Objective: To implement early rehabilitation interventions by physical therapists is recommended. However, the effectiveness of early rehabilitation for severe coronavirus disease 2019 (COVID-19) patients in the prevention of post-intensive care syndrome (PICS) is unclear. We analyzed a multicenter prospective observational study (Post-Intensive Care outcomeS in patients with COronaVIrus Disease 2019) to examine the association between early rehabilitation interventions and PICS physical impairment. Methods: An analysis was performed on COVID-19 patients who were admitted to intensive care units (ICUs) between March 2020 and March 2021, and required mechanical ventilation. The primary outcome was the incidence of PICS physical impairment (Barthel Index≤90) after one year. Multivariate logistic regression analysis was used to estimate the association between early rehabilitation interventions and PICS physical impairment by adjusting ICU mobility scale (IMS) during seven-day following ICU admission, and clinically relevant risk factors. Results: The analysis included 259 patients, 54 of whom developed PICS physical impairment one year later. In 81 patients, physical therapists intervened within seven days of ICU admission. There was no significant difference in mean IMS by day seven of admission between the early and non-early rehabilitation patients (0.70 and 0.61, respectively). Multivariate logistic regression analysis showed that early rehabilitation interventions were significantly associated with a low incidence of PICS physical impairment (odds ratio, 0.294; 95% confidence interval, 0.123–0.706; p=0.006). Conclusion Early rehabilitation interventions by physical therapists were an independent factor associated with the decreased development of PICS physical impairment at one year, even though early rehabilitation had no significant effect on IMS.

Objective: To implement early rehabilitation interventions by physical therapists is recommended. However, the effectiveness of early rehabilitation for severe coronavirus disease 2019 (COVID-19) patients in the prevention of post-intensive care syndrome (PICS) is unclear. We analyzed a multicenter prospective observational study (Post-Intensive Care outcomeS in patients with COronaVIrus Disease 2019) to examine the association between early rehabilitation interventions and PICS physical impairment. Methods: An analysis was performed on COVID-19 patients who were admitted to intensive care units (ICUs) between March 2020 and March 2021, and required mechanical ventilation. The primary outcome was the incidence of PICS physical impairment (Barthel Index≤90) after one year. Multivariate logistic regression analysis was used to estimate the association between early rehabilitation interventions and PICS physical impairment by adjusting ICU mobility scale (IMS) during seven-day following ICU admission, and clinically relevant risk factors. Results: The analysis included 259 patients, 54 of whom developed PICS physical impairment one year later. In 81 patients, physical therapists intervened within seven days of ICU admission. There was no significant difference in mean IMS by day seven of admission between the early and non-early rehabilitation patients (0.70 and 0.61, respectively). Multivariate logistic regression analysis showed that early rehabilitation interventions were significantly associated with a low incidence of PICS physical impairment (odds ratio, 0.294; 95% confidence interval, 0.123–0.706; p=0.006). Conclusion Early rehabilitation interventions by physical therapists were an independent factor associated with the decreased development of PICS physical impairment at one year, even though early rehabilitation had no significant effect on IMS.

Objective: To implement early rehabilitation interventions by physical therapists is recommended. However, the effectiveness of early rehabilitation for severe coronavirus disease 2019 (COVID-19) patients in the prevention of post-intensive care syndrome (PICS) is unclear. We analyzed a multicenter prospective observational study (Post-Intensive Care outcomeS in patients with COronaVIrus Disease 2019) to examine the association between early rehabilitation interventions and PICS physical impairment. Methods: An analysis was performed on COVID-19 patients who were admitted to intensive care units (ICUs) between March 2020 and March 2021, and required mechanical ventilation. The primary outcome was the incidence of PICS physical impairment (Barthel Index≤90) after one year. Multivariate logistic regression analysis was used to estimate the association between early rehabilitation interventions and PICS physical impairment by adjusting ICU mobility scale (IMS) during seven-day following ICU admission, and clinically relevant risk factors. Results: The analysis included 259 patients, 54 of whom developed PICS physical impairment one year later. In 81 patients, physical therapists intervened within seven days of ICU admission. There was no significant difference in mean IMS by day seven of admission between the early and non-early rehabilitation patients (0.70 and 0.61, respectively). Multivariate logistic regression analysis showed that early rehabilitation interventions were significantly associated with a low incidence of PICS physical impairment (odds ratio, 0.294; 95% confidence interval, 0.123–0.706; p=0.006). Conclusion Early rehabilitation interventions by physical therapists were an independent factor associated with the decreased development of PICS physical impairment at one year, even though early rehabilitation had no significant effect on IMS.

Objective: To investigate an association between the gut microbiome and efficacy of poly(ADP-ribose) polymerase inhibitors (PARPi) in ovarian cancer. Methods: This study conducted fecal microbiome analysis (16S rRNA gene sequencing) and circulating tumor DNA (ctDNA) profiling for ovarian cancer patients who underwent PARPi maintenance therapy. Fecal and blood samples were collected at the baseline and the progressive disease (PD) or last follow-up. The relative abundance of gut microbes and progression-free survival (PFS) were analyzed using linear discriminant analysis of effect size and the Cox proportional hazard model according to BRCA1/2 mutation (BRCA1/2mut) status detected by ctDNA sequencing. Results: Baseline samples were available from 23 BRCA1/2mut-positive patients and 33 BRCA1/2mut-negative patients. The microbes enriched in the baseline samples with long PFS were Bifidobacterium, Roseburia, Dialister, Butyricicoccus, and Bilophila for BRCA1/2mut-positive patients and Phascolarctobacterium for BRCA1/2mut-negative patients. In multivariate analyses dividing patients by the median values of relative abundances, no bacteria were associated with PFS in BRCA1/2mut-positive patients, whereas high Phascolarctobacterium abundances (≥1.11%) was significantly associated with longer PFS in BRCA1/2mut-negative patients (median 14.0 vs. 5.9 months, hazard ratio=0.28; 95% confidence interval=0.11–0.69; p=0.014). In the last samples, the relative abundances of Phascolarctobacterium were significantly higher in patients without PD (n=5) than those with PD (n=15) (median 1.25% vs. 0.06%; p=0.016). Conclusion High fecal composition of Phascolarctobacterium was associated with prolonged PFS in patients with BRCA1/2mut-negative ovarian cancer receiving PARPi therapy. Our results would provide new insights for future research.

Background/Aims: Acute cholangitis (AC) is a potentially life-threatening bacterial infection, and timely antimicrobial treatment, faster than that achieved with bacterial cultures, is recommended.Although the current guidelines refer to empirical antimicrobial treatment, various kinds of antimicrobial agents have been cited because of insufficient analyses on the spectrum of pathogens in AC. Enterococcus spp. is one of the most frequently isolated Gram-positive bacteria from the bile of patients with AC, but its risk factors have not been extensively studied. This study aimed to analyze the risk factors of AC caused by Enterococcus faecalis and Enterococcus faecium. Methods: Patients with AC who were hospitalized in a Japanese tertiary center between 2010 and 2015 were retrospectively analyzed. Patients’ first AC episodes in the hospital were evaluated. Results: A total of 266 patients with AC were identified. E. faecalis and/or E. faecium was isolated in 56 (21%) episodes of AC. Prior endoscopic sphincterotomy (EST), the presence of a biliary stent, prior cholecystectomy, and past intensive care unit admission were more frequently observed in AC patients with E. faecalis and/orE. faecium than in those without such bacteria. Prior EST was identified as an independent risk factor for AC caused by E. faecalis and/or E. faecium in the multivariate analysis. Conclusions Given the intrinsic resistance of E. faecalis and E. faecium to antibiotics, clinicians should consider empirical therapy with anti-enterococcal antibiotics for patients with prior EST.

Background/Aims: Acute cholangitis (AC) is a potentially life-threatening bacterial infection, and timely antimicrobial treatment, faster than that achieved with bacterial cultures, is recommended.Although the current guidelines refer to empirical antimicrobial treatment, various kinds of antimicrobial agents have been cited because of insufficient analyses on the spectrum of pathogens in AC. Enterococcus spp. is one of the most frequently isolated Gram-positive bacteria from the bile of patients with AC, but its risk factors have not been extensively studied. This study aimed to analyze the risk factors of AC caused by Enterococcus faecalis and Enterococcus faecium. Methods: Patients with AC who were hospitalized in a Japanese tertiary center between 2010 and 2015 were retrospectively analyzed. Patients’ first AC episodes in the hospital were evaluated. Results: A total of 266 patients with AC were identified. E. faecalis and/or E. faecium was isolated in 56 (21%) episodes of AC. Prior endoscopic sphincterotomy (EST), the presence of a biliary stent, prior cholecystectomy, and past intensive care unit admission were more frequently observed in AC patients with E. faecalis and/orE. faecium than in those without such bacteria. Prior EST was identified as an independent risk factor for AC caused by E. faecalis and/or E. faecium in the multivariate analysis. Conclusions Given the intrinsic resistance of E. faecalis and E. faecium to antibiotics, clinicians should consider empirical therapy with anti-enterococcal antibiotics for patients with prior EST.

Primary penile melanomas are rare tumors that represent less than 0.1% of all melanomas. We report a case of a 60-year-old Japanese male with a mucosal penile melanoma and describe an increased CD8⁺ T cell infiltration in brain after dacarbazine (DTIC) administration. After partial penectomy and left inguinal lymphadenectomy, he developed multiple lung, bone, spleen, brain and skin metastases. He was treated with interferon-β, DTIC and nivolumab. However, the metastases were not reduced in size. Immunohistochemistry showed an increase of CD8⁺ T cell infiltration and programmed death-ligand 1 (PD-L1) expression after the administration of DTIC, but the expression of programmed cell death protein 1 (PD-1) was negative. We speculate that DTIC exerted immunostimulatory effects, but nivolumab was ineffective due to the negative expression of PD-1 and/or an insufficient infiltration of CD8⁺ T cells. Although this is only one case, this case report could be the first step to discuss the development of effective therapies against melanoma to take advantage of the increased CD8⁺ T cell infiltration elicited by chemotherapeutic agents. It would be beneficial to pay more attention to the relationship between DTIC and immune checkpoint modulators.
Asian Continental Ancestry Group ; Brain ; Cell Death ; Dacarbazine* ; Humans ; Immunohistochemistry ; Lung ; Lymph Node Excision ; Male ; Melanoma* ; Middle Aged ; Neoplasm Metastasis ; Skin ; Spleen ; T-Lymphocytes*

Enteric pathogens cause considerable public health concerns worldwide including tropical regions. Here, we review the roles of carbohydrates in the infection strategies of various enteric pathogens including viruses, bacteria and protozoa, which infect the epithelial lining of the human and animal intestine. At host cell entry, enteric viruses, including norovirus, recognize mainly histo-blood group antigens. At the initial step of bacterial infections, carbohydrates also function as receptors for attachment. Here, we describe the function of carbohydrates in infection by Salmonella enterica and several bacterial species that produce a variety of fimbrial adhesions. During invasion by enteropathogenic protozoa, apicomplexan parasites utilize sialic acids or sulfated glycans. Carbohydrates serve as receptors for infection by these microbes; however, their usage of carbohydrates varies depending on the microbe. On the surface of the mucosal tissues of the gastrointestinal tract, various carbohydrate moieties are present and play a crucial role in infection, representing the site of infection or route of access for most microbes. During the infection and/or invasion process of the microbes, carbohydrates function as receptors for various microbes, but they can also function as a barrier to infection. One approach to develop effective prophylactic and therapeutic antimicrobial agents is to modify the drug structure. Another approach is to modify the mode of inhibition of infection depending on the individual pathogen by using and mimicking the interactions with carbohydrates. In addition, similarities in mode of infection may also be utilized. Our findings will be useful in the development of new drugs for the treatment of enteric pathogens.

Enteric pathogens cause considerable public health concerns worldwideincluding the tropical regions. Here, we review the roles of carbohydrates inthe infection strategies of various enteric pathogens including viruses,bacteria and protozoa, which infect the epithelial lining of human and animalintestine. At host cell entry, enteric viruses, including norovirus, recognize mainlyhisto-blood group antigens. At the initial step of bacterial infections,carbohydrates also function as receptors for attachment. Here, we describe the functionsof carbohydrates in infection by Salmonellaenterica and several bacterial species that produce varieties of fimbrialadhesions. During invasion by enteropathogenic protozoa, apicomplexan parasitesutilize sialic acids or sulfated glycans. Carbohydrates serve as receptors forinfections by these microbes; however, the usage of carbohydrates by themvaries depending on the microbe. On the surface of the mucosal tissues of thegastrointestinal tracts, various carbohydrate moieties are present and playcrucial roles in infection, representing the site of infection or route ofaccess for most microbes. During the infectionand/or invasion processes of the microbes, carbohydrates function as receptorsfor various microbes, while they can also function as abarrier to infection. One approach to develop effective prophylactic and therapeutic antimicrobialagents is to modify the drug structure. Another approach is to modify the modeof inhibition of infection depending on the individual pathogen by using andmimicking these interactions with carbohydrate. In addition, similarities inmode of infection may also be utilized. Thesefindings we described are useful in development of the new drugs for treatmentsof enteric pathogens.

Saffron (Crocus sativus L.) is classified as a beneficial herb in the treatment of “Oketsu,” eliminating blood stagnation. The clinical symptoms of “Oketsu” include feeling cold and arthralgia. The pathological condition of “Oketsu” is considered to be increased blood viscosity and microvascular disorders.However, no useful biomarker has been reported for evaluation of the degree of “Oketsu.” Here, we investigated the clinical effect of saffron on the symptoms of “Oketsu” in patients with autoimmune diseases. At the same time, we measured the plasma levels of platelet factor 4 (PF-4) and beta-thromboglobulin (β-TG) as platelet activation markers. Seventy-one patients (66 women and 5 men, mean age 52.3 ± 16.1) were studied. They were administered saffron (300mg∼900mg) with traditional Kampo medicine. The clinical symptoms of “Oketsu” improved (80.9%, n=38/47) and we measured PF-4 and β-TG in pre-and post-saffron treatment periods. The plasma levels of PF-4 and β-TG significantly decreased after saffron therapy (PF-4 : before 49.6 ± 29.8, after 24.0 ± 19.6ng/ml, β-TG : before 117.5 ± 64.0, after 64.6 ± 47.1ng/ml;paired t-test, p < 0.0001, respectively). These results suggest that saffron is effective in treatment of the symptoms of “Oketsu” in allergy and collagen disease patients. Moreover, PF-4 and β-TG may be useful biomarkers of the degree of “Oketsu.”