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Multifocal lymphangioendotheliomatosis with thrombocytopenia (MLT) is a rare disease characterized by the presence of multiple cutaneous lesions and bleeding from the gastrointestinal tract with thrombocytopenia. Because of the varied phenotypes and rarity of MLT, a treatment strategy has not been standardized thus far. We describe a case of infantile MLT that did not respond to treatment with propranolol, prednisolone, or vincristine. We successfully treated the patient with everolimus, an inhibitor of the mammalian target of rapamycin. Our case provides the first evidence of the effectiveness of everolimus for the treatment of MLT.

Purpose: To investigate the development of diaphragmatic dysfunction in ventilated extremely preterm infants (EPI) using diaphragm ultrasound (DU). Methods: EPI of less than 28 weeks’ gestational age who required mechanical ventilation within six hours of birth were included in this prospective, observational study. The DU was performed once a day until four days of life. End-inspiratory and end-expiratory thicknesses of the diaphragm were measured and the diaphragm thickening fraction was calculated. Results: A total of 20 EPI were enrolled. After intubation, there was a progressive reduction in end-inspiratory thicknesses of the diaphragm from baseline to day 1 (P < 0.001), but not from day 1 to day 2 (P = 0.078), day 2 to day 3 (P = 1.0), or day 3 to day 4 (P = 1.0). There was also a significant reduction in the diaphragm thickening fraction from baseline to day 1 (P < 0.001), but not from day 1 to day 2 (P = 1.0), day 2 to day 3 (P = 1.0), or day 3 to day 4 (P = 1.0). Conclusions: This study provides the first evidence of diaphragmatic dysfunction in ventilated EPI. We demonstrated a rapid progression of ventilator-induced diaphragmatic dysfunction, with a significant reduction in diaphragm thickness and thickening fraction within 24 hours of ventilation.

Objective To assess the impact of gravity and time on the changes in the distribution patterns of loss of aeration and atelectasis development in very preterm infants. Study design Preterm infants less than 32 weeks gestation were included in this prospective, observational study. Infants were assessed via serial lung ultrasound (LUS) score in four lung zones, performed on days 7, 14, 21, and 28 after birth. Result Eighty-eight patients were enrolled. There was a significant main effect of gravity (P

Long-chain-fatty-acid (LCFA) metabolism is a fundamental cellular process in bacteria that is involved in lipid homeostasis, energy production, and infection. However, the role of LCFA metabolism in Salmonella enterica serovar Typhimurium (S. Tm) gut infection remains unclear. Here, using a murine gastroenteritis infection model, we demonstrate involvement of LCFA metabolism in S. Tm gut colonization. The LCFA metabolism-associated transcriptional regulator FadR contributes to S. Tm gut colonization. fadR deletion alters the gene expression profile and leads to aberrant flagellar motility of S. Tm. Colonization defects in the fadR mutant are attributable to altered swimming behavior characterized by less frequently smooth swimming, resulting from reduced expression of the phase 2 flagellin FljB. Notably, changes in lipid LCFA composition by fadR deletion lead to reduced expression of fljB, which is restored by exogenous LCFA. Therefore, LCFA homeostasis may maintain proper flagellar motility by activating fljB expression, contributing to S. Tm gut colonization. Our findings improve the understanding of the effect of luminal LCFA on the virulence of enteric pathogens.

What is known and objective While bioavailability of oral voriconazole is known to be >90%, several reports have observed much lower oral bioavailability. The aim of the present study was to assess the oral bioavailability of voriconazole in clinical use by evaluating the change in serum voriconazole concentration in patients who received intravenous-to-oral switch therapy with the same dose of voriconazole. Methods A single-centre, retrospective cohort study was conducted at the 614-bed Gifu University Hospital in Japan. Patients who received intravenous-to-oral switch therapy with the same dose of voriconazole between 1 January 2011 and 31 December 2018 were enrolled in the present study. We evaluated changes in serum voriconazole concentration before and after switch therapy. Results Voriconazole trough concentrations significantly decreased following oral compared to intravenous treatment (2.5 ± 1.5 µg/mL vs 3.3 ± 2.0 µg/mL, p = 0.021). The median change rate of serum concentration by switching the route of administration was 82.7%, with wide inter-individual variability (range 27.2-333.3%). Further, concomitant glucocorticoid administration was a significant protective factor for reducing serum concentration (OR 0.16, 95% CI 0.03-0.79, p = 0.025). What is new and conclusion Switching from intravenous to oral treatment resulted in a significant decline in voriconazole trough concentrations with wide inter-individual variability. Therefore, measurement of serum concentration for dose adjustment should be performed after switching to the oral form.

Objective This study aimed to investigate the utility of lung ultrasound (LUS) with whole chest scanning for predicting respiratory outcomes in patients with bronchopulmonary dysplasia (BPD). Study Design We performed a prospective observational study. Preterm infants of less than 32 weeks' gestational age requiring oxygen therapy at 28 days of life were included. LUS was performed on day 28, at 36 weeks' postmenstrual age, and at the time of discharge. Each lung was divided into three regions by the anterior and posterior axillary lines and received an LUS score of 0 to 3 points; the total score was obtained by adding the six regional scores. The classification of BPD was determined based on the National Institute of Child and Human Development. The outcomes of this study were the development of moderate-to-severe BPD and the need for home oxygen therapy (HOT). Results We enrolled 87 patients; 39, 33, and 15 infants had mild, moderate, and severe BPD, respectively. The LUS score correlated with BPD severity and exhibited an improvement trend with time toward the point of discharge. LUS at 28 days of life predicted moderate-to-severe BPD with an area under the curve of 0.95 (95% confidence interval: 0.91–0.99) and HOT with an area under the curve of 0.95 (95% confidence interval: 0.81–1.0). Conclusion LUS with whole chest scanning is useful for predicting respiratory outcomes in patients with BPD, as well as for understanding BPD severity or clinical improvement trends. Key Points

Background: Gravity affects the distribution of lung injuries due to gravity-induced nonhomogeneous ventilation leading to lung collapse and subsequently non-uniform lung lesions. Moreover, lung injury gradients gradually develop over time. However, changes in injury distribution after birth have not been investigated in very preterm infants. Methods: Preterm infants of less than 32 weeks’ gestational age were included in this prospective observational study. Gravity-dependent lungs (DL) were defined as dorsal lungs in a supine position or ventral lungs in a prone position, and non-dependent lungs (NDL) were defined as ventral lungs in a supine position or dorsal lungs in a prone position. Infants were assessed using lung ultrasound (LUS), which was performed on days 7, 14, 21, and 28 post-birth. Each anterior and posterior lung was scanned and received an LUS score of 0–3 points. LUS scores of the DL and NDL were compared. Total LUS scores were provided using a 0–6 point scale, which was obtained by adding the scores for each region of each lung. Results: Eighty–eight patients were enrolled in this study. On days 7, 14, and 21, LUS scores between the DL and NDL groups were significantly different (day 7, P = 0.01; day 14, P < 0.001; and day 21, P = 0.003). However, on day 28, there was no significant difference between groups (P = 0.064). Conclusions: LUS can be used to detect gravity-induced lung injury gradients in very preterm infants. Moreover, LUS revealed a trend of gradient improvement over time.

ImportanceThe risk of premature infants in neonatal incubators exposed to evaporated alcohol from alcohol-based disinfectants (ABDs) is unknown.ObjectiveTo assess alcohol concentrations in the peripheral blood of premature infants and neonatal incubators.Design, Setting, and ParticipantsA quality improvement study comparing 2 different populations before and after introduction of ABD practice (ABD-PRAC) was conducted in a neonatal intensive care unit of a single tertiary hospital in Japan. Participants included premature infants who were born before 34 weeks of gestational age and received medical care in neonatal incubators. The study consisted of 3 periods: (1) September 1, 2020, to August 1, 2021 (prospective observation of pre–ABD-PRAC, (2) August 2 to August 22, 2021 (introduction of ABD-PRAC to medical staff and parents in the neonatal intensive care unit), and (3) August 23, 2021, to March 31, 2022 (prospective observation of post–ABD-PRAC). No follow-up studies were initiated.InterventionsAn ABD-PRAC that aimed to reduce alcohol evaporation from ABDs inside neonatal incubators was instituted: (1) place alcohol preps in the incubator just before use and remove them from the incubator as soon as possible and (2) withhold placing hands into the incubators until 60 seconds after using ABDs for disinfection (applied only to family members).Main Outcomes and MeasuresBlood alcohol concentration and evaporated alcohol concentrations in neonatal incubators.ResultsDisinfectant practice was assessed among 28 infants during the pre–ABD-PRAC (17 infants [10 girls]; median gestational age at birth, 29.4 [IQR, 26.3-30.3] weeks) and post–ABD-PRAC (11 infants [3 girls]; median gestational age at birth, 30.0 [IQR, 25.3-32.2] weeks) study periods. The median blood alcohol concentration was 7.0 (IQR, 5.4-9.3) mg/dL pre–ABD-PRAC and 4.2 (IQR, 2.5-7.2) mg/dL post–ABD-PRAC. The median evaporated alcohol concentration inside neonatal incubators during pre–ABD-PRAC during the day was 23.6 (IQR, 15.9-36.5) ppm and, at night, was 13.2 (IQR, 8.9-19.4) ppm; during post–ABD-PRAC, the concentration was 9.4 (IQR, 6.0-16.0) ppm during the day and 5.7 (IQR, 3.6-9.7) ppm at night. The introduction of ABD-PRAC at 22 weeks’ corrected gestational age was associated with a lower blood alcohol concentration in premature infants: regression coefficient value, −8.3 (95% CI, −12.0 to −4.7).Conclusions and RelevanceIn this study, alcohol evaporated from ABDs was absorbed by premature infants in neonatal incubators. The findings suggest that introduction of ABD-PRAC was associated with lower alcohol concentrations in neonatal incubators and in the blood of premature infants.

Background The purpose of this study was to investigate the usefulness of ultrasonography (US) for confirmation of endotracheal tube (ETT) placement during resuscitation in extremely low birthweight (ELBW) infants. Methods We conducted a retrospective review of the medical records of ELBW infants in whom ETT position was verified using US between June 2016 and September 2017. We investigated the backgrounds of the patients and US investigators, and the time required for the detection of exhaled carbon dioxide using the colorimetric method and US. Results Eleven ELBW infants were evaluated using US by four neonatologists. The median duration required to determine the ETT position by the colorimetric method and US were 11 s and 3 s, respectively. In six ELBW infants, we were able to verify the ETT position more rapidly using US than using the colorimetric method, and were able to perform prompt resuscitation. Unnecessary reintubations were avoided in three ELBW infants. Conclusion Ultrasonography allowed the swift confirmation of the tracheal intubations. The colorimetric method yielded false negative results; in such cases, unnecessary reintubation could have been avoided if US was used. We assessed the mechanism of false negative results and performed appropriate resuscitation.

Do apprenticeships enhance product quality? Whether guilds and apprenticeships have promoted technological change has been debated, but the issue remains unsettled because of the lack of data which...

Neovascular retinal diseases are the leading causes of blindness in advanced countries. To date, anti-VEGF (vascular endothelial growth factor) drugs are clinically effective and widely used for these diseases. However, recent animal and clinical studies reported that potent and long-term VEGF antagonism may induce chorioretinal atrophy. Thus, physiological amount of VEGF is required for the homeostasis in the retina. Hypoxia-inducible factors (HIFs) are transcription factors located upstream of VEGF. We hypothesized that ectopically stabilized HIFs induce pathological amount of VEGF involved with retinal neovascularization. Therefore, HIF inhibition could be an alternative therapeutic candidate targeting the pathological amount of VEGF while holding a physiological amount of VEGF. To test this hypothesis, topotecan and doxorubicin, HIF inhibitors with different mechanisms were administered to the murine oxygen-induced retinopathy (OIR) model. We found that both topotecan and doxorubicin significantly prevented pathological but not physiological neovascularization in OIR. Furthermore, impaired visual function observed in OIR can also be suppressed by administering topotecan. These data suggested that HIF inhibition may be effective for pathological angiogenesis and neurodegeneration of the retina.

This study deals with the estimation of the changes that occur in the Business-to-Business (B2B) networks in the Japanese textile and apparel industry by applying datasets of about 2000 companies from 2011/2012 to 2015/2016. Network analysis was used to examine the properties of the B2B networks. A factor of innovation in information and communications technology (ICT) and logistics technology was introduced into an agent-based model to demonstrate changes occurring in the related structures of B2B networks. The agent-based model was designed and tested based on qualitative information on Japanese textile and apparel industries. Consequently, network analysis revealed power-law properties and the structures of centralized hub companies. Moreover, in the simulation experiments, the centralizations of the networks generated by the agent-based model due to innovation in ICT and logistics technology were illustrated. Therefore, one of the predicted cases regarding changes that occur in the B2B networks was explained as centralizations to hub companies.

In this study, observed food effects of 473 drugs were categorized into positive, negative, or no effects and compared with the predictions made by machine learning (ML), the Biopharmaceutics Classification System (BCS) and refined Developability Classification System (rDCS). All methods used primarily in silico estimates for prediction, and for ML, four algorithms were evaluated using nested cross-validation to select important information from 371 features calculated based on the chemical structure. Approximately 18 features, including estimated solubility in biorelevant media, were selected as important, and the random forest classifier was the best among four algorithms with 36.6% error rate (ER) and 10.8% opposite prediction rate (OPR). The prediction by rDCS utilizing solubility in a biorelevant medium was somewhat inferior, but not by much; 41.0% ER and 11.4% OPR. Compared with these two methods, the prediction by BCS was inferior; 54.5% ER and 21.4% OPR. ER was improved modestly by using measured features instead of in silico estimates when BCS was applied to a subset of 151 drugs (46.4% from 55.0%). ML and rDCS predicted the food effects of the same subset using in silico estimates with ERs of 37.7% and 42.4%, respectively, suggesting that the predictions by ML and rDCS using in silico features are similar or more accurate than those by BCS using measured features. These results suggest that ML was useful in revealing essential features from complex information and, together with rDCS, is effective in predicting food effects during drug development, including early drug discovery.

Salmonella enterica serovar Typhimurium is an important foodborne pathogen that causes diarrhea. S. Typhimurium elicits inflammatory responses and colonizes the gut lumen by outcompeting the microbiota. Although evidence is accumulating with regard to the underlying mechanism, the infectious stage has not been adequately defined. Peptidoglycan amidases are widely distributed among bacteria and play a prominent role in peptidoglycan maintenance by hydrolyzing peptidoglycans. Amidase activation is required for the regulation of at least one of two cognate activators, NlpD or EnvC (also called YibP). Recent studies established that the peptidoglycan amidase AmiC-mediated cell division specifically confers a fitness advantage on S. Typhimurium in the inflamed gut. However, it remains unknown which cognate activators are involved in the amidase activation and how the activators influence Salmonella sp. pathogenesis. Here, we characterize the role of two activators, NlpD and EnvC, in S. Typhimurium cell division and gut infection. EnvC was found to contribute to cell division of S. Typhimurium cells through the activation of AmiA and AmiC. The envC mutant exhibited impairments in gut infection, including a gut colonization defect and reduced ability to elicit inflammatory responses. Importantly, the colonization defect of the envC mutant was unrelated to the microbiota but was conferred by attenuated motility and chemotaxis of S. Typhimurium cells, which were not observed in the amiA amiC mutant. Furthermore, the envC mutant was impaired in its induction of mucosal inflammation and sustained gut colonization. Collectively, our findings provide a novel insight into the peptidoglycan amidase/cognate activator circuits and their dependent pathogenesis.

The acetylcholinesterase inhibitor, acotiamide, improves gastric motility and is clinically used to treat functional dyspepsia. The present study aimed to identify the transporters involved in the distribution of acotiamide in stomach tissue. Acotiamide uptake by the gastric cancer-derived model cell line, Hs746 T, was Na+- and pH-independent. The initial uptake velocity of acotiamide was saturable with increasing concentrations of acotiamide and was inhibited by selective serotonin reuptake inhibitors, which are potent inhibitors of the plasma membrane monoamine transporter (PMAT). The uptake of acotiamide by PMAT gene-transfected HEK293 cells was saturable, with similar Km (197.9 μM) values to those of uptake by Hs 746T cells (106 μM). Moreover, immunoreactivity of PMAT was found in the gastric smooth muscle and vascular endothelial cells. These results suggest that PMAT contributes to the distribution of acotiamide in the stomach, where it exerts its pharmacological effects.

The twin-arginine translocation (Tat) system is involved in not only a wide array of cellular processes but also pathogenesis in many bacterial pathogens; thus, this system is expected to become a novel therapeutic target to treat infections. To the best of our knowledge, involvement of the Tat system has not been reported in the gut infection caused by Citrobacter rodentium. Here, we studied the role of Tat in C. rodentium gut infection, which resembles human infection with enterohemorrhagic Escherichia coli (EHEC) and enteropathogenic E. coli (EPEC). A C. rodentium Tat loss-of-function mutant displayed prolonged gut colonization, which was explained by reduced inflammatory responses and, particularly, neutrophil infiltration. Further, the Tat mutant had colonization defects upon coinfection with the wild-type strain of C. rodentium. The Tat mutant also became hypersensitive to bile acids, and an increase in fecal bile acids fostered C. rodentium clearance from the gut lumen. Finally, we show that the chain form of C. rodentium cells, induced by a Tat-dependent cell division defect, exhibits impaired resistance to bile acids. Our findings indicate that the Tat system is involved in gut colonization by C. rodentium, which is associated with neutrophil infiltration and resistance to bile acids. Interventions that target the Tat system, as well as luminal bile acids, might thus be promising therapeutic strategies to treat human EHEC and EPEC infections.

In patients with Scimitar syndrome, right pulmonary artery hypoplasia is considered to lead to right lung hypoplasia because of decrease in blood flow. However, there are no reports wherein the change was actually detected. Thus, the exact developmental mechanism of right pulmonary artery hypoplasia and right lung hypoplasia in patients with Scimitar syndrome is unclear. We experienced a case of Scimitar syndrome preceding right lung hypoplasia, and right pulmonary artery hypoplasia gradually revealed with time. We hypothesized that, in our patient, the lung hypoplasia led to pulmonary artery hypoplasia due to decrease in blood flow. If there are no differences in the diameter of the left and right pulmonary artery in patients with Scimitar syndrome at birth, we propose the necessity of careful observation due to the possibility that pulmonary artery hypoplasia may develop in the future.

The human mass balance of [14 C]Z-215, a novel proton pump inhibitor, was characterised in six healthy male volunteers following single oral administration of [14 C]Z-215 (20 mg, 3.7 MBq) to determ...

In this study, a method for determining the viscoelastic material properties from displacement fields is proposed. Stress-strain relationship represented by the superposition integral is employed as the viscoelastic constitutive equation. Thus, the unknown properties are relaxation bulk and shear moduli. The virtual fields method based on the principle of virtual work is used as a method for the inverse analysis. The unknown material properties are determined by solving nonlinear simultaneous equations of the virtual work containing the constitutive equations. The validity of the proposed method is demonstrated by identifying the viscoelastic properties of a soft epoxy resin. Results show that the two independent viscoelastic material properties can be identified by proposed method.

BACKGROUND Appropriate management of the endotracheal tube (ETT) insertion depth is important. The depth calculated using Tochen's formula is overestimated in extremely-low- birthweight infants, particularly those with a birthweight

Congenital diaphragmatic eventration (CDE) is always diagnosed by fluoroscopic examination. However, this technique is inappropriate for premature neonates because of risks of transport, hypothermia and ionising radiation. Herein, we describe two cases of premature neonates suspected to have CDE on radiography. We could not perform fluoroscopic examination due to their prematurity status. Therefore, we performed ultrasound examination and succeeded in diagnosing CDE without any risks. Using ultrasound examination, we could evaluate movement and thickness of the diaphragm. We consider this additional information useful for CDE diagnosis. This is the first report on CDE diagnosis using ultrasound examination.

Schuurs-Hoeijmakers syndrome is a rare disease characterized by intellectual disability and dysmorphic facial features among various physical abnormalities due to PACS1 mutation. To date, 28 patients with a recurrent de novo PACS1 mutation (c.607C > T) have been reported, primarily in Western populations. Here, we describe two Japanese patients with Schuurs-Hoeijmakers syndrome with a recurrent PACS1 mutation. In addition to the typical clinical symptoms, each patient presented novel clinical phenotypes. One patient presented with involuntary movements and was treated with trihexyphenidyl hydrochloride. We hypothesized that the PACS1 mutation leads to an inherent dopaminergic insufficiency that underlies the developing symptoms along with the neurodevelopmental processes. The second patient was diagnosed with lipomyelomeningocele during an examination for severe constipation at the age of 2 years and 8 months. The diagnosis of lipomyelomeningocele in this patient was delayed due to the lack of cutaneous lesions. As the majority of patients with PACS1 mutation present constipation, underdiagnosis of lipomyelomeningocele is a possibility. As the phenotypic expansion of the patients with Schuurs-Hoeijmakers syndrome was not fully recognized, additional studies are needed to clarify the clinical spectrum.

Members of the organic anion transporting polypeptide (OATP) transporter family are involved in drug absorption and disposition, and therefore drug–drug and drug–food interactions at these transporters may have both pharmacological and toxicological effects. Accordingly, a detailed understanding of the substrates and modulators, including inhibitors and stimulators, of the transporters, as well as the resulting interactions, is required. However, this is not straightforward, since OATP transporters have multiple binding sites, which exhibit different selectivity for substrates and modulators. Here, we focused on the characterization of the binding sites of OATP2B1, which contributes to the intestinal absorption and hepatic disposition of drugs. Site-directed mutagenesis studies indicated that histidine residues His579 and His618 are involved in the low- and high-affinity sites for estrone-3-sulfate (E13S) transport, respectively. Uptakes of pravastatin, rosuvastatin and sulfasalazine were decreased by mutations of His579 and His618 of OATP2B1, whereas uptakes of fexofenadine and prostaglandin E2 were not affected. Naringin, an OATP inhibitor, reduced the uptakes of pravastatin, rosuvastatin, sulfasalazine and low-concentration E13S, but not other substrates. In addition, progesterone stimulated the uptake of low-concentration E13S but did not affect or even decreased the uptakes of other substrates. These observations confirm that multiple binding sites are present on OATP2B1, resulting in differential characteristics in the recognition of substrates and modulators. Accordingly, identification of the locations of binding sites on OATP2B1 and their detailed characterization will be necessary to improve the prediction of drug–drug and drug–food interactions on OATP2B1.

How does a small start-up become a platform leader from the viewpoint of inducing complementors? Previous researches on platform management seem to focus on platform design and the relationship between complementors and platform leaders. However, samples used in these researches are large, established leaders, and strategies for start-ups have not been studied in detail. From single case studies about the progression of a Japanese platform leader, we found that collaborations with organisations at the centre of networks are useful because: 1) these collaborations provide start-ups paths to complementors; 2) these collaborations enhance the trustworthiness of start-ups; 3) the higher the number of collaborations, the more neutral the position enjoyed by platform leaders, even as start-ups.