolescent patients, and to explore relationships between the PK, administered dose, and laboratory test results. In total, data from 24 pediatric or adolescent patients (18 males and 6 females) were used for the analysis. For the measurement of plasma voriconazole concentrations, 103 blood samples were collected from the 24 patients. As a whole, median plasma voriconazole concentrations following intravenous and oral administrations were comparable, and the trough plasma concentrations at steady state (C (12,ss)) increased with increasing voriconazole doses (mg/kg). However, no systematic trend was observed between C (12,ss) and laboratory test results.

[Acute monoblastic leukemia with MLL/AF9 rearrangement which developed 18 months after myeloid sarcoma onset].

We describe a 36-month-old boy with acute monoblastic leukemia (AMoL M5a) and mixed-lineage leukemia (MLL)-AF9 rearrangement. At 18 months of age, he presented with swelling on the back of his hand that was considered to be an inflammatory change, but no hematological abnormalities were found. However, blasts with MLL-AF9 rearrangement were detected in biopsied tissue taken at the time and in peripheral blood samples taken 18 months later. These findings indicate that myeloid sarcoma with MLL-AF9 rearrangement may ultimately, though slowly, progress to AMoL.

Postpartum Neonatal Disseminated Herpes Simplex Virus-1 Infection in Which Herpes Simplex Virus-1 Was Detected in Mother's Breast Milk.

A 17-d-old girl was diagnosed with disseminated herpes simplex virus-1 infection-associated hemophagocytic lymphohistiocytosis. The virus was detected in the neonate's blood and mandible. The neonate was treated with dexamethasone and acyclovir and discharged without neurological sequelae. The mother had no history of a herpes simplex virus-1 infection and did not have visible genital herpetic lesions; moreover, the neonate was delivered via an elective cesarean section. However, the day before the delivery, the mother had met with the neonate's grandmother, who had herpes labialis. Viral DNA was detected in bilateral breast milk samples; however, no superficial herpetic lesions were noted on both breasts. The authors speculated that the neonate may have acquired the infection via contaminated breast milk. Thus far, only one neonatal case of this infection contracted via breast milk has been reported. Further studies on breast milk as a transmission route for these infections are required.

Intravenous tocilizumab for Takayasu arteritis with aortic aneurysms, bilateral renal artery stenosis, and atypical aortic coarctation in a 2-year-old girl.

Takayasu arteritis (TAK) is classified as large vessel vasculitis, and continuous inflammation of the vessel results in aneurysm or stenosis, which leads to various serious complications. Recently, a TAKT [TAK treated with tocilizumab (TCZ)] study showed that subcutaneous TCZ, a humanised anti-interleukin-6 receptor monoclonal antibody, is an effective treatment in patients with TAK above 12 years of age; however, the effectiveness of TCZ for juvenile TAK under 12 years old remains unclear. Here, we described the case of a 2-year-old girl with TAK, which was successfully treated with intravenous TCZ. She was diagnosed with TAK type V (Numano's angiographic classification system) with aortic aneurysms, bilateral renal arteries stenosis, and atypical descending aortic coarctation based on contrast-enhanced computed tomography findings. Treatment was started with 2 mg/kg/day prednisolone (PSL) and methotrexate instead of methylprednisolone pulse due to renovascular hypertension. She was immediately afebrile and her C-reactive protein level decreased, although it was elevated 4 weeks after starting PSL. Intravenous TCZ of 8 mg/kg/2 weeks was added because the progression of aneurysms or stenosis might lead to a poor prognosis. PSL was steadily reduced under intravenous TCZ. Magnetic resonance imaging showed that aortic aneurysms, renal arteries stenosis, and aortic coarctation ameliorated 4 months after starting TCZ, with the amelioration maintained at 1 year after starting TCZ. Aneurysms and stenosis improved; therefore, TCZ may be effective for the treatment of inflammation of vessels, aneurysms, and stenosis. It is desirable to examine the effect of TCZ on TAK patients under 12 years of age.

Metagenomic analysis of ecological niche overlap and community collapse in microbiome dynamics.

Species utilizing the same resources often fail to coexist for extended periods of time. Such competitive exclusion mechanisms potentially underly microbiome dynamics, causing breakdowns of communities composed of species with similar genetic backgrounds of resource utilization. Although genes responsible for competitive exclusion among a small number of species have been investigated in pioneering studies, it remains a major challenge to integrate genomics and ecology for understanding stable coexistence in species-rich communities. Here, we examine whether community-scale analyses of functional gene redundancy can provide a useful platform for interpreting and predicting collapse of bacterial communities. Through 110-day time-series of experimental microbiome dynamics, we analyzed the metagenome-assembled genomes of co-occurring bacterial species. We then inferred ecological niche space based on the multivariate analysis of the genome compositions. The analysis allowed us to evaluate potential shifts in the level of niche overlap between species through time. We hypothesized that community-scale pressure of competitive exclusion could be evaluated by quantifying overlap of genetically determined resource-use profiles (metabolic pathway profiles) among coexisting species. We found that the degree of community compositional changes observed in the experimental microbiome was correlated with the magnitude of gene-repertoire overlaps among bacterial species, although the causation between the two variables deserves future extensive research. The metagenome-based analysis of genetic potential for competitive exclusion will help us forecast major events in microbiome dynamics such as sudden community collapse (i.e., dysbiosis).

Alternative stable states, nonlinear behavior, and predictability of microbiome dynamics.

BACKGROUND: Microbiome dynamics are both crucial indicators and potential drivers of human health, agricultural output, and industrial bio-applications. However, predicting microbiome dynamics is notoriously difficult because communities often show abrupt structural changes, such as "dysbiosis" in human microbiomes. METHODS: We integrated theoretical frameworks and empirical analyses with the aim of anticipating drastic shifts of microbial communities. We monitored 48 experimental microbiomes for 110 days and observed that various community-level events, including collapse and gradual compositional changes, occurred according to a defined set of environmental conditions. We analyzed the time-series data based on statistical physics and non-linear mechanics to describe the characteristics of the microbiome dynamics and to examine the predictability of major shifts in microbial community structure. RESULTS: We confirmed that the abrupt community changes observed through the time-series could be described as shifts between "alternative stable states" or dynamics around complex attractors. Furthermore, collapses of microbiome structure were successfully anticipated by means of the diagnostic threshold defined with the "energy landscape" analysis of statistical physics or that of a stability index of nonlinear mechanics. CONCLUSIONS: The results indicate that abrupt microbiome events in complex microbial communities can be forecasted by extending classic ecological concepts to the scale of species-rich microbial systems. Video Abstract.