A novel zinc-chelating compound has antifungal activity against a wide range of Candida species, including multidrug-resistant Candida auris.

Objectives: In recent years, the incidence of invasive fungal infections has increased, resulting in considerable morbidity and mortality, particularly among immunocompromised individuals. Potential challenges in treating these infections with the few existing antifungal agents highlight the urgency of developing new ones. Here, we evaluated six alkyl polyamine compounds (APCs), not previously reported as antifungal drugs to our knowledge, that could deprive fungi of essential transition metals. Methods: The APC with confirmed antifungal activity against Candida spp. was analysed by using transcriptomics, followed by metal-addition experiments, mass spectrometric analyses and intracellular zinc quantification with a fluorescent probe. Results: A cyclic APC with three pyridylmethyl groups, APC6, had high antifungal activity against a wide range of Candida species, including MDR Candida auris. We conclusively demonstrated that APC6 was able to capture zinc within fungal cells. APC6 not only exhibited activity against C. auris as a single agent but also enhanced the efficacy of an azole antifungal agent, voriconazole, in vitro and in vivo. APC6 disrupted the biofilms formed by Candida species. Conclusions: This zinc-chelating compound has potential as an antifungal agent, and the control of zinc levels in Candida species could be a powerful approach to treating drug-resistant candidiasis.

Bloodstream infection caused by Wickerhamiella pararugosa in a patient with intestinal obstruction: A case report.

The fungus Wickerhamiella pararugosa (Candida pararugosa) has been detected in various human organs but has rarely caused bloodstream infections. This report presents a case of central venous catheter-related bloodstream infection (CRBSI) of W. pararugosa in an adult. A female patient in her 80s was admitted to our facility for intestinal obstruction caused by colorectal cancer. The patient's ability to consume food was hindered, necessitating the insertion of a central venous catheter (CVC) into the internal jugular vein. On day 3 after admission, the patient developed a fever, prompting blood and CVC tip cultures to be performed. On day 5, yeast-like fungi were discovered in the blood cultures, and fosfluconazole (fluconazole [FLCZ] pro-drug) treatment was initiated. On day 8, yeast-like fungi were identified in both the blood and CVC tip cultures, leading to a diagnosis of CRBSI. The fungus was identified as W. pararugosa through biochemical and genetic characterization. This finding justified the use of micafungin (MCFG) for combination therapy. On day 17, the minimum inhibitory concentrations (MIC) for FLCZ and MCFG were 4-8 and 0.06 µg/mL, respectively. Accordingly, the treatment was changed to monotherapy with MCFG. After a 21-day treatment regimen, the patient was discharged on day 31. We present a case of CRBSI caused by W. pararugosa in an adult with intestinal obstruction. The notable increase in the MIC of FLCZ necessitated monotherapy with MCFG, which resulted in successful recovery of the patient.

Pre-Transplant Seroprevalence, Associated Factors, and Post-Transplant Incidence of Toxoplasma gondii Infection Among Heart Transplant Recipients in Japan.

BACKGROUND: Among solid organ transplant (SOT) recipients, heart transplant (HT) recipients are at a higher risk of Toxoplasma gondii infection. As Toxoplasma seroprevalence varies by geographic location, updated local epidemiology is essential to guide preventive and therapeutic strategies. However, the Toxoplasma seroprevalence and incidence of post-transplant toxoplasmosis among SOT recipients in Japan are unknown. METHODS: We performed a single-center retrospective observational study at an HT center in Tokyo, Japan. All HT recipients aged ≥18 years between 2006 and April 2019 were included. We reviewed patient charts and conducted a questionnaire survey to investigate the risk factors for infection. RESULTS: Among 105 recipients included in the study, 11 (10.5%) were seropositive before transplant. Ninety-five recipients (90.5%), including all pre-transplant seropositive recipients, answered the questionnaire. The recipients who had lived in Okinawa (odds ratio [OR] 7.5 [95% CI 1.42-39.61]; P = .032) and who reported raw-meat eating habits (OR 4.64 [95% CI 1.04-23.3]; P = .021) were more likely to be seropositive. None of the patients developed symptoms of toxoplasmosis. The post-transplant incidence of other major adverse outcomes was not significantly different according to the pre-transplant serostatus. CONCLUSIONS: About 10% of HT recipients at an HT center in Tokyo were seropositive for Toxoplasma pre-transplant, and none developed symptomatic toxoplasmosis post-transplant on trimethoprim-sulfamethoxazole. The history of raw meat consumption was associated with seropositivity; therefore, avoiding it might be recommended for HT recipient candidates.

Waning cellular immune responses and predictive factors in maintaining cellular immunity against SARS-CoV-2 six months after BNT162b2 mRNA vaccination.

Several clinical trials have shown that the humoral response produced by anti-spike antibodies elicited by coronavirus disease 2019 (COVID-19) vaccines gradually declines. The kinetics, durability and influence of epidemiological and clinical factors on cellular immunity have not been fully elucidated. We analyzed cellular immune responses elicited by BNT162b2 mRNA vaccines in 321 health care workers using whole blood interferon-gamma (IFN-γ) release assays. IFN-γ, induced by CD4 + and CD8 + T cells stimulated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike epitopes (Ag2), levels were highest at 3 weeks after the second vaccination (6 W) and decreased by 37.4% at 3 months (4 M) and 60.0% at 6 months (7 M), the decline of which seemed slower than that of anti-spike antibody levels. Multiple regression analysis revealed that the levels of IFN-γ induced by Ag2 at 7 M were significantly correlated with age, dyslipidemia, focal adverse reactions to full vaccination, lymphocyte and monocyte counts in whole blood, Ag2 levels before the second vaccination, and Ag2 levels at 6 W. We clarified the dynamics and predictive factors for the long-lasting effects of cellular immune responses. The results emphasize the need for a booster vaccine from the perspective of SARS-CoV-2 vaccine-elicited cellular immunity.

Paralytic Ileus during Treatment of Pulmonary and Renal Tuberculosis in a Non-Human Immunodeficiency Virus Patient: An Unusual Presentation of Tuberculosis-immune Reconstitution Inflammatory Syndrome.

Paralytic ileus as tuberculosis-immune reconstitution inflammatory syndrome (TB-IRIS) is extremely rare. We herein report a 44-year-old man with pulmonary and renal tuberculosis who developed paralytic ileus 14 days after starting antituberculosis therapy (ATT) despite an initial favorable response to ATT. Paralytic ileus was successfully managed with conservative care. He initially required hemodialysis because of obstructive uropathy due to renal tuberculosis, but he was able to withdraw from dialysis after placement of ureteral stents. TB-IRIS can affect organs other than the original sites of tuberculosis, and the combined use of steroids may be effective for its prevention and treatment.

Multicenter, single-blind, randomized controlled study of the efficacy and safety of favipiravir and nafamostat mesilate in patients with COVID-19 pneumonia.

OBJECTIVES: To evaluate the efficacy and safety of nafamostat combined with favipiravir for the treatment of COVID-19. METHODS: We conducted a multicenter, randomized, single-blind, placebo-controlled, parallel assignment study in hospitalized patients with mild-to-moderate COVID-19 pneumonia. Patients were randomly assigned to receive favipiravir alone (n = 24) or nafamostat with favipiravir (n = 21). The outcomes included changes in the World Health Organization clinical progression scale score, time to improvement in body temperature, and improvement in oxygen saturation (SpO2). RESULTS: There was no significant difference in the changes in the clinical progression scale between nafamostat with favipiravir and favipiravir alone groups (median, -0.444 vs -0.150, respectively; least-squares mean difference, -0.294; P = 0.364). The time to improvement in body temperature was significantly shorter in the combination group (5.0 days; 95% confidence interval, 4.0-7.0) than in the favipiravir group (9.0 days; 95% confidence interval, 7.0-18.0; P =0.009). The changes in SpO2 were greater in the combination group than in the favipiravir group (0.526% vs -1.304%, respectively; least-squares mean difference, 1.831; P = 0.022). No serious adverse events or deaths were reported, but phlebitis occurred in 57.1% of the patients in the combination group. CONCLUSION: Although our study showed no differences in clinical progression, earlier defervescence, and recovery of SpO2 were observed in the combination group.

The association between adverse reactions and immune response against SARS-CoV-2 spike protein after vaccination with BNT162b2 among healthcare workers in a single healthcare system: a prospective observational cohort study.

Adverse reactions after vaccination with COVID-19 mRNA vaccines are common; however, the association between adverse reactions and humoral responses is uncertain. To determine whether humoral immune responses after BNT162b2 vaccine administration were associated with local and systemic adverse reactions, we conducted a prospective observational cohort study in a single tertiary referral center. Healthcare workers who received the first dose of BNT162b2 vaccine were recruited. SARS-CoV-2 anti-spike IgG antibody titers were measured three weeks after the second dose and information about adverse reactions after vaccination was collected. Among the 887 participants, 641 (72.3%) were women. The median age was 38 (range, 22-74) years. All but one showed anti-spike IgG levels well above the cutoff, with a median level of 13,600 arbitrary units/mL. Overall, 800 (92.2%) participants reported some reactions after the first dose and 822 (96.3%) after the second dose. Significantly more participants reported systemic reactions after the second dose than after the first dose (P < .01), and 625 (73.6%) reported that reactions were stronger after the second dose. Factors positively associated with elevation of anti-spike IgG levels were history of asthma (24% higher if present, P = .01) and stronger reactions after the second dose (19% higher if experienced, P = .02). The majority of participants showed good humoral responses and reported some adverse reactions after vaccination. Anti-spike IgG levels were significantly higher if adverse reactions after the second dose were stronger than those after the first dose. These findings may help inform current and future vaccine recipients.

Human abdominal abscess caused by Necropsobacter rosorum and tips for its identification: A case report.

Necropsobacter rosorum is a gram-negative facultative anaerobe, which was reclassified from the family Pasteurellaceae in 2011. It has been detected in the gastrointestinal and respiratory tracts of mammals; however, reports of infection in humans are scarce. We report a case of an abdominal abscess in which N. rosorum was detected; it was successfully treated with drainage and antimicrobial therapy. Routine laboratory testing such as matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and an identification system using biochemical phenotypes could not identify N. rosorum. Instead, it was misidentified as other Pasteurellaceae species, including Aggregatibacter spp. or Pasteurella spp. Sequencing of 16S rRNA was required to identify N. rosorum. We suggest the application of simple methods, such as indole production, oxidase, and catalase tests, to differentiate N. rosorum from genetically similar species.

Plesiomonas shigelloides Septic Shock Following Ingestion of Dojo Nabe (Loach Hotpot).

Plesiomonas shigelloides is a gram-negative bacillus that commonly causes self-limited diarrhea in humans. We present the case of P shigelloides bacteremia in a 49-year-old man with alcoholic cirrhosis who developed septic shock a day after eating Dojo nabe (loach hotpot), a Japanese traditional dish.

Dynamic changes in fibrinogen and D-dimer levels in COVID-19 patients on nafamostat mesylate.

Critical illnesses associated with coronavirus disease 2019 (COVID-19) are attributable to a hypercoagulable status. There is limited knowledge regarding the dynamic changes in coagulation factors among COVID-19 patients on nafamostat mesylate, a potential therapeutic anticoagulant for COVID-19. First, we retrospectively conducted a cluster analysis based on clinical characteristics on admission to identify latent subgroups among fifteen patients with COVID-19 on nafamostat mesylate at the University of Tokyo Hospital, Japan, between April 6 and May 31, 2020. Next, we delineated the characteristics of all patients as well as COVID-19-patient subgroups and compared dynamic changes in coagulation factors among each subgroup. The subsequent dynamic changes in fibrinogen and D-dimer levels were presented graphically. All COVID-19 patients　were classified into three subgroups: clusters A, B, and C, representing low, intermediate, and high risk of poor outcomes, respectively. All patients were alive 30 days from symptom onset. No patient in cluster A required mechanical ventilation; however, all patients in cluster C required mechanical ventilation, and half of them were treated with venovenous extracorporeal membrane oxygenation. All patients in cluster A maintained low D-dimer levels, but some critical patients in clusters B and C showed dynamic changes in fibrinogen and D-dimer levels. Although the potential of nafamostat mesylate needs to be evaluated in randomized clinical trials, admission characteristics of patients with COVID-19 could predict subsequent coagulopathy.

FWNet: Semantic Segmentation for Full-Waveform LiDAR Data Using Deep Learning.

In the computer vision field, many 3D deep learning models that directly manage 3D point clouds (proposed after PointNet) have been published. Moreover, deep learning-based-techniques have demonstrated state-of-the-art performance for supervised learning tasks on 3D point cloud data, such as classification and segmentation tasks for open datasets in competitions. Furthermore, many researchers have attempted to apply these deep learning-based techniques to 3D point clouds observed by aerial laser scanners (ALSs). However, most of these studies were developed for 3D point clouds without radiometric information. In this paper, we investigate the possibility of using a deep learning method to solve the semantic segmentation task of airborne full-waveform light detection and ranging (lidar) data that consists of geometric information and radiometric waveform data. Thus, we propose a data-driven semantic segmentation model called the full-waveform network (FWNet), which handles the waveform of full-waveform lidar data without any conversion process, such as projection onto a 2D grid or calculating handcrafted features. Our FWNet is based on a PointNet-based architecture, which can extract the local and global features of each input waveform data, along with its corresponding geographical coordinates. Subsequently, the classifier consists of 1D convolutional operational layers, which predict the class vector corresponding to the input waveform from the extracted local and global features. Our trained FWNet achieved higher scores in its recall, precision, and F1 score for unseen test data-higher scores than those of previously proposed methods in full-waveform lidar data analysis domain. Specifically, our FWNet achieved a mean recall of 0.73, a mean precision of 0.81, and a mean F1 score of 0.76. We further performed an ablation study, that is assessing the effectiveness of our proposed method, of the above-mentioned metric. Moreover, we investigated the effectiveness of our PointNet based local and global feature extraction method using the visualization of the feature vector. In this way, we have shown that our network for local and global feature extraction allows training with semantic segmentation without requiring expert knowledge on full-waveform lidar data or translation into 2D images or voxels.

Clipping Surgery for Unruptured Middle Cerebral Artery Aneurysms.

Clipping surgeries for 139 consecutive unruptured middle cerebral aneurysms were performed between April 1991 and March 2014. Left hemiparesis occurred in one case (0.7 %). Transient symptoms arose in six patients due to perforator injury, arterial branch occlusion, damage to the venous system, or chronic subdural hematoma. Neither mortality nor decline in cognitive function was noted in this study. Clipping surgery for unruptured middle cerebral artery aneurysms can be done with minimal morbidity. However, meticulous management during the perioperative period as well as the use of modern technologies during the surgery, such as MEP monitoring and ICG videoangiography, are needed for safe and secure clipping surgery.

Spinal cerebrospinal fluid leaks detected by radionuclide cisternography and magnetic resonance imaging in patients suspected of intracranial hypotension.

PURPOSE: Although many studies have described various features of neuroimaging tests associated with intracranial hypotension, few have examined their validity and reliability. We evaluated the association between CSF leaks detected by radionuclide cisternography and abnormal MRI findings in the accurate diagnosis of intracranial hypotension. PATIENTS/METHODS: We retrospectively assessed 250 patients who were suspected of intracranial hypotension and underwent subsequent radionuclide cisternography. We obtained 159 sagittal and 153 coronal T2-weighted MRI images and 101 gadolinium-enhanced T1-weighted MRI images. We assessed the CSF leaks in relation to a sagging brain, the maximum subdural space in sagittal and coronal images, and dural enhancement. RESULTS: Overall, 186 (74%) patients showed CSF leaks on radionuclide cisternography. A sagging brain was observed in 21 (13%) of the 159 patients with sagittal MRIs. A sagging brain was not associated with CSF leaks (14% vs. 10%; p=0.49). Compared to patients without CSF leaks, those with CSF leaks tended to have a larger maximum subdural space in both the sagittal (3.7 vs. 4.1mm) and coronal (2.5 vs. 2.8mm) images; however, the differences were not significant (p=0.18 and p=0.53, respectively). Dural enhancement was observed only in one patient, who presented with CSF leaks on radionuclide cisternography. CONCLUSIONS: Our study, which included a relatively large population, did not find any association between the findings of radionuclide cisternography and MRI. Future research should focus on identifying more valid neuroimaging findings to diagnose intracranial hypotension accurately.

YY1 binds to α-synuclein 3'-flanking region SNP and stimulates antisense noncoding RNA expression.

α-synuclein (SNCA) is an established susceptibility gene for Parkinson's disease (PD), one of the most common human neurodegenerative disorders. Increased SNCA is considered to lead to PD and dementia with Lewy bodies. Four single-nucleotide polymorphisms (SNPs) in SNCA 3' region were prominently associated with PD among different ethnic groups. To examine how these SNPs influence disease susceptibility, we analyzed their potential effects on SNCA gene expression. We found that rs356219 showed allele-specific features. Gel shift assay using nuclear extracts from SH-SY5Y cells showed binding of one or more proteins to the protective allele, rs356219-A. We purified the rs356219-A-protein complex with DNA affinity beads and identified a bound protein using mass spectrometry. This protein, YY1 (Yin Yang 1), is an ubiquitous transcription factor with multiple functions. We next investigated SNCA expression change in SH-SY5Y cells by YY1 transfection. We also analyzed the expression of antisense noncoding RNA (ncRNA) RP11-115D19.1 in SNCA 3'-flanking region, because rs356219 is located in intron of RP11-115D19.1. Little change was observed in SNCA expression levels; however, RP11-115D19.1 expression was prominently stimulated by YY1. In autopsied cortices, positive correlation was observed among RP11-115D19.1, SNCA and YY1 expression levels, suggesting their functional interactions in vivo. Knockdown of RP11-115D19.1 increased SNCA expression significantly in SH-SY5Y cells, suggesting its repressive effect on SNCA expression. Our findings of the protective allele-specific YY1 and antisense ncRNA raised a novel possible mechanism to regulate SNCA expression.

Relationship between time from ambulance call to arrival at emergency center and level of consciousness at admission in severe stroke patients.

INTRODUCTION: Timely access to acute medical treatment can be critical for patients suffering from severe stroke. Little information is available about the impact of prehospital delays on the clinical conditions of stroke patients, but it is possible that prehospital delays lead to neurological deterioration. The aim of this study was to examine the impact of prehospital delays related to emergency medical services on the level of consciousness at admission in patients with severe stroke. METHODS: This retrospective study assessed 712 consecutive patients diagnosed with cerebrovascular diseases who were admitted to an intensive care unit in Tokyo, Japan, from April 1998 through March 2008. Data, including the time from the call to the ambulance service to the arrival of the ambulance at the patient location (on-scene), and the time from the arrival of the ambulance on-scene to its arrival at the emergency center were obtained. The following demographic and clinical information also were obtained from medical records: sex, age, and Glasgow Coma Scale (GCS) score at admission. RESULTS: The mean time from ambulance call to arrival on-scene was 7 (SD=3) minutes, and the mean time from ambulance call to arrival at the center was 37 (SD=8) minutes. A logistic regression model for predicting GCS scores of 3 and 4 at admission was produced. After adjusting for sex, age, and time from arrival on-scene to arrival at the center, a longer call-to-on-scene time was significantly associated with poor GCS scores (OR = 1.056/min; 95% confidence interval, [CI] = 1.008-1.107). After adjusting for sex and age, a longer call-to-arrival at the center time also was significantly associated with poor GCS scores (OR = 1.020; 95% CI = 1.002-1.038). CONCLUSIONS: Prehospital delays were significantly associated with decreased levels of consciousness at admission in patients suffering from a stroke. As level of consciousness is the strongest predictor of outcome, reducing prehospital delays may be necessary to improve the outcomes in patients with severe stroke.

Importance of the initial grade of subarachnoid hemorrhage in the patients with the age of 80 years and older from a single center analysis.

In the developed countries, especially Japan, elderly population is rapidly increasing, but outcomes of elderly patients with the age of 80 years and older suffering from subarachnoid hemorrhage (SAH) remain still unclear. We retrospectively reviewed the medical records of nontraumatic SAH patients aged 80 years and older, who were hospitalized in a single center between 1998 and 2009. There were 28 patients (80-90 years old and 75% female), representing 5.9% of all non-traumatic SAHs (n = 474). Of those, 16 patients received an intervention (ten clipping and six endovascular coiling) and the remaining 12 patients were managed conservatively. The median survival time of intervention group was 110 days and that of conservative group 49 days (p = 0.12, log rank analysis). Cox's proportional hazards model yielded two variables, the Japan Coma Scale (JCS) grade on admission ( hazard ratio: 2.93 [p = 0.009]) and conservative treatment (hazard ratio: 2.14 [p = 0.054]). In the outcome of the modified Rankin Scale between these two groups, logistic regression analysis had significant variable; the JCS grade on admission (odds ratio: 280, [p = 0.020]). In the elderly patients with good initial clinical condition, an acute intervention may have good outcome.

[Acute onset of visual disturbance in a patient with arachnoid cyst in the middle cranial fossa].

Intracranial arachnoid cyst occurs most frequently in the middle fossa. Most of them are asymptomatic with or without neurological involvement. However some develop neurological deficits such as increased intracranial pressure, which manifests as headache, epilepsy and focal neurological deficits. Here we present an adult case of arachnoid cyst in the middle cranial fossa: the patient demonstrated rapidly deteriorating visual field defect and decreased visual acuity. The symptoms were improved by an emergency surgery. This is the first case report describing optic nerve compression due to an arachnoid cyst. Result of the coronal and sagittal magnetic resonance imaging (MRI) scans showed effective optic nerve compression. Long-standing asymptomatic arachnoid cysts might progress rapidly to cause cranial nerve deficits thus meticulous MRI follow-up are important in these patients.

Ossicular reconstruction using hydroxyapatite prostheses with interposed cartilage.

PURPOSE: Despite the excellent biocompatibility of hydroxyapatite ossicular prostheses, extrusion of the prosthesis may be found during long-term follow-up, mainly due to the retraction of the eardrum. Although interposition of autologous cartilage between the eardrum and the prosthesis is empirically used to prevent extrusion, the clinical effect of this procedure has not been confirmed. The purpose of this study was to evaluate the effect of interposing a cartilage on the extrusion rate and hearing outcome. MATERIALS AND METHODS: Fifty-four ears in which cartilage was interposed with a hydroxyapatite prosthesis were compared with 53 ears without interposition. Three years after surgery, the otoscopic findings and hearing outcome were evaluated. RESULTS: The extrusion rate was 1.9% in the group with interposition and 13.2% in the group without interposition. The difference between the two groups was statistically different (chi(2) = 4.986; P =.03). There was no significant difference between the two groups in the postoperative air-bone gap. CONCLUSION: This procedure is an effective method for reducing the extrusion rate of hydroxyapatite prostheses without reducing the hearing gain resulting from ossiculoplasty.

Neurotrophic factor intervention restores auditory function in deafened animals.

A primary cause of deafness is damage of receptor cells in the inner ear. Clinically, it has been demonstrated that effective functionality can be provided by electrical stimulation of the auditory nerve, thus bypassing damaged receptor cells. However, subsequent to sensory cell loss there is a secondary degeneration of the afferent nerve fibers, resulting in reduced effectiveness of such cochlear prostheses. The effects of neurotrophic factors were tested in a guinea pig cochlear prosthesis model. After chemical deafening to mimic the clinical situation, the neurotrophic factors brain-derived neurotrophic factor and an analogue of ciliary neurotrophic factor were infused directly into the cochlea of the inner ear for 26 days by using an osmotic pump system. An electrode introduced into the cochlea was used to elicit auditory responses just as in patients implanted with cochlear prostheses. Intervention with brain-derived neurotrophic factor and the ciliary neurotrophic factor analogue not only increased the survival of auditory spiral ganglion neurons, but significantly enhanced the functional responsiveness of the auditory system as measured by using electrically evoked auditory brainstem responses. This demonstration that neurotrophin intervention enhances threshold sensitivity within the auditory system will have great clinical importance for the treatment of deaf patients with cochlear prostheses. The findings have direct implications for the enhancement of responsiveness in deafferented peripheral nerves.