The effect of celecoxib for treatment of preterm labor on fetuses during the second trimester of pregnancy: A pilot case series

OBJECTIVE: Although cyclooxygenase inhibitors effectively suppress uterine contraction, constriction of the fetal ductus arteriosus (DA) and oligohydramnios are major concerns. Celecoxib, a selective cyclooxygenase 2 inhibitor, is a potential potent tocolytic agent, but there are no studies that have evaluated the beneficial or adverse effects of celecoxib use on fetuses for more than 48 hours in pregnant women. We therefore aimed to evaluate the effect of middle-long-term celecoxib administration on the fetus during the second trimester of pregnancy, particularly in terms of fetal DA and amniotic fluid volume. MATERIALS AND METHODS: We retrospectively extracted and reviewed data from patients with preterm labor who received celecoxib for tocolysis for more than 48 hours between 2016 and 2020. Celecoxib was used for tocolysis only when treatment of patients with conventional tocolytic agents was ineffective. Data on the peak systolic velocity in ductus arteriosus (PSV-DA) and the maximum vertical pocket (MVP) were collected. RESULTS: A total of 15 patients were eligible. The median gestational age at celecoxib introduction was 22.6 weeks, and the median period of administration was 9 days (range 3-40 days). The median gestational age at delivery was 27.1 weeks, and the median duration from initial celecoxib administration to delivery was 40 days. The Z scores of PSV-DA and MVP did not change significantly after celecoxib administration. During administration, PSV-DA exceeded the 95th percentile of the corresponding normal reference range in three cases, but the levels returned to normal after reduction or discontinuation of treatment. There was no oligohydramnios during the treatment. CONCLUSION: Celecoxib administration for more than 48 hours in the second trimester of pregnancy might be safe and tolerable in terms of fetal PSV-DA and amniotic fluid volume as long as careful ultrasound monitoring is performed. Celecoxib could be an alternative for preterm labor when conventional tocolysis is not effective

Obstetric pelvimetry by three-dimensional computed tomography in non-pregnant Japanese women: a retrospective single-center study

OBJECTIVE: While a basic understanding of pelvic size and typology is still important for obstetricians, pelvic measurement data for Japanese women are very scarce. To our best knowledge, no large-scale pelvimetry studies of Japanese women have been made for the past 50 years. This study aimed to investigate the accurate size, particularly the obstetric conjugate (OC) and transverse diameter of the pelvic inlet (TD), of modern Japanese women, using three-dimensional (3D) computed tomography (CT), and to obtain their reference values. METHODS: This retrospective, single-center observational study enrolled Japanese non-pregnant women aged between 20 and 40 years, who underwent pelvic CT examination from 2016 to 2021. CT was performed for various reasons, including acute abdomen, search for cancer metastases, and follow-up of existing disease. However, no cases were taken for pelvic measurements. Pelvimetry was performed retrospectively using a 3D workstation. The OC was measured on a strict lateral view and the TD was measured on an axial-oblique view. Other clinical data, such as age, height, and weight, were also extracted from the medical charts and analyzed. RESULTS: A total of 1, 263 patients were enrolled, with the mean age of 32.7 years (standard deviation [SD] 6.2). The mean height, weight, and body mass index were 158.8 cm (SD 5.8), 54.8 kg (SD 11.7), and 21.7 kg/m2 (SD 4.4), respectively. The mean OC length was 127.0 mm (SD 9.5, 95% confidence interval [CI] 126.5-127.5), while the mean TD length was 126.8 mm (SD 7.5, 95% CI 126.4-127.2). Both values were normally distributed. Height was significantly associated with OC (regression coefficient = 0.75 [95% CI 0.66-0.84], p < .001) and TD (regression coefficient = 0.63 [95% CI 0.56-0.70], p < .001). Age showed a weak but statistically significant positive association with TD (regression coefficient = 0.14 [95% CI 0.07-0.20], p < .001) and OC (regression coefficient = -0.10 [95% CI -0.18 to -0.01], p = .026). CONCLUSION: The 3D CT pelvimetry in 1, 263 non-pregnant Japanese women of childbearing age revealed the mean OC and TD of 127.0 mm, and 126.8 mm, which were 11.8 mm and 4.3 mm larger, respectively, than those in the survey in 1972. Our data will be referred to in clinical practice as the standard pelvic measurement values for the Japanese population

PETREL for Astrophysics and Carbon Business

A multi-purpose 50kg class microsatellite hosting astrophysical mission and earth remote sensing, PETREL , will be launched in 2023. In the night side, PETREL observe the ultra-violet sky with a wide-field telescope covering 50 deg^2 for surveying transient objects related to supernovae, tidal disruption events, and gravitational wave events. Our UV telescope can detect the early phase UV emission from a neutron star merger occurred within 150 Mpc. In addition to the satellite observation, PETREL sends a detection alert including the coordinate and brightness of the UV transient to the ground via the real time communication network within several minutes after detection to conduct follow-up observations with the collaborating ground based observatories over the world. In the day side, PETREL observes the surface of the earth by using the tunable multi-spectral cameras and a ultra-compact hyperspectral camera. Our potential targets are the tropical forests (Green Carbon) and coastal zones (Blue Carbon) in the tropical areas to evaluating the global biological carbon strages. For this purpose PETREL will conduct multiple scale mapping collaborating with drones and small aircraft not only satellite. The obtained data will be used for academical research and for business applications. The technical difficulty of this satellite is that carries out multi-purpose with different requirements, such as astronomical observations which requires a quite high attitude stability and the earth observations requiring a high pointing accuracy, with limited resources. If it is possible, a novel small satellite system or a business style can be realized that can share the payload with academia and industry. PETREL has been adopted as Innovative Satellite Technology Demonstration Program No.3 led by JAXA, and development is underway with the aim of launching in FY2023

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

Fertility, Gap Between Ideal and Reality: Cross-Sectional Analysis of Fertility Decline in 17 High-Income Countries

To maintain the current population of a country in the long run, the key threshold of the fertility level is 2.1 births per women. Among the approximately 80 countries that so far have reached this so-called replacement level fertility, almost all have not stabilized fertility at this level. Instead, their fertility has moved below the 2.1 replacement rate (United Nations, 2017; World Bank, 2019). We define the end of the demographic transition as the period when the fertility rate reaches 2.1 births per women, and label what follows as a “post-transition period”, which, if they continue, will result in a decline in the native-born population. This thesis investigates the trends of actual fertility measured by TFR and CFR and compares with variation of the ideal number of children (fertility ideal) in 17 high-income countries that are in the posttransition period. First, the analysis of actual fertility using TFR and CFR measures indicated a general downward trend of fertility among 17 high-income countries under study. We find the fertility trend of posttransition countries is quite established as either having “moderately low” or “very low” fertility regardless of which fertility measure we use. Second, using the cross-sectional data derived from the ISSP 2012, the analysis of expressed fertility ideal shows that the perceived fertility ideal in all the countries under study is higher than the actual fertility rates. Moreover, the fertility ideal is higher than the replacement level of 2.1 in 16 out of the 17 countries under study. Our analysis further reveals that the gap between actual fertility and expressed ideal fertility is smaller in countries where the level of individualism and realized gender equality are known to be high. We argue that the prevalence of individualism that support gender equality may contribute to the decline of fertility ideal because individuals’ goals and achievements, regardless of gender, are encouraged in individualistic societies. In such a society, the gap between actual and ideal fertility, however, may become smaller as people are better able to realize fertility ideal because individualistic societies may put larger efforts in creating social settings such as generous family-friendly policies, where the childrearing does not constrain one’s goals and achievements

Community-acquired pneumonia caused by carbapenem-resistant Streptococcus pneumoniae: re-examining its prevention and treatment

Asako Doi,1,2 Kentaro Iwata,3 Hiroshi Takegawa,4 Kanji Miki,5 Yumi Sono,1,2 Hiroaki Nishioka,2 Jumpei Takeshita,6 Keisuke Tomii,7 Tsunekazu Haruta11Department of Infectious Diseases, 2Department of General Internal Medicine, Kobe City Medical Center General Hospital, 3Division of Infectious Diseases, Kobe University Hospital, Japan; 4Department of Laboratory Medicine, Kobe City Medical Center General Hospital, Japan; 5Hyogo Health Service Association, Hyogo, 6Foundation of Biochemical Research and Innovation, Osaka, 7Department of Pulmonary Medicine, Kobe City Medical Center General Hospital, Hyogo, JapanAbstract: A 73-year-old man with no significant past medical history or any history of health care visits was hospitalized for pneumonia. Sputum culture revealed multidrug-resistant Streptococcus pneumoniae, even to carbapenems. The patient was later treated successfully with levofloxacin. Throat cultures from his two grandchildren revealed S. pneumoniae with the same susceptibility pattern. Analysis for resistant genes revealed gPRSP (pbp1a + pbp2x + pbp2b gene variants) in both the patient and his grandchildren, none of whom had received pneumococcal vaccines of any kind. This case illustrates the importance of the emergence of carbapenem-resistant S. pneumoniae. Non-rational use of carbapenems for community-acquired infections may be counterproductive. This case also highlights the importance of pneumococcal vaccinations in children and the elderly.Keywords: carbapenem resistance, Streptococcus pneumoniae, pneumoni

ATM depletion induces proteasomal degradation of FANCD2 and sensitizes neuroblastoma cells to PARP inhibitors

Abstract Background Genomic alterations, including loss of function in chromosome band 11q22-23, are frequently observed in neuroblastoma, which is the most common extracranial childhood tumour. In neuroblastoma, ATM, a DNA damage response-associated gene located on 11q22-23, has been linked to tumorigenicity. Genetic changes in ATM are heterozygous in most tumours. However, it is unclear how ATM is associated with tumorigenesis and cancer aggressiveness. Methods To elucidate its molecular mechanism of action, we established ATM-inactivated NGP and CHP-134 neuroblastoma cell lines using CRISPR/Cas9 genome editing. The knock out cells were rigorously characterized by analyzing proliferation, colony forming abilities and responses to PARP inhibitor (Olaparib). Western blot analyses were performed to detect different protein expression related to DNA repair pathway. ShRNA lentiviral vectors were used to knockdown ATM expression in SK-N-AS and SK-N-SH neuroblastoma cell lines. ATM knock out cells were stably transfected with FANCD2 expression plasmid to over-expressed the FANCD2. Moreover, knock out cells were treated with proteasome inhibitor MG132 to determine the protein stability of FANCD2. FANCD2, RAD51 and γH2AX protein expressions were determined by Immunofluorescence microscopy. Results Haploinsufficient ATM resulted in increased proliferation (p < 0.01) and cell survival following PARP inhibitor (olaparib) treatment. However, complete ATM knockout decreased proliferation (p < 0.01) and promoted cell susceptibility to olaparib (p < 0.01). Complete loss of ATM suppressed the expression of DNA repair-associated molecules FANCD2 and RAD51 and induced DNA damage in neuroblastoma cells. A marked downregulation of FANCD2 expression was also observed in shRNA-mediated ATM-knockdown neuroblastoma cells. Inhibitor experiments demonstrated that the degradation of FANCD2 was regulated at the protein level through the ubiquitin–proteasome pathway. Reintroduction of FANCD2 expression is sufficient to reverse decreased proliferation mediated by ATM depletion. Conclusions Our study revealed the molecular mechanism underlying ATM heterozygosity in neuroblastomas and elucidated that ATM inactivation enhances the susceptibility of neuroblastoma cells to olaparib treatment. These findings might be useful in the treatment of high-risk NB patients showing ATM zygosity and aggressive cancer progression in future