A preliminary study on the development of care staff's Final-Stage Decision-Making Support Scale for older adults with dementia.

AIM: This preliminary study aimed to develop a care staff Final Life-Stage Decision-Making Support Scale (FS-DM) for older adults with dementia (OwDs) in geriatric facilities. METHODS: The FS-DM items were developed from focus group interviews with care staff and reviewed through discussions with several experts in dementia care. A questionnaire survey was conducted among care staff in geriatric facilities from February to March 2021. RESULTS: In total, 138 carers (110 [79.7%] women and 28 [20.3%] men, mean age: 41.5 ± 2.3 years) participated. Among them, 91 (65.9%) were professional caregivers, and 36 (26.1%) were nurses. The FS-DM was developed using a factor analysis, which resulted in 11 items grouped into three factors', as it is the three factors: (1) support for the realization of the wills of OwDs in their final life-stages through collaboration with families and multiple professionals; (2) consideration of communication regarding the formation and expression of the wills of OwDs in their final life-stages; and (3) support for eliciting the wills of OwDs during their final life-stages according to their decision-making ability and values. The factor loadings ranged from 0.385 to 0.827, and the accumulated contribution ratio was 61.03%. The reliability analysis yielded a Cronbach's α of 0.740-0.855. The first and second factors of the FS-DM were significantly correlated with the Approaches to Dementia Questionnaire item "Nurses' attitudes towards support for decision-making." CONCLUSION: Our results suggest that the FS-DM could provide supportive care for OwDs to formulate, express, and realize their will, and that it has a degree of reliability and validity. Geriatr Gerontol Int 2024; 24: 130-134.

A CCR4 antagonist attenuates atopic dermatitis-like skin inflammation by inhibiting the recruitment and expansion of Th2 cells and Th17 cells.

CCR4 is a major trafficking receptor for T-helper (Th) 2 cells and Th17 cells and is considered as a potential therapeutic target for atopic dermatitis (AD). The CCR4 ligands CCL17 and CCL22 have been reported to be upregulated in the skin lesions of AD patients. Of note, thymic stromal lymphopoietin (TSLP), a master regulator of the Th2 immune response, promotes the expression of CCL17 and CCL22 in AD skin lesions. Here, we investigated the role of CCR4 in an AD mouse model induced by MC903, a TSLP inducer. Topical application of MC903 to ear skin increased the expression of not only TSLP but also CCL17, CCL22, the Th2 cytokine IL-4, and the Th17 cytokine IL-17A. Consistently, MC903 induced AD-like skin lesions as shown by increased epidermal thickness; increased infiltration of eosinophils, mast cells, type 2 innate lymphoid cells, Th2 cells, and Th17 cells; and elevated serum levels of total IgE. We also found increased expansion of Th2 cells and Th17 cells in the regional lymph nodes (LNs) of AD mice. Compound 22, a CCR4 inhibitor, ameliorated AD-like skin lesions with reduction of Th2 cells and Th17 cells in the skin lesions and regional LNs. We further confirmed that compound 22 diminished the expansion of Th2 cells and Th17 cells in the coculture of CD11c+ dendritic cells (DCs) and CD4+ T cells derived from the regional LNs of AD mice. Collectively, CCR4 antagonists may exhibit anti-allergic effects by inhibiting both the recruitment and expansion of Th2 cells and Th17 cells in AD.

[Change in end-of-life care and staff thinking at a geriatric health services facility after the introduction of the "My Wishes" notebook].

AIM: A geriatric health services facility had been working to improve end-of-life care since 2014. In 2017, the facility introduced the My Wishes notebook, which confirms individual's medical choices and distributed the Explaining Practices and Intentions of End-of-life Care book in 2018, in order to help their staff improve care for older adults. Care staff used their learning in caregiving for older adults. This study aimed to clarify the change in end-of-life care and staff thinking at a geriatric health services facility after the introduction of the My Wishes notebook. METHODS: We requested cooperation from all care staff at a geriatric health services facility, and focus group interviews were conducted with 13 staff members over two days in June 2019. The responses in relation to two parameters, the staff members' thoughts and the change in end-of-life care, following the introduction of My Wishes were recorded and qualitatively analyzed. RESULTS: Six categories of responses were extracted from the qualitative analysis: "Difficulty in using My Wishes", "Effects of the use of My Wishes ", "The practice of sought care", "Intentional involvement with patients' families", "Self-confidence in end-of-life care", and "End-of-life care becoming common practice". CONCLUSION: After the introduction of My Wishes, the care staff found that there were difficulties in using My Wishes, such as writing on paper and difficulties in them hearing. On the other hand, they felt the effects of using My Wishes, such as knowing a new side, feeling further possibilities of care, and activating communication among interdisciplinary healthcare providers. Then, while intentionally engaging with patients' families, they will seek and practice the care that the older adults want. Furthermore, while repeatedly searching for and practicing the care that older adults want, they will gain confidence in providing care and change to normalize these care practices.

Care Staff's Daily Living Decision-Making Support Scale for Older Adults with Dementia in Japan: Development of Validity and Reliability.

This study aimed to develop and validate a scale to assess the daily-living decision-making support of care staff for older adults with dementia (OwDs) in Japan. A questionnaire survey was conducted among 138 care staff at two geriatric healthcare facilities from February to March 2021. The Daily Living Decision-Making Support Scale for Older Adults with Dementia (DL-DM) was developed using item analysis, factor analysis, and covariance structure analysis. The factor analysis yielded 12 items and three factors: (1) support for the formation and expression of intentions in daily life based on the life background and values of OwDs; (2) attitudes and devising ways to communicate regarding the formation and expression of intentions in OwDs daily lives; and (3) devising ways to support OwDs in realizing their intentions in daily life. The internal consistency reliability analysis yielded a Cronbach's α of 0.87 for the total scale. The DL-DM correlated with the concurrent validity measures as expected. The DL-DM demonstrated validity and reliability as a potential scale to assess support for OwDs in daily life decision-making. The results also suggest an association between the DL-DM and person-centered care for OwDs.

[Decision-making support for elderly individuals with dementia in a geriatric health service facility: A questionnaire survey on concrete care methods to draw wills of individuals].

PURPOSE: The purpose of this study was to clarify the care methods used by healthcare staff in service facilities to draw up wills for elderly individuals with dementia in daily life and the final stage in decision-making support. METHODS: A questionnaire survey was conducted among healthcare staff in a geriatric health service facility in August 2020. RESULTS: There were 45 subjects (16 males [35.6%]; 29 females [64.4%]). The average age was 42.2 (±12.3) years old, and the mean number of years of experience in a geriatric health service facility was 17.4 (±10.7) years. Deathbed care was provided to ≥90% of the subjects. A factor analysis of items related to decision making in elderly individuals with dementia revealed the first factor to be "support and communication to draw wills", the second factor to be "support and communication for expression to realize decision making", and the third factor to be "understanding, communication, and family support for decision-making realization." The totals of each of these three factors and "having confidence in care focusing on the viewpoint of elderly individuals with dementia" were significantly different. The correction between the Personhood of Approaches to Dementia Questionnaire Japanese version and the three subscales of decision making in elderly individuals with dementia had a significant coefficient of correlation. CONCLUSION: More polite communication methods are necessary for the formation, expression, and realization of the intentions of elderly individuals with dementia to support their decision making.

Anti-allergic effect of ascorbic acid derivative DDH-1 in a mouse model of atopic dermatitis.

Atopic dermatitis (AD) is the most common inflammatory skin disease, which is characterized by excessive Th2 immune responses. In AD patients, the expression of the chemokines CCL17 and CCL22 is increased in skin lesions, leading to the infiltration of Th2 cells. In addition, typical pro-inflammatory cytokines, including TNF-α, IL-1ß and IL-6, have also been shown to be associated with the pathogenesis of AD. Recently, DDH-1, an ascorbic acid derivative, has been synthesized and demonstrated to have a more stabilized structure and better skin penetrability. Furthermore, DDH-1 has been shown to suppress pro-inflammatory cytokine expression in vitro and in vivo. Therefore, using an AD mouse model, we evaluated the effect of DDH-1 to reduce allergic skin inflammation. We found that cutaneous administration of DDH-1 significantly reduced the expression levels of TNF-α, IL-1ß and IL-6 in the skin lesions of AD-like mice. Additionally, DDH-1 administration also significantly reduced the expression levels of CCL17 and CCL22, resulting in decreased skin infiltration of Th2 cells. Consequently, DDH-1 reduced ear and epidermal thickness, the serum IgE levels and the number of infiltrating inflammatory cells and mast cells into the AD-like skin lesions. Combination treatment with DDH-1 and corticosteroid more efficiently improved the skin lesions compared with corticosteroid alone. Collectively, our results suggest that DDH-1 has an anti-allergic effect in an AD mouse model by reducing not only the pro-inflammatory cytokine expression but also the Th2-associated chemokine expression. Thus, DDH-1 may be beneficial for AD treatment and prevention as a monotherapy or in combination with corticosteroids.

Role of phlebotomy in the treatment of liver damage related to erythropoietic porphyria.

Liver damage affects the prognosis of patients with erythropoietic protoporphyria (EPP). However, there is no radical cure for EPP patients with severe liver damage. This study aims to investigate the effectiveness of phlebotomy in patients with severe liver damage. We examined seven patients diagnosed with EPP and liver damage between 2010 and 2020. Of the 7 cases, phlebotomy was performed in 3 cases with severe hepatic disorder, and the improvement effect of hepatic disorder was observed in all cases. In addition, as an additional study, we also investigated the mechanism by which liver damage becomes more severe. Liver biopsy samples were stained with hematoxylin and eosin and immunohistochemistry was used to examine the expression of adenosine triphosphate-binding transporter G2 (ABCG2). Liver biopsies were performed in 3 of 7 patients with EPP. Of these three patients, ABCG2 expression was low in two patients, especially in the protoporphyrin (PP) deposition area. Two patients with reduced ABCG2 expression subsequently developed severe liver damage. However, the causal relationship between the decreased expression of ABCG2 and the exacerbation of liver damage has not been directly proved, and further investigation is required in the future. This study demonstrated the effectiveness of phlebotomy in EPP patients with severe liver damage.

Effectiveness of Lee Silverman Voice Treatment® LOUD on Japanese-Speaking Patients with Parkinson's Disease.

Background. Lee Silverman Voice Treatment® LOUD (LSVT®) is an intensive program devised in the United States to train patients with Parkinson's disease (PD) to speak louder, at normal intensity, while keeping a good voice quality. Four weeks of LSVT® has been shown to increase vocal loudness and improve intelligibility among Japanese-speaking PD patients. However, the long-term effects of LSVT® have not been examined in these patients. Objective. This study aimed to investigate the long-term effects of LSVT® on Japanese-speaking PD patients. Methods. Twenty-one Japanese PD patients underwent a standardized course (four sessions over four consecutive days, for four weeks) of LSVT® at our hospital. Vocal loudness and intelligibility were assessed at the following three time-points: pretreatment (baseline), immediately after treatment, and at the end of the 12 month follow-up (12FU). Sound pressure levels (dB SPL) were measured during the following tasks: sustained phonation of /a/, reading a standardized text, and delivery of a monologue. Three experienced speech-language pathologists, who were blinded to patients' identities and assessment points, assessed speech intelligibility based on recorded audio samples of each participant during the reading and monologue tasks. Results. Fourteen patients were evaluated at 12FU. Changes in dB SPL from baseline to immediately after treatment were +6.5 dB, +4.2 dB, and +2.8 dB, and those from baseline until 12FU were +4.7 dB, +3.5 dB, and +2.5 dB in sustained phonation of /a/, reading a passage, and delivery of a monologue, respectively. These changes were significant (p < 0.025) in both the baseline-to-immediately-after-treatment and baseline-to-12FU intervals. Intelligibility relative to baseline was significantly improved immediately after treatment, but not at 12FU. Conclusions. LSVT® had a long-term effect on the vocal loudness of Japanese-speaking PD patients. A short-term effect was seen in intelligibility, however, there was no significant long-term effect.

Analysis of key clinical features for achieving complete remission in stage III and IV non-small cell lung cancer patients.

BACKGROUND: Although development of immune checkpoint inhibitors and various molecular target agents has extended overall survival time (OS) in advanced non-small cell lung cancer (NSCLC), a complete cure remains rare. We aimed to identify features and treatment modalities of complete remission (CR) cases in stages III and IV NSCLC by analyzing long-term survivors whose OS exceeded 3 years. METHODS: From our hospital database, 1,699 patients, registered as lung cancer between 1st Mar 2004 and 30th Apr 2011, were retrospectively examined. Stage III or IV histologically or cytologically confirmed NSCLC patients with chemotherapy initiated during this period were enrolled. A Cox proportion hazards regression model was used. Data collection was closed on 13th Feb 2017. RESULTS: There were 164 stage III and 279 stage IV patients, including 37 (22.6%) and 51 (18.3%) long-term survivors and 12 (7.3%) and 5 (1.8%) CR patients, respectively. The long-term survivors were divided into three groups: 3 ≤ OS < 5 years, 5 years ≤ OS with tumor, and 5 years ≤ OS without tumor (CR). The median OS of these groups were 1,405, 2,238, and 2,876 days in stage III and 1,368, 2,503, and 2,643 days in stage IV, respectively. The mean chemotherapy cycle numbers were 16, 20, and 10 in stage III and 24, 25, and 5 in stage IV, respectively. In the stage III CR group, all patients received chemoradiation, all oligometastases were controlled by radiation, and none had brain metastases. Compared with non-CR patients, the stage IV CR patients had smaller primary tumors and fewer metastases, which were independent prognostic factors for OS among long-term survivors. The 80% stage IV CR patients received radiation or surgery for controlling primary tumors, and the surgery rate for oligometastases was high. Pathological findings in the stage IV CR patients revealed that numerous inflammatory cells existed around and inside resected lung and brain tumors, indicating strong immune response. CONCLUSIONS: Multiple line chemotherapies with primary and oligometastatic controls by surgery and/or radiation might achieve cure in certain advanced NSCLC. Cure strategies must be changed according to stage III or IV. This study was retrospectively registered on 16th Jun 2019 in UMIN Clinical Trials Registry (number UMIN000037078).

Did kindergarteners who experienced the Great East Japan earthquake as infants develop traumatic symptoms? Series of questionnaire-based cross-sectional surveys: A concise and informative title: traumatic symptoms of kindergarteners who experienced disasters as infants.

BACKGROUND: The Great East Japan Earthquake (GEJE) and tsunami of March 11, 2011 left behind many survivors, including children. This study aimed to assess changes in traumatic symptoms with time among kindergarteners who experienced GEJE as infants and to discuss the relationship between these symptoms and the disaster experience. METHODS: The 15-item Post-Traumatic Stress Symptoms for Children (PTSSC-15) questionnaire were distributed to the parents of kindergarteners (children aged 4-5 years) at 8, 20, 30, and 42 months after GEJE. Questionnaires regarding environmental damage conditions affecting the children were distributed to teachers 8 months after the tsunami. RESULTS: The number of kindergarteners was 262, 255, 236, and 202 at 8, 20, 30, and 42 months after the disaster. The PTSSC-15 total score was not different between kindergartners with and without environmental damage conditions. After 8 and 20 months, the PTSSC-15 total score of children who usually ate breakfast was significantly higher than that of children who did not. Moreover, after 30 and 42 months, the PTSSC-15 total score of kindergarteners who usually ate breakfast was not significantly higher than that of kindergarteners who did not. CONCLUSIONS: The traumatic symptoms of kindergarteners were not related to disaster experiences.

External dose evaluation based on detailed air dose rate measurements in living environments.

A method was devised to estimate the realistic external doses of residents expected to return to their homes after evacuation orders are lifted. For 196 residents expected to return to six towns and villages, surveys were administered in FY 2014-2016. After interviewing residents about their expected life patterns after their return, detailed air dose rate measurements were taken along their reported personal routes representing patterns of movement in their daily life. The maximum and average annual additional external effective dose were estimated at 4.9 mSv and 0.86 mSv, respectively. Although the mean values and dispersion of external effective doses differed depending on the level of evacuation, for 93.3% of all residents, the estimated annual additional external effective doses were less than 2 mSv. Measuring air dose rates inside houses was found to be important to obtain a realistic evaluation of the external exposure dose because our research revealed that the average time spent indoors was 87% of the total living time. Moreover, the average exposure dose at home accounted for 66.8% of the annual exposure dose.

Prevalence of Rapid Eye Movement-related Obstructive Sleep Apnea in Adult Narcolepsy.

Objective The association between narcolepsy and rapid eye movement (REM)-related obstructive sleep apnea (OSA) has not been reported. This study aimed to examine the prevalence of REM-related OSA in narcolepsy patients. Methods From January 2013 to April 2018, 141 adult patients were diagnosed with narcolepsy using nocturnal polysomnography and the multiple sleep latency test. The prevalence of REM-related OSA in narcolepsy patients was retrospectively reviewed. Three criteria were used to determine REM-related OSA: Definition #1, an overall apnea-hypopnea index (AHI) ≥5 and AHI during REM (AHIREM)/AHI during non-rapid eye movement (NREM) (AHINREM) ≥2; Definition #2, an overall AHI ≥5 and AHIREM/AHINREM≥2 and AHINREM <15; and Definition #3, an overall AHI ≥5 and AHIREM/AHINREM≥2 and AHINREM <8 plus an REM sleep duration >10.5 minutes. Results Of the 141 narcolepsy patients, 26 were diagnosed with narcolepsy with cataplexy (NA-CA) and 115 with narcolepsy without cataplexy (NA w/o CA). Seventeen patients with NA-CA and 39 with NA w/o CA had OSA. According to Definition #1, the prevalence of REM-related OSA was 47.1% and 41.0%, respectively, in OSA patients with NA-CA and NA w/o CA; according to Definition #2, the respective prevalence was 47.1% and 38.5%, while that according to Definition #3 was 41.2% and 25.6%. No significant differences were found in the prevalence of REM-related OSA for each definition. Conclusion A high prevalence of REM-related OSA was confirmed in adult narcolepsy patients with OSA. Compared to previous reports, we noted a high frequency of REM-related OSA satisfying the relatively strict Definition #3. These results might reflect the pathophysiological characteristics of narcolepsy.

Recessive Resistance Governed by a Major Quantitative Trait Locus Restricts Clover Yellow Vein Virus in Mechanically but Not Graft-Inoculated Cultivated Soybeans.

Clover yellow vein virus (ClYVV) infects and causes disease in legume plants. However, here, we found that ClYVV isolate No. 30 (ClYVV-No.30) inefficiently multiplied or spread via cell-to-cell movement in mechanically inoculated leaves of a dozen soybean (Glycine max) cultivars and resulted in failure to spread systemically. Soybean plants also had a similar resistance phenotype against additional ClYVV isolates. In contrast, all but one of 24 tested accessions of wild soybeans (G. soja) were susceptible to ClYVV-No.30. Graft inoculation of cultivated soybean TK780 with ClYVV-No.30-infected wild soybean B01167 scion resulted in systemic infection of the cultivated soybean rootstock. This suggests that, upon mechanical inoculation, the cultivated soybean inhibits ClYVV-No.30, at infection steps prior to the systemic spread of the virus, via vascular systems. Systemic infection of all F1 plants from crossing between TK780 and B01167 and of 68 of 76 F2 plants with ClYVV-No.30 indicated recessive inheritance of the resistance. Further genetic analysis using 64 recombinant inbred lines between TK780 and B01167 detected one major quantitative trait locus, designated d-cv, for the resistance that was positioned in the linkage group D1b (chromosome 2). The mapped region on soybean genome suggests that d-cv is not an allele of the known resistance genes against soybean mosaic virus.

Hormonal Therapy Resistant Estrogen-receptor Positive Metastatic Breast Cancer Cohort (HORSE-BC) Study : Current Status of Treatment Selection in Japan.

The Hormonal therapy resistant estrogen-receptor positive metastatic breast cancer cohort (HORSE-BC) study is a multicenter observational study evaluating the efficacy and safety of secondary endocrine therapy (ET) for postmenopausal cases of metastatic breast cancer (MBC) with poor response to primary ET. In this initial report we analyze the HORSE-BC baseline data to clarify the current status of treatment selection for MBC in Japan. Baseline data for the 50 patients enrolled in HORSE-BC were analyzed, including patient characteristics, types of secondary ET, and reasons for selecting secondary ET. Postoperative recurrence was detected in 84% of patients (42/50) and de novo stage IV breast cancer in 16% (8/50). Forty-one patients (41/50; 82%) received fulvestrant, 5 patients (10%) received selective estrogen receptor modulators (SERMs), 3 patients (6%) received ET plus a mammalian target of rapamycin (mTOR) inhibitor, and 1 patient received an aromatase inhibitor (AI) as the secondary ET. Forty-five patients selected their secondary ET based on its therapeutic effect, while 14 patients selected it based on side effects. Most patients with progression after primary ET selected fulvestrant as the secondary ET based on its therapeutic and side effects. We await the final results from the HORSE-BC study.

Dysphagia Causes Symptom Fluctuations after Oral L-DOPA Treatment in a Patient with Parkinson Disease.

OBJECTIVE: The causes of "delayed-on" and "no-on" phenomena in Parkinson disease (PD) are thought to have some impact on the progress of L-DOPA from the time of ingestion until it reaches the brain and is converted to dopamine. Dysphagia can cause fluctuating symptom expression in L-DOPA therapy for PD. CASE DESCRIPTION: A 69-year-old man with PD presented with "delayed-on" and "no-on" phenomena. The patient developed a gait disorder at age 60 years, and he began coughing on his food during breakfast at age 64 years. Even though he was independent in daily life, he could not eat because of dysphagia in an "off" state. Videofluoroscopic examination of swallowing in an "off" state revealed bradykinesia of the tongue and the retention of tablets in the epiglottic vallecula. We trained him to keep his tongue in strong contact with the upper incisors before swallowing. After rehabilitation of dysphagia, the frequency of "delayed-on" and "no-on" phenomena decreased, and his peak L-DOPA plasma concentration was elevated. Additionally, transdermal rotigotine (RTG) was initiated at a maintenance dose of 9.0 mg. The patient reported improvement in swallowing, and the frequency of "no-on" phenomena decreased. CONCLUSION: In PD patients, the "no-on" phenomenon can be caused by posterior contractile dysfunction of the tongue, and it can be improved with training of the tongue and transdermal RTG administration.

Bi-weekly eribulin therapy for metastatic breast cancer: a multicenter phase II prospective study (JUST-STUDY).

BACKGROUND: This study aimed to investigate whether schedule modification is safe and effective in patients intolerant to the standard eribulin dose and schedule. METHODS: Patients with metastatic breast cancer (MBC) treated with both anthracycline and taxane and ≤ 3 prior regimens of chemotherapy for MBC received eribulin at the standard dose and schedule (1.4 mg/m2 on days 1 and 8 of a 21-day cycle) in the first cycle; change of dosing schedule (1.4 mg/m2 on days 1 and 15 of a 28-day cycle) was determined by change in neutrophil count, platelet count, aspartate aminotransferase, alanine aminotransferase, total bilirubin, serum creatinine, and non-hematological toxicity on day 8 of the first cycle or day 1 of the second cycle. Clinical benefit rate (CBR; primary endpoint), time to treatment failure (TTF), overall survival (OS), and safety were evaluated. RESULTS: Of the 88 patients who were enrolled and received standard eribulin therapy in the first cycle, 42 patients were moved to the bi-weekly therapy group and 40 continued standard therapy. In the bi-weekly and standard therapy groups, mean relative dose intensity was 62.7 and 90.9%, CBR was 31.0 and 25.0%, median TTF was 81.5 and 75 days, and OS was 523 and 412 days, respectively. Neither group reported severe adverse events. CONCLUSION: This is the first study to show that a bi-weekly eribulin schedule is tolerable and has comparable efficacy in patients intolerant to the standard eribulin schedule. CLINICAL TRIAL REGISTRATION: University Hospital Medical Information Network (UMIN) Center (ID: UMIN 000008491).

The therapeutic candidate for immune checkpoint inhibitors elucidated by the status of tumor-infiltrating lymphocytes (TILs) and programmed death ligand 1 (PD-L1) expression in triple negative breast cancer (TNBC).

BACKGROUND: The status of tumor-infiltrating lymphocytes (TILs) is a prognostic factor for triple negative breast cancer (TNBC). Recent studies have shown that programmed cell death 1 (PD-1) or programmed death ligand 1 (PD-L1) is expressed on T lymphocytes or tumor cells modulating antitumor immunity. The regulation of immune checkpoints between tumor cells and T lymphocytes may serve as a target for improvement of TNBC prognosis. We investigated TILs and PD-L1 status in TNBCs before or after preoperative systemic therapy (PST) to elucidate the clinical significance of PD-L1 expression. METHODS: Ninety patients received PST, and materials of core needle biopsies (CNB) taken before PST were available for 32 patients. TILs were scored as "% stromal", and tumors were defined as High-TILs (≥30%) or Low-TILs (<30%). The expression of PD-L1 was assessed by immunohistochemistry. RESULTS: TILs status in CNB is significant in pathological therapeutic grade: 1 vs. 2 or 3 (p = 0.0359). Disease-free survival (DFS) in patients with Low-TIL tumors were significantly worse than those with High-TIL tumors (p = 0.0383), but overall survival (OS) showed no significance (p = 0.0772). However, in patients with Low-TIL tumors, both DFS and OS in patients with High-PD-L1 expression were extremely unfavorable than in patients with Low-PD-L1 expression (p = 0.0032, p = 0.0002). CONCLUSION: The patients with TNBCs with combined Low-TILs and High-PD-L1 status in pre-PST situation showed unfavorable prognosis. The subset of TNBCs with Low-TILs and High-PD-L1 status could be the therapeutic target for immune checkpoint inhibitor.

rgs-CaM Detects and Counteracts Viral RNA Silencing Suppressors in Plant Immune Priming.

Primary infection of a plant with a pathogen that causes high accumulation of salicylic acid in the plant typically via a hypersensitive response confers enhanced resistance against secondary infection with a broad spectrum of pathogens, including viruses. This phenomenon is called systemic acquired resistance (SAR), which is a plant priming for adaption to repeated biotic stress. However, the molecular mechanisms of SAR-mediated enhanced inhibition, especially of virus infection, remain unclear. Here, we show that SAR against cucumber mosaic virus (CMV) in tobacco plants (Nicotiana tabacum) involves a calmodulin-like protein, rgs-CaM. We previously reported the antiviral function of rgs-CaM, which binds to and directs degradation of viral RNA silencing suppressors (RSSs), including CMV 2b, via autophagy. We found that rgs-CaM-mediated immunity is ineffective against CMV infection in normally growing tobacco plants but is activated as a result of SAR induction via salicylic acid signaling. We then analyzed the effect of overexpression of rgs-CaM on salicylic acid signaling. Overexpressed and ectopically expressed rgs-CaM induced defense reactions, including cell death, generation of reactive oxygen species, and salicylic acid signaling. Further analysis using a combination of the salicylic acid analogue benzo-(1,2,3)-thiadiazole-7-carbothioic acid S-methyl ester (BTH) and the Ca2+ ionophore A23187 revealed that rgs-CaM functions as an immune receptor that induces salicylic acid signaling by simultaneously perceiving both viral RSS and Ca2+ influx as infection cues, implying its autoactivation. Thus, secondary infection of SAR-induced tobacco plants with CMV seems to be effectively inhibited through 2b recognition and degradation by rgs-CaM, leading to reinforcement of antiviral RNA silencing and other salicylic acid-mediated antiviral responses.IMPORTANCE Even without an acquired immune system like that in vertebrates, plants show enhanced whole-plant resistance against secondary infection with pathogens; this so-called systemic acquired resistance (SAR) has been known for more than half a century and continues to be extensively studied. SAR-induced plants strongly and rapidly express a number of antibiotics and pathogenesis-related proteins targeted against secondary infection, which can account for enhanced resistance against bacterial and fungal pathogens but are not thought to control viral infection. This study showed that enhanced resistance against cucumber mosaic virus is caused by a tobacco calmodulin-like protein, rgs-CaM, which detects and counteracts the major viral virulence factor (RNA silencing suppressor) after SAR induction. rgs-CaM-mediated SAR illustrates the growth versus defense trade-off in plants, as it targets the major virulence factor only under specific biotic stress conditions, thus avoiding the cost of constitutive activation while reducing the damage from virus infection.

Post-bronchoscopy pneumonia in patients suffering from lung cancer: Development and validation of a risk prediction score.

BACKGROUND: The incidence, risk factors, and consequences of pneumonia after flexible bronchoscopy in patients with lung cancer have not been studied in detail. METHODS: We retrospectively analyzed the data from 237 patients with lung cancer who underwent diagnostic bronchoscopy between April 2012 and July 2013 (derivation sample) and 241 patients diagnosed between August 2013 and July 2014 (validation sample) in a tertiary referral hospital in Japan. A score predictive of post-bronchoscopy pneumonia was developed in the derivation sample and tested in the validation sample. RESULTS: Pneumonia developed after bronchoscopy in 6.3% and 4.1% of patients in the derivation and validation samples, respectively. Patients who developed post-bronchoscopy pneumonia needed to change or cancel their planned cancer therapy more frequently than those without pneumonia (56% vs. 6%, p<0.001). Age ≥70 years, current smoking, and central location of the tumor were independent predictors of pneumonia, which we added to develop our predictive score. The incidence of pneumonia associated with scores=0, 1, and ≥2 was 0, 3.7, and 13.4% respectively in the derivation sample (p=0.003), and 0, 2.9, and 9.7% respectively in the validation sample (p=0.016). CONCLUSIONS: The incidence of post-bronchoscopy pneumonia in patients with lung cancer was not rare and associated with adverse effects on the clinical course. A simple 3-point predictive score identified patients with lung cancer at high risk of post-bronchoscopy pneumonia prior to the procedure.