Digital marketing innovation: New business models for pharmaceutical and medical device product marketing.

Background: Within the rapidly evolving healthcare landscape in Japan, digital marketing innovations are transforming pharmaceutical and medical device marketing. This study explores the emergence of new business models in the digital marketing, highlighting a transition from traditional methods to more dynamic, data-driven strategies. Methods: InsighTCROSS® is a business model that qualitatively and quantitatively examines three steps based on stratified persona images: (1) verifying the effectiveness of product marketing promotions, (2) identifying competitors from the users' perspective, and (3) developing marketing strategies to counter competition. To demonstrate the effectiveness of this model, a case study was conducted focusing on the current anticoagulant drugs, including apixaban, dabigatran, edoxaban, rivaroxaban, and warfarin. Results: Rivaroxaban, the only drug prescribed for the prevention of thrombus and embolism formation in patients with peripheral artery disease after lower limb revascularization, garnered the most interest from interventional cardiologists performing peripheral vascular interventions, as determined by InsighTCROSS® factor analysis, confirming that the manufacturer's marketing activities have effectively penetrated the market. A survey conducted between 20 September 2023 and 3 October 2023, among members of a cardiology website, identified edoxaban as the market leader with a 39.1% share, followed by apixaban (32.7%) and rivaroxaban (16.8%). The main competitor of edoxaban was warfarin, whereas that of rivaroxaban was apixaban. Decision tree analysis was conducted using InsighTCROSS®, highlighting the strengths and weaknesses of each anticoagulant, providing strategic approaches to exploit competitive weaknesses. For edoxaban, increased use was driven by elderly and poorly adherent patients; for apixaban, high-volume percutaneous coronary intervention centers; and for rivaroxaban, the influence of medical representative detailing. It is recommended to avoid markets where these drugs have a strong presence and to focus marketing activities on leveraging their specific strengths. Conclusion: The findings suggest that digital marketing enhances product visibility and patient engagement, providing valuable insights into market behavior and consumer preferences.

Characteristics of Bleeding Complications in Patients with Severe COVID-19 Requiring Veno-venous Extracorporeal Membrane Oxygenation in Japan.

BACKGROUND: Complications during veno-venous extracorporeal membrane oxygenation (VV-ECMO) are associated with in-hospital mortality. Asian patients on extracorporeal membrane oxygenation (ECMO) have higher risks of bleeding and in-hospital mortality than Caucasian patients. This study aimed to characterize and identify bleeding complications and their associated factors related to in-hospital mortality in patients with severe coronavirus disease 2019 (COVID-19) requiring VV-ECMO in Japan. METHODS: In this retrospective observational analysis, the prospective nationwide multicenter registry was used to track real-time information from intensive care units throughout Japan during the COVID-19 pandemic. VV-ECMO patients' registry data between February 1, 2020 and October 31, 2022 were used. RESULTS: This study included 441 patients; 178 (40%) had bleeding complications in the following sites: 20% at the cannulation site, 16% in the gastrointestinal tract, 16% in the ear-nose-throat, 13% at the tracheostomy site, 9% intrathoracic, 6% intracranial, and 5% in the iliopsoas. Anticoagulation was discontinued in >50% of patients with intracranial, iliopsoas, and gastrointestinal tract bleeding. ECMO was discontinued in one-third of patients with intracranial, intramuscular, and iliopsoas hemorrhages. Multivariable logistic regression analysis revealed that only gastrointestinal tract bleeding was associated with in-hospital mortality (odds ratio: 2.49; 95% confidence interval: 1.11-5.60; p = 0.03). CONCLUSION: Incidence of bleeding complications was 40% in the Japanese population. Gastrointestinal tract bleeding emerged as a significant predictor of adverse outcomes, necessitating further research into preventive strategies and optimized care protocols. These findings can guide the management of VV-ECMO patients with COVID-19.

Selection Criteria in the Era of Perfect Competition for Drug-Eluting Stents in Association With Operator Volumes: An Operator-Volume Analysis of the Selection DES Study.

Background: This study aimed to explore the factors influencing the drug-eluting stent (DES) selection criteria of cardiologists in association with percutaneous coronary intervention (PCI) volumes and to determine whether they value further DES improvements and modifications. Methods: The survey was conducted on a group of cardiologist operators from April 10 to 30, 2023. Results: The analysis included 126 operators who answered the questions. Of these, low-, intermediate-, and high-volume operators accounted for 49 (38.9%), 47 (37.3%), and 30 (23.8%), respectively. Overall, Xience™ everolimus-eluting stent (CoCr-EES) was most frequently used, with > 70% of cardiologists using it in > 20% of their PCI practice. The percentage of selection by low-, intermediate-, and high-volume operators among the DESs used demonstrated no difference, except for dual-therapy sirolimus-eluting and CD34+ antibody-coated Combo® stent (DTS). Logistic regression analysis revealed that low-volume operators are less likely to be affected in terms of company/sales representative (odds ratio (OR): 0.402, P = 0.031) and bending lesions (OR: 0.339, P = 0.037) for selecting DES. Low-volume operators less frequently selected Resolute Onyx™ zotarolimus-eluting stents (OR: 0.689, P = 0.043) and DTS (Drug-Eluting Stents) (OR: 0.361, P = 0.006) for PCI. Conclusions: The current study results indicate that patient background, DES performance, and product specifications were not criteria for DES selection in cardiologists with different PCI volumes in routine PCI.

Selection criteria for anticoagulants: survey of Japanese cardiologists based on their daily clinical practice: the Selection DOAC study.

BACKGROUND: In patients with atrial fibrillation (AF), direct oral anticoagulants (DOACs) have been utilized as an alternative to warfarin, which is known to have several limitations. This study aimed to clarify the selection criteria for anticoagulants, considering both individual patient factors and the differences between various drugs. METHODS: This study conducted a web-based questionnaire from September 20, 2023 to October 3, 2023, among physicians who were members of a cardiology-specific website. RESULTS: In total, 172 respondents were enrolled in this study. Edoxaban was the most frequently selected anticoagulant (39.1%), followed by apixaban (32.7%) and rivaroxaban (16.8%). Logistic regression analysis revealed that increased concern for adherence enhanced the frequency of selecting edoxaban (odds ratio [OR] = 2.42; p = 0.047), with the opposite trend observed for dabigatran (OR = 0.404; p = 0.029). The selection of apixaban is related to whether the patient is able to maintain a regular lifestyle, including adherence to medication schedules (OR = 1.874; p = 0.031). Furthermore, detailing activities from a medical representative, especially regarding a new indication, were found to influence drug selection for rivaroxaban (OR = 2.422; p = 0.047). CONCLUSION: This study revealed that edoxaban is the most frequently selected anticoagulant. Although prescribing cardiologists select drugs based on background factors, adherence to medication and information from medical representatives were also crucial factors in the selection process.

No improvement in mortality among critically ill patients with carbapenems as initial empirical therapy and more detection of multi-drug resistant pathogens associated with longer use: a post hoc analysis of a prospective cohort study.

Whether empirical therapy with carbapenems positively affects the outcomes of critically ill patients with bacterial infections remains unclear. This study aimed to investigate whether the use of carbapenems as the initial antimicrobial administration reduces mortality and whether the duration of carbapenem use affects the detection of multidrug-resistant (MDR) pathogens. This was a post hoc analysis of data acquired from Japanese participating sites from a multicenter, prospective observational study [Determinants of Antimicrobial Use and De-escalation in Critical Care (DIANA study)]. A total of 268 adult patients with clinically suspected or confirmed bacterial infections from 31 Japanese intensive care units (ICUs) were analyzed. The patients were divided into two groups: patients who were administered carbapenems as initial antimicrobials (initial carbapenem group, n = 99) and those who were not administered carbapenems (initial non-carbapenem group, n = 169). The primary outcomes were mortality at day 28 and detection of MDR pathogens. Multivariate logistic regression analysis revealed that mortality at day 28 did not differ between the two groups [18 (18%) vs 27 (16%), respectively; odds ratio: 1.25 (95% confidence interval (CI): 0.59-2.65), P = 0.564]. The subdistribution hazard ratio for detecting MDR pathogens on day 28 per additional day of carbapenem use is 1.08 (95% CI: 1.05-1.13, P < 0.001 using the Fine-Gray model with death regarded as a competing event). In conclusion, in-hospital mortality was similar between the groups, and a longer duration of carbapenem use as the initial antimicrobial therapy resulted in a higher risk of detection of new MDR pathogens.IMPORTANCEWe found no statistical difference in mortality with the empirical use of carbapenems as initial antimicrobial therapy among critically ill patients with bacterial infections. Our study revealed a lower proportion of inappropriate initial antimicrobial administrations than those reported in previous studies. This result suggests the importance of appropriate risk assessment for the involvement of multidrug-resistant (MDR) pathogens and the selection of suitable antibiotics based on risk. To the best of our knowledge, this study is the first to demonstrate that a longer duration of carbapenem use as initial therapy is associated with a higher risk of subsequent detection of MDR pathogens. This finding underscores the importance of efforts to minimize the duration of carbapenem use as initial antimicrobial therapy when it is necessary.

Association Between In-hospital Mortality and the Institutional Factors of Intensive Care Units with a Focus on the Intensivist-to-bed Ratio: A Retrospective Cohort Study.

Purpose: To elucidate the relationship between in-hospital mortality and the institutional factors of intensive care units (ICUs), with a focus on the intensivist-to-bed ratio. Methods: A retrospective cohort study was conducted using a Japanese ICU database, including adult patients admitted between April 1, 2020 and March 31, 2021. We used a multilevel logistic regression model to investigate the associations between in-hospital mortality and the following institutional factors: the intensivist-to-bed ratios on weekdays or over weekends/holidays, different work shifts, hospital-to-ICU-bed ratio, annual-ICU-admission-to-bed ratio, type of hospital, and the presence of other medical staff. Results: The study population comprised 46 503 patients admitted to 65 ICUs. The in-hospital mortality rate was 8.1%. The median numbers of ICU beds and intensivists were 12 (interquartile range [IQR] 8-14) and 4 (IQR 2-9), respectively. In-hospital mortality decreased significantly as the intensivist-to-bed ratio at 10 am on weekdays increased: the average contrast indicated a 20% (95% confidence interval [CI]: 1%-38%) reduction when the ratio increased from 0 to 0.5, and a 38% (95% CI: 9%-67%) reduction when the ratio increased from 0 to 1. The other institutional factors did not present a significant effect. Conclusions: The intensivist-to-bed ratio at 10 am on weekdays had a significant effect on in-hospital mortality. Further investigation is needed to understand the processes leading to improved outcomes.

Potential for expanding indications and curability criteria of endoscopic resection for early gastric cancer in elderly patients: results from a Japanese multicenter prospective cohort study.

BACKGROUND AND AIMS: Evidence for endoscopic resection (ER) in elderly patients with early gastric cancer (EGC) is limited. We assessed its clinical outcomes and explored new indications and curability criteria. METHODS: We analyzed data from a Japanese multicenter, prospective cohort study. Patients aged ≥75 years with EGC treated with ER were included. We classified eCuraC-2 (corresponding to noncurative ER, defined in the Japanese gastric cancer treatment guidelines) into elderly-high (>10% estimated metastatic risk) and elderly-low (EL-L) (≤10% estimated metastatic risk). RESULTS: In total, 3371 patients with 3821 EGCs were included; endoscopic submucosal dissection was the prominent treatment choice. Among them, 3586 lesions met the guidelines' ER indications, and 235 did not. The proportions of en bloc and R0 resections and perforations were 98.9%, 94.4%, and 0.8%, respectively, in EGCs within the indications. In EGCs beyond the indications, they were 99.5%, 85.4%, and 5.9%, respectively, for lesions diagnosed as ≤3 cm and 96.0%, 64.0%, and 18.0%, respectively, for those >3 cm. Curative ER and EL-L were observed in 83.6% and 6.2% of lesions within the indications, respectively, and in 44.2% and 16.8% of lesions <3 cm beyond the indications, respectively. The 5-year cumulative gastric cancer death rates after curative ER and elderly-high were 0.3% (95% confidence interval [CI], 0.2-0.6) and 3.5% (95% CI, 2.0-5.7), respectively. After EL-L, the rate was 0.9% (95% CI, 0.2-3.5) even without subsequent treatment. CONCLUSIONS: The usefulness of endoscopic submucosal dissection for elderly EGC patients was confirmed by their clinical outcomes. Lesions of ≤3 cm and EL-L emerged as new ER indication and curability criteria, respectively. (Clinical trial registration number: UMIN000005871.).

Defining the Standard of the Terminology of the Mechanical Ventilation Data in Japan.

To effectively use data from intensive care unit patient information systems at multiple hospitals, it is necessary to standardize the data into a well-ordered form. However, terms often vary between devices. We designed a mechanical ventilation concept model and applied data to that model using existing tools and expert opinions. The JSICM glossary was revised based on this study.

Relationship between critical care nutrition and post-intensive care syndrome in surviving ventilated patients with COVID-19: a multicenter prospective observational study.

The impact of nutrition therapy in the acute phase on post-intensive care syndrome (PICS) remains unclear. We conducted a multicenter prospective study on adult patients with COVID-19 who required mechanical ventilation for more than three days. The questionnaire was mailed after discharge. Physical PICS, defined as less than 90 points on the Barthel index (BI), was assigned as the primary outcome. We examined the types of nutrition therapy in the first week that affected PICS components. 269 eligible patients were evaluated 10 months after discharge. Supplemental parenteral nutrition (SPN) >400 kcal/day correlated with a lower occurrence of physical PICS (10% vs 21.92%, p = 0.042), whereas the amounts of energy and protein provided, early enteral nutrition, and a gradual increase in nutrition delivery did not, and none correlated with cognitive or mental PICS. A multivariable regression analysis revealed that SPN had an independent impact on physical PICS (odds ratio 0.33, 95% CI 0.12-0.92, p = 0.034), even after adjustments for age, sex, body mass index and severity. Protein provision ≥1.2 g/kg/day was associated with a lower occurrence of physical PICS (odds ratio 0.42, 95% CI 0.16-1.08, p = 0.071). In conclusion, SPN in the acute phase had a positive impact on physical PICS for ventilated patients with COVID-19.

Effect of the Japanese medical office system on job satisfaction, loyalty, engagement, and organizational commitment of medical practitioners: a survey of cardiologists in the acute care setting.

BACKGROUND: In Japan, medical doctors have traditionally been assigned from university medical offices, under the medical office system. The present study examined the effects of the medical office system on job satisfaction, engagement, loyalty, and organizational commitment among cardiologists. METHODS: In this study, a survey of 156 cardiologists was conducted, from April 22, 2023, to May 21, 2023, to examine the effect of the medical office system on employee job satisfaction, employee engagement, and organizational commitment. RESULTS: Compared with the group that belonged to a medical office system (affiliated group, n = 117), the group that did not belong to a medical office system (non-affiliated group, n = 39) was affiliated to hospitals with a smaller number of beds. The results of the factor analysis showed that four types of hospital management styles were generated, namely, environment-, loyalty-building-, treatment-, and philosophy-oriented hospitals. There is an indication that the philosophy-oriented management style was adopted at the workplaces of the non-affiliated group. The treatment-oriented style also tended to be higher in the non-affiliated group than in the affiliated group. Furthermore, the non-affiliated group had higher organizational commitment, indicating that they were more likely to agree with the management philosophy set forth by hospital executives. CONCLUSION: Although the medical office system did not affect job satisfaction, compared with medical doctors with the affiliated group, those with the non-affiliated group tended to work in hospitals that emphasized philosophy-oriented management, and they received moderate compensation while practicing in an environment suitable for their specialty. These results suggest that the medical office system makes it difficult for medical doctors to have high workplace loyalty, engagement, and commitment to the hospital to which they are dispatched.

Association between regional critical care capacity and the incidence of invasive mechanical ventilation for coronavirus disease 2019: a population-based cohort study.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has exposed critical care supply shortages worldwide. This study aimed to investigate the association between regional critical care capacity and the incidence of invasive mechanical ventilation following novel COVID-19 during the pandemic in Japan, a country with a limited intensive care unit (ICU) bed capacity of a median of 5.1 ICU beds per 100,000 individuals. METHODS: This population-based cohort study used data from the CRoss Icu Searchable Information System database and publicly available databases provided by the Japanese government and Japanese Society of Intensive Care Medicine. We identified patients recently diagnosed with COVID-19, those who received invasive mechanical ventilation, and those who received extracorporeal membrane oxygenation (ECMO) between February 2020 and March 2023. We analyzed the association between regional critical care capacity (ICU beds, high-dependency care unit (HDU) beds, resource-rich ICU beds, and intensivists) and the incidence of invasive mechanical ventilation, ECMO, and risk-adjusted mortality across 47 Japanese prefectures. RESULTS: Among the approximately 127 million individuals residing in Japan, 33,189,809 were recently diagnosed with COVID-19, with 12,203 and 1,426 COVID-19 patients on invasive mechanical ventilation and ECMO, respectively, during the study period. Prefecture-level linear regression analysis revealed that the addition of ICU beds, resource-rich ICU beds, and intensivists per 100,000 individuals increased the incidence of IMV by 5.37 (95% confidence interval, 1.99-8.76), 7.27 (1.61-12.9), and 13.12 (3.48-22.76), respectively. However, the number of HDU beds per 100,000 individuals was not statistically significantly associated with the incidence of invasive mechanical ventilation. None of the four indicators of regional critical care capacity was statistically significantly associated with the incidence of ECMO and risk-adjusted mortality. CONCLUSIONS: The results of prefecture-level analyses demonstrate that increased numbers of ICU beds, resource-rich ICU beds, and intensivists are associated with the incidence of invasive mechanical ventilation among patients recently diagnosed with COVID-19 during the pandemic. These findings have important implications for healthcare policymakers, aiding in efficiently allocating critical care resources during crises, particularly in regions with limited ICU bed capacities. Registry and the registration no. of the study/trial The approval date of the registry was August 20, 2020, and the registration no. of the study was lUMIN000041450.

A simpler diagnostic algorithm of the Japan Esophageal Society classification for Barrett's esophagus-related superficial neoplasia.

BACKGROUND: We previously developed a Japan Esophageal Society Barrett's Esophagus (JES-BE) magnifying endoscopic classification for superficial BE-related neoplasms (BERN) and validated it in a nationwide multicenter study that followed a diagnostic flow chart based on mucosal and vascular patterns (MP, VP) with nine diagnostic criteria. Our present post hoc analysis aims to further simplify the diagnostic criteria for superficial BERN. METHODS: We used data from our previous study, including 10 reviewers' assessments for 156 images of high-magnifying narrow-band imaging (HM-NBI) (67 dysplastic and 89 non-dysplastic histology). We statistically analyzed the diagnostic performance of each diagnostic criterion of MP (form, size, arrangement, density, and white zone), VP (form, caliber change, location, and greenish thick vessels [GTV]), and all their combinations to achieve a simpler diagnostic algorithm to detect superficial BERN. RESULTS: Diagnostic accuracy values based on the MP of each single criterion or combined criteria showed a marked trend of being higher than those based on VP. In reviewers' assessments of visible MPs, the combination of irregularity for form, size, or white zone had the highest diagnostic performance, with a sensitivity of 87% and a specificity of 91% for dysplastic histology; in the assessments of invisible MPs, GTV had the highest diagnostic performance among the VP of each single criterion and all combinations of two or more criteria (sensitivity, 93%; specificity, 92%). CONCLUSION: The present post hoc analysis suggests the feasibility of further simplifying the diagnostic algorithm of the JES-BE classification. Further studies in a practical setting are required to validate these results.

Non-COVID-19 intensive care admissions during the pandemic: a multinational registry-based study.

BACKGROUND: The COVID-19 pandemic resulted in a large number of critical care admissions. While national reports have described the outcomes of patients with COVID-19, there is limited international data of the pandemic impact on non-COVID-19 patients requiring intensive care treatment. METHODS: We conducted an international, retrospective cohort study using 2019 and 2020 data from 11 national clinical quality registries covering 15 countries. Non-COVID-19 admissions in 2020 were compared with all admissions in 2019, prepandemic. The primary outcome was intensive care unit (ICU) mortality. Secondary outcomes included in-hospital mortality and standardised mortality ratio (SMR). Analyses were stratified by the country income level(s) of each registry. FINDINGS: Among 1 642 632 non-COVID-19 admissions, there was an increase in ICU mortality between 2019 (9.3%) and 2020 (10.4%), OR=1.15 (95% CI 1.14 to 1.17, p<0.001). Increased mortality was observed in middle-income countries (OR 1.25 95% CI 1.23 to 1.26), while mortality decreased in high-income countries (OR=0.96 95% CI 0.94 to 0.98). Hospital mortality and SMR trends for each registry were consistent with the observed ICU mortality findings. The burden of COVID-19 was highly variable, with COVID-19 ICU patient-days per bed ranging from 0.4 to 81.6 between registries. This alone did not explain the observed non-COVID-19 mortality changes. INTERPRETATION: Increased ICU mortality occurred among non-COVID-19 patients during the pandemic, driven by increased mortality in middle-income countries, while mortality decreased in high-income countries. The causes for this inequity are likely multi-factorial, but healthcare spending, policy pandemic responses, and ICU strain may play significant roles.

National ICU Registries as Enablers of Clinical Research and Quality Improvement.

OBJECTIVES: Clinical quality registries (CQRs) have been implemented worldwide by several medical specialties aiming to generate a better characterization of epidemiology, treatments, and outcomes of patients. National ICU registries were created almost 3 decades ago to improve the understanding of case-mix, resource use, and outcomes of critically ill patients. This narrative review describes the challenges, proposed solutions, and evidence generated by National ICU registries as facilitators for research and quality improvement. DATA SOURCES: English language articles were identified in PubMed using phrases related to ICU registries, CQRs, outcomes, and case-mix. STUDY SELECTION: Original research, review articles, letters, and commentaries, were considered. DATA EXTRACTION: Data from relevant literature were identified, reviewed, and integrated into a concise narrative review. DATA SYNTHESIS: CQRs have been implemented worldwide by several medical specialties aiming to generate a better characterization of epidemiology, treatments, and outcomes of patients. National ICU registries were created almost 3 decades ago to improve the understanding of case-mix, resource use, and outcomes of critically ill patients. The initial experience in European countries and in Oceania ensured that through locally generated data, ICUs could assess their performances by using risk-adjusted measures and compare their results through fair and validated benchmarking metrics with other ICUs contributing to the CQR. The accomplishment of these initiatives, coupled with the increasing adoption of information technology, resulted in a broad geographic expansion of CQRs as well as their use in quality improvement studies, clinical trials as well as international comparisons, and benchmarking for ICUs. CONCLUSIONS: ICU registries have provided increased knowledge of case-mix and outcomes of ICU patients based on real-world data and contributed to improve care delivery through quality improvement initiatives and trials. Recent increases in adoption of new technologies (i.e., cloud-based structures, artificial intelligence, machine learning) will ensure a broader and better use of data for epidemiology, healthcare policies, quality improvement, and clinical trials.

Selection criteria in the era of perfect competition for drug-eluting stents - a survey of interventional cardiologists in Japan: the selection-DES study.

BACKGROUND: More than 20 years have passed since the first company introduced drug-eluting stent (DES) in 2002, but competing companies still have improved their DESs under regulatory approval. This study aimed to investigate the criteria for interventional cardiologists performing percutaneous coronary intervention (PCI) in selecting a DES. RESEARCH DESIGN AND METHODS: From 10 April 2023, to 30 April 2023, 3,422 cardiologists were requested to complete a questionnaire, of whom 126 responded to the survey. RESULTS: Overall, 86.5% of the respondents used Xience cobalt-chromium everolimus-eluting stent (Xience) in > 10% of PCI procedures. For Xience, brand loyalty and calcified lesions were important independent variables for the DES selection criteria. Ultimaster sirolimus-eluting stent (Ultimaster) was not affected by the clinical data delivered by the company, whereas the respondents were shown to seek support for their activities from the Ultimaster supplier. The relationship with the company and/or sales representative and the planned surgical procedure affected the use of Coroflex ISAR NEO sirolimus-eluting polymer-free stent. CONCLUSIONS: Patient background and lesion characteristics had little impact on the DES selection criteria, suggesting that DES performance has already reached its physical limitations to the extent that respondents may not value further improvements in performance or characteristics of DES.

Factors associated with bleeding complications in patients with coronavirus disease 2019 admitted to intensive care units: A multicenter retrospective cohort study.

AIMS/INTRODUCTION: Diabetes is a major risk factor for coronavirus disease 2019 (COVID-19) severity. We aimed to retrospectively investigate the rates of patients with no diabetes, untreated diabetes, treated diabetes, COVID-19-related diabetes and the factors associated with bleeding complications in a cohort of patients with severe COVID-19. MATERIALS AND METHODS: This was a multicenter, retrospective, observational study. Participants were COVID-19 patients enrolled in the Cross-sectional ICU Information Search System (CRISIS) from February 2020 to March 2022. Patients were classified into four groups according to diabetes status and treatment status. Hemorrhagic complications were defined as bleeding requiring transfusion of four or more red blood cell units, a drop of hemoglobin of ≥2 g in 24 h and retroperitoneal, airway or intracranial bleeding. Logistic regression analysis was carried out to examine factors associated with bleeding complications. RESULTS: A total of 1,076 patients were included in the analysis. The rates of patients in the no diabetes, untreated diabetes, treated diabetes and COVID-19-related diabetes groups were 17.4, 23.0, 23.9 and 35.7%, respectively. Bleeding complications were observed in 7.5% of all patients. Glycated hemoglobin level and renal failure were significantly correlated with bleeding complications (odds ratio 1.16, 95% confidence interval 1.02-1.33 and 2.77, 95% confidence interval 1.16-6.63, respectively). Patients with diabetes, including those with COVID-19-related diabetes, accounted for approximately 83% of all cases. CONCLUSIONS: In patients with severe COVID-19 with high glycated hemoglobin and renal failure, we recommend additional attention to the course of COVID-19, given the risk of bleeding complications.

Clinical efficacy and safety of multipotent adult progenitor cells (invimestrocel) for acute respiratory distress syndrome (ARDS) caused by pneumonia: a randomized, open-label, standard therapy-controlled, phase 2 multicenter study (ONE-BRIDGE).

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a life-threatening inflammatory lung injury with high mortality; no approved medication exists. Efficacy and safety of bone marrow-derived, allogeneic, multipotent adult progenitor cells (invimestrocel) plus standard treatment in patients with ARDS caused by pneumonia was evaluated. METHODS: A randomized, open-label, standard therapy-controlled, phase 2 study (January 2019-September 2021) conducted in 29 centers in Japan. Patients with ARDS caused by pneumonia, with extensive early fibroproliferation on high-resolution computed tomography and low risk of systemic organ failure identified by an Acute Physiology and Chronic Health Evaluation (APACHE II) score were included. Patients were randomized 2:1 to receive a single intravenous infusion of 9.0 × 108 cells of invimestrocel (administered at a rate of up to 10 mL/min over 30-60 min by free flow) plus standard treatment (N = 20) or standard treatment (N = 10) consistent with the clinical practice guidelines of the Japanese Respiratory Society for the management of ARDS. Primary endpoint was ventilator-free days (VFDs) through day 28 after study treatment. Analysis of covariance was performed with treatment group, age, partial pressure arterial oxygen/fraction of inspired oxygen ratio, and APACHE II score as covariates. RESULTS: Median (interquartile range) number of VFDs was numerically higher in the invimestrocel group versus standard group (20.0 [0.0-24.0] vs 11.0 [0.0-14.0]) but was not statistically significantly different (least square [LS] means [95% confidence interval (CI)]: invimestrocel group, 11.6 [6.9-16.3]; standard group, 6.2 [- 0.4 to 12.8]; LS mean difference [95% CI], 5.4 [- 1.9 to 12.8]; p = 0.1397). Ventilator weaning rate at day 28 was 65% (13/20) versus 30% (3/10), and mortality rate was 21% (4/19) versus 29% (2/7) at day 28 and 26% (5/19 patients) versus 43% (3/7 patients) at day 180, for the invimestrocel and standard groups, respectively. No allergic or serious adverse reactions were associated with invimestrocel. CONCLUSIONS: In Japanese patients with ARDS caused by pneumonia, invimestrocel plus standard treatment resulted in no significant difference in the number of VFDs but may result in improved survival compared with standard treatment. Invimestrocel was well tolerated. TRIAL REGISTRATION: ClinicalTrials.gov, Identifier: NCT03807804; January 8, 2019; https://clinicaltrials.gov/ct2/show/NCT03807804 .

Multisystem inflammatory syndrome in adults with COVID-19 requiring mechanical ventilation: A retrospective cohort study.

Aim: Multisystem inflammatory syndrome in adults (MIS-A) is a hyperinflammatory multisystem condition associated with coronavirus disease (COVID-19). Critically ill COVID-19 patients may develop multiorgan damage and elevated inflammatory responses, thus making it difficult to differentiate between progression to organ damage due to COVID-19 itself or MIS-A. This study aimed to explore the characteristics and complications of MIS-A in critical COVID-19 patients. Methods: The Japan Extracorporeal Membrane Oxygenation (ECMO) Network and ICU Collaboration Network developed a web-based database system called the CRoss Intensive Care Unit Searchable Information System (CRISIS) to monitor critical COVID-19 patients throughout Japan. We retrospectively identified patients with MIS-A among critical COVID-19 patients enrolled from March 2020 to December 2021, using CRISIS. Our MIS-A definition required patients to be at least 18 years of age, have laboratory evidence of inflammation, severe dysfunction of at least two extrapulmonary organ systems, and no plausible alternative diagnoses. Results: Of the 1052 patients, 26 (2.5%) were diagnosed with MIS-A. The MIS-A patients had a higher likelihood of using ECMO (13% vs. 46%, p < 0.001) and lower overall survival (77% vs. 42%, p < 0.001) than non-MIS-A patients. More than 80% of the MIS-A cases occurred 3 weeks after the COVID-19 onset. Conclusion: Multisystem inflammatory syndrome in adults can occur in 2.5% of critically ill COVID-19 patients, and the mortality rate is high. Multisystem inflammatory syndrome in adults may be considered when there is a re-elevation of the unexplained inflammatory response and severe dysfunction of at least two extrapulmonary organ systems several weeks after the onset of COVID-19.