Nirmatrelvir Resistance in an Immunocompromised Patient with Persistent Coronavirus Disease 2019.

Although the coronavirus disease 2019 (COVID-19) pandemic is coming to an end, it still poses a threat to the immunocompromised and others with underlying diseases. Especially in cases of persistent COVID-19, new mutations conferring resistance to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) therapies have considerable clinical implications. We present a patient who independently acquired a T21I mutation in the 3CL protease after nirmatrelvir exposure. The T21I mutation in the 3CL protease is one of the most frequent mutations responsible for nirmatrelvir resistance. However, limited reports exist on actual cases of SARS-CoV-2 with T21I and other mutations in the 3CL protease. The patient, a 55 year-old male, had COVID-19 during chemotherapy for multiple myeloma. He was treated with nirmatrelvir early in the course of the disease but relapsed, and SARS-CoV-2 with a T21I mutation in the 3CL protease was detected in nasopharyngeal swab fluid. The patient had temporary respiratory failure but later recovered well. During treatment with remdesivir and dexamethasone, viruses with the T21I mutation in the 3CL protease showed a decreasing trend during disease progression while increasing during improvement. The impact of drug-resistant SARS-CoV-2 on the clinical course, including its severity, remains unknown. Our study is important for examining the clinical impact of nirmatrelvir resistance in COVID-19.

Real-World Data on Subsequent Therapy for First-Line Osimertinib-Induced Pneumonitis: Safety of EGFR-TKI Rechallenge (Osi-risk Study TORG-TG2101).

BACKGROUND: Although osimertinib is a promising therapeutic agent for advanced epidermal growth factor receptor (EGFR) mutation-positive lung cancer, the incidence of pneumonitis is particularly high among Japanese patients receiving the drug. Furthermore, the safety and efficacy of subsequent anticancer treatments, including EGFR-tyrosine kinase inhibitor (TKI) rechallenge, which are to be administered after pneumonitis recovery, remain unclear. OBJECTIVE: This study investigated the safety of EGFR-TKI rechallenge in patients who experienced first-line osimertinib-induced pneumonitis, with a primary focus on recurrent pneumonitis. PATIENTS AND METHODS: We retrospectively reviewed the data of patients with EGFR mutation-positive lung cancer who developed initial pneumonitis following first-line osimertinib treatment across 34 institutions in Japan between August 2018 and September 2020. RESULTS: Among the 124 patients included, 68 (54.8%) patients underwent EGFR-TKI rechallenge. The recurrence rate of pneumonitis following EGFR-TKI rechallenge was 27% (95% confidence interval [CI] 17-39) at 12 months. The cumulative incidence of recurrent pneumonitis was significantly higher in the osimertinib group than in the first- and second-generation EGFR-TKI (conventional EGFR-TKI) groups (hazard ratio [HR] 3.1; 95% CI 1.3-7.5; p = 0.013). Multivariate analysis revealed a significant association between EGFR-TKI type (osimertinib or conventional EGFR-TKI) and pneumonitis recurrence, regardless of severity or status of initial pneumonitis (HR 3.29; 95% CI 1.12-9.68; p = 0.03). CONCLUSIONS: Osimertinib rechallenge after initial pneumonitis was associated with significantly higher recurrence rates than conventional EGFR-TKI rechallenge.

Emergence of SARS-CoV-2 with Dual-Drug Resistant Mutations During a Long-Term Infection in a Kidney Transplant Recipient.

Introduction: Various therapeutic agents are being developed for the treatment of coronavirus disease 2019 (COVID-19). Therefore, it is crucial to accumulate information regarding the features of drug-resistant viruses to these antiviral drugs. Methods: We investigated the emergence of dual-drug resistance in a kidney transplant recipient who received sotrovimab (from day 0) and remdesivir (RDV) (from day 8 to day 17). We sequenced the whole viral genomes from nasopharyngeal swabs taken on day 0 and seven points after starting treatment (on days 12, 19, 23, 37, 43, 48, and 58). The genetic traits of the wild-type (day 0) and descendant viruses (after day 12) were determined by comparing the genomes with those of a Wuhan strain and the day 0 wild-type strain, respectively. Three viral isolates (from samples collected on days 0, 23, and 37) were investigated for their escape ability and growth kinetics in vitro. Results: The sotrovimab resistant mutation (S:E340K) and the RDV resistant mutation RdRp:V792I (nt: G15814A) emerged within 12 days (day 12) and 11 days (day 19) after the treatment, respectively. The day 23 isolate harboring S:E340K/RdRp:V791I was resistant to both sotrovimab and RDV, showing 364- and 2.73-fold higher resistance respectively, compared with the wild-type. Moreover, compared with the day 23 isolate, the day 37 isolate accumulated multiple additional mutations and had a higher level of resistance to both drugs. Conclusion: Drug-resistant variants with double mutations (S:E340K/RdRp:V791I) became dominant within 23 days after starting treatment, suggesting that even a combination therapy involving sotrovimab and RDV, dual-drug resistant viruses may emerge rapidly in immunocompromised patients. The dual-resistant variants had lower virus yields than those of the wild-type virus in vitro, suggesting that they paid a fitness cost.

Influence of certified perioperative nurses on the establishment of preoperative outpatient clinic and rate of preoperative assessment in Japan.

This study aimed to investigate the influence of certified perioperative nurses on preoperative outpatient clinic and preoperative assessments. The study was conducted from February 2021 to September 2022; data were collected and analyzed using a questionnaire at 247 hospitals in Japan. To analyze the factors affecting the rate of preoperative assessment with the primary endpoint of preoperative outpatient care and preoperative nursing visits, we performed multiple linear regression analysis of facility characteristics, perioperative nurse background, and the presence or absence of certified perioperative nurses. Regarding the presence or absence of a preoperative outpatient clinic, patients from 68 (52.3%) and 41 (35.0%) institutions in the enrolled and nonenrolled groups. Respectively, underwent a preoperative assessment; the rate of preoperative assessments in the enrolled group was significantly higher than that in the nonenrolled group. Multivariate analysis of factors influencing the preoperative assessment rate revealed a significant association with certified perioperative nurse attendance. Facilities with certified perioperative nurses have a significantly higher prevalence of preoperative outpatient clinic and significantly higher rates of preoperative assessments than facilities without certified perioperative nurses. Enrollment of certified perioperative nurses may lead to the improvement of the quality of preoperative nursing interventions.

SARS-CoV-2 RT-PCR as a universal screening on planned admission in asymptomatic patients.

Universal screening for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on admission is reportedly beneficial in preventing nosocomial infections. However, some issues remain, including low positivity rate, cost, and time required for testing. We describe SARS-CoV-2 reverse transcription polymerase chain reaction (PCR) for universal screening in asymptomatic patients on planned admissions. In total, 14,574 patients were included between October 12, 2020, and June 23, 2022. The PCR-positive rate for the period was 0.44 % (64/14,574). The PCR positivity for the epidemic period by strain was 0.28 % (95 % confidence interval [CI] 0.12-0.56 %), 0.16 % (95 % CI 0.05-0.37 %), 0.21 % (95 % CI 0.09-0.41 %), and 0.9 % (95 % CI 0.65-1.2 %) for the wild-type strain, Alpha, Delta, and Omicron variants, respectively. The proportion of Ct values < 30 was higher in the first half of the epidemic (first vs. second, 29.4 % [95 % CI 16.9-44.8 %] vs. 16.7 % [95 % CI 6.0-28.5 %]), whereas that of Ct values ≥ 35 increased significantly in the second half (first vs. second, 32.4 % [95 % CI 19.3-47.8 %] vs. 70.0 % [95 % CI 53.5-83.4 %]). Of all positives, 50 % (32/64) had a coronavirus disease (COVID-19) history before PCR screening, with a median of 28 days (10-105) from COVID-19 onset or positive to PCR screening. PCR screening may help detect positives with high viral loads early in the epidemic for each mutant strain, with an increasing proportion of positives with low viral loads later in the epidemic. PCR testing may be unnecessary for recently diagnosed cases and patients in whom reinfection is unlikely.

Endobronchial metastasis of hepatocellular carcinoma treated with Lenvatinib: A case report.

Endobronchial metastasis (EBM) of hepatocellular carcinoma (HCC) is rare though HCC often metastasizes to the lungs. In this case report, a 74-year-old man with a history of HCC with chronic hepatitis C experienced hemoptysis and a dry cough. During immunotherapy for postoperative recurrent HCC, chest computed tomography (CT) revealed soft tissue shadows in the right upper and lower lobe bronchi, and we pathologically diagnosed as EBM of HCC using bronchoscopy. Although the prognosis of HCC with EBM is poor, lenvatinib, a tyrosine kinase inhibitor, was administered and resulted in improved symptoms, decreased tumour markers, and reduced EBM shadows on chest CT scans. To the best of our knowledge, this is the first case of lenvatinib monotherapy for EBM of HCC. It is important to perform a bronchoscopy for early diagnosis of EBM, followed by lenvatinib treatment.

Overexpression profiling reveals cellular requirements in the context of genetic backgrounds and environments.

Overexpression can help life adapt to stressful environments, making an examination of overexpressed genes valuable for understanding stress tolerance mechanisms. However, a systematic study of genes whose overexpression is functionally adaptive (GOFAs) under stress has yet to be conducted. We developed a new overexpression profiling method and systematically identified GOFAs in Saccharomyces cerevisiae under stress (heat, salt, and oxidative). Our results show that adaptive overexpression compensates for deficiencies and increases fitness under stress, like calcium under salt stress. We also investigated the impact of different genetic backgrounds on GOFAs, which varied among three S. cerevisiae strains reflecting differing calcium and potassium requirements for salt stress tolerance. Our study of a knockout collection also suggested that calcium prevents mitochondrial outbursts under salt stress. Mitochondria-enhancing GOFAs were only adaptive when adequate calcium was available and non-adaptive when calcium was deficient, supporting this idea. Our findings indicate that adaptive overexpression meets the cell's needs for maximizing the organism's adaptive capacity in the given environment and genetic context.

A case of adult multisystem Langerhans histiocytosis successfully treated by smoking cessation and radiotherapy for bone lesion.

An adult patient was diagnosed with multisystem Langerhans cell histiocytosis with lung and bone lesions. Her lung lesions improved after smoking cessation. Radiotherapy was performed for the bone lesions. Follow-up assessment at 2 years after diagnosis showed no recurrence. Our case shows that remission is possible even without systemic treatment.

The Quality of Life of Patients with Suspected Lung Cancer before and after Bronchoscopy and the Effect of Mirtazapine on the Depressive Status.

Objective Patients with suspected lung cancer often experience adverse side effects such as anxiety, depression, and a decreased appetite. These side effects influence the patients' quality of life and their ability to make decisions concerning appropriate treatment. This study examined the psychological status and quality of life of patients with suspected lung cancer before and after bronchoscopy treatment and evaluated the effect of mirtazapine prescribed to patients with depression. Methods To assess patient characteristics (e.g. age, gender, and medical history), a questionnaire including the Hospital Anxiety and Depression Scale - Japanese version and the Functional Assessment of Cancer Therapy-L was administered. Patients Forty-three patients admitted for bronchoscopy treatment between May 2017 and April 2018 were included. Results The results showed that patients with depression reported a worse quality of life than those without depression. Compared with no medication, the administration of mirtazapine alleviated depressive symptoms. Furthermore, the patients' depressive status was affected by their physical symptoms, including coughing, tightness of chest, and dyspnea. Conclusion Our results emphasize the importance of detecting depression in the early stages of a cancer diagnosis and have significant implications concerning pharmacological intervention in patients with cancer displaying signs of depression.

IgA Vasculitis Developed as an Adverse Effect of Tofacitinib Taken for Rheumatoid Arthritis.

Tofacitinib is a new small-molecule inhibitor of the JAK/STAT signaling pathway used to treat rheumatoid arthritis. We herein report a case of IgA vasculitis apparently caused by tofacitinib. A 67-year-old woman with rheumatoid arthritis developed IgA vasculitis after taking tofacitinib for 6 months. She presented with proteinuria and purpura of the lower extremities. Biopsy specimens from her skin and kidney were compatible with IgA vasculitis. Following termination of tofacitinib, the patient completely recovered from the IgA vasculitis. Drug-induced IgA vasculitis has been previously described for anti-tumor necrosis factor-(TNF)α therapies, but this is the first report of this adverse effect with anti-JAK therapy.

Large correction in opening wedge high tibial osteotomy with resultant joint-line obliquity induces excessive shear stress on the articular cartilage.

PURPOSE: The purpose of this study was to analyse the resultant stress induced by joint-line obliquity after HTO for varus knee deformity using a three-dimensional (3D) finite element model analysis. METHODS: The geometrical bone data used in this study were derived from commercially available human bone digital anatomy media. The 3D knee models were developed using 3D computer-aided design software. The articular surface was overlaid with a 2-mm-thick cartilage layer for both femoral and tibial condyles. Ligament structures were simulated based on properties reported in previous anatomical studies. Regarding the loading condition, isolated axial loads of 1200 N with lateral joint-line inclinations of 2.5°, 5°, 7.5°, and 10° in reference to the horizontal axis were applied to the femur to simulate the mechanical environment in a knee with joint-line obliquity. RESULTS: A steep rise of shear stress in the medial compartment was noted in the model with obliquity of 5° or more. This laterally directed shear stress exhibited an incremental increase in accordance with the obliquity angle. The maximum shear stress value in the medial cartilage increased from 1.6 MPa for the normal knee to 3.3, 5.2, and 7.2 MPa in the joint-line obliquity models with 5°, 7.5°, and 10° of obliquity, respectively. CONCLUSIONS: The effects of HTO for varus knee deformity on the amount/distribution of stresses in the articular cartilage were analysed using a 3D finite element model. It was shown that joint-line obliquity of more than 5° induced excessive shear stress in the tibial articular cartilage. A large amount of correction in OWHTO with a resultant joint-line obliquity of 5° or more may induce detrimental stress to the articular cartilage. Double-level osteotomy should be considered as a surgical option in this situation.

Differential mRNA expression and the uptake of methotrexate in primary MAEC and MLF cells: involvement of the Abc and Slco/Oatp transporters in alveolar epithelial cell toxicity.

Drug transporters play a pivotal role in the disposition and elimination of a wide variety of organic compounds across the biological membrane of the body. Recent studies have revealed that some drug transporters are involved in drug-induced toxicity. We have previously reported that methotrexate (MTX)-induced cytotoxicity and apoptosis in primary mouse alveolar epithelial cells (MAEC) are more sensitive than primary mouse lung fibroblasts (MLF). In the present study, we investigated the mRNA expression of ABCs, Slco/Slc/Oatp transporters by RT-PCR and quantitative real-time PCR (qRT-PCR) techniques in mouse lung tissues and primary lung cells. The ABC transporters (Mdr1, Mrp1, 3, 4, 5, and Bcrp) and the Slco/Oatp transporters (Rfc, Oatp1a1, 1a4, 1a5, 1b2, 2a1, 2b1, 3a1, 4c1, and 5a1) were detected in mouse lung tissues, whereas some ABCs, Slcs/Oats, and Slco/Oatps transporters were not expressed in the mouse lung. Additionally, we found that some Abc transporters are expressed predominantly in MLF whereas Mrp3 and Oatp4c1 are expressed predominantly in MAEC. The transport activity of [(3)H]MTX mediated via MAEC was significantly higher than the MLF-mediated transport. When MLF was treated with MK571, accumulated [(3)H]MTX significantly increased when compared with MAEC. Thus, our results indicate that depending on the type of cells, several types of drug transporters are expressed in mouse lung tissues. Our results also suggest that MTX-induced fibrosis with cell dysfunction may be caused by the accumulation within the alveolar epithelial cells of MTX in the lung.

The usefulness of body image tests in the prevention of eating disorders.

PURPOSE: Individual psychological factors such as mental conditions and self-esteem and family relational factors are thought to be predisposing factors in the development of eating disorders. In this study, we conducted a survey of 12-15 year-old public junior high school students to extract factors related to abnormal eating behavior and determine what information could be used by schools to prevent eating disorders. METHOD: Self-descriptive surveys were distributed and collected during homeroom time at school. The survey consisted of the 26-item Eating Attitude Test (EAT-26) to measure the degree of abnormal eating behavior, Stunkard, Sorensen and Schlusinger's Body Image Scale to determine predisposing factors, the Family Adaptability and Cohesion Scale III (FACES III), General Health Questionnaire (GHQ), and Rosenberg's Self-Esteem Scale. 483 students (263 boys and 220 girls) participated in the survey. School-year height and weight data was used to calculate BMI. RESULTS: Approximately 7% of girls and 3% of boys showed clear indications of abnormal eating behavior. We found no direct relationship between abnormal eating behavior and family factors in this study, but an indirect relationship was suggested through other factors such as psychological complaints and self-esteem. There were relationships between abnormal eating behavior and the individual factors of psychological complaints, current and ideal body image, and low self-esteem. Furthermore, cluster analysis showed that there were students with high BMI who thought of themselves as fat, as well as students who perceived themselves as fat despite having average BMI. These students had a high frequency of abnormal eating behaviors, a great deal of psychological complaints, and low self-esteem. DISCUSSION: An understanding of BMI, along with body image, is essential for students who feel that they are overweight. Schools can practice preventative education by teaching these students about healthy body weight and by screening for the eating disorders that have become so rampant in our thin-worshiping culture.

Nephrotic syndrome with crescent formation and massive IgA deposition following allogeneic bone marrow transplantation for natural killer cell leukemia/lymphoma.

We describe herein a case of nephrotic syndrome (NS) following allogeneic bone marrow transplantation (allo-BMT) for natural killer cell leukemia/lymphoma. Histologic studies defined the diagnosis as crescentic glomerulonephritis with massive immunoglobulin A (IgA) deposition, which has never been reported in NS cases following allo-BMT. Most of the massive infiltrated cells in the interstice were CD3(+)CD4(-)CD8(+) T cells derived from the donor. We observed mesangial deposition of Haemophilus parainfluenza outer membrane (OMHP) antigen and decreased glycosylation of the IgA1 hinge in the recipient's samples is consistent with the recently reported pathogenesis of IgA nephropathy. Further, the titer of IgA antibody against the donor serum was as high as other IgA nephropathy cases. These findings suggest that NS and crescentic glomerulonephritis in this case occurred as one of the forms of chronic graft-versus-host disease (GVHD), and that IgA deposition was associated with H parainfluenza and decreased glycosylation of the IgA1 hinge.