Impact of refractory and unexplained chronic cough on disease burden: a qualitative study.

BACKGROUND: Chronic cough lasting for > 8 weeks is a common medical condition that burdens patients. This study aimed to qualitatively describe knowledge, awareness, experiences, and subtypes of burdens (physical, social, psychological) among Japanese patients with refractory chronic cough (refractory to treatment of underlying relevant medical conditions) and unexplained chronic cough (symptoms of unexplained origin). METHODS: This non-interventional, cross-sectional study was conducted between February and March 2021 among patients (aged ≥ 20 years) with self-reported refractory or unexplained chronic cough. Subjects with a history of comorbid respiratory conditions were excluded. Eligible subjects participated in a 60-min online semi-structured interview. Verbatim terms from interviews were qualitatively transcribed and generated into word clouds, followed by a clustering analysis in which meaningful clusters were chosen, manually coded, and utterances and burdens categorized. RESULTS: A total of 21 participants (95.2% with refractory chronic cough, mean age 53.5 years, and 76.2% being males) with Leicester Cough Questionnaire mean ± standard deviation scores of physical 4.8 ± 1.1, psychological 4.4 ± 1.3, social 4.9 ± 1.4, and total 14.1 ± 3.5 were included. The word cloud identified the most frequently used word ('cough'); etiology ('asthma'); and words associated with change in states ('influence,' 'changing,' 'change') and expressions ('tough,' 'pain,' 'hard,' 'terrible,' 'unpleasant'). The patients experienced 'mental/social burden,' 'physical burden,' 'impact on sleep and meals,' 'impact on work and housework,' 'impact on communication,' 'impact on hobbies and leisure,' and 'economic burden.' By closed coding analysis, the situations or types of burden patients experienced from the cough were ordered sequentially as emotion, working style, acquaintanceship, hobbies and leisure, and sleeping pattern. CONCLUSIONS: The present study indicated that there were two types of participant clusters, in which one showed mainly the burdens in the social communications such as work-related communication and another one showed the burdens of relationships with others. Also, some participants highlighted 'mental burden,' on social life due to the current pandemic. To relieve these burdens, disease awareness and knowledge should be improved for patients with refractory and unexplained chronic cough. Trial registration The trial was registered under UMIN-CTR as UMIN000042772, on 17/12/2020. The study was approved by the Medical Corporation Toukeikai Kitamachi Clinic (IRB registration number: 11001110).

Exploring Neurofeedback Training for BMI Power Augmentation of Upper Limbs: A Pilot Study.

Electroencephalography neurofeedback (EEG-NFB) training can induce changes in the power of targeted EEG bands. The objective of this study is to enhance and evaluate the specific changes of EEG power spectral density that the brain-machine interface (BMI) users can reliably generate for power augmentation through EEG-NFB training. First, we constructed an EEG-NFB training system for power augmentation. Then, three subjects were assigned to three NFB training stages, based on a 6-day consecutive training session as one stage. The subjects received real-time feedback from their EEG signals by a robotic arm while conducting flexion and extension movement with their elbow and shoulder joints, respectively. EEG signals were compared with each NFB training stage. The training results showed that EEG beta (12-40 Hz) power increased after the NFB training for both the elbow and the shoulder joints' movements. EEG beta power showed sustained improvements during the 3-stage training, which revealed that even the short-term training could improve EEG signals significantly. Moreover, the training effect of the shoulder joints was more obvious than that of the elbow joints. These results suggest that NFB training can improve EEG signals and clarify the specific EEG changes during the movement. Our results may even provide insights into how the neural effects of NFB can be better applied to the BMI power augmentation system and improve the performance of healthy individuals.

Elevated Membrane Cholesterol Disrupts Lysosomal Degradation to Induce ß-Amyloid Accumulation: The Potential Mechanism Underlying Augmentation of ß-Amyloid Pathology by Type 2 Diabetes Mellitus.

The endocytic membrane trafficking system is altered in the brains of early-stage Alzheimer disease (AD) patients, and endocytic disturbance affects the metabolism of ß-amyloid (Aß) protein, a key molecule in AD pathogenesis. It is widely accepted that type 2 diabetes mellitus (T2DM) is one of the strongest risk factors for development of AD. Supporting this link, experimentally induced T2DM enhances AD pathology in various animal models. Spontaneous T2DM also enhances Aß pathology with severe endocytic pathology, even in nonhuman primate brains. However, it remains unclear how T2DM accelerates Aß pathology. Herein, we demonstrate that cholesterol metabolism-related protein levels are increased and that membrane cholesterol level is elevated in spontaneous T2DM-affected cynomolgus monkey brains. Moreover, in vitro studies that manipulate cellular cholesterol reveal that elevated membrane cholesterol disrupts lysosomal degradation and enhances chemical-induced endocytic disturbance, resulting in great accumulation of Aß in Neuro2a cells. These findings suggest that an alteration of cerebral cholesterol metabolism may be responsible for augmentation of Aß pathology in T2DM-affected brains, which, in turn, may increase the risk for developing AD.

Functional Evaluation of a Force Sensor-Controlled Upper-Limb Power-Assisted Exoskeleton with High Backdrivability.

A power-assisted exoskeleton should be capable of reducing the burden on the wearer's body or rendering his or her work improved and efficient. More specifically, the exoskeleton should be easy to wear, be simple to use, and provide power assistance without hindering the wearer's movement. Therefore, it is necessary to evaluate the backdrivability, range of motion, and power-assist capability of such an exoskeleton. This evaluation identifies the pros and cons of the exoskeleton, and it serves as the basis for its subsequent development. In this study, a lightweight upper-limb power-assisted exoskeleton with high backdrivability was developed. Moreover, a motion capture system was adopted to measure and analyze the workspace of the wearer's upper limb after the exoskeleton was worn. The results were used to evaluate the exoskeleton's ability to support the wearer's movement. Furthermore, a small and compact three-axis force sensor was used for power assistance, and the effect of the power assistance was evaluated by means of measuring the wearer's surface electromyography, force, and joint angle signals. Overall, the study showed that the exoskeleton could achieve power assistance and did not affect the wearer's movements.

Retromer and Rab2-dependent trafficking mediate PS1 degradation by proteasomes in endocytic disturbance.

Accumulating evidence suggests that endocytic pathway deficits are involved in Alzheimer's disease pathogenesis. Several reports show that endocytic disturbance affects ß-amyloid peptide (Aß) cleavage from ß-amyloid precursor protein (APP). Presenilin-1 (PS1) is the catalytic core of the γ-secretase complex required for Aß generation. Previously, we showed that aging induces endocytic disturbance, resulting in the accumulation of Aß and APP in enlarged endosomes. It remains unclear, however, whether PS1 localization and function are affected with endocytic disturbance. Here, we report that in endocytic disturbance, PS1 is transported from endosomes to ER/Golgi compartments via retromer trafficking, and that PS1 interacts with vacuolar protein sorting-associated protein 35 both in vitro and in vivo. Moreover, PS1 is degraded by proteasomes via a Rab2-dependent trafficking pathway, only during endocytic disturbance. These findings suggest that PS1 levels and localization in endosomes are regulated by retromer trafficking and ER-associated degradation system, even if endocytic disturbance significantly induces the endosomal accumulation of APP and ß-site APP-cleaving enzyme 1. Results of this study also suggest that retromer deficiency can affect PS1 localization in endosomes, where Aß cleavage mainly occurs, possibly leading to enhanced Aß pathology. We proposed the following mechanism for intracellular transport of presenilin-1 (PS1). When endosome/lysosome trafficking is disturbed, PS1 is transported from endosome to endoplasmic reticulum (ER)/Golgi compartments via retromer and Rab2-mediated trafficking, and then degraded by endoplasmic reticulum-associated degradation (ERAD). Perturbations in this trafficking can cause abnormal endosomal accumulation of PS1, and then may lead to exacerbated Aß pathology. Cover Image for this issue: doi: 10.1111/jnc.13318.

Genomic and serological detection of bat coronavirus from bats in the Philippines.

Bat coronavirus (BtCoV) is assumed to be a progenitor of severe acute respiratory syndrome (SARS)-related coronaviruses. To explore the distribution of BtCoVs in the Philippines, we collected 179 bats and detected viral RNA from intestinal or fecal samples by RT-PCR. The overall prevalence of BtCoVs among bats was 29.6 %. Phylogenetic analysis of the partial RNA-dependent RNA polymerase gene suggested that one of the detected BtCoVs was a novel alphacoronavirus, while the others belonged to the genus Betacoronavirus. Western blotting revealed that 66.5 % of bat sera had antibodies to BtCoV. These surveys suggested the endemic presence of BtCoVs in the Philippines.

Detection of bat coronaviruses from Miniopterus fuliginosus in Japan.

Bats have great potential as reservoirs for emerging viruses such as severe acute respiratory syndrome-coronavirus. In this study, bat coronaviruses (BtCoVs) were detected by RT-PCR from intestinal and fecal specimens of Miniopterus fuliginosus breeding colonies in Wakayama Prefecture caves, where we previously identified bat betaherpesvirus 2. Two primer sets were used for the detection of BtCoV: one was for the RNA-dependent RNA polymerase (RdRp) region and the other was for the spike (S) protein region. Eleven and 73% of intestinal and fecal specimens, respectively, were positive for RdRp region, and 2 and 40% of those were positive for S protein region. Sequencing and phylogenetic analysis showed that the detected BtCoV belonged to the group 1 (alpha) coronaviruses. These data suggest that BtCoV is endemic in M. fuliginosus in Japan.

Incremental medical cost of delirium in elderly patients with cognitive impairment: analysis of a nationwide administrative database in Japan.

OBJECTIVES: Delirium is a neuropsychiatric disorder that commonly occurs in elderly patients with cognitive impairment. The economic burden of delirium in Japan has not been well characterised. In this study, we assessed incremental medical costs of delirium in hospitalised elderly Japanese patients with cognitive impairment. DESIGN: Retrospective, cross-sectional, observational study. SETTING: Administrative data collected from acute care hospitals in Japan between April 2012 and September 2020. PARTICIPANTS: Hospitalised patients ≥65 years old with cognitive impairment were categorised into groups-with and without delirium. Delirium was identified using a delirium identification algorithm based on the International Classification of Diseases 10th Revision codes or antipsychotic prescriptions. OUTCOME MEASURES: Total medical costs during hospitalisation were compared between the groups using a generalised linear model. RESULTS: The study identified 297 600 hospitalised patients ≥65 years of age with cognitive impairment: 39 836 had delirium and 257 764 did not. Patient characteristics such as age, sex, inpatient department and comorbidities were similar between groups. Mean (SD) unadjusted total medical cost during hospitalisation was 979 907.7 (871 366.4) yen for patients with delirium and 816 137.0 (794 745.9) yen for patients without delirium. Adjusted total medical cost was significantly greater for patients with delirium compared with those without delirium (cost ratio=1.09, 95% CI: 1.09 to 1.10; p<0.001). Subgroup analyses revealed significantly higher total medical costs for patients with delirium compared with those without delirium in most subgroups except patients with hemiplegia or paraplegia. CONCLUSIONS: Medical costs during hospitalisation were significantly higher for patients with delirium compared with those without delirium in elderly Japanese patients with cognitive impairment, regardless of patient subgroups such as age, sex, intensive care unit admission and most comorbidities. These findings suggest that delirium prevention strategies are critical to reducing the economic burden as well as psychological/physiological burden in cognitively impaired elderly patients in Japan.

Demographic and clinical characteristics of patients with delirium: analysis of a nationwide Japanese medical database.

OBJECTIVES: Delirium commonly occurs during hospitalisation and is associated with increased mortality, especially in elderly patients. This study aimed to determine the demographic and clinical characteristics of patients with delirium in the Japanese real-world clinical setting using a nationwide database comprising claims and discharge abstract data. DESIGN: This was an observational, cross-sectional, retrospective study in hospitalised patients with an incident delirium identified by a diagnosis based on International Classification of Diseases, 10th Revision codes or initiating antipsychotics recommended for delirium treatment in Japan during their hospitalisation. SETTING: Patients from the Medical Data Vision database including more than 400 acute care hospitals in Japan were evaluated from admission to discharge. PARTICIPANTS: Of the 32 910 227 patients who were included in the database between April 2012 and September 2020, a total of 145 219 patients met the criteria for delirium. PRIMARY AND SECONDARY OUTCOME MEASURES: Demographic and baseline characteristics, comorbidities, clinical profiles and pharmacological treatments were evaluated in patients with delirium. RESULTS: The mean (SD) patient age was 76.5 (13.8) years. More than half of the patients (n=82 159; 56.6%) were male. The most frequent comorbidities were circulatory system diseases, observed in 81 954 (56.4%) patients. Potentially inappropriate medications (PIMs) with risk of delirium including benzodiazepines and opioids were prescribed to 76 798 (52.9%) patients. Approximately three-fourths of these patients (56 949; 74.2%) were prescribed ≥4 PIMs. The most prescribed treatment for delirium was injectable haloperidol (n=82 490; 56.8%). Mean (SD) length of hospitalisation was 16.0 (12.1) days. CONCLUSIONS: The study results provide comprehensive details of the clinical characteristics of patients with delirium and treatment patterns with antipsychotics in the Japanese acute care setting. In this patient population, the prescription rate of injectable haloperidol and PIMs was high, suggesting the need for improved understanding among healthcare providers about the appropriate management of delirium, which may benefit patients.

Proton conductivity in mixed cation phosphate, KMg1-xH2x(PO3)·yH2O, with a layered structure at low-intermediate temperatures.

Proton solid electrolytes, which exhibit high proton conductivity at a wide range of low-intermediate temperatures (150-300 °C), are key materials for the development of fuel cells for automobiles and cogeneration systems. In this study, a benitoite-type polyphosphate, KMg1-xH2x(PO3)·yH2O, which has a non-combustible and layered structure, was investigated as a new proton conductor. The benitoite-type KMg1-xH2x(PO3)·yH2O was synthesised by a coprecipitation method. The solid solution formed in the range of x = 0-0.100 in KMg1-xH2x(PO3)3·yH2O. Multi-step weight loss due to dehydration was observed for TG/DTA measurement at 30 °C and 150 °C. We observed enhanced peaks of the vibration bands at around 1117 cm-1 and 1229 cm-1, which were attributed to the symmetric and asymmetric PO2 vibration modes, and at 743 cm-1 and 970 cm-1 due to the ns(P-O-P) and nas(P-O-P) modes as well as broad absorbance peaks at 2300 cm-1 and 2700 cm-1 corresponding to the vibration modes of ns(P-O-H) with increasing x for FTIR spectra, which suggest the introduction of protons to the crystal structure. Proton conductivity increased from x = 0 to 0.10 and then decreased at x = 0.125, where the impurity phase was observed. The sample with x = 0.10 in benitoite-type KMg1-xH2x(PO3)3·yH2O exhibited high proton conductivity of 1.4 × 10-3 S cm-1 at 150 °C and 6.5 × 10-3 S cm-1 at 250 °C under a non-humidified N2 gas flow.

Novel betaherpesvirus in bats.

Because bats are associated with emerging zoonoses, identification and characterization of novel viruses from bats is needed. Using a modified rapid determination system for viral RNA/DNA sequences, we identified a novel bat betaherpesvirus 2 not detected by herpesvirus consensus PCR. This modified system is useful for detecting unknown viruses.

Bat coronaviruses and experimental infection of bats, the Philippines.

Fifty-two bats captured during July 2008 in the Philippines were tested by reverse transcription-PCR to detect bat coronavirus (CoV) RNA. The overall prevalence of virus RNA was 55.8%. We found 2 groups of sequences that belonged to group 1 (genus Alphacoronavirus) and group 2 (genus Betacoronavirus) CoVs. Phylogenetic analysis of the RNA-dependent RNA polymerase gene showed that groups 1 and 2 CoVs were similar to Bat-CoV/China/A515/2005 (95% nt sequence identity) and Bat-CoV/HKU9-1/China/2007 (83% identity), respectively. To propagate group 2 CoVs obtained from a lesser dog-faced fruit bat (Cynopterus brachyotis), we administered intestine samples orally to Leschenault rousette bats (Rousettus leschenaulti) maintained in our laboratory. After virus replication in the bats was confirmed, an additional passage of the virus was made in Leschenault rousette bats, and bat pathogenesis was investigated. Fruit bats infected with virus did not show clinical signs of infection.

Molecular cloning and expression analysis of bat toll-like receptors 3, 7 and 9.

In this study, cDNA of Toll-like receptors (TLR) 3, 7 and 9 were synthesized and completely sequenced. The coding regions of cDNA for bat TLR3, TLR7 and TLR9 were 2,718, 3,150 and 3,090 bp in length, respectively. The open reading frames encoded 905, 1,049 and 1,029 amino acids for TLR3, TLR7 and TLR9, respectively. The nucleotide sequences, predicted amino acid sequences and predicted domain structures of the three bat TLRs had high homology with those of other mammals. In addition, the expression profiles of each TLR in main organs were analyzed. Expression of TLR3 was highest in the liver, whereas the expressions of TLR7 and TLR9 were highest in the spleen.

Detection of a new bat gammaherpesvirus in the Philippines.

A new bat herpesvirus was detected in the spleen of an insectivorous bat (Hipposideros diadema, family Hipposideridae) collected on Panay Island, the Philippines. PCR analyses were performed using COnsensus-DEgenerate Hybrid Oligonucleotide Primers (CODEHOPs) targeting the herpesvirus DNA polymerase (DPOL) gene. Although we obtained PCR products with CODEHOPs, direct sequencing using the primers was not possible because of high degree of degeneracy. Direct sequencing technology developed in our rapid determination system of viral RNA sequences (RDV) was applied in this study, and a partial DPOL nucleotide sequence was determined. In addition, a partial gB gene nucleotide sequence was also determined using the same strategy. We connected the partial gB and DPOL sequences with long-distance PCR, and a 3741-bp nucleotide fragment, including the 3' part of the gB gene and the 5' part of the DPOL gene, was finally determined. Phylogenetic analysis showed that the sequence was novel and most similar to those of the subfamily Gammaherpesvirinae.

Molecular cloning and sequencing of the cDNAs encoding the bat interleukin (IL)-2, IL-4, IL-6, IL-10, IL-12p40, and tumor necrosis factor-alpha.

This is the first report on the cDNA sequences of bat interleukin (IL)-2, IL-4, IL-6, IL-10, IL-12 p40, and tumor necrosis factor (TNF)-alpha. The cDNAs of bat IL-2, IL-4, IL-6, IL-10, IL-12 p40, and TNF-alpha comprise 459, 405, 624, 537, 990, and 699 base pairs respectively. Moreover, each of the cDNAs of bat IL-2, IL-4, IL-6, IL-10, IL-12 p40, and TNF-alpha contain a single open reading frames encoding 152, 134, 207, 178, 329, and 232 amino acids, respectively. The comparison of bat cytokines with Perrissodactyla (horse), Carnivora (dog and cat), and Cetartiodactyla (cattle and pig) orthologs revealed a high degree of homology. Although the N-terminal amino acids and cysteine residues are highly conserved in each mature cytokine, the deduced N-linked glycosylation sites vary across species.

Feature Extraction of Shoulder Joint's Voluntary Flexion-Extension Movement Based on Electroencephalography Signals for Power Assistance.

Brain-Machine Interface (BMI) has been considered as an effective way to help and support both the disabled rehabilitation and healthy individuals' daily lives to use their brain activity information instead of their bodies. In order to reduce costs and control exoskeleton robots better, we aim to estimate the necessary torque information for a subject from his/her electroencephalography (EEG) signals when using an exoskeleton robot to perform the power assistance of the upper limb without using external torque sensors nor electromyography (EMG) sensors. In this paper, we focus on extracting the motion-relevant EEG signals' features of the shoulder joint, which is the most complex joint in the human's body, to construct a power assistance system using wearable upper limb exoskeleton robots with BMI technology. We extract the characteristic EEG signals when the shoulder joint is doing flexion and extension movement freely which are the main motions of the shoulder joint needed to be assisted. Independent component analysis (ICA) is used to extract the source information of neural components, and then the average method is used to extract the characteristic signals that are fundamental to achieve the control. The proposed approach has been experimentally verified. The results show that EEG signals begin to increase at 300⁻400 ms before the motion and then decrease at the beginning of the generation of EMG signals, and the peaks appear at about one second after the motion. At the same time, we also confirmed the relationship between the change of EMG signals and the EEG signals on the time dimension, and these results also provide a theoretical basis for the delay parameter in the linear model which will be used to estimate the necessary torque information in future. Our results suggest that the estimation of torque information based on EEG signals is feasible, and demonstrate the potential of using EEG signals via the control of brain-machine interface to support human activities continuously.

The spontaneously diabetic Torii rat with gastroenteropathy.

The spontaneously diabetic Torii (SDT) rat was recently recognized as a new animal model of non-obese type 2 diabetes. As the severe diabetic ocular complications seen in SDT rats already have been investigated, we examined another common diabetic complication, gastroenteropathy. Male SDT rats developed diabetes at 20 weeks and diarrhea at 28 weeks of age. Gastrointestinal motility was evaluated at 28 weeks by measuring the distance of small intestinal transit by oral administration of the non-absorbed marker, arabic gum. SDT rats exhibited greater intestinal transit distance than control SD rats (54.1+/-2.6% versus 43.0+/-1.2%). Insulin treatment of SDT rats begun at 20 weeks of age produced improved stool and reduced intestinal transit distance (41.4+/-0.3%). Morphologically, the SDT rats exhibited longer villi and heavier weight of intestine compared to control SD rats. These results suggest that the SDT rat may be a useful animal model for studies of diabetic gastroenteropathy.

Factors responsible for deteriorating glucose tolerance in newly diagnosed type 2 diabetes in Japanese men.

Hyperglycemia frequently continues to worsen even after the diagnosis of overt diabetes. The aim of this study is to evaluate the factors contributing to increasing glucose intolerance after onset of type 2 diabetes in Japanese subjects. Five hundred fifty newly diagnosed type 2 diabetic patients were classified into 3 degrees of hyperglycemia based on plasma glucose levels estimated by 75-g oral glucose tolerance test: diabetes mellitus with isolated fasting hyperglycemia (DM/IFH), DM with isolated postchallenge hyperglycemia (DM/IPH), and DM with fasting and postchallenge hyperglycemia (DM/FPH). In addition, the DM/IFH and DM/IPH groups were subdivided to clarify the determinants of fasting and postchallenge hyperglycemia. Insulin secretion was evaluated by insulinogenic index, and insulin sensitivity was evaluated by composite index of insulin sensitivity (ISI composite). The insulinogenic index in DM/IFH was highest of the 3 groups (P < .0001). The insulinogenic index in DM/IPH was higher than in DM/FPH (P < .0001). The international sensitivity index composite in DM/IPH was highest of the 3 groups (P < .05). Although impaired early-phase insulin secretion plays the crucial role in deterioration from DM/IFH to DM/FPH in Japanese subjects, impaired early-phase insulin secretion and decreased insulin sensitivity both are factors in deterioration from DM/IPH to DM/FPH. In addition, comparison of subgroups of DM/IFH and DM/IPH shows that although decreased early-phase insulin secretion plays the more significant role in postchallenge hyperglycemia in Japanese subjects, insulin sensitivity is the more important factor in fasting hyperglycemia.

Insulin secretion and insulin sensitivity in Japanese subjects with impaired fasting glucose and isolated fasting hyperglycemia.

Impaired fasting glucose (IFG) is a subgroup of impaired glucose regulation exhibiting an elevated fasting glucose levels without elevated 2-h glucose levels on oral glucose tolerance test (OGTT). Diabetes mellitus with isolated fasting hyperglycemia (DM/IFH) is a similar subgroup of diabetes having higher fasting glucose levels with 2-h glucose levels within the non-diabetic range. The aim of this study is to profile the characteristics of these subgroups to estimate the factors involved in the development from normal glucose tolerance (NGT) via IFG to DM/IFH. Five hundred and sixty seven Japanese males were classified on the basis of 75 g OGTT into four groups, NGT, IFG, DM/IFH, and isolated impaired glucose tolerance (isolated IGT). Insulin secretion was evaluated by insulinogenic index, insulin sensitivity was evaluated by ISI composite, and insulin secretory patterns were compared additionally. IFG and DM/IFH subjects exhibited both lower insulin secretion and lower insulin sensitivity than NGT subjects. There was an insulin peak in NGT, IFG, and DM/IFH at 60 min, which did not occur in isolated IGT. Impaired early-phase and basal insulin secretion and decreased insulin sensitivity both are estimated as factors in progression from NGT via IFG to DM/IFH in these subjects. IFG and DM/IFH subjects have definite fasting hyperglycemia in contrast to isolated IGT subjects, 2-h glucose levels being maintained within the non-diabetic range partly by the insulin peak at 60 min.