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BackgroundEpidemiological data regarding differences in durability and its determinants of humoral immunity following 2- and 3-dose COVID-19 vaccination are scarce.MethodsWe repeatedly assessed the anti-spike IgG antibody titers of 2- and 3-dose mRNA vaccine recipients among the staff of a medical and research center in Tokyo. Linear mixed models were used to estimate trajectories of antibody titers from 14 to 180 days after the last immune-conferred event (vaccination or infection) and compare antibody waning rates across prior infection and vaccination status, and across background factors in infection-naïve participants.ResultsA total of 6901 measurements from 2964 participants (median age, 35 years; 30% male) were analyzed. Antibody waning rate (per 30 days [95% CI]) was slower after 3-dose (25% [23–26]) than 2-dose (36% [35–37]). Participants with hybrid immunity (vaccination and infection) had further slower waning rates: 2-dose plus infection (16% [9–22]); 3-dose plus infection (21% [17–25]). Older age, male sex, obesity, coexisting diseases, immunosuppressant use, smoking, and alcohol drinking were associated with lower antibody titers, whereas these associations disappeared after 3-dose, except for sex (lower in female participants) and immunosuppressant use. Antibody waning was faster in older participants, females, and alcohol drinkers after 2-dose, whereas it did not differ after 3-dose across except sex.ConclusionsThe 3-dose mRNA vaccine conferred higher durable antibody titers, and previous infection further enhanced its durability. The antibody levels at a given time point and waning speed after 2-dose differed across background factors; however, these differences mostly diminished after 3-dose.

ImportanceInvestigating the role of pre-infection humoral immunity against Omicron BA.5 infection risk and long COVID development is critical to inform public health guidance.ObjectiveTo investigate the association between pre-infection immunogenicity after the third vaccine dose and the risks of Omicron BA.5 infection and long coronavirus disease.Design, Setting, and ParticipantsThis nested case-control analysis was conducted among tertiary hospital staff in Tokyo, Japan who donated blood samples in June 2022 (1 month before Omicron BA.5 dominant wave onset [July–September 2022]) approximately 6 months after receiving the third dose of the historical monovalent coronavirus disease 2019 mRNA vaccine.ExposuresLive virus-neutralizing antibody titers against Wuhan and Omicron BA.5 (NT50) and anti-SARS-CoV-2 spike protein antibody titers with Abbott (AU/mL) and Roche (U/mL) assays at pre-infection.Main Outcomes and MeasuresSymptomatic SARS-CoV-2 breakthrough infections during the Omicron BA.5 dominant wave vs. undiagnosed controls matched using a propensity score. Incidence of long COVID (persistent symptoms ≥4 weeks after infection) among breakthrough infection cases.ResultsAnti-spike antibody titers were compared between 243 breakthrough infection cases and their matched controls among the 2360 staff members who met the criteria. Neutralizing antibodies in 50 randomly selected matched pairs were measured and compared. Pre-infection anti-spike and neutralizing antibody titers were lower in breakthrough cases than in undiagnosed controls. Neutralizing antibody titers against Wuhan and Omicron BA.5 were 64% (95% CI: 42–77) and 72% (95% CI: 53–83) lower, respectively, in breakthrough cases than in undiagnosed controls. Individuals with previous SARS-CoV-2 infections were more frequent among undiagnosed controls than breakthrough cases (19.3% vs. 4.1%), and their neutralizing antibody titers were higher than those of infection-naïve individuals. Among the breakthrough cases, pre-infection antibody titers were not associated with the incidence of long COVID.Conclusions and RelevancePre-infection immunogenicity against SARS-CoV-2 may play a role in protecting against the Omicron BA.5 infection, but not in preventing long COVID.Key PointsQuestionDoes pre-infection anti-SARS-CoV-2 humoral immunity protect against Omicron BA.5 infection and long-COVID development?FindingsPre-infection neutralizing antibody titers against Omicron BA.5 were lower in subsequent Omicron BA.5 breakthrough infection cases than in matched controls in this nested case-control study of healthcare workers who received the third dose of historical COVID-19 mRNA vaccines approximately 6 months prior. Pre-infection antibody titers could not predict the incidence of long COVID among breakthrough infection cases.MeaningHigher pre-infection humoral immunity approximately 6 months after the third vaccination may correlate with protection against Omicron BA.5 infection but not against long-COVID development.

To describe the trend of cumulative incidence of coronavirus disease 19 (COVID-19) and undiagnosed cases over the pandemic through the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants among healthcare workers in Tokyo, we analysed data of repeated serological surveys and in-house COVID-19 registry among the staff of National Center for Global Health and Medicine. Participants were asked to donate venous blood and complete a survey questionnaire about COVID-19 diagnosis and vaccine. Positive serology was defined as being positive on Roche or Abbott assay against SARS-CoV-2 nucleocapsid protein, and cumulative infection was defined as either being seropositive or having a history of COVID-19. Cumulative infection has increased from 2.0% in June 2021 (pre-Delta) to 5.3% in December 2021 (post-Delta). After the emergence of the Omicron, it has increased substantially during 2022 (16.9% in June and 39.0% in December). As of December 2022, 30% of those who were infected in the past were not aware of their infection. Results indicate that SARS-CoV-2 infection has rapidly expanded during the Omicron-variant epidemic among healthcare workers in Tokyo and that a sizable number of infections were undiagnosed.

Background While increasing coverage of effective vaccines against coronavirus disease 2019 (COVID-19), emergent variants raise concerns about breakthrough infection. Data are limited, however, whether breakthrough infection during the epidemic of the variant is ascribed to insufficient vaccine-induced immunogenicity. Methods We describe incident COVID-19 in relation to the vaccination program among workers of a referral hospital in Tokyo. During the predominantly Delta epidemic, we followed 2415 fully vaccinated staff (BNT162b2) for breakthrough infection and selected 3 matched controls. We measured post-vaccination neutralizing antibodies against the wild-type, Alpha (B.1.1.7), and Delta (B.1.617.2) strains using live viruses and anti-spike antibodies using quantitative assays, and compared them using the generalized estimating equation model between the 2 groups. Results No COVID-19 cases occurred 1–2 months after the vaccination program during the fourth epidemic wave in Japan, dominated by the Alpha variant, while 22 cases emerged 2–4 months after the vaccination program during the fifth wave, dominated by the Delta variant. In the vaccinated cohort, all 17 cases of breakthrough infection were mild or asymptomatic and participants had returned to work early. There was no measurable difference between cases and controls in post-vaccination neutralizing antibody titers against the wild-type, Alpha, Delta, and anti-spike antibody titers, while neutralizing titers against the variants were considerably lower than those against the wild-type. Conclusions Post-vaccination neutralizing antibody titers were not decreased among patients with breakthrough infection relative to their controls under the Delta variant outbreak. The result points to the importance of infection-control measures in the post-vaccination era, irrespective of immunogenicity profile.

BackgroundData on the role of immunogenicity following the third vaccine dose against Omicron infection and coronavirus disease 2019 (COVID-19)-compatible symptoms of infection are limited.MethodsFirst we examined vaccine effectiveness (VE) of the third-dose against the second dose during the Omicron wave among the staff at a tertiary hospital in Tokyo. In a case-control study of a cohort of third vaccine recipients, we compared the pre-infection levels of live-virus neutralizing antibodies (NAb) against Omicron between breakthrough cases and their controls, who had close contact with COVID-19 patients. Among these cases, we examined the association between pre-infection NAb levels and the number of COVID-19-compatible symptoms experienced during the Omicron wave.ResultsAmong the 1456 participants for VE analysis, 60 (4%) breakthrough infections occurred during the Omicron wave (January to March 2022). The third-dose VE for infection, relative to the second dose was 54.6% (95% CI: 14.0–76.0). Among the recipients of the third vaccine, pre-infection NAb levels against Omicron did not significantly differ between the cases and controls. Among the cases, those who experienced COVID-19-compatible symptoms had lower pre-infection NAb levels against Omicron than those who did not.ConclusionsThe third vaccine dose was effective in decreasing the risk of severe acute respiratory syndrome coronavirus 2 infection during the Omicron wave compared with the second dose. Among third-dose recipients, higher pre-infection NAb levels may not be associated with a lower risk of Omicron infection. Contrarily, they may be associated with fewer symptoms of infection.SummaryThe third vaccine dose reduced SARS-CoV-2 infection risk during the Omicron wave. Higher neutralizing antibody levels may not reduce Omicron infection risk in third-dose patients. On the contrary, it may be associated with fewer symptoms of infection.

BackgroundWhile increasing coverage of effective vaccines against coronavirus disease 2019 (COVID-19), emergent variants raise concerns about breakthrough infections. Data are limited, however, whether breakthrough infection during the epidemic of the variant is ascribed to insufficient vaccine-induced immunogenicity.MethodsWe described incident COVID-19 in relation to the vaccination program among workers of a referral hospital in Tokyo. During the predominantly Delta epidemic, we followed 2,473 fully vaccinated staff (BNT162b2) for breakthrough infection and selected three matched controls. We measured pre-infection neutralizing antibodies against the wild-type, Alpha (B.1.1.7), and Delta (B.1.617.2) strains using live viruses and anti-spike antibodies using quantitative assays, and compared them using the generalized estimating equation model between the two groups.ResultsNo COVID-19 cases occurred 1–2 months after the vaccination program during the fourth epidemic wave in Japan, dominated by the Alpha variant, while 22 cases emerged 2–4 months after the vaccination program during the fifth wave, dominated by the Delta variant. In the vaccinated cohort, all 17 cases of breakthrough infection were mild or asymptomatic and had returned to work early. There was no measurable difference between cases and controls in pre-infection neutralizing antibody titers against the wild-type, Alpha, and Delta, and anti-spike antibody titers, while neutralizing titers against the variants were considerably lower than those against the wild-type.ConclusionsPre-infection neutralizing antibody titers were not decreased among patients with breakthrough infection under the Delta variant rampage. The result points to the importance of infection control measures in the post-vaccination era, irrespective of immunogenicity profile.

The effect of cetuximab plus mFOLFOX on downsizing of the tumors for curative resection has yet to be assessed for patients with advanced colorectal liver metastases (CRLMs). This study aimed to assess the oncologic benefit of cetuximab plus mFOLFOX for wild-type KRAS patients with advanced CRLMs. In this multicenter phase 2 trial, patients with technically unresectable tumor and/or five or more CRLMs harboring wild-type KRAS were treated with mFOLFOX plus cetuximab. The patients were assessed for resectability after 4 treatments, and then every 2 months up to 12 treatments. Patients with resectable disease were offered surgery after a waiting period of 1 month. The primary end point of the study was the R0 resection rate. The secondary end points were safety, progression-free survival (PFS), and overall survival (OS). The study is registered with the University Hospital Medical Information Network-Clinical Trials Registry Clinical Trials Registry (no. C000007923). Between 2012 and 2015, 50 patients from 13 centers were enrolled in this trial. Two patients were excluded because they had not received induction therapy. The 48 patients had a complete response rate of 0% and a partial response rate of 64.6%. For 26 R0 resections (54.2%) and 5 R1 resections (10.4%), no mortality occurred. During a median follow-up period of 31 months, the median OS for all the patients was calculated to be 41 months (95% confidence interval, 28–not reached). The 3-year OS rate was 59%. For patients with advanced CRLMs harboring wild-type KRAS, cetuximab administered in combination with mFOLFOX yields high response rates, leading to significantly high R0 resection rates and favorable prognoses.

We report the case of a 65-year-old woman who had a high level of serum pepsinogen II. Several months earlier, she had found a mass on the right side of her upper abdomen. Esophagogastroduodenoscopy did not reveal atrophic or inflammatory findings. She had not taken proton pump inhibitors, and there was no indication of renal dysfunction. Imaging tests showed a mass of approximately 80mm in the pancreatic head. We performed pancreatoduodenectomy, and the histopathological examination revealed an intraductal papillary mucinous neoplasm (IPMN) of gastric type. Serum pepsinogen II levels substantially lowered after surgery. To the best of our knowledge, this is the first report on a relationship between IPMN and serum pepsinogen II.

The psychiatric population has been reported to be accompanied with a higher morbidity and mortality in several situations. However, little is known about the effect of co-morbid psychiatric disorders on surgical risk during major digestive surgery for malignancies. Our purpose in the present study, therefore, was to evaluate the impact of co-morbid psychiatric disorders on the outcome of surgery for digestive malignancies. We retrospectively reviewed medical records of 568 consecutive patients who underwent hepatectomies, gastrectomies, or colorectal resections between June 1998 and May 2006. Of these, 86 patients had psychiatric disorders (disorder group: DG) and the remaining 482 patients did not (non-disorder group: NG). Postoperative parameters including morbidity, mortality, length of postoperative hospital stay in the surgical ward, and the incidence of psychiatric disorder-associated problems were assessed. Overall, there was 1 patient who died within 30 days in hospital in the DG and 2 patient deaths in the NG. Thirty complications developed in 24 patients of the DG, whereas 138 complications developed in 129 patients of the NG. There was no significant difference in the morbidity or mortality rate between the two groups. The length of the postoperative hospital stay was also similar between the two groups, and the incidence of psychiatric disorder-associated postoperative problems was about ten times higher in the DG than in the NG. Patients with psychiatric disorders are not accompanied with excess surgical risk during major surgery for digestive malignancies as compared to patients without psychiatric disorders.

経過観察中に増大傾向を呈し, 胆嚢摘出により除去しえた胆嚢嚢胞の1例を報告する. 症例は80歳の男性で, 胃癌術後の経過観察中に胆嚢底部に径8mmの嚢胞性小隆起性病変を指摘された. この嚢胞性病変は1年の経過観察にて径13mmと増大した. 診断的治療として胆嚢摘出術が施行された. 標本では胆嚢底部に径13mmの単房性嚢胞を認め, 内腔は黄白色の粘液で満たされていた. 組織学的には嚢胞内面は1層の円柱～立方上皮でおおわれており, 外面の胆嚢粘膜は軽度の炎症所見のみで, 異型性を認めなかった. 周囲にRokitansky-Aschoff sinus(以下, RASと略記)の散在を認め, RASの閉塞による貯留嚢胞と考えられた. 胆嚢嚢胞はまれな疾患であるが, 超音波機器の性能が向上した近年では報告例も増えつつあり, 胆嚢の小隆起性病変の鑑別診断として念頭におく必要があると考えられた.

S状結腸憩室の遊離穿孔に対し縫合閉鎖にて1期的に治療しえた2例を経験した.症例1は66歳,男性.朝排便後に急な腹痛にて発症.腹部所見は下腹部正中を中心とした腹膜炎で,発症後7時間で開腹. S状結腸に1cm程の憩室が多発しており,そのうちの一つが5mm大に穿孔していた.穿孔部が小さく炎症所見が軽いため単純縫合閉鎖し,洗浄,誘導とした.第47病日退院した.症例2は79歳,男性.午後2時に急な腹痛にて発症.腹部所見は汎発性腹膜炎で,発症後5時間で開腹. S状結腸に3mm大の憩室穿孔を認めた.穿孔部が小さく炎症所見が軽いため同様に単純縫合閉鎖し,洗浄,誘導とした.第49病日退院した.左側結腸憩室の遊離穿孔は一般に重篤な糞便性腹膜炎を伴い2期的術式を採用されることが多い.だが最近では2期的術式と1期的術式に合併症,死亡率において差はないとする報告もあり,症例の的確な選択により1期的縫合閉鎖も可能と思われる.

A 69-year-old female was referred to our hospital with hematochezia. Dynamic computed tomography demonstrated a large tumor with rim enhancement and central necrosis that invaded into the transverse colon. The tumor was resected, and histopathological examination revealed mixed adenocarcinoma and squamous cell carcinoma with partial abscess formation. On the basis of a literature review and the findings from the present case, rim enhancement with central necrosis on imaging appears to be characteristic of this disease.

Surgical treatment of 45 patients presenting with extremely thick and contracted gallbladder of less than 5 cm in length has been reviewed. They corresponded to 4.8% of 938 patients with benign biliary diseases operated on during the last 12 years in our hospital. Though 44 patients had stones in the biliary trees, coexistence of background lesions was noted, that is, internal biliary fistula in 15, confluence stones in 5, and endoscopic papillotomy in 10 cases. Preoperative detection of contracted gallbladder was capable in 86% by computerized tomography, while it was not easy to visualize by ultrasound, and 61% of the cases were therefore estimated as such by acoustic shadow and/or strong echo.Surgical treatment principally consisted of cholecystectomy with or without T tube drainage. Standard cholecystectomy with serosal dissection, however, was possible in only 5 cases. Partial resection of the gallbladder with remnant mucosal destruction was the choice of operation in 10 difficult cases. Bile duct injury as the main complication in the operation was repaired by hepaticojejunostomy in one case. Association of cancer of the gallbladder was noted in 2 cases (4.4%).We conclude from this study that operation of contracted gallbladder should intend as much mucosal removal as possible within the limits of safety. Since preoperative evaluation for coexistence of cancer is almost impossible, intraoperative pathological diagnosis of the specimen is indispensable.

Relatively rare hernias include obturator hernia in aged patients. We experienced 3 cases of obturator hernia presenting with complicated manifestations. Case 1 presented with an intermuscular abscess in the left thigh. The abscess was drainaged, and the herniation was cured thereafter. Case 2 showed recurrent ipsilateral obturator hernia ten years after former herniation was cured operatively. Case 3 presented with panperitonitis due to perforation of iluem, and emergent operation saved the patient. All 3 cases had peculiar manifestations and we had difficulties in the preoperative diagnosis and treatment. The key points for diagnosing obturator hernia are: 1) to doubt of its existence; and 2) to relay on CT among imaging methods. While it is emphasized for treatment that the hilus should be reinforced by covering not only with peritoneum but also with ovary and its ligament. A review of more than 200 cases of obturator hernia reported in Japan since 1926 is also described.

Interleukin-3 (IL-3), a multilineage colony stimulating factor, has been shown to augment alloreactive bone marrow-derived suppressor cell activity in vivo and in vitro. The present study examined the effect of IL-3 on autoimmune-mediated diabetes in NOD mice. Administration of IL-3 twice weekly starting at 2-4 weeks of age delayed the onset and reduced the overall incidence of diabetes. Bone marrow cells obtained from IL-3-treated NOD mice protected NOD mice from cyclophosphamide-induced diabetes but failed to prevent adoptively transferred diabetes. In vitro culture of bone marrow cells in medium containing IL-3 produced a Thy-1+CD3epsilonloCD4-CD8-CD25- immature T cell clone which prevented cyclophosphamide-induced diabetes. The cloned cells also effectively delayed the development of diabetes induced by transfer of T cells in adult thymectomized, irradiated, bone marrow-reconstituted NOD mice. These results suggest that IL-3 is capable of regulating extrathymic T cell development from the bone marrow and that these cells mediate strong immunoregulatory function.