Development and external validation of the DOAT and DOATS scores: simple decision support tools to identify disease progression among nonelderly patients with mild/moderate COVID-19.

BACKGROUND: During the fifth wave of the coronavirus disease 2019 (COVID-19) pandemic in Japan, which took place between June and September 2021, a significant number of COVID-19 cases with deterioration occurred in unvaccinated individuals < 65 years old. However, the risk factors for COVID-19 deterioration in this specific population have not yet been determined. This study developed a prediction method to identify COVID-19 patients < 65 years old who are at a high risk of deterioration. METHODS: This retrospective study analyzed data from 1,675 patients < 65 years old who were admitted to acute care institutions in Fukushima with mild-to-moderate-1 COVID-19 based on the Japanese disease severity criteria prior to the fifth wave. For validation, 324 similar patients were enrolled from 3 hospitals in Yamagata. Logistic regression analyses using cluster-robust variance estimation were used to determine predictors of disease deterioration, followed by creation of risk prediction scores. Disease deterioration was defined as the initiation of medication for COVID-19, oxygen inhalation, or mechanical ventilation starting one day or later after admission. RESULTS: The patients whose condition deteriorated (8.6%) tended to be older, male, have histories of smoking, and have high body temperatures, low oxygen saturation values, and comorbidities, such as diabetes/obesity and hypertension. Stepwise variable selection using logistic regression to predict COVID-19 deterioration retained comorbidities of diabetes/obesity (DO), age (A), body temperature (T), and oxygen saturation (S). Two predictive scores were created based on the optimism-corrected regression coefficients: the DOATS score, including all of the above risk factors, and the DOAT score, which was the DOATS score without oxygen saturation. In the original cohort, the areas under the receiver operating characteristic curve (AUROCs) of the DOATS and DOAT scores were 0.81 (95% confidence interval [CI] 0.77-0.85) and 0.80 (95% CI 0.76-0.84), respectively. In the validation cohort, the AUROCs for each score were both 0.76 (95% CI 0.69-0.83), and the calibration slopes were both 0.80. A decision curve analysis confirmed the clinical practicability of both scores in the validation cohort. CONCLUSIONS: We established two prediction scores that can quickly evaluate the risk of COVID-19 deterioration in mild/moderate patients < 65 years old.

[Case of Lung Cancer with High-Grade Fetal Lung Adenocarcinoma Components Treated with Chemotherapy].

A woman in her 70s presented to our hospital with complaints of cough and dyspnea. Computed tomography(CT) images showed a large amount of left pleural effusion, pleural tumors, and mediastinal lymphadenopathy. Left thoracic drainage was performed, and high-grade fetal lung adenocarcinoma was suspected upon pleural effusion-cell block immunostaining. Pathological evaluation of the CT-guided biopsy specimen provided a diagnosis of carcinoma with high-grade fetal lung adenocarcinoma. Although the tumor progressed rapidly, chemotherapy with atezolizumab/bevacizumab/carboplatin/ paclitaxel was highly effective. However, subsequent maintenance therapy with atezolizumab/bevacizumab led to disease progression.

An unusual case of eosinophilic lung disease with multiple cyst formation.

We report here an unusual case of eosinophilic necrotizing inflammation of the lung that mimicked chronic eosinophilic pneumonia. A 71-year-old man who lived in an unsanitary environment and was referred to our hospital with suspected pneumonia. Peripheral blood eosinophilia was observed, and computed tomography indicated extensive consolidation with multiple cystic lesions, mainly in the left lung. A histological analysis using video-assisted thoracic surgery revealed diffuse infiltration of inflammatory cells into the alveolar wall and massive accumulation of macrophages and eosinophils in the airspace. Many tiny eosinophilic abscesses were scattered through the tissue. These findings were more severe than those associated with chronic eosinophilic pneumonia. Immunostaining revealed the deposition of eosinophil granular protein and the presence of extracellular traps and Charcot-Leyden crystals, which suggested excessive eosinophil activation. Interestingly, the patient's symptoms and clinical findings gradually improved without treatment after admission. He was discharged to a clean residence and did not have a recurrence for 19 months. The observations suggest a hypersensitivity reaction to an environmental allergen and consequent multiple cyst formation in association with eosinophilic necrotizing inflammation, although further studies are warranted.

Atezolizumab-associated encephalitis in metastatic lung adenocarcinoma: a case report.

BACKGROUND: In recent years, immune checkpoint inhibitors have been widely used as a crucial therapy in malignant tumors. Immune checkpoint inhibitors can cause various autoimmune side effects called immune-related adverse events because they generate an exaggerated inflammatory response. Encephalitis associated with atezolizumab has rarely been reported as an immune-related adverse event. A case of encephalitis caused by treatment with atezolizumab is presented. CASE PRESENTATION: A 56-year-old Japanese man with lung cancer previously treated with surgery and chemotherapy was admitted with high fever, consciousness disorder, and motor aphasia. His first atezolizumab treatment was 17 days earlier. Admission brain magnetic resonance imaging with gadolinium enhancement showed no abnormalities. Cerebrospinal fluid showed cell count 20/l, protein 166 mg/dl, glucose 73 mg/dl, and interleukin 6 82.9 pg/ml (normal< 8.7 pg/ml). Atezolizumab-induced encephalitis was diagnosed. His symptoms improved the day after steroid pulse therapy was started. Following steroid pulse therapy, oral prednisolone 30 mg was started and tapered. The cerebrospinal fluid findings normalized on day 14. He was discharged on day 16 without neurological sequelae. CONCLUSION: In this case of encephalitis associated with atezolizumab, prompt steroid pulse therapy led to a successful response, and the outcome was good. The cerebrospinal fluid level of interleukin 6 reflected the severity of the encephalitis well. Clinicians should be aware of the possibility of encephalitis after initiation of immune checkpoint inhibitors.

[A Case of Primary Thymic Carcinoid Treated with Everolimus and Octreotide].

A 54-year-old woman had a history of precordial pain since February 20XX and had undergone a clinical examination at a nearby medical clinic in April 20XX. Because a plain chest radiograph revealed a mass shadow, the patient was referred to us for medical evaluation. Chest computerized tomography(CT)revealed a mass measuring 12 cm in size along its major axis diameter in the anterior mediastinal region, along with the enlargement of the anterior mediastinal, parasternal, hilar, and supradiaphragmatic lymph nodes, suggesting a thymic tumor. Histopathological examination of a needle biopsy specimen revealed a carcinoid. Thus, the patient was diagnosed with a primary thymic carcinoid. The patient was treated by partial excision of the mediastinal tumor owing to the presence of pericardial dissemination. Because of the histopathologic diagnosis of atypical carcinoid, the patient was additionally administered everolimus therapy in May. A repeat CT in July revealed shrinkage of the mass, but a subsequent CT in November revealed slight enlargement of the tumor. Because the somatostatin receptor(SSTR-2)tested positive, concomitant octreotide acetate injection was initiated in December. Follow-up CT examinations revealed stabilization of the disease at first. However, the gradual enlargement of the tumor was noted thereafter. This case constitutes one of the few reports of the treatment of primary thymic carcinoid with everolimus and octreotide.

[A case of lung tuberculosis which also incidentally found intestinal tuberculosis by 18F-fluorodeoxyglucose-positron emission tomography].

A 60-year-old women presenting with an abnormal shadow on a chest X-ray film was admitted to our hospital in June 2004. Her CT scan of the chest showed a cavitary mass shadow in the left upper lobe. FDG-PET was performed to examine whether this shadow was the lung cancer or not, and incidentally it showed an additional accumulation of FDG in the ileocecal resion. The colonoscopy was then carried out. Luminal narrowing with circumferential ulcer in the ileocecal resion could be observed, and pathological findings of the biopsy specimen revealed epithelioid cell granulomas. Partial lobectomy of the left upper lung was also performed, and the histological examination revealed typical pulmonary tuberculosis. Since the antituberculosis therapy was effective to the ileocecal lesion, we assert that the ileocecal lesion was intestinal tuberculosis.

Expression and localization of diacylglycerol kinase isozymes and enzymatic features in rat lung.

Diacylglycerol kinase (DGK) catalyzes phosphorylation of diacylglycerol to generate phosphatidic acid, and both molecules are known to serve as second messengers as well as important intermediates for the synthesis of various lipids. In this study, we investigated the spatiotemporal expression patterns of DGK isozymes together with the developmental changes of the mRNA expression and enzymatic property in rat lung. Northern blot and RT-PCR analyses showed that mRNAs for DGKalpha, -epsilon, and -zeta were detected in the lung. By immunohistochemical examination, DGKalpha and -zeta were shown to be coexpressed in alveolar type II cells and macrophages. Interestingly, these isozymes were localized at distinct subcellular locations, i.e., DGKalpha in the cytoplasm and DGKzeta in the nucleus, suggesting different roles for these isozymes. In the developing lung, the expression for DGKalpha and -zeta was transiently elevated on embryonic day 21 (E21) to levels approximately two- to threefold higher than on postnatal day 0 (P0). On the other hand, the expression for DGKepsilon was inversely elevated approximately twofold on P0 compared with that on E21. These unique changes in the expression pattern during the perinatal period suggest that each isozyme may play a distinct role in the adaptation of the lung to air or oxygen breathing at birth.

Selective translocation of diacylglycerol kinase zeta in hippocampal neurons under transient forebrain ischemia.

The molecular mechanisms responsible for differential neuronal vulnerability to ischemic injury are incompletely understood. Previous studies have reported that the expression and activity of protein kinase C (PKC), some subtypes of which are activated by Ca(2+) and diacylglycerol (DG), are altered after ischemic insults. Therefore, DG kinase (DGK), which is responsible for controlling PKC activity through DG metabolism, may also be involved in this process. DGKzeta, which is abundantly expressed in the brain, contains a nuclear localization signal (NLS), suggesting its involvement in some nuclear processes in neuronal cells. To elucidate the functional implications of DGKzeta in ischemia, we examined detailed localization of DGKzeta in rat brain after ischemic insults. We used an ischemic model of global cerebral ischemia for 20 min by bilateral common carotid artery occlusion combined with hypotension and followed time-points of reperfusion. DGKzeta expression was evaluated by immunohistochemistry using affinity-purified anti-DGKzeta antibody. In sham-operated rats, a strong DGKzeta-immunoreactivity was observed in the nucleus of neurons in various parts of the brain. In the global ischemic model DGKzeta-immunoreactivity was reduced in intensity in the hippocampal formation and detected in the cytoplasm of CA1 pyramidal neurons throughout reperfusion time courses. Change in the subcellular localization was restricted to the pyramidal cells in CA1 and later in CA3, but not observed in other areas of hippocampus. No change was observed in the cerebral and cerebellar cortices. The present study suggests that DGKzeta might be involved in the process of selective vulnerability of hippocampal pyramidal neurons in postischemic brain.

Mesenchymal-epithelial transition during somitic segmentation is regulated by differential roles of Cdc42 and Rac1.

Mesenchymal-epithelial transitions (MET) are crucial for vertebrate organogenesis. The roles of Rho family GTPases in such processes during actual development remain largely unknown. By electroporating genes into chick presomitic mesenchymal cells, we demonstrate that Cdc42 and Rac1 play important and different roles in the MET that generates the vertebrate somites. Presomitic mesenchymal cells, which normally contribute to both the epithelial and mesenchymal populations of the somite, were hyperepithelialized when Cdc42 signaling was blocked. Conversely, cells taking up genes that elevate Cdc42 levels remained mesenchymal. Thus, Cdc42 activity levels appear critical for the binary decision that defines the epithelial and mesenchymal somitic compartments. Proper levels of Rac1 are necessary for somitic epithelialization, since cells with activated or inhibited Rac1 failed to undergo correct epithelialization. Furthermore, Rac1 appears to be required for Paraxis to act as an epithelialization-promoting transcription factor during somitogenesis.