An evaluation of venous thromboembolism by whole-body enhanced CT scan for critical COVID-19 pneumonia with markedly rises of coagulopathy related factors: a case series study.

BACKGROUND: Coronavirus disease (COVID-19) pneumonitis associated with severe respiratory failure has a high mortality rate. Based on recent reports, the most severely ill patients present with coagulopathy, and disseminated intravascular coagulation (DIC)-like massive intravascular clot formation is frequently observed. Coagulopathy has emerged as a significant contributor to thrombotic complications. Although recommendations have been made for anticoagulant use for COVID-19, no guidelines have been specified. We describe four cases of critical COVID-19 with thrombosis detected by enhanced CT scan. The CT findings of all cases demonstrated typical findings of COVID-19 and pulmonary embolism or deep venous thrombus without critical exacerbation. Two patients died of respiratory failure due to COVID-19. DISCUSSION: Previous reports have suggested coagulopathy with thrombotic signs as the main pathological feature of COVID-19, but no previous reports have focused on coagulopathy evaluated by whole-body enhanced CT scan. Changes in hemostatic biomarkers, represented by an increase in D-dimer and fibrin/fibrinogen degradation products, indicated that the essence of coagulopathy was massive fibrin formation. Although there were no clinical symptoms related to their prognosis, critical COVID-19-induced systemic thrombus formation was observed. CONCLUSIONS: Therapeutic dose anticoagulants should be considered for critical COVID-19 because of induced coagulopathy, and aggressive follow-up by whole body enhanced CT scan for systemic venous thromboembolism (VTE) is necessary.

Temporal change in Syndecan-1 as a therapeutic target and a biomarker for the severity classification of COVID-19.

BACKGROUND: Coronavirus disease 2019 (COVID-19) pneumonitis associated with severe respiratory failure is associated with high mortality. The pathogenesis of COVID-19 is associated with microembolism or microvascular endothelial injuries. Here, we report that syndecan-1 (SDC-1), a component of the endothelial glycocalyx, may be a biomarker of severity classification for COVID-19 related to endothelial injury. METHODS AND ANALYSIS: We analyzed the data of COVID-19 patients for 1 year from February 2020 at Yokohama City University Hospital and Yokohama City University Medical Center Hospital. We selected COVID-19 patients who required admission care, including intensive care, and analyzed the classification of severe and critical COVID-19 retrospectively, using various clinical data and laboratory data with SDC-1 by ELISA. RESULTS: We analyzed clinical and laboratory data with SDC-1 in five severe COVID-19 and ten critical COVID-19 patients. In the two groups, their backgrounds were almost the same. In laboratory data, the LDH, CHE, and CRP levels showed significant differences in each group (P = 0.032, P < 0.0001, and P = 0.007, respectively) with no significant differences in coagulation-related factors (platelet, PT-INR, d-dimer, ISTH score; P = 0.200, 0.277, 0.655, and 0.36, respectively). For the clinical data, the SOFA score was significantly different from admission day to day 14 of admission (p < 0.0001). The SDC-1 levels of critical COVID-19 patients were significantly higher on admission day and all-time course compared with the levels of severe COVID-19 patients (P = 0.009 and P < 0.0001, respectively). CONCLUSIONS: Temporal change of SDC-1 levels closely reflect the severity of COVID-19, therefore, SDC-1 may be a therapeutic target and a biomarker for the severity classification of Covid-19.

Role of KRAS in regulating normal human airway basal cell differentiation.

BACKGROUND: KRAS is a GTPase that activates pathways involved in cell growth, differentiation and survival. In normal cells, KRAS-activity is tightly controlled, but with specific mutations, the KRAS protein is persistently activated, giving cells a growth advantage resulting in cancer. While a great deal of attention has been focused on the role of mutated KRAS as a common driver mutation for lung adenocarcinoma, little is known about the role of KRAS in regulating normal human airway differentiation. METHODS: To assess the role of KRAS signaling in regulating differentiation of the human airway epithelium, primary human airway basal stem/progenitor cells (BC) from nonsmokers were cultured on air-liquid interface (ALI) cultures to mimic the airway epithelium in vitro. Modulation of KRAS signaling was achieved using siRNA-mediated knockdown of KRAS or lentivirus-mediated over-expression of wild-type KRAS or the constitutively active G12 V mutant. The impact on differentiation was quantified using TaqMan quantitative PCR, immunofluorescent and immunohistochemical staining analysis for cell type specific markers. Finally, the impact of cigarette smoke exposure on KRAS and RAS protein family activity in the airway epithelium was assessed in vitro and in vivo. RESULTS: siRNA-mediated knockdown of KRAS decreased differentiation of BC into secretory and ciliated cells with a corresponding shift toward squamous cell differentiation. Conversely, activation of KRAS signaling via lentivirus mediated over-expression of the constitutively active G12 V KRAS mutant had the opposite effect, resulting in increased secretory and ciliated cell differentiation and decreased squamous cell differentiation. Exposure of BC to cigarette smoke extract increased KRAS and RAS protein family activation in vitro. Consistent with these observations, airway epithelium brushed from healthy smokers had elevated RAS activation compared to nonsmokers. CONCLUSIONS: Together, these data suggest that KRAS-dependent signaling plays an important role in regulating the balance of secretory, ciliated and squamous cell differentiation of the human airway epithelium and that cigarette smoking-induced airway epithelial remodeling is mediated in part by abnormal activation of KRAS-dependent signaling mechanisms.

The role of vascular endothelial growth factor receptor-1 signaling in compensatory contralateral lung growth following unilateral pneumonectomy.

Compensatory lung growth models have been widely used to investigate alveolization because the remaining lung can be kept intact and volume loss can be controlled. Vascular endothelial growth factor (VEGF) plays an important role in blood formation during lung growth and repair, but the precise mechanisms involved are poorly understood; therefore, the aim of this study was to investigate the role of VEGF signaling in compensatory lung growth. After left pneumonectomy, the right lung weight was higher in VEGF transgenic mice than wild-type (WT) mice. Compensatory lung growth was suppressed significantly in mice injected with a VEGF neutralizing antibody and in VEGF receptor-1 tyrosine kinase-deficient mice (TK(-/-) mice). The mobilization of progenitor cells expressing VEGFR1(+) cells from bone marrow and the recruitment of these cells to lung tissue were also suppressed in the TK(-/-) mice. WT mice transplanted with bone marrow from TK(-/-)transgenic GFP(+) mice had significantly lower numbers of GFP(+)/aquaporin 5(+), GFP(+)/surfactant protein A(+), and GFP(+)/VEGFR1(+) cells than WT mice transplanted with bone marrow from WTGFP(+) mice. The GFP(+)/VEGFR1(+) cells also co-stained for aquaporin 5 and surfactant protein A. Overall, these results suggest that VEGF signaling contributes to compensatory lung growth by mobilizing VEGFR1(+) cells.

Clinical impact of lung age on postoperative readmission in non-small cell lung cancer.

BACKGROUND: Recently, the Japanese Respiratory Society (JRS) proposed using lung age (LA) as an indicator of lung function; however, reports regarding the association of LA with the risk of postoperative readmission within 90 d after surgical treatment for non-small cell lung cancer (NSCLC) are limited. Here, we analyze the clinical relationship between LA and readmission within 90 d after surgical treatment for NSCLC. METHODS: A total of 979 patients underwent curative resections for NSCLC from January 2000-September 2012 at the Kitasato University Hospital. We selected patients who required readmission because of surgical complications within 90 d of surgery and retrospectively analyzed various clinical data. LA was calculated based on the formula given by the Japanese Respiratory Society, which relies on preoperative respiratory function. We also calculated the age gap (AG) between the calculated LA and the true age (TA). RESULTS: There were 216 patients who needed to be readmitted within 90 d of surgery, 33 (3%) of whom were hospitalized for surgical complications. Twenty-four patients (73%) had respiratory complications, and 7 patients (21%) died. There were significant differences between the readmitted and no readmitted patients in terms of preoperative factors, such as gender, LA, AG, smoking status, and smoking index (P < 0.05). In addition, there were significant differences in intraoperative blood loss, postoperative complications, histologic type, duration of hospitalization, and hospitalization after surgery (P < 0.05). Multivariate analysis using logistic regression indicated that LA, AG, blood loss, and postoperative complications were independent factors that predicted readmission. Additionally, the 5-y survival rates were 78% and 44% for the no readmitted and readmitted groups, respectively (P < 0.001). CONCLUSIONS: The AG between TA and LA was significantly associated with postoperative complications and remained an independent predictive factor after multiple regressions. LA was shown to be a useful factor for predicting the risk of surgery-related readmission within 90 d after surgery for NSCLC.

Angiotensin II type 1A receptor signaling facilitates tumor metastasis formation through P-selectin-mediated interaction of tumor cells with platelets and endothelial cells.

Angiotensin II is involved in tumor growth; however, the precise mechanism is not known. Platelets also contribute to tumor growth, and angiotensin II type 1 receptor (AT1) is expressed on the platelet surface. We hypothesized that interaction of platelets with tumor cells through AT1 receptor signaling promotes tumor metastasis. B16F1 melanoma cells were intravenously injected into Agtr1a knockout mice (AT1a(-/-)) and wild-type littermates (WT); the AT1a(-/-) mice exhibited a reduction in lung colonies. Angiotensin II induced expression of P-selectin on platelets in WT but not in AT1a(-/-) mice. A selective P-selectin neutralizing antibody decreased lung colony numbers in WT but not in AT1a(-/-) mice. Levels of vascular endothelial growth factor (VEGF) and stromal cell-derived factor 1 (SDF-1) receptor in platelets at metastatic locus were lower in AT1a(-/-) mice. Treatment of neutralizing antibodies against VEGF and CXCR4 decreased lung colony numbers in WT but not in AT1a(-/-) mice. In AT1a(-/-) mice, and both mobilization of progenitor cells expressing CXCR4(+)VEGFR1(+) cells from bone marrow and their recruitment to lung tissues were suppressed. These results suggest that AT1A signaling plays a critical role in tumor metastasis through P-selectin-mediated interactions of platelets with tumor and endothelial cells and through the AT1A signaling-dependent production of VEGF and SDF-1, which may be involved in mobilization of CXCR4(+)VEGFR1(+) cells.

Clinical impact of lung age on postoperative complications in non-small cell lung cancer patients aged >70 y.

BACKGROUND: Surgery for elderly patients with primary lung neoplasms has become relatively common as populations age; however, the high frequency of postoperative complications has prevented its broad application. Recently, the Japanese Respiratory Society proposed lung age (LA) as an index of lung function, but reports on the association between LA and the risk factors for postoperative complications with non-small cell lung cancer (NSCLC) surgery have been limited. In this study, we analyzed the clinical applicability of LA for elderly patients with NSCLC. MATERIALS AND METHODS: We studied 320 patients aged >70 y underwent curative resections for NSCLC. LA was calculated based on the formula provided by the Japanese Respiratory Society, which depended on the patient's preoperative respiratory function and was divided into four age gap (AG) groups between the LA and the true age (TA). The categorical data were compared among the four groups. RESULTS: The numbers of patients in groups A, B, C, and D were 80, 77, 79, and 84, respectively. For the univariate analysis, the preoperative factors for postoperative complications were gender, AG, and smoking (P < 0.05). In a multivariate analysis, AG proved to be an independent factor. Although we found no significant differences, there was a tendency for the prognosis to worsen with an increase in the AG (P = 0.06). CONCLUSIONS: The AG was significantly associated with and an independent predictive factor for postoperative complications. We conclude that LA and AG are useful factors for predicting the risk of postoperative complications.

Surgical removal of pulmonary arteriovenous malformations subsequent to total cavopulmonary connection conversion long after a Björk procedure.

Because the cavopulmonary shunt procedure is widely used for palliation of complex congenital heart diseases, pulmonary arteriovenous malformations (PAVMs) are relatively well-known complications. The reported patient was a 23-year-old woman who experienced PAVMs in the right lower lobe after a classical Glenn anastomosis and Björk procedure for tricuspid atresia. Her arterial oxygen saturation (SaO2) 14 years after the Björk procedure was ~80 %. She then underwent a total cavopulmonary connection (TCPC) conversion to reduce her PAVMs in the right lower lobe using the "hepatic factor." However, her situation remained unchanged, and she experienced severe systemic cyanosis (SaO2, 70 %) and dyspnea during physical exertion without hemoptysis due to increased blood flow to the PAVMs. Although interventional embolization was considered, it was impossible due to considerable dilation of the main PAVM. Thus, right lower lung lobectomy was performed. After surgery, the patient's SaO2 increased to 90 %. To the authors' knowledge, this is the first case report of a lung resection for residual PAVMs after TCPC conversion.

[A case of advanced gastric cancer with bulky lymph node metastases responding to S-1/CDDP neoadjuvant chemotherapy and leading to less invasive surgery and a pathologically complete response].

A 53-year-old man was diagnosed with advanced gastric cancer(cT4aN2M0, StageIII B), with regional bulky lymph node metastases invading the splenic artery. S-1 plus cisplatin treatment(S-1/CDDP)was administered as neoadjuvant chemo- therapy(NAC). S-1(80mg/m2)was administered orally for 21 days, followed by 14 drug-free days as a course. CDDP(60 mg/m2)was administered by intravenous drip on day 8. After two courses, significant tumor reduction was obtained, and the patient then had total gastrectomy and splenectomy performed with a D2 dissection. Distal pancreatectomy was avoided. Macroscopically, the stomach seemed to be penetrated by the tumor into the serosa, yet the histological diagnosis revealed complete disappearance of cancer cells in all of the lymph nodes, and very few residual tumor cells were noted, only on the gastric mucosa(pT1aN0M0, Stage I A). Therefore, downstaging was confirmed. S-1/CDDP as a NAC regimen for advanced gastric cancer appears to be an effective treatment.

Association of obesity paradox with prognosis of veno-venous-extracorporeal membrane oxygenation in patients with coronavirus disease 2019.

Aim: Although the obesity paradox is known for various diseases, including cancer and acute respiratory distress syndrome, little is known about veno-venous extracorporeal membrane oxygenation (VV-ECMO) in patients with coronavirus disease 2019 (COVID-19). In this study, we aimed to investigate the association between body mass index (BMI) and prognosis in critical patients with COVID-19 requiring VV-ECMO. Methods: We conducted a retrospective observational single-center study at Yokohama City University Civic General Medical Center between March 2020 and October 2021. Participants were patients with COVID-19 who required VV-ECMO. They were classified into two groups: BMI ≤30 kg/m2 and >30 kg/m2. Results: In total, 23 patients were included in the analysis, with a median BMI of 28.7 kg/m2. Overall, 22 patients were successfully weaned from the ECMO. When comparing the two groups, there was a trend toward fewer days from onset to ECMO induction in the BMI >30 kg/m2 group. Moreover, the two groups had a similar prognosis. There were no statistically significant differences in the number of days from onset to hospitalization or the duration of ECMO induction between the groups. Conclusion: VV-ECMO induction for patients with COVID-19 may lead to earlier indications in patients with BMI >30 kg/m2 than in those with BMI ≤30 kg/m2.

Combining blood glucose and SpO2/FiO2 ratio facilitates prediction of imminent ventilatory needs in emergency room COVID-19 patients.

The increasing requirement of mechanical ventilation (MV) due to the novel coronavirus disease (COVID-19) is still a global threat. The aim of this study is to identify markers that can easily stratify the impending use of MV in the emergency room (ER). A total of 106 patients with COVID-19 requiring oxygen support were enrolled. Fifty-nine patients were provided MV 0.5 h (interquartile range: 0.3 to 1.4) post-admission. Clinical and laboratory data before intubation were collected. Using a multivariate logistic regression model, we identified four markers associated with the impending use of MV, including the ratio of peripheral blood oxygen saturation to fraction of inspired oxygen (SpO2/FiO2 ratio), alanine aminotransferase, blood glucose (BG), and lymphocyte counts. Among these markers, SpO2/FiO2 ratio and BG, which can be measured easily and immediately, showed higher accuracy (AUC: 0.88) than SpO2/FiO2 ratio alone (AUC: 0.84), despite no significant difference (DeLong test: P = 0.591). Moreover, even in patients without severe respiratory failure (SpO2/FiO2 ratio > 300), BG (> 138 mg/dL) was predictive of MV use. Measuring BG and SpO2/FiO2 ratio may be a simple and versatile new strategy to accurately identify ER patients with COVID-19 at high risk for the imminent need of MV.

The microsomal prostaglandin E synthase-1/prostaglandin E2 axis induces recovery from ischaemia via recruitment of regulatory T cells.

AIMS: Microsomal prostaglandin E synthase-1 (mPGES-1)/prostaglandin E2 (PGE2) induces angiogenesis through the prostaglandin E2 receptor (EP1-4). Among immune cells, regulatory T cells (Tregs), which inhibit immune responses, have been implicated in angiogenesis, and PGE2 is known to modulate the function and differentiation of Tregs. We hypothesized that mPGES-1/PGE2-EP signalling could contribute to recovery from ischaemic conditions by promoting the accumulation of Tregs. METHODS AND RESULTS: Wild-type (WT), mPGES-1-deficient (mPges-1-/-), and EP4 receptor-deficient (Ep4-/-) male mice, 6-8 weeks old, were used. Hindlimb ischaemia was induced by femoral artery ligation. Recovery from ischaemia was suppressed in mPges-1-/- mice and compared with WT mice. The number of accumulated forkhead box protein P3 (FoxP3)+ cells in ischaemic muscle tissue was decreased in mPges-1-/- mice compared with that in WT mice. Expression levels of transforming growth factor-ß (TGF-ß) and stromal cell derived factor-1 (SDF-1) in ischaemic tissue were also suppressed in mPges-1-/- mice. The number of accumulated FoxP3+ cells and blood flow recovery were suppressed when Tregs were depleted by injecting antibody against folate receptor 4 in WT mice but not in mPges-1-/- mice. Recovery from ischaemia was significantly suppressed in Ep4-/- mice compared with that in WT mice. Furthermore, mRNA levels of Foxp3 and Tgf-ß were suppressed in Ep4-/- mice. Moreover, the number of accumulated FoxP3+ cells in ischaemic tissue was diminished in Ep4-/- mice compared with that in Ep4+/+ mice. CONCLUSION: These findings suggested that mPGES-1/PGE2 induced neovascularization from ischaemia via EP4 by promoting the accumulation of Tregs. Highly selective EP4 agonists could be useful for the treatment of peripheral artery disease.

Prediction of prognosis in patients with severe COVID-19 pneumonia using CT score by emergency physicians: a single-center retrospective study.

We aimed to develop a method to determine the CT score that can be easily obtained from CT images and examine its prognostic value for severe COVID pneumonia. Patients with COVID pneumonia who required ventilatory management by intubation were included. CT score was based on anatomical information in axial CT images and were divided into three sections of height from the apex to the bottom. The extent of pneumonia in each section was rated from 0 to 5 and summed. The primary outcome was the prediction of patients who died or were managed on extracorporeal membrane oxygenation (ECMO) based on the CT score at admission. Of the 71 patients included, 12 (16.9%) died or required ECMO management, and the CT score predicted death or ECMO management with ROC of 0.718 (0.561-0.875). The death or ECMO versus survival group (median [quartiles]) had a CT score of 17.75 (14.75-20) versus 13 (11-16.5), p = 0.017. In conclusion, a higher score on our generated CT score could predict the likelihood of death or ECMO management. A CT score at the time of admission allows for early preparation and transfer to a hospital that can manage patients who may need ECMO.

Thromboxane A2 receptor signaling facilitates tumor colonization through P-selectin-mediated interaction of tumor cells with platelets and endothelial cells.

Thromboxane A(2) (TXA(2) ) is a prostanoid formed by thromboxane synthase using the cyclooxygenase product, prostaglandin H(2), as the substrate. TXA(2) was shown to enhance tumor metastasis, but the underlying mechanism remains unclear. B16F1 melanoma cells were intravenously injected into TXA(2) receptor (TP) knockout mice (TP(-/-) ) and wild-type littermates (WT). TP(-/-) showed a reduction in B16F1 lung colonization and mortality rate, which were associated with a decreased number of platelets. Platelet activation as assessed by P-selectin expression was suppressed in TP(-/-) . A selective P-selectin neutralizing antibody decreased the lung colonization in WT mice, but not in TP(-/-) . The expression of P-selectin glycoprotein ligand-1 in B16F1 and HUVEC were enhanced by treatment with U46619, a thromboxane analog. The plasma levels of vascular endothelial growth factor (VEGF) and stromal-derived factor (SDF)-1 were lower in TP(-/-) . In TP(-/-) , the mobilization of progenitor cells expressing CXCR4(+) VEGFR1(+) from bone marrow and the recruitment of those cells to lung tissues were suppressed. These results suggest that TP signaling plays a critical role in tumor colonization through P-selectin-mediated interactions between platelets-tumor cells and tumor cells-endothelial cells through the TP signaling-dependent production of VEGF and SDF-1, which might be involved in the mobilization of VEGFR1(+) CXCR4(+) cells. Blockade of TP signaling might be useful in the treatment of tumor metastasis.

Peripheral venous lactate levels substitute arterial lactate levels in the emergency department.

BACKGROUND: Arterial lactate (AL) level is an important predictor of patient prognosis. AL and peripheral venous lactate (PVL) in blood gas analysis have a low concordance rate, and PVL cannot be used as a substitute for AL. However, if the AL range can be predicted from PVL, PVL may be an alternative method for predicting patient prognosis, and the risk of arterial puncture complications with AL may be reduced. This could be a safe and rapid test method. METHODS: This was a retrospective observational study of 125 cases in which blood gas analysis was performed on both arterial and venous blood with an infectious disease in an emergency department. Spearman's rank correlation coefficient (r) and Bland-Altman analyses were performed. Sensitivity, specificity, and area under the curve (AUC) were calculated for PVL to predict AL < 2 mmol/L or < 4 mmol/L. RESULTS: The median [interquartile range] AL and PVL were 1.82 [1.25-2.46] vs. 2.08 [1.57-3.28], respectively, r was 0.93 (p < 0.0001), and a strong correlation was observed; however, Bland-Altman analysis showed disagreement. When AL < 2 mmol/L was used as the outcome, AUC was 0.970, the PVL cutoff value was 2.55 mmol/L, sensitivity was 85.71%, and specificity was 96.05%. If PVL < 2 mmol/L was the outcome, the sensitivity for AL < 2mmol/L was 100%, and for PVL levels ≥ 3 mmol/L, the specificity was 100%. When AL < 4 mmol/L was used as the outcome, AUC was 0.967, the PVL cutoff value was 3.4 mmol/L, sensitivity was 100%, and specificity was 85.84%. When PVL < 3.5 mmol/L was the outcome, the sensitivity for AL < 4 mmol/L was 100%, and for PVL levels ≥ 4 mmol/L, the specificity was 93.81%. CONCLUSIONS: This study revealed that PVL and AL levels in the same critically ill patients did not perfectly agree with each other but were strongly correlated. Furthermore, the high accuracy for predicting AL ranges from PVL levels explains why PVL levels could be used as a substitute for AL level ranges.

Severity predictors of COVID-19 in SARS-CoV-2 variant, delta and omicron period; single center study.

BACKGROUND: The outcomes of coronavirus disease 2019 (COVID-19) treatment have improved due to vaccination and the establishment of better treatment regimens. However, the emergence of variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes COVID-19, and the corresponding changes in the characteristics of the disease present new challenges in patient management. This study aimed to analyze predictors of COVID-19 severity caused by the delta and omicron variants of SARS-CoV-2. METHODS: We retrospectively analyzed the data of patients who were admitted for COVID-19 at Yokohama City University Hospital from August 2021 to March 2022. RESULTS: A total of 141 patients were included in this study. Of these, 91 had moderate COVID-19, whereas 50 had severe COVID-19. There were significant differences in sex, vaccination status, dyspnea, sore throat symptoms, and body mass index (BMI) (p <0.0001, p <0.001, p <0.001, p = 0.02, p< 0.0001, respectively) between the moderate and severe COVID-19 groups. Regarding comorbidities, smoking habit and renal dysfunction were significantly different between the two groups (p = 0.007 and p = 0.01, respectively). Regarding laboratory data, only LDH level on the first day of hospitalization was significantly different between the two groups (p<0.001). Multiple logistic regression analysis revealed that time from the onset of COVID-19 to hospitalization, BMI, smoking habit, and LDH level were significantly different between the two groups (p<0.03, p = 0.039, p = 0.008, p<0.001, respectively). The cut-off value for the time from onset of COVID-19 to hospitalization was four days (sensitivity, 0.73; specificity, 0.70). CONCLUSIONS: Time from the onset of COVID-19 to hospitalization is the most important factor in the prevention of the aggravation of COVID-19 caused by the delta and omicron SARS-CoV-2 variants. Appropriate medical management within four days after the onset of COVID-19 is essential for preventing the progression of COVID-19, especially in patients with smoking habits.

Open mesh removal combined with laparoscopic totally extraperitoneal inguinal hernia repair: A case report of a novel surgical technique for chronic postoperative inguinal pain.

A 74-year-old man presented for surgical treatment to alleviate chronic post-herniorrhaphy inguinal pain. Physical and imaging examinations suggested that his pain was due to his ilioinguinal nerve being entrapped by a meshoma composed of bilayer mesh and plug mesh. The patient strongly desired mesh removal, although it appeared challenging because of adhesion of the meshes from the previous herniorrhaphies. Anticipating technical difficulty, we performed laparoscopic totally extraperitoneal repair followed by open mesh removal. Thus, the risk of damaging the peritoneum and visceral organs during open mesh removal was eliminated because the peritoneum had already been separated from the pathogenic mesh during the laparoscopic repair. The patient's chronic pain was drastically relieved. Combination surgery may therefore be a safe and useful technique in select patients with chronic postoperative inguinal pain. This approach could also prevent hernia recurrence.

A Case of Central Pontine Myelinolysis Occurred During Treatment of Hyperosmolar Hyperglycemic Syndrome.

Central pontine myelinolysis (CPM) is a rare demyelinating condition which has been reported to occur in a variety of clinical settings, but most commonly in association with a rapid rise in plasma osmolality during correction of chronic hyponatremia. The clinical consequences can vary from a mild motor weakness that resolves completely over time to the devastating locked-in syndrome. In this presentation, we report a case of hyperosmolar hyperglycemic syndrome (HHS) with ponto-occipital disintegration. A 71-year-old female was transferred to our ER by an ambulance due to consciousness disorder and continuous fever for 10 days. We diagnosed septic shock caused by urinary tract infection (UTI), cerebral multiple infarctions, acute kidney injury (AKI) and HHS without treatment for diabetes. Then, we started therapeutic interventions for them based on the guideline with severe control for blood sugar (BS; primary 1635 mg/dl) under insulin therapy and hypernatremia (primary 153 mEq/l) under crystal infusion control in advanced care unit, apparently on routine lab data. However, the initial serum sodium value of 153 mEq/l was slowly compensated to 148 mEq/l in 60 hours under guideline on routine lab data, the initial compensated sodium value with osmolality was changed from 178 mEq/l to 150 mEq/l in the period. She recovered from her primary diagnosis and unconsciousness. After stabilized sepsis and HHS, we detected CPM on brain MRI due to following up multiple cerebral infarctions with left leg paralysis and verbal disorder. She gradually recovered over several months with intensive rehabilitation and eventually regained near normal functional capacity with stabilized BS. When we consider HHS with hypernatremia, it may be necessary to pay attention to not only to BS control and sodium control according to the guideline but also to osmolality changes to prevent CPM.

Long-Term Decreased Exercise Capacity of COVID-19 Patients Who Received Mechanical Ventilation in Japan: A Case Series.

ABSTRACT: The long-term exercise capacity of coronavirus disease 2019 patients with acute respiratory distress syndrome is not clear. The 6-min walking distance of four patients with coronavirus disease 2019-associated acute respiratory distress syndrome was followed for 6 mos after admission to the hospital. These four patients were admitted to the intensive care unit of our hospital and received mechanical ventilation. Rehabilitation therapy (positioning, postural drainage, and passive range-of-motion exercises) was started after intensive care unit admission. Mobilization therapy, including muscle power training, sitting on the edge of the bed, and endurance training, was performed after the end of sedation. The Medical Research Council sum scores and Barthel Indexes for the patients improved after intensive care unit discharge and completely recovered 6 mos after admission to the hospital. However, the 6-min walking distance of the four patients remained shorter than those of healthy persons of the same age at 6 mos after admission to the hospital. Furthermore, the minimum Spo2 during the 6-min walking test remained less than 96%. It is possible that patients who receive mechanical ventilation due to coronavirus disease 2019-associated acute respiratory distress syndrome have decreased long-term exercise capacity, despite muscle power and activities of daily living recovering completely.

Prostaglandin-E2 receptor-4 stimulant rescues cardiac malfunction during myocarditis and protects the heart from adverse ventricular remodeling after myocarditis.

Cardioprotective effect of prostaglandin-E2 receptor-4 (EP4) stimulation on the ischemic heart has been demonstrated. Its effect on the heart affected by myocarditis, however, remains uncertain. In this study, we investigated therapeutic effect of EP4 stimulant using a mouse model of autoimmune myocarditis (EAM) that progresses to dilated cardiomyopathy (DCM). EP4 was present in the hearts of EAM mice. Treatment with EP4 agonist (ONO-0260164: 20 mg/kg/day) improved an impaired left ventricular (LV) contractility and reduction of blood pressure on day 21, a peak myocardial inflammation. Alternatively, DCM phenotype, characterized by LV dilation, LV systolic dysfunction, and collagen deposition, was observed on day 56, along with activation of matrix metalloproteinase (MMP)-2 critical for myocardial extracellular matrix disruption, indicating an important molecular mechanism underlying adverse ventricular remodeling after myocarditis. Continued treatment with ONO-0260164 alleviated the DCM phenotype, but this effect was counteracted by its combination with a EP4 antagonist. Moreover, ONO-0260164 inhibited in vivo proteolytic activity of MMP-2 in association with up-regulation of tissue inhibitor of metalloproteinase (TIMP)-3. EP4 stimulant may be a promising and novel therapeutic agent that rescues cardiac malfunction during myocarditis and prevents adverse ventricular remodeling after myocarditis by promoting the TIMP-3/MMP-2 axis.