The Flight Evacuation Mission for COVID-19 from Wuhan, China to Tokyo, Japan from January 28 to February 17, 2020.

Multiple countries have reported evacuation missions to repatriate their citizens in the early phase of the emergence of COVID-19 from China. However, a paucity of data exists on how to optimally execute an evacuation while balancing the risk of transmission during the flight and avoiding spread to the evacuees' home countries. We describe the collective findings of the flight evacuation mission from Wuhan, China to Tokyo, Japan from January 28 to February 17, 2020. The evacuation team established the evacuation processing flow, including a focused health questionnaire, temperature monitoring, ticketing and check-in, and boarding procedure planning. The evacuees were seated according to pre-planned zones. Additionally, to facilitate the triage of evacuees for medical needs, we conducted in-flight quarantine to determine the disposition of the evacuees. All evacuees, regardless of their health condition, were required to perform rigorous hand hygiene frequently and to wear surgical masks throughout the flight. We implemented strict infection prevention and control throughout the mission, including in-flight quarantine. The pre-planned protocol and vigilant observation during the flight were crucial elements of this mission. Our experience is of value in developing a more refined plan for the next outbreak.

Infectious Disease Emergency Specialist (IDES) Training Program in Japan: an innovative governmental challenge to respond to global public health emergencies.

In 2015, Japan created a unique governmental program to train experts in health emergencies called Infectious Disease Emergency Specialist (IDES). This is a concept paper to set out the goal and structure of the program, and to describe the achievement and the way forward to further contribute to global health security. The IDES program background, mission, structure, achievement, and future directions were reviewed and discussed by the IDES trainees, graduates, and program coordinators/supervisors. Since 2015, thirteen Japanese medical doctors have graduated from the program while five are currently in training. The IDES core competencies were identified in the context of a wide range of skillsets required for health emergencies. A large national and global network has been created through the training. Coordinated work with surge capacity of experts is of paramount importance to prepare for and respond to public health emergencies. The IDES program can be a good model to many other governments, and contribute to global health security.

Successful Treatment of Amyloid Light-chain Amyloidosis in a Charcot-Marie-Tooth Disease Patient with Lenalidomide, Cyclophosphamide, and Dexamethasone.

A 70-year-old woman with Charcot-Marie-Tooth disease (CMT) suffered from nephrotic syndrome and a renal biopsy revealed non-AA amyloid depositions that contained immunoglobulin light chain λ. Her serum λ free LC was elevated to 80.8 mg/L and she was diagnosed with primary amyloid light-chain (AL) amyloidosis. She was subsequently treated with lenalidomide, cyclophosphamide, and dexamethasone (RCD). After 14 cycles of RCD, she achieved complete remission. Her serum albumin levels gradually normalized to 3.1 g/dL. No exacerbation of neurologic symptoms related to CMT was observed. Thus, RCD may be a well-tolerated and effective regimen for treating AL amyloidosis in patients with CMT disease.

Combined use of bortezomib, cyclophosphamide, and dexamethasone induces favorable hematological and organ responses in Japanese patients with amyloid light-chain amyloidosis: a single-institution retrospective study.

Amyloid light-chain amyloidosis (ALA) is a rare disease with poor prognosis and is often associated with monoclonal gammopathy of undetermined significance, multiple myeloma, or Waldenström macroglobulinemia. Only high-dose melphalan with auto-peripheral blood stem cell transplantation (PBSCT) has shown high long-term hematological response rates, but combinations with novel agents, including bortezomib or lenalidomide, have recently shown high hematological response rates for AL amyloidosis patients. In the present study, we treated eight Japanese patients with AL amyloidosis using bortezomib, cyclophosphamide, and dexamethasone (CyBorD). Overall response rate was 100 %; four patients (50 %) had complete remissions (CR), two (25 %) had very good partial responses, and two (25 %) had partial responses. Five of six patients (83 %) had organ responses in the heart and/or kidney. A relapsed patient repeatedly achieved CR with the CyBorD treatment. One patient died of sudden cardiac arrest a month after normalization of his serum free light chain level, which may be attributable to his spending the previous 6 months undergoing PBSCT collection and high-dose melphalan with auto-PBSCT. Altogether, the CyBorD regimen achieved high levels of hematological responses relatively quickly (within 2-3 months). The CyBorD regimen, rather than high-dose melphalan treatment, could serve as a first-line therapy for Japanese patients with ALA.

Loss of the protease dimerization inhibition activity of tipranavir (TPV) and its association with the acquisition of resistance to TPV by HIV-1.

Tipranavir (TPV), a protease inhibitor (PI) inhibiting the enzymatic activity and dimerization of HIV-1 protease, exerts potent activity against multi-PI-resistant HIV-1 isolates. When a mixture of 11 multi-PI-resistant (but TPV-sensitive) clinical isolates (HIV(11MIX)), which included HIV(B) and HIV(C), was selected against TPV, HIV(11MIX) rapidly (by 10 passages [HIV(11MIX)(P10)]) acquired high-level TPV resistance and replicated at high concentrations of TPV. HIV(11MIX)(P10) contained various amino acid substitutions, including I54V and V82T. The intermolecular FRET-based HIV-1 expression assay revealed that TPV's dimerization inhibition activity against cloned HIV(B) (cHIV(B)) was substantially compromised. The introduction of I54V/V82T into wild-type cHIV(NL4-3) (cHIV(NL4-3(I54V/V82T))) did not block TPV's dimerization inhibition or confer TPV resistance. However, the introduction of I54V/V82T into cHIV(B) (cHIV(B)(I54V/V82T)) compromised TPV's dimerization inhibition and cHIV(B)(I54V/V82T) proved to be significantly TPV resistant. L24M was responsible for TPV resistance with the cHIV(C) genetic background. The introduction of L24M into cHIV(NL4-3) (cHIV(NL4-3(L24M))) interfered with TPV's dimerization inhibition, while L24M increased HIV-1's susceptibility to TPV with the HIV(NL4-3) genetic background. When selected with TPV, cHIV(NL4-3(I54V/V82T)) most readily developed TPV resistance and acquired E34D, which compromised TPV's dimerization inhibition with the HIV(NL4-3) genetic background. The present data demonstrate that certain amino acid substitutions compromise TPV's dimerization inhibition and confer TPV resistance, although the loss of TPV's dimerization inhibition is not always associated with significantly increased TPV resistance. The findings that TPV's dimerization inhibition is compromised with one or two amino acid substitutions may explain at least in part why the genetic barrier of TPV against HIV-1's development of TPV resistance is relatively low compared to that of darunavir.

Novel HIV-1 protease inhibitors (PIs) containing a bicyclic P2 functional moiety, tetrahydropyrano-tetrahydrofuran, that are potent against multi-PI-resistant HIV-1 variants.

We identified GRL-1388 and -1398, potent nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs) containing a bicyclic P2 functional moiety, tetrahydropyrano-tetrahydrofuran (Tp-THF). GRL-1388 was as potent as darunavir (DRV) against various drug-resistant HIV-1 laboratory strains with 50% effective concentration (EC(50)s) of 2.6 to 32.6 nM. GRL-1398 was significantly more potent against such variants than DRV with EC(50)s of 0.1 to 5.7 nM. GRL-1388 and -1398 were also potent against multiple-PI-resistant clinical HIV-1 variants ((CL)HIV-1(MDR)) with EC(50)s ranging from 2.7 to 21.3 nM and from 0.3 to 4.8 nM, respectively. A highly DRV-resistant HIV-1 variant selected in vitro remained susceptible to GRL-1398 with the EC(50) of 21.9 nM, while the EC(50) of DRV was 214.1 nM. When HIV-1(NL4-3) was selected with GRL-1398, four amino acid substitutions--leucine to phenylalanine at a position 10 (L10F), A28S, L33F, and M46I--emerged, ultimately enabling the virus to replicate in the presence of >1.0 µM the compound beyond 57 weeks of selection. When a mixture of 10 different (CL)HIV-1(MDR) strains was selected, the emergence of resistant variants was more substantially delayed with GRL-1398 than with GRL-1388 and DRV. Modeling analyses revealed that GRL-1398 had greater overall hydrogen bonding and hydrophobic interactions than GRL-1388 and DRV and that GRL-1388 and -1398 had hydrogen bonding interactions with the main chain of the active-site amino acids (Asp29 and Asp30) of protease. The present findings warrant that GRL-1398 be further developed as a potential drug for treating individuals with HIV-1 infection.

Synthesis and biological evaluation of novel allophenylnorstatine-based HIV-1 protease inhibitors incorporating high affinity P2-ligands.

A series of stereochemically defined cyclic ethers as P2-ligands were incorporated in an allophenylnorstatine-based isostere to provide a new series of HIV-1 protease inhibitors. Inhibitors 3b and 3c, containing conformationally constrained cyclic ethers, displayed impressive enzymatic and antiviral properties and represent promising lead compounds for further optimization.

Potent activity of a nucleoside reverse transcriptase inhibitor, 4'-ethynyl-2-fluoro-2'-deoxyadenosine, against human immunodeficiency virus type 1 infection in a model using human peripheral blood mononuclear cell-transplanted NOD/SCID Janus kinase 3 knockout mice.

4'-Ethynyl-2-fluoro-2'-deoxyadenosine (EFdA), a recently discovered nucleoside reverse transcriptase inhibitor, exhibits activity against a wide spectrum of wild-type and multidrug-resistant clinical human immunodeficiency virus type 1 (HIV-1) isolates (50% effective concentration, 0.0001 to 0.001 microM). In the present study, we used human peripheral blood mononuclear cell-transplanted, HIV-1-infected NOD/SCID/Janus kinase 3 knockout mice for in vivo evaluation of the anti-HIV activity of EFdA. Administration of EFdA decreased the replication and cytopathic effects of HIV-1 without identifiable adverse effects. In phosphate-buffered saline (PBS)-treated mice, the CD4+/CD8+ cell ratio in the spleen was low (median, 0.04; range, 0.02 to 0.49), while that in mice receiving EFdA was increased (median, 0.65; range, 0.57 to 1.43). EFdA treatment significantly suppressed the amount of HIV-1 RNA (median of 9.0 x 10(2) copies/ml [range, 8.1 x 10(2) to 1.1 x 10(3) copies/ml] versus median of 9.9 x 10(4) copies/ml [range, 8.1 x 10(2) to 1.1 x 10(3) copies/ml]; P < 0.001), the p24 level in plasma (2.5 x 10(3) pg/ml [range, 8.2 x 10(2) to 5.6 x 10(3) pg/ml] versus 2.8 x 10(2) pg/ml [range, 8.2 x 10(1) to 6.3 x 10(2) pg/ml]; P < 0.001), and the percentage of p24-expressing cells in the spleen (median of 1.90% [range, 0.33% to 3.68%] versus median of 0.11% [range, 0.00% to 1.00%]; P = 0.003) in comparison with PBS-treated mice. These data suggest that EFdA is a promising candidate for a new age of HIV-1 chemotherapy and should be developed further as a potential therapy for individuals with multidrug-resistant HIV-1 variants.

Design and synthesis of stereochemically defined novel spirocyclic P2-ligands for HIV-1 protease inhibitors.

The synthesis of a series of stereochemically defined spirocyclic compounds and their use as novel P2-ligands for HIV-1 protease inhibitors are described. The bicyclic core of the ligands was synthesized by an efficient nBu 3SnH-promoted radical cyclization of a 1,6-enyne followed by oxidative cleavage. Structure-based design, synthesis of ligands, and biological evaluations of the resulting inhibitors are reported.

Oral melphalan, dexamethasone, and thalidomide for the treatment of refractory multiple myeloma.

We present a patient with refractory multiple myeloma who showed a good response to a combination therapy with oral melphalan, dexamethasone, and thalidomide (MDT). A 48-year-old woman with myeloma refractory to thalidomide, dexamethasone, and clarithromycin received 6 mg melphalan for 4 days every 6 weeks in combination with thalidomide (100 mg daily) and dexamethasone (5 mg daily for 2 days every week). Four months after the initiation of MDT therapy, a 78% reduction of monoclonal protein was achieved. Although the efficacy of oral MDT combination therapy in elderly patients with newly diagnosed myeloma has been reported, the present data demonstrate the effectiveness of MDT therapy for refractory myeloma and warrant further exploration with this MDT regimen to treat myeloma.