Published papers

＜文献概要＞プライマリケアでここまでできる!・潜在性結核感染症(LTBI)の病態を理解し,活動性結核を診断するのか,LTBIの診断をするのか,理解したうえでインターフェロンγ遊離試験(IGRA)を提出しよう.・活動性結核発病のリスクの高さを考慮して,LTBIの治療を実施するか検討してから,IGRAを実施しよう.ここからは専門医に任せよう!・LTBIの治療で,活動性結核の発症を完全に予防できるわけではない.LTBIの治療中や治療後でも活動性結核の発症に留意し,万が一発症した場合にはすぐに専門医に相談しよう.・海外からの入国者で,薬剤耐性結核菌によるLTBIが疑われる場合,治療レジメンの選択は困難である.このような場合には専門医に相談しよう.

▼人間は科学的事実に基づいた合理的な選択や判断のみを行うのではなく、非合理的な選択を行い、また非合理ななかにも一定の法則性があることが、行動経済学によって示されてきた。本稿では、感染対策の実施を妨げる行動経済学的メカニズムについて、主に医療従事者における手指衛生を例に解説した。▼過去の文献で指摘された、医療従事者が手指衛生を実施できないバイアス/ヒューリスティックにはさまざまなものがある。このようなメカニズムを逆に利用し、医療従事者が「つい行いたくなる」ナッジ戦略を確立することで、医療施設での感染対策の改善が期待できる。(著者抄録)

＜文献概要＞●医療関連感染は,何か1つのシステムを作っておけば自動的に予防できるというものではない.ICTの役割や感染対策の必要性を理解したうえで,病院で勤務するそれぞれの職員が感染対策を実施することが必要である.●医療現場では,スタッフの汚染された手指によって医療関連感染が伝播する.手指衛生は最も基本的で重要な感染対策の1つであるが,医療行為としての手指衛生はこれまで幼少期から培ってきた日常生活における手洗いとは別ものであることをしっかり理解し,新たに訓練し習得する必要がある.

＜文献概要＞Point　◎肺炎球菌は,肺炎をはじめとする気道関連感染症,髄膜炎,感染性心内膜炎,敗血症,脾摘後の劇症型感染症などを生じる.◎αレンサ球菌は,口腔内から腸管に至る経路の常在菌で,亜急性心内膜炎が最も重要な感染症である.S. anginosus groupは口腔内や咽頭の膿瘍,脳膿瘍,腹腔内膿瘍などを形成する場合がある.◎β溶血性レンサ球菌は咽頭炎や皮膚軟部組織感染症のほかに,感染性心内膜炎,化膿性関節炎,敗血症などのさまざまな感染症を引き起こす.◎レンサ球菌のほとんどはペニシリンに感受性であるが,感染性心内膜炎や骨髄炎などの治療が長期化する感染症を引き起こす場合があるため,狭域抗菌薬での十分な治療が重要である.

＜文献概要＞「感染症」にかかわる状況は常に変化しています。近年は、突発的に流行したり、今まで「常識」と思われていた流行パターンと異なる時期に流行するなどの状況から、特に注意しておきたい感染症がいくつかあります。「感染症が流行する時期といえば冬」という認識も、じつは少しずつ変わってきていますが、まずはこれからのシーズンでおさえておきたい感染症について、基礎知識から最新の状況までをふまえて解説します。

＜文献概要＞Point　●薬剤耐性微生物検査には近年さまざまな進歩がある.検査を実施する場合は目的や,耐性菌検出後のフローをあらかじめ明確にしておくことが重要である.●多項目遺伝子検査などで検体から迅速に遺伝子を検出できるようになってきているが,遺伝子検査は検索したものしか検出されないため,最終的には表現型でも耐性菌の検出を確認する必要がある.●海外から多剤耐性結核をもち込ませないことは重要な課題である.リファンピシン耐性遺伝子も含めた核酸増幅検査が有用である.●多剤耐性のCandida aurisは真菌の新興感染症として注目されており,現時点での同定には質量分析による検査が有用である.

＜文献概要＞新型コロナウイルス(SARS-CoV-2)は,インフルエンザウイルスと同じくエンベロープを有するRNAウイルスであり,主として飛沫感染(一部エアロゾル感染)および接触感染によって,上咽頭～呼吸器系および結膜から感染する。新型コロナウイルス感染症(COVID-19)の潜伏期間は1～14日間であり,流行株による違いはあるが曝露から5日前後,近年流行しているオミクロン株では3日前後で発症することが多い。発症前から感染性があり,発症前1～2日から発症時頃が最も感染性が高いと言われている。感染性は発症後7～10日間程度続くとされるが,無症候者でも感染性を有することが,感染対策をより困難にしている。

MicroRNA (miRNA) has been recently recognized as a biomarker of various diseases; however, there are no known miRNAs associated with Mycobacterium avium complex (MAC) pulmonary disease. In addition, there are no known biomarkers to precisely reflect disease activity after the diagnosis of MAC pulmonary disease. Thus, we sought to identify a miRNA which is a candidate biomarker of MAC pulmonary disease activity. Serum hsa-miR-346 concentrations of 16 patients with M. avium pulmonary disease were significantly higher than those of 16 healthy controls (p = 0.047). The secretion of hsa-miR-346 increased in a multiplicity of infection-dependent manner in M. avium-infected macrophages. Serum hsa-miR-346 levels of 5 patients with bacterial conversion at the end of follow-up were significantly lower than those at the beginning of the follow-up (p = 0.043). In addition, the longitudinal change in serum hsa-miR-346 concentration correlated with bacterial load in 2 patients with M. avium pulmonary disease. Based on our results, it is supposed that MAC-infected macrophages in pulmonary lesions produce hsa-miR-346, which is then secreted into the bloodstream. The magnitude of this process could be quantitatively controlled by the bacterial load, suggesting that serum hsa-miR-346 is a potentially useful biomarker of MAC pulmonary disease activity. (C) 2017 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Background: In bronchiectasis patients, chronic Pseudomonas aeruginosa (PA) infection has been associated with worse health-related quality of life (HRQL), but little is known about Mycobacterium avium complex lung disease (MACLD) patients in this context. This study aimed to evaluate HRQL and investigate the impact of chronic PA infection in MACLD patients. Methods: This cross-sectional study was conducted using the Registry of Prospective Cohort Study including MACLD patients. The 36-item Short-Form health survey (SF-36) and St. George's Respiratory Questionnaire (SGRQ) were administered to assess clinical outcomes. Clinical variables included treatment and sputum culture status, pulmonary function tests, cavitary lesions, and modified Reiff scores on high-resolution computed tomography. Results: The study included 244 MACLD patients (median age, 68 years; 196 women), 19 of whom had chronic PA infection. Modified Reiff score was higher in patients with chronic infection than in those without (P = 0.028). Regarding SF-36 scores, physical functioning subscale scores were significantly lower in patients with chronic infection (P = 0.029). Additionally, SGRQ symptoms, impact, and total scores were significantly higher in patients with chronic infection. During analysis of covariance comparisons, SGRQ symptoms and impact scores were significantly higher for patients with chronic infection (P = 0.043 and 0.021, respectively). Conclusions: MACLD patients with chronic PA infection exhibited significantly higher SGRQ scores, indicating impaired HRQL. Chronic PA infection was significantly associated with the severity of bronchiectasis.

BACKGROUND: Mycobacterium abscessus complex (MABC) pulmonary disease is notoriously difficult to treat due to intrinsic resistance to many common antibiotics. MABC is β-lactam-resistant as it produces class A β-lactamases, such as blaMab, which are inhibited by diazabicyclooctane (DBO) β-lactamase inhibitors. OBJECTIVES: To investigate the microbiological effects of the combination of β-lactam and DBO β-lactamase inhibitors (relebactam and nacubactam) against MABC and determine if the effects are associated with the MABC subspecies and colony morphotypes. METHODS: We evaluated the antimicrobial susceptibility of three type strains and 20 clinical isolates of MABC to the combination of seven β-lactams with relebactam or nacubactam by broth microdilution checkerboard assays. For these strains, we assessed blaMab expression levels by quantitative real-time polymerase chain reaction and the genotypic diversity by 18-locus variable number tandem repeat assay. RESULTS: Relebactam and nacubactam lowered the minimum inhibitory concentrations of β-lactams, especially imipenem, meropenem, tebipenem, against MABC. There was no difference in efficacy of combination treatment between three subspecies, but rough morphotypes tended to be less susceptible than smooth morphotypes. There were no differences in blaMab expression levels and genotypic diversity between the morphotypes. CONCLUSIONS: The combination of β-lactam with relebactam or nacubactam improved the efficacy of β-lactams against all MABC subspecies, but higher concentrations of β-lactams are needed for rough morphotypes.

Vaccine immunogenicity is influenced by the vaccinee's genetic background. Here, we perform a genome-wide association study of vaccine-induced SARS-CoV-2-specific immunoglobulin G (IgG) antibody titers and T cell immune responses in 1,559 mRNA-1273 and 537 BNT162b2 vaccinees of Japanese ancestry. SARS-CoV-2-specific antibody titers are associated with the immunoglobulin heavy chain (IGH) and major histocompatibility complex (MHC) locus, and T cell responses are associated with MHC. The lead variants at IGH contain a population-specific missense variant (rs1043109-C; p.Leu192Val) in the immunoglobulin heavy constant gamma 1 gene (IGHG1), with a strong decreasing effect (β = −0.54). Antibody-titer-associated variants modulate circulating immune regulatory proteins (e.g., LILRB4 and FCRL6). Age-related hematopoietic expanded mosaic chromosomal alterations (mCAs) affecting MHC and IGH also impair antibody production. MHC-/IGH-affecting mCAs confer infectious and immune disease risk, including sepsis and Graves’ disease. Impacts of expanded mosaic loss of chromosomes X/Y on these phenotypes were examined. Altogether, both germline and somatic mutations contribute to adaptive immunity functions.

BACKGROUND: A health-economic evaluation related to COVID-19 is urgently needed to allocate healthcare resources efficiently; however, relevant medical cost data in Japan concerning COVID-19 are scarce. METHODS: This cross-sectional study investigated the healthcare cost for hospitalized COVID-19 patients in 2021 at Keio University Hospital. We calculated the healthcare costs during hospitalization using hospital claims data and investigated the variables significantly related to the healthcare cost with multivariable analysis. RESULTS: The median healthcare cost per patient for the analyzed 330 patients was Japanese yen (JPY) 1,304,431 (US dollars ~ 11,871) (interquartile range: JPY 968,349-1,954,093), and the median length of stay was 10 days. The median healthcare cost was JPY 798,810 for mild cases; JPY 1,113,680 for moderate I cases; JPY 1,643,909 for moderate II cases; and JPY 6,210,607 for severe cases. Healthcare costs increased by 4.0% for each additional day of hospitalization; 1.26 times for moderate I cases, 1.64 times for moderate II cases, and 1.84 times for severe cases compared to mild cases; and 2.05 times for cases involving ICU stay compared to those not staying in ICU. CONCLUSIONS: We clarified the healthcare cost for hospitalized COVID-19 patients by severity in a Japanese university hospital. These costs contribute as inputs for forthcoming health economic evaluations for strategies for preventing and treating COVID-19.

Epstein–Barr virus (EBV) infects approximately 90–95% of the global population1,2 and persists in B cells as a lifelong infection3. Previous EBV infection is associated with autoimmune and neoplastic disease4. Still, the biological basis of host control during EBV persistence remains unclear. Here we report the identification of non-genetic and genetic factors that are associated with EBV control during persistent infection. Using blood-based genome sequence data from 486,315 UK Biobank and 336,123 All of Us participants, we identified short-read pairs mapping to the EBV genome in 16.2% and 21.8% of individuals, respectively. EBV read detection (EBVread+) reflects increased viral load in blood cells, as shown by orthogonal measurements, and was associated with HIV infection, immunosuppressive drug intake and current smoking. Genome-wide analyses of EBVread+ identified strong associations at the major histocompatibility complex (MHC), including 54 independent human leukocyte antigen (HLA) alleles of MHC classes I and II, and at 27 genomic regions outside MHC. Epistasis with distinct HLA alleles of MHC class I was observed at the ERAP2 locus. Analysis of individuals with EBV-associated diseases4 revealed a higher polygenic burden of EBVread+ for HLA alleles at MHC class I in multiple sclerosis (driven by HLA-A*02:01) and at MHC class II in rheumatoid arthritis. Phenome-wide analyses identified a polygenic overlap of EBVread+ with inflammatory bowel disease, hypothyroidism and type 1 diabetes. Our study establishes by-products of human genome sequencing as a surrogate marker of EBV viral load. This will facilitate investigation and treatment for EBV and other persistent viral infections.

Males and females exhibit differences in proteome profiles associated with disease risk. However, sex-dimorphic protein quantitative trait loci (SD-pQTL) and their effects on sex differences in health disorders have not been thoroughly investigated. We conducted a sex-stratified, genome-wide association study on 2,922 proteins using data from 30,272 individuals of Caucasian ancestry from the UK Biobank and compared the estimated effects on protein levels of these variants in the men and women to identify SD-pQTLs. The identified SD-pQTLs were replicated using data from two Japanese cohorts (comprising 2,886 and 1,394 individuals, respectively), as well as from 1,990 Finnish, 630 South Asian, and 662 Black ancestry individuals. Sex-dimorphic pleiotropy and the causal relationship between protein levels and health disorders were assessed using the identified SD-pQTLs. We identified 113 SD-pQTLs associated with 65 proteins. Of the 113 SD-pQTLs, 52 were significant in both sexes, five were not significant in either sex, and 42 and 14 were significant only in males and females, respectively. Variant rs2270416 was significantly associated with the CDH15 protein in both sexes but showed opposite effect direction in men and women. Of the 113 SD-pQTLs identified, a total of 41 were replicated in a meta-analysis encompassing Japanese, South Asian, and Black ancestry individuals. SD-pQTLs for proteins APOE (rs157581) and SNAP25 (rs4420638) exhibited sex-dimorphic associations with dementia, indicating sex dimorphic pleiotropy in both proteins and health disorders. From sex-stratified Mendelian randomization using the SD-pQTLs, proteins NCAM1 and PZP showed significant causal relationship with dementia in males and females, respectively. The present study provides evidence of sex-dimorphic genetic architecture in protein-level regulation, elucidating the proteo-genetic architecture for sex differences in human variation.

BACKGROUND: Headache is an adverse event of coronavirus 2019 (COVID-19) vaccination. Whether patients with history of headache suffer more from vaccination-induced headaches is unknown. We aimed to uncover if headache patients develop more headaches after COVID-19 mRNA vaccination than healthy controls. METHODS: We performed a questionnaire survey for nursing staff in our hospital from April to May 2021. Based on baseline characteristics, we divided the participants into migraine, non-migrainous headache, and healthy control, and examined the occurrence and features of headache after COVID-19 vaccinations. RESULTS: We included 171 participants (15.2% migraine and 24.6% non-migrainous headache). Headache incidence after vaccinations was significantly higher in the migraine (69.2%) and non-migrainous headache (71.4%) groups than in the healthy control (37.9%) group. The incidence of headaches was significantly higher after the second dose compared to the first (45.6% vs. 20.5%). CONCLUSION: Migraineurs and non-migrainous headache participants developed more headaches compared to the healthy controls after COVID-19 vaccination.