RD Group Research Articles

Stereotactic Radiosurgery Dose Reduction for Melanoma Brain Metastases Patients on Immunotherapy or Target Therapy: A Single-Center Experience.

Better local control but higher rates of adverse radiation events (ARE) have been reported when combining American Society for Radiation Oncology (ASTRO)-guideline-suggested dose (SD) stereotactic radiosurgery (SRS) with immunotherapy or targeted therapy for melanoma brain metastases. The objective of this study is to explore the efficacy and safety of lower prescription doses compared with ASTRO guidelines for single-fraction SRS for patients with melanoma metastases who are concurrently receiving immunotherapy or targeted therapy. We conducted a retrospective, single-center study on 194 patients who underwent SRS between 2009 and 2022. After propensity score matching, 71 patients with 292 metastases were included in the ASTRO-SD (20-24 Gy for <2 cm, 18 Gy for ≥2 to <3 cm) group and 33 patients with 292 metastases in the reduced dose (RD, <20 Gy for <2 cm, <18 Gy for ≥2 to <3 cm) group. The median diameter (5.4 vs 5.2 mm, P = .6), prescription volume (0.2 vs 0.2 cm3, P = .2), and radiographic follow-up (11 vs 12 months, P = .2) were similar in the 2 groups. The cumulative incidence of progressing metastases was significantly higher in the SD compared with the RD group (P = .018). Higher prescription volumes and ASTRO-suggested radiation doses were associated with local progression in multivariable analysis. Radiographic AREs were significantly more common in the SD compared with the RD group (8.6% vs 3.1%, P = .005). BRAF and other tyrosine kinase inhibitors' concurrent use, higher prescription volumes, and ASTRO-suggested radiation doses were associated with an increased risk of radiographic ARE. This study provides evidence that RD SRS could offer reduced toxicity rates, while maintaining high local control as compared with the current guideline-SDs for the treatment of melanoma brain metastases.

Parvovirus B19 remains an underestimated pathogen among infections during gestation in Argentina: Insights through the study of symptomatic and asymptomatic pregnant patients and newborns from Córdoba

BackgroundParvovirus B19 (B19 V) infection during pregnancy can cause adverse fetal outcomes. Our aim was to characterize both clinical and asymptomatic maternal and neonatal cases by studying virological and serological markers of B19 V infection, and to sequence the complete genome of the circulating virus in Argentina. MethodsSymptomatic patients were included based on maternal and/or fetal-neonatal signs attributable to B19 V infection during gestation. Pregnant patients were analyzed in either the timely diagnosis group (TD, samples obtained when symptoms were present and infection was suspected) or the retrospective diagnosis group (RD, samples collected immediately postpartum), and newborns were analyzed at birth. A sample of asymptomatic individuals was also analyzed. Diagnostic tests (PCR/qPCR/serology) and sequencing were performed on archived serum samples from 2018 to 2023, and clinical data were obtained from medical records. ResultsWe studied 328 symptomatic patients, including 185 pregnant patients (73 TD and 112 RD) and 143 newborns. Among them, we identified 27/328 (8.2 %) positive cases (B19V+): 12/73 (16.4 %) in the TD group, 6/112 (5.4 %) in the RD group, and 9/143 (6.3 %) newborns. Within the 77 mother-newborn pairs included, there were 8 (10.4 %) B19 V infections and 6 cases of vertical transmission. Additionally, B19 V infection was detected in 26/310 (8.4 %) asymptomatic patients. Phylogenetic analysis identified genotype 1a as a circulating strain in Argentina. ConclusionsOur findings highlight the need to raise awareness and enhance diagnostic approaches in Argentina to more effectively identify and manage B19 V infections during pregnancy in our region.

Deep hematologic response to RD treatment in patients with multiple myeloma is associated with overexpression of IL-17R in CD138+ plasma cells

Lenalidomide (LEN) is widely used immunomodulatory drug (IMiD). Nonetheless, despite its efficacy, over time patients become resistant to LEN and relapse. Due to high clinical relevance, drug resistance in MM is being thoroughly investigated. However, less is known about predictors of good response to LEN-based treatment. The aim of this study was to identify molecular pathways associated with good and long response to LEN. The study included newly diagnosed MM patients (NDMM) and MM patients treated with first-line LEN and dexamethasone (RD) who achieved and least very good partial remission (VGPR). RNA was isolated from MM cells and new-generation sequencing was performed. Obtained results were validated with qRT-PCR. A global increase in gene expression was found in the RD group compared to NDMM, suggesting the involvement of epigenetic mechanisms. Moreover, upregulation of genes controlling the interaction within MM niche was detected. Next, genes controlling immune response were upregulated. In particular, the gene encoding the IL-17 receptor was overexpressed in the RD group which is a novel finding. This should be emphasized because IL-17-related signaling can potentially be targeted, providing the rationale for future research. Establishing the molecular background associated with long-lasting and profound response to LEN may improve LEN-based chemotherapy regimens and facilitate the development of adjuvant therapies to enhance its anti-MM activity.

Contribution of resting-state functional connectivity of the subgenual anterior cingulate to prediction of antidepressant efficacy in patients with major depressive disorder

This study investigated how resting-state functional connectivity (rsFC) of the subgenual anterior cingulate cortex (sgACC) predicts antidepressant response in patients with major depressive disorder (MDD). Eighty-seven medication-free MDD patients underwent baseline resting-state functional MRI scans. After 12 weeks of escitalopram treatment, patients were classified into remission depression (RD, n = 42) and nonremission depression (NRD, n = 45) groups. We conducted two analyses: a voxel-wise rsFC analysis using sgACC as a seed to identify group differences, and a prediction model based on the sgACC rsFC map to predict treatment efficacy. Haufe transformation was used to interpret the predictive rsFC features. The RD group showed significantly higher rsFC between the sgACC and regions in the fronto-parietal network (FPN), including the bilateral dorsolateral prefrontal cortex (DLPFC) and bilateral inferior parietal lobule (IPL), compared to the NRD group. These sgACC rsFC measures correlated positively with symptom improvement. Baseline sgACC rsFC also significantly predicted treatment response after 12 weeks, with a mean accuracy of 72.64% (p < 0.001), mean area under the curve of 0.74 (p < 0.001), mean specificity of 0.82, and mean sensitivity of 0.70 in 10-fold cross-validation. The predictive voxels were mainly within the FPN. The rsFC between the sgACC and FPN is a valuable predictor of antidepressant response in MDD patients. These findings enhance our understanding of the neurobiological mechanisms underlying treatment response and could help inform personalized treatment strategies for MDD.

A Randomised Clinical Trial to Compare the Efficacy and Safety of Dexmedetomidine-Ropivacaine Versus Fentanyl-Ropivacaine for Epidural Labour Analgesia.

Background An epidural block is a superior potent approach to labour analgesia, and ropivacaine combined with fentanyl has been successfully practised for it. Dexmedetomidine, as a novel form of labour analgesia, must be researched further. Our study results give insight into the epidural block and come up with a pioneering approach for labour analgesia. Methodology A total of 68 parturients were assigned to two equal groups and received either dexmedetomidine with ropivacaine (Group RD) or fentanylwith ropivacaine (Group RF). Parturients received a loading dose and maintenance was given using a patient-controlled analgesia (PCA) pump. Analgesia onset time, labour duration, rescue dose requirement, and Visual Analogue Scale (VAS) pain scores were noted. Appearance, Pulse, Grimace, Activity and Respiration (APGAR) scores of newborns, Ramsay Sedation Scale (RSS) scores of mothers, and maternal side effects were observed. Results Group RDshowed a shorter onset time of analgesia (group RD: 12.50 ± 1.31 minutes vs. group RF: 15.26 ± 1.46 min), less local anaesthetics requirement (group RD: 47.54 ±5.37 ml vs. group RF: 59.05 ± 6.62 ml), less number of bolus doses (group RD: 0.15 ± 0.36 vs. group RF: 1.21 ± 0.95), and shorter duration from the epidural administration to the delivery (group RD: 312.97 ± 42.40 minutes vs. group RF: 345.94 ±14.67 minutes) than group RF. VAS values of the RD group were significantly less than the RF group. The RSS scores were comparably low in both groups, and excessive sedation was not seen in any group. Newborn APGAR values were comparably on the higher side in the two groups. Adverse effects were observed in the two groups, like hypotension, nausea/vomiting, bradycardia, shivering, and pruritus, which were insignificant. Conclusion The RD group showed an improved analgesic effect with a quicker onset of action,reduced requirement of local anaesthetics, and lower VAS scores compared to the RF group. With ropivacaine, dexmedetomidine shows more efficacy than fentanyl during epidural block and is a safe alternative for labour pain management.

Feedback timing-modulated weather prediction reveals relative deficits in both procedural and declarative learning in adults with dyslexia.

A topic of recent debate is the hypothesis that deficits associated with developmental disorders of language, such as reading disability, can be explained by a selective weakness in procedural memory. Adults with (n = 29; RD) and without (n = 29; TD) reading disability completed a weather prediction task under immediate and delayed feedback conditions, that rely on the striatal (procedural) and hippocampal (declarative) circuits, respectively. We examined trial-by-trial accuracy by feedback condition (immediate vs. delayed) and group (RD vs. TD). In the immediate feedback condition, we found the TD group to have a higher learning rate than the RD group. In the delayed feedback condition, we found the TD group reach a high level of accuracy early, and outperform the RD group for the duration of the task. The TD group also made gains in reaction time under both conditions, while the RD group slowed in their responses. Taken together, it appears that while procedural memory is indeed impaired in adults with reading disability, to a lesser extent, declarative memory is also affected. This lends partial support to the PDH, and more broadly to the position that reading disability is associated with general (non-linguistic) difficulties in learning.

P-662 Effect of rescue-dose progesterone in patients with low serum progesterone levels on the day of embryo transfer in frozen embryo transfer cycles

Abstract Study question What is the effect of rescue-dose progesterone in patients with low serum progesterone on the day of embryo transfer in frozen embryo transfer cycles? Summary answer In patients with low serum progesterone on the day of embryo transfer, rescue dose progesterone results in significantly higher clinical pregnancy rates. What is known already Frozen embryo transfer (FET) has become more common lately with many centers utilizing hormone replacement therapy (HRT) to electively plan embryo transfer with improved compliance rates. Serum progesterone level on the day of embryo transfer is a very simple, useful investigation which can be used as a predictor of clinical outcomes. Patients with lower progesterone levels (&amp;lt;5ng/ml) are associated with lower clinical pregnancy and ongoing pregnancy rates. Progesterone levels of &amp;gt; 10ng/ml are considered optimal by various studies. There is limited data on the efficacy of progesterone supplementation in patients with low progesterone levels. Study design, size, duration This study was conducted to assess the effect of rescue dose progesterone in patients with low serum progesterone levels on the day of embryo transfer in patients with HRT-FET cycles. This was a retrospective study and data was collected from prospectively maintained records of patients undergoing treatment at Miracles IVF and fertility center, Gurgaon, India between December, 2021 to November, 2023. Participants/materials, setting, methods All were HRT-FET cycles with vaginal progesterone supplementation of 800 mg/day. Serum progesterone levels were done on day of embryo transfer and if 5-10 ng/ml, rescue dose progesterone (100 mg intramuscular) was given. Single blastocyst embryo transfer was done. Inclusion criteria: 1.Age 25-35 years, 2.Endometrial thickness &amp;gt;7.5mm on day of start of progesterone. Exclusion criteria: 1.Transfer day progesterone &amp;lt;5ng/ml, 2. BMI &amp;gt; 30, 3. Previously failed embryo transfer The primary outcome was clinical pregnancy rate. Main results and the role of chance A total of 121 patients underwent 165 cycles during the study period with 93 patients included in the study after fulfilling the inclusion and exclusion criteria. 35 patients (37.6%) received rescue dose progesterone (RD group) and remaining 58 patients (62.4%) received no rescue dose (NRD group) as per their serum progesterone levels. All these patients were followed as per protocol and serum bhcg was done after 14 days of embryo transfer. Patients with positive values were monitored till positive clinical pregnancy. Biochemical pregnancy rates were 20 out of 35 (57.1%), 35 out of 58 ( 60.3%) and 55 out of 93 ( 59.1%) in RD group, NRD group and overall respectively. Clinical pregnancy rates were 18 out of 35 (51.4%), 34 out of 58 ( 58.6%) and 52 out of 93 ( 55.9%) in RD group, NRD group and overall respectively. RD group had significantly improved outcomes in terms of clinical pregnancy rates which were comparable to NRD group Limitations, reasons for caution Limitations, reasons for caution: Ours was a single center retrospective study with limited sample size. Though, our study revealed comparable outcome between the two groups but large volume multicenter studies are needed for making conclusive recommendations. Wider implications of the findings This study provides an insight into the role of serum progesterone levels on the day of embryo transfer. Rescue progesterone dosage for patients with sub-optimal serum progesterone levels may help in achieving similar clinical pregnancy rates and improving overall outcomes. Trial registration number not applicable

Analysis of potential diagnostic markers and therapeutic targets for rheumatoid arthritis with comorbid depression immunologic indicators

ObjectiveDepression can impact the severity of rheumatoid arthritis (RA). This study aimed to investigate the relationship between Th1, Th2, Th17, Treg cell subsets, and their associated cytokines (e.g., IL-2, IL-4, IL-6, IL-10, IL-17, IFN-γ, and TNF-α), and the occurrence of RA both with and without comorbid depression. The objective is to identify potential biological markers, therapeutic targets, and the therapeutic effects of RA with comorbid depression. Results53 RA patients,46 RA with comorbid depression patients and 51 healthy subjects were included in the RA,RD and HC group from August 2021 and October 2022. Among RA patients, 46.46 % were comorbid with depression. IL-6 concentrations were significantly higher in RD group than in RA group.Comparison between the HC and RA and RD groups revealed that Th1 %, Th17 %, Th1, Th17, Th1/Th2, Th17/Treg and Th1/Treg were significantly higher in the RA and RD groups, and conversely, Th2 %, Treg%, Th2 and Treg were significantly lower than in the HC group.The RA group compared to the RD group found that Th17 %, Th17 and Th17/Treg were significantly higher in the RD group than in the RA group, however, Th1 %, Treg and Th2/Treg were significantly lower than in the RA group. The total HAMD score had a medium strength positive correlation with IL-6. ConclusionThese findings suggest that elevated the autoimmunity status was overactivated in RA with or without depression activates patients, IL-6 may be a predictor of the severity of RA with comorbid depression, IL-6 concentrations and an imbalance in the Th17/Treg may underlie the comorbidity of RA and depression, offering potential targets for therapeutic intervention, prompting further evaluation of the role of indirect inflammatory markers in RA with comorbid depression, highlighting the need for additional research to clarify the complex relationship between inflammation and psychological health.

Phase II trial of weekly or bi-weekly tocilizumab with ipilimumab and nivolumab in advanced melanoma: Clinical outcomes and biomarker analysis.

9553 Background: Combination immune-checkpoint inhibitors (ICIs) improved outcomes in a plethora of cancer subtypes. However, up to 60% of patients (pts) receiving ipilimumab (ipi) plus nivolumab (nivo) experience grade 3/4 (G 3/4) immune-related adverse events (irAEs), often leading to treatment discontinuation. We evaluated two therapeutic strategies targeting interleukin-6 receptor (IL-6R) to reduce irAEs while enhancing ICls efficacy. Methods: Phase Il trial (NCT04940299) investigating safety/efficacy of frontline tocilizumab (toci; IL-6R inhibitor) combined with ipi 3mg/kg + nivo 1mg/kg Q3 weeks (wks) for 12 wks in advanced melanoma. Initially, toci was given as 162 mg subcutaneously (SQ) bi-weekly for 6 doses (regular dosing regimen; RD). Then, we escalated to a dose dense (DD) regimen (162 mg SQ weekly for 6 wks then bi-weekly for 6 wks; 9 doses total). Primary objective was rate of G 3/4 irAEs. Secondary objectives were objective response rates (ORR) and disease control rate (DCR) per RECIST 1.1. Exploratory objectives involved immune analysis (gene expression, CyTOF, cytokine analysis) on longitudinal blood and tissue samples to identify drivers of auto- vs antitumor immunity. Results: As of Feb 2024, 35 pts were enrolled (25 pts to RD regimen; 10 pts to DD regimen). In RD group, median follow-up is 18 months (6 - 25 months). By 12 wks, 44% of pts developed G 3/4 irAEs including colitis (20%), hepatitis (16%), pancreatitis (12%), type I diabetes and serum sickness (4% each) and 20% of pts required hospitalization due to irAEs. Median time to G 3/4 irAEs onset was 7.4 wks. 16% of pts discontinued ICIs due to irAEs. ORR was 56% at 12 wks including 40% in pts with high LDH and DCR was 80%. Gene expression analysis showed a trend towards higher expression of IL-17 pathway genes in pts who developed G 3/4 irAEs, suggesting IL-6/Th17 pathway was not sufficiently inhibited. Thus, we enrolled 10 pts into the DD regimen aiming to achieve better inhibition of the IL-6/Th17 pathway. In DD group, median follow-up is 7 months (3 - 13 months). By 12 wks, 40% of pts developed G 3/4 irAEs, including colitis (10%), hepatitis (20%), and uveitis (10%) and 30% of pts required hospitalization due to irAEs. Median time to G 3/4 irAEs onset was 4.9 wks. 30% of pts discontinued ICIs due to irAEs. ORR was 70% at 12 wks including 75% in pts with high LDH and DCR was 80%. Conclusions: To our knowledge, this is the first study to investigate toci in combination with high dose ipi3/nivo1. Although our cohort is small, preliminary data suggests IL-6R blockade using the DD regimen could decrease the rate of G 3/4 irAEs while maintaining antitumor responses of ipi3/nivo1. A randomized phase ll trial investigating this strategy is underway. Ongoing immune analysis comparing treatment regimens aims to identify distinct pathways involved in auto- vs antitumor immunity and IL-6/Th17 independent pathways of toxicity. Clinical trial information: NCT04940299 .

Comparative Study of Dexmedetomidine versus Fentanyl as an adjuvant to Ropivacaine (0.75%) in Epidural Anaesthesia in Lower Limb Orthopaedic Surgery

Background: Dexmedetomidine and Fentanyl both possess hypnotic, sedative, analgesic properties and have been utilised as an additive in epidural anaesthesia. The purpose of this study is to compare the sedative and analgesic effects of Dexmedetomidine and Fentanyl when added epidurally with Ropivacaine (0.75%) during lower limb orthopaedic surgery.&#x0D; Methods: The study comprised of 60 patients, both male and female, aged 18 to 60, who had ASA classification I or II for tibia fibula surgery. Two groups of patients were split up at random: Group RD contains– Ropivacaine (0.75%) 15ml + Dexmedetomidine (1microgm/kg) 0.5ml + 0.5ml sterile water (Total volume-16ml) and Group RF - Ropivacaine 15ml (0.75%) + 1ml Fentanyl (1microgm/kg) (Total volume-16 ml). The epidural space was maintained 4 cm within and situated between L3 and L4 space. Investigations were conducted on parameters such as sensory and motor block features, sedation score, hemodynamic factors and pain assessment. Using the student `t` test, statistical analysis was performed using STATAIC13 software.&#x0D; Results: Onset of sensory analgesia at L1 and Complete sensory and motor blockage occurred much earlier in the RD group. Higher sedation scores and significantly prolonged postoperative analgesia was observed in RD group.&#x0D; Conclusion: Dexmedetomidine is a safer and more effective epidural adjuvant than fentanyl because it provides stable hemodynamics, extended post-operative analgesia, early onset and development of sensory and motor effects and sedation.

Comparative profiling of the skin and gut microbiota during metamorphosis in Chinese spiny frogs (Quasipaa spinosa) highlights microbial communities involved in disease pathogenesis

The symbiotic microbiota inhabiting the skin and gut of amphibians exerts roles in maintaining host health, especially during the critical stage of complete metamorphosis where failure to remodel the microbiota can result in various diseases. However, the composition and alterations in the amphibian microbiota in diverse diseased populations, as well as the exact mechanisms underlying disruptions in skin and gut microbial communities leading to diseases, are not yet well established. Herein, skin and gut microbiota were sampled from healthy Chinese spiny frogs (CTL group) as well as individuals with ascites disease (AD group), cataract disease (CD group), and rotten-skin disease (RD group) for Illumina high-throughput sequencing analysis to comprehensively explore potential associations between microbiota composition and the health status of the host. Venn diagrams and UpSet analysis revealed that the CTL group exhibited the highest number of unique amplicon sequence variants (ASVs) in their skin, while the CD group displayed the lowest abundance of ASVs in their gut. Compared to the CTL group, the alpha-diversity of skin microbiota was dramatically depressed in diseased groups, and notable variations in the beta-diversity of both skin and gut microbiota were observed. Further compositional analysis identified Firmicutes, Proteobacteria, and Bacteroidota as the dominant bacterial phyla in both skin and gut microbiota, although their relative abundances varied widely among groups. The linear discriminant analysis effect size (LEfSe) analysis identified various bacteria species with substantial differences between skin and gut microbiota groups including beneficial populations as well as opportunistic ones. Functional predictions indicated significant differences between CTL and diseased groups mainly enriched in metabolism-relevant pathways. Furthermore, in vitro culture experiments confirmed the presence of a total of 19 strains of bacteria from the skin microbiota of RD group, including opportunistic bacteria population Acinetobacter closely associated with spiny frog rotten-skin disease. Taken together, this work provides insights into the composition dynamics of skin and gut microbiota under different health conditions in spiny frogs, highlighting potential applications for symbiotic microbiota modification in promoting healthy amphibian culture practices as well as preventing diseases.

Assessment of Quality of Pain and Patient Satisfaction using ASSIST Questionnaire Following Intraperitoneal Instillation of Ropivacaine Compared with the Addition of Adjuncts Ketamine versus Dexmedetomidine in Laparoscopic Cholecystectomy patients

Background: Evaluation of patient satisfaction score and to assess quality of pain relief following intraperitoneal instillation of Ropivacaine with adjuncts Dexmedetomidine vs Ketamine using modified version of revised APS-POQ in patients undergoing laparoscopic cholecystectomy. Methods: Sixty patients undergoing laparoscopic cholecystectomy were randomised into three groups of 20 each and received Ropivacaine 0.2 % (group R), Ropivacaine 0.2 % with Dexmedetomidine 0.7µg/ kg (group RD) and Ropivacaine with Ketamine 0.5 mg/kg (group RK) in a total volume of 40 ml. Pain severity, subjective pain complaints, pain interference in physical activity, and patient's and caregiver's satisfaction were evaluated using a modified version of the revised APS-POQ at 24 hours postoperatively. Result: Mean pain scores for worst pain were observed to be least in Group RD, with mean values being 1.75±1.743, followed by 5.45±1.701 in Group R and mean value of 5.60±0.754 in Group RK. Mean patient satisfaction scores were found to be highest in Group RD (94.00±8.826), followed by Group R (80.00±15.218), and least in Group RK (78.50±12.258). This difference was observed to be statistically significant (p&lt;0.05) in all groups. Primary care physicians caring for the RD group had higher satisfaction scores (9.40±0.883) compared to Group RK (7.85±1.226) and Group R (8.05±1.468) Conclusion: Quality of pain relief improved the best with Dexmedetomidine followed by Ketamine and least when Ropivacaine used alone for intraperitoneal instillation. The overall patients' satisfaction was found to be more with Ropivacaine with Dexmedetomidine when compared to Ropivacaine alone or with Ketamine

Comparative Analysis of Very Reduced vs Full Dose BCG Treatment for High-Risk Non-Muscle Invasive Bladder Cancer: A Contemporary Experience from Chile.

Adjuvant bacillus Calmette-Guérin (BCG) is recommended for high-risk (HR) non-muscle invasive bladder cancer (NMIBC), but BCG shortages have led to exploration of reduced-dose regimens and shortened maintenance durations out of necessity, with limited data on treatment efficacy in Latin America. Oncological outcomes of HR-NMIBC patients treated with reduced (RD,1/4th dose) vs full dose (FD) BCG instillations of Danish Strain 1331 BCG. We performed a retrospective study of HR-NMIBC patients treated with BCG between 2003 and 2022 at our center in Santiago Chile. We stratified patients according to either RD (1/4th dose) or FD BCG. Univariate and multivariable Cox regression models were used to predict recurrence. Kaplan-Meier method was used to calculate survival estimates. Of a total of 200 patients, 116 (58%) had RD and 84 (42%) FD BCG. Median follow-up was 57 months (IQR: 29-100). Patients who received FD BCG had a lower risk of recurrence (HR: 0.41, 95% CI 0.22-0.74) and high-grade (HG)-recurrence (HR: 0.30, 95% CI 0.15-0.61; p = 0.001). More patients in the RD vs FD group progressed to MIBC (10/84 vs 2/116; p = 0.18). Additionally, patients were less likely to stop BCG treatment in the RD group compared to the FD group due to toxicity (5% vs 11%, p = 0.14). A 1/4th dose of Danish Strain 1331 BCG treatment was associated with worse recurrence free rate and HG-recurrence rate in our cohort. Patients with RD had lower discontinuation treatment rates due to a reduced toxicity profile. These findings would suggest that RD BCG would compromise oncological outcomes in HR-NMIBC patients.

Cytomegalovirus-Seronegative Plus Leukoreduced Blood Products Are Still Superior to Only Leukoreduced Products in Preventing Transfusion-Transmitted Cytomegalovirus Infection

Introduction Cytomegalovirus (CMV) is one of the most important pathogens causing complications after hematopoietic stem cell transplantation (HSCT). Transfusion-transmitted CMV infection (TT-CMV) in CMV-seronegative patients is a major issue. Leukoreduced (LR) blood products were unavailable before 2004. However, they have gradually become widespread, and all blood products in Japan have been LR since 2007. This study aimed to assess the incidence of TT-CMV in CMV-seronegative HSCT recipients undergoing autologous HSCT (auto-HSCT) or allogeneic HSCT (allo-HSCT) from CMV-seronegative stem cell donors, who received transfusions with “CMV-seronegative products” from CMV-seronegative donors or “random donor products” from donors not tested for anti-CMV antibodies during the periods of availability and unavailability of LR products. Methods We retrospectively evaluated 3590 CMV-seronegative recipients registered in the TRUMP database of the Japanese Society for Transplantation and Cellular Therapy from 1999 to 2018. The recipients undergoing HSCT were categorized into three periods: Period A (when LR products were unavailable), 1999-2003 (n = 136); Period B (when there were both non-LR and LR products), 2004-2006 (n = 200); and Period C (when only LR products were available), 2007-2018 (n = 3254). TT-CMV was defined by the presence of CMV antigenemia and/or CMV diseases. This study was approved by the Ethics Committee of Kobe University Hospital and was conducted in accordance with the principles of the Declaration of Helsinki. Results The median age of the patients at HSCT was 40 years (range, 0-79 years). Among auto-HSCT patients (n = 1628) transfused with “CMV-negative products”(CN group) and “random donor products” (RD group), the incidences of TT-CMV in the CN and RD groups were 0% (0/4) and 3.1% (1/32) during Period A (P = 1.0), 22.2% (2/9) and 10.6% (7/66) during Period B (P = 0.29), and 3.8% (4/105) and 5.0% (71/1412) during Period C (P = 0.81), respectively. Among the allo-HSCT patients (n = 1962), the incidences of TT-CMV in the CN and RD groups were 10.0% (3/30) and 27.1% (19/70) during Period A (P = 0.07), 17.9% (5/28) and 29.9% (29/97) during Period B (P = 0.24), and 11.6% (41/355) and 28.0% (387/1382) during Period C (P &amp;lt; 0.001), respectively. During Period C, 99 patients in the CN group always underwent transfusion with leukocyte reduction filters, of which 11 (11.1%) were diagnosed with TT-CMV. In contrast, 202 patients in the CN group always underwent transfusion without the filters, of which 26 (12.9%) were diagnosed with TT-CMV (P = 0.78). In the RD group, 494 patients always underwent transfusion with leukocyte reduction filters, of which 124 (25.1%) were diagnosed with TT-CMV. On the other hand, 807 patients in the RD group always underwent transfusion without the filters, of which 245 (30.4%) were diagnosed with TT-CMV (P = 0.10). Multivariate analysis revealed that random donor products (hazard ratio [HR]: 3.11, 95% confidence interval [CI]: 2.13-4.52; P &amp;lt; 0.001) and age ≥16 years (HR: 2.90, 95% CI: 2.06-4.09; P &amp;lt; 0.001) were associated with an increased risk of TT-CMV in allo-HSCT. No significant difference was observed in the incidence of CMV diseases between the CN group (3.7%; 13/355) and the RD group (3.8%; 52/1382) (P = 1.00). The major CMV diseases included CMV colitis (n = 5) and pneumonia (n = 2) in the CN group, and CMV colitis (n = 30), pneumonia (n = 9), and retinitis (n = 4) in the RD group. Interestingly, among the patients with TT-CMV during Period C, 27/41 patients (65.9%) in the CN group and 333/387 patients (86.1%) in the RD group received early intervention with anti-CMV agents (P = 0.002). The limitation included that complement-fixation test for anti-CMV antibody was used in Japan Marrow Donor Program in this cohort. Conclusion This is the largest study demonstrating that CMV-seronegative plus LR products are still superior to only LR products from random donors in terms of TT-CMV prevention among allo-HSCT CMV-seronegative recipients. However, no significant difference was observed in the incidence of CMV diseases, possibly because of early intervention with anti-CMV agents.

Effect of fed dietary yeast (Rhodotorula paludigena CM33) on shrimp growth, gene expression, intestinal microbial, disease resistance, and meat composition of Litopenaeus vannamei

Yeast is a health-promoting and bio-therapeutic probiotic that is commonly used in aquaculture. Rhodotorula paludigena CM33 can accumulate amounts of intracellular carotenoids and lipid, which are regarded as nutritionally beneficial compounds in various aspects. The aim of this study was to evaluate the impact of different levels of R. paludigena CM33 (RD) incorporated in a dietary composition at 0% (control), 1% (1% RD), 2% (2% RD), and 5% (5% RD) on the growth of shrimp (Litopenaeus vannamei), their immune-related gene expression, intestinal health, resistance to Vibrio parahaemolyticus (VPAHPND) infection, and meat composition. The results showed significant improvements in the specific growth rate, weight gain, and survival of shrimp fed with 1% RD, 2% RD, and 5% RD, which were higher than the control group after 4 weeks of administration. The administration of 5% RD group resulted in a decrease in cumulative mortality upon VPAHPND challenge when compared to the control group. Furthermore, the expression levels of immune-responsive genes, including proPO system (prophenoloxidase-2: PO2), antioxidant enzyme (superoxide dismutase: SOD, glutathione peroxidase: GPX, and catalase: CAT), JAK/STAT pathway (signal transducer and activator of transcription: STAT, gamma interferon inducible lysosomal thiol reductase: GILT), IMD pathway (inhibitor of nuclear factor kappa-B kinase subunit beta and epsilon: IKKb and IKKe), and Toll pathway (Lysozyme) genes, were up-regulated in the 5% RD group. In the context of microbiota, microbiome analysis revealed that the main phyla in shrimp intestines were Proteobacteria, Firmicutes, Bacteroidota, Campilobacterota, Actinobacteriota, and Verrucomicrobiota. At the genus level, Vibrio was found to be reduced in the 5% RD group, whereas the abundance of potentially beneficial bacteria Bifidobacterium was increased. The 5% RD group showed a significant increase in the levels of crude protein and crude lipid, both of which are essential nutritious components. Our results show the capability of R. paludigena CM33 as a probiotic supplement in shrimp feed in improving growth, antimicrobial responses against VPAHPND, and meat quality by increasing protein and lipid content in shrimp.

Effect of tumor microenvironment on chemotherapy response of patients with triple-negative breast cancer receiving neoadjuvant chemotherapy.

590 Background: Triple-negative breast cancer (TNBC) is a breast cancer subtype that has poor prognosis and exhibits a unique tumor microenvironment, including the corresponding immunological environment. Analysis of the tumor microbiome has indicated a relationship between the tumor microenvironment and treatment response. Therefore, we attempted to reveal the role of the tumor microbiome in patients with TNBC that were receiving neoadjuvant chemotherapy. Methods: We collected TNBC patient RNA-seq samples from the Gene Expression Omnibus (GEO; n of pathological complete response [pCR] = 38, n of residual disease [RD] = 50) and extracted microbiome count data using Kraken2 and Bracken. Differential and relative abundance were estimated with linear discriminant analysis effect size (LEfSe). We calculated the immune cell fraction with CIBERSORTx and conducted survival analysis using the Cancer Genome Atlas patient data (n = 115). Correlations between the microbiome and immune cell compositions were analyzed and a prediction model was constructed to estimate drug response using random forest (RF) and support vector machine (SVM). Results: Among the drug response group, the beta diversity varied considerably; consequently, 20 genera and 24 species were observed to express a significant differential and relative abundance using LEfSe analysis. The drug response prediction model accuracy exhibited 76.47 and 88.24 percent in RF and SVM, respectively; specifically, Pandoraea pulmonicola and Brucella melitensis were found to be important features in determining drug response. In correlation analysis, Geosporobacter ferrireducens, Streptococcus sanguinis, and resting natural killer cells were the most correlated factors in the pCR group, whereas Nitrosospira briensis, Plantactinospora sp. BC1, and regulatory T cells (Tregs) were key features in the RD group. Further, M2 macrophages and Brucella showed significant differences in survival between the pCR and RD groups (p &lt; 0.05). Conclusions: Our study demonstrated that the microbiome analysis of tumor tissue can predict chemotherapy response of patients with TNBC receiving neoadjuvant chemotherapy. Further, the immunological tumor microenvironment may be impacted by the tumor microbiome, thereby affecting the corresponding survival and treatment response.

Failure pattern and radiotherapy exploration in malignant pleural effusion non-small cell lung cancer treated with targeted therapy.

Actionable mutations are common in non-small cell lung cancer(NSCLC)with malignant pleural effusion(MPE)(MPE-NSCLC). The pattern of failure in MPE-NSCLC treated with targeted therapy after MPE control remains unclear. We aimed to investigate the failure pattern of such patients in a cohort study and explore the possibility of radiotherapy. Computed tomography scans of 86 patients were reviewed in this study. We classified first pattern of failure after MPE control as initial disease sites only (IF), new distant sites only (NF), or IF and NF detected simultaneously (INF). Patients evaluated suitable for radiotherapy after disease progression were divided into two groups: D group without radiotherapy and RD group with radiotherapy. The Kaplan-Meier method and log-rank test were used for survival analyses. Disease progression after MPE control was observed in 42 patients with complete serial imaging. Median time to any progression was 9.5 months. Rate of the IF, NF and INF were 50%, 17% and 33% for all patients,60%,0% and 40% for patients with MPE recurrence (n=10,23.8%) and 47%, 22% and 31% for patients (n=32,76.2%) without MPE recurrence, respectively. Out of 10 patients(23.8%) with MPE recurrence, 7 patients simultaneous underwent primary tumor progression and 5 MPE were cytologically confirmed in 7 patients with examination. The overall survival (OS )rates at 1, 2, 3 years for the RD group and D group were 88.2%, 50.5%, 21.7% and 80.0%, 20.3%, 0%, respectively; the corresponding MST were 26.1 months and 17.5 months, respectively (χ2 = 4.959, p =0.026). Our data indicates that 50% of patients with actionable mutations MPE- NSCLC after MPE control are likely to fail at their initial sites of disease and the use of radiotherapy may bring OS benefits during the course of their disease. Multicenter RCT is necessary to confirm the result in the future.

Axial length, vitreoretinal pathology, and anterior chamber depth can predict postoperative refractive outcomes in phacovitrectomy/silicone oil removal.

To evaluate the postoperative refractive prediction error (PE) and determine the factors that affect the refractive outcomes of combined pars plana vitrectomy (PPV) or silicone oil removal (SOR) with cataract surgery. The study is a retrospective, case-series study. Totally 301 eyes of 301 patients undergoing combined PPV/SOR with cataract surgery were enrolled. Eligible individuals were separated into four groups according to their preoperative diagnoses: silicone oil-filled eyes after PPV (group 1), epiretinal membrane (group 2), macular hole (group 3), and primary retinal detachment (RD; group 4). The variables affecting postoperative refractive outcomes were analyzed, including age, gender, preoperative best-corrected visual acuity (BCVA), axial length (AL), keratometry average, anterior chamber depth (ACD), intraocular tamponade, and vitreoretinal pathology. The outcome measurements include the mean refractive PE and the proportions of eyes with a PE within ±0.50 diopter (D) and ±1.00 D. For all patients, the mean PE was -0.04±1.17 D, and 50.17% of patients (eyes) had a PE within ±0.50 D. There was a significant difference in refractive outcomes among the four groups (P=0.028), with RD (group 4) showing the least favorable refractive outcome. In multivariate regression analysis, only AL, vitreoretinal pathology, and ACD were strongly associated with PE (all P<0.01). Univariate analysis revealed that longer eyes (AL>26 mm) and a deeper ACD were correlated with hyperopic PE, and shorter eyes (AL<26 mm) and a shallower ACD were correlated with myopic PE. RD patients have the least favorable refractive outcome. AL, vitreoretinal pathology, and ACD are strongly associated with PE in the combined surgery. These three factors affect refractive outcomes and thus can be used to predict a better postoperative refractive outcome in clinical practice.

Effect of intraperitoneal infusion of ropivacaine combined with dexmedetomidine in patients undergoing total laparoscopic hysterectomy: a single-center randomized double-blinded controlled trial

PurposeTo investigate the effect of intraperitoneal infusion of ropivacaine combined with dexmedetomidine and ropivacaine alone on the quality of postoperative recovery of patients undergoing total laparoscopic hysterectomy (TLH).MethodsFemale patients scheduled to undergo a TLH under general anesthesia at Fujian Maternity and Child Health Hospital were included. Before the end of pneumoperitoneum, patients were laparoscopically administered an intraperitoneal infusion of 0.25% ropivacaine 40 ml (R group) or 0.25% ropivacaine combined with 1 µg/kg dexmedetomidine 40 ml (RD group). The primary outcome was QoR-40, which was assessed before surgery and 24 h after surgery. Secondary outcomes included postoperative NRS scores, postoperative anesthetic dosage, the time to ambulation, urinary catheter removal, and anal exhaust. The incidence of dizziness, nausea, and vomiting was also analyzed.ResultsA total of 109 women were recruited. The RD group had higher QoR scores than the R group at 24 h after surgery (p < 0.05). Compared with the R group, NRS scores in the RD group decreased at 2, 6, 12, and 24 h after surgery (all p < 0.05). In the RD group, the time to the first dosage of postoperative opioid was longer and the cumulative and effective times of PCA compression were less than those in the R group (all p < 0.05). Simultaneously, the time to ambulation (p = 0.033), anal exhaust (p = 0.002), and urethral catheter removal (p = 0.018) was shortened in the RD group. The RD group had a lower incidence of dizziness, nausea, and vomiting (p < 0.05).ConclusionIntraperitoneal infusion of ropivacaine combined with dexmedetomidine improved the quality of recovery in patients undergoing TLH.Trial registrationChiCTR2000033209, Registration Date: May 24, 2020.

Rescue doses of antenatal corticosteroids, children's neurodevelopment, and salivary cortisol after a threatened preterm labor: a 30-month follow-up study

Antenatal corticosteroids (ACS) reduce neonatal complications when are administered to women at risk of preterm birth. Moreover, ACS rescue doses are recommended in women who remain at risk after the initial course. However, there is controversy about the most appropriate frequency and exact timing for administering additional ACS doses since there are potential long-term negative effects on infants´ neurodevelopment and physiological stress functioning. The aims of this study were: i) to assess the long-term neurodevelopmental effects of receiving ACS rescue doses vs. receiving only the initial course; ii) to measure cortisol levels of infants that received ACS rescue doses; iii) to examine a potential dose-response effect of the number of ACS rescue doses on children´s neurodevelopment and salivary cortisol. The study followed 110 mother-infant pairs who underwent a spontaneous episode of threatened preterm labor (TPL) until the children were 30 months old, regardless of their gestational age at birth. Among the participants, 61 received only the initial course of corticosteroids (no rescue dose [NRD] group), and 49 participants required at least one rescue dose of corticosteroids (rescue doses [RD] group). The follow-up was carried out at three different times: [T1] at TPL diagnosis, [T2] at the children´s age of 6 months, and [T3] at the children's age of 30 months, corrected age for prematurity. Neurodevelopment was assessed using the Ages & Stages Questionnaires-Third Edition. Saliva samples were collected for cortisol level determination. First, the RD group showed lower problem-solving skills at age 30-months compared to the NRD group. Second, the RD group demonstrated higher salivary cortisol levels at 30-months. Third, a dose-response effect was found, indicating that the higher number of rescue doses the RD group received, the lower the problem-solving skills and the higher the salivary cortisol levels they showed at 30 months of age. Our findings reinforce the hypothesis that additional doses provided after the initial course of ACS may have long-term effects on offspring's neurodevelopment and glucocorticoid metabolism. In this regard, the results raise concerns about the negative effects of repeated doses in addition to a full course of ACS. Further studies are necessary to confirm this hypothesis and help physicians to reassess the standard ACS treatment regimens.