神田 直樹

OBJECTIVES: To evaluate how heterogeneous diagnostic definitions of persistent inflammation, immunosuppression, and catabolism syndrome (PICS), identified through a systematic review, influence patient identification and associated clinical outcomes when applied to a nationwide Japanese ICU cohort. DESIGN: Systematic review and retrospective cohort study. SETTING: The multicenter inpatient administrative claims database with laboratory test values in Japan. PATIENTS: Critically ill adult patients admitted to ICUs in Japan between March 2010 and September 2021. A total of 215,474 ICU patients were analyzed. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A systematic review identified 23 clinical studies using varying diagnostic criteria for PICS. Definitions differed substantially in laboratory thresholds, assessment timing, and inclusion requirements. PICS definitions extracted from the review were applied to the Medical Data Vision cohort, and overlap among definitions was assessed using an UpSet plot. The number of patients meeting each definition varied widely (211-47,888 patients), demonstrating that even small differences in thresholds or timing markedly influence patient identification. The prevalence of PICS varied widely across definitions (range, 0.1-22.2%). In-hospital mortality also showed marked variability (range, 11.4-64.0%). Functional outcomes were consistently poor, with a high proportion of patients discharged with a Barthel Index less than 90 (range, 46.5-78.9%) and a prolonged hospital stay greater than 28 days (range, 54.9-94.7%). CONCLUSIONS: The present study revealed marked heterogeneity among existing PICS definitions, resulting in wide variations in prevalence and outcomes. Despite this variability, PICS consistently identified patients with prolonged hospitalization and physical impairment. These findings highlight the need for standardized diagnostic criteria to improve comparability across studies and support earlier identification and intervention for at-risk ICU survivors.

BackgroundPersistent inflammation, immunosuppression, and catabolism syndrome (PICS) that develops following critical illness is one of the most challenging issues in critical care medicine. While corticosteroids are widely used in septic shock, their impact on PICS remains unclear. While corticosteroids may reduce inflammation, they potentially increase infection risk and affect muscle function.MethodsThis retrospective cohort study analyzed 3186 patients with septic shock from a Japanese administrative claims database, which was supplied by Medical Data Vision Co., Ltd (Tokyo, Japan). Using propensity score matching, we compared outcomes between patients who received corticosteroids within the first two days of admission (steroid group) and those who did not (control group). The primary outcome was the incidence of PICS on day 28, defined as meeting at least two of the following criteria: C-reactive protein >2.0 mg/dL, albumin <3.0 g/dL, and lymphocyte count <800/μL.ResultsA total of 4054 patients were enrolled in this retrospective cohort study. After the exclusion of 868 patients, 3186 eligible patients (906 in the steroid group and 2280 in the control group) were included in the propensity score analysis. After matching, there was no significant difference in the incidence of PICS on day 28 between the steroid and control groups (16.7% vs 13.6%; risk difference, 2.22%; 95% CI, -1.89% to 6.34%; P = 0.095). Additionally, no significant differences were observed in 28-day mortality (15.2% vs 15.2%), in-hospital mortality, PICS on day 14, the Barthel Index at discharge or the percentage of patients meeting PICS criteria for each component on day 14 and day 28.ConclusionsThe administration of corticosteroids in patients with septic shock was not associated with the incidence of PICS.

OBJECTIVES: To describe trends in the incidences of chronic hepatitis C, hepatocellular carcinoma (HCC), and related healthcare burden after the introduction of interferon-free direct-acting antivirals (DAAs). METHODS: This repeated cross-sectional study (time trend analysis) examined chronic hepatitis C and related healthcare, including HCC, using national claims data covering >98% of healthcare services in Japan between fiscal years 2013 and 2022. RESULTS: During the study period, 357,877 patients were treated with DAAs. The prevalence of individuals receiving care for chronic hepatitis C decreased by 40% (95% confidence interval [CI]: 40-40%), from 0.54% in 2013 to 0.33% in 2022. Among individuals with HIV, the reduction was smaller, at 16% (95% CI: 10-20%), with a prevalence of 3.82% in 2022. The annual incidence of newly diagnosed HCC decreased by 69% (95% CI: 68-70%), accompanied by a reduction in HCC treatments. Annual healthcare costs for individuals with chronic hepatitis C peaked in 2015 and decreased to 65% of 2013 levels by 2022. CONCLUSION: During the 10-y DAA era, the healthcare burden of hepatitis C declined substantially in Japan. Enhanced efforts in prevention, screening, and treatment are critical for the eradication of hepatitis C, particularly among high-risk populations, such as individuals with HIV.

BACKGROUND: Tocilizumab, an IL-6 receptor antagonist, may prevent functional impairments in critically ill patients by attenuating the cytokine storm. This study investigated a potential effect of tocilizumab on preventing functional impairments in patients with severe coronavirus infection 2019 (COVID-19). METHODS: In a multicenter prospective observational study, patients with COVID-19 ≥ 20 years requiring mechanical ventilation admitted to the intensive care unit between April 2021 and September 2021 and discharged alive were followed for one year. A self-administered questionnaire on sequelae and functional impairments was mailed in August 2022, and data were collected. A multivariate logistic regression was used to assess the impact of tocilizumab on physical function, mental health, and Long COVID. RESULTS: Of 157 analyzed patients, 41 received tocilizumab. The tocilizumab group had more severe illness, but a lower prevalence of physical impairment (17.1 % vs. 23.3 %, p = 0.41) and mental disorders (19.5 % vs. 39.7 %, p = 0.009) than the non-tocilizumab group. The prevalence of Long COVID was higher in the tocilizumab group (92.7 % vs. 80.2 %, p = 0.06), whereas fatigue/malaise was significantly lower (19.5 % vs. 37.1 %, p = 0.039). Adjusted odds ratios (95 % confidence interval) for physical impairment, mental disorders, and Long COVID with tocilizumab were 0.70 (0.2-2.1), 0.40 (0.16-1.01), and 2.94 (0.7-12.3), respectively, with no significant difference. CONCLUSIONS: Tocilizumab was associated with a lower prevalence of physical impairment and mental disorders at 1 year in patients with severe COVID-19. Furthermore, Long COVID had a weaker impact on physical and cognitive functions.

BACKGROUND: Research on the effectiveness of Japan's national action plan on antimicrobial resistance, including among individuals with HIV, remains scarce. OBJECTIVES: To evaluate the impact of policies on antibiotic prescription practices. METHODS: Outpatient oral antibiotic prescription data from 2012 to 2020 were extracted from a national claims database comprising >98% of the Japanese population. Prescription rates were stratified according to antibiotic class, diagnosis and HIV status. An interrupted time-series analysis was performed to assess the impact of the national action plan. RESULTS: An average of 129,989,400 prescriptions were issued annually (1024 per 1000 population-years). Between 2012 and 2020, the oral antibiotic prescription rate decreased by 54%. The prescription rate showed a significant downward trend post-intervention (additional annual reduction in incidence rate ratio, 0.889; 95% confidence interval, 0.889-0.990). However, broad-spectrum antibiotics (third-generation cephalosporins, macrolides and fluoroquinolones) remained prevalent, comprising 84.7% and 71.4% of prescriptions in 2012 and 2020, respectively. Antibiotic prescriptions during outpatient visits for pharyngitis, sinusitis, bronchitis and viral upper respiratory infections decreased significantly (rate ratios = 0.66, 0.76, 0.51 and 0.49, respectively). The antibiotic prescription rate was ∼2.5-fold higher in individuals with HIV than in those without. CONCLUSIONS: Antibiotic prescription rates significantly decreased following the implementation of the national action plan. However, a sharp decline in 2020, likely due to the coronavirus disease pandemic, requires continued rebound monitoring. Reducing broad-spectrum oral antibiotic overuse remains a critical focus.

Background/Objectives: The Global Leadership Initiative on Malnutrition (GLIM) is suggested by major societies. The etiologic criteria for inflammation in critically ill patients remain unclear. Because an initial nutritional assessment is recommended within 48 h, it is also possible to use C-reactive protein (CRP) up to 3 days after admission. The purpose of the present study is to explore the utility of CRP in identifying malnutrition and to determine whether a nutritional assessment incorporating CRP criteria can effectively identify malnourished patients in the intensive care unit (ICU). Methods: This was a retrospective cohort study of ICU patients. The primary outcome was a composite of in-hospital mortality, Barthel index < 60 at discharge, and length of hospital stay of 14 days or more. The area under the curve (AUC) for the primary outcome was calculated using CRP between days 0 and 2. We divided the patients into four groups using inflammation criteria with the optimal cut-off and low body mass index (BMI) criteria of the GLIM: CRP+/-, and BMI+/-. Results: A total of 38,981 patients were included. The AUC of the highest CRP between days 0 and 2 was 0.65, which was higher than the CRP on day 0 and the highest CRP between days 0 and 1 (0.59 and 0.63). The AUC and optimal cut-offs varied depending on diagnoses, with a maximum of 0.75 in neurology. The optimal cut-off for the maximum CRP was 3.82 mg/dL. In the four groups of CRP+BMI+, CRP+BMI-, CRP-BMI+, and CRP-BMI-, the in-hospital mortality values were 22.7, 14.4, 10.8, and 4.8% (p < 0.001 between all the groups). Conclusions: In an initial nutritional assessment of critically ill patients, it would be appropriate to use the maximum CRP over 3 days from ICU admission.

Abstract Background Post-intensive care syndrome (PICS) affects the quality of life (QOL) of survivors of critical illness. Although PICS persists for a long time, the longitudinal changes in each component and their interrelationships over time both remain unclear. This multicenter prospective study investigated the 2-year trajectory of PICS and its components as well as factors contributing to deterioration or recovery in mechanically ventilated patients with coronavirus disease 2019 (COVID-19), and also attempted to identify possible countermeasures. Methods Patients who survived COVID-19 requiring mechanical ventilation completed questionnaires on the Barthel index, Short-Memory Questionnaire, Hospital Anxiety and Depression Scale, and EuroQol 5 dimensions 5-level every six months over a two-year period. Scores were weighted to account for dropouts, and the trajectory of each functional impairment was evaluated with alluvial diagrams. The prevalence of PICS and factors impairing or restoring function were examined using generalized estimating equations considering trajectories. Results Among 334 patients, PICS prevalence rates in the four completed questionnaires were 72.1, 78.5, 77.6, and 82.0%, with cognitive impairment being the most common and lower QOL being noted when multiple impairments coexisted. Physical function and QOL indicated that many patients exhibited consistent trends of either recovery or deterioration. In contrast, cognitive function and mental health revealed considerable variability, with many patients showing fluctuating ratings in the later surveys. Delirium was associated with worse physical and mental health and poor QOL, while prolonged ventilation was associated with poor QOL. Living with family was associated with the recovery of all functions and QOL, while extracorporeal membrane oxygenation (ECMO) was associated with the recovery of cognitive function and mental health. Conclusions Critically ill patients had PICS for a long period and followed different trajectories for each impairment component. Based on trajectories, known PICS risk factors such as prolonged ventilation and delirium were associated with impaired recovery, while ECMO and the presence of family were associated with recovery from PICS. In critically ill COVID-19 patients, delirium management and family interventions may play an important role in promoting recovery from PICS. Trial registration number: UMIN000041276, August 01, 2020.

OBJECTIVES: Antibiotic prescription trends in dentistry in Japan remain underexplored. This study aimed to describe these trends and evaluate the impact of the national antimicrobial stewardship program launched in 2016. METHODS: Using Japan's national administrative claims database from fiscal year (FY) 2015 to FY 2020, this cross-sectional study comprehensively analyzed trends in antibiotic prescription by dentists. Prescription rates were computed per 1000 inhabitants yearly and standardized to the FY 2015 national population. Changes in prescription rates were evaluated using Poisson regression analysis. RESULTS: In FY 2020, the total number of antibiotic prescriptions was 134.4 per 1000 inhabitants per year, showing a 6% decline over the 6-year period (95% confidence interval, 6%-6%). Third-generation cephalosporins constituted 52.3% of dental antibiotic prescriptions in FY 2020, though the proportion had slightly decreased. In hospitals, prescriptions of third-generation cephalosporins decreased from 64.9% in 2015 to 20.3% in 2020, being replaced by penicillin (from 15.0% to 64.0%). However, in clinics, the magnitude of the change was small (third-generation cephalosporins, 60.5%-53.1%; penicillin, 10.2%-22.2%). CONCLUSIONS: Third-generation cephalosporins continue to dominate dental antibiotic prescriptions. The increase in penicillin use was much more pronounced in hospitals than in clinics. Strengthening antimicrobial stewardship, particularly in clinics where the majority of dental care is provided, is crucial.

OBJECTIVES: Laboratory experiments have indicated that calcium channel blockers (CCBs) inhibit the entry and replication of influenza A virus in cells. However, no clinical studies have assessed the incidence of influenza among patients receiving CCBs. This study aimed to investigate the association between CCB use and the incidence of influenza among patients with hypertension using administrative claims data in Japan. DESIGN: Retrospective cohort study. SETTING: Administrative health insurance claims database of Kumamoto Prefecture, Japan. PARTICIPANTS: 360 515 patients with hypertension (10th edition of the International Classification of Diseases code I10) who were prescribed CCBs and 171 142 patients who were prescribed angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) between 2012 and 2016. PRIMARY OUTCOME: We compared the incidence of influenza between the CCB and ACEI/ARB groups using high-dimensional propensity-score (HD-PS) matching. RESULTS: A total of 166 814 HD-PS matched pairs were obtained. Before HD-PS matching, the CCB group had a significantly lower influenza incidence than the ACEI/ARB group in the overall analysis (2.4% vs 2.5%, p=0.007; risk ratio 0.95, 95% CI 0.92 to 0.99). However, no significant difference was observed between the two groups after HD-PS matching (2.4% vs 2.5%, p=0.067; risk ratio 0.96, 95% CI 0.92 to 1.00); only in 2012 did the CCB group have a significantly lower likelihood of influenza than the ACEI/ARB group. CONCLUSIONS: No significant difference was observed in the influenza incidence between the CCB and ACEI/ARB groups. A direct comparative study between background-matched patients with and without CCBs is warranted to confirm the effect of CCBs on reducing the incidence of influenza.

INTRODUCTION: The association between sodium-glucose cotransporter-2 (SGLT2) inhibitors and the risk of urogenital infections remains controversial. This study aimed to investigate the association between SGLT2 inhibitors and the incidence of perineal soft tissue infections, including Fournier's gangrene (FG), genital bacterial infections, and urinary tract infections (UTIs), using administrative claims data in Japan. METHODS: In this retrospective cohort study, we utilized the JMDC Claims Database. The study included patients aged 18 years or older diagnosed with type 2 diabetes mellitus, identified by a diagnostic code, who received new prescriptions for SGLT2 inhibitors or dipeptidyl peptidase 4 (DPP-4) inhibitors between April 2014 and August 2020. Using one-to-one propensity score (PS) matching, we compared the incidence of perineal soft tissue infections, including FG, genital bacterial infection, and UTIs between groups treated with SGLT2 and DPP-4 inhibitors. Hazard ratios (HR) and their 95% confidence intervals (CI) were estimated using the Cox proportional hazards model. RESULTS: We identified 34,897 patients in the SGLT2 inhibitor group and 135,311 patients in the DPP-4 inhibitor group. After one-to-one PS matching, 31,665 pairs were generated. The mean age of the patients was 51 years, with approximately 70% being male. The use of SGLT2 inhibitors was associated with a decreased risk of UTI (HR 0.90, 95% CI 0.83-0.98) and an increased risk of genital bacterial infection (HR 1.23, 95% CI 1.03-1.46) compared to DPP-4 inhibitors. However, no significant association was observed with perineal soft tissue infection (HR 1.05, 95% CI 0.61-1.81). CONCLUSIONS: SGLT2 inhibitors were associated with a reduced risk of UTI and an increased risk of genital bacterial infection. They showed no significant association with perineal soft tissue infection when compared to DPP-4 inhibitors. Future research should explore broader demographics, focusing on the elderly and achieving gender balance, to gain a comprehensive understanding of infection risks.

BACKGROUND: Sepsis is a life-threatening condition caused by severe infection. The efficacy of intravenous immunoglobulin (IVIG) as adjunctive therapy on mortality remains controversial. Moreover, IVIG may favorably affect sepsis-induced immunosuppression like persistent inflammation, immunosuppression, and catabolism syndrome (PICS). METHODS: This study was a retrospective cohort study using inpatient claims database provided by Medical Data Vision, which included approximately 190,000 episodes of intensive care unit admissions in Japanese acute care hospitals between April 2008 and September 2021. We used a propensity score-matched analysis to compare outcomes between the IVIG and control groups. Primary outcomes were 28-day mortality, while secondary outcomes included in-hospital mortality, the Barthel Index at discharge, length of hospital stay and laboratory data (albumin, C-reactive protein (CRP), and lymphocyte count) on days 14 and 28. RESULTS: Of the 17,626 patients enrolled, 15,159 (786 in the IVIG group and 14,373 in the control group) were included in the analysis. Propensity score matching generated 758 matched pairs. Before matching, 28-day mortality and in-hospital mortality were lower in the control group; however, in the matched cohort, 28-day mortality was significantly lower in the IVIG group than in the control group (90/758 [11.9%] vs 124/758 [16.4%]; risk difference [95% confidence intervals (CI)], -4.5% [-8.0% to -1.0%]; P = 0.015). In-hospital mortality in the matched cohort was also significantly more favorable in the IVIG group (137/758 [18.1%] vs 177/758 [23.4%]; risk difference [95%CI], -5.3% [-9.3% to -1.2%]; P = 0.013). Favorable outcomes in terms of albumin on days14 and 28 and CRP levels on day 28 were observed in the IVIG group. CONCLUSIONS: The administration of IVIG was associated with a reduction in sepsis mortality and favorable outcomes in laboratory parameters and the functional status. These results will contribute to the ongoing debate on the efficacy of IVIG for sepsis. The results obtained herein suggest the benefit of IVIG, particularly in mitigating PICS. Further research, including prospective studies, is warranted to confirm these results and examine long-term outcomes.

BACKGROUND: Whether GPT-4, the conversational artificial intelligence, can accurately diagnose and triage health conditions and whether it presents racial and ethnic biases in its decisions remain unclear. OBJECTIVE: We aim to assess the accuracy of GPT-4 in the diagnosis and triage of health conditions and whether its performance varies by patient race and ethnicity. METHODS: We compared the performance of GPT-4 and physicians, using 45 typical clinical vignettes, each with a correct diagnosis and triage level, in February and March 2023. For each of the 45 clinical vignettes, GPT-4 and 3 board-certified physicians provided the most likely primary diagnosis and triage level (emergency, nonemergency, or self-care). Independent reviewers evaluated the diagnoses as "correct" or "incorrect." Physician diagnosis was defined as the consensus of the 3 physicians. We evaluated whether the performance of GPT-4 varies by patient race and ethnicity, by adding the information on patient race and ethnicity to the clinical vignettes. RESULTS: The accuracy of diagnosis was comparable between GPT-4 and physicians (the percentage of correct diagnosis was 97.8% (44/45; 95% CI 88.2%-99.9%) for GPT-4 and 91.1% (41/45; 95% CI 78.8%-97.5%) for physicians; P=.38). GPT-4 provided appropriate reasoning for 97.8% (44/45) of the vignettes. The appropriateness of triage was comparable between GPT-4 and physicians (GPT-4: 30/45, 66.7%; 95% CI 51.0%-80.0%; physicians: 30/45, 66.7%; 95% CI 51.0%-80.0%; P=.99). The performance of GPT-4 in diagnosing health conditions did not vary among different races and ethnicities (Black, White, Asian, and Hispanic), with an accuracy of 100% (95% CI 78.2%-100%). P values, compared to the GPT-4 output without incorporating race and ethnicity information, were all .99. The accuracy of triage was not significantly different even if patients' race and ethnicity information was added. The accuracy of triage was 62.2% (95% CI 46.5%-76.2%; P=.50) for Black patients; 66.7% (95% CI 51.0%-80.0%; P=.99) for White patients; 66.7% (95% CI 51.0%-80.0%; P=.99) for Asian patients, and 62.2% (95% CI 46.5%-76.2%; P=.69) for Hispanic patients. P values were calculated by comparing the outputs with and without conditioning on race and ethnicity. CONCLUSIONS: GPT-4's ability to diagnose and triage typical clinical vignettes was comparable to that of board-certified physicians. The performance of GPT-4 did not vary by patient race and ethnicity. These findings should be informative for health systems looking to introduce conversational artificial intelligence to improve the efficiency of patient diagnosis and triage.

There have been few reports on the diagnostic performance of soluble interleukin-2 receptor (sIL-2R) for lymphoma. A cross-sectional study was conducted at a university hospital; all patients who were admitted to the Division of General Internal Medicine and underwent serum sIL-2R testing were included. Patients were divided into two groups based on the presence of fever (≥ 38.0 °C). Among 602 patients, 421 had fever and 76 were diagnosed with lymphoma (48 of the 76 were in the febrile group). In all patients, the area under the receiver operating characteristic curve (AUROC) of sIL-2R for the diagnosis of lymphoma was 0.81 [95% confidence interval (CI), 0.75-0.87]. The AUROC was significantly higher in the febrile group (0.88; 95% CI, 0.81-0.94) than in the afebrile group (0.75; 95% CI, 0.65-0.85). In the febrile group, the sensitivity and specificity were 81.2% and 82.3%, respectively, with an optimal cutoff value of 3,250 U/mL. In the afebrile group, they were 89.3% and 54.9%, respectively, with a cutoff value of 868 U/mL. Serum sIL-2R showed high performance as an adjunctive diagnostic marker for lymphoma, particularly among febrile patients. Different cutoff values should be used for patients with and without fever to maximize diagnostic performance.

INTRODUCTION: Days of antibiotic spectrum coverage (DASC), a novel metric for both antimicrobial volume and spectrum, was proposed to measure inpatient antimicrobial consumption in 2022. The DASC may better reflect efforts toward antimicrobial stewardship; however, no previous study has described the distribution of trends in DASC in hospitals or the association between the trend in DASC and days of therapy (DOT). This study assessed trends in antimicrobial consumption for inpatients at acute care hospitals in Japan using the DOT and DASC. METHODS: This retrospective observational study used the nationwide administrative inpatient claims database of Japanese acute care hospitals between 2014 and 2018. The prescriptions of all antibiotics were identified to calculate DOT/1000 patient-days, DASC/1000 patient-days, and DASC/DOT. We described the five-year trend in these metrics and examined the association between the trends in DOT and DASC. RESULTS: In total, 26,301,685 admissions from 634 hospitals were included. The DOT/1000 patient-days and DASC/1000 patient-days increased significantly by 6.1% and 5.6%, respectively. The DASC/DOT ratio did not change significantly (P = 0.35). Moreover, there was little correlation between DOT/1000 patient-days and DASC/DOT (R2 = 0.01). There was also little correlation between the five-year changes in DOT/1000 patient-days and those in DASC/DOT (R2 = 0.02). CONCLUSIONS: It may be difficult to assess trends in the antibiotic spectrum using DASC alone. However, the combination of DOT as a quantity indicator and DASC/DOT as a spectrum indicator may allow for a more appropriate evaluation of stewardship efforts.

BACKGROUND: Antimicrobial stewardship in dentistry and antibiotic prophylaxis for tooth extraction have been areas of concern in Japan, with limited research available. METHODS: This cross-sectional study utilized the regional health insurance claims database in Japan to examine antibiotic prescription trends by dentists, including antibiotic regimens, timing of prescription, and days of supply for prophylactic antibiotic use during tooth extraction. Antibiotic prophylaxis for patients with prosthetic heart valves was also investigated. FINDINGS: Antibiotic prescriptions by dentists decreased by 7% in 2019 compared to those in 2015, with third-generation cephalosporins still accounting for 48.5% in 2019. Amoxicillin prescription increased 3.9 times in 2019, although it only accounted for 8.4% of all antibiotic prescriptions. In 2019, amoxicillin was prescribed for 17.1% of all prophylactic antibiotics associated with tooth extraction, and 80% of prophylactic antibiotics were prescribed for 3 days or more, with 85% prescribed on the day of the procedure. However, only 60-70% of patients with prosthetic heart valves received antibiotic prophylaxis. INTERPRETATION: Despite the increasing trend after the implementation of the National Action Plan on antimicrobial resistance, the proportion of amoxicillin prescriptions in dentistry remains low. Antimicrobial stewardship issues related to long-term prescription and timing of administration of prophylactic antibiotics for tooth extraction should be addressed. Dentists must recognize the risks associated with high-risk patients with prosthetic heart valves who require antibiotic prophylaxis, and physicians providing valve replacement therapy should inform patients of the requirement for prophylaxis before invasive dental procedures.

Persistent inflammation, immunosuppression, and catabolism syndrome (PICS) is a serious condition after critical care. We examined the efficacy of antithrombin, which may attenuate coagulopathy with the control of inflammation, for PICS among patients with sepsis-induced disseminated intravascular coagulation (DIC). The present study used the inpatient claims database with laboratory findings to identify patients admitted to intensive care units and diagnosed with sepsis and DIC. A composite of the incidence of PICS on day 14 or 14-day mortality as the primary outcome was compared between the antithrombin and control groups using a propensity-score-matched analysis. Secondary outcomes were the incidence of PICS on day 28, 28-day mortality, and in-hospital mortality. A total of 324 well-balanced matched pairs were generated from 1622 patients. The primary outcome did not differ between the antithrombin and control groups (63.9% vs. 68.2%, respectively, p = 0.245). However, the incidences of 28-day and in-hospital mortality were significantly lower in the antithrombin group (16.0% vs. 23.5% and 24.4% vs. 35.8%, respectively). Similar results were obtained in a sensitivity analysis using overlap weighting. Antithrombin did not reduce the occurrence of PICS on day 14 in patients with sepsis-induced DIC; however, it was associated with a better mid-term (day 28) prognosis.

OBJECTIVES: The COVID-19 pandemic has forced people to change many behaviours, including physical distancing, hygiene measures and lifestyles. This study aimed to evaluate the indirect impact of the COVID-19 pandemic on the incidence of non-COVID-19 infections and medical care costs/visits using health insurance claims. STUDY DESIGN: This was an observational study using patient-based administrative claims covering approximately 800,000 insured persons and their dependents in the Mie Prefecture in Japan. METHODS: This study identified non-COVID-19 infectious disease incidences, number of outpatient visits and healthcare costs between 2017 and 2021. Each year was divided into quarters. The adjusted incidence rate ratios (IRRs) during the pandemic (January 2020 to September 2021) and during the prepandemic period (January 2017 to December 2019) were determined using Poisson regression. RESULTS: The adjusted influenza IRRs from April 2020 were close to zero. The incidence of upper respiratory tract infections and bacterial pneumonia was significantly reduced (IRRs range: 0.39-0.73 and 0.43-0.84, respectively). Gastrointestinal and urinary tract infection incidences decreased by approximately 30% and 10%, respectively. In contrast, sexually transmitted infections (STIs), including syphilis, gonococcal infection and Chlamydia trachomatis infection, did not decrease during the pandemic but increased significantly between April and June 2021 (adjusted IRR, 1.37; 95% confidence interval, 1.18-1.60). The adjusted IRRs for outpatient visits and healthcare costs were 0.86-0.93 and 0.91-0.97, respectively. CONCLUSIONS: In contrast to other infections, STIs did not decrease during the COVID-19 pandemic. The IRR of STIs during the pandemic period is an area of public health concern. Appropriate screening and medical consultations are strongly recommended.

INTRODUCTION: Post-intensive care syndrome (PICS) is an emerging problem in critically ill patients and the prevalence and risk factors are unclear in patients with severe coronavirus disease 2019 (COVID-19). This multicenter prospective observational study aimed to investigate the prevalence and risk factors of PICS in ventilated patients with COVID-19 after ICU discharge. METHODS: Questionnaires were administered twice in surviving patients with COVID-19 who had required mechanical ventilation, concerning Barthel Index, Short-Memory Questionnaire, and Hospital Anxiety and Depression Scale scores. The risk factors for PICS were examined using a multivariate logistic regression analysis. RESULTS: The first and second PICS surveys were obtained at 5.5 and 13.5 months (mean) after ICU discharge, with 251 and 209 patients completing the questionnaires and with a prevalence of PICS of 58.6% and 60.8%, respectively, along with the highest percentages of cognitive impairment. Delirium (with an odds ratio of (OR) 2.34, 95% CI 1.1-4.9, and p = 0.03) and the duration of mechanical ventilation (with an OR of 1.29, 95% CI 1.05-1.58, and p = 0.02) were independently identified as the risk factors for PICS in the first PICS survey. CONCLUSION: Approximately 60% of the ventilated patients with COVID-19 experienced persistent PICS, especially delirium, and required longer mechanical ventilation.

BACKGROUND: Disseminated infections of Mycolicibacter arupensis, a slowly growing nontuberculous mycobacteria (NTM) which causes synovitis, osteomyelitis, or pulmonary infections have rarely been reported. We report a case of disseminated M. arupensis and Mycobacterium avium co-infection in a patient with anti-interferon (IFN)-γ neutralizing autoantibody-associated immunodeficiency syndrome. CASE PRESENTATION: A 68-year-old Japanese male without human immunodeficiency virus infection was referred with complaints of persistent low-grade fever, arthralgia of the upper limbs, and weight loss of 10 kg. Cervical and mediastinal lymphadenopathies as well as a nodular opacity in the right lung were detected, and biopsy specimens of the cervical lymph node yielded M. arupensis without evidence of malignant cells. M. arupensis was also detected in sputum and peripheral blood. Computed tomography (CT) revealed deterioration of the right supraclavicular lymphadenopathy with internal necrosis and multiple low-density splenic lesions. Bone marrow and aspirates from the cervical lymph node collected at initiation of treatment yielded M. avium. The presence of anti-IFN-γ neutralizing autoantibodies was detected, leading to a diagnosis of co-infection of M. arupensis and M. avium with anti-IFN-γ neutralizing autoantibody-associated immunodeficiency syndrome. Post initiation of treatment with clarithromycin, ethambutol, and rifabutin, his fever declined, and his polyarthritis resolved. He developed disseminated varicella zoster during treatment; however, a follow-up CT scan six months after treatment revealed improvement of the lymphadenopathies, consolidation in the right lung, and splenic lesions. CONCLUSION: This is the first report of disseminated M. arupensis and M. avium co-infection in a patient with anti-IFN-γ neutralizing autoantibody-associated immunodeficiency syndrome.

INTRODUCTION: Rapid diagnostic tests have been developed recently for rapid species or resistance genes identification, offering the potential to improve the selection of appropriate antibiotics. The newly developed FilmArray Blood Culture Identification 2 (BCID2) panel, which can identify more species and resistance genes, such as extended-spectrum beta-lactamase, is expected to make an impact on antimicrobial practice. METHODS: The consecutive 50 inpatients with Gram-negative bacilli bacteremia were enrolled to this retrospective single-center study. In addition to the existing FilmArray Blood Culture Identification (BCID) panel, we have implemented BCID2 panel for positive blood culture. The sensitivity and specificity of BCID and BCID2 panel were respectively calculated, and a simulation study of time to effective, optimal and de-escalation therapy was performed based on BCID or BCID2 result. RESULTS: A total of 52 Gram-negative organisms in 50 patients were identified from blood cultures. Of these, 45 (87%) organisms were detected by BCID2 panel, which was more than BCID panel (41 organisms, 79%). BCID2 panel detected 5 CTX-M genes, which were concordant with conventional method. The time to effective therapy did not differ between BCID arm and BCID2 arm; however, the median time to optimal therapy (34 h in BCID arm and 26 h in BCID2 arm, P = 0.0007) and the median time to de-escalation therapy (42 h in BCID arm and 22 h in BCID2 arm, P = 0.0005) were significantly shortened. CONCLUSIONS: This simulation study of BCID2 panel showed high sensitivity and specificity, and the potential impact on shortening the time to optimal and de-escalation therapy.

AIM: This study aimed to evaluate whether nurse-initiated sedation management could provide more appropriate sedation compared to usual care in a Japanese intensive care unit (ICU). METHODS: We conducted a single-center, prospective observational study before and after implementing nurse-initiated sedation using instruction sheets. Patients who had been admitted to a general adult ICU were enrolled. Before our ICU started nurse-initiated sedation (pre-implementation care), adjustment of sedatives and analgesics was performed only by a physician's written or verbal order; however, after implementing nurse-initiated sedation, nurses titrated drugs using instruction sheets. The primary outcome was the efficacy of nurse-initiated sedation, evaluated by the proportion achieving the target Richmond Agitation-Sedation Scale (RASS) score. The analgesic status evaluated by Critical-Care Pain Observation Tool (CPOT), days of delirium, ventilator days, ICU mortality and hospital mortality were also evaluated. RESULTS: The study examined 30 patients in the pre-implementation care phase and 30 patients in the nurse-initiated sedation phase. The proportions achieving the target RASS were 68% in the nurse-initiated sedation group and 42% in the pre-implementation care group (mean difference, 25%; 95% confidence interval, 13.4%-37.5%; P <.001). Almost all measured CPOT were within the range of 0-3 during both phases. Days of delirium, ventilator days, ICU survival, and hospital survival did not differ significantly between the two groups. CONCLUSIONS: Nurse-initiated sedation management achieved a significantly higher degree of target sedation status and was incorporated as part of the care in our ICU. It is a safe approach in countries, such as Japan, where sedation protocols are not widely used.

BACKGROUND: Optimal nutrition therapy has not yet been established for the acute phase of severe coronavirus disease 2019 (COVID-19) infection. OBJECTIVES: To examine the effects of nutrition delivery in the acute phase on the mortality and long-term outcomes of post-intensive care syndrome (PICS). METHODS: A multicenter prospective study was conducted on adult patients with COVID-19 infection requiring mechanical ventilation during an intensive care unit (ICU) stay. Daily total energy (kcal/kg) and protein (g/kg) deliveries in the first week of the ICU stay were calculated. The questionnaire for the PICS evaluation was mailed within a median of 6 months after hospital discharge. The primary outcome was in-hospital mortality, and secondary outcomes were PICS components of physical, cognitive dysfunction and mental illness. RESULTS: Among 414 eligible patients, 297 who received mechanical ventilation for 7 days or longer were examined. PICS was evaluated in 175 patients among them. High protein delivery on days 4-7 correlated with a low in-hospital mortality rate. In contrast, high protein delivery on days 1-3 correlated with physical impairment. A multivariate logistic regression analysis adjusted for age, sex, body mass index, and severity revealed that average energy and protein deliveries on days 4-7 correlated with decreased in-hospital mortality; odds ratio 0.94 (95%CI 0.89,0.99) (P = 0.013) and 0.40 (95%CI 0.17,0.93) (P = 0.031), respectively. Nutrition delivery did not correlate with PICS outcomes after adjustments. In the multivariate regression using restricted cubic spline model, in-hospital mortality monotonically decreased with increases in average nutrition delivery on days 4-7. CONCLUSIONS: In patents with COVID-19 on mechanical ventilation ≥ 7 days, nutrition delivery in the late period of the acute phase was monotonically associated with a decrease in in-hospital mortality. Adequate protein delivery is needed on days 4-7.

OBJECTIVES: To investigate the impact of switching from tenofovir disoproxil fumarate (TDF)- to tenofovir alafenamide (TAF)-containing regimens on bone, kidney, serum lipids and body weight among Asian patients. METHODS: A prospective, multicentre, observational cohort study was conducted at three centres for HIV infection in Japan during 2017-2019. HIV-infected adults previously treated with TDF-containing regimens and scheduled to switch to TAF-containing regimens were included. Bone mineral density (BMD), renal markers, lipids and weight were measured consecutively from 12 months before to 12 months after the switch. RESULTS: Among 118 patients evaluated, the mean percentage change to spine BMD during 1 year of TAF treatment was higher than that during 1 year of TDF treatment (mean difference = 1.9%; 95% confidence interval (CI): 0.8-3.1). Urine protein and β2 -microglobulin levels decreased significantly after the switch, while low-density lipoprotein cholesterol and triglycerides increased. During the TDF and TAF periods, the mean weight gains were 0.2 and 1.9 kg, respectively (mean difference = 1.6 kg; 95% CI: 0.9-2.3). Subgroup analysis revealed a significant difference between the mean body weight change associated with an integrase inhibitor (INSTI) (+2.8 kg) and that associated with a non-INSTI (+1.2 kg) third agent treatment only during the TAF period. CONCLUSIONS: Among predominantly Japanese HIV-infected patients, BMD and renal tubular markers improved, while lipid profiles worsened significantly after the switch. Weight gain during the TAF period was larger than that during the TDF period. Concurrent use of INSTI with TAF may act synergistically to gain body weight.

BACKGROUND: While time in targeted blood glucose range (TIR) 70-140 mg/dL is a known factor associated with mortality in critically ill patients, it remains unclear whether TIR is associated with 28-day mortality under the glycemic control with a less tight target glucose range of 70-180 mg/dL. We aimed to examine whether TIR 70-180 mg/dL was associated with 28-day mortality. METHODS: This is a retrospective cohort study using data from a tertiary care center in Japan collected from January 2016 through October 2019. We included adult patients (aged ≥20 years) admitted to the ICU. We excluded patients 1) with diabetic ketoacidosis patients, 2) discharged within 48 hours, 3) with repeated ICU admissions. We calculated TIR 70-180 mg/dL using the measured blood glucose values (≥3 times per day). The primary outcome was 28-day mortality. We examined the association between TIR and 28-day mortality using a logistic regression and Cox proportional hazard models with a stratification by glycosylated hemoglobin (HbA1c) level of 6.5%. Additionally, we repeated the analyses using the TIR category to assess the optimal TIR. For the sensitivity analysis, we repeated the primary analysis using TIR during the first three days from ICU admission. RESULTS: Of 1,230 patients, the median age was 72 years, 65% were male, and 250 patients (20%) had HbA1c ≥6.5% on admission. In patients with HbA1c <6.5%, TIR <80% was associated with an increased risk of 28-day mortality, with an adjusted odds ratio (OR) of 1.88 (95%CI: 1.36-2.61). Likewise, when using 10% incremental TIR as a categorical variable, lower TIR was associated with a worse 28-day mortality compared with TIR ≥90% (e.g., adjusted OR of TIR <60%, 3.62 [95%CI 2.36-5.53]). Similar associations were found in the analyses using Cox proportional hazards model and using TIR during the first three days. By contrast, in patients with HbA1c ≥6.5%, there was no consistent association of TIR with 28-day mortality. CONCLUSIONS: We found that lower TIR 70-180 mg/dL was associated with a higher 28-day mortality in critically ill patients with HbA1c <6.5%, whereas there was no consistent association in patients with HbA1c ≥6.5%.

A specific antibiogram is necessary for the empiric antibiotic treatment of community-acquired urinary tract infections (UTI) because of the global spread of antimicrobial resistance. This study aimed to develop an antibiogram specific for community-acquired UTI and assess the risk factors associated with community-acquired UTI caused by antimicrobial-resistant organisms. This cross-sectional observational retrospective study included patients with community-acquired UTI caused by Gram-negative rods (GNR) who were admitted to the emergency department at a tertiary care hospital in Ibaraki, Japan, in 2017-2018. A total of 172 patients were enrolled (including 38 nursing home residents). Of the 181 GNR strains considered as causative agents, 135 (75%) were Escherichia coli, and 40 (22%) exhibited third-generation cephalosporin resistance. Extended-spectrum β-lactamase (ESBL)-producing E. coli accounted for 25/40 (63%) of resistant GNR. Overall susceptibility rate of Enterobacterales was 92%, 81%, 100%, 75%, and 89% for cefmetazole, ceftriaxone, meropenem, levofloxacin, and trimethoprim-sulfamethoxazole, respectively. Residence in a nursing home (odds ratio (OR), 2.83; 95% confidence interval (CI), 1.18-6.79) and recent antibiotic use (OR, 4.52; 95% CI, 1.02-19.97) were independent risk factors for UTI with resistant GNR. ESBL-producing E. coli was revealed to have a strong impact on antimicrobial resistance pattern. Therefore, an antibiotic strategy based on a disease-specific antibiogram is required.

BACKGROUND: β-Hydroxy-β-methylbutyrate (HMB), a metabolite of leucine, can strongly induce muscle protein synthesis. We evaluated the efficacy of HMB complex on muscle volume loss during critical care. METHODS: For this prospective, single-center, randomized control trial, we created control and HMB groups by random assignment of intensive care unit (ICU) patients for whom enteral nutrition could be performed. From 164 ICU patients, 88 severely ill patients were included and assigned: 43 to control and 45 to HMB. From day 2 after admission, HMB group were administered 3 g HMB, 14 g arginine, and 14 g glutamine daily in addition to standard nutrition therapy. Early rehabilitation with electrical muscle stimulation was started from day 2 in both groups. As a primary outcome, we evaluated femoral muscle volume using computed tomography on days 1 and 10. RESULTS: Femoral muscle volumes of 24 control and 26 HMB group participants were analyzed as per protocol. Volumes decreased significantly during days 1-10 (P < 0.0001). Volume loss rates were 14.4 ± 7.1% for control participants and 11.4 ± 8.1% for HMB participants (P = 0.18). In a subgroup of the sequential organ failure assessment scores <10, femoral muscle volume loss was 14.0 ± 6.9% for control participants and 8.7 ± 6.4% for HMB (P = 0.0474). Results of intention-to-treat analysis of the 2 groups showed no differences in basic characteristics or outcomes. CONCLUSIONS: For critically ill patients, HMB complex supplementation from the acute phase of intensive care does not inhibit muscle volume loss.

Background: Tuberculous peritonitis is difficult to diagnose due to its varying clinical features, in addition to the low yield on bacterial culture or polymerase chain reaction using ascitic fluid samples. This study aimed to investigate the sensitivity and specificity of elevated adenosine deaminase (ADA) levels as a diagnostic marker for tuberculous peritonitis. Methods: A retrospective cohort of 181 adult patients who underwent ascitic fluid ADA level examination at Jichi Medical University Hospital between January 2006 and December 2015 were included. We collected data regarding ascitic fluid analyses including ADA levels, bacteriology and cytology, final diagnosis (cause of ascites), basis of the diagnosis, duration to diagnosis, and disease outcome. Results: Among 181 patients, elevated ascitic ADA levels (≥40 IU/L) were observed in 15 patients (median, 87.2 IU/L; range, 44.0-176.1 IU/L); 8 patients had tuberculous peritonitis, 4 had lymphoma-related ascites, and 2,had peritoneal carcinomatosis with bacterial coinfection, and 1 had chlamydial pelvic inflammatory disease. Among 166 patients without ascitic ADA level elevation (median, 7.3 IU/L; range, <2.0-39.1 IU/L), none had tuberculosis, 4 had lymphoma-related ascites, 28 had cancer/mesothelioma-related ascites, and 134 had ascites due to other causes. In our cohort, elevated ascitic fluid ADA levels (≥40 IU/L) showed 100% sensitivity, 96.0% specificity, 53.3% positive predictive value (PPV), and 100% negative predictive value for the diagnosis of peritoneal tuberculosis. Conclusions: Ascitic fluid ADA levels ≥40 IU/L showed excellent sensitivity, despite a low PPV, for the diagnosis of tuberculous peritonitis. Lymphoma-related ascites is an important mimic of tuberculous peritonitis that can result in high ascitic fluid ADA levels with similar clinical manifestations.

OBJECTIVES: Belt electrode skeletal muscle electrical stimulation can induce muscle contraction of the whole lower body. This study examined the efficacy of belt electrode skeletal muscle electrical stimulation on reducing loss of muscle volume in critically ill patients. METHODS: Intensive care unit patients were randomly assigned to control and electrical muscle stimulation groups. In both groups, early rehabilitation was administered from day 2 of admission. In the electrical muscle stimulation group, belt electrode skeletal muscle electrical stimulation was administered. Femoral muscle volume was evaluated with computed tomography on days 1 and 10. RESULTS: Ninety-Four severely ill patients were included 47 patients were assigned to each group. Femoral muscle volumes of 16 control and 21 electrical muscle stimulation group patients were measured. For both groups, femoral muscle volume decreased significantly from day 1 to day 10 (p < 0.0001). The mean rate of muscle volume loss was 17.7% (standard deviation (SD) 10.8%) for the control group and 10.4% (SD 10.1%) for the electrical muscle stimulation group (p = 0.04). The score for stair-climbing of Barthel Index was significantly better in the electrical muscle stimulation group 3.9 (SD 4.0) than in the control group 1.5 (1.5) (p = 0.04). CONCLUSION: Belt electrode skeletal muscle electrical stimulation has the potential to inhibit muscle volume loss in critical care.

A 58-year-old man presented with a 2-month history of arthralgia and bilateral temporal region pain, and a 1-month history of fever. He had had refractory neck pain since his 20s. Reduced cervical and lumbar mobility was observed. Radiographs of cervical and thoracic vertebrae disclosed syndesmophytes. Pelvic radiographs showed sclerosis in the right sacroiliac joint and ankylosis in the left sacroiliac joint. MRI with contrast enhancement showed enthesitis in the upper extremities and enhancement in the bilateral temporal muscle, which indicated enthesitis of temporal muscle. He was diagnosed with ankylosing spondylitis based on the limitation in mobility of the lumbar spine and radiographic findings. To the best of our knowledge, this is the first report describing enthesitis of the temporal muscle. This case highlights that ankylosing spondylitis can be accompanied with enthesitis at the temporal muscle and fever of unknown origin at the initial presentation.

Vertebral osteomyelitis can result in serious complications if diagnosis is delayed. Magnetic resonance imaging (MRI) is considered the most useful modality for the early diagnosis of vertebral osteomyelitis. We examined three patients with vertebral osteomyelitis whose initial MRI (obtained <2 weeks after the onset of symptoms) did not reveal obvious findings of pyogenic vertebral osteomyelitis. However, follow-up MRI clearly demonstrated typical findings of the disease. This case series illustrates that a repeat MRI must be performed 2-4 weeks after the onset of symptoms in patients presenting with clinical manifestations and microbiological findings suggestive of vertebral osteomyelitis.

BACKGROUND: Several studies have reported that daptomycin induced artificial prolongation of prothrombin time (PT) in some test reagents, particularly in warfarin users. However, it remains unknown whether the artificial prolongation can be affected by coagulation abnormalities other than the use of warfarin. Thus, we investigated the effect of daptomycin on PT with two types of coagulation abnormalities. METHODS: Plasma samples were pooled by four groups: healthy volunteers (Plasma A), warfarin users with a PT-international normalized ratio (INR) of approximately 2.0 (Plasma B) or 3.0 (Plasma C), and patients with liver cirrhosis with a PT-INR of approximately 2.0 (Plasma D). Plasma A was composed of plasma from two healthy individuals (9 mL from each individual). Plasma B, C, and D were composed of plasma from 36 patients (0.5 mL from each patient). Daptomycin was added to each sample to create solutions with several concentrations (0-150 μg/mL). The PT-INR for each solution was measured with three PT reagents. Linear regression analyses were used to determine the association between daptomycin concentration and PT-INR. The relative change in PT-INR due to daptomycin concentrations was calculated. RESULTS: Strong linear correlations were observed between daptomycin concentrations and PT-INR for all the plasma groups and reagents (R2 > 0.7, P < 0.01). At a daptomycin concentration of 150 μg/mL, the relative increase of PT-INR was ≥10% in the majority of the plasma groups with an elevated baseline PT-INR in all reagents tested. CONCLUSIONS: Daptomycin induced the artificial prolongation of PT-INR in a concentration-dependent manner, particularly in plasma samples with an elevated baseline PT-INR. PT should be evaluated at the trough levels of daptomycin.

A 91-year-old man was referred to our hospital with intermittent dysphagia. He had undergone esophagectomy for esophageal cancer (T3N2M0 Stage III) 11 years earlier. Endoscopic examination revealed an anastomotic stricture; signs of inflammation, including redness, erosion, edema, bleeding, friability, and exudate with white plaques; and multiple depressions in the residual esophagus. Radiographical examination revealed numerous fine, gastrografin-filled projections and an anastomotic stricture. Biopsy specimens from the area of the anastomotic stricture revealed inflammatory changes without signs of malignancy. Candida glabrata was detected with a culture test of the biopsy specimens. The stricture was diagnosed as a benign stricture that was caused by esophageal intramural pseudodiverticulosis. Accordingly, endoscopic balloon dilatation was performed and anti-fungal therapy was started in the hospital. Seven weeks later, endoscopic examination revealed improvement in the mucosal inflammation; only the pseudodiverticulosis remained. Consequently, the patient was discharged. At the latest follow-up, the patient was symptom-free and the pseudodiverticulosis remained in the residual esophagus without any signs of stricture or inflammation.