Oral mouthwashes for asymptomatic to mildly symptomatic adults with COVID-19 and salivary viral load: a randomized, placebo-controlled, open-label clinical trial.

BACKGROUND: Recent randomized clinical trials suggest that the effect of using cetylpyridinium chloride (CPC) mouthwashes on the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load in COVID-19 patients has been inconsistent. Additionally, no clinical study has investigated the effectiveness of on-demand aqueous chlorine dioxide mouthwash against COVID-19. METHODS: We performed a randomized, placebo-controlled, open-label clinical trial to assess for any effects of using mouthwash on the salivary SARS-CoV-2 viral load among asymptomatic to mildly symptomatic adult COVID-19-positive patients. Patients were randomized to receive either 20 mL of 0.05% CPC, 10 mL of 0.01% on-demand aqueous chlorine dioxide, or 20 mL of placebo mouthwash (purified water) in a 1:1:1 ratio. The primary endpoint was the cycle threshold (Ct) values employed for SARS-CoV-2 salivary viral load estimation. We used linear mixed-effects models to assess for any effect of the mouthwashes on SARS-CoV-2 salivary viral load. RESULTS: Of a total of 96 eligible participants enrolled from November 7, 2022, to January 19, 2023, 90 were accepted for the primary analysis. The use of 0.05% CPC mouthwash was not shown to be superior to placebo in change from baseline salivary Ct value at 30 min (difference vs. placebo, 0.640; 95% confidence interval [CI], -1.425 to 2.706; P = 0.543); 2 h (difference vs. placebo, 1.158; 95% CI, -0.797 to 3.112; P = 0.246); 4 h (difference vs. placebo, 1.283; 95% CI, -0.719 to 3.285; P = 0.209); 10 h (difference vs. placebo, 0.304; 95% CI, -1.777 to 2.385; P = 0.775); or 24 h (difference vs. placebo, 0.782; 95% CI, -1.195 to 2.759; P = 0.438). The use of 0.01% on-demand aqueous chlorine dioxide mouthwash was also not shown to be superior to placebo in change from baseline salivary Ct value at 30 min (difference vs. placebo, 0.905; 95% CI, -1.079 to 2.888; P = 0.371); 2 h (difference vs. placebo, 0.709; 95% CI, -1.275 to 2.693; P = 0.483); 4 h (difference vs. placebo, 0.220; 95% CI, -1.787 to 2.226; P = 0.830); 10 h (difference vs. placebo, 0.198; 95% CI, -1.901 to 2.296; P = 0.854); or 24 h (difference vs. placebo, 0.784; 95% CI, -1.236 to 2.804; P = 0.447). CONCLUSIONS: In asymptomatic to mildly symptomatic adults with COVID-19, compared to placebo, the use of 0.05% CPC and 0.01% on-demand aqueous chlorine dioxide mouthwash did not lead to a significant reduction in SARS-CoV-2 salivary viral load. Future studies of the efficacy of CPC and on-demand aqueous chlorine dioxide mouthwash on the viral viability of SARS-CoV-2 should be conducted using different specimen types and in multiple populations and settings.

Construction of pyrazolodiazepines using AuI, a dual functional gold catalyst.

N,N'-5,7-Fused compounds are important molecules exhibiting medicinal potential. Herein, we report a practical and robust method for synthesising pyrazolodiazepines from N-piperidinyl alkynylhydrazides using a AuI catalyst. The broad substrate scope of alkynylhydrazides and synthetic application of pyrazolodiazepines are demonstrated. In addition, control experiments provide detailed information on the reaction mechanism, in which AuI promotes both the sequential intramolecular nucleophilic addition and the double nucleophilic substitution reaction as a π-acidic and nucleophilic dual functional catalyst.

Protein-losing enteropathy caused by disseminated Mycobacterium avium complex infection in a patient receiving antiretroviral therapy: an autopsy case report.

BACKGROUND: Disseminated Mycobacterium avium complex infection is an important indicator of acquired immunodeficiency syndrome (AIDS) in patients with advanced human immunodeficiency virus (HIV) infection. Effective antiretroviral therapy has dramatically reduced the incidence of and mortality due to HIV infection, although drug resistance and poor medication adherence continue to increase the risk of disseminated M. avium complex infection. However, gastrointestinal lesions in cases of disseminated M. avium complex infection resulting in protein-losing enteropathy have been rarely discussed. Therefore, we present a case of protein-losing enteropathy caused by disseminated M. avium complex infection in a patient undergoing antiretroviral therapy. CASE PRESENTATION: A 29-year-old man was diagnosed with AIDS 4 years ago and was admitted for a 10-month history of refractory diarrhea and fever. Despite receiving antiretroviral therapy, the viral load remained elevated due to poor medication adherence. The patient was diagnosed with disseminated M. avium complex infection and started on antimycobacterial drugs 2 years before admission. However, the infection remained uncontrolled. The previous hospitalization 1 year before admission was due to hypoalbuminemia and refractory diarrhea. Upper gastrointestinal endoscopy revealed a diagnosis of protein-losing enteropathy caused by intestinal lymphangiectasia, and treatment with intravenous antimycobacterial drugs did not resolve his intestinal lymphangiectasia. The patient inevitably died of sepsis. CONCLUSIONS: Clinical remission is difficult to achieve in patients with AIDS and protein-losing enteropathy caused by disseminated M. avium complex infection due to limited options of parenteral antiretroviral drugs. This report highlights the importance of identifying alternative treatments (such as an injectable formulation) for patients who do not respond to antiretroviral therapy due to protein-losing enteropathy with disseminated M. avium complex infection.

Epidemiological trends of imported infectious diseases in Japan: Analysis of imported 2-year infectious disease registry data.

INTRODUCTION: The epidemiology of infectious diseases in Japan remains undefined despite the increasing tourism. GeoSentinel, an epidemiological surveillance system for reporting imported infectious diseases, has only two participating facilities in Japan. Although the number of infectious diseases is reported by the National Institute of Infectious Diseases, there is no detailed clinical information about these cases. Therefore, we established J-RIDA (Japan Registry for Infectious Diseases from Abroad) to clarify the status of imported infectious diseases in Japan and provide detailed information. METHODS: J-RIDA was started as a registry of imported infectious diseases. Case registration began in October 2017. Between October 2017 and September 2019, 15 medical institutions participated in this clinical study. The registry collected information about the patient's age, sex, nationality, chief complaint, consultation date, date of onset, whether visit was made to a travel clinic before travel, blood test results (if samples were collected), travel history, and final diagnosis. RESULTS: Of the 3046 cases included in this study, 46.7% to Southeast Asia, 13.0% to Africa, 13.7% to East Asia, 11.5% to South Asia, 7.5% to Europe, 3.8% to Central and South America, 4.6% to North America, 3.9% to Oceania, and 2.8% to Central and west Asia. More than 85% of chief complaints were fever and general symptoms, gastrointestinal symptoms, respiratory symptoms, or dermatologic problems. The most common diseases were travelers' diarrhea, animal bite, upper respiratory infection, influenza, and dengue fever. CONCLUSIONS: We summarized two-year cases registered in Japan's imported infectious disease registry. These results will significantly contribute to the epidemiology in Japan.

Copper-Catalyzed Cycloisomerization of Cyclopropenylimine for Synthesis of Pyrroles.

Copper-catalyzed cycloisomerization of 3-iminocyclopropenes for synthesis of pyrroles has been developed. The reaction allows regioselective construction of pyrroles with various substitution patterns, including fully substituted pyrroles. The method was successfully applied to synthesis of steroidal pyrroles as well as a N-fused pyrrole.

Design of time-delayed connection parameters for inducing amplitude death in high-dimensional oscillator networks.

The present paper studies time-delayed-connection induced amplitude death in high-dimensional oscillator networks. We provide two procedures for design of a coupling strength and a transmission delay: these procedures do not depend on the topology of oscillator networks (i.e., network structure and number of oscillators). A graphical procedure based on the Nyquist criterion is proposed and then is numerically confirmed for the case of five-dimensional oscillators, called generalized Rössler oscillators, which have two pairs of complex conjugate unstable roots. In addition, for the case of high-dimensional oscillators having two unstable roots, the procedure can be systematically carried out using only a simple algebraic calculation. This systematic procedure is numerically confirmed for the case of three-dimensional oscillators, called Moore-Spiegel oscillators, which have two positive real unstable roots.

Delay-induced amplitude death in multiplex oscillator network with frequency-mismatched layers.

The present paper analytically investigates the stability of amplitude death in a multiplex Stuart-Landau oscillator network with a delayed interlayer connection. The network consists of two frequency-mismatched layers, and all oscillators in each layer have identical frequencies. We show that, if the matrices describing the network topologies of each layer commute, then the characteristic equation governing the stability can be reduced to a simple form. This form reveals that the stability of amplitude death in the multiplex network is equally or more conservative than that in a pair of frequency-mismatched oscillators coupled by a delayed connection. In addition, we provide a procedure for designing the delayed interlayer connection such that amplitude death is stable for any commuting matrices and for any intralayer coupling strength. These analytical results are verified through numerical examples. Moreover, we numerically discuss the results for the case in which the commutative property does not hold.

Protocol for a Randomized, Open-Label Clinical Trial on the Effect of Mouthwash on Salivary SARS-CoV-2 Load.

Mouthwashes containing cetylpyridinium chloride (CPC) or on-demand aqueous chlorine dioxide (ACD) have potential to reduce the salivary severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) load in individuals with SARS-CoV-2 infection. This study will evaluate the effect of CPC and on-demand ACD mouthwashes on salivary SARS-CoV-2 levels in individuals with acute asymptomatic or mild SARS-CoV-2 infection (COVID-19) staying in a residential recuperation facility in Osaka, Japan. This randomized, open-label clinical trial will include three equal-sized groups (CPC mouthwash, on-demand ACD mouthwash, and placebo), with 30 participants per group. A stratified replacement block method will be used to ensure balanced allocation based on symptom presence and days since symptom onset. Participants will use mouthwash at set times for 7 days or until the end of recuperation. Saliva samples will be collected at multiple time points and tested for SARS-CoV-2 using quantitative reverse transcription polymerase chain reaction. The primary outcome will be changes in salivary SARS-CoV-2 viral load 2 h after the first mouthwash use compared with the pre-mouthwash level. Secondary outcomes will include changes in salivary viral load and clinical parameters at different time points. This study was registered with the Japan Registry of Clinical Trials on 18 October 2022 (jRCTs051220107).

Amplitude death in delay-coupled oscillators on directed graphs.

The present paper investigates amplitude death (AD) in delay-coupled oscillators on directed graphs, in which the connection delays among oscillators are heterogeneous. We reveal that a linear stability analysis of AD can be significantly simplified by focusing on directed cycles in the graph. First, it is proven that the characteristic function of a steady state can be factorized into several functions that can be analyzed independently. Second, we show that the number of connection parameters to be considered for the stability analysis can be reduced, because the stability depends on the sums of connection delays for directed cycles and is independent of the connection delays on edges that do not form directed cycles. The theoretical results are verified through numerical simulations.

Synchronization of relaxation oscillators with adaptive thresholds and application to automated guided vehicles.

The present paper proposes an adaptive control law for inducing in-phase and antiphase synchronization in a pair of relaxation oscillators. We analytically show that the phase dynamics of the oscillators coupled by the control law is equivalent to that of Kuramoto phase oscillators and then extend the results for a pair of oscillators to three or more oscillators. We also provide a systematic procedure for designing the controller parameters for oscillator networks with all-to-all and ring topologies. Our numerical simulations demonstrate that these analytical results can be used to solve a dispatching problem encountered by automated guided vehicles (AGVs) in factories. AGV congestion can be avoided and the peak value of the amount of materials or parts in buffers can be suppressed.

Sarcopenia among people living with HIV and the effect of antiretroviral therapy on body composition.

To investigate the prevalence of sarcopenia among people living with HIV (PLWH) in Japan and analyze the relationship between HIV infection and ART effects on the body composition of Japanese PLWH for more appropriate drug selection and lifestyle guidance. Cross-sectional observational study. We included male patients aged ≥ 60 years whose body composition was measured by InBody 570 body composition analyzer during outpatient visits. Patients were classified by body shape based on body mass index (BMI) and body fat percentage measurements and by tenofovir alafenamide administration. Hidden obesity is a condition wherein the BMI is within the standard range but the body fat percentage is higher than the reference. Patients with low muscle mass and strength were considered to have sarcopenia, whereas those with only low muscle strength were considered to have pre-sarcopenia. In total, 87 patients were included. Based on body shape determined by BMI and body fat percentage, most patients had hidden obesity (40 patients, 46.0%). Sarcopenia was detected in 9 patients (10.3%) and pre-sarcopenia in 14 patients (16.1%). The tenofovir alafenamide (TAF) use group had significantly higher BMI, higher skeletal muscle mass, body fat mass, and skeletal muscle mass index relative to the non-TAF use group. Hidden obesity is a risk for lifestyle diseases. It is important to recognize it based on body composition measurements because it can be missed by BMI measurement alone. Tenofovir alafenamide therapy increases skeletal muscle mass, which may result in the prevention of sarcopenia. To clarify how TAF affects the development of sarcopenia and lifestyle diseases, future studies on a larger cohort are warranted.

Design of external forces for eliminating traveling wave in a piecewise linear FitzHugh-Nagumo model.

Elimination and control of nonlinear phenomena in excitable media are important for academic interests and practical applications. This paper provides a systematic procedure to design external forces for eliminating a traveling wave in a one-dimensional piecewise linear FitzHugh-Nagumo model. This procedure allows us to design nonfeedback and feedback control systems. The feedback control systems are designed using classical control theory. Furthermore, this procedure is extended to a two-dimensional model and verified using numerical simulation.

Experimental verification of synchronization in pulse-coupled oscillators with a refractory period and frequency distribution.

We propose herein globally pulse-coupled electronic-circuit oscillators with a refractory period and frequency distribution. The synchronization of such oscillators, which was analyzed by Konishi and Kokame [Chaos 18, 033132 (2008)], is verified by circuit experiments. Furthermore, we investigate a cluster state in the oscillators and analytically derive a simple condition to estimate the maximum possible number of clusters, which is confirmed by the circuit experiments.

Effects of frequency mismatch on amplitude death in delay-coupled oscillators.

The present paper analytically reveals the effects of frequency mismatch on the stability of an equilibrium point within a pair of Stuart-Landau oscillators coupled by a delay connection. By analyzing the roots of the characteristic function governing the stability, we find that there exist four types of boundary curves of stability in a coupling parameters space. These four types depend only on the frequency mismatch. The analytical results allow us to design coupling parameters and frequency mismatch such that the equilibrium point is locally stable. We show that, if we choose appropriate frequency mismatches and delay times, then it is possible to induce amplitude death with strong stability, even by weak coupling. In addition, we show that parts of these analytical results are valid for oscillator networks with complete bipartite topologies.

Chronic cystoisosporiasis in an immunocompetent adult: A case report.

RATIONALE: Cystoisosporiasis is an intestinal infectious disease caused by a coccidian protozoa, Cystoisospora belli (C. belli). It can cause prolonged and refractory diarrhea most commonly in immunocompromised patients, while immunocompetent individuals usually exhibit no symptoms or self-limited diarrhea. PATIENT CONCERNS: We herein report a case of chronic cystoisosporiasis in an immunocompetent patient. A 62-year-old man, who had been first diagnosed with cystoisosporiasis 15 years ago and had been treated with oral administration of trimethoprim-sulfamethoxazole (TMP-SMX), complained of persistent watery diarrhea. He was negative for anti-human immunodeficiency virus antibody and anti-human T-cell leukemia virus type 1 (HTLV-1) antibody. DIAGNOSIS: Biopsy specimens from the duodenum revealed oocysts in the atrophic absorptive epithelium and protozoa were detected through stool examination, indicating the recurrence of cystoisosporiasis. Capsule endoscopy showed diffuse atrophic mucosa with white villi in the entire small intestine. We diagnosed him with chronic cystoisosporiasis that occurred in an immunocompetent adult. INTERVENTIONS: Since oral administration of TMP-SMX and ciprofloxacin were ineffective, the intravenous administration of TMP-SMX was initiated. OUTCOMES: Intravenous TMP-SMX exhibited a significant improvement. LESSONS: This case indicates that even immunocompetent individuals may develop recurrent and refractory cystoisosporiasis. Furthermore, intravenous treatment of antibiotic agents should be considered when the impaired absorptive ability from the small intestine is suspected.

Copper-Catalyzed Sequential Cyclization/Migration of Alkynyl Hydrazides for Construction of Ring-Expanded N-N Fused Pyrazolones.

A copper-catalyzed sequential cyclization/migration reaction of alkynyl hydrazides for the synthesis of ring-expanded N-N fused pyrazolones was developed. Control experiments indicate that the copper-ligand complex plays an essential role in the reaction. This approach features a broad scope including some functional group tolerance as well as a nucleophilic addition/1,3-migration/formal 1,2-migration sequence. This protocol provides simple manipulation and less waste due to high yield and atom economy. The synthetic utility of N-N fused pyrazolones was also demonstrated by further transformations.

Amplitude suppression of oscillators with delay connections and slow switching topology.

The present paper shows that the amplitudes of oscillators in delay-coupled oscillator networks can be suppressed by switching the network topology at a rate much lower than the oscillator frequencies. The mechanism of suppression was clarified numerically, and a procedure for determining the connection parameters to induce suppression is presented. The analytical and numerical results were obtained with Stuart-Landau oscillators and were experimentally validated using double-scroll chaotic circuits.

Synthesis of Pyrazoles Utilizing the Ambiphilic Reactivity of Hydrazones.

A Brønsted acid-mediated synthesis of pyrazoles from conjugated hydrazones through a ß-protonation/nucleophilic addition/cyclization/aromatization sequence was developed. This protocol utilizing the ambiphilic reactivity of hydrazones enables not only self-condensation but also cross-condensation, affording multisubstituted pyrazoles in high yields, with a broad substrate scope. This sequential reaction proceeds under mild conditions via a simple operation. Moreover, the method can be applied to the synthesis of a nonsteroidal anti-inflammatory drug, Lonazolac.

Factors affecting the physician-patient relationship regarding patient participation in medical encounters in primary care.

BACKGROUND: Supporting the patient's right to participate more actively in medical encounters is recommended. However, the physician-patient relationship in the context of the respect for patient participation is unclear. OBJECTIVE: To reveal the factors affecting the physician-patient relationship regarding patient participation in medical encounters in primary care. METHODS: A qualitative study incorporating a focus group interview with five female participants. They belonged to a consumer organization, which represents patients who actively participate in medical consultations. Patient behaviors, which constitute active participation, are designated as expressing their concern, asking questions, and stating their expectations in medical consultations. The recorded interview was transcribed, and analyzed with a constant comparison method. RESULTS: Four categories explaining the physician-patient relationship were extracted: Physicians' attitude; Patients' attitude; Other medical professionals' attitudes; Time environmental factors. Story lines were described; Other Medical professionals' attitudes and Time environmental factors were involved in the physician-patient relationship in accordance with the situation; Physicians' attitude and Patients' attitude had borne some mutual relations; when Patients' attitude to consultation had been active, physicians sometimes could have an aversion to these patients. CONCLUSIONS: The patients' behaviors of active participation in medical encounters contributed to physicians' aversion to patients and lead the physician-patient relationship in an unfavorable direction. Physicians' attitude is of central concern for establishing the physician-patient relationship.

Amplitude death in time-delay nonlinear oscillators coupled by diffusive connections.

This paper analyzes the stability of the amplitude death phenomenon that occurs in a pair of scalar time-delay nonlinear oscillators coupled by static, dynamic, and delayed connections. Stability analysis shows that static connections never induce death in time-delay oscillators. Further, for the case of dynamic and delayed connections, a simple instability condition under which death never occurs is derived. A systematic procedure for estimating the boundary curves of death regions is also provided. These analytical results are then verified by electronic circuit experiments.