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Adjuvant therapy; Breast cancer; Olaparib Terapia adyuvante; Cáncer de mama; Olaparib Teràpia adjuvant; Càncer de mama; Olaparib Background The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety. Patients and methods One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015. Results With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Δ 3.4%, 95% CI −0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome. Conclusion With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals. Funding for this work, which was conducted as a collaborative partnership among the Breast International Group, NRG Oncology, Frontier Science, AstraZeneca, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, U.S.A. (MSD), was provided by the National Institutes of Health (grant numbers: U10CA 180868, UG1CA 189867, and U10CA 180822) and by AstraZeneca as part of an alliance between AstraZeneca and MSD. Provision of olaparib and placebo was from AstraZeneca.

Understanding the composition of stroke thrombi retrieved by mechanical thrombectomy is essential to clarify the pathogenesis of stroke. However, it is difficult to evaluate thrombus composition precisely and objectively. Immunohistochemical staining was used to evaluate thrombus composition and age.Consecutive thrombi (n = 108) retrieved from patients who underwent mechanical thrombectomy for acute large-vessel ischemic stroke were retrospectively analyzed. Lytic features of granulocytes and CD163 were estimated as indicators of the age of the cardioembolic (CE) thrombus.The stroke subtypes were as follows: CE, 74 cases; large artery atherosclerosis, 11; undetermined etiology, 12; and other determined etiology, 11. There were no statistical differences in thrombi composition according to stroke subtypes. The fibrin area was positively correlated with the red blood cell (RBC) and platelet areas. The following analysis was performed using CE only. Regarding age, the thrombus was judged as fresh in 30.0 % and older in 70.0 % based on the lytic features. The RBC areas of older thrombi were smaller than those of fresh thrombi. The puncture-to-reperfusion time of older thrombi was longer than that of fresh thrombi. Platelet-rich thrombi were associated with a greater number of maneuvers, a smaller prevalence of TICI 3, and unfavorable functional outcomes compared to platelet-poor thrombi. The number of CD163 positive cells in thrombi with anticoagulants was higher than in those without anticoagulants.Thrombus composition correlated with revascularization and clinical outcomes. The composition of an acute ischemic thrombus may reflect the pathophysiology of stroke and influence treatment efficacy.

OBJECTIVE To test the hypothesis that intraplaque hemorrhage is a predictor of restenosis after carotid artery stenting (CAS), the association between intraplaque high-intensity signal (HIS) on time-of-flight MR angiography (TOF-MRA), as a marker of intraplaque hemorrhage, and restenosis after CAS was assessed in the present observational study. METHODS Consecutive patients who underwent initial CAS for atherosclerotic stenosis in the cervical internal carotid artery in the authors’ department were enrolled. Of these, patients without preprocedural cervical TOF-MRA were excluded. Outcome measures were ≥ 50% restenosis, defined as a peak systolic velocity of > 1.3 m/sec; or occlusion and ≥ 70% restenosis, defined as a peak systolic velocity of > 2.1 m/sec; or occlusion on carotid duplex ultrasound. RESULTS Of 230 consecutive patients who underwent initial CAS, 22 without preprocedural cervical TOF-MRA were excluded. Of the remaining 208 patients (mean age 73 years; 33 women), 46 had intraplaque HIS. Ultrasound follow-up was not performed in 4 patients. The median follow-up duration was 3.2 years (interquartile range 1.7–5.1 years). During the follow-up period, 102 patients had ≥ 50% restenosis and 36 had ≥ 70% restenosis. Intraplaque HIS was significantly associated with increased risk of ≥ 50% restenosis (adjusted hazard ratio 2.18; 95% CI 1.28–3.68) and ≥ 70% restenosis (adjusted hazard ratio 3.12; 95% CI 1.32–7.52). CONCLUSIONS Intraplaque HIS on TOF-MRA was associated with increased risk of restenosis after CAS. The present results indicate that intraplaque hemorrhage is a predictor of restenosis after CAS.

This study aimed to ascertain the physical-fitness trends among community-dwelling older adults using performance testing. The results of the evaluation conducted during the COVID-19 pandemic were compared to data from the pre-pandemic period.A total of 240 community-dwelling older adults who participated in a health checkup program from 2016-2020 underwent the following tests: grip strength (upper limb muscle), single-leg balance with eyes open (static balance), sit-and-reach test (flexibility), timed up-and-go test (TUG, functional mobility), 5 meter habitual walk (walking ability), and hand working with pegboard (hand dexterity). Linear mixed effect models were applied to the hierarchical dataset: repeated data (Level 1), pre-pandemic (2016-2019), pandemic (2019-2020) (Level 2), and individuals (Level 3). Fixed effects and interactions were estimated for the survey year (Level 1), and between the survey year and pre- and post-pandemic (Level 2), with the range of decline set measured in terms of its standardized partial regression coefficient, "B," from 2019-2020.The items for which significant cross-level interactions were identified. In males, the following items showed significant cross-level interactions: sit and reach test (B=-2.56, 95% CI: -4.45--0.66 cm), TUG (+0.39, 0.21-0.56 sec) and 5 meter habitual walk (+0.15, 0.04-0.27 sec). In females items except single-leg balance with eyes open showed significant cross-level interactions: grip strength (-0.58, -1.11--0.05 kg), sit-and-reach test (-3.53, -5.11--1.95 cm), TUG (+0.15, 0.03-0.27 sec), for 5 meter habitual walk (+0.14, 0.04-0.24 sec), and hand working with pegboard (+0.89, 0.28-1.51 sec).In both males and females, a significant deterioration in flexibility and mobility movement ability was observed in 2019-2020. In addition, upper limb muscle strength and hand dexterity movement deteriorated in females.

A comparison between atezolizumab plus bevacizumab (ATEZO/BEVA) and lenvatinib (LEN) for the treatment of hepatocellular carcinoma (HCC) remains unclear.This study aimed to compare the therapeutic effects and safety of ATEZO/BEVA and LEN as first-line therapies for HCC.This study was a retrospective analysis of 810 patients with HCC who underwent ATEZO/BEVA (n = 186) or LEN (n = 624) as first-line systemic therapy between March 2018 to March 2022 at 14 facilities. After propensity score matching, 304 patients (ATEZO/BEVA group: n = 152; LEN group: n = 152) were analyzed.After propensity score matching, although there was no significant difference in objective response rates (ORRs) between the ATEZO/BEVA and LEN groups (ORR 44.8% vs. 46.7%, p = 0.644), the median progression-free survival (PFS) and median overall survival (OS) in the ATEZO/BEVA group were significantly higher than those in the LEN group (median PFS: 8.3 months vs. 6.0 months, p = 0.005; median OS: not reached vs. 20.2 months, p = 0.039). The rates of appetite loss, fatigue, and proteinuria of grade 3 or higher in the ATEZO/BEVA group were lower than those in the LEN group. However, the rate of bleeding of grade 3 or higher in the ATEZO/BEVA group was higher than that in the LEN group. The conversion rate was higher in the ATEZO/BEVA group than that in the LEN group (8.6% vs. 1.9%, p = 0.007).ATEZO/BEVA showed superiority to LEN in terms of prognosis and conversion rate as first-line therapy. Moreover, ATEZO/BEVA had a lower rate of severe adverse events, except for bleeding, than LEN.

Outcomes with and without bevacizumab as first-line chemotherapy in Japanese-only ovarian cancer patients have not been reported. In this study, we report a retrospective study conducted at the Tohoku Gynecologic Cancer Unit.The study included 453 patients with stage III/IV ovarian, fallopian tube, and primary peritoneal cancer who received first-line platinum-based chemotherapy. The patients were divided into two groups: bevacizumab (168 patients) and without bevacizumab (285 patients). The primary endpoint was the rate of platinum-resistant recurrence and the secondary endpoints were the antitumor response, progression-free survival, overall survival, and adverse events.The objective response rates for patients with measurable diseases treated with and without bevacizumab were 84.5% and 73.0%, respectively (P = 0.0066). Platinum-resistant recurrence in the groups treated with and without bevacizumab was noted in 31 (18.4%) and 111 (38.6%) patients, respectively (P 0.0001). The median progression-free survival for the bevacizumab and without bevacizumab groups was 23 and 15 months, respectively (P = 0.0002), and the median overall survival was not reached and 49 months, respectively (P = 0.0005). Hypertension of grade 3 or higher was observed in 21 patients (12.5%) in the bevacizumab group (P 0.001), and proteinuria was observed in 18 patients (10.7%) and 1 patient (0.3%) in the bevacizumab and without bevacizumab groups, respectively (P 0.001). Intestinal perforation was observed in only one patient (0.6%) in the bevacizumab group.Combination and maintenance with bevacizumab in primary chemotherapy for advanced ovarian, fallopian tube, and primary peritoneal cancer was effective in reducing platinum-resistant recurrence rates and prolonging progression-free and overall survival.

In coronary artery bypass grafting (CABG) for haemodialysis patients, arteriovenous fistula can reduce blood flow from the internal mammary artery (IMA) graft. The purpose of this study was to delineate the rationale of ipsilateral IMA grafting to the arteriovenous fistula by assessing graft flow and patency.The clinical records of 139 haemodialysis patients who underwent off-pump CABG, including IMA grafting to the left anterior descending artery (LAD) between April 2007 and December 2018, were retrospectively reviewed. Clinical outcomes and transit-time flowmetry results of IMA to LAD bypass grafts during off-pump CABG and postoperative angiography were examined.An ipsilateral IMA to the arteriovenous fistula (Ipsi-IMA) was used in 89 patients, and a contralateral IMA to the arteriovenous fistula (Contra-IMA) was used in 50 patients and no hospital deaths occurred. The mean graft flow and angiographic patency rate did not differ between the Ipsi-IMA and Contra-IMA groups. In patients with 51 to 90% stenosis of LAD, there was no significant difference in the mean graft flow. In comparison, in the patients with 91 to 100% stenosis of LAD, the mean graft flow in the Ipsi-IMA group was significantly lower than that in the Contra-IMA group (p=0.03). Kaplan-Meier analyses showed a 5-year survival rate of 57.6% for Ipsi-IMA and 64.8% for Contra-IMA (p=0.47).In the revascularisation of the LAD, the graft patency rate of the Ipsi-IMA was not inferior to that of the Contra-IMA. However, when the LAD has 91 to 100% stenosis, a Contra-IMA to arteriovenous fistula may be beneficial in terms of sufficient flow capacity.

Preoperative systemic inflammation has been reported to predict survival in patients with various cancer types. In patients with colorectal liver metastasis (CRLM), the prognosis is poor despite therapeutic advances in the field. Here, we aimed to evaluate the prognostic role of the lymphocyte-to-C-reactive protein (CRP) ratio (LCR) in patients with CRLM after hepatic resection.This retrospective study included 104 patients who underwent hepatic resection for CRLM between October 2010 and 2021 at the National Hospital Organization Fukuyama Medical Center, Hiroshima, Japan. The association between clinicopathological variables, including various inflammatory biomarkers [LCR, platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), CRP-to-albumin ratio (CAR), and prognostic nutritional index (PNI)], and overall survival of the patients was investigated using univariate and multivariate analyses.The optimal cut-off values for each biomarker by receiver-operating characteristic analysis were as follows: LCR: 12,720; PLR: 150; NLR: 4; CAR: 0.023; and PNI: 44.8. The 1-, 3-, and 5-year overall survival rates were 97.0%, 71.3%, and 56.8%, respectively. On univariate analysis, LCR12, 720, PLR0.14, body mass index24 kg/mLCR may be an independent prognostic predictor in patients after hepatic resection for CRLM. Therefore, the assessment of LCR as a biomarker may help in treatment planning.

BackgroundEosinophilic chronic rhinosinusitis (ECRS) is a chronic inflammatory condition of the paranasal sinuses characterized by intractable nasal polyps with prominent eosinophil infiltration. These eosinophils are presumably recruited from peripheral blood via vessels expressing peripheral lymph node addressin (PNAd), a set of glycoproteins decorated with 6-sulfo sialyl Lewis x (sLex) glycans that serve as L-selectin ligands. Based on the severity classification algorithm proposed by the Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis (JESREC) study group, ECRS is divided into mild, moderate and severe groups; however, as yet there are few reports comparing the clinicopathological differences among these groups.ObjectiveOur goal was to elucidate clinicopathological differences among the three different severities of ECRS with special reference to eosinophils and PNAd-expressing vessels.MethodsWe performed quantitative immunohistochemical analysis of PNAd-expressing vessels using surgical specimens of nasal polyps from patients exhibiting varying severity of ECRS ( n = 35) and from individuals with non-ECRS ( n = 10). To this end, we immunostained tissue sections with anti-PNAd and anti-CD34 monoclonal antibodies, and then determined the number of vessels immunolabeled with each antibody.ResultsThe number of eosinophils infiltrating nasal polyps was correlated with ECRS severity. We also found that the PNAd + /CD34 + vessel ratio, namely, the percentage of PNAd-expressing vessels among all vessels, was positively correlated not only with ECRS severity but also with the number of eosinophils infiltrating nasal polyps formed in ECRS.ConclusionThese results strongly suggest that PNAd-expressing vessels play at least a partial role in eosinophil recruitment to nasal polyps and consequent severity of ECRS.

Purpose : This study aimed to investigate the short-term outcomes of laparoscopic gastrectomy / robotic gastrectomy after chemotherapy in patients with advanced gastric cancer and compare these outcomes with those of open gastrectomy. Methods : Fifty patients who underwent radical gastrectomy for advanced gastric cancer after chemotherapy between 2007 and 2021 were retrospectively analyzed. The patients were divided into two groups : the laparoscopic gastrectomy / robotic gastrectomy (n = 11) and open gastrectomy (n = 39) groups. The short-term outcomes of these procedures were subsequently examined. Results : The laparoscopic gastrectomy / robotic gastrectomy group had significantly shorter hospital stays and lower intraoperative blood loss than the open gastrectomy group. The overall complication rates were 12.8% (5 of 39 patients) and 0% (0 of 11 patients) in the open gastrectomy and laparoscopic gastrectomy / robotic gastrectomy groups, respectively (P = 0.1). Conclusions : Laparoscopic gastrectomy / robotic gastrectomy may be a surgical option after chemotherapy for patients with advanced gastric cancer. J. Med. Invest. 69 : 261-265, August, 2022.

In cutaneous squamous cell carcinoma (cSCC), adherence to guideline-recommended fixed surgical margins is often difficult, and narrower margins are preferable. This study aimed to evaluate relapse and disease-specific death with narrower margins for high or very high-risk cSCC.We retrospectively investigated high or very high-risk cSCC patients who underwent tumor excision. Patients were divided into guideline-recommended standard margin group (SMG) and narrower-margin group (NMG). Co-primary outcomes were local relapse, SCC relapse, and SCC death. Cumulative incidence function (CIF) was used to describe SCC death probability and competing risk mortality. Gray's test was used to compare differences in CIF between the groups.In total, 1,000 patients with cSCC (high-risk, 570; very high-risk, 430) were included. In the high-risk cohort, there were no significant differences in incomplete excision rate (IER) between SMG and NMG (2.6 % vs. 3.0 %, P 0.99). However, in the very high-risk cohort, IER in SMG was significantly lower than in NMG (8.9 % vs. 16.2 %, P = 0.03). No significant differences were observed between SMG and NMG for local relapse (high-risk, P = 0.56; very high-risk, P = 0.70), SCC relapse (high-risk, P = 0.30; very high-risk, P = 0.47), and SCC death (high-risk, P = 0.23; very high-risk, P = 0.83).Surgical margin size has limited impact on margin control, relapse, and disease-specific death in high-risk cSCC.

Indications for adjuvant chemotherapy for advanced gastric cancer are determined based on the pathological diagnosis. However, macroscopic diagnoses have been reported as predictors of peritoneal recurrence and survival. This study investigated the predictability of peritoneal recurrence and survival based on macroscopically (sT) and pathologically (pT) diagnosed serosal invasion to identify more sensitive predictors of peritoneal recurrence.This study included 396 patients who underwent R0 resection without adjuvant chemotherapy with S-1 in the JCOG0110 study. Tumor depth limited to the subserosa (SS) was defined as serosal invasion negative (T-), while tumors with serosal invasion (SE, SI) were defined as serosal invasion positive (T+). The predictability of peritoneal recurrence based on sT and pT was evaluated using the Fine and Gray model. Cox regression analyses were performed for overall survival (OS) and relapse-free survival (RFS) with sT or pT as covariates.A total of 150 patients (37.9%) were sT+ and 82 (26.3%) were pT+. Sixty-two patients (15.7%) were sT+/pT+, 88 (22.2%) were sT+/pT-, 20 (5.1%) were sT-/pT+, and 226 (57.1%) were sT-/pT-. Both sT and pT were found to be independent predictors of peritoneal recurrence, OS, and RFS. The 5-year RFS rates of sT+/pT+, sT+/pT-, sT-/pT+, and sT-/pT-patients were 45.2%, 63.6%, 55.0%, and 81.8%, respectively.Intraoperatively diagnosed macroscopic serosal invasion showed a similar predictive value for peritoneal recurrence as pathologically diagnosed serosal invasion. The establishment of a novel staging system incorporating macroscopic serosal invasion is recommended.

OBJECTIVE: To establish a liquid-biopsy assay to predict response to neoadjuvant therapy (NAT) in esophageal squamous cell carcinoma (ESCC) patients. SUMMARY BACKGROUND DATA: Pretreatment prediction of resistance to NAT is of great significance for the selection of treatment options in ESCC patients. In this study, we comprehensively translated tissue-based microRNA (miRNA) and messenger RNA (mRNA) expression biomarkers into a liquid biopsy assay. METHODS: We analyzed 186 clinical ESCC samples, which included 128 formalin-fixed paraffin-embedded and a matched subset of 58 serum samples, from 2 independent institutions. We performed quantitative reverse-transcription polymerase chain reaction, and developed a resistance-prediction model using the logistic regression analyses. RESULTS: We first evaluated the potential of 4-miRNAs and 3-mRNAs panel, which robustly predicted resistance to NAT (area under the curve [AUC]: 0.85). Moreover, addition of tumor size to this panel increased predictive potential to establish a combination signature (AUC: 0.92). We successfully validated this signature performance in independent cohort, and our model was more accurate when the signature was combined with clinical predictors (AUC: 0.81) to establish a NAT resistance risk (NATRR) model. Finally, we successfully translated our NATRR model into a liquid biopsy assay (AUC: 0.78), and a multivariate regression analysis revealed this model as an independent predictor for response to NAT (odds ratio: 6.10; P < 0.01). CONCLUSIONS: We successfully developed a liquid biopsy-based assay that allows robust prediction of response to NAT in ESCC patients, and our assay provides fundamentals of developing precision-medicine.

This study was performed to assess the impact of osteopenia on chemotherapy-induced neutropenia and the prognosis for patients treated with FOLFOXIRI for colorectal cancer.In total, 77 patients who underwent FOLFOXIRI for un-resectable metastatic and advanced colorectal cancer were retrospectively evaluated. Osteopenia was evaluated by the bone mineral density, which was measured using the average pixel density of the trabecular bone in the 11th thoracic vertebra by computed tomography before the introduction of chemotherapy. The relationship between osteopenia and neutropenia was evaluated. Progression-free survival and overall survival of patients with osteopenia and patients with neutropenia were evaluated.Grade ≥ 3 neutropenia was significantly more common in patients with than without osteopenia (p = 0.002). The multivariate analysis showed that osteopenia was a significant independent predictive factor for grade ≥ 3 neutropenia (p = 0.016). There was no significant difference in progression-free survival or overall survival between patients with and without osteopenia. Patients with grade ≥ 3 neutropenia tended to have a higher progression-free survival rate than others (p = 0.059). The overall survival rate was significantly higher in patients with grade ≥ 3 neutropenia than in others (p = 0.011).Osteopenia might be a predictor of chemotherapy-induced neutropenia, and neutropenia might be a prognostic factor for progression-free survival and overall survival in patients with colorectal cancer treated with FOLFOXIRI.

This study aimed to develop a novel polymer-infiltrated ceramic network (PICN) composite fabricated via a slip-casting method for a dental training model tooth with machinability compatible to human enamel. A PICN model tooth comprised of silica/acrylic-resin was fabricated via the slip-casting method. A commercial resin-based model tooth and human enamel were used as the control sample. The samples were evaluated based on Vickers hardness, inorganic contents, density, and machinability. The machinability was characterized by a grinding amount obtained from the grinding test using a device equipped with a dental micromotor handpiece with a diamond bur. The properties of the PICN model tooth yielded a silica content of 84.7% and a density of 1.99 g/cm

Urethral injury is one of the most important complications in transanal total mesorectal excision (TaTME) in male patients with rectal cancer. The purpose of this study was to investigate holographic image-guided surgery in TaTME.Polygon (stereolithography) files were created and exported from SYNAPSE VINCENT, and then uploaded into the Holoeyes MD system (Holoeyes Inc., Tokyo, Japan). After uploading the data, the three-dimensional image was automatically converted into a case-specific hologram. The hologram was then installed into the head mount display, HoloLens (Microsoft Corporation, Redmond, WA). The surgeons and assistants wore the HoloLens when they performed TaTME.In a Wi-Fi-enabled operating room, each surgeon, wearing a HoloLens, shared the same hologram and succeeded in adjusting the hologram by making simple hand gestures from their respective angles. The hologram contributed to better comprehension of the positional relationships between the urethra and the surrounding pelvic organs during surgery. All surgeons were able to properly determine the dissection line.This first experience suggests that intraoperative holograms contributed to reducing the risk of urethral injury and understanding transanal anatomy. Intraoperative holograms have the potential to become a new next-generation surgical support tool for use in spatial awareness and the sharing of information between surgeons.

Saliva contributes to the innate immune system, which suggests that it can prevent SARS-CoV-2 entry. We studied the ability of healthy salivary proteins to bind to angiotensin-converting enzyme 2 (ACE2) using biolayer interferometry and pull-down assays. Their effects on binding between the receptor-binding domain of the SARS-CoV-2 spike protein S1 (S1) and ACE2 were determined using an enzyme-linked immunosorbent assay. Saliva bound to ACE2 and disrupted the binding of S1 to ACE2 and four ACE2-binding salivary proteins were identified, including cationic histone H2A and neutrophil elastase, which inhibited the S1-ACE2 interaction. Calf thymus histone (ct-histone) also inhibited binding as effectively as histone H2A. The results of a cell-based infection assay indicated that ct-histone suppressed SARS-CoV-2 pseudoviral invasion into ACE2-expressing host cells. Manufactured polypeptides, such as ε-poly-L-lysine, also disrupted S1-ACE2 binding, indicating the importance of the cationic properties of salivary proteins in ACE2 binding. Overall, we demonstrated that positively charged salivary proteins are a barrier against SARS-CoV-2 entry by cloaking the negatively charged surface of ACE2 and provided a view that the cationic polypeptides represent a preventative and therapeutic treatment against COVID-19.

Background The joint committee of the Japanese Society of Intensive Care Medicine/Japanese Respiratory Society/Japanese Society of Respiratory Care Medicine on ARDS Clinical Practice Guideline has created and released the ARDS Clinical Practice Guideline 2021. Methods The 2016 edition of the Clinical Practice Guideline covered clinical questions (CQs) that targeted only adults, but the present guideline includes 15 CQs for children in addition to 46 CQs for adults. As with the previous edition, we used a systematic review method with the Grading of Recommendations Assessment Development and Evaluation (GRADE) system as well as a degree of recommendation determination method. We also conducted systematic reviews that used meta-analyses of diagnostic accuracy and network meta-analyses as a new method. Results Recommendations for adult patients with ARDS are described: we suggest against using serum C-reactive protein and procalcitonin levels to identify bacterial pneumonia as the underlying disease (GRADE 2D); we recommend limiting tidal volume to 4–8 mL/kg for mechanical ventilation (GRADE 1D); we recommend against managements targeting an excessively low SpO2 (PaO2) (GRADE 2D); we suggest against using transpulmonary pressure as a routine basis in positive end-expiratory pressure settings (GRADE 2B); we suggest implementing extracorporeal membrane oxygenation for those with severe ARDS (GRADE 2B); we suggest against using high-dose steroids (GRADE 2C); and we recommend using low-dose steroids (GRADE 1B). The recommendations for pediatric patients with ARDS are as follows: we suggest against using non-invasive respiratory support (non-invasive positive pressure ventilation/high-flow nasal cannula oxygen therapy) (GRADE 2D), we suggest placing pediatric patients with moderate ARDS in the prone position (GRADE 2D), we suggest against routinely implementing NO inhalation therapy (GRADE 2C), and we suggest against implementing daily sedation interruption for pediatric patients with respiratory failure (GRADE 2D). Conclusions This article is a translated summary of the full version of the ARDS Clinical Practice Guideline 2021 published in Japanese (URL: https://www.jsicm.org/publication/guideline.html). The original text, which was written for Japanese healthcare professionals, may include different perspectives from healthcare professionals of other countries.

Atypical teratoid/rhabdoid tumor (AT/RT) is a rare pediatric brain tumor with abnormalities in SMARCB1 located in 22q11.2. We report a case of AT/RT associated with Phelan-McDermid syndrome (PMS) characterized by congenital developmental disorder, mental retardation, and ring chromosome 22 with 22q13.3-qter depletion, for which we performed whole-genome sequencing (WGS). A 4-year-old girl with a developmental disability was referred to our hospital due to dysphoria. Brain magnetic resonance imaging showed a 5-cm well-demarcated mass that extended bilaterally in the frontal lobes. G-banding was performed preoperatively due to a history of developmental retardation. Ring chromosome 22 and deletion of 22q13.3-qter were observed, and she was diagnosed with PMS. She underwent gross total resection of the tumor, and the pathological diagnosis was AT/RT. WGS showed somatic SMARCB1 mutation (p.R201X) and somatic loss of the entire chromosome 22 in the tumor, but not in the blood sample. WGS confirmed previously unreported BRCA2 mutations, 6q loss, and 14q acquisition during tumor progression, but no other significant findings associated with tumor progression. The present case is discussed with reference to a systematic review of previous reports of AT/RT associated with PMS. PMS patients with ring chromosome 22 should be carefully followed up for AT/RT occurrence.

Sentinel node navigation surgery (SNNS) is used in clinical practice for the treatment of cervical cancer. This study aimed to elucidate the appropriate sentinel lymph node (SLN) mapping method and assess the safety and benefits of SNNS. We searched the PubMed, Ichushi, and Cochrane Library databases for randomized controlled trials (RCT) and studies on SLN in cervical cancer from January 2012 to December 2020. Two authors independently assessed study quality and extracted data. We quantitatively analyzed the detection rate, sensitivity/specificity, and complications and reviewed information, including the survival data of SLN biopsy (SLNB) without pelvic lymphadenectomy (PLND). The detection rate of SLN mapping in the unilateral pelvis was median 95.7% and 100% and in the bilateral pelvis was median 80.4% and 90% for technetium-99 m (Tc) with/without blue dye (Tc w/wo BD) and indocyanine green (ICG) alone, respectively. The sensitivity and specificity of each tracer were high; the area under the curve of each tracer was 0.988 (Tc w/wo BD), 0.931 (BD w/wo Tc), 0.966 (ICG), and 0.977 (carbon nanoparticle). Morbidities including lymphedema, neurological symptoms and blood loss were associated with PLND. One RCT and five studies all showed SNNS without systematic PLND does not impair recurrence or survival in early-stage cervical cancer with a tumor size ≤ 2-4 cm. Both Tc w/wo BD and ICG are appropriate SLN tracers. SNNS can reduce the morbidities associated with PLND without affecting disease progression in early-stage cervical cancer.

Background The present observational study aimed to clarify the association between bridging therapy with heparin before starting rivaroxaban and clinical outcomes after ischemic stroke or transient ischemic attack (TIA) in patients with non-valvular atrial fibrillation (NVAF).Methods and Results:Patients with NVAF who experienced acute ischemic stroke or TIA of the middle cerebral artery territory and started rivaroxaban within 30 days after onset were enrolled and were followed up for 90 days. Outcome measures were ischemic events, major bleeding, their composite, and death or disability 90 days after onset. Ischemic events were defined as ischemic stroke, TIA, and systemic embolism. Of 1,308 analyzed patients, 638 received bridging therapy with unfractionated or low-molecular-weight heparin with a median of 10,000 IU/day. Associations between bridging therapy and ischemic events or major bleeding were not statistically significant individually, but the association between bridging therapy and their composite was statistically significant (multivariable-adjusted hazard ratio, 1.80; 95% confidence interval, 1.01-3.29). The association between bridging therapy and death or disability 90 days after onset was not statistically significant. Conclusions The composite of ischemic events and major bleeding was more frequent in patients with NVAF who received bridging therapy with low-dose heparin than in those who started treatment directly with rivaroxaban after ischemic stroke or TIA.

Organizing pneumonia (OP) is a complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT) and a manifestation of peripheral airway/alveolar inflammation. Recently, alveolar nitric oxide concentration (Calv) has been revealed as a noninvasive marker of peripheral airway inflammation; however, whether Calv levels are associated with OP and peripheral airway in patients after allo-HSCT remains unclear. Herein, we evaluated whether Calv levels could reflect the presence of OP and structural airway changes in patients after allo-HSCT. We measured the eNO levels of 38 patients (6 with OP and 32 without OP) who underwent allo-HSCT. Three-dimensional computed tomography (CT) analysis of the airway was performed in 19 patients. We found that in patients with OP, Calv levels were significantly higher than in those without OP (10.6 vs. 5.5 ppb, p 0.01). Receiver-operating characteristic analyses revealed a Calv cut-off value for OP detection of 10.2 ppb. No significant differences in the patient characteristics, except for the presence of OP (p 0.01), were noted between the two groups stratified by the Calv cut-off value. Three-dimensional CT images of the airway revealed gradually increasing positive correlations between Calv levels and airway wall area of the third-, fourth-, and fifth-generation bronchi (r = 0.20, 0.31, 0.38; p = 0.42, 0.19, 0.038, respectively), indicating that Calv levels are strongly correlated with the wall thickness of the distal bronchi. Our results suggest that the Calv level may be a useful noninvasive detectable marker for OP after an allo-HSCT.

Background: The “1-3-6-12-day rule” for starting direct oral anticoagulants (DOACs) in patients with nonvalvular atrial fibrillation after acute ischemic stroke or transient ischemic attack recommends timings that may be later than used in clinical practice. We investigated more practical optimal timing of DOAC initiation according to stroke severity. Methods: The combined data of prospective registries in Japan, Stroke Acute Management with Urgent Risk-factor Assessment and Improvement-nonvalvular atrial fibrillation (September 2011 to March 2014) and RELAXED (February 2014 to April 2016) were used. Patients were divided into transient ischemic attack and 3 stroke subgroups by the National Institutes of Health Stroke Scale score: mild (0–7), moderate (8–15), and severe (≥16). The early treatment group was defined as patients starting DOACs earlier than the median initiation day in each subgroup. Outcomes included a composite of recurrent stroke or systemic embolism, ischemic stroke, and severe bleeding within 90 days. Six European prospective registries were used for validation. Results: In the 1797 derivation cohort patients, DOACs were started at median 2 days after transient ischemic attack and 3, 4, and 5 days after mild, moderate, and severe strokes, respectively. Stroke or systemic embolism was less common in Early Group (n=785)—initiating DOACS within 1, 2, 3, and 4 days, respectively—than Late Group (n=1012) (1.9% versus 3.9%; adjusted hazard ratio, 0.50 [95% CI, 0.27–0.89]), as was ischemic stroke (1.7% versus 3.2%, 0.54 [0.27–0.999]). Major bleeding was similarly common in the 2 groups (0.8% versus 1.0%). On validation, both ischemic stroke (2.4% versus 2.2%) and intracranial hemorrhage (0.2% versus 0.6%) were similarly common in Early (n=547) and Late (n=1483) Groups defined using derivation data. Conclusions: In Japanese and European populations, early DOAC initiation within 1, 2, 3, or 4 days according to stroke severity seemed to be feasible to decrease the risk of recurrent stroke or systemic embolism and no increase in major bleeding. These findings support ongoing randomized trials to better establish the optimal timing of DOAC initiation.

BACKGROUND AND PURPOSE: Noninvasive perfusion-weighted imaging with short scanning time could be advantageous in order to determine presumed penumbral regions and subsequent treatment strategy for acute ischemic stroke (AIS). Our aim was to evaluate interobserver agreement and the clinical utility of intravoxel incoherent motion MR imaging in patients with acute ischemic stroke. MATERIALS AND METHODS: We retrospectively studied 29 patients with AIS (17 men, 12 women; mean age, 75.2 [SD, 12.0 ] years; median, 77 years). Each patient underwent intravoxel incoherent motion MR imaging using a 1.5T MR imaging scanner. Diffusion-sensitizing gradients were applied sequentially in the x, y, and z directions with 6 different b-values (0, 50, 100, 150, 200, and 1000 seconds/mm(2)). From the intravoxel incoherent motion MR imaging data, diffusion coefficient, perfusion fraction, and pseudodiffusion coefficient maps were obtained using a 2-step fitting algorithm based on the Levenberg-Marquardt method. The presence of decreases in the intravoxel incoherent motion perfusion fraction and pseudodiffusion coefficient values compared with the contralateral normal-appearing brain was graded on a 2-point scale by 2 independent neuroradiologists. Interobserver agreement on the rating scale was evaluated using the κ statistic. Clinical characteristics of patients with a nondecreased intravoxel incoherent motion perfusion fraction and/or pseudodiffusion coefficient rated by the 2 observers were also assessed. RESULTS: Interobserver agreement was shown for the intravoxel incoherent motion perfusion fraction (κ = 0.854) and pseudodiffusion coefficient (κ = 0.789) maps, which indicated almost perfect and substantial agreement, respectively. Patients with a nondecreased intravoxel incoherent motion perfusion fraction tended to show recanalization of the occluded intracranial arteries more frequently than patients with a decreased intravoxel incoherent motion perfusion fraction. CONCLUSIONS: Intravoxel incoherent motion MR imaging could be performed in

Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is a severe syndrome of acute encephalopathy that affects infants and young children. AESD is a polygenic disorder preceded by common viral infections with high fever. We conducted an association study of human leukocyte antigen (HLA) regions with AESD using HLA imputation. SNP genotyping was performed on 254 Japanese patients with AESD and 799 healthy controls. We conducted 3-field HLA imputation for 14 HLA genes based on Japanese-specific references using data from our previous genome-wide association study. After quality control, 208 patients and 737 controls were included in the analysis of HLA alleles. We then compared the carrier frequencies of HLA alleles and haplotypes between the patients and controls. HLA-DPB1*04:01:01 showed a significant association with AESD, exerting a protective effect against the disease (p = 0.0053, p

Identifying lateral pelvic lymph node (LPN) metastasis in low rectal cancer is crucial before treatment. Several risk factors and prediction models for LPN metastasis have been reported. However, there is no useful tool to accurately predict LPN metastasis. Therefore, we aimed to construct a nomogram for predicting LPN metastasis in rectal cancer.We analyzed the risk factors for potential LPN metastasis by logistic regression analysis in 705 patients who underwent primary resection of low rectal cancer. We included patients at 49 institutes of the Japan Society of Laparoscopic Colorectal Surgery between June 2010 and February 2012. Clinicopathological factors and magnetic resonance imaging findings were evaluated. The nomogram performance was assessed using the c-index and calibration plots, and the nomogram was validated using an external cohort.In the univariable logistic regression analysis, age, sex, carcinoembryonic antigen, tumor location, clinical T stage, tumor size, circumferential resection margin (CRM), extramural vascular invasion (EMVI), and the short and long axes of LPN and perirectal lymph node (PRLN) were nominated as risk factors for potential LPN metastasis. We identified a combination of the short axis of LPN, tumor location, EMVI, and short axis of PRLN as optimal for predicting potential LPN metastasis and developed a nomogram using these factors. This model had a c-index of 0.74 and was moderately calibrated and well-validated.This is the first study to construct a well-validated nomogram for predicting potential LPN metastasis in rectal cancer, and its performance was high.

Endovascular therapy for acute ischemic stroke is generally avoided when the infarction is large, but the effect of endovascular therapy with medical care as compared with medical care alone for large strokes has not been well studied.We conducted a multicenter, open-label, randomized clinical trial in Japan involving patients with occlusion of large cerebral vessels and sizable strokes on imaging, as indicated by an Alberta Stroke Program Early Computed Tomographic Score (ASPECTS) value of 3 to 5 (on a scale from 0 to 10, with lower values indicating larger infarction). Patients were randomly assigned in a 1:1 ratio to receive endovascular therapy with medical care or medical care alone within 6 hours after they were last known to be well or within 24 hours if there was no early change on fluid-attenuated inversion recovery images. Alteplase (0.6 mg per kilogram of body weight) was used when appropriate in both groups. The primary outcome was a modified Rankin scale score of 0 to 3 (on a scale from 0 to 6, with higher scores indicating greater disability) at 90 days. Secondary outcomes included a shift across the range of modified Rankin scale scores toward a better outcome at 90 days and an improvement of at least 8 points in the National Institutes of Health Stroke Scale (NIHSS) score (range, 0 to 42, with higher scores indicating greater deficit) at 48 hours.A total of 203 patients underwent randomization; 101 patients were assigned to the endovascular-therapy group and 102 to the medical-care group. Approximately 27% of patients in each group received alteplase. The percentage of patients with a modified Rankin scale score of 0 to 3 at 90 days was 31.0% in the endovascular-therapy group and 12.7% in the medical-care group (relative risk, 2.43; 95% confidence interval [CI], 1.35 to 4.37; P = 0.002). The ordinal shift across the range of modified Rankin scale scores generally favored endovascular therapy. An improvement of at least 8 points on the NIHSS score at 48 hours was observed in 31.0% of the patients in the endovascular-therapy group and 8.8% of those in the medical-care group (relative risk, 3.51; 95% CI, 1.76 to 7.00), and any intracranial hemorrhage occurred in 58.0% and 31.4%, respectively (P0.001).In a trial conducted in Japan, patients with large cerebral infarctions had better functional outcomes with endovascular therapy than with medical care alone but had more intracranial hemorrhages. (Funded by Mihara Cerebrovascular Disorder Research Promotion Fund and the Japanese Society for Neuroendovascular Therapy; RESCUE-Japan LIMIT ClinicalTrials.gov number, NCT03702413.).

OBJECTIVE There have been no accurate surveillance data regarding the incidence rate of spinal arteriovenous shunts (SAVSs). Here, the authors investigate the epidemiology and clinical characteristics of SAVSs. METHODS The authors conducted multicenter hospital-based surveillance as an inventory survey at 8 core hospitals in Okayama Prefecture between April 1, 2009, and March 31, 2019. Consecutive patients who lived in Okayama and were diagnosed with SAVSs on angiographic studies were enrolled. The clinical characteristics and the incidence rates of each form of SAVS and the differences between SAVSs at different spinal levels were analyzed. RESULTS The authors identified a total of 45 patients with SAVSs, including 2 cases of spinal arteriovenous malformation, 5 cases of perimedullary arteriovenous fistula (AVF), 31 cases of spinal dural AVF (SDAVF), and 7 cases of spinal epidural AVF (SEAVF). The crude incidence rate was 0.234 per 100,000 person-years for all SAVSs including those at the craniocervical junction (CCJ) level. The incidence rate of SDAVF and SEAVF combined increased with advancing age in men only. In a comparative analysis between upper and lower spinal SDAVF/SEAVF, hemorrhage occurred in 7/14 cases (50%) at the CCJ/cervical level and in 0/24 cases (0%) at the thoracolumbar level (p = 0.0003). Venous congestion appeared in 1/14 cases (7%) at the CCJ/cervical level and in 23/24 cases (96%) at the thoracolumbar level (p < 0.0001). CONCLUSIONS The authors reported detailed incidence rates of SAVSs in Japan. There were some differences in clinical characteristics of SAVSs in the upper spinal levels and those in the lower spinal levels.

Background The Safari study (UMIN000015168) was a retrospective, multicenter study in which 1072 consecutive cases of estrogen receptor-positive advanced breast cancer treated using 500 mg fulvestrant were registered. We previously reported the relationship between the patient factors and overall survival after the diagnosis using the same cases and the same factors for the analysis of time to treatment failure in patients with estrogen receptor-positive advanced breast cancer. The current study is an ad hoc analysis that focused on the relationship between the patient factors and overall survival after recurrence by adding factors generally associated with overall survival after recurrence. Methods The overall survival after recurrence in patients with estrogen receptor-positive human epidermal growth factor receptor 2 negative recurrent breast cancer was analyzed via univariate and multivariate analyses with a Cox proportional hazards model. Results A total of 598 cases were used for the analysis of overall survival after recurrence. Multivariate analysis revealed that favorable overall survival (median, 6.4 years) was significantly correlated with long time from recurrence to fulvestrant use (≥3 years), low nuclear or histological grade (G3 vs. G1), long time to treatment failure of initial palliative endocrine therapy (≥12 months) and long time to initial palliative chemotherapy (≥2 years). Conclusion The results of this study indicate that sequential endocrine monotherapy may be a useful treatment option for patients with estrogen receptor-positive/human epidermal growth factor receptor 2 negative recurrent breast cancer who have been successfully treated with initial long-term palliative endocrine therapy.

Background & Aims A detailed understanding of antitumor immunity is essential for optimal cancer immune therapy. Although defective mutations in the B2M and HLA-ABC genes, which encode molecules essential for antigen presentation, have been reported in several studies, the effects of these defects on tumor immunity have not been quantitatively evaluated. Methods Mutations in HLA-ABC genes were analyzed in 114 microsatellite instability–high colorectal cancers using a long-read sequencer. The data were further analyzed in combination with whole-exome sequencing, transcriptome sequencing, DNA methylation array, and immunohistochemistry data. Results We detected 101 truncating mutations in 57 tumors (50%) and loss of 61 alleles in 21 tumors (18%). Based on the integrated analysis that enabled the immunologic subclassification of microsatellite instability–high colorectal cancers, we identified a subtype of tumors in which lymphocyte infiltration was reduced, partly due to reduced expression of HLA-ABC genes in the absence of apparent genetic alterations. Survival time of patients with such tumors was shorter than in patients with other tumor types. Paradoxically, tumor mutation burden was highest in the subtype, suggesting that the immunogenic effect of accumulating mutations was counterbalanced by mutations that weakened immunoreactivity. Various genetic and epigenetic alterations, including frameshift mutations in RFX5 and promoter methylation of PSMB8 and HLA-A, converged on reduced expression of HLA-ABC genes. Conclusions Our detailed immunogenomic analysis provides information that will facilitate the improvement and development of cancer immunotherapy.

Despite the growing population of long-term survivors with human immunodeficiency virus 1 (HIV) exhibiting asthma-like features worldwide, the pathogenesis underlying airway hyperresponsiveness (AHR) and airway inflammation remains unclear. We aimed to investigate AHR and airway inflammation in an HIV-infected Japanese population.Of 94 Japanese participants, 10 HIV-infected participants with asthma were excluded from the study. We compared the characteristics of HIV-infected (n = 34) and non-HIV-infected participants (n = 50). Eosinophilic, neutrophilic, mixed (eosinophilic and neutrophilic), and paucigranulocytic airway inflammatory phenotypes were classified based on induced sputum characteristics.The prevalence of AHR in HIV-infected participants (32.4%) was significantly higher than that in their non-HIV-infected counterparts (10.0%) (P = 0.0213). The multivariate nominal logistic regression analysis revealed HIV as an independent risk factor for AHR. HIV-infected participants were significantly more likely to have a neutrophilic airway inflammatory phenotype than non-HIV-infected participants (P = 0.0358). Furthermore, HIV-infected participants with AHR demonstrated a significant correlation between AHR levels and the percentage of sputum neutrophils (r = -0.65, P = 0.0316). The percentage of sputum neutrophils was negatively associated with the blood CD4 cell count (r = -0.66, P = 0.0266).We observed the high prevalence of AHR and neutrophilic airway inflammatory phenotype in Japanese participants with stable HIV infection. Our findings provide insight into the mechanisms of AHR and may facilitate the development of novel treatment for individuals with AHR and HIV infection.

Difficult laparoscopic cholecystectomy (DLC) may increase the risk of complications and extend the duration of hospitalization. The aims of this study were to evaluate the predictive value of C-reactive protein/albumin ratio (CAR) for DLC in patients with acute cholecystitis (AC) diagnosed according to the Tokyo Guidelines 2018 and to develop a preoperative predictive model for DLC.We retrospectively analyzed 205 patients who had laparoscopic cholecystectomy for AC between January 2012 and December 2020. We defined DLC cases as having one of the following factors: blood loss ≥50 mL, operative time ≥150 minutes, or conversion to open surgery. We classified the remaining cases into the non-DLC group.Overall, 127 (62.0%) and 78 (38.0%) patients were grouped into the DLC and non-DLC groups, respectively. Patients in the DLC group had: higher severity grade, which was assessed using the Tokyo Guidelines 2018; higher incidence of postoperative complications; and more hospitalization days than those in the non-DLC group. Multivariate analysis revealed that male, CAR (≥3.20), and pericholecystic fat hyperdensity on computed tomography (CT) were independent predictors of DLC. We developed a predictive scoring system for DLC based on these three factors (cutoff value, 2.0; area under the curve, 0.75; sensitivity, 71.7%; and specificity, 70.5%).CAR could predict DLC independently in AC patients. We identified male gender, CAR, and pericholecystic fat hyperdensity on CT as predictive factors for DLC and established a preoperative prediction system based on these three factors.

Background: Tokyo, the capital of Japan, is a densely populated city of >13 million people, so the population is at high risk of epidemic severe acute respiratory coronavirus 2 (SARS-CoV-2) infection. A serologic survey of anti–SARS-CoV-2 IgG would provide valuable data for assessing the city’s SARS-CoV-2 infection status. Therefore, this cross-sectional study estimated the anti–SARS-CoV-2 IgG seroprevalence in Tokyo. Methods: Leftover serum of 23,234 hospital visitors was tested for antibodies against SARS-CoV-2 using an iFlash 3000 chemiluminescence immunoassay analyzer (Shenzhen YHLO Biotech, Shenzhen, China) with an iFlash–SARS-CoV-2 IgG kit (YHLO) and iFlash–SARS-CoV-2 IgG-S1 kit (YHLO). Serum samples with a positive result (≥10 AU/mL) in either of these assays were considered seropositive for anti–SARS-CoV-2 IgG. Participants were randomly selected from patients visiting 14 Tokyo hospitals between September 1, 2020 and March 31, 2021. No participants were diagnosed with coronavirus disease 2019 (COVID-19), and none exhibited COVID-19-related symptoms at the time of blood collection. Results: The overall anti–SARS-CoV-2 IgG seroprevalence among all participants was 1.83% (95% confidence interval [CI], 1.66–2.01%). The seroprevalence in March 2021, the most recent month of this study, was 2.70% (95% CI, 2.16–3.34%). After adjusting for population age, sex, and region, the estimated seroprevalence in Tokyo was 3.40%, indicating that 470,778 individuals had a history of SARS-CoV-2 infection. Conclusions: The estimated number of individuals in Tokyo with a history of SARS-CoV-2 infection was 3.9-fold higher than the number of confirmed cases. Our study enhances understanding of the SARS-CoV-2 epidemic in Tokyo.

Several prior studies involving "expected" single-leg landings have not succeeded in establishing a difference between copers and a control group.Does expected and unanticipated single-leg landing affect dynamic postural stability in lateral ankle sprain individuals with chronic ankle instability (CAI), copers, and controls?In this prospective cross-sectional study, physically active adults with CAI (n = 12), copers (n = 12), and controls (n = 12) were included. Participants performed expected single-leg landing by stepping off a 30-cm box. They also performed unanticipated landings including side-step cutting, side-step cutting at 60°, single-leg landing, and forward stepping. The expected and unanticipated conditions of each groups were compared in terms of time to stabilization (TTS) and center of pressure (COP) for the anterior-posterior (AP) and medial-lateral (ML) conditions. To analyze the data, a mixed-model one-way analysis of variance and a Tukey-Kramer post hoc test were performed.A significant condition × group interaction was observed in only TTS ML, with the CAI group demonstrating a significantly longer TTS ML than the coper (p 0.001) and control (p 0.001) groups during unanticipated trials. In addition, group interaction effects were observed for COP AP and TTS AP. The coper group demonstrated significantly longer COP AP and TTS AP than the control group (p 0.001).The CAI group demonstrated a significantly longer TTS ML than the coper and control groups during the unanticipated condition, and the coper group demonstrated significantly longer TTS AP and COP AP than the control group. Thus, longer COP AP and TTS AP sway time in the coper group may be a protection mechanism, allowing greater freedom in the AP plane while quickly controlling ML sway and preventing lateral ankle sprains. These findings can help in the prevention of lateral ankle sprains and assessment of dynamic postural control.

The SARS-CoV-2 Omicron BA.1 variant emerged in 20211 and has multiple mutations in its spike protein2. Here we show that the spike protein of Omicron has a higher affinity for ACE2 compared with Delta, and a marked change in its antigenicity increases Omicron’s evasion of therapeutic monoclonal and vaccine-elicited polyclonal neutralizing antibodies after two doses. mRNA vaccination as a third vaccine dose rescues and broadens neutralization. Importantly, the antiviral drugs remdesivir and molnupiravir retain efficacy against Omicron BA.1. Replication was similar for Omicron and Delta virus isolates in human nasal epithelial cultures. However, in lung cells and gut cells, Omicron demonstrated lower replication. Omicron spike protein was less efficiently cleaved compared with Delta. The differences in replication were mapped to the entry efficiency of the virus on the basis of spike-pseudotyped virus assays. The defect in entry of Omicron pseudotyped virus to specific cell types effectively correlated with higher cellular RNA expression of TMPRSS2, and deletion of TMPRSS2 affected Delta entry to a greater extent than Omicron. Furthermore, drug inhibitors targeting specific entry pathways3 demonstrated that the Omicron spike inefficiently uses the cellular protease TMPRSS2, which promotes cell entry through plasma membrane fusion, with greater dependency on cell entry through the endocytic pathway. Consistent with suboptimal S1/S2 cleavage and inability to use TMPRSS2, syncytium formation by the Omicron spike was substantially impaired compared with the Delta spike. The less efficient spike cleavage of Omicron at S1/S2 is associated with a shift in cellular tropism away from TMPRSS2-expressing cells, with implications for altered pathogenesis.

BackgroundPost-extubation airway obstruction is an important complication of tracheal intubation. The cuff leak test is traditionally used to estimate the risk of this complication. However, the cuff leak test parameters are not constant and may depend on the respiratory system and ventilator settings. Furthermore, deflating the cuff also be a risk factor for patient-ventilator asynchrony and ventilator-associated pneumonia.Instead of using the cuff leak test, we measured the pressure of the leak to the upper airway through the gap between the tube and glottis with a constant low flow from the lumen above the cuff without deflating the cuff and called it "pressure above the cuff."The purpose of this study was to investigate whether pressure above the cuff can be used as an alternative to the cuff leak volume.MethodsThis prospective observational study was conducted at Kumamoto University Hospital after obtaining approval from the institutional review board. The pressure above the cuff was measured using an endotracheal tube with an evacuation lumen above the cuff and an automated cuff pressure modulation device. We pumped 0.16 L per minute of air and measured the steady-state pressure using an automated cuff pressure modulation device. Then, the cuff leak test was performed, and the cuff leak volume was recorded. The cuff leak volume was defined as the difference between the expiratory tidal volume with the cuff inflated and deflated. The relationship between the pressure above the cuff and cuff leak volume was evaluated. The patient-ventilator asynchrony during each measurement was also examined.ResultsThe pressure above the cuff was measured, and the cuff leak volume was assessed 27 times. The pressure above the cuff was significantly correlated with the cuff leak volume (r = -0.76,p ConclusionsThis study suggests that pressure above the cuff measurement may be a less complicated alternative to the conventional cuff leak test for evaluation of the risk of post-extubation airway obstruction.Trial registrationUniversity Hospital Medical Information Network Clinical Trials Registry (UMIN000039987; March 30, 2020).https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000044604