Detailed Changes in Oxygenation following Awake Prone Positioning for Non-Intubated Patients with COVID-19 and Hypoxemic Respiratory Failure-A Historical Cohort Study.

Few studies have reported on the effectiveness of awake prone therapy in the clinical course of coronavirus disease (COVID-19) patients. This study aimed to investigate the effects of awake prone therapy during spontaneous breathing on the improvement of oxygenation over 3 weeks for COVID-19 acute respiratory failure. Data of consecutive COVID-19 patients with lung disorder with a fraction of inspired oxygen (FIO2) ≥ 0.4 and without tracheal intubation were analyzed. We examined changes in SpO2/FIO2, ROX index ((SpO2/FIO2)/respiratory rate) and the seven-category ordinal scale after the initiation of FIO2 ≥ 0.4 and compared these changes between patients who did and did not receive prone therapy. Of 58 patients, 27 received awake prone therapy, while 31 did not. Trend relationships between time course and change in SpO2/FIO2 and ROX index were observed in both groups, although a significant interaction in the relationship was noted between prone therapy and change in SpO2/FIO2 and ROX index. The seven-category ordinal scale also revealed a trend relationship with time course in the prone therapy group. The awake prone therapy was significantly associated with a lower rate of tracheal intubation. In patients with COVID-19 pneumonia treated with FIO2 ≥ 0.4, awake prone therapy may improve oxygenation within two weeks.

Impact of tissue properties on time-dependent alterations in apparent diffusion coefficient: a phantom study using oscillating-gradient spin-echo and pulsed-gradient spin-echo sequences.

PURPOSE: The purpose of this study was to investigate whether the changes in apparent diffusion coefficients (ADCs) due to differences in diffusion time reflect tissue properties in actual measurements of phantoms. MATERIALS AND METHODS: Various n-alkane phantoms and sucrose/collagen phantoms with various collagen densities were set up with and without polyvinyl alcohol (PVA) foam with an average pore diameter of 300 µm. Thus, n-alkanes or sucrose/collagen represented substrate viscosity and the presence of PVA foam represented tissue structure with septum. Diffusion-weighted images with various diffusion times (7.71-60 ms) were acquired using pulsed-gradient spin-echo (PGSE) and oscillating-gradient spin-echo (OGSE) sequences. The ADCs of the phantoms with and without PVA foam were calculated. RESULTS: The ADCs of some of the phantoms without PVA decreased with diffusion times decreased. In the n-alkane phantoms, only C8H18 showed significantly different ADCs depending on the use of PVA foam in the OGSE sequence. On the other hand, sucrose/collagen phantoms showed significant differences according to diffusion time. The ADCs of the phantoms decreased as the molecular size of the n-alkanes or collagen density of the sucrose/collagen phantom increased. Compared to phantoms without PVA foam, the ADC of the phantoms with PVA foam decreased as the diffusion time increased. CONCLUSION: Changes in ADCs due to differences in diffusion time reflect tissue properties in actual measurements of phantoms. These changes in ADCs can be used for tissue characterization in vivo.

Diffusion-weighted image analysis along the perivascular space (DWI-ALPS) for evaluating interstitial fluid status: age dependence in normal subjects.

PURPOSE: The purpose of this study was to evaluate the interstitial fluid status in a wide range of age groups using diffusion-weighted image analysis along the perivascular space (DWI-ALPS) method, which is a simplified variation of diffusion tensor image analysis along the perivascular space (DTI-ALPS). MATERIALS AND METHODS: This retrospective study included data from 128 patients who underwent clinical magnetic resonance imaging (MRI) studies, including DWI, and were found to have no abnormal findings in the brain on MRI. Three motion-probing gradients of the DWI were applied in an orthogonal direction to the imaging plane. Apparent diffusion coefficient images in the x-, y-, and z-axes were retrospectively generated, and composite color images were created to locate the projection and association fiber area on the slice including the body of the lateral ventricle. ALPS indices were calculated, and correlations with age were evaluated using linear and second-degree regression analysis. Linear regression analysis was also performed for a subgroup of patients older than 40 years. In addition, an analysis of variance (ANOVA) test among the generations was performed. RESULTS: The linear regression analysis between age and the ALPS index showed a correlation coefficient of -0.20 for all age group and -0.51 for the subgroup older than 40 years. The second-degree regression analysis showed a correlation coefficient of 0.39. ANOVA showed that the 40's generation showed a statistically significant higher value of ALPS index compared to all other generations except for the 30's generation. While, the 70's generation showed a statistically significant lower value of the ALPS index compared to all other generations. CONCLUSIONS: The analysis of the DWI-APLS method showed a correlation between age and the ALPS index in second-degree distribution which peaked in the 40's generation. This finding in normal subjects may be fundamental in the analysis of disease cases. We tried to evaluate the glymphatic system status in a wide range of age groups using diffusion-weighted image analysis along the perivascular space (DWI-ALPS) method, and the results showed a correlation between age and the ALPS index in second-degree distribution which peaked in the 40's generation.

MR Imaging of Endolymphatic Hydrops in Five Minutes.

In this study, we present images acquired by a fast-imaging method for the evaluation of endolymphatic hydrops after intravenous administration of a single dose of gadolinium-based contrast agent. We utilized the hybrid of reversed image of MR cisternography and a positive perilymph signal by heavily T2- weighted 3D-fluid attenuated inversion recovery-multiplied by T2 (HYDROPS2-Mi2) method combined with deep learning reconstruction denoising. The scan time for the fast protocol was approximately 5 mins, which is far shorter than previously reported scan times. The fast acquisition provides similar image quality and less motion artifacts compared to the longer method.

Reproducibility of diffusion tensor image analysis along the perivascular space (DTI-ALPS) for evaluating interstitial fluid diffusivity and glymphatic function: CHanges in Alps index on Multiple conditiON acquIsition eXperiment (CHAMONIX) study.

PURPOSE: The diffusion tensor image analysis along the perivascular space (DTI-ALPS) method was developed to evaluate the brain's glymphatic function or interstitial fluid dynamics. This study aimed to evaluate the reproducibility of the DTI-ALPS method and the effect of modifications in the imaging method and data evaluation. MATERIALS AND METHODS: Seven healthy volunteers were enrolled in this study. Image acquisition was performed for this test-retest study using a fixed imaging sequence and modified imaging methods which included the placement of region of interest (ROI), imaging plane, head position, averaging, number of motion-proving gradients, echo time (TE), and a different scanner. The ALPS-index values were evaluated for the change of conditions listed above. RESULTS: This test-retest study by a fixed imaging sequence showed very high reproducibility (intraclass coefficient = 0.828) for the ALPS-index value. The bilateral ROI placement showed higher reproducibility. The number of averaging and the difference of the scanner did not influence the ALPS-index values. However, modification of the imaging plane and head position impaired reproducibility, and the number of motion-proving gradients affected the ALPS-index value. The ALPS-index values from 12-axis DTI and 3-axis diffusion-weighted image (DWI) showed good correlation (r = 0.86). Also, a shorter TE resulted in a larger value of the ALPS-index. CONCLUSION: ALPS index was robust under the fixed imaging method even when different scanners were used. ALPS index was influenced by the imaging plane, the number of motion-proving gradient axes, and TE in the imaging sequence. These factors should be uniformed in the planning ALPS method studies. The possibility to develop a 3-axis DWI-ALPS method using three axes of the motion-proving gradient was also suggested.

Use of electrical muscle stimulation body massager (EMS-BMs) improves deep venous blood flow.

We investigated whether using electrical muscle stimulation body massagers (EMS-BMs) for the passive contraction of the lower extremity muscles reduces venous stasis in the deep veins of the lower extremities. In this randomized crossover design study of 20 healthy volunteers between November 2018 and February 2019, we measured both the popliteal and femoral vein peak velocities (PV, cm/s) and blood flow volumes (BFV,mL/min), using pulsed-wave Doppler ultrasound at rest (baseline), and at 2 and 10 min after starting EMS-BM use. Two EMS types: types A (two small pads) and B (one large pad) devices respectively, were examined. The PVs of the femoral (A: 23±7, B: 25±8) and popliteal (A: 26±12, B: 27±12) veins and BFV of types A (107±46) and B (141±88) of the femoral vein were significantly increased compared to the baseline (PV of femoral vein: 19±9, PV of popliteal vein: 14±5, BFV of popliteal vein: 81±46) (P<0.01). No significant differences occurred between the devices in the PV or BFV at either 2 or 10 min. Regardless of the type of stimulation or the shape of the pad, contraction of the lower limb muscles by EMS-BM effectively reduces venous stasis in the lower limb.

Diffusion analysis of fluid dynamics with incremental strength of motion proving gradient (DANDYISM) to evaluate cerebrospinal fluid dynamics.

PURPOSE: To visualize and analyze the dynamics of cerebrospinal fluid (CSF) motion in the cranium, we evaluated the distribution of motion-related signal dephasing by CSF on Diffusion ANalysis of fluid DYnamics with Incremental Strength of Motion proving gradient (DANDYISM) method, a composite imaging method using various low b values. MATERIALS AND METHODS: This study examined ten subjects aged 25-58. We acquired DWIs on a 3T clinical scanner with b values 0, 50, 100, 200, 300, 500, 700, and 1000 s/mm2 in total imaging time of 4 min. We constructed DANDYISM images and evaluated the CSF area distribution with decreased motion-dephasing signal using a scoring method. RESULTS: The DANDYISM images showed statistically significant higher CSF scores in the ventral posterior fossa, suprasellar cistern, and Sylvian vallecula compared to the lateral ventricle and frontal and parietal CSF spaces, indicating greater CSF movement in the former areas. CONCLUSION: The results indicated prominent CSF motions in the ventral portion of the posterior fossa, suprasellar cistern, and Sylvian fissure but smaller motions in the lateral ventricles and parietal subarachnoid space. This method may provide information of CSF dynamics in the clinical settings within short imaging time.

Preoperative sepsis is a predictive factor for 30-day mortality after major lower limb amputation among patients with arteriosclerosis obliterans and diabetes.

BACKGROUND: While many patients with lower limb ischemia also have severe infections, few studies have investigated whether the presence of preoperative sepsis affects patient prognosis following lower limb amputation (LLA). Therefore, we investigated the factors (including sepsis as defined in SEPSIS-3) that contribute to the acute mortality rate in patients who underwent LLA due to arteriosclerosis obliterans (ASO) or diabetes mellitus (DM). METHODS: In this retrospective, single-center, 10-year chart review study, 122 adult patients who underwent LLA due to ASO and/or DM were identified from 56,438 surgery cases. Patient characteristics, including co-morbidities, surgical conditions, the presence/absence of sepsis, and acute physiological condition after surgery, were investigated in patients who died within 30 days of LLA and those who survived. Univariate analysis between groups was performed using the chi-square test. Comparisons of age and American Society of Anesthesiologists-Physical Status classification between groups were performed using the Mann-Whitney U test. Risk factors for 30-day mortality after LLA were examined using stepwise logistic regression (backward elimination). Statistical results were considered significant at P < 0.05. RESULTS: Eight cases of mortality (6.6%) were found; we identified the causes as sepsis, myocardial infarction, fatal arrhythmia, and mesenteric artery occlusive disease in 5 (62.5%), 1 (12.5%), 1 (12.5%), and 1 (12.5%) cases, respectively. Using univariate analysis, we identified that age (≥74), delirium, sepsis, intensive care unit admission, non-DM (ASO only), hemodialysis, and acute kidney injury were significantly higher in the mortality group. In logistic regression analysis, non-DM (odds ratio [OR]: 35.2, 95% confidence interval [CI]: 2.8-432) and sepsis (OR: 80.7, 95% CI: 6.7-959) were potential risk factors for 30-day mortality. CONCLUSIONS: This study suggests that cases resulting in amputation due to ASO pathology alone might have poor prognosis and that preoperative sepsis can increase perioperative mortality; hence, the decision to amputate must be considered before the development of sepsis.

Excellent Islet Yields after 18-h Porcine Pancreas Preservation by Ductal Injection, Pancreas Preservation with MK Solution, Bottle Purification, and Islet Purification Using Iodixanol with UW Solution and Iodixanol with MK Solution.

Successful islet isolation is the key to successful islet transplantation. Our group recently modified the islet isolation protocol to include pancreatic ductal injection of the preservation solution, pancreas storage in modified extracellular-type trehalose-containing Kyoto (MK) solution, and use of an iodixanol-based purification solution and bottle purification. In this study, we applied these methods to porcine islet isolation after 18-h pancreas preservation and compared two solutions with different compositions in bottle purification. Islet yield before purification was 651,661 ± 157,719 islet equivalents (IE) and 5576 ± 1538 IE/g pancreas weight. An IU solution was made by adding iodixanol to University of Wisconsin solution and an IK solution was made by adding iodixanol to MK solution. The efficacy of the two solutions for islet isolation was compared. There were no significant differences between the two purification methods with regard to islet yield, survival rate, purity, score, or stimulation index. These results indicate that our isolation protocol produces efficient islet yields from prolonged cold-stored pancreas and that IU and IK solutions are equally useful for islet purification.

[Anesthetic Management of Laparoscopic Cholecystectomy in a Patient with Mitochondrial Encephalomyopathy].

We report the anesthetic management during the laparoscopic cholecystectomy in a 60-year-old woman (height 150 cm, 'Weight 46 kg) with mitochondrial encephalopathy (chronic progressive external ophthal- moplegia, or CPEO). CPEO causes a disorder of aero- bic energy metabolism in various organs due to mito- chondrial dysfunction. It is thus very important in anesthetic management to maintain energy balance of demand and supply in organs and to protect the patient's respiratory muscles. Our patient had devel- oped CPEO 46 years earlier, and at her presentation she was bedridden and receiving both respiratory assistance via tracheostomy and tube feeding. Her hearing and understanding were intact, but she was blind due to lagophthalmos. We performed intravenous anesthesia with propofol (TCI) and remifentanil com- bined with epidural anesthesia. Rocuronium was injected under a train-of-four (TOF) monitoring. The operative time for the laparoscopic cholecystectomy was 4 hours. A total of 50 mg of rocuronium and 2,050 ml of bicarbonic ringer was injected during the opera- tion. The patient's blood lactate and glucose remained at normal levels throughout the operation. Because of severe adhesion, the laparoscopic procedure was changed to a laparotomy. However, during the peri-and post-operative periods, epidural anesthesia was valuable for analgesia during the management of the patient's respiratory care with a decreasing amount of narcotic medication. Post-operatively, the patient was monitored in an intensive care unit with the spontaneous respira- tory rate of 15 · min⁻¹ under oxygen 1l without any analgesics. The day after the operation she was returned to the ward, as her general condition was satisfactory.

Fever-range whole-body heat treatment stimulates antigen-specific T-cell responses in humans.

Increase in body temperature has been thought to play an important role in the regulation of immune responses, although its precise mechanisms are still under investigation. Here, we examined the effects of physiologically relevant thermal stress on the cytokine production from human peripheral T cells. Volunteers were heated using a whole-body hyperthermia device, the rectal temperature was maintained above 38.5 °C for more than 60 min, and peripheral blood mononuclear cells (PBMCs) were obtained before and after the treatment. When T cells were stimulated with anti-CD3/CD28 antibodies, marked increases in the production of interferon-γ (IFN-γ) and interleukin-2 were observed in PBMCs prepared immediately after and 24h after the treatment. Similarly, enhanced production of IFN-γ in response to the tuberculin purified protein derivative or antigenic viral peptides was also observed immediately after and 24h after the treatment. Fluorescence photo-bleaching analyses showed heat-induced increase of membrane fluidity in T cells, which probably enables them to induce rapid and efficient cluster formation of molecules involved in antigen recognition and signal transduction for T-cell stimulation. We concluded that physiologically relevant thermal stress could efficiently modify T-cell responsiveness to various stimuli, including enhanced responses to specific antigens.

[Anesthetic management of posterior lumbar spinal fusion in a patient suspected of having acute exacerbation of chronic interstitial pneumonia].

A patient complicated with interstitial pneumonia required emergency posterior lumbar spinal fusion. The blood gas analysis showed relatively benign values (PaO2 81 torr, PaCO2 44 torr, under room air), but the honeycombing lungs were noted in the bilateral lung fields on CT, and the KL-6 level was high (1,000 U x ml(-1)), for which the acute exacerbation of interstitial pneumonia was suspected. Sivelestat sodium administration was initiated during the surgery and continued postoperatively. During surgery, setting the FIO2 at 0.34, the P/F ratio and intra-airway pressure could be maintained at 500 and 25 mmHg, respectively. To reduce postoperative respiratory complication, anesthesia was maintained with desflurane, which is dissipated easily, and 0.5% ropivacaine 15 ml was subcutaneously injected to the surgical field at the time of wound closure to reduce the total doses of intraoperative fentanyl and postoperative analgesics. After the completion of surgery, the endotracheal tube was removed with head elevated position, and the patient was transported back to the ward. No acute exacerbation occurred thereafter, and the patient was discharged 67 days after surgery. The prediction of acute exacerbation of interstitial pneumonia is difficult. Moreover, there is no established preventive method, although the mortality is high. Therefore, physicians should be thoroughly informed about the currently available evidence, including developmental factors.

Analysis of cytotoxic T lymphocytes from a patient with hepatocellular carcinoma who showed a clinical response to vaccination with a glypican­3­derived peptide.

Glypican-3 (GPC3), which is a carcinoembryonic antigen, is overexpressed in human hepatocellular carcinoma (HCC). Previously, we performed a phase I clinical trial of GPC3­derived peptide vaccination in patients with advanced HCC, and reported that GPC3 peptide vaccination is safe and has clinical efficacy. Moreover, we proposed that a peptide­specific CTL response is a predictive marker of overall survival in patients with HCC who receive peptide vaccination. In this study, we established GPC3­derived peptide-specific CTL clones from the PBMCs of an HLA-A*02:07-positive patient with HCC who was vaccinated with an HLA-A2-restricted GPC3 peptide vaccine and showed a clinical response in the phase I clinical trial. Established CTL clones were analyzed using the IFN-γ ELISPOT assay and a cytotoxicity assay. GPC3 peptide-specific CTL clones were established successfully from the PBMCs of the patient. One CTL clone showed cytotoxicity against cancer cell lines that expressed endogenously the GPC3 peptide. The results suggest that CTLs have high avidity, and that natural antigen-specific killing activity against tumor cells can be induced in a patient with HCC who shows a clinical response to vaccination with the GPC3144-152 peptide.

[Induction of human dendritic cells from peripheral blood mononuclear cells by using a HydroCellTM].

Cancer immunotherapy using dendritic cells (DCs) is widely known to produce an anticancer effects. However, there is no approved DC vaccine in Japan, possibly because the culture and harvesting of DC is complicated. To further enable DC vaccine therapy, an easier, safer, and inexpensive culture system is needed, and we therefore aimed to build an automated DC culture system. In a previous study using a HydroCellTM, we successfully cultured and harvested DCs from peripheral blood monocytes without using enzymes, and showed that HydroCellTM is a useful tool for automated DC culture. In this study, we performed a similar process of DC culture from peripheral blood mononuclear cells and demonstrated the safe and easy culturing and harvesting of DCs. Furthermore, CD83-positive mature DCs were increased compared to the usual plate method. These results demonstrate the utility of HydroCellTM as an automated DC culture system.

A glypican-3-derived peptide vaccine against hepatocellular carcinoma.

The results of a Phase I clinical trial in which a glypican-3 (GPC3)-derived peptide was tested in advanced hepatocellular carcinoma patients point to a strong correlation between immunological and clinical responses. This commentary reviews our fundamental studies and clinical trials on the GPC3-derived peptide vaccine.

[In vitro culture of human dendritic cells by using a HydroCell™].

Cancer Immunotherapy using dendritic cells would be a feasible and useful tool for cancer treatment. However, no immunotherapy has been approved in Japan because of a lack of any randomized clinical studies. We are now trying to develop an automatic dendritic cell culture system in order to perform a large-scale randomized clinical trial. In this study, we investigated the utility of a HydroCell™ for in vitro culture of human dendritic cells induced from peripheral blood monocytes. The dendritic cells grew one and a half times when they were cultured in a HydroCell™. All the cells were floating and harvested easily without any enzymes. The cells expressed the CD80 and CD83 molecules on their surface and still had strong phagocytosis. This results demonstrated that a HydroCell™ was a useful tool for in vitro culture of dendritic cells.

[Treatment results of acute leukemia in elderly patients: analysis of 61 consecutive patients in a single institution].

In order to investigate the clinical characteristics and management of elderly patients with acute leukemia, we retrospectively analyzed treatment results for 61 acute leukemia patients aged 65 years or more (median age 72) admitted to our department between October 1995 and September 2006. There were 6 elderly patients with ALL (acute lymphocytic leukemia) and 55 patients with AML (acute myelogenous leukemia). Among them, 51 patients could receive chemotherapy, but 10 patients received symptomatic therapy only. Complete remission was achieved in 50% of 46 patients who received chemotherapy, and median overall survival was 237 days. We analyzed treatment results for AML patients who underwent chemotherapy as follows. The intensive chemotherapy group and the de novo leukemia group showed a significantly higher CR rate and longer survival. No differences were found in karyotype, performance status or complications. Intensive chemotherapy was effective for 65-74-year-old patients with de novo AML. In future, we consider that the prognosis for elderly patients with acute leukemia will improve, if made-to-order treatment is given, depending on evidence-based stratification of patients with organs having low reserve capacity.

Acute myelogeneous leukemia (M5a) that demonstrated chromosomal abnormality of robertsonian 13;21 translocation at onset.

A 27-year-old woman had congenital lissencephaly syndrome and mental retardation. She had a fever of unknown origin and visited her local physician. Blood test indicated leukocytosis, so she was referred to our hospital for detailed examination. She was diagnosed to have acute myelogeneous leukemia (M5a). The chromosome analysis in blast cells revealed Robertsonian 13;21 translocation. Complete remission was obtained by induction chemotherapy. As normal karyotype (46, XX) was observed in the chromosome analysis of bone marrow cells after remission, it was considered that the patient had acquired Robertsonian 13;21 translocation complicated by acute myelogeneous leukemia.