Surveillance of Wastewater to Monitor the Prevalence of Gastroenteritis Viruses in Chiba Prefecture (2014-2019).

BACKGROUND: In Japan, sentinel surveillance is used to monitor the trend of infectious gastroenteritis. Another method of pathogen surveillance, wastewater-based epidemiology, has been used recently because it can help to monitor infectious disease without relying on patient data. Here, we aimed to determine the viral trends reflected in the number of reported patients and number of gastroenteritis virus-positive samples. We focused on gastroenteritis viruses present in wastewater and investigated the usefulness of wastewater surveillance for the surveillance of infectious gastroenteritis. METHODS: Real-time polymerase chain reaction was used for viral gene detection in wastewater. The number of reported patients per pediatric sentinel site and number of viral genome copies were compared for correlation potential. The number of gastroenteritis virus-positive samples reported by National Epidemiological Surveillance of Infectious Disease (NESID) and the status of gastroenteritis viruses detected in wastewater were also evaluated. RESULTS: Genes of norovirus genotype I, norovirus genotype II, sapovirus, astrovirus, rotavirus group A, and rotavirus group C were detected in wastewater samples. Viruses were detected in wastewater during periods when no gastroenteritis virus-positive samples were reported to NESID. CONCLUSION: Norovirus genotype II and other gastroenteritis viruses were detected in wastewater even during periods when no gastroenteritis virus-positive samples were found. Therefore, surveillance using wastewater can complement sentinel surveillance and is an effective tool for the surveillance of infectious gastroenteritis.

Long-term course of the changes in the nipple position after breast-conserving surgery.

PURPOSE: Even if favorable cosmetic outcomes are obtained shortly after breast-conserving surgery (BCS), cosmetic changes may occur up to several years after BCS. In the present study, we evaluated cosmetic changes while focusing on changes in the nipple position after BCS. METHODS: We examined the long-term course of changes in the nipple position over time after BCS using the proportion of the distance between the sternal notch and nipple (PDSN) in 196 patients. We also evaluated risk factors for long-term nipple position changes. RESULTS: The median follow-up period was 9.9 years. Nipple position changes occurred within eight years after BCS and seemed to plateau beyond that point. The body mass index (BMI), breast size, proportion of excision volume and axillary treatment were significantly associated with the nipple position changes within one to five years after BCS. The BMI, breast size, axillary treatment, chemotherapy and hormonal therapy were significantly associated with the nipple position changes within five to eight years after BCS. CONCLUSIONS: After BCS, the nipple position changes occur within about eight years. Obesity, large breast size, large excision volume, axillary treatment, chemotherapy and hormone therapy were factors that affected the treated breast shrinkage and increase in the left-right difference after BCS.

Educational challenges for 22q11.2 deletion syndrome in Japan: Findings from a mixed methods survey.

BACKGROUND: The 22q11.2 deletion syndrome (22q11DS) is characterised by a changing pattern of overlapping intellectual, physical, and mental disabilities along the course of one's life. However, the impact of overlapping disorders (multimorbidity) on educational challenges remains unclear. METHOD: A survey was conducted with 88 caregivers of individuals with 22q11DS. A quantitative analysis of educational challenges and support needs divided into age groups (7-12, 13-15, 16-18, and 19 years and over) and a qualitative analysis of the free-text items in the questionnaire was conducted. RESULTS: Caregivers were more interested in comprehensive developmental support when their children were younger, and the emphasis shifted to concerns regarding environments that matched individual characteristics at older ages. Furthermore, when there are multiple disabilities or disorders, support is concentrated on the more obvious disabilities, and the lack of support for the less superficially obvious disabilities associated with multiple difficulties, including mental health problems, can be a challenge for people with 22q11DS and their families. CONCLUSIONS: This study suggests a need for increased focus on multimorbidity and associated disabilities in school education that are difficult to observe because of their mildness or borderline levels if present alone.

[Neutralizing antibody titer after recommended early vaccination against Japanese encephalitis].

Objective　Following the case of a 10-month-old with Japanese encephalitis in Chiba in 2015, the Chiba Pediatric Association and Chiba Medical Association recommended that children receive the Japanese encephalitis vaccine at six months of age. In this study, we investigated early vaccinations and standard vaccinations of children in a patient outbreak area. Additionally, we examined changes in the timing of vaccination initiation and the acquisition and maintenance of protective immunity before and after the early vaccination recommendation.Methods　With the cooperation of the medical institution designated for Type II Infectious Diseases, which treated affected children in 2015, the history and timing of vaccinations for children who visited the hospital between October 2018 and March 2020 were investigated, and serum samples were collected. The data obtained in this study and the Ministry of Health, Labour and Welfare's Community Health Service Report were used to investigate the timing of vaccinations. Neutralizing antibody titers in serum were quantified with the focus measurement method and examined with respect to the number of vaccinations, doses, and number of days since vaccination.Results　A total of 154 samples were obtained, with 89 from the vaccinated group and 65 from the unvaccinated group. There was no difference in the percentage of children based on the age of first vaccination between Japan, Chiba Prefecture, and the study subjects until FY2015, but from FY2016 onward, the percentage of children vaccinated early was higher among the study subjects, as well as for children from Chiba Prefecture and Japan, in that order. The antibody possession rate by vaccination frequency was 9.2% for the unimmunized, 87.5% for those vaccinated once, 95.1% for those vaccinated twice, and 100% for those vaccinated three times. In the group vaccinated twice, antibody titers of children who received half the vaccine dose were significantly lower than those of children who received the normal dose.Conclusion　In the districts targeted in this study, significantly more children under three years of age were vaccinated before the early vaccination recommendation, suggesting the effectiveness of that recommendation. In addition, the high rate of antibody positivity among unvaccinated children suggests that it is important to promote early vaccination in areas at high risk for Japanese encephalitis. In this study, there was no evidence of attenuation of antibody titers over time after early immunization, but the possibility remains that the children who completed early immunization received a booster due to pathogen exposure and maintained antibody titers, given that Japanese encephalitis was endemic in the target area.

Medical, welfare, and educational challenges and psychological distress in parents caring for an individual with 22q11.2 deletion syndrome: A cross-sectional survey in Japan.

Parents of children with 22q11.2 deletion syndrome (22q11DS) experience distress not only due to multimorbidity in the patients, but also due to professionals' lack of understanding about 22q11DS and insufficient support systems. This study investigated relationships between medical, welfare, and educational challenges and parental psychological distress. A cross-sectional survey was conducted on primary caregivers of children with 22q11DS. Participants included 125 parents (114 mothers, 91.2%; average age = 44.3 years) who reported their challenges, psychological distress, and child's comorbidities of 22q11DS. Results showed that the difficulty in going to multiple medical institutions (ß = 0.181, p < 0.05) and lack of understanding by welfare staff and insufficient welfare support systems for 22q11DS (ß = 0.220-0.316, all p < 0.05) were associated with parental psychological distress, even after adjusting for child's comorbidities. In the subsample of parents whose child attended an educational institution, inadequate management in classroom and mismatch between service and users in educational settings were associated with psychological distress (ß = 0.222-0.296, all p < 0.05). This study reveals the importance of assessing not only severity of comorbidities in 22q11DS, but also the medical, welfare, and educational challenges for parental mental health.

Diagnostic significance of lactate dehydrogenase in measles virus reinfection cases.

Lactate dehydrogenase (LDH) levels in measles virus (MeV) reinfection cases for the diagnosis of measles have not been extensively studied. Thus, we evaluated the significance of serum LDH in the immune response of patients with MeV reinfection in comparison with those of patients with primary infection. Among 70 patients who tested positive for MeV-RNA, 42 with high MeV-specific IgG avidity (HA) were suspected as cases of reinfection and 28 with low MeV-specific IgG (LA) were suspected as cases of primary infection. The viral loads in the HA group were also lower than those in the LA group (P < 0.001). The titers of MeV-specific IgM and IgG in the HA group were significantly lower and higher, respectively, than those in the LA group (P < 0.001). The total LDH and LDH isozyme levels were elevated in the LA group compared with those in the HA group (P < 0.001). Through receiver operating characteristic curve analyses, we determined that the area under the curve of total LDH level was 0.87 (95% CI 0.74-1.00) and that the discriminatory accuracy was high for total LDH and all isozymes. By stepwise binary logistic regression analysis considering MeV-specific IgG avidity, we developed a model using IgG, IgM, and total LDH as explanatory variables, which was optimal for distinguishing the LA and HA groups (adjusted R2 = 0.773, P < 0.001). Thus, the serum LDH level in addition to IgM and IgG may be useful parameters for differentiating MeV reinfection from primary infection.

Tenascin-C Induces Phenotypic Changes in Fibroblasts to Myofibroblasts with High Contractility through the Integrin αvß1/Transforming Growth Factor ß/SMAD Signaling Axis in Human Breast Cancer.

Tenascin-C (TNC) is strongly expressed by fibroblasts and cancer cells in breast cancer. To assess the effects of TNC on stromal formation, we examined phenotypic changes in human mammary fibroblasts treated with TNC. The addition of TNC significantly up-regulated α-smooth muscle actin (α-SMA) and calponin. TNC increased the number of α-SMA- and/or calponin-positive cells with well-developed stress fibers in immunofluorescence, which enhanced contractile ability in collagen gel contraction. The treatment with TNC also significantly up-regulated its own synthesis. Double immunofluorescence of human breast cancer tissues showed α-SMA- and/or calponin-positive myofibroblasts in the TNC-deposited stroma. Among several receptors for TNC, the protein levels of the αv and ß1 integrin subunits were significantly increased after the treatment. Immunofluorescence showed the augmented colocalization of αv and ß1 at focal adhesions. Immunoprecipitation using an anti-αv antibody revealed a significant increase in coprecipitated ß1 with TNC in lysates. The knockdown of αv and ß1 suppressed the up-regulation of α-SMA and calponin. The addition of TNC induced the phosphorylation of SMAD2/3, whereas SB-505124 and SIS3 blocked myofibroblast differentiation. Therefore, TNC enhances its own synthesis by forming a positive feedback loop and increases integrin αvß1 heterodimer levels to activate transforming growth factor-ß signaling, which is followed by a change to highly contractile myofibroblasts. TNC may essentially contribute to the stiffer stromal formation characteristic of breast cancer tissues.

Risk Factors for Ipsilateral Breast Tumor Recurrence in Triple-Negative or HER2-Positive Breast Cancer Patients Who Achieve a Pathologic Complete Response After Neoadjuvant Chemotherapy.

BACKGROUND: Attention has been focused on attempts to eliminate breast surgery for breast cancer patients who achieve a pathologic complete response after neoadjuvant chemotherapy (NAC). However, there are few data on ipsilateral breast tumor recurrence (IBTR) among patients with triple-negative or epidermal growth factor receptor 2-positive (HER2+) tumors who achieve a pathologic complete response after NAC and breast-conserving treatment. METHODS: Using a multi-institutional retrospective database, this study evaluated the risk factors for IBTR among patients with newly diagnosed stages 1 to 3 breast cancer involving triple-negative or HER2+ tumors who achieved ypT0 after NAC and breast-conserving treatment. RESULTS: During a median follow-up period of 4.8 years (range, 0.1-15.5 years), the 5-year IBTR-free survival rate was 95.5%. The breast cancer subtype was not associated with IBTR-free survival. Patients younger than 40 years at diagnosis had significantly worse IBTR-free survival than those who were 40 years of age or older (5-year IBTR-free survival, 87.7 vs 96.9%; p = 0.002). CONCLUSIONS: This retrospective study demonstrated that age at diagnosis was independently associated with IBTR-free survival. Special caution is needed when clinical trials analyzing omission of breast surgery after NAC are enrolling younger patients (UMIN-CTR No. UMIN000037067).

Arsenite suppresses IL-2-dependent tumoricidal activities of natural killer cells.

Chronic exposure to arsenic causes cancers in various organs including the skin, liver, lung, and bladder in humans, but the mechanisms of the multi-organ carcinogenicity of arsenic remain unknown. Natural killer (NK) cells play important roles in the immune surveillance and elimination of tumor cells. Although accumulating evidence has indicated that arsenic has immunosuppressive properties, little is known about the effects of arsenic on the tumoricidal functions of NK cells. We examined the effects of arsenite on the cytotoxic activities of human and mouse NK cells toward target tumor cells. Exposure of human NK-92 cells and primary mouse NK cells to sublethal doses of arsenite reduced the IL-2-activated cytotoxic activities toward human K562 cells and murine YAC-1 cells, respectively. NK cells recognize target cells via integrated signals from both activating and inhibitory receptors and induce apoptosis of target cells via a granzyme/perforin system. We found that exposure of NK-92 cells to arsenite diminished the IL-2-activated down-regulation of the inhibitory receptors, KIR2DL2 and KIR2DL3, and the up-regulation of granzyme B and lymphotoxin-α. The IL-2-activated increases in secretion of interferon-γ and IL-10 were also slightly reduced by arsenite. Thus, arsenite suppressed the IL-2-activated cytotoxic activity of NK cells by disrupting multiple pathways required for the recognition and killing of target tumor cells. Our findings provide new insights into the roles of NK cell-mediated tumor immunity in cancer development by arsenic.

Clinical features, pathogenesis, and management of stroke-like episodes due to MELAS.

Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) is a disease that should be considered as a differential diagnosis to acute ischemic stroke taking into account its onset pattern and neurological symptoms, which are similar to those of an ischemic stroke. Technological advancements in neuroimaging modalities have greatly facilitated differential diagnosis between stroke and MELAS on diagnostic imaging. Stroke-like episodes in MELAS have the following features: (1) symptoms are neurolocalized according to lesion site; (2) epileptic seizures are often present; (3) lesion distribution is inconsistent with vascular territory; (4) lesions are common in the posterior brain regions; (5) lesions continuously develop in adjacent sites over several weeks or months; (6) neurological symptoms and stroke-like lesions tend to be reversible, as presented on magnetic resonance imaging; (7) the rate of recurrence is high; and; (8) brain dysfunction and atrophy are slowly progressive. The m.3243ANG mutation in the MT-TL1 gene encoding the mitochondrial tRNALeu(UUR) is most commonly associated with MELAS. Although the precise pathophysiology is still unclear, one possible hypothesis for these episodes is a neuronal hyperexcitability theory, including neuron-astrocyte uncoupling. Supplementation, such as with L-arginine or taurine, has been proposed as preventive treatments for stroke-like episodes. As this disease is still untreatable and devastating, numerous drugs are being tested, and new gene therapies hold great promise for the future. This article contributes to the understanding of MELAS and its implications for clinical practice, by deepening their insight into the latest pathophysiological hypotheses and therapeutic developments.