Risk Factors for COVID-19 Cluster Infection in Hospitalized Patients.

Introduction In Japan, in the seventh wave of coronavirus disease 2019 (COVID-19) from July 2022 to September 2022, followed by the eighth wave of COVID-19 from November 2022 to January 2023, nosocomial clusters became more frequent in many healthcare facilities. If a cluster occurs in a hospital, the restrictions on general healthcare and the impact on hospital management, as well as the impact on community healthcare, are enormous. We analyzed the risk factors for COVID-19 cluster infection in hospitalized patients. Methods We retrospectively collected cases of COVID-19 infection among hospitalized patients in the seventh and eighth waves. The occurrence of a COVID-19 patient in a hospitalized patient was defined as one event. Results A total of 40 events were observed in the seventh and eighth waves. There were 17 events that developed into clusters. The following factors showed a significant association with cluster infection in a univariate analysis: "seventh wave," "originated from healthcare worker," and "initial examination according to contact list." The multivariate analysis revealed that "originated from healthcare worker" was independently associated with cluster infection. Conclusion Preventing the development of COVID-19 clusters is very important for nosocomial infection control. Our study suggests that COVID-19 infection in a healthcare worker is a risk factor for the development of a cluster. When healthcare workers are infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), it is often due to household transmission. Measures against household transmissions are important to prevent infection among healthcare workers.

Enhanced Orientation of Liquid Crystals Inside Micropores of Metal-Organic Frameworks Having Thermoresponsivity.

With the aim of controlling the orientation of liquid crystals (LCs) toward realizing external stimuli-responsive materials with tunable functionalities, we synthesized a composite of LCs and metal-organic frameworks (MOFs) by filling LCs into the pores of MOFs (LC@MOFs) for the first time. The included LCs interact with the MOFs through coordination bonds between the cyano groups of the LCs and the metal ions of the MOFs, enabling the orientation of the LC molecules inside the pores of the MOFs and the realization of birefringence of LC@MOFs. The three-dimensional nanometer interstice frameworks maintained the LC orientation even at temperatures much higher than the isotropic phase transition temperature of bulk LCs. Furthermore, the orientational state changed upon heating or cooling, inducing temperature-dependent birefringence. This study provides a new approach to the development of stimuli-responsive optical materials and stimuli-responsive MOFs.

Phase 2 study of ibrutinib plus venetoclax in Japanese patients with relapsed/refractory mantle cell lymphoma.

BACKGROUND: Despite high response rates to initial therapy, most patients with mantle cell lymphoma (MCL) experience relapsed or refractory (R/R) disease. Here, we report the efficacy, safety, and pharmacokinetics of the Phase 2, single-arm M20-075 study (NCT04477486) of ibrutinib and venetoclax combination therapy in Japanese patients with R/R MCL. METHODS: Patients received 560 mg ibrutinib and 400 mg venetoclax (after a 5-week ramp-up from 20 mg) once daily for up to 104 weeks. Primary endpoint was complete response (CR) rate by independent review committee (IRC). Secondary endpoints included overall response rate (ORR), duration of response (DOR), undetectable minimal residual disease (uMRD) rate, progression-free survival (PFS), overall survival (OS), safety including dose-limiting toxicity (DLT) assessment in the first six patients, and pharmacokinetic parameters. Full analysis set (FAS) comprised all treated patients. Per protocol set (PPS) excluded treated patients with non-evaluable disease at baseline by IRC. RESULTS: Thirteen patients were treated (FAS n = 13; PPS, n = 12). Median age was 71 years, patients had a median of two prior treatments. After a median follow-up of 9.6 months, IRC-assessed CR rate and ORR were both 83% (PPS). All six MRD-evaluable patients had uMRD. Median DOR, PFS, and OS were unreached. The most common Grade ≥ 3 treatment-emergent adverse event (TEAE) was neutropenia (23%); 1 patient discontinued due to squamous cell carcinoma of the lung. No DLTs, tumor lysis syndrome, or deaths related to TEAEs were observed. CONCLUSION: Ibrutinib plus venetoclax exhibited high response rates and a well-tolerated safety profile in Japanese patients with R/R MCL.

Intermediate-dose cyclophosphamide and bortezomib for PBSC mobilization in multiple myeloma.

Although the incorporation of bortezomib into induction regimens has improved response rates in patients with multiple myeloma (MM), the role of bortezomib in the peripheral blood stem cell (PBSC) mobilization remains unclear. We assessed the PBSC mobilization efficacy, safety, and disease response of intermediate-dose cyclophosphamide and bortezomib in the PBSC mobilization. Twenty-one patients with newly diagnosed MM were enrolled in a phase II, non-randomized study that used bortezomib (1.3 mg/m2/day on days 1, 4, 8, and 11) and intermediate-dose cyclophosphamide (2 g/m2/day on days 2, 3) (Bor-ID-CY). The data from 15 patients who received intermediate-dose cyclophosphamide (ID-CY) were used as a historical control group. The total CD34 + cell yield of Bor-ID-CY and ID-CY groups were not significantly different (median 6.3 ×106/kg vs. 6.5 ×106/kg, p = 0.26). All three patients with mobilization failure of two groups had t(11;14). Six patients in Bor-ID-CY group were upgraded from a status that was less than a very good partial response (VGPR) at the time of PBSC mobilization to a VGPR or better after PBSC mobilization (p = 0.014). Four patients in Bor-ID-CY group developed sepsis. The time to engraftment was similar in the two groups. The addition of bortezomib to ID-CY did not impact the stem cell yield or quality.

Fludarabine plus reduced-intensity busulfan versus fludarabine plus myeloablative busulfan in patients with non-Hodgkin lymphoma undergoing allogeneic hematopoietic cell transplantation.

Allogeneic hematopoietic cell transplantation (HCT) offers a possible cure for patients with relapsed and refractory non-Hodgkin lymphoma (NHL) through potentially beneficial graft versus lymphoma effects. However, allogeneic HCT is associated with high nonrelapse mortality (NRM). Fludarabine with reduced-intensity busulfan (Flu/Bu2) and myeloablative busulfan (Flu/Bu4) are commonly used in conditioning regimens for allogeneic HCT; however, data on their use in patients with NHL is limited. We investigated the effect of busulfan dose on outcomes by comparing Flu/Bu2 and Flu/Bu4 in patients with NHL who underwent allogeneic HCT. Our study included 415 adult patients with NHL who received Flu/Bu2 (315 patients) or Flu/Bu4 (100 patients) between January 2008 and December 2019. All patients were enrolled in the Transplant Registry Unified Management Program 2 of the Japanese Data Center for Hematopoietic Cell Transplantation. The primary endpoint was the 5-year overall survival (OS). To minimize potential confounding factors that may influence outcomes, we performed propensity score matching. The 5-year OS was 50.6% (95% confidence interval (CI), 39.4%-60.8%) and 32.2% (95% CI, 22.4-42.4%) in the Flu/Bu2 and Flu/Bu4 groups, respectively (p = 0.006). The hazard ratio comparing the two groups was 2.13 (95% CI, 1.30-3.50; p = 0.003). Both groups had a similar 5-year cumulative incidence of relapse (38.2% vs 41.3%; p = 0.581), and the Flu/Bu4 group had a higher cumulative incidence of 5-year NRM (15.7% vs 31.9%; p = 0.043). In this study, Flu/Bu4 was associated with worse OS compared with Flu/Bu2 because of high NRM in patients with NHL.

Sutimlimab provides clinically meaningful improvements in patient-reported outcomes in patients with cold agglutinin disease: Results from the randomised, placebo-controlled, Phase 3 CADENZA study.

Cold agglutinin disease (CAD) is a rare chronic autoimmune haemolytic anaemia, driven mainly by classical complement pathway activation, leading to profound fatigue and poor quality of life. In the Phase 3 CADENZA trial, sutimlimab-a C1s complement inhibitor-rapidly halted haemolysis, increased haemoglobin levels and improved fatigue versus placebo in patients with CAD without a recent history of transfusion. Patient-reported outcomes (PROs) included Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue), 12-Item Short Form Health Survey (SF-12), EuroQol visual analogue scale (EQ-VAS), Patient Global Impression of Change (PGIC) and Patient Global Impression of (fatigue) Severity (PGIS). Sutimlimab resulted in significant rapid and meaningful improvements versus placebo in PROs. From Week 1, the FACIT-Fatigue mean score increased >5 points above baseline (considered a clinically important change [CIC]). Least-squares (LS) mean change in FACIT-Fatigue score from baseline to treatment assessment timepoint was 10.8 vs. 1.9 points (sutimlimab vs. placebo; p < 0.001). Improvements in physical (PCS) and mental (MCS) component scores of the SF-12 were also considered CICs (LS mean changes from baseline to Week 26: PCS 5.54 vs. 1.57 [p = 0.064]; MCS 5.65 vs. -0.48 [p = 0.065]). These findings demonstrate that in addition to improving haematologic parameters, sutimlimab treatment demonstrates significant patient-reported benefits. Study registered at www.clinicaltrials.gov: NCT03347422.

Altered levels of salivary cytokines in patients with major depressive disorder.

OBJECTIVE: Accumulating evidence indicate the involvement of inflammation in the pathogenesis of mental disorders. Numerous studies have shown that proinflammatory cytokines were elevated in peripheral blood of patients with major depressive disorder (MDD). A few recent research have explored the possibility of using saliva as a biomarker for depressive symptoms. The objective of this study is to examine the salivary cytokine levels in patients with MDD and healthy controls. METHODS: Participants were 19 patients with MDD and 50 healthy controls. The levels of 27 cytokines in saliva were measured by multiplex bead array assay. RESULTS: The Mann-Whitney U-test showed that the levels of IL-1ß, IL-6, IL-9, IL-12p70, IL-13, Chemokine CCL11 (Eotaxin), MIP-1α, RANTES, and VEGF were significantly higher in patients than controls. The quantile regression analysis showed that IL-1ß, IL-12p70, CCL11, and VEGF remained significant after controlling for possible confounding factors. CONCLUSION: The findings were in line with previous studies that showed elevated peripheral levels of cytokines in patients with MDD. Our present data provide preliminary support for altered salivary cytokine levels in patients with MDD and suggest that salivary cytokines may serve as a novel target for elucidating the pathophysiology underlying MDD.

Sutimlimab in patients with cold agglutinin disease: results of the randomized placebo-controlled phase 3 CADENZA trial.

Sutimlimab, a first-in-class humanized immunoglobulin G4 (IgG4) monoclonal antibody that selectively inhibits the classical complement pathway at C1s, rapidly halted hemolysis in the single-arm CARDINAL study in recently transfused patients with cold agglutinin disease (CAD). CADENZA was a 26-week randomized, placebo-controlled phase 3 study to assess safety and efficacy of sutimlimab in patients with CAD without recent (within 6 months prior to enrollment) transfusion history. Forty-two patients with screening hemoglobin ≤10 g/dL, elevated bilirubin, and ≥1 CAD symptom received sutimlimab (n = 22) or placebo (n = 20) on days 0 and 7 and then biweekly. Composite primary endpoint criteria (hemoglobin increase ≥1.5 g/dL at treatment assessment timepoint [mean of weeks 23, 25, 26], avoidance of transfusion, and study-prohibited CAD therapy [weeks 5-26]) were met by 16 patients (73%) on sutimlimab, and 3 patients (15%) on placebo (odds ratio, 15.9 [95% confidence interval, 2.9, 88.0; P < .001]). Sutimlimab, but not placebo, significantly increased mean hemoglobin and FACIT-Fatigue scores at treatment assessment timepoint. Sutimlimab normalized mean bilirubin by week 1. Improvements correlated with near-complete inhibition of the classical complement pathway (2.3% mean activity at week 1) and C4 normalization. Twenty-one (96%) sutimlimab patients and 20 (100%) placebo patients experienced ≥1 treatment-emergent adverse event. Headache, hypertension, rhinitis, Raynaud phenomenon, and acrocyanosis were more frequent with sutimlimab vs placebo, with a difference of ≥3 patients between groups. Three sutimlimab patients discontinued owing to adverse events; no placebo patients discontinued. These data demonstrate that sutimlimab has potential to be an important advancement in the treatment of CAD. This trial was registered at www.clinicaltrials.gov as #NCT03347422.

Efficacy and safety of Wilms' tumor 1 helper peptide OCV-501 in elderly patients with acute myeloid leukemia: a multicenter, randomized, double-blind, placebo-controlled phase 2 trial.

PURPOSE: Complete remission (CR) of acute myeloid leukemia (AML) in elderly patients has a short duration, and there is no suitable post-remission therapy. We explored the role of the Wilms' tumor 1 helper peptide OCV-501 to prevent recurrence after remission. METHODS: This placebo-controlled phase 2 study was designed to evaluate accurately the efficacy and immunogenicity of OCV-501 in elderly AML patients. Elderly AML patients who achieved first CR were randomly allocated to receive either OCV-501 (N = 69) or placebo (N = 65) once a week for eight weeks and then every two weeks until week 104. The primary endpoint was disease-free survival (DFS). RESULTS: Nineteen (27.5%) patients in the OCV-501 group and 23 (35.4%) patients in the placebo group completed the study without relapse. The median DFS in the OCV-501 and placebo groups was 12.1 and 8.4 months, respectively (p = 0.7671, hazard ratio [95% confidence interval]: 0.933 [0.590, 1.477]). The major drug adverse reactions were injection-site reactions. Although treatment with OCV-501 did not prolong DFS for elderly AML patients, post hoc analysis found that immune responders to OCV-501 whose specific IgG was > 10,000 ng/mL (N = 16) and whose WT1-specific interferon-γ response was > 10 pg/mL (N = 26) had significantly longer overall survival compared with placebo. CONCLUSIONS: The placebo-controlled design of this study and quantitative immunological monitoring provides new insight into the relationship between peptide-induced immune responses and survival, suggesting future perspectives for cancer immunotherapy.

Impact of short-term storage of plasma samples on quantitation of ultra-low levels of interleukin-6.

OBJECTIVE: To quantitate plasma interleukin-6 (IL-6) levels in healthy individuals and to clarify how these levels are affected by blood sample handling procedures during short-term storage. METHODS: Ethylenediaminetetraacetic acid (EDTA)-treated plasma samples were simultaneously collected from 14 healthy individuals and stored on ice prior to analysis of the IL-6 levels. White blood cells (WBCs), red blood cells, and platelets were counted immediately after blood collection. IL-6 levels were analyzed every 30 minutes using a commercial electrochemiluminescence immunoassay. RESULTS: Correlation coefficients between plasma IL-6 levels and WBC counts ranged between 0.605 and 0.554, higher than those for other cell types. The lowest IL-6 value in healthy individuals was estimated at 0.04 pg/mL and the mean values remained under 2 pg/mL over time. CONCLUSION: Analysis of IL-6 levels in EDTA-treated plasma samples centrifuged within 1 hour and stored on ice can be performed within 90 minutes of short-term storage if the analytical method has a sensitivity in the range of 10 fg/mL.

Possible utilization of salivary IFN-γ/IL-4 ratio as a marker of chronic stress in healthy individuals.

INTRODUCTION: Several studies show that psychological stress reduces Th1/Th2 ratio in blood samples. However, evidence is scarce regarding the cytokine alterations during stress in saliva. We investigated the influence of chronic stress on Th1/Th2 ratio and cytokine profiles in the saliva of healthy individuals. Further, we examined the associations of the salivary cytokine levels with sleep and attention problems, which are closely related with psychological stress. METHODS: Salivary levels of 27 cytokines were measured by multiplex bead array assays in 31 healthy young individuals (health science students and hospital staff consisting of 11 men and 20 women, mean age [standard deviation] =21.5 [0.8] years). The Kessler Psychological Distress scale (K10) and Athens Insomnia Scale (AIS) were administered to assess subjective chronic psychological stress and sleep problems. Further, participants were asked to wear Actigraph GT3X accelerometers for 3 days to assess the total sleep time. Attention problems were assessed by administering the Integrated Visual and Auditory Continuous Performance Test (IVA-CPT). RESULTS: Thirteen cytokines with >80% detectable results were included in the main analyses. The IFN-γ/IL-4 ratio, which is a commonly used index for Th1/Th2 ratio, showed significant negative correlations with the K10 and AIS scores. None of the cytokines were significantly associated with sex, body mass index, sleep index measured by Actigraph, or IVA-CPT scores. CONCLUSION: Chronic stress may be associated with alterations of the Th1/Th2 balance in salivary cytokine production. IFN-γ/IL-4 ratio in saliva may serve as a potential biomarker of chronic stress in healthy individuals.

Gene rearrangements of MLL and RUNX1 sporadically occur in normal CD34+ cells under cytokine stimulation.

Gene rearrangements of MLL/KMT2A or RUNX1 are the major cause of therapy-related leukemia. Moreover, MLL rearrangements are the major cause of infant leukemia, and RUNX1 rearrangements are frequently detected in cord blood. These genes are sensitive to topoisomerase II inhibitors, and various genes have been identified as potential fusion partners. However, fetal exposure to these inhibitors is rare. Therefore, we postulated that even a proliferation signal itself might induce gene rearrangements in hematopoietic stem cells. To test this hypothesis, we detected gene rearrangements in etoposide-treated or non-treated CD34+ cells cultured with cytokines using inverse PCR. In the etoposide-treated cells, variable-sized rearrangement bands were detected in the RUNX1 and MLL genes at 3 hours of culture, which decreased after 7 days. However, more rearrangement bands were detected in the non-treated cells at 7 days of culture. Such gene rearrangements were also detected in peripheral blood stem cells mobilized by cytokines for transplantation. However, none of these rearranged genes encoded the leukemogenic oncogene, and the cells with rearrangements did not expand. These findings suggest that MLL and RUNX1 rearrangements, which occur with very low frequency in normal hematopoietic progenitor cells, may be induced under cytokine stimulation. Most of the cells with gene rearrangements are likely eliminated, except for leukemia-associated gene rearrangements, resulting in the low prevalence of leukemia development.

Microfabrication of re-entrant surface with hydrophobicity/oleophobicity for liquid foods.

Re-entrant texturing may potentially improve the hydrophobicity and oleophobicity of a surface. The food industry requires a microfabrication method to keep surfaces clean without leaving a packaging residue for applications such as food bottles, food containers, and preservation bags. The goal of this study is thus to establish a microfabrication method for re-entrant texturing with spherical curvature to produce hydrophobic/oleophobic surfaces for liquid foods, such as soy sauce and canola oil. Samples with a spherical curvature are created from an ultra-violet-cure (UV-cure) resin and poly (tetrafluoroethylene) (PTFE) microbeads with diameters between 2.26 to 1,353 microns by spin coating on a glass substrate. The resin thickness, the mass and diameter of the microbeads, and the spin coater rotation speed are used as the microfabrication parameters. A side view of samples showing the spherical curvature reveals that a re-entrant texture indeed forms. Distilled water, soy sauce, and canola oil are dropped softly onto the re-entrant surface, however, the droplets cannot be placed stably. For appropriate microbead diameters, the apparent contact angles of soy sauce and canola oil showed 130.2 and 119.4 degrees, respectively. This facile fabrication method for re-entrant surfaces could prove useful for generating hydrophobic/oleophobic surfaces for Newtonian liquid foods.

Evaluation of a biosimilar granulocyte colony-stimulating factor for peripheral blood stem cell mobilization in Japanese healthy donors: a prospective study.

A "biosimilar" is a biotechnological product with a lower cost profile and equivalent efficacy and safety to the originator, but post-marketing clinical evaluation of biosimilar products has not been adequately conducted. We prospectively investigated the utility of biosimilar filgrastim in 13 peripheral blood stem cell (PBSC) donors from June 2014 to January 2017. In addition, we retrospectively compared these to another 13 PBSC donors mobilized with the originator filgrastim in the same period. Donor characteristics were equivalent between the groups. The median number of CD34+ cells per donor body weight (BW) and blood volume processed (BV) were 4.87 × 106/kg and 25.5 × 103/mL in the biosimilar group and 4.93 × 106/kg and 16.6 × 103/mL in the originator group, respectively. There were no significant differences between the groups in the number of CD34+ cells per donor BW or BV. All adverse events associated with G-CSF were permissive. The total G-CSF cost was significantly lower in the biosimilar group than in the originator group. These findings suggest that biosimilar filgrastim has the same efficacy and short-term safety as originator filgrastim for PBSC mobilization in healthy donors, with economic superiority. Longer follow-up studies are needed to evaluate the incidence of long-term adverse events.

Motion analysis of operating a balance exercise assist robot system during forward and backward movements.

[Purpose] Stand-and-ride personal mobility devices controlled by movements of the user's center of gravity are used for balance training. We aimed to describe the physical activity required to operate this type of mobility device. [Participants and Methods] Eleven healthy males performed the following tasks: 1) moving their center of gravity forward or backward while standing on the floor (control task) and, 2) moving the mobility device forward or backward by moving their center of gravity (experimental task). [Results] We observed that the displacement of the center of gravity and the center of pressure, as well as angular displacements of the hips and knee joints, and maximum muscle activities of the biceps femoris, the medial head of the gastrocnemius and peroneus longus muscles were lesser during the experimental than during the control task. The distance moved by the device was significantly greater than the displacement of the user's center of gravity during the experimental task. [Conclusion] We observed that moving the device forward or backward required lesser physical activity than that required to shift the user's center of gravity forward or backward while standing on the floor. Additionally, we observed that even a small displacement of the user's center of gravity produced a large displacement of the device. We concluded that during balance training, the greater and more easily perceived movement of the mobility device would provide helpful feedback to the user.

[Mild hemophilia A diagnosed in an adult patient on the occasion of post-operative bleeding following a second knee surgery].

A 48-year-old male underwent an osteosynthesis surgery for right patellar fracture without bleeding episodes around the surgery. After 7 months, he presented with a bleeding episode after a nail extraction surgery from his knee joint. He was diagnosed with mild hemophilia A after his second surgery. The patient's clinical course suggested that he had mild hemophilia A, although he had a past surgical history without any bleeding episodes. Early diagnosis is important in patients with mild hemophilia A because bleeding episodes complicated with surgery can be prevented by the administration of prophylactic replacement therapy.

Microcapsule-Based Signal Amplification Method for Biomolecules.

The direct signal amplification of target molecules could be an effective means of increasing the sensitivity and reducing the size of biosensors. The purpose of this study was to propose a novel signal amplification method suitable for the detection of biomolecules using microcapsules that can quickly respond to concentration variation. This microcapsule-based amplification method consists of two elements-microcapsules and a well-array. The microcapsules consist of (i) an inner shell fabricated through layer-by-layer assembly, (ii) a lipid bilayer, and (iii) loaded target molecules. In this method, the inner surface of the well-array was modified using TiO2 as a photocatalyst. The diameter and thickness of the fabricated micro-capsules for biomarker loading were shown to be 2.7 µm and 78 nm, respectively. An ultraviolet (UV) irradiation time of 5 min was needed when the change in optical density reached 90% saturation of the optical density change. Dye molecules were incorporated into the microcapsules and were subsequently released, and the concentration of the released solution changed in proportion with the encapsulated dye concentration. This demonstrates the proof of concept for this novel signal amplification method based on microcapsules.

Osteosarcoma Manifesting Systemic Inflammation and Histological Features Mimicking Plasma Cell-type Castleman Disease.

A 73-year-old man was referred to our hospital with a persistent fever, anemia, and a mass in the left pubic region. The findings of biopsy evaluations of the mass and a left inguinal lymph node were consistent with Castleman disease (CD) of plasma cell type. His serum interleukin 6 (IL-6) level was remarkably elevated, supporting the diagnosis of CD. However, imaging analyses revealed destruction of the pubic bone by the mass, which was atypical for CD. Therefore, another deeper biopsy was performed, which finally led to the diagnosis of IL-6-producing osteosarcoma. We conclude that clinicians should carefully exclude malignancies prior to making a CD diagnosis.

Magnetically triggered transgene expression in mammalian cells by localized cellular heating of magnetic nanoparticles.

To develop a remote control system of transgene expression through localized cellular heating of magnetic nanoparticles, a heat-inducible transgene expression system was introduced into mammalian cells. Cells were labeled with magnetic nanoparticles and exposed to an alternating magnetic field. The magnetically labeled cells expressed the transgene in a monolayer and multilayered cell sheets in which cells were heated around the magnetic nanoparticles without an apparent temperature increase in the culture medium. Magnetic cells were also generated by genetically engineering with a ferritin gene, and transgene expression could be induced by exposure to an alternating magnetic field. This approach may be applicable to the development of novel gene therapies in cell-based medicine.