Relationship between 2nd-generation angiotensin receptor blockers and the risk of hypotension in COVID-19 patients admitted to hospital.

It has not yet been established whether angiotensin II receptor blockers (ARB), statins, and multiple drugs affect the severity of COVID-19. Therefore, we herein performed an observational study on the effects of 1st- and 2nd-generation ARB, statins, and multiple drugs, on COVID-19 in patients admitted to 15 Japanese medical facilities. The results obtained showed that ARB, statins, and multiple drugs were not associated with the primary outcome (odds ratio: 1.040, 95% confidence interval: 0.688-0.571; 0.696, 0.439-1.103; 1.056, 0.941-1.185, respectively), each component of the primary outcome (in-hospital death, ventilator support, extracorporeal membrane oxygenation support, and admission to the intensive care unit), or the secondary outcomes (oxygen administration, disturbed consciousness, and hypotension, defined as systolic blood pressure ≤90 mmHg). ARB were divided into 1st- and 2nd-generations based on their approval for use (before 2000 and after 2001), with the former consisting of losartan, candesartan, and valsartan, and the latter of telmisartan, olmesartan, irbesartan, and azilsartan. The difference of ARB generation was not associated with the primary outcome (odds ratio with 2nd-generation ARB relative to 1st-generation ARB: 1.257, 95% confidence interval: 0.613-2.574). The odd ratio for a hypotension as one of the secondary outcomes with 2nd-generation ARB was 1.754 (95% confidence interval: 1.745-1.763) relative to 1st-generation ARB. These results suggest that patients taking 2nd-generation ARB may be at a higher risk of hypotension than those taking 1st-generation ARB and also that careful observations are needed. Further studies are continuously needed to support decisions to adjust medications for co-morbidities.

Beat-to-Beat Estimation of Peripheral Arterial Stiffness From Local PWV for Quantitative Evaluation of Sympathetic Nervous System Activity.

OBJECTIVE: Sympathetic nervous system activity (SNSA) can rapidly modulate arterial stiffness, thus making it an important biomarker for SNSA evaluation. Pulse wave velocity (PWV) is a well-known quantitative indicator of arterial stiffness, but its functional responsivity to SNSA has not been elucidated. This paper reports a method to estimate rapid changes in peripheral arterial stiffness induced by SNSA using local PWV (LPWV) and to further quantify SNSA based on the estimated stiffness. METHODS: LPWV was measured from the artery near the wrist to the artery near the forefinger using a biodegradable piezoelectric sensor and a photoplethysmography sensor in an electrocutaneous stimulus experiment in which pain evokes the SNSA. The relationship between LPWV, simultaneously measured peripheral arterial stiffness index, and self-reported pain intensity was quantified. RESULTS: The stiffness estimated by LPWV alone and the stiffness estimated by LPWV and arterial pressure both approximate the peripheral arterial stiffness index (R2 = 0.9775 and 0.9719). Pain intensity can be quantitatively evaluated in a sigmoidal relationship by either the estimated stiffness based on LPWV alone (r = 0.8594) or the estimated stiffness based on LPWV and arterial pressure (r = 0.9738). CONCLUSION: Our results demonstrated the validity of LPWV in the quantitative evaluation of SNSA and the optionality of blood pressure correction depending on application scenarios. SIGNIFICANCE: This study advances the understanding of sympathetic innervation of peripheral arteries through the sympathetic responsivity of LPWV and contributes a quantitative biomarker for SNSA evaluation.

Assessment of Ureters at Dangerous Locations in Lateral Lumbar Interbody Fusion.

INTRODUCTION: This study aimed to investigate the ureteral running position from the viewpoint of the spine, and to identify the spinal level and left-right difference in the ureter at a dangerous location of ureteral injury during surgery. METHODS: This retrospective study included 100 consecutive patients (39 males and 61 females; average age, 70.4 years). Preoperative contrast-enhanced computerized tomography (CT) scans obtained in the supine position for patients who underwent lateral lumbar interbody fusion (LLIF) were analyzed. The ureter location was divided into four regions on the axial CT images based on the lumbar disk levels as follows: A (ventral-medial), B (ventral-lateral), C (dorsal-medial), and D (dorsal-lateral). The C region surrounded by the vertebral body and the psoas muscle was assumed to have the highest probability of ureteral injury. We examined the characteristics of the ureteral position at each disc level. RESULTS: In the upper lumbar spine, the ureter was outside the lateral dorsoventral axis from the contact point of the psoas muscle, while in the lower lumbar spine, it was inside the axis. The ureters located in the C region increased significantly in the lower lumbar disk levels (L1-L2 and L2-L3: 0%; L3-L4: 5.5%; L4-L5: 14.8%; L5-S: 31.5%). Comparing the left and right sides, especially at L4-L5, the ureter in the C region was observed in 21% of all ureters on the left side and in 9% on the right side. With respect to gender differences, the ureters present in the C region were significantly more common in women at lumbar disk levels L3-L4, L4-L5, and L5-S. CONCLUSIONS: The ureters in the C region were common on the left side and at lower lumbar disk levels. To avoid ureteral injury, it is necessary to confirm the location of the ureter by using preoperative images and performing LLIF carefully.

Pressure-based Detection of Heart and Respiratory Rates from Human Body Surface using a Biodegradable Piezoelectric Sensor.

This study investigates the relationship between respiration and autonomic nervous system (ANS) activity and proposes a parallel detection method that can simultaneously extract the heart rate (HR) and respiration rate (RR) from different pulse waves measured using a novel biodegradable piezoelectric sensor. The synchronous changes in heart rate variability and respiration reveal the interaction between respiration and the cardiovascular system and their interconnection with ANS activity. Following this principle, respiration was extracted from the HR calculated beat-by-beat from pulse waves. Pulse waves were measured using multiple biodegradable piezoelectric sensors each attached to the human body surface. The Valsalva maneuver experiment was conducted on seven healthy young adults, and the extracted respiratory wave was compared with a reference respiratory wave measured simultaneously. The experimental results are consistent with the observations from reference waves, where R2 = 0.9506, p < 0.001 for the extracted RR and the reference RR, thus demonstrating the detection capability under different respiratory statuses.

Two distinct prions in fatal familial insomnia and its sporadic form.

Fatal familial insomnia is a genetic prion disease, which is associated with the aspartic acid to asparagine substitution at codon 178 of the prion protein gene. Although the hallmark pathological feature is thalamic and olivary degeneration, there is a patient with an atypical fatal familial insomnia without the hallmark feature. The cause of the pathological variability is unclear. We analysed a Japanese fatal familial insomnia kindred and compared one atypical clinicopathological fatal familial insomnia phenotype case and typical fatal familial insomnia phenotype cases with transmission studies using multiple lines of knock-in mice and with protein misfolding cyclic amplification. We also analysed the transmissibility and the amplification properties of sporadic fatal insomnia. Transmission studies revealed that the typical fatal familial insomnia with thalamic and olivary degeneration showed successful transmission only using knock-in mice expressing human-mouse chimeric prion protein gene. The atypical fatal familial insomnia with spongiform changes showed successful transmission only using knock-in mice expressing bank vole prion protein gene. Two sporadic fatal insomnia cases with thalamic and olivary degeneration showed the same transmissibility as the typical fatal familial insomnia phenotype. Interestingly, one sporadic fatal insomnia case with thalamic/olivary degeneration and spongiform changes showed transmissibility of both the typical and atypical fatal familial insomnia phenotypes. Protein misfolding cyclic amplification could amplify both typical fatal familial insomnia cases and sporadic fatal insomnia cases but not the atypical fatal familial insomnia phenotype or other sporadic Creutzfeldt-Jakob disease subtypes. In addition to clinical findings and neuropathological features, the transmission properties and the amplification properties were different between the typical and atypical fatal familial insomnia phenotypes. It is suggested that two distinct prions were associated with the diversity in the fatal familial insomnia phenotype, and these two prions could also be detected in sporadic fatal insomnia.

A survey on infection control in emergency departments in Japan.

AIM: Infection control in the emergency department is important for hospital risk management; however, few clinical guidelines have been established. This study aimed to determine whether hospitals in Japan have infection control manuals, and investigate the contents of manuals, consulting systems, and isolation facilities for emergency departments. METHODS: A total of 517 hospitals certified as educational institutions for board-certified acute care physicians in Japan were requested between March and May 2015 to provide a written evaluation of the infection control in the emergency department. RESULTS: A total of 51 of 303 (16.8%) hospitals had no manuals regarding infection control in the emergency department. Among 250 hospitals having emergency department manuals, 115 (46.0%) did not include contents regarding disinfection and sterilization for imaging examination rooms, and only 44 (17.6%) had criteria for contacting the emergency medical service when patients are suspected of, or diagnosed with, communicable diseases. Of the 303 hospitals, 277 (91.4%) prepared specific manuals for the 2009 pandemic influenza. Of the 303 hospitals, 80 (26.4%) did not prepare manuals for the Ebola virus disease outbreak in West Africa in 2014. Furthermore, 92 (30.4%) of the 303 hospitals did not have any negative-pressure isolation rooms. CONCLUSIONS: Practices and guidelines necessary for infection control in the emergency department were not sufficiently covered in the hospitals studied. Education, information sharing, and a checklist for preparing manuals are needed to establish better infection control systems in emergency departments.

Efficacy of isoproterenol for treating amlodipine overdose resulting in bradycardia.

Case: Amlodipine predominantly affects vascular smooth muscle cells. Amlodipine overdose usually presents with vasodilatory shock, accompanied by reflex tachycardia rather than bradycardia.An 81-year-old woman presented with impaired consciousness 8 h after ingesting 50 5-mg amlodipine tablets with suicidal intent. On admission, her blood pressure was 50/40 mmHg and her heart rate was 45 b.p.m. Serum amlodipine level was extremely high (474.4 ng/mL), causing refractory bradycardia. She remained hypotensive despite fluid resuscitation, and therefore was administered dopamine and norepinephrine. She was also administered glucagon and calcium gluconate, and underwent high-dose insulin euglycemic therapy. Outcome: Although her blood pressure improved, bradycardia progressively worsened and isoproterenol infusion was initiated, which resulted in an improvement in her heart rate. The patient discharged on day 14 without any complications. Conclusion: Isoproterenol is effective for treating bradycardia after amlodipine overdose.

Distinctive properties of plaque-type dura mater graft-associated Creutzfeldt-Jakob disease in cell-protein misfolding cyclic amplification.

There are two distinct subtypes of dura mater graft-associated Creutzfeldt-Jakob disease (dCJD) with methionine homozygosity at codon 129 of the PRNP gene. The majority of cases is represented by a non-plaque-type (np-dCJD) resembling sporadic CJD (sCJD)-MM1 or -MV1, while the minority by a plaque-type (p-dCJD). p-dCJD shows distinctive phenotypic features, namely numerous kuru plaques and an abnormal isoform of prion protein (PrP(Sc)) intermediate in size between types 1 and 2. Transmission studies have shown that the unusual phenotypic features of p-dCJD are linked to the V2 prion strain that is associated with sCJD subtypes VV2 or -MV2. In this study, we applied protein misfolding cyclic amplification (PMCA) using recombinant human prion protein as a substrate and demonstrated that p-dCJD prions show amplification features that are distinct from those of np-dCJD. Although no amplification of np-dCJD prions was observed with either 129 M or 129 V substrate, p-dCJD prions were drastically amplified with the 129 V substrates, despite the PRNP codon 129 incompatibility between seed and substrate. Moreover, by using a type 2 PrP(Sc)-specific antibody not recognizing PrP(Sc) in p-dCJD, we found that type 2 products are generated de novo from p-dCJD prions during PMCA with the 129 V substrates. These findings suggest that our cell-PMCA is a useful tool for easily and rapidly identifying acquired CJD associated with the transmission of the V2 CJD strain to codon 129 methionine homozygotes, based on the preference for the 129 V substrate and the type of the amplified products.

Efficient propagation of variant Creutzfeldt-Jakob disease prion protein using the cell-protein misfolding cyclic amplification technique with samples containing plasma and heparin.

BACKGROUND: To prevent the iatrogenic spread of variant Creutzfeldt-Jakob disease (vCJD) between humans via blood products or transfusion, highly sensitive in vitro screening tests are necessary. Protein misfolding cyclic amplification (PMCA) is one such candidate test. However, plasma has been reported to inhibit the PMCA reaction. Therefore, we investigated the cell-PMCA conditions that permit vCJD prion amplification in the presence of plasma. STUDY DESIGN AND METHODS: Cell-PMCA of vCJD samples was performed by adding various final concentrations of pooled plasma, citrate-phosphate-dextrose (CPD), albumin, globulin, or pooled plasma treated with ion exchangers. After heparin and plasma concentrations were optimized, multiround cell-PMCA was performed. RESULTS: When 1% to 50% of pooled plasma was added to heparinized cell-PMCA, amplification efficiency showed a double-peaked profile at less than 1% and 40% final plasma concentrations, indicating that plasma contains not only PMCA inhibitors but also promoters. Intravenous globulin did not inhibit cell-PMCA, but the protein G-bound fraction did. CPD, albumin-depleted plasma, and the unbound fraction of anion-exchange chromatography inhibited cell-PMCA, but albumin and the unbound fraction of the cation-exchange chromatography did not. The detection limit of abnormal prion protein in multiround cell-PMCA, when maintaining the final plasma concentration at 40% at each round, was 10(-10) dilutions of a vCJD brain specimen. CONCLUSION: We have established a novel cell-PMCA format in the presence of plasma without any pretreatment, where vCJD prion protein was amplified at comparable levels to that found without plasma. Our data suggest the feasibility of cell-PMCA as a practical blood test for vCJD prions.

Cerebral Protection During Mitral Valve Repair in a Patient With Moyamoya Syndrome.

In patients with moyamoya syndrome requiring heart surgery, the brain blood flow during the low perfusion state under cardiopulmonary bypass is a concern. We report on a successful mitral valve repair and tricuspid repair in a patient with moyamoya syndrome, performed using an integrated cerebral protection strategy with cerebral oxygen saturation monitoring, intraaortic balloon pumping, and cardiopulmonary bypass perfusion at a relatively high pressure. An integrated approach with a thorough discussion among cardiac surgeons, anesthesiologists, and perfusionists was invaluable to protect brain perfusion in a patient with moyamoya syndrome.

Evaluating prion models based on comprehensive mutation data of mouse PrP.

The structural details of the essential entity of prion disease, fibril prion protein (PrP(Sc)), are still elusive despite the large body of evidence supporting the prion hypothesis. Five major working models of PrP(Sc) structure, which are not compatible with each other, have been proposed. However, no systematic evaluation has been performed on those models. We devised a method that combined systematic point mutation with threading on knowledge-based amino acid potentials. A comprehensive mutation experiment was performed on mouse prion protein, and the PrP(Sc) conversion efficiency of each mutant was examined. The models were evaluated based on the mutation data by using the threading method. Although the data turned out to be rather more consistent with the models that assumed a conversion of the N-terminal region of core PrP into a ß helix than with others, substantial modifications were also required to further improve the current model based on recent experimental results.

Molecular barriers to zoonotic transmission of prions.

The risks posed to human health by individual animal prion diseases cannot be determined a priori and are difficult to address empirically. The fundamental event in prion disease pathogenesis is thought to be the seeded conversion of normal prion protein to its pathologic isoform. We used a rapid molecular conversion assay (protein misfolding cyclic amplification) to test whether brain homogenates from specimens of classical bovine spongiform encephalopathy (BSE), atypical BSE (H-type BSE and L-type BSE), classical scrapie, atypical scrapie, and chronic wasting disease can convert normal human prion protein to the abnormal disease-associated form. None of the tested prion isolates from diseased animals were as efficient as classical BSE in converting human prion protein. However, in the case of chronic wasting disease, there was no absolute barrier to conversion of the human prion protein.

Surgical outcomes for 131 cases of carcinosarcoma of the hepatobiliary tract.

Carcinosarcoma of the hepatobiliary tract is highly aggressive and has a poor prognosis even after curative resection. The purpose of this study was to collate and analyze published data to clarify the surgical outcome of carcinosarcoma of the hepatobiliary tract and the relationships between potential prognostic factors and survival after surgery. We surveyed worldwide literature from 1970 to 2012 and obtained clinicopathological data for 131 patients who had undergone surgical resection for carcinosarcoma of the hepatobiliary tract, including one patient from our clinic. The relationships between potential prognostic factors and survival rates were examined using the Kaplan-Meier method and the log-rank test. The overall 1-, 3-, and 5-year survival rates for patients with carcinosarcoma of the hepatobiliary tract after surgery were 44.0, 29.3, and 27.0 %, respectively. In univariate analyses, age and gender were not significant prognostic factors; however, advanced stage according to the classification of the Union for International Cancer Control in resected specimens was significantly associated with a shorter survival time after surgery. Although carcinosarcoma of the hepatobiliary tract remains a rare disease worldwide, its poor prognosis, even after curative resection, demands further epidemiological and pathological study that could lead to the development of new management strategies.

Primary liposarcoma of the duodenum: a first case presentation.

A 55-year-old man suffering from melena was admitted to our hospital. A blood test showed severe anemia. Contrast-enhanced computed tomography (CT) revealed a huge lesion in the duodenum and dilatation of the common bile duct. Upper gastrointestinal endoscopy also identified hemorrhaging from the tumor in the duodenum. Due to the low density of the tumor mass, we performed emergency pylorus-preserving pancreaticoduodenectomy. Histology revealed an area of well-differentiated liposarcoma as well as an area of high-grade spindle cells and pleomorphic sarcoma without obvious differentiation. The final pathological diagnosis was dedifferentiated liposarcoma. This is the first case report of primary liposarcoma of the duodenum.

Total arch replacement under flow monitoring during selective cerebral perfusion using a single pump.

BACKGROUND: Flow in individual vessels is passively determined when a single pump is used for selective cerebral perfusion during aortic arch surgery. We installed a Doppler flowmeter in the circuit and measured flow in the supraaortic vessels to determine flow distribution during selective cerebral perfusion. METHODS: We cannulated and perfused three supraaortic vessels using a single pump in 203 patients who underwent elective (n = 158) or emergency or urgent (n = 45) total arch replacement using a four-branched prosthetic graft. Flow rates in each branch were continuously monitored during selective cerebral perfusion. RESULTS: The respective mean flow rates in the brachiocephalic, left common carotid, and left subclavian arteries and total flow rates were 5.8, 3.3, 3.4, and 12.5 mL·kg(-1)·min(-1). The ratios of flow in these vessels to total flow were 46.5%, 26.5%, and 27.0%, respectively, and they were not affected by the total flow rate. In-hospital mortality rates among the patients who underwent elective and emergency or urgent surgery were 1.9% (n = 3) and 11.1% (n = 5), respectively, and the rates of postoperative stroke were 2.5% (n = 4) and 8.9% (n = 4), respectively. Total flow in the supraaortic vessels during selective cerebral perfusion was significantly lower in patients with neurologic complications than in those without (732 versus 806 mL/min; p = 0.034). CONCLUSIONS: Flow monitoring showed that selective perfusion using a single pump adequately distributed flow among all supraaortic vessels. This monitoring system might help to improve brain protection and outcomes during total aortic arch replacement.

Heparin enhances the cell-protein misfolding cyclic amplification efficiency of variant Creutzfeldt-Jakob disease.

Highly sensitive in vitro screening tests are required to prevent the iatrogenic spread of variant Creutzfeldt-Jakob disease (vCJD). Protein misfolding cyclic amplification (PMCA) is a candidate for such a test, but the sensitivity of this method is insufficient. Polyanions were reported to enhance PMCA efficiency, but their effects on vCJD are unclear. We developed a cell-PMCA of vCJD, wherein cell lysate containing exogenously expressed human PrP was used as substrates, to investigate the effects of various sulfated polysaccharides on amplification efficiency. PrP(res) amounts after cell-PMCA were analyzed by western blotting. Heparin, dermatan sulfate, and dextran sulfate (average molecular weight [MW] 1400kDa) enhanced efficiency, but dextran sulfate (average MW 8kDa) and a heparin pentasaccharide analog had no effect. Pentosan polysulfate inhibited cell-PMCA reaction. The amplification efficiency of cell-PMCA of vCJD increased to >100-fold per round with heparin. The enhancing effects of heparin on cell-PMCA were seed dependent: it was high for vCJD, low for sporadic Creutzfeldt-Jakob disease, and low to negligible for hamster-adapted scrapie-derived 263K. In multi-round PMCA, signals were detected at earlier rounds with heparin than without heparin, and PrP(Sc) in 10(-10) diluted vCJD brain was detected by the sixth round. Heparin-assisted cell-PMCA of vCJD represents a significant step toward detecting very minute amounts of PrP(Sc) in the body fluids of asymptomatic vCJD patients.

Deduction of the evaluation limit and termination timing of multi-round protein misfolding cyclic amplification from a titration curve.

In this study, the efficacy of disinfectants in reducing the partially protease-resistant isoform of prion protein was evaluated by a multi-round protein misfolding cyclic amplification (PMCA) technique. Hamster brains infected with scrapie-derived strain 263K were homogenized, treated under inactivating or mock conditions, and subjected to multi-round PMCA. Four sets of serial 10-fold dilutions of mock-treated samples were analyzed. Although considerable variability was observed in the signal patterns, between the second and sixth rounds the number of the PMCA round correlated in a linear fashion with the mean dilution factor of mock-treated, infected brains, corresponding to a log reduction factor (LRF) of 3.8-7.3 log. No signals were observed in the PMCA products amplified from normal hamster brain homogenates. The mean numbers of rounds at the first appearance of the signal for 1 M and 2 M NaOH-treated samples were 4.33 and 4, respectively. Using the linear regression line as the titration curve, the LRFs of these disinfectants were found to be 6.1 and 5.8 log, respectively; these values were not significantly different. The mean number of rounds for the alkaline cleaner and sodium dodecyl sulfate were 9 and 10.33, respectively, and were outside the range of both the linear regression line and evaluation limit. The disinfectants were considered very effective because their LRFs were ≥7.3 log. These estimations were concordant with previous bioassay-based reports. Thus, the evaluation limit seems to be valuable in some applications of multi-round PMCA, such as disinfectant assessment and process validation.