Association of subpleural ground-glass opacities with respiratory failure and RNAemia in COVID-19.

OBJECTIVES: To examine the radiological patterns specifically associated with hypoxemic respiratory failure in patients with coronavirus disease (COVID-19). METHODS: We enrolled patients with COVID-19 confirmed by qPCR in this prospective observational cohort study. We explored the association of clinical, radiological, and microbiological data with the development of hypoxemic respiratory failure after COVID-19 onset. Semi-quantitative CT scores and dominant CT patterns were retrospectively determined for each patient. The microbiological evaluation included checking the SARS-CoV-2 viral load by qPCR using nasal swab and serum specimens. RESULTS: Of the 214 eligible patients, 75 developed hypoxemic respiratory failure and 139 did not. The CT score was significantly higher in patients who developed hypoxemic respiratory failure than in those did not (median [interquartile range]: 9 [6-14] vs 0 [0-3]; p < 0.001). The dominant CT patterns were subpleural ground-glass opacities (GGOs) extending beyond the segmental area (n = 44); defined as "extended GGOs." Multivariable analysis showed that hypoxemic respiratory failure was significantly associated with extended GGOs (odds ratio [OR] 29.6; 95% confidence interval [CI], 9.3-120; p < 0.001), and a CT score > 4 (OR 12.7; 95% CI, 5.3-33; p < 0.001). The incidence of RNAemia was significantly higher in patients with extended GGOs (58.3%) than in those without any pulmonary lesion (14.7%; p < 0.001). CONCLUSIONS: Extended GGOs along the subpleural area were strongly associated with hypoxemia and viremia in patients with COVID-19. KEY POINTS: • Extended ground-glass opacities (GGOs) along the subpleural area and a CT score > 4, in the early phase of COVID-19, were independently associated with the development of hypoxemic respiratory failure. • The absence of pulmonary lesions on CT in the early phase of COVID-19 was associated with a lower risk of developing hypoxemic respiratory failure. • Compared to patients with other CT findings, the extended GGOs and a higher CT score were also associated with a higher incidence of RNAemia.

Epstein-Barr virus-associated inflammatory pseudotumor variant of follicular dendritic cell sarcoma of the liver: a case report and review of the literature.

BACKGROUND: Follicular dendritic cell sarcoma is a rare stromal tumor with no standard treatment. However, some reports have revealed that follicular dendritic cell sarcoma has an inflammatory pseudotumor variant associated with Epstein-Barr virus infection that has a relatively good prognosis. In this report, we present a case of a resected inflammatory pseudotumor variant of follicular dendritic cell sarcoma of the liver, and have reviewed the literature on the clinicopathological, molecular, and genomic features of this tumor. CASE PRESENTATION: The inflammatory pseudotumor variant of follicular dendritic cell sarcoma originates only in the liver or spleen, causes no symptoms, and is more common in middle-aged Asian women. It has no characteristic imaging features, which partially explains why the inflammatory pseudotumor variant of follicular dendritic cell sarcoma is difficult to diagnose. Pathologically, the inflammatory pseudotumor variant of follicular dendritic cell sarcoma has spindle cells mixed with inflammatory cells and is variably positive for follicular dendritic cell markers (CD21, CD23, and CD35) and Epstein-Barr virus-encoded RNA. On genetic analysis, patients with this tumor high levels of latent membrane protein 1 gene expression and extremely low levels of host C-X-C Chemokine Receptor type 7 gene expression, indicating that the inflammatory pseudotumor variant of follicular dendritic cell sarcoma has a latent Epstein-Barr virus type 2 infection. CONCLUSIONS: The inflammatory pseudotumor variant of follicular dendritic cell sarcoma is an Epstein-Barr virus-associated tumor and a favorable prognosis by surgical resection, similar to Epstein-Barr virus-associated gastric cancer.

Clinic-level factors associated with collaboration with community pharmacies in Japan.

The aim of this study was to clarify the clinic-level factors related to experiences of and attitudes toward collaboration with community pharmacies. We conducted a postal questionnaire survey of all clinics in Gifu, Japan, assessing the experiences and attitudes of representative clinical staff regarding the following activities in collaboration with community pharmacists: regional care meetings/service adjustment meetings, case study conferences, joint workshops/continuing education conferences, community services, information sharing through medical cooperation networks, and accompanying community pharmacists during home care. The factors significantly related to experiences of joint workshops/continuing education conferences included home care visits (odds ratio [OR] 2.39) and a 100 % out-of-hospital prescription ratio (OR 4.80). In contrast, only home care visits were significantly associated with consideration of information sharing through medical cooperation networks and accompanying community pharmacists during home care (OR 2.06 and 11.91, respectively). Finally, the factors significantly associated with considering implementing case study conferences and joint workshops/continuing education conferences included home care visits (OR 4.64 and 2.98, respectively) and a 100% out-of-hospital prescription ratio (OR 4.64 and 6.38). Overall, having more opportunities to communicate with community pharmacists and other healthcare professionals appeared to facilitate clinics' consideration of collaboration with community pharmacies, along with actual experiences.

Ingestion of paddy rice increases intestinal mucin secretion and goblet cell number and prevents dextran sodium sulfate-induced intestinal barrier defect in chickens.

Paddy rice is a potential feed grain for chickens, whose strong gizzards can crush the hull. Here, we investigated whether paddy rice rich in hull-derived water-insoluble dietary fiber stimulates intestinal mucin secretion and production, as well as the possible involvement of paddy rice in intestinal barrier function. Layer male chicks at 7 d of age were divided into four groups according to the diet: corn, polished rice, brown rice, or paddy rice (650 g/kg diet), which they ate for 14 consecutive days. At 21 d of age, the birds were refed their experimental diets, and small intestinal mucin fractions were collected to determine intestinal mucin content. Small intestinal mucin secretion was induced most strongly in the paddy rice group (Experiment 1). The rank order of diet-induced mucin secretion was paddy rice > corn = brown rice > polished rice. Ileal MUC2 gene expression and ileal number of goblet cells were highest in the paddy rice group (Experiment 1). A study of bromodeoxy-U uptake into ileal epithelial cells indicated the increase in goblet cells in the paddy rice group was related to accelerate epithelial cell migration (Experiment 2). A single supplementation of isolated rice hulls without kernels increased MUC2 gene expression and goblet cell numbers (Experiment 3), suggesting the importance of the hull's bulk-forming capacity on mucin production. Finally, chicks fed corn or paddy rice were orally administered dextran sodium sulfate (DSS) to disrupt intestinal barrier function. In the DSS-treated birds, the intestinal permeability of fluorescein isothiocyanate dextran in the everted gut sacs was much lower in the paddy rice group than in the corn group (Experiment 4), showing that paddy rice protects against mucosal disruption. In conclusion, ingestion of paddy rice increases intestinal mucin secretion and production through enhanced MUC2 gene expression and epithelial turnover and prevents DSS-induced intestinal barrier defects in chickens.

Numerical study of plasma generation process and internal antenna heat loadings in J-PARC RF negative ion source.

A numerical model of plasma transport and electromagnetic field in the J-PARC (Japan Proton Accelerator Research Complex) radio frequency ion source has been developed to understand the relation between antenna coil heat loadings and plasma production/transport processes. From the calculation, the local plasma density increase is observed in the region close to the antenna coil. Electrons are magnetized by the magnetic field line with absolute magnetic flux density 30-120 Gauss which leads to high local ionization rate. The results suggest that modification of magnetic configuration can be made to reduce plasma heat flux onto the antenna.

Pre-conditioning procedure suitable for internal-RF-antenna of J-PARC RF-driven H⁻ ion source.

The Japan Proton Accelerator Research Complex (J-PARC) cesiated RF-driven H(-) ion source has been successfully operated for about 1 yr. By the world brightest level beam, the J-PARC design beam power of 1 MW was successfully demonstrated. Although no internal-RF-antenna failure, except for the once caused by an excess cesium due to a misoperation, occurred in the operation, many antennas failed in pre-conditionings for the first hundred days. The antenna failure rate was drastically decreased by using an antenna with coating thicker than a standard value and the pre-conditioning procedure repeating 15 min 25 kW RF-power operation and impurity-gas evacuation a few times, before the full power (50 kW) operation.

Fine-tuning to minimize emittances of J-PARC RF-driven H⁻ ion source.

The Japan Proton Accelerator Research Complex (J-PARC) cesiated RF-driven H(-) ion source has been successfully operated for about one year. By the world's brightest level beam, the J-PARC design beam power of 1 MW was successfully demonstrated. In order to minimize the transverse emittances, the rod-filter-field (RFF) was optimized by changing the triple-gap-lengths of each of pairing five piece rod-filter-magnets. The larger emittance degradation seems to be caused by impurity-gases than the RFF. The smaller beam-hole-diameter of the extraction electrode caused the more than expected improvements on not only the emittances but also the peak beam intensity.

Status of the RF-driven H⁻ ion source for J-PARC linac.

For the upgrade of the Japan Proton Accelerator Research Complex linac beam current, a cesiated RF-driven negative hydrogen ion source was installed during the 2014 summer shutdown period, with subsequent operations commencing on September 29, 2014. The ion source has been successfully operating with a beam current and duty factor of 33 mA and 1.25% (500 µs and 25 Hz), respectively. The result of recent beam operation has demonstrated that the ion source is capable of continuous operation for approximately 1100 h. The spark rate at the beam extractor was observed to be at a frequency of less than once a day, which is an acceptable level for user operation. Although an antenna failure occurred during operation on October 26, 2014, no subsequent serious issues have occurred since then.

Characterization of ASKP1240, a fully human antibody targeting human CD40 with potent immunosuppressive effects.

Blocking the CD40-CD154 interaction is reported to be effective for transplantation management and autoimmune disease models in rodents and nonhuman primates. However, clinical trials with anti-CD154 mAbs were halted because of high incidence of thromboembolic complications. Thus, we generated and characterized a fully human anti-CD40 mAb ASKP1240, as an alternative to anti-CD154 mAb. In vitro ASKP1240 concentration-dependently inhibited human peripheral blood mononuclear cell proliferation induced by soluble CD154. In addition, ASKP1240 did not destabilize platelet thrombi under physiological high shear conditions while mouse anti-human CD154 mAb (mu5C8) did. And ASKP1240 itself did not activate platelet and endothelial cells. In vivo administration of ASKP1240 (1 or 10 mg/kg, intravenously) to cynomolgus monkeys, weekly for 3 weeks, significantly attenuated both delayed-type hypersensitivity and specific antibody formation evoked by tetanus toxoid. The immunosuppressive effect was well correlated with the CD40 receptor saturation. Thus, these results suggest that ASKP1240 is immunosuppressive but not prothromboembolic, and as such appears to be a promising therapeutic candidate for the management of solid organ transplant rejection and autoimmune diseases therapy.

Dependence of beam emittance on plasma electrode temperature and rf-power, and filter-field tuning with center-gapped rod-filter magnets in J-PARC rf-driven H(-) ion source.

The prototype rf-driven H(-) ion-source with a nickel plated oxygen-free-copper (OFC) plasma chamber, which satisfies the Japan Proton Accelerator Research Complex (J-PARC) 2nd stage requirements of a H(-) ion beam current of 60 mA within normalized emittances of 1.5 π mm mrad both horizontally and vertically, a flat top beam duty factor of 1.25% (500 µs × 25 Hz) and a life-time of more than 50 days, was reported at the 3rd international symposium on negative ions, beams, and sources (NIBS2012). The experimental results of the J-PARC ion source with a plasma chamber made of stainless-steel, instead of nickel plated OFC used in the prototype source, are presented in this paper. By comparing these two sources, the following two important results were acquired. One was that the about 20% lower emittance was produced by the rather low plasma electrode (PE) temperature (TPE) of about 120 °C compared with the typically used TPE of about 200 °C to maximize the beam current for the plasma with the abundant cesium (Cs). The other was that by using the rod-filter magnets with a gap at each center and tuning the gap-lengths, the filter-field was optimized and the rf-power necessary to produce the J-PARC required H(-) ion beam current was reduced typically 18%. The lower rf-power also decreases the emittances.

Operation and development status of the J-PARC ion source.

A cesium-free H(-) ion source driven with a LaB6 filament is being operated at the Japan Proton Accelerator Research Complex (J-PARC) without any serious trouble since the restoration from the March 2011 earthquake. The H(-) ion current from the ion source is routinely restricted approximately 19 mA for the lifetime of the filament. In order to increase the beam power at the linac beam operation (January to February 2013), the beam current from the ion source was increased to 22 mA. At this operation, the lifetime of the filament was estimated by the reduction in the filament current. According to the steep reduction in the filament current, the break of the filament was predicted. Although the filament has broken after approximately 10 h from the steep current reduction, the beam operation was restarted approximately 8 h later by the preparation for the exchange of new filament. At the study time for the 3 GeV rapid cycling synchrotron (April 2013), the ion source was operated at approximately 30 mA for 8 days. As a part of the beam current upgrade plan for the J-PARC, the front end test stand consisting of the ion source and the radio frequency quadrupole is under preparation. The RF-driven H(-) ion source developed for the J-PARC 2nd stage requirements will be tested at this test stand.

Novel morphological features in the death of MCF-7 human breast cancer cells after exposure to anticancer drugs.

Cell death of human breast cancer cell line MCF-7/pDsRed2-Mito, caused by independent- or multi-administration of three anticancer drugs, cyclophosphamide [CPA], doxorubicin [DXR], and 5-fluorouracil [5-FU], was studied using fluorescence and electron microscopy. In our previous study using cell viability assays, microscopic inspection of heterochromatin condensation, a DNA fragmentation assay, and flow cytometric analyses, the death of MCF-7 cells was classified into two groups. The cell death induced by CPA or 5-FU was classified as apoptotic, while the cell death induced by DXR treatment or a mixture of all three anticancer drugs was classified as non-apoptotic. Here, we examined the morphology of the whole cell and its organelles, including the mitochondria, using electron microscopy. Mitochondria are of particular interest because they are the key organelle for the molecular apoptotic-death cascade. To monitor mitochondrial morphology, we used our previously constructed MCF-7/pDsRed2-Mito line, generated by introducing the pDsRed2-Mito vector into MCF-7 cells. The mitochondria in these cells emit red fluorescence. We found that the administration of DXR alone or of all three anticancer drugs together resulted in the clumping of the red-fluorescent materials on both sides of the round dying cells, interrupted by the nucleus. Detailed electron microscopic observation revealed that the novel morphology of the dying MCF-7 cells might be owing, not to destruction of the mitochondrial membrane, but to the tight structure of the nuclear membrane. Other anticancer drugs showed different, characteristic features in electron microscopic images, which suggested that death induced by anti-cancer drugs in the human breast cancer cell line, MCF-7, may result from any of a number of diverse processes.

Development of an H- ion source for Japan Proton Accelerator Research Complex upgrade.

A cesium (Cs) free H(-) ion source driven with a lanthanum hexaboride (LaB(6)) filament was adopted as an ion source for the first stage of the Japan Proton Accelerator Research Complex (J-PARC). At present, the maximum H(-) ion current produced by the ion source is 38 mA, using which J-PARC can produce a proton beam power of 0.6 MW by accelerating it with the 181 MeV linac and the 3 GeV rapid cycling synchrotron. In order to satisfy the beam power of 1 MW required for the second stage of the J-PARC in the near future, we have to increase the ion current to more than 60 mA. Therefore, we have started to develop a Cs-seeded ion source by adding an external Cs-seeding system to a J-PARC test ion source that has a structure similar to that of the J-PARC ion source except for the fact that the plasma chamber is slightly larger. As a result, a H(-) ion current of more than 70 mA was obtained from the ion source using a tungsten filament instead of a LaB(6) filament with a low arc discharge power of 15 kW (100 V, 150 A).

Recent operation status of Japan Proton Accelerator Research Complex H- ion source.

A cesium-free H(-) ion source driven with a LaB(6) filament is being operated at the Japan Proton Accelerator Research Complex for approximately three years without any serious trouble. In the beam commissioning or supply runs, the ion source has been operated in two different modes such as low current mode of 5 mA and high current mode of 30 mA. The total interruption time during the runs due to the ion source failure is approximately 50 h, which correspond to the ion source availability of 99%. After a long-term operation, the surface of the filament and the plasma electrode become discolored with dark partially. The result of surface analysis with field emission scanning electron microscope showed that most of the dark material is formed with boron. At the beam test performed in the interval of the run, we demonstrated that the H(-) current increased by miniaturizing the LaB(6) filament.

A survey of optimal filament shape in a Japan Proton Accelerator Research Complex H- ion source.

Dependence of various shapes of lanthanum hexaboride (LaB(6)) filaments on H(-) ion currents (I_H(-)'s) was examined by using the first Japan Proton Accelerator Research Complex (J-PARC) test ion source. It is almost the same with the J-PARC H(-) ion source (J-PARC-IS) except for the maximum arc current (290 A instead of 400 A). An I_H(-) of 35.2 mA was extracted by using a cylindrical double-spiral LaB(6) filament with a diameter of 29.5 mm and a length of 35.5 mm, which is the same one used in J-PARC-IS. It increased to 43.4 mA with a flat triple-hairpin LaB(6) filament. The I_H(-) is considered to be increased by the enlargement of the high density plasma region near the plasma electrode aperture and the reduction of the LaB(6) filament unemission area located in the high density plasma region.

An innovative high-power constant-current pulsed-arc power-supply for a high-density pulsed-arc-plasma ion-source using a LaB6-filament.

An innovative high-power constant-current (CC) pulsed-arc (PA) power-supply (PS) indispensable for a high-density PA plasma ion-source using a lanthanum hexaboride (LaB(6)) filament was devised by combining a constant-voltage (CV) PA-PS, which is composed of an insulated gate bipolar transistor (IGBT) switch, a CV direct-current (dc) PS and a 270 mF capacitor with a CC-PA-PS, which is composed of an IGBT-switch, a CC-dc-PS and a 400 microH inductor, through the inductor. The hybrid-CC-PA-PS succeeded in producing a flat arc-pulse with a peak power of 56 kW (400 A x 140 V) and a duty factor of more than 1.5% (600 micros x 25 Hz) for Japan Proton Accelerator Research Complex (J-PARC) H(-) ion-source stably. It also succeeded in shortening the 99% rising-time of the arc-pulse-current to about 20 micros and tilting up or down the arc-pulse-current arbitrarily and almost linearly by changing the setting voltage of its CV-dc-PS.

Interesting experimental results in Japan Proton Accelerator Research Complex H- ion-source development (invited).

The following interesting experimental results observed in Japan Proton Accelerator Research Complex (J-PARC) H(-) ion-source developments are reviewed. It was proven that almost all of H(-) ions were produced with surface reactions in cesium (Cs)-free J-PARC H(-) ion-sources. The world's most intense class H(-) ion current of 38 mA in Cs-free ion sources for a high-energy linac was attained by an optimal shape and high temperature of the plasma electrode (PE), usage of a lanthanum hexaboride (LaB(6)) filament, and a newly devised high-power constant-current pulsed-arc power supply indispensable for it. It was also proven that the H(-) ion current could be increased to more than 40 mA by optimizing LaB(6)-filament shape. The surface elemental analysis of the PE after operation with a LaB(6)-filament showed that it was coated by boron (B) 95.5%, lanthanum (La) 2.5%, and oxygen (O) 1.9%. The H(-) ion current decreased by about 20% when a tungsten (W) filament was used instead of a LaB(6)-filament. The H(-) ion current could not be increased by seeding cesium (Cs) if the LaB(6)-filament was used. On the other hand, it was increased to more than 70 mA with much lower arc current of 150 A if Cs was seeded when a W-filament was used.