Effectiveness of remdesivir in patients with COVID-19 and severe renal insufficiency: a nationwide cohort study in Japan.

BACKGROUND: The effectiveness of remdesivir in patients with coronavirus disease 2019 (COVID-19) and severe renal insufficiency remains underexplored. OBJECTIVES: To evaluate whether remdesivir reduces the risk of mortality or invasive mechanical ventilation/extracorporeal membrane oxygenation (IMV/ECMO) in this population. METHODS: This retrospective observational study utilising the COVID-19 Registry Japan (COVIREGI-JP) included noncritical patients with COVID-19 and severe renal insufficiency (defined as serum creatinine levels ≥3 mg/dL, on maintenance dialysis, or kidney transplant recipients) admitted to Japanese hospitals within 7 days of symptom onset between January 1, 2020 and May 8, 2023. Patients were classified into the remdesivir group if remdesivir was initiated within the first 2 days of admission. We estimated the multivariable-adjusted hazard ratio (HR) for mortality and initiation of IMV/ECMO using landmark analysis to address immortal time bias. RESULTS: Among the 1,449 patients included in the landmark analysis (median age, 74 years [interquartile range 62-84 years]; 992 [68.5%] were male), 272 initiated remdesivir within the first 2 days of admission. During the 28 days from the landmark timepoint, 19 (7.0%) and 136 (11.6%) patients in the remdesivir and control groups, respectively, had an outcome. The remdesivir group had a lower risk of mortality or IMV/ECMO initiation than the control group (adjusted HR, 0.44; 95% confidence interval, 0.23-0.83). CONCLUSIONS: In noncritical patients with COVID-19 and severe renal insufficiency at admission, initiating remdesivir early after disease onset, within the first 2 days of admission, led to a lower risk of mortality or IMV/ECMO initiation, compared with non-initiation of remdesivir.

The first case of primary malignant melanoma of the esophagus to achieve pathologic complete response after preoperative ipilimumab + nivolumab followed by resection.

Primary malignant melanoma of the esophagus is a rare disease with a poor prognosis. Surgical resection is common, but there is no consensus on perioperative treatment. Studies have reported the efficacy of programmed cell death-1 inhibitors (e.g., nivolumab, pembrolizumab) and anti-cytotoxic T-lymphocyte-associated antigen 4 agents (e.g., ipilimumab) in treating malignant melanoma. Here, we present the first case of primary malignant melanoma of the esophagus with lymph node metastases treated with nivolumab and ipilimumab followed by resection, achieving a pathologic complete response. A 75-year-old man presented with dysphagia. Esophagogastroduodenoscopy revealed a black, elevated lesion in the mid-thoracic esophagus. Biopsy confirmed primary malignant melanoma of the esophagus, showing tumor cells with melanin deposition, positive for HBM45 and S-100 staining. Computed tomography showed enlarged lymph nodes in the subclavian and mediastinum regions, suggesting metastases. After two courses of preoperative chemotherapy with ipilimumab and nivolumab, which significantly shrank the tumor, the patient underwent robot-assisted subtotal esophagectomy and 3-field lymph node dissection. Histopathological examination revealed no tumors or lymph node metastases, confirming a pathologic complete response. Given the rarity and poor prognosis of primary malignant melanoma of the esophagus, this case provides valuable insights for treatment strategies.

Anti-inflammatory effect of covalent PPARγ ligands that have a hybrid structure of GW9662 and a food-derived cinnamic acid derivative.

Peroxisome proliferator-activated receptor γ (PPARγ) belongs to the nuclear receptor superfamily and is involved in the inflammatory process. Previously, we synthesized the ligands of PPARγ that possess the hybrid structure of a food-derived cinnamic acid derivative (CA) and GW9662, an irreversible PPARγ antagonist. These ligands activate the transcription of PPARγ through the covalent bond formation with the Cys285 residue of PPARγ, whereas their anti-inflammatory effect has not been examined yet. Here, we show the anti-inflammatory effect of the covalent PPARγ ligands in RAW264 cells, murine macrophage-like cells. GW9662 suppressed the production of nitric oxide (NO) stimulated by lipopolysaccharide and exerted a synergistic effect in combination with CA. The compounds bearing their hybrid structure dramatically inhibited NO production and transcription of proinflammatory cytokines. A comparison study suggested that the 2-chloro-5-nitrobenzoyl group of the ligands is important for anti-inflammation. Furthermore, we synthesized an alkyne-tagged analogue that becomes an activity-based probe for future mechanistic study.

Steroid therapy for patients with septic shock: A multicenter observational study conducted in Japan.

Objectives The Clinical Practice Guidelines for the Management of Sepsis and Septic Shock weakly recommend steroids for septic shock resistant to fluid resuscitation and vasopressors. This study aimed to describe the clinical practices for septic shock in the real world and to compare the association between the intermittent or continuous infusion of steroids and the prognosis. Methods This was a retrospective cohort study based on the AMOR-VENUS, in which Japanese intensive care unit (ICU) inpatients were enrolled between January and March 2018. Adult patients with sepsis who received vasopressors within 72 h of ICU admission were included. The patients were divided into non-steroid and steroid groups, which were further divided into intermittent and continuous infusion groups. The patient characteristics and details of the steroids are described. To investigate the association between intermittent or continuous infusion, shock reversal, and mortality, logistic regression analyses were performed after adjusting for possible confounding factors. Results A total of180 patients with septic shock from 18 ICUs were enrolled. The mean age was 69.6 (SD, 14.3) years. Sixty-three patients (35.0%) received steroids (26 intermittently, 37 continuously). In the steroid group, hydrocortisone was used in 85.7%, the median daily dose was 192 mg, and the steroids were administered within 6 h of initiating vasopressor in 71.4%. The adjusted odds ratios of shock reversal on the 7th day and the ICU mortality for continuous versus intermittent infusion were 1.90 (95%CI, 0.43-8.40) and 0.61 (0.10-3.85), respectively. Conclusions There was considerable variation in the criteria for the selection of patients and in the decision to use continuous or intermittent steroid infusion.

Clinical Outcomes of Preserving Bronchial Arteries During Radical Esophagectomy: A Propensity-Score Matched Analysis.

BACKGROUND: Postoperative pneumonia is a common and major cause of mortality after radical esophagectomy. Intraoperative preservation of the bronchial arteries is often aimed at avoiding tracheobronchial ischemia; however, it is unknown whether this contributes to a reduction in postoperative pneumonia. PATIENTS AND METHODS: We enrolled 348 consecutive patients who underwent radical esophagectomy for esophageal cancer at Toranomon Hospital from January 2011 to July 2018. We classified patients into a bronchial artery-resected (BA-R) group (n = 93) and a bronchial artery-preserved (BA-P) group (n = 255) and compared the incidence of postoperative pneumonia between the two groups. A propensity score-matching analysis for bronchial artery preservation versus resection was performed. RESULTS: Overall, 182 patients were matched. Univariate analysis of the propensity score-matched groups showed that Brinkman index ≥ 400, vital capacity (%VC) < 80%, and bronchial artery resection were associated with the development of postoperative pneumonia. Multivariate analysis revealed three significant factors associated with postoperative pneumonia: Brinkman index ≥ 400 [p = 0.006, odds ratio (HR) 3.302, 95% confidence interval (95% CI) 1.399-7.790], %VC < 80% (p = 0.034, HR 6.365, 95% CI 1.151-35.205), and bronchial artery resection (p = 0.034, HR 2.131, 95% CI 1.060-4.282). The incidence of postoperative complications (CD grade III) was higher in the BA-R group (BA-R 42.8% versus BA-P 27.5%, p = 0.030). There was no significant difference in overall survival between the two groups at 5 years (BA-R 63.1% versus BA-P 72.1%, p = 0.130). CONCLUSION: Preserving the bronchial artery is associated with a decreased incidence of postoperative pneumonia.

Longitudinal Association Between Social Isolation and COVID-19 Vaccine Uptake in Japanese Older Citizen: an Observational Study.

BACKGROUND: Social isolation is associated with decreased intent to receive vaccination against coronavirus disease 2019 (COVID-19); however, its association with COVID-19 vaccine uptake is unknown. OBJECTIVE: The present study aimed to determine the association between social isolation and subsequent COVID-19 vaccination using the data from a representative Japanese sample. DESIGN: Longitudinal observational study. PARTICIPANTS: Japanese citizens aged ≥ 65 years who participated in the Quality of Life in COVID-19 Era (QoLCoVE) study which began in March 2020. MAIN MEASURES: Social isolation was assessed in March 2020 using the abbreviated Lubben Social Network Scale, with a score of ≤ 11 indicating social isolation. To evaluate the relationship between social isolation at the baseline and COVID-19 vaccine uptake (including reservation for vaccine administration) between August and September 2021, we estimated adjusted risk ratios with 95% CIs using modified Poisson regression with adjustment for potential confounders. KEY RESULTS: A total of 921 participants met the inclusion criteria in the initial survey, of whom 720 (78.2%) completed the follow-up survey. Median age was 70 years (interquartile range: 66-72), and 329 (45.7%) participants were male. Twenty-one (16.5%) of 127 socially isolated participants, and 48 (8.1%) of 593 non-socially isolated participants did not receive the COVID-19 vaccine. Socially isolated participants were less likely to take COVID-19 vaccine than non-socially isolated participants (adjusted risk ratio 1.98, 95% CI: 1.18-3.32). CONCLUSIONS: Social isolation is associated with reduced COVID-19 vaccine uptake among older adults. To further promote COVID-19 vaccination in the older population, support for social isolation might be necessary.

Twenty-year follow-up of promising clinical studies reported in highly circulated newspapers: a meta-epidemiological study.

OBJECTIVES: Researchers have identified cases in which newspaper stories have exaggerated the results of medical studies reported in original articles. Moreover, the exaggeration sometimes begins with journal articles. We examined what proportion of the studies quoted in newspaper stories were confirmed. METHODS: We identified newspaper stories from 2000 that mentioned the effectiveness of certain treatments or preventions based on original studies from 40 main medical journals. We searched for subsequent studies until June 2022 with the same topic and stronger research design than each original study. The results of the original studies were verified by comparison with those of subsequent studies. RESULTS: We identified 164 original articles from 1298 newspaper stories and randomly selected 100 of them. Four studies were not found to be effective in terms of the primary outcome, and 18 had no subsequent studies. Of the remaining studies, the proportion of confirmed studies was 68.6% (95% CI 58.1% to 77.5%). Among the 59 confirmed studies, 13 of 16 studies were considered to have been replicated in terms of effect size. However, the results of the remaining 43 studies were not comparable. DISCUSSION: In the dichotomous judgement of effectiveness, about two-thirds of the results were nominally confirmed by subsequent studies. However, for most confirmed results, it was impossible to determine whether the effect sizes were stable. CONCLUSIONS: Newspaper readers should be aware that some claims made by high-quality newspapers based on high-profile journal articles may be overturned by subsequent studies within the next 20 years.

App-based interventions for the prevention of postpartum depression: a systematic review and meta-analysis.

BACKGROUND: This study explored whether psychosocial intervention applications (apps) are effective in preventing postpartum depression. METHODS: We conducted an initial article search on 26 March 2020, and the updated search on 17 March 2023 on the electronic databases of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE via Ovid, Scopus, PsycINFO, CINAHL, and ProQuest Dissertations & Theses A&I. Furthermore, we searched the International Clinical Trials Platform Search Portal (ICTRP), and Clinical Trials. RESULTS: We identified 2515 references, and sixteen studies were ultimately included in this review. We conducted a meta-analysis of two studies on the onset of postpartum depression. There were no significant differences between the intervention and control groups (RR 0.80; 95% CI 0.62 to 1.04; P = 0.570). We performed a meta-analysis of the Edinburgh Postnatal Depression Scale (EPDS). The intervention group had significantly lower EPDS scores than the control group (mean difference -0.96; 95% CI -1.44 to -0.48; P < 0.001, I2 = 82%, Chi2 = 62.75, P < 0.001; high heterogeneity). CONCLUSION: This study presents the results of current RCTs on interventions with apps, including an app with an automated psychosocial component for preventing postpartum depression that has been conducted. These apps improved the EPDS score; furthermore, they may prevent postpartum depression.

Prehospital shock index predicts 24-h mortality in trauma patients with a normal shock index upon emergency department arrival.

BACKGROUND: The shock index (heart rate divided by systolic blood pressure) of trauma patients upon emergency department arrival predicts blood loss and death. However, some patients with normal shock indices (0.4 < shock index <0.9) upon emergency department arrival also have poor prognoses. This study aimed to determine whether abnormal prehospital shock indices in trauma patients with normal shock indices upon emergency department arrival were predictors of a high risk of mortality. METHODS: We conducted a retrospective cohort study of emergency department-admitted trauma patients from 2004 to 2017. The study included 89,495 consecutive trauma patients aged ≥16 years, with Abbreviated Injury Scale score of ≥3, who were transported to the emergency department directly from the field and had a normal shock index upon emergency department arrival. According to the prehospital shock index scores, the patients were categorized into low shock index (≤ 0.4), normal shock index, and high shock index (≥0.9) groups. Odds ratios and 95% confidence intervals were calculated using logistic regression analysis. RESULTS: The 89,495 patients had a median age of 64 (interquartile range: 43-79) years, and 55,484 (62.0%) of the patients were male. There were 1350 (1.5%) 24-h deaths in total; 176/4263 (4.1%), 1017/78,901 (1.3%), and 157/6331 (2.5%) patients were in the low, normal, and high prehospital shock index groups, respectively. The adjusted odds ratios for 24-h mortality compared with the normal shock index group were 1.63 (95% confidence interval: 1.34-1.99) in the low shock index group and 1.62 (95% confidence interval: 1.31-1.99) in the high shock index group. CONCLUSION: Trauma patients with abnormal prehospital shock indices but normal shock indices upon emergency department arrival are at a higher risk of 24-h mortality. Identifying these indices could improve triage and targeted care for patients.

Trends in Prescribing Antipsychotics for Children and Adolescents in Japan: A Descriptive Epidemiological Study Using a Large-Scale Pharmacy Dataset.

Little is known about antipsychotic prescription patterns among children and adolescents in Japan, particularly in outpatient settings. We investigated the prevalence and trends of antipsychotic prescription for outpatients aged ≤ 17 years receiving a first antipsychotic prescription from 2006 to 2012 based on a large-scale dispensation dataset. Measurements included age, sex, department of diagnosis and treatment, type of prescription (monotherapy or polytherapy), antipsychotic dosage, and concomitant psychotropic drugs. Of the 10,511 patients, 65.1% were aged 13-17 years, and 52.9% were males. Second-generation antipsychotic monotherapy prescriptions increased from 53.8% in 2006 to 78.3% in 2012. Risperidone was the most frequently prescribed antipsychotic, followed by aripiprazole and olanzapine. Approximately 25.0% of patients were prescribed an initial dose less than recommended. Second-generation antipsychotic monotherapy is currently the most frequent prescription pattern among outpatients aged ≤ 17 years receiving an initial antipsychotic prescription.

Decline in oral antimicrobial prescription in the outpatient setting after nationwide implementation of financial incentives and provider education: An interrupted time-series analysis.

OBJECTIVES: To assess the impact of nationwide outpatient antimicrobial stewardship interventions in the form of financial incentives for providers and provider education when antimicrobials are deemed unnecessary for uncomplicated respiratory infections and acute diarrhea. METHODS: We collected data from a large claims database from April 2013 through March 2020 and performed a quasi-experimental, interrupted time-series analysis. The outcome of interest was oral antimicrobial prescription rate defined as the number of monthly antimicrobial prescriptions divided by the number of outpatient visits each month. We examined the effects of financial incentive to providers (ie, targeted prescriptions for those aged ≤2 years) and provider education (ie, targeted prescriptions for those aged ≥6 years) on the overall antimicrobial prescription rates and how these interventions affected different age groups before and after their implementation. RESULTS: In total, 21,647,080 oral antimicrobials were prescribed to 2,920,381 unique outpatients during the study period. At baseline, prescription rates for all age groups followed a downward trend throughout the study period. Immediately after the financial incentive implementation, substantial reductions in prescription rates were observed among only those aged 0-2 years (-47.5 prescriptions per 1,000 clinic visits each month; 95% confidence interval, -77.3 to -17.6; P = .003), whereas provider education immediately reduced prescription rates in all age groups uniformly. These interventions did not affect the long-term trend for any age group. CONCLUSION: These results suggest that the nationwide implementation of financial incentives and provider education had an immediate effect on the antimicrobial prescription but no long-term effect.

Effectiveness of psychological first aid in infectious disease pandemics: An overview of systematic reviews.

There is insufficient research on the usefulness of psychological interventions, such as psychological first aid (PFA), during outbreaks. We searched for and critically appraised systematic reviews that examined the effectiveness of PFA during infectious disease outbreaks, such as the novel coronavirus disease (COVID-19). Systematic reviews that examined the efficacy of PFA in the severe acute respiratory syndrome, Middle East respiratory syndrome coronavirus, Ebola virus disease, and COVID-19 outbreaks were searched through PubMed on February 19, 2021. The three included systematic reviews were critically appraised and assessed using AMSTAR-2. One review's overall confidence in its findings was evaluated as "high," which suggested that PFA training had a favorable effect on healthcare personnel. Furthermore, the review also demonstrated that PFA was commonly used during outbreaks and could be delivered through multiple methods, such as a phone or video call. Although it was anticipated that PFA would improve subjective well-being, reports showed no evidence of reduced depression or insomnia. Future studies should examine additional numbers of PFA recipients and conduct quasi-experimental studies to better understand the effectiveness of PFA. Evidence on its effectiveness in infectious disease outbreaks is still lacking, along with research and evaluation methods. Quasi-experimental studies, such as comparisons with other psychological interventions, are required to better understand the effectiveness of PFA.

Early corticosteroid dose tapering in patients with acute exacerbation of idiopathic pulmonary fibrosis.

BACKGROUND: Although corticosteroid therapy with dose tapering is the most commonly used treatment for acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF), there is no consensus on the tapering regimen. This study aimed to investigate the association between early corticosteroid dose tapering and in-hospital mortality in patients with AE-IPF. METHODS: In this retrospective cohort study, we analyzed the data of a cohort from eight Japanese tertiary care hospitals and routinely collected administrative data from a cohort from 185 Japanese hospitals. Patients with AE-IPF were classified into the early and non-early tapering groups depending on whether the maintenance dose of corticosteroids was reduced within two weeks of admission. Propensity score analysis with inverse probability weighting (IPW) was performed to estimate the effect of early corticosteroid dose tapering. RESULTS: The multi-center cohort included 153 eligible patients, of whom 47 (31%) died, whereas the administrative cohort included 229 patients, of whom 51 (22%) died. Patients with early tapering tended to have a better prognosis than those without it (unadjusted hazard ratio [95% confidence interval] 0.41 [0.22-0.76] and 0.65 [0.36-1.18] in the multi-center and administrative cohorts, respectively). After IPW, the early tapering group had a better prognosis than the non-early tapering group (IPW-adjusted hazard ratio [95% confidence interval] 0.37 [0.14-0.99] and 0.27 [0.094-0.83] in the multi-center and administrative cohorts, respectively). CONCLUSION: Early corticosteroid dose tapering was associated with a favorable prognosis in patients with AE-IPF. Further studies are warranted to confirm the effects of early corticosteroid dose tapering in patients with AE-IPF.

Mood Stabilizers and Antipsychotics for Acute Mania: Systematic Review and Meta-Analysis of Augmentation Therapy vs Monotherapy From the Perspective of Time to the Onset of Treatment Effects.

BACKGROUND: Existing meta-analytic evidence on bipolar mania treatment has revealed that augmentation therapy (AUG) with antipsychotics and mood stabilizers is more effective than monotherapy. However, the speed of the onset of treatment effects and subsequent changes in risk/benefit are unclear. METHODS: We searched the Cochrane CENTRAL, MEDLINE, and EMBASE databases until January 2021. Our primary outcomes were response and tolerability. We set 3 time points: 1, 3, and 6 weeks after randomization. RESULTS: Seventeen studies compared AUG therapy and MS monotherapy (comparison 1), and 8 studies compared AUG therapy and antipsychotics monotherapy (comparison 2). In comparison 1, AUG therapy resulted in significantly more responses than monotherapy, with an odds ratio of 1.45 (95% confidence interval [CI]: 1.17 to 1.80) at 3 weeks and 1.59 (95% CI: 1.28 to 1.99) at 6 weeks. Significant improvement was observed in the first week with a standardized mean difference of -0.25 (95% CI: -0.38 to -0.12). In comparison 2, AUG therapy was significantly more effective than monotherapy, with an odds ratio of 1.73 (95% CI: 1.25 to 2.40) at 3 weeks and 1.74 (95% CI: 1.11 to 2.73) at 6 weeks. Significant improvement was observed in the first week with an standardized mean difference of -0.23 (95% CI: -0.39 to -0.07). Regarding tolerability, there was no significant difference between AUG therapy and monotherapy at 3 and 6 weeks in both comparisons. CONCLUSIONS: Early AUG therapy should be considered, as it has shown efficacy from weeks 1 to 6, although attention to side effects is necessary for acute mania treatment.

Calf circumference and stroke are independent predictors for an improvement in the food intake level scale in the Japanese sarcopenic dysphagia database.

PURPOSE: The purpose of this study was to use the food intake level scale (FILS) to clarify whether calf circumference (CC) and stroke contribute to an improvement of inpatient dysphagia. METHODS: We used the Japanese sarcopenic dysphagia database (n = 467) to analyze FILS data recorded at admission and after follow-up in 322 cases. A multivariate analysis was performed to determine whether CC and stroke improved the FILS by two points or more. RESULTS: The patient characteristics were as follows: 177 (55%) men; median age, 81 years; median body mass index, 20.3 kg/m2; median CC, 28.2 cm; presence of sarcopenic dysphagia, 183 (56.8%); history of stroke, 103 (32%); median FILS on admission (interquartile range (IQR)), 6 (2-7); and median FILS at the end of the observation (IQR), 7 (7-8). Comparison of FILS at admission and discharge showed that 137 patients had an improvement in the scale of two points or more, whereas 185 patients had no improvement. Multivariate logistic regression analysis showed the factors that were associated independently with an improvement in dysphagia were: age < 80 years (odds ratio (OR) 2.20, 95% confidence interval (CI) 1.36-3.54, p = 0.001); CC ≥ 29.4 cm (OR 2.19, 95% CI 1.33-3.61, p = 0.002); sex (OR 1.67, 95% CI 1.03-2.71, p = 0.037); and stroke (OR 1.85, 95% CI 1.09-3.16, p = 0.023). CONCLUSIONS: Our results suggest that a CC ≥ 29.4 cm and history of stroke contributed to an improvement of inpatient dysphagia at discharge. The contribution of the easy-to-measure CC to predict an improvement in swallowing function may be very useful in daily clinical practice.