Search

Abstract Objective To reveal the clinical features and assess risk factors linked to brain fog and its societal implications, including labor productivity, providing valuable insights for the future care of individuals who have experienced coronavirus disease 2019 (COVID‐19). Methods We analyzed a comprehensive cohort dataset comprising 1,009 patients with COVID‐19 admitted to Japanese hospitals. To assess brain fog, we analyzed patients who responded to a questionnaire indicating symptoms such as memory impairment and poor concentration. Results The prevalence of brain fog symptoms decreased 3 months posthospitalization but remained stable up to 12 months. Neurological symptoms such as taste and smell disorders and numbness at hospitalization correlated with a higher frequency of identifying brain fog as a long COVID manifestation. Our findings indicated that advanced age, female sex, a high body mass index, oxygen required during hospitalization, chronic obstructive pulmonary disease, asthma, and elevated C‐reactive protein and elevated D‐dimer levels were risk factors in patients exhibiting brain fog. Additionally, we demonstrated the negative impact of brain fog on labor productivity by presenteeism scores. Interpretations This study clarified the clinical characteristics of patients experiencing brain fog as a long COVID manifestation, specifically emphasizing neurological symptoms during hospitalization and their correlation with brain fog. Additionally, the study identified associated risk factors for its onset and revealed that the emergence of brain fog was linked to a decline in labor productivity.

Background: Multiple prolonged symptoms are observed in patients who recover from an acute COVID-19 infection, which is defined as long COVID. General fatigue is frequently observed in patients with long COVID during acute and post-acute phases. This study aimed to identify the specific risk factors for general fatigue in long COVID. Methods: Hospitalized patients with COVID-19 aged over 18 years were enrolled in a multicenter cohort study at 26 medical institutions. Clinical data during hospitalization and patient-reported outcomes after discharge were collected from medical records, paper-based questionnaires, and smartphone apps. Results: Among prolonged symptoms through 1-year follow-ups, general fatigue was the most interfering symptom in daily life. Patients with protracted fatigue at all follow-up periods had lower quality of life scores at the 12-month follow-up. Univariate logistic regression analysis of the presence or absence of general fatigue at the 3-month, 6-month, and 12-month follow-ups identified asthma, younger age, and female sex as risk factors for prolonged fatigue. Multivariable logistic regression analysis revealed that asthma was an independent risk factor for persistent fatigue during the 12-month follow-up period. Longitudinal changes in the symptoms of patients with or without asthma demonstrated that general fatigue, not cough and dyspnea, was significantly prolonged in patients with asthma. Conclusions: In a Japanese population with long COVID, prolonged general fatigue was closely linked to asthma. A preventive approach against COVID-19 is necessary to avoid sustained fatigue and minimize social and economic losses in patients with asthma.

Background Multiple prolonged symptoms observed in patients who recovered from COVID-19 are defined as long COVID. Although diverse phenotypic combinations are possible, they remain unclear. This study aimed to perform a cluster analysis of long COVID in Japan and clarify the association between its characteristics and background factors and quality of life (QOL).Methods This multicentre prospective cohort study collected various symptoms and QOL after COVID-19 from January 2020 to February 2021. This study included 935 patients aged ≥18 years with COVID-19 at 26 participating medical facilities. Hierarchical cluster analysis was performed using 24 long COVID symptom at 3 months after diagnosis.Results Participants were divided into the following five clusters: numerous symptoms across multiple organs (cluster 1, n=54); no or minor symptoms (cluster 2, n=546); taste and olfactory disorders (cluster 3, n=76); fatigue, psychoneurotic symptoms and dyspnoea (low prevalence of cough and sputum) (cluster 4, n=207) and fatigue and dyspnoea (high prevalence of cough and sputum) (cluster 5, n=52). Cluster 1 included elderly patients with severe symptoms, while cluster 3 included young female with mild symptoms. No significant differences were observed in the comorbidities. Cluster 1 showed the most impaired QOL, followed by clusters 4 and 5; these changes as well as the composition of symptoms were observed over 1 year.Conclusions We identified patients with long COVID with diverse characteristics into five clusters. Future analysis of these different pathologies could result in individualised treatment of long COVID.Trial registration number The study protocol is registered at UMIN clinical trials registry (UMIN000042299).

Abstract Background Multiple prolonged symptoms are observed in patients who recover from acute coronavirus disease 2019 (COVID-19), defined as long COVID. Cough and sputum are presented by patients with long COVID during the acute and post-acute phases. This study aimed to identify specific risk factors for cough and sputum in patients with long COVID. Methods Hospitalized patients with COVID-19 aged 18 years were enrolled in a multicenter cohort study at 26 medical institutions. Clinical data during hospitalization and patient-reported outcomes after discharge were collected from medical records, paper-based questionnaires, and smartphone apps. Results At the 3-, 6-, and 12-month follow-ups, there were no differences in the incidence rates of wet and dry coughs. In contrast, the proportion of patients presenting sputum without coughing increased over time compared to those with sputum and coughing. Univariate analyses of cough and sputum at all follow-up visits identified intermittent mandatory ventilation (IMV), smoking, and older age as risk factors for prolonged symptoms. At the 12-month follow-up, persistent cough and sputum were associated with the characteristics of severe COVID-19 based on imaging findings, renal and liver dysfunction, pulmonary thromboembolism, and higher serum levels of LDH, KL-6, and HbA1C. The Kaplan–Meier curves showed that the severity of acute COVID-19 infection was correlated with prolonged cough and sputum production. Multivariable logistic regression analysis showed that IMV ventilator management were independent risk factors for prolonged cough and sputum at 12 months. Conclusions In a Japanese population with long COVID, prolonged cough and sputum production were closely associated with severe COVID-19. These findings emphasize that a preventive approach including appropriate vaccination and contact precaution and further development of therapeutic drugs for COVID-19 are highly recommended for patients with risk factors for severe infection to avoid persistent respiratory symptoms.

Abstract Background Companion diagnostic tests play a crucial role in guiding treatment decisions for patients with non‐small cell lung cancer (NSCLC). The Oncomine Dx Target Test (ODxTT) Multi‐CDx System has emerged as a prominent companion diagnostic method. However, its efficacy in detecting driver gene mutations, particularly rare mutations, warrants investigation. Aims This study aimed to assess the performance of the ODxTT in detecting driver gene mutations in NSCLC patients. Specifically, we aimed to evaluate its sensitivity in detecting epidermal growth factor receptor (EGFR) mutations, a key determinant of treatment selection in NSCLC. Materials and Methods We conducted a retrospective analysis of NSCLC patients who underwent testing with the ODxTT at Keio University Hospital between May 2020 and March 2022. Patient samples were subjected to both DNA and RNA tests. Driver gene mutation status was assessed, and instances of missed mutations were meticulously examined. Results Of the 90 patients, five had nucleic acid quality problems, while 85 underwent both DNA and RNA tests. Driver gene mutations were detected in 56/90 (62.2%) patients. Of the 34 patient specimens, driver mutations were not detected using the ODxTT; however, epidermal growth factor receptor (EGFR) mutations were detected using polymerase chain reaction‐based testing in two patients, and a KRAS mutation was detected by careful examination of the sequence data obtained using the ODxTT in one patient. For the above three cases, carefully examining the gene sequence information obtained using the ODxTT could identify driver mutations that were not mentioned in the returned test results. Additionally, we confirmed comparable instances of overlook results for EGFR mutations in the dataset from South Korea, implying that this type of oversight could occur in other countries using the ODxTT. EGFR mutation was missed in ODxTT in Japan (6.3%, 2/32), South Korea (2.0%, 1/49), and overall (3.7%, 3/81). Conclusion Even if sufficient tumor samples are obtained, rare EGFR mutations (which are excluded from the ODxTT's genetic mutation list) might not be detected using the current ODxTT system due to the program used for sequence analysis. However, such rare EGFR mutations can still be accurately detected on ODxTT's sequence data using next‐generation sequencing.

Abstract Objective This study aimed to investigate the clinical features of long COVID cases presenting with upper respiratory symptoms, a topic not yet fully elucidated. Study Design Prospective cohort study. Setting A multicenter study involving 26 medical facilities in Japan. Methods Inclusion criteria were patients aged ≥18 years old with a confirmed COVID‐19 diagnosis via severe acute respiratory syndrome coronavirus 2 polymerase chain reaction or antigen testing, who were hospitalized at the participating medical facilities. Analyzing clinical information and patient‐reported outcomes from 1009 patients were analyzed. The outcome measured the degree of initial symptoms for taste or olfactory disorders and assessed the likelihood of these symptoms persisting as long COVID, as well as the impact on quality of life if the upper respiratory symptoms persisted as long COVID. Results Patients with high albumin, low C‐reactive protein, and low lactate dehydrogenase in laboratory tests tended to experience taste or olfactory disorders as part of long COVID. Those with severe initial symptoms had a higher risk of experiencing residual symptoms at 3 months, with an odds ratio of 2.933 (95% confidence interval [CI], 1.282‐6.526) for taste disorders and 3.534 (95% CI, 1.382‐9.009) for olfactory disorders. Presence of upper respiratory symptoms consistently resulted in lower quality of life scores. Conclusion The findings from this cohort study suggest that severe taste or olfactory disorders as early COVID‐19 symptoms correlate with an increased likelihood of persistent symptoms in those disorders as long COVID.

We conducted a subgroup analysis of a study on the long-term effects of COVID-19 (long COVID) in Japan to assess the effect of vaccination on long COVID symptoms. We assessed the clinical course of 111 patients with long COVID at the time of vaccination. The follow-up period was one year from the onset of COVID-19 or until the administration of the third vaccine dose. Of the 111 patients, 15 (13.5%) reported improvement, four (3.6%) reported deterioration, and 92 (82.9%) reported no change in their long COVID symptoms after vaccination. The most common long COVID symptoms before vaccination were alopecia, dyspnea, muscle weakness, fatigue, and headache among participants whose symptoms improved. Reduced dyspnea and alopecia were the most frequently reported improvements in symptoms after vaccination. Some symptoms persisted, including sleep disturbance, myalgia, and hypersensitivity. Vaccination did not appear to have a clinically important effect on patients with long COVID symptoms.

Summary: Human lung cancer is a constellation of tumors with various histological and molecular properties. To build a preclinical platform that covers this broad disease spectrum, we obtained lung cancer specimens from multiple sources, including sputum and circulating tumor cells, and generated a living biobank consisting of 43 lines of patient-derived lung cancer organoids. The organoids recapitulated the histological and molecular hallmarks of the original tumors. Phenotypic screening of niche factor dependency revealed that EGFR mutations in lung adenocarcinoma are associated with the independence from Wnt ligands. Gene engineering of alveolar organoids reveals that constitutive activation of EGFR-RAS signaling provides Wnt independence. Loss of the alveolar identity gene NKX2-1 confers Wnt dependency, regardless of EGFR signal mutation. Sensitivity to Wnt-targeting therapy can be stratified by the expression status of NKX2-1. Our results highlight the potential of phenotype-driven organoid screening and engineering for the fabrication of therapeutic strategies to combat cancer.

Abstract The overall effect of lifestyle habits, such as alcohol consumption, on general health remains controversial and it is important to clarify how such habits affect aging-related health impairments. To discover novel impacts of lifestyle on general health, we employed a mathematical approach to perform a comprehensive, unbiased, cross-sectional analysis of data from 6036 subjects who participated in a Japanese health checkup. Notably, we found that moderate alcohol consumption was positively correlated with lung function, muscle mass, and strength. Health checkup data were collected periodically from the same subjects. These people were light to moderate drinkers who had high health awareness and were basically free of major underlying diseases. We next analyzed 5 years of data from 1765 of these subjects. We found that higher baseline alcohol consumption, as well as increased alcohol intake over 5 years attenuated time-related deterioration of forced vital capacity without affecting total lung volume. This effect was independent of smoking. Our study suggests a possible protective effect of moderate amounts of alcohol on lung function, due to increased muscle mass/strength and forced vital capacity.

Acquired immunodeficiency in thymoma (Good's syndrome) without hypogammaglobulinemia is a rare condition. Here we describe the case of a 29-year-old Japanese woman with thymoma-associated T cell immunodeficiency after radiation therapy. She was admitted to the hospital with refractory pneumonia, which resulted from as T cell immunodeficiency, as revealed through low peripheral lymphocytes and oral candidiasis triggered through radiotherapy and required long-term antimicrobial therapy. Although radiotherapy is commonly administered for thymoma, our findings suggest that physicians should consider carrying out lymphocyte counts during thymoma treatment.

Background Not all non-small cell lung cancer (NSCLC) patients possess drug-targetable driver mutations, and response rates to immune checkpoint blockade therapies also remain unsatisfactory. Therefore, more effective treatments are still needed. Here, we report the results of a phase 2 clinical trial of adoptive cell therapy using zoledronate-expanded autologous Vγ9Vδ2 T-cells for treatment-refractory NSCLC.Methods NSCLC patients who had undergone at least two regimens of standard chemotherapy for unresectable disease or had had at least one treatment including chemotherapy or radiation for recurrent disease after surgery were enrolled in this open-label, single-arm, multicenter, phase 2 study. After preliminary testing of Vγ9Vδ2 T-cell proliferation, autologous peripheral blood mononuclear cells were cultured with zoledronate and IL-2 to expand the Vγ9Vδ2 T-cells. Cultured cells (>1×109) were intravenously administered every 2 weeks for six injections. The primary endpoint of this study was progression-free survival (PFS), and secondary endpoints included overall survival (OS), best objective response rate (ORR), disease control rate (DCR), safety and immunomonitoring. Clinical efficacy was defined as median PFS significantly >4 months.Results Twenty-five patients (20 adenocarcinoma, 4 squamous cell carcinoma and 1 large cell carcinoma) were enrolled. Autologous Vγ9Vδ2 T-cell therapy was administered to all 25 patients, of which 16 completed the foreseen course of 6 injections of cultured cells. Median PFS was 95.0 days (95% CI 73.0 to 132.0 days); median OS was 418.0 days (179.0–479.0 days), and best overall responses were 1 partial response, 16 stable disease (SD) and 8 progressive disease. ORR and DCR were 4.0% (0.1%–20.4%) and 68.0% (46.5%–85.1%), respectively. Severe adverse events developed in nine patients, mostly associated with disease progression. In one patient, pneumonitis and inflammatory responses resulted from Vγ9Vδ2 T-cell infusions, together with the disappearance of a massive tumor.Conclusions Although autologous Vγ9Vδ2 T-cell therapy was well tolerated and may have an acceptable DCR, this trial did not meet its primary efficacy endpoint.Trial registration number UMIN000006128

Objective: Targeted therapy-induced facial skin toxicities may reduce overall quality of life (QoL) in cancer patients. We investigated whether facial skin toxicities affect QoL and attempted to identify factors related to QoL in patients with advanced/recurrent cancer. Methods: We performed a cross-sectional study in 34 outpatients with advanced/recurrent cancer showing targeted therapy-induced facial skin toxicities in Japan between November 2016 and February 2017. For measurement, we used the Kessler Psychological Distress Scale (K6), Mental Adjustment to Cancer (MAC) Scale, and Dermatology Life Quality Index (DLQI). Data were analyzed using Spearman's rank correlation coefficient. Results: Mean DLQI score in 34 patients was 4.59 (standard deviation ± 4.70), which was interpreted as a small effect on a patient's life. Acneiform rash was the most common skin condition noted, followed by xerosis, pruritus, and erythema. Analysis of DLQI scores revealed that symptoms and feelings was the domain most commonly affected among different domains constituting the DLQI. MAC analysis revealed that the fighting spirit score was the highest among MAC scales. We found that age, K6, and fatalism construct in MAC were significantly correlated with total DLQI scores (age: Spearman's ρ= −0.48, P = 0.004; K6: ρ= 0.58, P < 0.001; fatalism; ρ= −0.39, P = 0.025). Conclusions: This is the first study investigating targeted therapy-induced facial skin toxicities in cancer patients. Our results suggest potential negative effects of facial skin toxicities on overall QoL in patients with advanced/recurrent cancer in middle and early old age.

Malignant pleural mesothelioma (MPM) is an aggressive disease with a poor prognosis. Studies have shown that both MET and its key downstream intracellular signaling partners, PI3K and mTOR, are overexpressed in MPM. Here we determined the combinatorial therapeutic efficacy of a new generation small molecule inhibitor of MET, ARQ 197, and dual PI3K/mTOR inhibitors NVP-BEZ235 and GDC-0980 in mesothelioma cell and mouse xenograft models. Cell viability results show that mesothelioma cell lines were sensitive to ARQ 197, NVP-BEZ235 and GDC-0980 inhibitors. The combined use of ARQ 197 with either NVP-BEZ235 or GDC-0980, was synergistic (CI

The speciose mammalian order Eulipotyphla (moles, shrews, hedgehogs, solenodons) combines an unusual diversity of semi-aquatic, semi-fossorial, and fossorial forms that arose from terrestrial forbearers. However, our understanding of the ecomorphological pathways leading to these lifestyles has been confounded by a fragmentary fossil record, unresolved phylogenetic relationships, and potential morphological convergence, calling for novel approaches. The net surface charge of the oxygen-storing muscle protein myoglobin (ZMb), which can be readily determined from its primary structure, provides an objective target to address this question due to mechanistic linkages with myoglobin concentration. Here, we generate a comprehensive 71 species molecular phylogeny that resolves previously intractable intra-family relationships and then ancestrally reconstruct ZMb evolution to identify ancient lifestyle transitions based on protein sequence alone. Our phylogenetically informed analyses confidently resolve fossorial habits having evolved twice in talpid moles and reveal five independent secondary aquatic transitions in the order housing the world’s smallest endothermic divers.

The tiger population that once inhabited the Korean peninsula was initially considered a unique subspecies (Panthera tigris coreensis), distinct from the Amur tiger of the Russian Far East (P. t. altaica). However, in the following decades, the population of P. t. coreensis was classified as P. t. altaica and hence forth the two populations have been considered the same subspecies. From an ecological point of view, the classification of the Korean tiger population as P. t. altaica is a plausible conclusion. Historically, there were no major dispersal barriers between the Korean peninsula and the habitat of Amur tigers in Far Eastern Russia and northeastern China that might prevent gene flow, especially for a large carnivore with long-distance dispersal abilities. However, there has yet to be a genetic study to confirm the subspecific status of the Korean tiger. Bone samples from four tigers originally caught in the Korean peninsula were collected from two museums in Japan and the United States. Eight mitochondrial gene fragments were sequenced and compared to previously published tiger subspecies’ mtDNA sequences to assess the phylogenetic relationship of the Korean tiger. Three individuals shared an identical haplotype with the Amur tigers. One specimen grouped with Malayan tigers, perhaps due to misidentification or mislabeling of the sample. Our results support the conclusion that the Korean tiger should be classified as P. t. altaica, which has important implications for the conservation and reintroduction of Korean tigers.