Functional outcomes for speech-in-noise intelligibility of NAL-NL2 and DSL v.5 prescriptive fitting rules in hearing aid users.

PURPOSE: The primary aim of this research study is to assess whether differences exist in the application of the NAL-NL2 and DSL v.5 prescription formulas in terms of speech-in-noise intelligibility. METHODS: Data from 43 patients, were retrospectively evaluated and analyzed. Inclusion criteria were patients with bilateral conductive, sensorineural, or mixed hearing loss, already using hearing aids for at least 1 year, and aged 18 years or older. Patients were categorized into two groups based on the prescriptive method employed by the hearing aid: NAL-NL2 or DSL v.5. Pure tone audiometry, speech audiometry, free field pure tone and speech audiometry with the hearing aid, and Matrix sentence test were performed. The Abbreviated Profile of Hearing Aid Benefit (APHAB) questionnaire was used to assess the personal audiological benefit provided by the hearing aid. RESULTS: No statistically significant differences were found comparing the free-field pure tone average (FF PTA) and the free-field Word Recognition Score (FF WRS). Comparing the Speech Reception Threshold (SRT) parameter of patients with NAL-NL2 vs DSL v.5, no statistically significant difference was found, thus highlighting a condition of comparability between the two prescription methods in terms of speech-in-noise intelligibility. Comparing the results of the APHAB questionnaire, no statistically significant differences were evident for all subscales and overall benefit. When conducting a comparison between male and female patients using the NAL-NL2 method, no differences were observed in SRT values, however, the APHAB questionnaire revealed a difference in the AV subscale score for the same subjects. CONCLUSION: Our analysis revealed no statistically significant differences in speech-in-noise intelligibility, as measured by the SRT values from the Matrix Sentence Test, when comparing the two prescriptive methods. This compelling result reinforces the notion that, functionally, both methods are comparably effective in enhancing speech intelligibility in real-world, noisy environments. However, it is crucial to underscore that the absence of differences does not diminish the importance of considering individual patient needs and preferences in the selection of a prescriptive method.

Identification and Transcriptome Analysis of a Novel Allelic Mutant of NAL1 in Rice.

Leaf morphology is a crucial aspect of plant architecture, yet the molecular mechanisms underlying leaf development remain incompletely understood. In this study, a narrow leaf mutant, m625, was identified in rice (Oryza sativa L.), exhibiting pleiotropic developmental defects. Pigment measurement revealed reduced levels of photochromic pigments in m625. Cytological analysis demonstrated that the m625 gene affected vascular patterns and cell division. Specifically, the narrowing of the leaf was attributed to a decrease in small vein number, shorter vein spacing, and an abnormal V-shaped arrangement of bulliform cells, while the thickening was caused by longer leaf veins, thicker mesophyll cells, and an increased number of parenchyma cell layers. The dwarf stature and thickened internode were primarily due to shortened internodes and an increase in cell layers, respectively. Positional cloning and complementation assays indicated that the m625 gene is a novel allele of NAL1. In the m625 mutant, a nucleotide deletion at position 1103 in the coding sequence of NAL1 led to premature termination of protein translation. Further RNA-Seq and qRT-PCR analyses revealed that the m625 gene significantly impacted regulatory pathways related to IAA and ABA signal transduction, photosynthesis, and lignin biosynthesis. Moreover, the m625 mutant displayed thinner sclerenchyma and cell walls in both the leaf and stem, particularly showing reduced lignified cell walls in the midrib of the leaf. In conclusion, our study suggests that NAL1, in addition to its known roles in IAA transport and leaf photosynthesis, may also participate in ABA signal transduction, as well as regulate secondary cell wall formation and sclerenchyma thickness through lignification.

Diagnostic value of [99mTc]Tc-PSMA-I&S-SPECT/CT for the primary staging and restaging of prostate cancer.

Background: A large number of studies have proved that prostate-specific membrane antigen-positron emission tomography/computer tomography (PSMA-PET/CT) provides excellent accuracy in primary staging and restaging of prostate cancer. Less data exist with PSMA-single photon emission computed tomography (SPECT)/CT investigations. Objective: The aim of this study was to evaluate the performance of [99mTc]Tc-PSMA-I&S (for imaging and surgery) in prostate cancer. Design and methods: We retrospectively analysed PSMA-SPECT/CT scans of 20 healthy volunteers and 100 male patients with prostate cancer. All of them had histologically confirmed prostate cancer. In all, 28 patients were examined for primary staging and 72 for biochemical recurrence or progressive disease. Whole body SPECT/CT imaging was carried out 6 h after the intravenous administration of 666 ± 102 MBq [99mTc]Tc-PSMA-I&S. Images were evaluated visually and semi-quantitatively. Results: Patient-based sensitivity, specificity, positive predictive value, negative predictive value and accuracy for primary prostate cancer were 86%, 100%, 100%, 83% and 92%, respectively. For detecting metastases in primary staging, these values were 88%, 100%, 100%, 85% and 93%, respectively. The radiopharmaceutical uptake of primary prostate cancer was significantly higher than in normal prostate. The patient-based sensitivity, specificity, positive predictive value, negative predictive value and accuracy of the method in the visualization of local recurrence were 67%, 100%, 100%, 86% and 89%, and for detecting metastases in restaging were 91%, 92%, 98%, 75% and 91%, respectively. In restaging, detection rates were 37% under prostate-specific antigen level of 1 ng/mL, 74% between 1 and 5 ng/mL and 80% >5 ng/mL. Conclusion: [99mTc]Tc-PSMA-I&S-SPECT/CT can be easily integrated into the routine diagnostic practice, and it provides usable data in primary staging and restaging of prostate cancer. Quantitative assessment of PSMA-SPECT/CT has the potential to be used to differentiate between physiological and pathological intraprostatic tracer uptake.

Is There Room for Liposomal Irinotecan in Biliary Tract Cancer? A Meta-analysis of Randomised Trials.

AIMS: The combination of 5-fluorouracil/leucovorin (5-FU/LV) plus oxaliplatin (FOLFOX) is widely acknowledged as the standard regimen for second-line treatment in patients with advanced biliary tract cancer. Nanoliposomal irinotecan (nal-IRI) has demonstrated its activity in patients with advanced pancreatic cancer. Recent studies have investigated the activity of nal-IRI in combination with 5-FU/LV for biliary tract cancer. However, the results have been contradictory. We conducted a meta-analysis to assess survival outcomes and response rates in randomised trials investigating the activity of nal-IRI in previously treated biliary tract cancer patients. MATERIALS AND METHODS: We systematically collected potentially relevant findings from PubMed/Medline, the Cochrane library and EMBASE. Abstracts presented at major international oncological meetings were also reviewed. We extracted hazard ratios and 95% confidence intervals for progression-free survival and overall survival, as well as odds ratios and 95% confidence intervals for objective response rate. The outcomes of the accessible randomised studies evaluating the activity of nal-IRI plus 5-FU/LV were analysed. RESULTS: The combination therapy exhibited a statistically significant decrease in the risk of progression (hazard ratio 0.70; 95% confidence interval 0.50-0.97) when compared with 5-FU/LV alone. Additionally, the dual regimen yielded longer overall survival and a higher objective response rate. CONCLUSION: Our meta-analysis showed that nal-IRI plus 5-FU/LV had a superior activity in comparison with 5-FU/LV. Further investigations are required to elucidate the role of nal-IRI in this setting and to identify subgroups of patients who could derive the greatest benefit from its administration.

Interculturalidad e infancia rural: trabajo y cuidado en La Araucanía, Chile / Interculturality and rural childhood: work and care in La Araucanía, Chile

(analítico) Desde una mirada intercultural, se exploraron los significados de infancia en la agricultura familiar campesina, así como sus implicaciones en términos de trabajo y provisión de cuidados a niños y niñas. A partir de la tensión entre los significados universales de infancia basados en un enfoque de derechos y el trabajo en el campo del cual participan las personas desde temprana edad, se realizó un estudio cualitativo con diseño de teoría fundamentada y aplicación de entrevistas a mujeres cuidadoras y profesionales de programas de desarrollo rural en Chile. Se evidenció que a medida que la infancia aumenta en actoría social, disminuyen las prácticas de trabajo y se profundizan las de cuidado. Los resultados alientan a pensar en la proyección de una ontología de la niñez rural.

(analytical) Using an intercultural perspective, this study explores the meanings of childhood in the rural peasant population, as well as the implications of these meanings on the allocation of tasks and providing care to boys and girls. Taking into account the tension between universal meanings of childhood that draw on rights-based perspectives and the traditional practice of children working in agriculture, we conducted a qualitative study using a grounded theory methodology. Interviews were conducted with women caregivers and staff who work in rural development programs in Chile. The study's results show that as childhood has had an increasing value with children becoming more and more recognized as social actors, traditional child work practices in agriculture have decreased and care practices have been strengthened. The author concludes that the results of the research have consequences when thinking about an ontology for rural children.

(analítico) A partir de uma perspectiva intercultural, exploramos os significados da infância entre famílias voltadas para agricultura familiar camponesa, bem como suas implicações em termos de trabalho e prestação de cuidados às meninos e meninas. Considerando a tensão existente entre os significados universais da infância a partir de uma abordagem de direitos e o trabalho no campo, no qual as pessoas se engajam desde muito cedo, realizamos um estudo qualitativo, com base na teoria fundamentada, onde realizamos entrevistas com mulheres cuidadoras e profissionais dos programas de desenvolvimento rural no Chile. Evidenciamos que à medida que a infância adquiriu um valor ao nível da atuação social, as práticas de trabalho diminuíram e as práticas de cuidado se aprofundaram. Conclui-se sobre as consequências dos resultados para pensar uma ontologia da infância rural.

Identification of Genomic Regions for Deep-Water Resistance in Rice for Efficient Weed Control with Reduced Herbicide Use.

Deep-water (DW) management in rice fields is a promising technique for efficient control of paddy weeds with reduced herbicide use. Maintaining a water depth of 10-20 cm for several weeks can largely suppress the weed growth, though it also inhibits rice growth because the DW management is usually initiated immediately after transplanting. Improving the DW resistance of rice during the initial growth stage is essential to avoid suppressing growth. In this study, we demonstrate a large genetic variation in the above-ground biomass (AGB) after the end of DW management among 165 temperate japonica varieties developed in Japan. Because the AGB closely correlated with plant length (PL) and tiller number (TN) at the early growth stage, we analyzed genomic regions associated with PL and TN by conducting a genome-wide association study. For PL, a major peak was detected on chromosome 3 (qPL3), which includes a gene encoding gibberellin biosynthesis, OsGA20ox1. The rice varieties with increased PL had a higher expression level of OsGA20ox1 as reported previously. For TN, a major peak was detected on chromosome 4 (qTN4), which includes NAL1 gene associated with leaf morphological development and panicle number. Although there was less difference in the expression level of NAL1 between genotypes, our findings suggest that an amino acid substitution in the exon region is responsible for the phenotypic changes. We also found that the rice varieties having alternative alleles of qPL3 and qTN4 showed significantly higher AGB than the varieties with the reference alleles. Our results suggest that OsGA20ox1 and NAL1 are promising genes for improving DW resistance in rice.

A real-world analysis on the efficacy and tolerability of liposomal irinotecan plus 5-fluorouracil and folinic acid in metastatic pancreatic ductal adenocarcinoma in Belgium.

Background: Currently, nanoliposomal irinotecan (nal-IRI) + 5-fluorouracil/folinic acid (5-FU/LV) is the only approved second-line treatment for patients suffering from metastatic pancreatic ductal adenocarcinoma (mPDAC). However, also other chemotherapeutic regimens are used in this setting and due to the lack of clear real-world data on the efficacy of the different regimens, there is no consensus on the optimal treatment sequence for mPDAC patients. Objectives: To provide information on the safe and efficacious use of nal-IRI + 5-FU/LV in clinical practice in Belgium, which is needed for healthcare professionals to estimate the risk-benefit ratio of the intervention. Methods: Medical data of adult patients with mPDAC who were treated with nal-IRI + 5-FU/LV in one of the participating Belgian hospitals were retrospectively collected. Kaplan-Meier analysis was performed to obtain survival curves to estimate the median overall survival (OS) and progression-free survival (PFS). All other results were presented descriptively. Results: A total of 56 patients [median age at diagnosis: 69 years (range 43 years), 57.1% male] were included. Patients received a median of 5 (range 49 cycles) nal-IRI + 5-FU/LV cycles, extended over 10 weeks (range 130.8 weeks). The median start dose for nal-IRI was 70 mg/m² (range 49.24 mg/m²) and chemotherapy dose reduction and delay occurred in, respectively, 42.8% and 37.5% of the patients. The median OS was 6.8 months (95% CI: 5.6-8.4 months) with a 6-month survival rate of 57.4% and a 1-year survival rate of 27.8% in the overall study population. The median OS for patients treated with nal-IRI as second-line therapy or as later-line treatment was, respectively, 6.8 months (95% CI: 5.9-7.0 months) and 5.6 months (95% CI: 4.2-no upper limit). In the overall study population, a median PFS of 3.1 months (95% CI: 2.4-4.6 months) and a disease control rate of 48.3%, comprising 30.4% stable disease, 16.1% partial and 1.8% complete response, was observed. The median PFS for patients treated with nal-IRI as second-line therapy was 3.9 months (95% CI: 2.8-4.8 months) while this was 2.4 months (95% CI: 1.9-9.1 months) for those that received nal-IRI in a later-line treatment. In terms of safety, gastrointestinal problems occurred most (64.3% of the patients) and from all reported treatment emergent adverse events, 39.2% were grade 3 or 4. Conclusion: Nal-IRI + 5-FU/LV is a valuable, effective, and safe sequential treatment option following gemcitabine-based therapy in patients with mPDAC. Trial details: Retrospective study on the efficacy and tolerability of liposomal irinotecan (NALIRI); ClinicalTrials.gov Identifier: NCT0509506 (https://clinicaltrials.gov/ct2/show/NCT05095064?term=naliri&draw=2&rank=2).

Ciliated Cells Express a Novel Pattern of Brain-Derived Neurotrophic Factor in Allergic Rhinitis.

Background: Mounting research indicates that brain-derived neurotrophic factor (BDNF), has great potential to increase neuro-hyperresponsiveness and airway resistance in airway allergic disease. The expression level of BDNF has been found to be notably elevated in lung/nasal lavage (NAL) fluid. However, the expression and position of BDNF in ciliated cells with allergic rhinitis remains unclear. Methods: Nasal mucosal cells were collected from patients with allergic rhinitis (AR) and mice which were performed under different allergen challenge time, then observed the expression and position of BDNF located in ciliated cells through the immunofluorescence staining. Nasal mucosa, serum and NAL fluid were collected also. The expression level of BDNF and IL-4/5/13 were detected by RT-PCR. The expressions of BDNF (in serum and NAL fluid), and total-IgE, ovalbumin sIgE (in serum) were detected by ELISA. Results: We found that MFI of BDNF in AR group's ciliated cells was obviously lower than that in the control group, and a negative correlation was discovered between MFI and VAS score. It can be roughly divided into 5 patterns according to its location in the cytoplasm of ciliated cells. In the mouse model, the expressions of BDNF in serum and NAL fluid increased temporarily after allergen stimulation. The MFI of BDNF in ciliated cells displayed an initial increase followed by a subsequent decrease. Conclusion: Our study shows for the first time that, the expression and localization of BNDF were observed in the human nasal ciliated epithelial cells of allergic rhinitis, and the expression of level was less than the control group under the persistent state of allergy. BDNF expression in ciliated cells was transient increased after allergen stimulation and decreased to normal level after 24h in mouse model of allergic rhinitis. This might be the possible source of the transient increase of BNDF in serum and NAL fluid.

A Retrospective Study Investigating the Safety and Efficacy of Nanoliposomal Irinotecan in Elderly Patients with Unresectable Pancreatic Cancer.

Although nanoliposomal irinotecan combined with 5-fluorouracil and leucovorin (nal-IRI+5-FU/LV) has been used to treat first-line resistant unresectable pancreatic cancer, the efficacy and safety data among the elderly remain limited. We retrospectively analyzed clinical outcomes among elderly patients. Patients treated with nal-IRI+5-FU/LV were assigned to the elderly (≥75 years) and non-elderly (<75 years) groups. Herein, 85 patients received nal-IRI+5-FU/LV, with 32 assigned to the elderly group. Patient characteristics in the elderly and non-elderly groups were as follows: age: 78.5 (75-88)/71 (48-74), male: 17/32 (53%/60%), performance status (ECOG) 0:9/20 (28%/38%), nal-IRI+5-FU/LV in second line: 23/24 (72%/45%), respectively. A significantly high number of elderly patients exhibited aggravated kidney and hepatic functions. Median overall survival (OS) and progression-free survival (PFS) in the elderly group vs. non-elderly group were 9.4 months vs. 9.9 months (hazard ratio (HR) 1.51, 95% confidence interval (CI) 0.85-2.67, p = 0.16) and 3.4 months vs. 3.7 months (HR 1.41, 95% CI 0.86-2.32, p = 0.17). Both groups exhibited a similar incidence of efficacy and adverse events. There were no significant differences in OS and PFS between groups. We analyzed the C-reactive protein/albumin ratio (CAR) and neutrophil/lymphocyte ratio (NLR) as indicators that could determine eligibility for nal-IRI+5-FU/LV. The median CAR and NLR scores in the ineligible group were 1.17 and 4.23 (p < 0.001 and p = 0.018, respectively). Elderly patients with worse CAR and NLR score could be deemed ineligible for nal-IRI+5-FU/LV.

A convolutional neural network for face mask detection in IoT-based smart healthcare systems.

The new coronavirus that produced the pandemic known as COVID-19 has been going across the world for a while. Nearly every area of development has been impacted by COVID-19. There is an urgent need for improvement in the healthcare system. However, this contagious illness can be controlled by appropriately donning a facial mask. If people keep a strong social distance and wear face masks, COVID-19 can be controlled. A method for detecting these violations is proposed in this paper. These infractions include failing to wear a facemask and failing to maintain social distancing. To train a deep learning architecture, a dataset compiled from several sources is used. To compute the distance between two people in a particular area and also predicts the people wearing and not wearing the mask, The proposed system makes use of YOLOv3 architecture and computer vision. The goal of this research is to provide valuable tool for reducing the transmission of this contagious disease in various environments, including streets and supermarkets. The proposed system is evaluated using the COCO dataset. It is evident from the experimental analysis that the proposed system performs well in predicting the people wearing the mask because it has acquired an accuracy of 99.2% and an F1-score of 0.99.

Second-line and third-line therapy with nanoliposomal irinotecan (nal-IRI) in pancreatic cancer: a single-center experience and review of literature.

Background: Prognosis of patients with pancreatic cancer is still extremely poor. First-line palliative therapies with FOLFIRINOX or gemcitabine/nab-paclitaxel have been established in the last decade. In the second-line, 5-FU/LV in combination with nanoliposomal irinotecan (nal-IRI) after gemcitabine has been shown to be effective. However, the use of nal-IRI as third-line therapy after FOLFIRINOX and gemcitabine-based chemotherapies is still controversial. In this study, we report about the use of 5-FU/LV + nal-IRI in a daily practice and analyze whether nal-IRI is an option as third-line therapy after FOLFIRINOX and gemcitabine/nab-paclitaxel. Methods: This is a single center retrospective analysis of patients with irresectable pancreatic cancer who were treated with 5-FU/LV and nal-IRI from 2017 to 2021 as second- or third-line palliative treatment. Overall survival (OS), progression-free survival (PFS) and toxicity were analyzed, and multivariate analysis was used to identify independent prognostic factors. Results: Twenty-nine patients receiving 5-FU/LV and nal-IRI were included in the analysis. The majority of patients (n=19) received 5-FU/nal-IRI as third-line therapy after pre-exposition to FOLFIRINOX and gemcitabine/nab-paclitaxel. Median OS and PFS were 9.33 months (95% CI: 3.37, 15.30) and 2.90 months (95% CI: 1.64, 4.16), respectively. Furthermore, patients receiving nal-IRI + 5-FU/LV as third-line treatment also showed some benefits, with no OS difference compared to second-line patients (9.33 vs. 10.27 months; HR: 1.85; 95% CI: 0.64, 5.41; P=0.253). Adverse effects were similar to reported trials. Conclusions: In our study, the use of 5-FU/nal-IRI in unselected patients with advanced pancreatic cancer showed similar OS, PFS and tolerance as randomized prospective phase II/III trials. Interestingly, the use of 5-FU/nal-IRI seemed to be beneficial in third-line therapy, despite a pre-exposure to non-liposomal irinotecan.

Real-World Data Validation of NAPOLI-1 Nomogram for the Prediction of Overall Survival in Metastatic Pancreatic Cancer.

BACKGROUND: The nomogram derived from the pivotal phase III NAPOLI-1 study demonstrated a significant ability to predict median overall survival (OS) in gemcitabine-refractory metastatic pancreatic ductal adenocarcinoma (PDAC) treated with liposomal irinotecan plus fluorouracil and leucovorin (nal-IRI+5-FU/LV). However, the NAPOLI-1 nomogram has not been validated in a real-world setting and therefore the applicability of the NAPOLI-1 nomogram in daily practice remains unknown. This study aims to evaluate the NAPOLI-1 nomogram in a multicenter real-world cohort. METHODS: The NAPOLI-1 nomogram was applied to a previously established cohort of metastatic PDAC patients treated with nal-IRI+5-FU/LV in nine participating centers in Taiwan. Patients were divided into three risk groups according to the NAPOLI-1 nomogram. The survival impact of relative dose intensity at 6 weeks (RDI at 6 weeks) in different risk groups was also investigated. RESULTS: Of the 473 included patients, the median OSs of patients classified as low (n = 156), medium (n = 186), and high (n = 131) risk were 10.9, 6.3, and 4.3 months, respectively (p < 0.0001). The survival impact of RDI at 6 weeks remained significant after stratification by risk groups, adjustment with Cox regression, inverse probability weighting, or propensity score matching. CONCLUSIONS: Our results support the usefulness of the NAPOLI-1 nomogram for risk stratification in gemcitabine-refractory metastatic PDAC treated with nal-IRI+5-FU/LV in daily practice. We further showed that the RDI at 6 weeks is an independent prognostic factor beyond the NAPOLI-1 nomogram.

Investigation of hearing aid fitting according to the national acoustic laboratories' prescription for non-linear hearing aids and the desired sensation level methods in Japanese speakers: a crossover-controlled trial.

OBJECTIVE: Some studies have directly compared the National Acoustic Laboratories' prescription for non-linear hearing aids (HAs) version 2 (NAL-NL2) and Desired Sensation Level for non-linear HAs version 5 (DSLv5), although none were performed in Japan. As the Japanese language is a tonal language that has different linguistic characteristics than those of the studied languages, we compared the outcomes of the NAL-NL2 and DSLv5 in hearing-impaired Japanese participants. METHODS: A crossover-controlled trial was conducted on 18 first-time HA users with bilateral moderate sensorineural hearing loss. Participants wore HAs adjusted with each prescriptive method for four weeks. The prescriptions were assessed using speech discrimination testing and the abbreviated profile of hearing aid benefit (APHAB). Consequently, participants were asked to select their preferred prescription and determine which was better for "listening to a conversation" and when "noisy." RESULTS: The mean DSLv5 real ear insertion gain for an input level of 65 dB sound pressure level (SPL) was higher than that of the NAL-NL2 at 250 and 500 Hz. The average speech discrimination score was 78 ± 14% at a 65-dB SPL and 75 ± 17% at an 80-dB SPL for the NAL-NL2, and 79 ± 11% at a 65-dB SPL and 77 ± 17% at an 80-dB SPL for the DSLv5. These differences were not significant. No significant differences were observed in APHAB subscale scores between the two prescription methods. Ultimately, 11 (61%) and 7 (39%) participants preferred the NAL-NL2 and DSLv5, respectively, with no significant differences. CONCLUSION: Although the gain of the NAL-NL2 is smaller than that of the DSLv5, both had the same hearing effect. Therefore, the NAL-NL2 may be more useful than the DSLv5 in Japanese.

Correlation of UGT1A1 Gene Polymorphisms or Prior Irinotecan Treatment and Treatment Outcomes of Nanoliposomal-Irinotecan plus 5-Fluorouracil/Leucovorin for Pancreatic Ductal Adenocarcinoma: A Multicenter, Retrospective Cohort Study (HGCSG2101).

The effects of UGT1A1 gene polymorphisms or prior irinotecan treatment on treatment outcomes of nanoliposomal-irinotecan plus 5-fluorouracil/leucovorin (nal-IRI+5-FU/LV) in patients with unresectable pancreatic ductal adenocarcinoma (PDAC) are not established. This multicenter, retrospective cohort study compared treatment outcomes in patients with UGT1A1*1/*1 and those with UGT1A1*1/*6 or *1/*28 genotypes. We also analyzed the impact of prior irinotecan treatment on survival outcomes in 54 patients treated with nal-IRI+5-FU/LV. Comparable effectiveness was found regardless of the UGT1A1 genotypes. While no significant differences were found, grade ≥3 neutropenia and febrile neutropenia were more frequent in patients with UGT1A1*1/*6 or *1/*28 than in those with UGT1A1*1/*1 genotypes (grade ≥3 neutropenia, 50.0% vs. 30.8%, p = 0.24; febrile neutropenia, 9.1% vs. 0.0%, p = 0.20, respectively). No significant difference in progression-free survival (PFS) and overall survival (OS) was observed between irinotecan-naïve-patients and other patients. However, irinotecan-resistant patients showed significantly shorter PFS (hazard ratio (HR) 2.83, p = 0.017) and OS (HR 2.58, p = 0.033) than other patients. Our study indicated that patients with UGT1A1*1/*6 or *1/*28 may be prone to neutropenia, though further study is needed. The survival benefit of nal-IRI+5-FU/LV could be maintained in patients without disease progression after irinotecan therapy.

The DnaJ domain-containing heat-shock protein NAL11 determines plant architecture by mediating gibberellin homeostasis in rice (Oryza sativa).

Ideal Plant Architecture 1 (IPA1) is a key regulator of plant architecture. However, knowledge of downstream genes applicable for improving rice plant architecture is very limited. We identified the plant architecture regulatory gene NARROW LEAF 11 (NAL11), which encodes a heat-shock protein (HSP) containing a DnaJ domain. A promising rare allele of NAL11 (NAL11-923del-1552 ) positively selected in Aus cultivars was identified; this allele exhibited increased expression and generated relatively few tillers, thick stems, and large panicles, components of the ideal plant architecture (IPA). NAL11 is involved in regulating the cell cycle and cell proliferation. NAL11 loss-of-function mutants present impaired chloroplast development and gibberellin (GA) defects. Biochemical analyses show that IPA1 directly binds to elements in the missing fragment of the NAL11-923del-1552 promoter and negatively regulates NAL11 expression. Genetic analyses support the hypothesis that NAL11 acts downstream of IPA1 to regulate IPA by modulating GA homeostasis, and NAL11 may be an essential complement for IPA1. Our work revealed that avoidance of the inhibition of NAL11-923del-1552 caused by IPA1 represents a positive strategy for rescuing GA defects accompanied by the upregulation of IPA1 in breeding high-yield rice.

The association between UGT1A1 polymorphisms and treatment toxicities of liposomal irinotecan.

BACKGROUND: Initial dose adjustment is recommended for patients with known UGT1A1∗28 homozygosity for both conventional irinotecan and liposomal irinotecan (nal-IRI). A recent population pharmacokinetic (PK) study showed that Asian patients had a lower prevalence of UGT1A1∗28 homozygosity but a significantly higher maximum blood concentration of SN-38 (SN-38 Cmax) and a higher incidence of grade ≥3 neutropenia after nal-IRI administration than Caucasian patients. The current study investigated the association of UGT1A1 polymorphisms, including the Asian prevalent UGT1A1∗6, PK and toxicities of nal-IRI-based therapy in the Asian population. PATIENTS AND METHODS: A total of 162 patients with nal-IRI-based therapy and available UGT1A1∗6 and UGT1A1∗28 genotyping were included, with 82 Asian patients from six previous phase I or II studies of nal-IRI (cohort 1) and another 80 patients with nal-IRI + 5-fluorouracil/leucovorin every 2 weeks as real-world practice in a single institute in Taiwan (cohort 2). RESULTS: The frequency of UGT1A1∗6 or UGT1A1∗28 homozygosity/compound heterozygosity was 9.3%, with UGT1A1∗6/∗6 in 2.5%, UGT1A1∗28/∗28 in 1.9% and UGT1A1∗6/∗28 in 4.9%. Among the 53 patients in cohort 1 with available PK data, all 7 patients with homozygosity/compound heterozygosity harbored UGT1A1∗6 and had a significantly higher level of median dose-normalized area under the concentration-time curve (AUC) and Cmax of SN-38 than those with single heterozygosity/wild type. Of the entire study population, the incidence of grade ≥3 neutropenia and diarrhea was significantly higher in patients with homozygosity/compound heterozygosity than in those with single heterozygosity/wild type, 73.3% versus 38.1% (P = 0.012, Fisher's exact test) and 33.3% versus 9.5% (P = 0.018, Fisher's exact test), respectively. CONCLUSION: The results suggest that the recommendation of a lower starting dose of nal-IRI for patients with UGT1A1∗28 homozygosity should be extended to include patients with UGT1A1∗6 homozygosity/compound heterozygosity.

STNM01, the RNA oligonucleotide targeting carbohydrate sulfotransferase 15, as second-line therapy for chemotherapy-refractory patients with unresectable pancreatic cancer: An open label, phase I/IIa trial.

Background: The impact of stroma-targeting therapy on tumor immune suppression is largely unexplored. An RNA oligonucleotide, STNM01, has been shown to repress carbohydrate sulfotransferase 15 (CHST15) responsible for tumor proteoglycan synthesis and matrix remodeling. This phase I/IIa study aimed to evaluate the safety and efficacy of STNM01 in patients with unresectable pancreatic ductal adenocarcinoma (PDAC). Methods: This was an open-label, dose-escalation study of STNM01 as second-line therapy in gemcitabine plus nab-paclitaxel-refractory PDAC. A cycle comprised three 2-weekly endoscopic ultrasound-guided locoregional injections of STNM01 at doses of 250, 1,000, 2,500, or 10,000 nM in combination with S-1 (80-120 mg twice a day for 14 days every 3 weeks). The primary outcome was the incidence of dose-liming toxicity (DLT). The secondary outcomes included overall survival (OS), tumor response, changes in tumor microenvironment on immunohistopathology, and safety (jRCT2031190055). Findings: A total of 22 patients were enrolled, and 3 cycles were repeated at maximum; no DLT was observed. The median OS was 7.8 months. The disease control rate was 77.3%; 1 patient showed complete disappearance of visible lesions in the pancreas and tumor-draining lymph nodes. Higher tumoral CHST15 expression was associated with poor CD3+ and CD8+ T cell infiltration at baseline. STNM01 led to a significant reduction in CHST15, and increased tumor-infiltrating CD3+ and CD8+ T cells in combination with S-1 at the end of cycle 1. Higher fold increase in CD3+ T cells correlated with longer OS. There were 8 grade 3 adverse events. Interpretation: Locoregional injection of STNM01 was well tolerated in patients with unresectable PDAC as combined second-line therapy. It prolonged survival by enhancing T cell infiltration in tumor microenvironment. Funding: The present study was supported by the Japan Agency for Medical Research and Development (AMED).

Construção e validação de um instrumento de avaliação de cursos na modalidade a distância / Construction and validation of an evaluation instrument for distance learning courses / Construcción y validación de un instrumento de evaluación para cursos a distancia

Objetivos: construir, validar e aplicar um instrumento de avaliação de cursos de nível superior ofertados na modalidade a distância. Método: estudo metodológico. Para a elaboração do instrumento realizou-se revisão de literatura. A validação do pré-teste se deu pela triangulação de especialistas e a do conteúdo pelo Método Delphi. Para a análise da confiabilidade adotou-se a análise fatorial confirmatória e o coeficiente de Correlação de Spearman a partir da aplicação em dois cursos a distância. Resultados: a partir de onze referenciais (nacionais e internacionais) foram estratificados 70 critérios e agrupados em seis categorias que foram modificados na triangulação. Dois ciclos compuseram a Técnica Delphi com 17 especialistas inicialmente e alfa de Cronbach de 0,80 na segunda rodada. Na análise fatorial confirmatória, realizada com 221 participantes, inicialmente, não gerou índices satisfatórios, resultando na exclusão de questões. O novo modelo ajustado, produziu índices próximos aos ideais: CFI = 0,806; TLI = 0,770 e RMSEA = 0,088 com associação positiva entre as variáveis, e melhor média (p<5%) quanto à correlação entre os aspectos práticos e a indicação do curso pelos discentes. Conclusão: o estudo produziu um instrumento validado e com a confiabilidade aferida que pode ser aplicado em cursos com diferentes desenhos pedagógicos e não se limita a uma área específica, uma relevante contribuição para a educação superior.

Objectives: To construct, validate and apply an instrument of evaluation of higher education courses offered in distance learning modality. Method: Methodologi- cal study. For the elaboration of the instrument, a literature review was carried out. The pre-test was validated by expert triangulation and the content was validated by the Delphi Method. For the reliability analysis we adopted the confirmatory factor analysis and Spe- arman's Correlation coefficient from the application in two distance learning courses. Re- sults: from eleven references (national and international) 70 criteria were stratified and grouped into six categories that were modified in the triangulation. Two rounds compri- sed the Delphi Technique with 17 experts initially and Cronbach's alpha of 0.80 in the second round. The confirmatory factor analysis, performed with 221 participants, did not initially generate satisfactory indexes, resulting in the exclusion of questions. The new adjusted model produced close to ideal indexes: CFI = 0.806; TLI = 0.770 and RMSEA regarding the correlation between practical aspects and students' recommendation of the course. Conclusion: the study produced a validated instrument with gauged reliability that can be applied in courses with different pedagogical designs and is not limited to a spe- cific area, a relevant contribution to higher education.

Objetivos: Construir, validar y aplicar un instrumento de evaluación de cur- sos de educación superior ofrecidos en la modalidad a distancia. Método: Estudio meto- dológico. Para la elaboración del instrumento se realizó una revisión bibliográfica. El pre- test fue validado por triangulación de expertos y el contenido fue validado por el Método Delphi. Para el análisis de fiabilidad adoptamos el análisis factorial confirmatorio y el coeficiente de correlación de Spearman a partir de la aplicación en dos cursos a distancia. Resultados: a partir de once referencias (nacionales e internacionales) se estratificaron 70 criterios que se agruparon en seis categorías que se modificaron en la triangulación. Se realizaron dos rondas con la técnica Delphi con 17 expertos inicialmente y un alfa de Cronbach de 0,80 en la segunda ronda. El análisis factorial confirmatorio, realizado con 221 par-ticipantes, no generó inicialmente índices satisfactorios, lo que dio lugar a la ex- clusión de preguntas. El nuevo modelo ajustado produjo índices cercanos al ideal: CFI = 0,806; TLI = 0,770 y RMSEA = 0,088 con una asociación positiva entre las variables, y una media mejor (p<5%) en cuanto a la correlación entre los aspectos prácticos y la re- comendación del curso por parte de los alumnos. Conclusión: el estudio produjo un ins- trumento validado con confiabilidad medida, que puede ser aplicado en cursos con dife- rentes diseños pedagógicos y no se limita a un área específica, una contribución relevante para la educación superior.

Dosing Pattern and Early Cumulative Dose of Liposomal Irinotecan in Metastatic Pancreatic Cancer: A Real-World Multicenter Study.

Introduction: This multicenter, real-world cohort study aimed to evaluate the effectiveness of early cumulative dose administration and dosing pattern of liposomal irinotecan plus fluorouracil/leucovorin (nal-IRI+5-FU/LV) in patients with gemcitabine-refractory metastatic pancreatic ductal adenocarcinoma (mPDAC). Material and Methods: The electronic medical records of mPDAC patients treated with nal-IRI+5-FU/LV in nine participating centers were manually reviewed. To accommodate to the NAPOLI-1 study population, only patients with an Eastern Cooperative Oncology Group Performance Score of 0-1 were included. The survival impact of the relative 6-week cumulative dose and dosing pattern (standard vs. reduced starting dose, with and without further dose modification) were investigated. Results: Of the 473 included patients, their median overall survival (mOS) was 6.8 [95% CI, 6.2-7.7] months. The mOS of patients who received a relative 6-week cumulative dose of >80%, 60%-80%, and <60% were 7.9, 8.2, and 4.3 months, respectively (p<0.0001). Their survival impact remained significant after covariate adjustment using Cox regression. The mOS was 8.0-8.2 months in patients with a standard starting dose with and without early dose modification, and 9.3 and 6.7 months in those who had a reduced starting dose with and without escalation in the subsequent treatment, respectively. The incidence of grade 3-4 neutropenia and diarrhea was 23.3% and 2.7%, respectively. Conclusion: Our results support the use of nal-IRI+5-FU/LV in gemcitabine-refractory mPDAC and suggest that a lower starting dose followed by a re-escalation strategy could achieve clinical outcomes comparable to those with standard starting doses in real-world practice.

Novel Drugs for the Management of Hepatic Encephalopathy: Still a Long Journey to Travel.

Hepatic encephalopathy (HE) is one of the reversible complications of chronic liver disease, associated with a higher mortality rate. In current clinical practice, treatment with rifaximin and lactulose/lactitol is the first line of treatment in HE. With the advance in pathophysiology, a new class of ammonia lowering drugs has been revealed to overcome the hurdle and disease burden. The mechanism of the novel agents differs significantly and includes the alteration in intestinal microbiota, intestinal endothelial integrity, oxidative stress, inflammatory markers, and modulation of neurotoxins. Most of the trials have reported promising results in the treatment and prevention of HE with fecal microbiota transplantation, albumin, probiotics, flumazenil, polyethylene glycol, AST-120, glycerol phenylbutyrate, nitazoxanide, branched-chain amino acid, naloxone, and acetyl-l-carnitine. However, their clinical use is limited due to the presence of major drawbacks in their study design, sample size, safety profile, bias, and heterogenicity. This study will discuss the novel therapeutic targets for HE in liver cirrhosis patients with supporting clinical trial data.