Tuberculous peritonitis after conservative treatment for acute perforated appendicitis: a case report.

BACKGROUND: Interval appendectomy is widely recommended for patients with abscesses due to perforated appendicitis. A concomitant malignancy-related problem was reported after conservative treatment of acute appendicitis with abscess, but perforated appendicitis-associated tuberculous peritonitis was never reported. CASE PRESENTATION: A 67-year-old male patient with a laryngeal cancer history presented to our hospital with an acute appendicitis-associated ileal abscess. He was scheduled for an interval appendectomy after conservative treatment. Fortunately, the symptoms subsided, and the patient was discharged for a later scheduled appendectomy. However, after 3 months, he was readmitted to our hospital with fever and abdominal pain, and emergency surgery was performed, which was suspected to be peritonitis. Intraoperative results revealed numerous white nodules in the abdominal cavity. The condition was diagnosed as tuberculous peritonitis based on macroscopic results, later pathological findings, and positive T-SPOT.TB. The antituberculosis medications were effective, and the patient recovered and was discharged from the hospital 8 days thereafter. CONCLUSION: Patients, particularly those immunocompromised, may develop tuberculous peritonitis after conservative treatment for acute perforated appendicitis.

Helix-based screening with structure prediction using artificial intelligence has potential for the rapid development of peptide inhibitors targeting class I viral fusion.

The rapid development of drugs against emerging and re-emerging viruses is required to prevent future pandemics. However, inhibitors usually take a long time to optimize. Here, to improve the optimization step, we used two heptad repeats (HR) in the spike protein (S protein) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as a model and established a screening system for peptide-based inhibitors containing an α-helix region (SPICA). SPICA can be used to identify critical amino acid regions and evaluate the inhibitory effects of peptides as decoys. We further employed an artificial intelligence structure-prediction system (AlphaFold2) for the rapid analysis of structure-activity relationships. Here, we identified that critical amino acid regions, DVDLGD (amino acids 1163-1168 in the S protein), IQKEIDRLNE (1179-1188), and NLNESLIDL (1192-1200), played a pivotal role in SARS-CoV-2 fusion. Peptides containing these critical amino acid regions efficiently blocked viral replication. We also demonstrated that AlphaFold2 could successfully predict structures similar to the reported crystal and cryo-electron microscopy structures of the post-fusion form of the SARS-CoV-2 S protein. Notably, the predicted structures of the HR1 region and the peptide-based fusion inhibitors corresponded well with the antiviral effects of each fusion inhibitor. Thus, the combination of SPICA and AlphaFold2 is a powerful tool to design viral fusion inhibitors using only the amino-acid sequence of the fusion protein.

Helical peptides with disordered regions for measles viruses provide new generalized insights into fusion inhibitors.

Despite effective vaccines, measles virus (MeV) outbreaks occur sporadically. Therefore, developing anti-MeV agents remains important for suppressing MeV infections. We previously designed peptide-based MeV fusion inhibitors, M1 and M2, that target MeV class I fusion protein (F protein). Here, we developed a novel fusion inhibitor, MEK35, that exerts potent activity against M1/M2-resistant MeV variants. Comparing MEK35 to M1 derivatives revealed that combining disordered and helical elements was essential for overcoming M1/M2 resistance. Moreover, we propose a three-step antiviral process for peptide-based fusion inhibitors: (i) disordered peptides interact with F protein; (ii) the peptides adopt a partial helical conformation and bind to F protein through hydrophobic interactions; and (iii) subsequent interactions involving the disordered region of the peptides afford a peptide-F protein with a high-affinity peptide-F protein interaction. An M1-resistant substitution blocks the second step. These results should aid the development of novel viral fusion inhibitors targeting class I F protein.

GRL-142 binds to and impairs HIV-1 integrase nuclear localization signal and potently suppresses highly INSTI-resistant HIV-1 variants.

Nuclear localization signal (NLS) of HIV-1 integrase (IN) is implicated in nuclear import of HIV-1 preintegration complex (PIC). Here, we established a multiclass drug-resistant HIV-1 variant (HIVKGD) by consecutively exposing an HIV-1 variant to various antiretroviral agents including IN strand transfer inhibitors (INSTIs). HIVKGD was extremely susceptible to a previously reported HIV-1 protease inhibitor, GRL-142, with IC50 of 130 femtomolar. When cells were exposed to HIVKGD IN-containing recombinant HIV in the presence of GRL-142, significant decrease of unintegrated 2-LTR circular cDNA was observed, suggesting that nuclear import of PIC was severely compromised by GRL-142. X-ray crystallographic analyses revealed that GRL-142 interacts with NLS's putative sequence (DQAEHLK) and sterically blocks the nuclear transport of GRL-142-bound HIVKGD's PIC. Highly INSTI-resistant HIV-1 variants isolated from heavily INSTI-experienced patients proved to be susceptible to GRL-142, suggesting that NLS-targeting agents would serve as salvage therapy agents for highly INSTI-resistant variant-harboring individuals. The data should offer a new modality to block HIV-1 infectivity and replication and shed light on developing NLS inhibitors for AIDS therapy.

Robot-assisted low anterior resection for a rectal cancer patient with ileal conduit: A case report.

Surgery for rectal cancer patients with an ileal conduit after total cystectomy is difficult because adhesions in the pelvis and around the ileal conduit are expected. In the present case, we performed robot-assisted low anterior resection of the rectum in a 69-year-old male patient with rectal cancer who underwent ileal conduit diversion after total cystectomy. In this procedure, the port was inserted into the left upper abdomen as a first step, and two additional ports were added on the left side. Low anterior resection was performed using two left hands to create more space in the abdominal cavity for the ileal conduit. We present this minimally invasive robotic procedure that is extremely useful for dissection of adhesions in a narrow pelvic cavity.

Cardiac Rehabilitation for Patients With Stable Ischemic Heart Disease Without Revascularization　- Rationale and Design of a Single-Arm Pilot Study.

Background: Clinical practice guidelines strongly recommend optimal medical therapy (OMT), including lifestyle modification, pharmacotherapy, and exercise-based cardiac rehabilitation (CR), in patients with stable ischemic heart disease (SIHD). However, the efficacy and safety of CR in patients with SIHD without revascularization remain unclear. Methods and Results: The Prospective Registry of STable Angina RehabiliTation (Pre-START) study is a multicenter, prospective, single-arm, open-label pilot study to evaluate the efficacy and safety of CR on health-related quality of life (HRQL), exercise capacity, and clinical outcomes in Japanese patients with SIHD without revascularization. In this study, all patients will undergo guideline-based OMT and are encouraged to have 36 outpatient CR sessions within 5 months after enrollment. The primary endpoint is the change in the Seattle Angina Questionnaire-7 summary score between baseline and the 6-month visit; an improvement of ≥5 points will be defined as a clinically important change. Secondary endpoints include changes in other HRQL scores and exercise capacity between baseline and the 6-month visit, as well as clinical outcomes between enrollment and the 6-month visit. Conclusions: The Pre-START study will provide valuable evidence to elucidate the efficacy and safety of CR in patients with SIHD and indispensable information for a subsequent randomized controlled trial. The study was registered with the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (ID: UMIN000045415) on April 1, 2022.

Robot-assisted surgery for rectal cancer with solitary sacrococcygeal metastasis after neoadjuvant chemoradiotherapy: A case report.

An 81-year-old man was referred to our hospital for anal bleeding. Colonoscopy revealed a type 3 tumor at the upper rectum and biopsy showed adenocarcinoma. An enhanced circumferential lesion at the upper rectum and a solitary soft-tissue shadow at the fifth sacral vertebra to the coccyx were detected on abdominal magnetic resonance imaging. Fluorodeoxyglucose uptake was observed at the same sites on positron emission tomography. The patient was diagnosed with rectal cancer with isolated sacrococcygeal metastasis and was treated with neoadjuvant chemoradiotherapy followed by robotic surgery. Hartmann's operation was performed in the lithotomy position. The left internal iliac artery and vein were then divided. The internal pudendal artery and vein, the piriformis muscle, and sacrospinous ligament were also divided while preserving the lumbosacral trunk. The scheduled transection line of the sacral surface was fully exposed to prevent massive bleeding during sacrectomy. The dorsal surface of the sacrum was then exposed in the prone position and communicated with the pelvic space. The sacrum was transected at the superior margin of S3 and a specimen was extracted. Pathological findings revealed the infiltration of cancer cells in the sacrococcygeal specimen. The postoperative course was uneventful and the patient was discharged on postoperative day 13.

Establishing an accurate and sensitive in vitro drug screening system for human adenovirus infection with human corneal cells.

Epidemic keratoconjunctivitis (EKC) is a hazardous and highly contagious disease, with the potential to cause epidemic outbreaks in hospitals and other community settings. There are currently no approved drugs for human adenovirus (HAdV), the causative agent of EKC. To establish a novel drug screening system for ocular HAdV infections, we employed CRL11516, a non-cancerous but immortalized human corneal epithelial cell line. Brincidoforvir and 3'-deoxy-3'-fluorothymidine inhibit replication of HAdV species C type 1 (C1), C2, E4, and C6 to the same extent. This alternative assay system may allow for the evaluation of anti-HAdV activity and cell cytotoxicity of compounds within 2 days and without the need of the rabbit eye infection model.

Identification of SARS-CoV-2 Mpro inhibitors containing P1' 4-fluorobenzothiazole moiety highly active against SARS-CoV-2.

COVID-19 caused by SARS-CoV-2 has continually been serious threat to public health worldwide. While a few anti-SARS-CoV-2 therapeutics are currently available, their antiviral potency is not sufficient. Here, we identify two orally available 4-fluoro-benzothiazole-containing small molecules, TKB245 and TKB248, which specifically inhibit the enzymatic activity of main protease (Mpro) of SARS-CoV-2 and significantly more potently block the infectivity and replication of various SARS-CoV-2 strains than nirmatrelvir, molnupiravir, and ensitrelvir in cell-based assays employing various target cells. Both compounds also block the replication of Delta and Omicron variants in human-ACE2-knocked-in mice. Native mass spectrometric analysis reveals that both compounds bind to dimer Mpro, apparently promoting Mpro dimerization. X-ray crystallographic analysis shows that both compounds bind to Mpro's active-site cavity, forming a covalent bond with the catalytic amino acid Cys-145 with the 4-fluorine of the benzothiazole moiety pointed to solvent. The data suggest that TKB245 and TKB248 might serve as potential therapeutics for COVID-19 and shed light upon further optimization to develop more potent and safer anti-SARS-CoV-2 therapeutics.

Potent and biostable inhibitors of the main protease of SARS-CoV-2.

Potent and biostable inhibitors of the main protease (Mpro) of SARS-CoV-2 were designed and synthesized based on an active hit compound 5h (2). Our strategy was based not only on the introduction of fluorine atoms into the inhibitor molecule for an increase of binding affinity for the pocket of Mpro and cell membrane permeability but also on the replacement of the digestible amide bond by a surrogate structure to increase the biostability of the compounds. Compound 3 is highly potent and blocks SARS-CoV-2 infection in vitro without a viral breakthrough. The derivatives, which contain a thioamide surrogate in the P2-P1 amide bond of these compounds (2 and 3), showed remarkably preferable pharmacokinetics in mice compared with the corresponding parent compounds. These data show that compounds 3 and its biostable derivative 4 are potential drugs for treating COVID-19 and that replacement of the digestible amide bond by its thioamide surrogate structure is an effective method.

Serine hydroxymethyltransferase as a potential target of antibacterial agents acting synergistically with one-carbon metabolism-related inhibitors.

Serine hydroxymethyltransferase (SHMT) produces 5,10-methylenetetrahydrofolate (CH2-THF) from tetrahydrofolate with serine to glycine conversion. SHMT is a potential drug target in parasites, viruses and cancer. (+)-SHIN-1 was developed as a human SHMT inhibitor for cancer therapy. However, the potential of SHMT as an antibacterial target is unknown. Here, we show that (+)-SHIN-1 bacteriostatically inhibits the growth of Enterococcus faecium at a 50% effective concentration of 10-11 M and synergistically enhances the antibacterial activities of several nucleoside analogues. Our results, including crystal structure analysis, indicate that (+)-SHIN-1 binds tightly to E. faecium SHMT (efmSHMT). Two variable loops in SHMT are crucial for inhibitor binding, and serine binding to efmSHMT enhances the affinity of (+)-SHIN-1 by stabilising the loop structure of efmSHMT. The findings highlight the potency of SHMT as an antibacterial target and the possibility of developing SHMT inhibitors for treating bacterial, viral and parasitic infections and cancer.

Disseminated tuberculosis with paradoxical reactions caused by a Mycobacterium tuberculosis strain belonging to the Indo-Oceanic lineage: An imported case in Japan.

Tuberculosis remains a major public health concern. Millions of tuberculosis cases and associated deaths have been reported worldwide. The Indo-Oceanic lineage Mycobacterium tuberculosis is common in Southeast Asia and causes extrapulmonary lesions. Only a few case studies on this lineage with genetic analysis using whole-genome sequencing have been reported in the literature. We present a case of disseminated tuberculosis, characterized by a variety of extrapulmonary lesions and paradoxical reactions, caused by the Indo-Oceanic lineage M. tuberculosis in a woman in Myanmar. A 22-year-old Burmese woman had arthritis in the right knee, with unknown aetiology, and was referred to our hospital. Computed tomography of the trunk revealed multiple nodular shadows in both lungs; swollen mediastinal lymph nodes; and small, low-density areas in the spleen. M. tuberculosis was detected in the sputum sample, joint aspirate, subcutaneous tumor, and exudate. She experienced a variety of paradoxical reactions together with aggressive tuberculosis dissemination in all areas of the body. Whole-genome sequencing of the DNA of MTB obtained from sputum and the right cervical subcutaneous abscess confirmed the Indo-Oceanic lineage of M. tuberculosis, the predominant strain in Myanmar. The Indo-Oceanic lineage M. tuberculosis causes disseminated tuberculosis all over the body including the periungual region. When patients show unusual symptoms, physicians should consider the introduction of new strains from foreign countries. Genetic analyses of the strains are recommended to define and confirm the lineages.

Fluorine Modifications Contribute to Potent Antiviral Activity against Highly Drug-Resistant HIV-1 and Favorable Blood-Brain Barrier Penetration Property of Novel Central Nervous System-Targeting HIV-1 Protease Inhibitors In Vitro.

To date, there are no specific treatment regimens for HIV-1-related central nervous system (CNS) complications, such as HIV-1-associated neurocognitive disorders (HAND). Here, we report that two newly generated CNS-targeting HIV-1 protease (PR) inhibitors (PIs), GRL-08513 and GRL-08613, which have a P1-3,5-bis-fluorophenyl or P1-para-monofluorophenyl ring and P2-tetrahydropyrano-tetrahydrofuran (Tp-THF) with a sulfonamide isostere, are potent against wild-type HIV-1 strains and multiple clinically isolated HIV-1 strains (50% effective concentration [EC50]: 0.0001 to ∼0.0032 µM). As assessed with HIV-1 variants that had been selected in vitro to propagate at a 5 µM concentration of each HIV-1 PI (atazanavir, lopinavir, or amprenavir), GRL-08513 and GRL-08613 efficiently inhibited the replication of these highly PI-resistant variants (EC50: 0.003 to ∼0.006 µM). GRL-08513 and GRL-08613 also maintained their antiviral activities against HIV-2ROD as well as severely multidrug-resistant clinical HIV-1 variants. Additionally, when we assessed with the in vitro blood-brain barrier (BBB) reconstruction system, GRL-08513 and GRL-08613 showed the most promising properties of CNS penetration among the evaluated compounds, including the majority of FDA-approved combination antiretroviral therapy (cART) drugs. In the crystallographic analysis of compound-PR complexes, it was demonstrated that the Tp-THF rings at the P2 moiety of GRL-08513 and GRL-08613 form robust hydrogen bond interactions with the active site of HIV-1 PR. Furthermore, both the P1-3,5-bis-fluorophenyl- and P1-para-monofluorophenyl rings sustain greater contact surfaces and form stronger van der Waals interactions with PR than is the case with darunavir-PR complex. Taken together, these results strongly suggest that GRL-08513 and GRL-08613 have favorable features for patients infected with wild-type/multidrug-resistant HIV-1 strains and might serve as candidates for a preventive and/or therapeutic agent for HAND and other CNS complications.

Antiviral Activity and Resistance Profile of the Novel HIV-1 Non-Catalytic Site Integrase Inhibitor JTP-0157602.

HIV-1 integrase (IN) is an essential enzyme for viral replication. Non-catalytic site integrase inhibitors (NCINIs) are allosteric HIV-1 IN inhibitors and a potential new class of antiretrovirals. In this report, we identified a novel NCINI, JTP-0157602, with an original scaffold. JTP-0157602 exhibited potent antiviral activity against HIV-1 and showed a serum-shifted 90% effective concentration (EC90) of 138 nM, which is comparable to those of the FDA-approved IN strand transfer inhibitors (INSTIs). This compound was fully potent against a wide range of recombinant viruses with IN polymorphisms, including amino acids 124/125, a hot spot of IN polymorphisms. In addition, JTP-0157602 retained potent antiviral activity against a broad panel of recombinant viruses with INSTI-related resistance mutations, including multiple substitutions that emerged in clinical studies of INSTIs. Resistance selection experiments of JTP-0157602 led to the emergence of A128T and T174I mutations, which are located at the lens epithelium-derived growth factor/p75 binding pocket of IN. JTP-0157602 inhibited HIV-1 replication mainly during the late phase of the replication cycle, and HIV-1 virions produced by reactivation from HIV-1 latently infected Jurkat cells in the presence of JTP-0157602 were noninfectious. These results suggest that JTP-0157602 and analog compounds can be used to treat HIV-1 infectious diseases. IMPORTANCE Non-catalytic site integrase inhibitors (NCINIs) are allosteric HIV-1 integrase (IN) inhibitors that bind to the lens epithelium-derived growth factor (LEDGF)/p75 binding pocket of IN. NCINIs are expected to be a new class of anti-HIV-1 agents. In this study, we present a novel NCINI, JTP-0157602, which has potent activity against a broad range of HIV-1 strains with IN polymorphisms. Furthermore, JTP-0157602 shows strong antiviral activity against IN strand transfer inhibitor-resistant mutations, suggesting that JTP-0157602 and its analogs are potential agents for treating HIV-1 infections. Structural modeling indicated that JTP-0157602 binds to the LEDGF/p75 binding pocket of IN, and the results of in vitro resistance induction revealed the JTP-0157602 resistance mechanism of HIV-1. These data shed light on developing novel NCINIs that exhibit potent activity against HIV-1 with broad IN polymorphisms and multidrug-resistant HIV-1 variants.

National survey of hepatobiliary and pancreatic surgery in hemophilia patients in Japan.

BACKGROUND: Approximately 8300 hemophiliacs are registered in Japan, but no comprehensive reports on hepatobiliary and pancreatic surgery (HBPS) have been conducted. This report investigates the current status of HPBS in hemophilia patients in Japan. METHODS: The subjects were hemophiliac patients seen between January 1 2007, and December 31 2017, at facilities participating in this study among the facilities for performing high-difficulty cases nationwide designated by the Japanese Society for HBPS. A retrospective examination of short-term outcomes in 49 cases was conducted to assess patient background, disease, surgical procedure, and complications. RESULTS: The types of hemophilia were A: 43 cases, B: four cases, and von Willebrand disease: two cases (hemophilia severity: mild 32, moderate seven, severe 10). The target malignant diseases for surgery were hepatocellular carcinoma (HCC) in 20 cases, intrahepatic cholangiocellular carcinoma (CCC) in four cases, combined HCC-CCC in two cases, hilar CCC in two cases, and pancreatic cancer in four cases. As for the surgical procedure, limited resection (subsegmentectomy and partial hepatectomy) was performed in 16 cases of HCC even with normal liver function tests. Pancreaticoduodenectomy and distal pacreatectomy were performed for pancreatic cancers as in the standard procedure. Postoperative complications were postoperative bleeding in two cases after hepatectomy and one after pancreatectomy in one case. When compared with Japanese National Clinical Data base, the complication rates after hepatectomy and pancreatectomy were not conspicuous in hemophilic patients. CONCLUSIONS: As long as they are performed in qualified centers, complication rate is not increased in hemophilic patients undergoing HBPS.

Preemptive Bundle Therapy for Subclinical Pulmonary Hypertension After Liver Transplant.

OBJECTIVES: After liver transplant, veno-occlusive disease and infectious complications may result from subclinical pulmonary hypertension. In this retrospective study, we investigated whether our preemptive bundle therapy was effective for subclinical pulmonary hypertension and extrasinusoidal platelet aggregation after liver transplant. MATERIALS AND METHODS: After January 2014, nutrition therapy with glutamine, synbiotics, phosphodiesterase 3 inhibitors, prostaglandin E1, prostaglandin I2, closedloop artificial pancreas, and sivelestat has been used to reduce bacterialtranslocation, vascular endothelial cell damage, and extrasinusoidal platelet aggregation, which is administered as preemptive bundle therapy for all livertransplantrecipients. In this study, we evaluated the prognosis of 84 liver transplant recipients who underwent liver transplants through 2018. Subclinical pulmonary hypertension was evaluated in 49 adult liver transplant recipients with an evaluable main pulmonary artery trunk cross-sectional area using enhanced computed tomography in the acute phase after transplant, with 14 of these patients receiving preemptive bundle therapy. RESULTS: Subclinical pulmonary hypertension was reduced in the preemptive bundle therapy group (n = 14) compared with the nontherapy group (n = 35). The preemptive bundle therapy group showed more rapid recovery of platelet, prothrombin time, and bilirubin levels afterlivertransplant compared with the nontherapy group. The prognosis of patients in the preemptive bundle therapy group was significantly better than in the nontherapy group. Extrasinusoidal platelet aggregation was significantly lower in the preemptive bundle therapy group than in the nontherapy group. CONCLUSIONS: Preemptive bundle therapy reduced sinusoidal endothelial cell injury, extrasinusoidal platelet aggregation, and subclinical pulmonary hypertension after liver transplant, resulting in good posttransplant recovery.

Clinical features of patients with pancreatic ductal adenocarcinoma with a history of other primary malignancies: A retrospective analysis.

Patients with pancreatic ductal adenocarcinoma (PDAC) that have a history of other primary malignancies are not well documented. The current study therefore aimed to evaluate the clinicopathological characteristics of patients with PDAC with or without a history of other primary malignancies. A total of 102 patients with surgically treated PDAC that presented with or without a history of other primary malignancies were retrospectively analyzed. A total of 25 patients (24.5%) had a history of other primary malignancies (age, with history of other primary malignancy vs. without, 74.2 vs. 68.9 years; P=0.005) and the reason for consultation (P<0.001) differed significantly between the groups with a history of other primary malignancies [HoM(+)] and without a history of other primary malignancies [HoM(-)]. Incidental indications during malignancy follow-up was the most common reason for the diagnosis of PDAC in the HoM(+) group. Conversely, there were no significant differences in the resectability (P=0.645), complete resection rate (P=0.774) and final stage (P=0.474) between the two groups. Disease-free survival was also not significantly different between the two groups (P=0.184). However, overall survival was significantly poorer in the HoM(+) group compared with the HoM(-) group (P=0.003). A history of other primary malignancies was also an independent predictor of poor overall survival (hazard ratio, 2.416; 95% confidence interval, 1.324-4.406; P=0.004). In conclusion, patients with PDAC and a history of other primary malignancies had significantly poorer overall survival than their counterparts, despite no differences in disease-free survival.

Analysis of perioperative glucose metabolism using an artificial pancreas.

Hyperglycemia associated with insulin resistance is common in surgical patients with and without diabetes and is associated with poor surgical outcomes. Several studies have recently shown that a closed-loop blood glucose monitoring system in the form of an artificial pancreas is safe and effective for surgical patients. In this study, we analyzed the risk factors for insulin resistance in patients using an artificial pancreas. We investigated 109 patients who underwent surgical management by an artificial pancreas for 24 hours from the start of surgery during either major hepatectomy (MH), defined as resection of more than two liver segments, or pancreaticoduodenectomy (PD). The target glucose range was from 80 to 110 mg/dL using an artificial pancreas. We analyzed the risk factors for and predictors of a high insulin dose, including sarcopenia markers, according to the median 24-hour total insulin infusion. The median total insulin dose and glycemic control rate (GCR), which is the rate of achieving the target blood glucose range, per 24 hours were 78.0 IU and 30.4% in the MH group and 82.6 IU and 23.5% in the PD group, respectively. The muscle volume was the only independent factor in the high-dose subgroup, and the GCR was significantly lower in the high-dose subgroup despite a high insulin dose in both the MH and PD groups. The results of this study suggest that preoperative sarcopenia is closely associated with insulin resistance in the perioperative period. Clinicians must effectively manage sarcopenia, which may result in improved perioperative glycemic control and reduced postoperative complications.

A small molecule compound with an indole moiety inhibits the main protease of SARS-CoV-2 and blocks virus replication.

Except remdesivir, no specific antivirals for SARS-CoV-2 infection are currently available. Here, we characterize two small-molecule-compounds, named GRL-1720 and 5h, containing an indoline and indole moiety, respectively, which target the SARS-CoV-2 main protease (Mpro). We use VeroE6 cell-based assays with RNA-qPCR, cytopathic assays, and immunocytochemistry and show both compounds to block the infectivity of SARS-CoV-2 with EC50 values of 15 ± 4 and 4.2 ± 0.7 µM for GRL-1720 and 5h, respectively. Remdesivir permitted viral breakthrough at high concentrations; however, compound 5h completely blocks SARS-CoV-2 infection in vitro without viral breakthrough or detectable cytotoxicity. Combination of 5h and remdesivir exhibits synergism against SARS-CoV-2. Additional X-ray structural analysis show that 5h forms a covalent bond with Mpro and makes polar interactions with multiple active site amino acid residues. The present data suggest that 5h might serve as a lead Mpro inhibitor for the development of therapeutics for SARS-CoV-2 infection.

[Laparoscopy Assisted Subtotal Gastrectomy(Billrothâ Reconstruction)for Gastric Cancer in the Upper Stomach-A Report of Three Cases].

We experienced 3 cases of upper gastric cancer who underwent BillrothⅠ reconstruction in laparoscopy assisted subtotal gastrectomy. Two cases were female and 1 was male. The postoperative course was uneventful in all cases without heartburn, and the surgical margin was negative. The body weight loss rate was 5.8-12.6%, and the short-term results were relatively acceptable. Although the number of cases in this study was small, reconstruction with BillrothⅠ/delta-shaped anastomosis after laparoscopy assisted subtotal gastrectomy were considered to be useful.