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BackgroundHealthcare workers (HCWs) who care for patients with the novel coronavirus infectious disease (COVID-19) are at an increased risk and fear contracting the infection themselves. HCWs are chronically exposed to very intense stress, both and physically and mentally. Hospitals must reduce both the physical and mental burden of HCWs on the front lines and ensure their safety. No prospective study has focused on the physical health complaints among HCWs engaged in the care of critically ill COVID-19 patients. This study aimed to investigate the occupational risk among HCWs of experiencing physical symptoms during the current COVID-19 pandemic.MethodsA twice-weekly questionnaire targeting HCWs who care for COVID-19 patients was performed at Osaka City University Hospital from April 30 to May 31, 2020 using a shareable Research Electronic Data Capture tool. The demographic characteristics of the participants, frequency of exposure to at-risk care, and physical complaints were evaluated.ResultsA total of 35 doctors, 88 nurses, and 35 technicians were engaged in the care of these critically ill COVID-19 patients. 76 HCWs participated in this study, of whom 24 (31.6%) were doctors, 43 (56.6%) were nurses, and 9 (11.8%) were technicians. The frequency of experiencing any physical symptom was 25.0% among HCWs. Exposure to at-risk care was significantly higher among nurses than among doctors (p < 0.001); likewise, the frequency of experiencing physical symptoms was higher among nurses than among doctors (p < 0.01). The multivariate analysis revealed that nurses (odds ratio 8.29; p = 0.01) might be independently at risk of experiencing physical symptoms.ConclusionsOur results indicate that occupational health care at hospitals must be allocated to HCWs who are highly exposed to at-risk care, particularly nurses engaged in the care of COVID-19 patients.

BACKGROUND AND OBJECTIVES: Vitamin D receptor activators and calcimimetics (calcium-sensing receptor agonists) are two major options for medical treatment of secondary hyperparathyroidism. A higher serum calcification propensity (a shorter T(50) value) is a novel surrogate marker of calcification stress and mortality in patients with CKD. We tested a hypothesis that a calcimimetic agent etelcalcetide is more effective in increasing T(50) value than a vitamin D receptor activator maxacalcitol. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A randomized, multicenter, open-label, blinded end point trial with active control was conducted in patients with secondary hyperparathyroidism undergoing hemodialysis in Japan. Patients were randomly assigned to receive intravenous etelcalcetide 5 mg thrice weekly (etelcalcetide group) or intravenous maxacalcitol 5 or 10 µg thrice weekly (maxacalcitol group). The primary, secondary, and tertiary outcomes were changes in T(50) value, handgrip strength, and score of the Dementia Assessment Sheet for Community-Based Integrated Care System from baseline to 12 months, respectively. RESULTS: In total, 425 patients from 23 dialysis centers were screened for eligibility, 326 patients were randomized (etelcalcetide, n=167; control, n=159), and 321 were included in the intention-to-treat analysis (median age, 66 years; 113 women [35%]). The median (interquartile range) of T(50) value was changed from 116 minutes (interquartile range, 90–151) to 131 minutes (interquartile range, 102–176) in the maxacalcitol group, whereas it was changed from 123 minutes (interquartile range, 98–174) to 166 minutes (interquartile range, 127–218) in the etelcalcetide group. The increase in T(50) value was significantly greater in the etelcalcetide group (difference in change, 20 minutes; 95% confidence interval, 7 to 34 minutes; P=0.004). No significant between-group difference was found in the change in handgrip strength or in the Dementia Assessment Sheet for Community-Based Integrated Care System score. CONCLUSIONS: Etelcalcetide was more effective in increasing T(50) value than maxacalcitol among patients on hemodialysis with secondary hyperparathyroidism. There was no difference in handgrip strength or cognition between the two drugs. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: VICTORY; UMIN000030636 and jRCTs051180156

Pain during cannulation for vascular access is a considerable problem for patients with kidney disease who are undergoing hemodialysis. We examined whether listening to music can reduce cannulation pain in these patients.We conducted a multicenter, single-blind, crossover, randomized trial of 121 patients who reported pain during cannulation for hemodialysis. We compared participants listening to "Sonata for Two Pianos in D Major, K.448" or white noise as control while undergoing the cannulation procedure. The cannulation operator was blinded to the intervention, and the hypothesized superiority of music over white noise was concealed during explanations to the participants. The primary end point was the visual analog scale score for cannulation pain independently evaluated by participants.The primary analysis was on the basis of the modified intention-to-treat principle. The median baseline visual analog scale pain score was 24.7 mm (interquartile range, 16.5-42.3). Median change of the visual analog scale pain score from the "no sound" to the music period was -2.7 mm (interquartile range, -9.2 to 3.6), whereas it was -0.3 mm (interquartile range, -5.8 to 4.5) from "no sound" to white noise. The visual analog scale pain score decreased when listening to music compared with white noise. (Adjusted difference of visual analog scale pain score: -12%; 95% confidence interval, -21 to -2;Listening to music reduced cannulation pain in patients on hemodialysis, although there was no significant effect on anxiety, BP, or stress markers.

Versican is a large proteoglycan in the extracellular matrix. During embryonic stages, it plays a crucial role in the development of cartilage, heart, and dermis. Previously, we reported thatPrx1-Vcanconditional knockout mice, lacking Vcan expression in mesenchymal condensation areas of the limb bud, show the impaired joint formation and delayed cartilage development. Here, we investigated their phenotype in adults and found that they develop swelling of the knee joint. Histologically, their newborn joint exhibited impaired formation of both anterior and posterior cruciate ligaments. Immunostaining revealed a decrease in scleraxis-positive cells in both articular cartilage and ligament ofPrx1-Vcanknee joint, spotty patterns of type I collagen, and the presence of type II collagen concomitant with the absence of versican expression. These results suggest that versican expression during the perinatal period is required for cruciate ligaments’ formation and that its depletion affects joint function in later ages.

Introduction Type 2 diabetes (T2DM) is associated with cardiovascular death, including sudden cardiac death due to arrhythmias. Patients with an implantable cardioverter-defibrillator (ICD) are also at high risk of developing a clinically significant ventricular arrhythmia. It has been reported that sodium–glucose cotransporter 2 (SGLT2) inhibitors can reduce cardiovascular deaths; however, the physiological mechanisms of this remain unclear. It is, however, well known that SGLT2 inhibitors increase blood ketone bodies, which have been suggested to have sympatho-suppressive effects. Empagliflozin (EMPA) is an SGLT2 inhibitor. The current clinical trial titled “Placebo-controlled, double-blind study of empagliflozin (EMPA) and implantable cardioverter-defibrillator (EMPA-ICD) in patients with type 2 diabetes (T2DM)” was designed to investigate the antiarrhythmic effects of EMPA. Methods The EMPA-ICD study is a prospective, multicenter, placebo-controlled, double-blind, randomized, investigator-initiated clinical trial currently in progress. A total of 210 patients with T2DM (hemoglobin A1c 6.5–10.0%) will be randomized (1:1) to receive once-daily placebo or EMPA, 10 mg, for 24 weeks. The primary endpoint is the number of clinically significant ventricular arrhythmias for 24 weeks before and 24 weeks after study drug administration, as documented by the ICD. The secondary endpoints of the study are the change from baseline concentrations in blood ketone and catecholamine 24 weeks after drug treatment. Conclusion The EMPA-ICD study is the first clinical trial to assess the effect of an SGLT2 inhibitor on clinically significant ventricular arrhythmias in patients with T2DM and an ICD. Trial registration Unique trial number, jRCTs031180120 (https://jrct.niph.go.jp/latest-detail/jRCTs031180120). Electronic Supplementary Material The online version of this article (10.1007/s13300-020-00924-9) contains supplementary material, which is available to authorized users.

Tazobactam/piperacillin (TAZ/PIPC) is an antimicrobial drug agent with a broad spectrum of antibacterial activity and is recommended as first-line therapy for hospital-acquired pneumonia, nursing- and healthcare-associated pneumonia, and other severe pneumonias. Nevertheless, in clinical settings, TAZ/PIPC is not fully effective in the treatment of pneumonia in the elderly. In the present study, we retrospectively investigated the efficacy of TAZ/PIPC for pneumonia in elderly patients and identified factors that reduced its efficacy. Ninety-nine patients (mean age of 83.4 years and no significant difference in the sex ratio) were included in the present study. The efficacy rate of TAZ/PIPC for pneumonia in elderly patients was 81.8%, which was approximately 7 to 10% lower than that in domestic phase III trials. A multivariate analysis identified the complications of chronic respiratory disease as a significant factor attenuating the therapeutic effects of TAZ/PIPC [odds ratio 4.050, 95% confidence interval (CI) 1.008-16.271]. In conclusion, TAZ/PIPC may not be sufficiently effective for pneumonia in elderly patients with the complications of chronic respiratory disease as a background.

Background: Repeated pain during haemodialysis access cannulations is a serious problem for haemodialysis patients even when prescribed oral or topical analgesics. Although some studies have observed the efficacy of music therapy for improving pain and anxiety, its effectiveness during haemodialysis access cannulations during dialysis is uncertain. The purpose of this study is to investigate the effects of music therapy for pain when cannulating haemodialysis access for haemodialysis patients. Methods: A prospective, multi-facility, single-blind, crossover, randomised controlled trial will be implemented. The intervention includes listening to Mozart, along with a white noise control condition. One hundred twenty haemodialysis patients will be enrolled across five facilities. Patients will be randomly allocated to either an Early-sequence group or a Later-sequence group. The Early-sequence group will receive cannulation while listening to Mozart's Sonata for two pianos in D major (K.448) during the second week (Music period) and white noise during the fourth week (White noise period). The Later-sequence group will receive cannulation along with white noise first, followed by Mozart. All patients will also undergo cannulation during a no-sound period (wearing only headphones) during the first and third week (No-sound period). The music or no-music protocol will begin 8 min prior to the cannulating procedure, and participants will finish listening after starting haemodialysis during each period. The primary outcomes that will be assessed include the Visual Analogue Scale (VAS) score for pain during cannulation, and secondary outcomes are blood pressure, heart rate, VAS anxiety score, State-Trait Anxiety Inventory score, and salivary amylase activity. The operators who are in charge of haemodialysis access cannulation will be blind to the listening condition and VAS report. Discussion: The proposed study has several methodological benefits. First, using white noise is a suitable control condition for addressing the role of sound in pain management. Additionally, using a crossover design with repeated measurements can help control individual differences between participants, which should better distinguish between- and within-participant variability. Overall, music therapy is a safe and inexpensive intervention that does not have the problematic side effects typically associated with pharmacological treatment. If effective, music therapy can be easily implemented for reducing pain and anxiety during cannulation. Trial registration: This trial was prospectively registered to UMIN Clinical Trials Registry on 1 July 2018 (UMIN 000032850)., Trials, 20(1), art.no.631; 2019

Background Repeated pain during shunt vessel punctures is a serious problem for haemodialysis patients, even when prescribed external analgesics. While some studies have observed the efficacy of music therapy for improving pain and anxiety, its effectiveness during vessel punctures during dialysis is uncertain. The purpose of this study is to investigate the effects of music therapy for pain when cannulating a shunt blood vessel for haemodialysis patients. Methods A prospective, multi-facility, single-blind, crossover, randomised controlled trial will be implemented. The intervention includes listening to Mozart, along with a white noise control condition. One hundred twenty haemodialysis patients will be enrolled across five facilities. Patients will be randomly allocated to either an Early-sequence group or a Later-sequence group. The Early-sequence group will receive puncture while listening to Mozart’s Sonata for 2 pianos in D major (K.448) during the second week (Music period) and white noise during the fourth week (White noise period). The Later-sequence group will receive puncture along with white noise first, followed by Mozart. All patients will also undergo puncture during a ‘no-sound period (only wearing headphones) during the first and third week (No-sound period). The music or no-music protocol will begin 8 minutes prior to the puncturing procedure, and participants will finish listening after starting haemodialysis during each period. The primary outcomes that will be assessed include the Visual Analogue Scale (VAS) score for pain during puncture, and secondary outcomes such as blood pressure, heart rate, VAS anxiety score, State-Trait Anxiety Inventory score, and salivary amylase activity. The operator will be blind to each listening condition and VAS report. Discussion The proposed study has several methodological benefits. First, using white noise is a suitable control condition for addressing the role of sound on pain management. Additionally, using a crossover design with repeated measurements can help control individual differences between participants, which should better distinguish between- and within-participant variability. Overall, music therapy is a safe and inexpensive intervention that does not have the problematic side effects typically associated with pharmacological treatment. If effective, music therapy can be easily implemented for reducing pain and anxiety during cannulation.

There are very few epidemiological studies on Japanese patients with deep vein thrombosis (DVT). In particular, mortality rate differences in Japanese DVT patients with and without malignancy have rarely been evaluated. To elucidate these differences, we enrolled 211 patients who had been diagnosed with de-novo acute DVT of the pelvis or lower extremities between January 2012 and December 2015. The clinical characteristics, treatment information, and follow-up data were retrospectively assessed. We compared these variables in patients with (n = 120) and without (n = 91) concomitant malignancies. The median age of patients was 67 years, 33.7% were male, and 82.9% patients were treated with oral anticoagulants including direct oral anticoagulants. The clinical characteristics and treatment provided were almost identical in the two groups with some exceptions. Three-year survival rates of the total population, patients with malignancy, and patients without malignancy were 80.6, 67.6, and 97.6%, respectively (log-rank p

Display Omitted CDISC SDTM is useful for new drug application studies and existing research data.A simulated clinical trial was used to evaluate a tool called REDCap2SDTM.SDTM data and the define.xml file were generated from REDCap using REDCap2SDTM.This tool will facilitate new drug application studies and reuse of research data. The Clinical Data Interchange Standards Consortium (CDISC) Study Data Tabulation Model (SDTM) can be used for new drug application studies as well as secondarily for creating a clinical research data warehouse to leverage clinical research study data across studies conducted within the same disease area. However, currently not all clinical research uses Clinical Data Acquisition Standards Harmonization (CDASH) beginning in the set-up phase of the study. Once already initiated, clinical studies that have not utilized CDASH are difficult to map in the SDTM format. In addition, most electronic data capture (EDC) systems are not equipped to export data in SDTM format; therefore, in many cases, statistical software is used to generate SDTM datasets from accumulated clinical data. In order to facilitate efficient secondary use of accumulated clinical research data using SDTM, it is necessary to develop a new tool to enable mapping of information for SDTM, even during or after the clinical research. REDCap is an EDC system developed by Vanderbilt University and is used globally by over 2100 institutions across 108 countries. In this study, we developed a simulated clinical trial to evaluate a tool called REDCap2SDTM that maps information in the Field Annotation of REDCap to SDTM and executes data conversion, including when data must be pivoted to accommodate the SDTM format, dynamically, by parsing the mapping information using R. We confirmed that generating SDTM data and the define.xml file from REDCap using REDCap2SDTM was possible. Conventionally, generation of SDTM data and the define.xml file from EDC systems requires the creation of individual programs for each clinical study. However, our proposed method can be used to generate this data and file dynamically without programming because it only involves entering the mapping information into the Field Annotation, and additional data into specific files. Our proposed method is adaptable not only to new drug application studies but also to all types of research, including observational and public health studies. Our method is also adaptable to clinical data collected with CDASH at the beginning of a study in non-standard format. We believe that this tool will reduce the workload of new drug application studies and will support data sharing and reuse of clinical research data in academia.

Further structural study of the xyloglucanase-derived eggplant xyloglucan oligosaccharides was carried out to investigate the oligosaccharide units of xyloglucan from the cell-walls of eggplant in detail. The result shows that a hexasaccharide, XSG, a heptasaccharide, XX2GG, an octasaccharide, LX2GG and a nonasaccahride, LSGGG, in addition to the major oligosaccharides XXGG, LXGG, XLGG, XSGG, LLGG and LSGG, the structures of which were previously reported, are included in oligosaccharide units of eggplant xyloglucan.

Controlled protein remodeling with O-linked glycans has been limited by our incomplete understanding of the process of glycosylation. Here we describe a secretable fibroblast growth factor (FGF) with multiple mucin-type O-glycans produced by introducing a minimum pentapeptide glycosylation unit in a decarepeat format at its N- or C-terminus. Expressed in Chinese hamster ovary cells, chemical and biochemical analyses of the resultant proteins (Nm10-FGF and Cm10-FGF, respectively) demonstrated that all O-glycosylation units were glycosylated and the dominant structure was sialylated Gal[β1–3]GalNAc. This indicates that minimum O-glycosylation unit in multirepeat format serves as a remarkably efficient acceptor in CHO cells. The Nm10-FGF and Cm10-FGF proteins maintained the mitogenic activity to vascular endothelial cells. In addition, intact Cm10-FGF and its desialylated form interacted with several lectins in the same way as mucin-type glycoproteins. The intact Cm10-FGF with multiple sialylated O-glycans exhibited a longer lifetime in circulating blood, whereas the Cm10-FGF with desialylated O-glycans exhibited a shorter lifetime than the deglycosylated form of Cm10-FGF. Our approach would thus appear to be highly effective for engineering neoglycoproteins, the characteristics of which are determined by their multiple mucin-type O-glycans.

The peptide signal sequence for protein O-glycosylation is not fully characterized, although a recent in vitro study proposed that the sequence motif, XTPXP, serves as a signal for mucin-type O-glycosylation. Here, we show that the AATPAP sequence acts as an efficient O-glycosylation signal, in vivo. A secreted fibroblast growth factor (secFGF) was used as a model to analyze glycosylation and its effects on the biological activity of FGF. Two constructs encoding [AATPAP]secFGF in which AATPAP was introduced at the N- or C-terminus of secFGF were constructed in an eukaryotic expression vector. [AATPAP]secFGF proteins were then expressed in Chinese hamster ovary (CHO) cells and secreted into the surrounding medium, primarily as modified forms sensitive to sialidase but not to peptide N-glycosidase F. The modifying groups were not seen when the AATPAP sequence was converted to AAAPAP or when [AATPAP]secFGF was expressed in mutant cells incapable of UDP-GalNAc biosynthesis. The results indicate that the modifying groups were mucin-type O-glycans and that the AATPAP served as an efficient O-glycosylation signal sequence. The O-glycosylated forms of [AATPAP]secFGF were as mitogenic toward human vascular endothelial cells as unmodified secFGF, suggesting that introduction of the signal into biologically active polypeptides is a promising approach with which O-glycosylation may be achieved without affecting original activity.

A simple, efficient, and rapid method is described for separation of the enantiomers of propoxyphene by capillary electrophoresis with neutral cyclodextrins as chiral separators. This method has several advantages over the crystallization method employed by some forensic laboratories, including unambiguous results, ease of use, and smaller sample-size requirement. The method enables baseline separation of the propoxyphene enantiomers in approximately six minutes, which is less than one-third of the time required for a previously published method.

The gene for fibroblast growth factor (FGF)-6/hst-2 was originally identified by its close homology with the FGF-4/hst-1 gene. Aside from its ability to transform cultured fibroblasts, the characteristics of FGF-6 protein have only been studied using a simple preparation from E. coli. In the present study, we expressed FGF-6 cDNA in CHO cells and characterized the resultant protein. We found that CHO cells secreted several forms of the FGF-6 polypeptide, and that there were multiple N-terminal modifications. The longest form (18-kDa) contained the sequence, SerProAlaGlyAlaArg, as its N-terminus, which was consistent with the signal peptide cleavage site predicted from its primary structure. The core polypeptide was primarily modified by heterogeneous N-glycans that were sialylated to a small degree; among them, biantennary structures were found to predominate. Moreover, possible O-glycosylation was also detected. N-glycosylated FGF-6 potently induced DNA synthesis and proliferation of human vascular endothelial cells, whereas in the absence of N-glycosylation, FGF-6 mitogenicity was substantially diminished. The results clearly indicate that FGF-6 expressed by mammalian cells is a glycosylated mitogen for vascular endothelial cells and further suggests that N-glycosylation plays a key role in determining the mitogenicity of FGF-6.

The effects of 19-oxygenated lanosterol derivatives on lanosterol 14 alpha-demethylase (P-450(14DM)) and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity were studied. 3 beta-Hydroxylanost-9(11)-en-19-oic acid (6) was found to be an effective inhibitor (IC50:0.5 microM) of P-450(14DM) in the reconstituted system using purified pig liver P-450(14DM) and was most active in inhibiting HMG-CoA reductase activity (IC50:1.0 microM) in mouse L cells. In [2-14C]acetate incorporation studies using mouse L cells, 6 was found to reduce the incorporation of acetate into C27-sterol (desmosterol) with a concomitant increase in radiolabeled C30-sterols. These results demonstrate that 6 is a dual-action inhibitor of cholesterol biosynthesis.

A gamma-chain variant with an apparently higher molecular weight than the normal gamma-chain was detected in a new congenital abnormal fibrinogen with impaired polymerization of the fibrin monomer and with normal release of fibrinopeptides A and B in a 51-year-old male. Purified fibrinogen analyzed on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) under the reduced condition in the system of Laemmli contained two protein bands in the gamma-chain region (molecular weight, 50,500 as compared with 50,000 for the normal), both with normal crosslinking ability. The presence of two types of gamma- chains was more clearly detected when reduced and carboxymethylated fibrinogen was analyzed by SDS-PAGE or when reduced fragment D2 was analyzed on SDS-PAGE followed by Western blotting, and identified by positive staining for anti gamma-chain monoclonal antibody. Cyanogen bromide- or lysylendopeptidase-cleavage of purified gamma-chains analyzed on reverse-phase high performance liquid chromatography showed the decrease of one peptide compared with the normal and the appearance of an abnormal peptide peak. Amino acid sequence analysis demonstrated that the gamma arginine-275 of gamma-chain variant was replaced by a cysteine. These data suggest that some regions or conformations containing gamma 275 will affect the polymerization of fibrin monomers. The propositus' two daughters had the same abnormal fibrinogen. This unique inherited abnormal fibrinogen was designated as fibrinogen Tochigi, and the gamma-chain variant as gamma Tochigi.