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Background: The coronavirus disease 2019 (COVID-19) pandemic has impacted the capacity for advance care planning between patients, families, and healthcare teams. The barriers to and facilitators of advance care planning vary with settings. This study sought to identify and review the barriers to and facilitators of advance care planning implementation for medical staff in different settings (e.g., hospitals, outpatients, care and nursing homes) during the COVID-19 pandemic. Methods: This study followed an overview of review design and was registered in the International Prospective Register of Systematic Reviews (CRD42022351362). A search of MEDLINE, CENTRAL, Web of Science, and Embase databases was performed through November 14, 2022. AMSTAR 2 was used to assess the risk of bias. Results: The final analyses included seven studies. Common barriers to advance care planning implementation included visitation restrictions, limited resources and personnel, and lack of coordination among health professionals. In care and nursing homes, the lack of palliative care physicians and the psychological burden on staff were identified as barriers. Using telemedicine for information-sharing was a common facilitator. In hospitals, facilitators were short-term training in palliative care and palliative care physicians joining the acute care team; in care homes and nursing homes, they were advance care planning education and emotional support for staff. Conclusions: Although inadequate staff education regarding advance care planning in hospitals and facilities and the lack of community-level information-sharing have long been noted, the pandemic highlighted these issues. Short-term training programs for staff and immediate information-sharing could facilitate advance care planning.

SARS-CoV-2 induces severe organ damage not only in the lung but also in the liver, heart, kidney, and intestine. It is known that COVID-19 severity correlates with liver dysfunction, but few studies have investigated the liver pathophysiology in COVID-19 patients. Here, we elucidated liver pathophysiology in COVID-19 patients using organs-on-a-chip technology and clinical analyses. First, we developed liver-on-a-chip (LoC) which recapitulating hepatic functions around the intrahepatic bile duct and blood vessel. We found that hepatic dysfunctions, but not hepatobiliary diseases, were strongly induced by SARS-CoV-2 infection. Next, we evaluated the therapeutic effects of COVID-19 drugs to inhibit viral replication and recover hepatic dysfunctions, and found that the combination of anti-viral and immunosuppressive drugs (Remdesivir and Baricitinib) is effective to treat hepatic dysfunctions caused by SARS-CoV-2 infection. Finally, we analyzed the sera obtained from COVID-19 patients, and revealed that COVID-19 patients, who were positive for serum viral RNA, are likely to become severe and develop hepatic dysfunctions, as compared with COVID-19 patients who were negative for serum viral RNA. We succeeded in modeling the liver pathophysiology of COVID-19 patients using LoC technology and clinical samples., 新型コロナウイルス感染症（COVID-19）研究のための肝臓チップの開発 --肝障害の病態解明と治療薬の評価--. 京都大学プレスリリース. 2023-03-08., Using organ-on-a-chip technology to elucidate the liver pathophysiology of COVID-19 patients. 京都大学プレスリリース. 2023-03-08.

It has been reported that many receptors and proteases are required for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Although angiotensin-converting enzyme 2 (ACE2) is the most important of these receptors, little is known about the contribution of other genes. In this study, we examined the roles of neuropilin-1, basigin, transmembrane serine proteases (TMPRSSs), and cathepsins (CTSs) in SARS-CoV-2 infection using the CRISPR interference system and ACE2-expressing human induced pluripotent stem (iPS) cells. Double knockdown of TMPRSS2 and cathepsin B (CTSB) reduced the viral load to 0.036% ± 0.021%. Consistently, the combination of the CTPB inhibitor CA-074 methyl ester and the TMPRSS2 inhibitor camostat reduced the viral load to 0.0078% ± 0.0057%. This result was confirmed using four SARS-CoV-2 variants (B.1.3, B.1.1.7, B.1.351, and B.1.1.248). The simultaneous use of these two drugs reduced viral load to less than 0.01% in both female and male iPS cells. These findings suggest that compounds targeting TMPRSS2 and CTSB exhibit highly efficient antiviral effects independent of gender and SARS-CoV-2 variant., Graphical abstract, Hashimoto et al. used iPS cells and the CRISPRi system to compare the functions of receptors and proteases involved in SARS-CoV-2 infection. Dual inhibition of TMPRSS2 and CTSB prevented SARS-CoV-2 infection. The combination of TMPRSS2 and CTSB inhibitor treatment exhibited highly efficient antiviral effects independent of gender and SARS-CoV-2 variant.

Coronavirus infections occurred in repeated waves caused by different variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with the number of patients increasing during each wave. A private after-hours house-call (AHHC) service provides hospital-at-home (HaH) services to patients in Japan requiring oxygen when hospital beds are in short supply. This retrospective study aimed to compare the characteristics of COVID-19 patients treated by the AHHC service during the COVID-19 waves caused by the Alpha (March–June 2021) and Delta (July–December 2021) SARS-CoV-2 variants. All patients with COVID-19 treated by the AHHC service from March to December 2021 while awaiting hospitalization were included. The data were collected from medical records and follow-up telephone interviews. The AHHC service treated 55 and 273 COVID-19 patients during the Alpha and Delta waves, respectively. The patients treated during the Delta wave were significantly younger than those treated during the Alpha wave (median: 63 years and 47 years, respectively; p < 0.001). Disease severity did not differ significantly between the two waves, but the crude case-fatality rate was significantly higher during the Alpha wave (10/55, 18.2%) than during the Delta wave (4/273, 1.4%; p < 0.001). The patient characteristics and outcomes differed between the Alpha and Delta waves.

Virotherapy using oncolytic adenovirus is an effective anticancer strategy. However, the tumor selectivity of oncolytic adenoviruses is not enough high. To develop oncolytic adenovirus with a low risk of off-tumor toxicity, we constructed a photoactivatable oncolytic adenovirus (paOAd). In response to blue light irradiation, the expression of adenoviral E1 genes, which are necessary for adenoviral replication, is induced and replication of this adenovirus occurs. In vitro, efficient lysis of various human cancer cell lines was observed by paOAd infection followed by blue light irradiation. Importantly, there was no off-tumor toxicity unless the cells were irradiated by blue light. In vivo, tumor growth in a subcutaneous tumor model and a mouse model of liver cancer was significantly inhibited by paOAd infection followed by blue light irradiation. In addition, paOAd also showed a therapeutic effect on cancer stem cells. These results suggest that paOAd is useful as a safe and therapeutically effective cancer therapy.

A liver-on-a-chip (liver-chip) is a microfluidic device carrying liver cells such as human hepatocytes. It is used to reproduce a part of liver function. Many microfluidic devices are composed of polydimethylsiloxane (PDMS), which is a type of silicone elastomer. PDMS is easy to process and suitable for cell observation, but its high hydrophobicity carries the risk of drug absorption. In this study, we evaluated drug absorption to the PDMS device and investigated the drug responsiveness of human hepatocytes cultured in the PDMS device (hepatocyte-chips). First, the absorption rates of 12 compounds to the PDMS device were measured. The absorption rates of midazolam, bufuralol, cyclosporine A, and verapamil were 92.9, 71.7, 71.4, and 99.6%, respectively, but the other compounds were poorly absorbed. Importantly, the absorption rate of the compounds was correlated with their octanol/water distribution coefficient (log D) values (R2 = 0.76). Next, hepatocyte-chips were used to examine the response to drugs, which are typically used to evaluate hepatic functions. Using the hepatocyte-chips, we could confirm the responsiveness of drugs including cytochrome P450 (CYP) inducers and farnesoid X receptor (FXR) ligands. We believe that our findings will contribute to drug discovery research using PDMS-based liver-chips.

Genetic differences are a primary reason for differences in the susceptibility and severity of COVID-19. As induced pluripotent stem (iPS) cells maintain the genetic information of the donor, they can be used to model individual differences in SARS-CoV-2 infection in vitro. We found that human iPS cells expressing the SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) (ACE2-iPS cells) can be infected w SARS-CoV-2. In infected ACE2-iPS cells, the expression of SARS-CoV-2 nucleocapsid protein, budding of viral particles, and production of progeny virus, double membrane spherules, and double-membrane vesicles were confirmed. We performed SARS-CoV-2 infection experiments on ACE2-iPS/ embryonic stem (ES) cells from eight individuals. Male iPS/ES cells were more capable of producing the virus compared with female iPS/ES cells. These findings suggest that ACE2-iPS cells can not only reproduce individual differences in SARS-CoV-2 infection in vitro but also are a useful resource to clarify the causes of individual differences in COVID-19 due to genetic differences., Graphical abstract, Health Sciences ; Virology ; Cell Biology

Genetic differences are a primary reason for differences in the susceptibility and severity of coronavirus disease 2019 (COVID-19). Because induced pluripotent stem (iPS) cells maintain the genetic information of the donor, they can be used to model individual differences in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infectionin vitro. Notably, undifferentiated human iPS cells themselves cannot be infected bySARS-CoV-2. Using adenovirus vectors, here we found that human iPS cells expressing the SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) (ACE2-iPS cells) can be infected with SARS-CoV-2. In infected ACE2-iPS cells, the expression of SARS-CoV-2 nucleocapsid protein, the budding of viral particles, the production of progeny virus, double membrane spherules, and double-membrane vesicles were confirmed. We also evaluated COVID-19 therapeutic drugs in ACE2-iPS cells and confirmed the strong antiviral effects of Remdesivir, EIDD-2801, and interferon-beta. In addition, we performed SARS-CoV-2 infection experiments on ACE2-iPS/ES cells from 8 individuals. Male iPS/ES cells were more capable of producing the virus as compared with female iPS/ES cells. These findings suggest that ACE2-iPS cells can not only reproduce individual differences in SARS-CoV-2 infectionin vitro, but they are also a useful resource to clarify the causes of individual differences in COVID-19 due to genetic differences.Graphical Abstract

The purpose of this study was to evaluate the appearance of artifacts by four types of root canal filling sealers on cone-beam computed tomography (CBCT) images. Thirty standardized tooth models were given the radiopacity equivalent to human teeth, and root canal preparation was performed using WaveOne Gold. Root canal filling by a single-point method was performed using WaveOne Gold gutta-percha points and four types of root canal sealers: AH Plus (AH), CANALS (CA), BioRoot RCS (BR), and MTA Fillapex (MTA). Samples were taken by periapical radiography at 60 kV and scanned by CBCT at three tube voltages (70, 85, and 100 kV). The gray-scale values (GVs) of the periapical radiographs were measured and the aluminum equivalents were calculated. On the CBCT axial images, the artifact and dentin area GVs were measured and the rate of change in the GV (RCGV) was calculated as follows: RCGV (%) = (dentin area GV − artifact GV)/dentin area GV × 100. High-density areas with artifacts on the CBCT images were also measured. On the periapical radiographs, the aluminum equivalent was largest for AH and smallest for MTA. On the CBCT images, AH showed the largest values for both RCGV and the high-density areas, while BR and MTA showed comparable values. Correlations were found between the radiopacity on the periapical radiographs and the degree of artifacts on the CBCT images. These findings suggest that the greater the contrast in the 2D image, the higher the artifacts in the 3D image.

Hypernatremia due to salt poisoning is clinically rare and standard care procedures have not been established. We report a case of salt poisoning due to massive intake of seasoning soy sauce. Aggressive rapid correction of serum sodium concentration should only be considered in acute phases of hypernatremia within 2–3 h of salt ingestion, before the brain cells adapt to high osmolarity., Background Hypernatremia due to salt poisoning is clinically rare and standard care procedures have not been established. We report a case of salt poisoning due to massive intake of seasoning soy sauce. Case Presentation A 40‐year‐old woman presented to the emergency department with seizures and remarkable hypernatremia with a serum sodium concentration of 183 mEq/L. The initial brain computed tomography scan showed brain shrinkage, which could occur during the acute phase of hypernatremia. We reduced her serum sodium level rapidly, rather than at the recommended slow rate. On day 3, the patient’s brain computed tomography scan showed widespread low‐density areas and edema. The patient died 8 days after admission. Conclusion After reviewing instances of resuscitation following salt intoxication, aggressive rapid correction of serum sodium concentration should only be considered in acute phases of hypernatremia within a few hours from ingestion, and 2–3 h could be one of the criteria.

Background Acute mitral regurgitation could occur without common symptoms like hemodynamic instability, but with dyspnea, hemoptysis, and right‐sided infiltration on radiography. We report a case of severe alveolar hemorrhage caused by acute mitral regurgitation, which occurred in the absence of shock. Case Presentation A 40‐year‐old man presented with dyspnea with bloody phlegm and hypoxia, despite being hemodynamically stable. Chest radiography revealed right‐sided infiltration, and bronchoscopy showed fresh bloody phlegm in his tracheae. No specific findings were detected with any tests. After treatment with several medications and support with extracorporeal membrane oxygenation, his condition improved, although the etiology of the disease remained unknown. Transthoracic and transesophageal echocardiogram revealed severe mitral valve regurgitation with ruptured mitral chordae tendineae. These suggested that the sudden onset of mitral valve regurgitation had caused severe alveolar hemorrhage. Conclusion Severe alveolar hemorrhage, especially with right‐sided infiltration on chest radiography, should be considered a symptom of acute mitral regurgitation., Acute mitral regurgitation could occur without common symptoms like hemodynamic instability, but with dyspnea, hemoptysis, and right‐sided infiltration on radiography. Severe alveolar hemorrhage, especially with right‐sided infiltration on chest radiography, should be considered a symptom of acute mitral regurgitation.

Human hepatocytes are essential materials in pharmaceutical researches. Not only primary human hepatocytes (PHH) but also human iPS cell-derived hepatocyte-like cells (human iPS-HLCs) are expected to be applied as materials for pharmaceutical researches. To date, several culture media have been developed for culturing human hepatocytes. However, there have been no reports comparing these media to determine which is most suitable for culturing human hepatocytes. In this study, we compared five commercial media (Hepatocyte Culture Medium (HCM), HepatoZYME-SFM, Cellartis Power Primary HEP Medium, DMEM/F12, and William's E Medium (WEM)) to determine which is most suitable for culturing PHH and human iPS-HLCs. In hepatic differentiation of human iPS cells (day 14-25 of differentiation), albumin (ALB) and urea secretion abilities and CYP2C9, CYP2C19, and CYP3A4 activities were the highest when using HCM or WEM. During maintenance of human iPS-HLCs, ALB and urea producing abilities and CYP2C9, CYP2C19, and CYP3A4 activities were the highest when using HCM. Importantly, we found that human iPS-HLCs cultured in HCM were maintained for 3 weeks or more without impairment of their hepatic functions. These results suggest that it is necessary to select an optimal medium for hepatic differentiation and maintenance of human iPS-HLCs. In the case of PHH culture, there was little difference in hepatic functions among the five media. However, the CYP2C9, CYP2C19, and CYP3A4 activities were the highest when using HCM and WEM. In conclusion, it is important to select the optimal medium for specific application when carrying out pharmaceutical researches using human hepatocytes.

The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2020 (J-SSCG 2020), a Japanese-specific set of clinical practice guidelines for sepsis and septic shock created as revised from J-SSCG 2016 jointly by the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine, was first released in September 2020 and published in February 2021. An English-language version of these guidelines was created based on the contents of the original Japanese-language version. The purpose of this guideline is to assist medical staff in making appropriate decisions to improve the prognosis of patients undergoing treatment for sepsis and septic shock. We aimed to provide high-quality guidelines that are easy to use and understand for specialists, general clinicians, and multidisciplinary medical professionals. J-SSCG 2016 took up new subjects that were not present in SSCG 2016 (e.g., ICU-acquired weakness [ICU-AW], post-intensive care syndrome [PICS], and body temperature management). The J-SSCG 2020 covered a total of 22 areas with four additional new areas (patient- and family-centered care, sepsis treatment system, neuro-intensive treatment, and stress ulcers). A total of 118 important clinical issues (clinical questions, CQs) were extracted regardless of the presence or absence of evidence. These CQs also include those that have been given particular focus within Japan. This is a large-scale guideline covering multiple fields; thus, in addition to the 25 committee members, we had the participation and support of a total of 226 members who are professionals (physicians, nurses, physiotherapists, clinical engineers, and pharmacists) and medical workers with a history of sepsis or critical illness. The GRADE method was adopted for making recommendations, and the modified Delphi method was used to determine recommendations by voting from all committee members.As a result, 79 GRADE-based recommendations, 5 Good Practice Statements (GPS), 18 expert consensuses, 27 answers to background questions (BQs), and summaries of definitions and diagnosis of sepsis were created as responses to 118 CQs. We also incorporated visual information for each CQ according to the time course of treatment, and we will also distribute this as an app. The J-SSCG 2020 is expected to be widely used as a useful bedside guideline in the field of sepsis treatment both in Japan and overseas involving multiple disciplines., other authors: Satoru Hashimoto,Daisuke Hasegawa,Junji Hatakeyama,Naoki Hara,Naoki Higashibeppu,Nana Furushima,Hirotaka Furusono,Yujiro Matsuishi,Tasuku Matsuyama,Yusuke Minematsu,Ryoichi Miyashita,Yuji Miyatake,Megumi Moriyasu,Toru Yamada,Hiroyuki Yamada,Ryo Yamamoto,Takeshi Yoshida,Yuhei Yoshida,Jumpei Yoshimura,Ryuichi Yotsumoto,Hiroshi Yonekura,Takeshi Wada,Eizo Watanabe,Makoto Aoki,Hideki Asai,Takakuni Abe,Yutaka Igarashi,Naoya Iguchi,Masami Ishikawa,Go Ishimaru,Shutaro Isokawa,Ryuta Itakura,Hisashi Imahase,Haruki Imura,Takashi Irinoda,Kenji Uehara,Noritaka Ushio,Takeshi Umegaki,Yuko Egawa,Yuki Enomoto,Kohei Ota,Yoshifumi Ohchi,Takanori Ohno,Hiroyuki Ohbe,Kazuyuki Oka,Nobunaga Okada,Yohei Okada,Hiromu Okano,Jun Okamoto,Hiroshi Okuda,Takayuki Ogura,Yu Onodera,Yuhta Oyama,Motoshi Kainuma,Eisuke Kako,Masahiro Kashiura,Hiromi Kato,Akihiro Kanaya,Tadashi Kaneko,Keita Kanehata,Ken-ichi Kano,Hiroyuki Kawano,Kazuya Kikutani,Hitoshi Kikuchi,Takahiro Kido,Sho Kimura,Hiroyuki Koami,Daisuke Kobashi,Iwao Saiki,Masahito Sakai,Ayaka Sakamoto,Tetsuya Sato,Yasuhiro Shiga,Manabu Shimoto,Shinya Shimoyama,Tomohisa Shoko,Yoh Sugawara,Atsunori Sugita,Satoshi Suzuki,Yuji Suzuki,Tomohiro Suhara,Kenji Sonota,Shuhei Takauji,Kohei Takashima,Sho Takahashi,Yoko Takahashi,Jun Takeshita,Yuuki Tanaka,Akihito Tampo,Taichiro Tsunoyama,Kenichi Tetsuhara,Kentaro Tokunaga,Yoshihiro Tomioka,Kentaro Tomita,Naoki Tominaga,Mitsunobu Toyosaki,Yukitoshi Toyoda,Hiromichi Naito,Isao Nagata,Tadashi Nagato,Yoshimi Nakamura,Yuki Nakamori,Isao Nahara,Hiromu Naraba,Chihiro Narita,Norihiro Nishioka,Tomoya Nishimura,Kei Nishiyama,Tomohisa Nomura,Taiki Haga,Yoshihiro Hagiwara,Katsuhiko Hashimoto,Takeshi Hatachi,Toshiaki Hamasaki,Takuya Hayashi,Minoru Hayashi,Atsuki Hayamizu,Go Haraguchi,Yohei Hirano,Ryo Fujii,Motoki Fujita,Naoyuki Fujimura,Hiraku Funakoshi,Masahito Horiguchi,Jun Maki,Naohisa Masunaga,Yosuke Matsumura,Takuya Mayumi,Keisuke Minami,Yuya Miyazaki,Kazuyuki Miyamoto,Teppei Murata,Machi Yanai,Takao Yano,Kohei Yamada,Naoki Yamada,Tomonori Yamamoto,Shodai Yoshihiro,Hiroshi Tanaka,Osamu Nishida, Guidelines

The present study aimed to investigate ecosystem dynamics in Tokyo Bay, a semi-enclosed bay surrounded by the Tokyo metropolitan area in Japan, which is one of the largest and most populous industrialized areas in the world. The bay has been subject to eutrophication since the 1960s, and excessive increase in phytoplankton biomass has led to hypoxia. Ecopath with Ecosim was used to simulate the phytoplankton dynamics, and it could closely reproduce the observed relative biomass. To evaluate the impacts of phytoplankton dynamics, hypoxia, and fishing on the dynamics, with a focus on high trophic levels (up to fish), 3 scenarios, “Yearly constant phytoplankton biomass,” “No hypoxia,” and “No fishing,” were tested. Comparisons with the “Control” scenario without any modifications suggested that (1) the dynamics was controlled by phytoplankton (bottom-up control), (2) hypoxia did not have a serious effect on the past dynamics, and (3) stopping fishing would not contribute to recover of the biomass of exploited fish. Predictions for future dynamics under the scenarios “DO deteriorated” and “DO unchanged” suggest that if DO deteriorates strongly enough to decrease the survival of most benthos, the ecosystem might undergo a non-negligible transformation through extinction or biomass decrease of some benthos.