Nephroprotective Effect of the Leaf Extract of Ajuga remota Benth Against Gentamicin-Induced Nephrotoxicity in Swiss Albino Mice.

Background: Drug-induced kidney injury was among the most common renal damages, from which gentamicin occupies around 25% of this injury. Gentamicin-induced renal damage is caused by increased free radicals with subsequent amplified inflammation. Ajuga remota leaf extract has many phytochemicals with antioxidant activities, which may improve gentamicin-induced renal damage. Thus, we aimed to investigate the nephroprotective effect of Ajuga remota leaf methanolic extract on gentamicin-induced nephrotoxicity in Swiss Albino Mice. Methods: An experimental study design was used on 30 experimental mice randomly allocated in six groups: Group I, II, II, IV, and VI, among which mice were given only distilled water, only gentamicin, 600 mg/kg Ajuga remota leaf extract only, gentamicin along with 200 mg/kg extract, gentamicin with 400 mg/kg extract and gentamicin with 600 mg/kg extract, respectively. At the end of the experiment, the mice were sacrificed after being anaesthetized, and blood samples were collected through a cardiac puncture for renal function tests while the kidneys were removed for histopathological evaluation. The data were entered into Epidata version 4.6 and exported to SPSS version 25 for further analysis using one-way analysis of variance. Statistical significance was set at p < 0.05. Results: Group II mice had significantly higher levels of serum creatinine and blood urea levels compared to group I and III. The body weight of the mice in group V and group VI showed a significant increase compared with Group II. Serum creatinine and blood urea levels were reduced significantly in the Ajuga remota leaf extract administered group of mice compared to group II. Abnormal kidney architectural changes were seen among group II mice; however, those changes were improved after administration of Ajuga remota leaf methanolic extract. Conclusion: Methanol extract of Ajuga remota leaf provided effective protection against gentamicin-induced oxidative renal damage through its antioxidant effects.

Serum Lipid Profiles, Blood Glucose, and High-Sensitivity C-Reactive Protein Levels Among People Living with HIV Taking Dolutegravir and Ritonavir-Boosted Atazanavir-Based Antiretroviral Therapy at Jimma University Medical Center, Southwest Ethiopia, 2021.

Background: Long-term use of antiretroviral therapy, especially dolutegravir and boosted-atazanavir, raises concerns about cardiovascular disease. Thus, this study aimed to assess lipid profiles, blood glucose, and high-sensitivity C-reactive protein levels among people living with HIV on dolutegravir and ritonavir-boosted atazanavir-based therapy. Methods: An institutional-based comparative cross-sectional study was conducted from November 4, 2021, to January 4, 2022. An equal number of dolutegravir- and ritonavir-boosted atazanavir-treated patients (n = 64 each) was enrolled. A consecutive sampling was used to select participants. The Chi-square, Student's t-test, Mann-Whitney U-test, and logistic regression were used as appropriate statistical tests using SPSS Version 25.0. Statistical significance was set at p < 0.05. Results: Dyslipidemia was found in 67.2% (43/64) of ritonavir-boosted atazanavir group and 48.4% (31/64) of dolutegravir group. The dolutegravir group had significantly higher mean and median values of high-density lipoprotein and random blood sugar, respectively, as well as lower median triglyceride and high-sensitivity C-reactive protein levels than the ritonavir-boosted atazanavir group. Ritonavir-boosted atazanavir-based regimens (AOR=3.4, 95% CI: 1.5, 8) and age >40 years were predictors of dyslipidemia, while BMI ≥25 kg/m2 (AOR=3.7, 95% CI: 1.3, 10.8) and dolutegravir-based regimens (AOR=4.6, 95% CI: 1.5, 14) were predictors of hyperglycemia. Ritonavir-boosted atazanavir-based regimens (ARR=3, 95% CI: 1.3, 8) and BMI ≥25 kg/m2 (ARR=2.5, 95% CI: 1.1, 6) were associated with increased high-sensitivity C-reactive protein by 1-3 mg/L. The risk of increased high-sensitivity C-reactive protein by >3 mg/L was greater in those patients with a CD4 cell count of <500 cells/mm3 (ARR=5, 95% CI: 1.1, 24). Conclusion: When compared to ritonavir-boosted atazanavir-based regimens, dolutegravir had favorable lipid profiles and high-sensitivity C-reactive protein but unfavorable blood glucose levels. Therefore, baseline blood glucose, lipid profiles, and high-sensitivity C-reactive protein levels should be routinely measured in patients on these regimens.

An Analysis of pre and post-Processing Semen Parameters at The Time of Intrauterine Insemination; and The Confounding Effects of Total Motile Sperm Counts on Pregnancy Outcome: A Prospective Cohort Study.

BACKGROUND: This study aims to determine whether pre or post-processing semen parameters obtained during intrauterine insemination (IUI) predict pregnancy when controlling for confounding effects. MATERIALS AND METHODS: A prospective cohort study of 2231 semen analyses was conducted at McGill University of IVF center. Any couples who underwent IUI with partner sperm, over a 2.5-year period, were included. Controlled ovarian stimulation was done with Clomiphene Citrate, Letrozole, or Gonadotropins. Statistical analysis was performed using t tests, two types of stepwise logistic regression, and stepwise discriminant analysis. A comparison of pre and post-processing semen parameters was undertaken to determine the probability of pregnancy. RESULTS: There were significant differences between pregnant and non-pregnant women in post-processing concentration (P=0.043), post-processing total motile sperm count (TMSC) (P=0.049), and post-linearity (P=0.012). However, when variable out-of-the-equation logistic regression or discriminant analysis, which controls for confounding effects between variables, were used, the findings were no longer significant. It was statistically proven that when a variable in the equation logistic regression was employed, post-processing concentration (P=0.005) and post-processing TMSC (P=0.009) remained reliable predictors of pregnancy. CONCLUSION: Two of three prediction models suggested that TMSC's relationship with pregnancy is due to confounding factors. One model maintained the validity of the TMSC. While TMSC has always been studied as an important predictor of insemination pregnancies, this finding may be due to confounding effects between semen parameters and therefore requires further investigation as to this relationship.

Exploring the benefits of in-diet versus repeated oral dosing of saracatinib (AZD0530) in chronic studies: insights into pharmacokinetics and animal welfare.

Saracatinib/AZD0530 (SAR), a Src tyrosine kinase inhibitor, mitigates seizure-induced brain pathology in epilepsy models upon repeated oral dosing. However, repeated dosing is stressful and can be challenging in some seizing animals. To overcome this issue, we have incorporated SAR-in-Diet and compared serum pharmacokinetics (PK) and brain concentrations with conventional repeated oral dosing. Saracatinib in solution or in-diet was stable at room temperature for >4 weeks (97 ± 1.56%). Adult Sprague Dawley rats on SAR-in-Diet consumed ~1.7 g/day less compared to regular diet (16.82 ± 0.6 vs. 18.50 ± 0.5 g/day), but the weight gain/day was unaffected (2.63 ± 0.5 g/day vs. 2.83 ± 0.2 g/day). Importantly, we achieved the anticipated SAR dose range from 2.5-18.7 mg/kg of rat in response to varying concentrations of SAR-in-Diet from 54 to 260 ppm of feed, respectively. There was a strong and significant correlation between SAR-in-Diet dose (mg/kg) and serum saracatinib concentrations (ng/ml). Serum concentrations also did not vary significantly between SAR-in-Diet and repeated oral dosing. The hippocampal saracatinib concentrations derived from SAR-in-Diet treatment were higher than those derived after repeated oral dosing (day 3, 546.8 ± 219.7 ng/g vs. 238.6 ± 143 ng/g; day 7, 300.7 ± 43.4 ng/g vs. 271.1 ± 62.33 ng/g). Saracatinib stability at room temperature and high serum and hippocampal concentrations in animals fed on SAR-in-Diet are useful to titer the saracatinib dose for future animal disease models. Overall, test drugs in the diet is an experimental approach that addresses issues related to handling stress-induced variables in animal experiments.

How dominant the load of bioaerosols in PM2.5 and PM10: a comprehensive study in the IGP during winter.

The winter period is most ideal for studying near-surface aerosols in the Indo-Gangetic plains (IGP) of India, since this period is inundated with significantly higher concentrations of aerosols across the unique geographical domain because of shallow atmospheric boundary layer. This study focuses on analysing the concentration of the biotic component of aerosols (bioaerosols) in a central location of the IGP and estimating their dominance in ambient particulate matter (PM) from 2021 to 2023. Observations showed that bioaerosol concentrations also increased significantly with the increasing concentrations of PM2.5 and PM10, suggesting that bioaerosols are a dominant component of the total aerosol load in the atmosphere. The total microbe's concentration (collectively fungi and bacteria) was found to be 94 to 226 cfu m-3 in PM2.5 and 167 to 375 cfu m-3 in PM10 where bacteria contributed 81.12 and 79.99%, respectively. The contribution of fungal spores in PM2.5 and PM10 remained as 18.88 and 20.01%, respectively, in the total microbes in the respective particulate matter. In the bioaerosols, fungi, namely Aspergillus, Cladosporium, and Penicillium, were dominant, and bacteria, namely E. coli, Mammaliicoccus and Enterobacter, were prevalent in both the PM size regimes. The most prominent microbial presence was observed when the temperature ranged between 16 and 20°C and relative humidity between 80 and 85%. The outcomes of the present study will be useful for further research on the health effect of the bioaerosols in the IGP.

Expression Analysis Reveals Differentially Expressed Genes in BPH and WBPH Associated with Resistance in Rice RILs Derived from a Cross between RP2068 and TN1.

BPH (brown planthopper) and WBPH (white backed planthopper) are significant rice pests that often co-occur as sympatric species and cause substantial yield loss. Despite their genetic similarities, different host-resistance genes confer resistance against these two hoppers. The defense mechanisms in rice against these pests are complex, and the molecular processes regulating their responses remain largely unknown. This study used specific recombinant inbred lines (RILs) derived from a cross between rice varieties RP2068-18-3-5 (BPH- and WBPH-resistant) and TN1 (BPH- and WBPH-susceptible) to investigate the mechanisms of interaction between these planthoppers and their rice hosts. WBPH and BPH were allowed to feed on specific RILs, and RNA-Seq was carried out on WBPH insects. Transcriptome profiling and qRT-PCR results revealed differential expression of genes involved in detoxification, digestion, transportation, cuticle formation, splicing, and RNA processing. A higher expression of sugar transporters was observed in both hoppers feeding on rice with resistance against either hopper. This is the first comparative analysis of gene expressions in these insects fed on genetically similar hosts but with differential resistance to BPH and WBPH. These results complement our earlier findings on the differential gene expression of the same RILs (BPH- or WBPH-infested) utilized in this study. Moreover, identifying insect genes and pathways responsible for countering host defense would augment our understanding of BPH and WBPH interaction with their rice hosts and enable us to develop lasting strategies to control these significant pests.

Validation of Immunotherapy Response Score as Predictive of Pan-solid Tumor Anti-PD-1/PD-L1 Benefit.

Immunotherapy response score (IRS) integrates tumor mutation burden (TMB) and quantitative expression biomarkers to predict anti-PD-1/PD-L1 [PD-(L)1] monotherapy benefit. Here, we evaluated IRS in additional cohorts. Patients from an observational trial (NCT03061305) treated with anti-PD-(L)1 monotherapy were included and assigned to IRS-High (-H) versus -Low (-L) groups. Associations with real-world progression-free survival (rwPFS) and overall survival (OS) were determined by Cox proportional hazards (CPH) modeling. Those with available PD-L1 IHC treated with anti-PD-(L)1 with or without chemotherapy were separately assessed. Patients treated with PD-(L)1 and/or chemotherapy (five relevant tumor types) were assigned to three IRS groups [IRS-L divided into IRS-Ultra-Low (-UL) and Intermediate-Low (-IL), and similarly assessed]. In the 352 patient anti-PD-(L)1 monotherapy validation cohort (31 tumor types), IRS-H versus IRS-L patients had significantly longer rwPFS and OS. IRS significantly improved CPH associations with rwPFS and OS beyond microsatellite instability (MSI)/TMB alone. In a 189 patient (10 tumor types) PD-L1 IHC comparison cohort, IRS, but not PD-L1 IHC nor TMB, was significantly associated with anti-PD-L1 rwPFS. In a 1,103-patient cohort (from five relevant tumor types), rwPFS did not significantly differ in IRS-UL patients treated with chemotherapy versus chemotherapy plus anti-PD-(L)1, nor in IRS-H patients treated with anti-PD-(L)1 versus anti-PD-(L)1 + chemotherapy. IRS associations were consistent across subgroups, including both Europeans and non-Europeans. These results confirm the utility of IRS utility for predicting pan-solid tumor PD-(L)1 monotherapy benefit beyond available biomarkers and demonstrate utility for informing on anti-PD-(L)1 and/or chemotherapy treatment. Significance: This study confirms the utility of the integrative IRS biomarker for predicting anti-PD-L1/PD-1 benefit. IRS significantly improved upon currently available biomarkers, including PD-L1 IHC, TMB, and MSI status. Additional utility for informing on chemotherapy, anti-PD-L1/PD-1, and anti-PD-L1/PD-1 plus chemotherapy treatments decisions is shown.

Antineoplastic activity of plant-derived compounds mediated through inhibition of histone deacetylase: a review.

In the combat of treating cancer recent therapeutic approaches are focused towards enzymatic targets as they occupy a pivotal participation in the cascade of oncogenesis and malignancy. There are several enzymes that modulate the epigenetic pathways and chromatin structure related to cancer mutation. Among several epigenetic mechanisms such as methylation, phosphorylation, and sumoylation, acetylation status of histones is crucial and is governed by counteracting enzymes like histone acetyl transferase (HAT) and histone deacetylases (HDAC) which have contradictory effects on the histone acetylation. HDAC inhibition induces chromatin relaxation which forms euchromatin and thereby initiates the expression of certain transcription factors attributed with apoptosis, which are mostly correlated with the expression of the p21 gene and acetylation of H3 and H4 histones. Most of the synthetic and natural HDAC inhibitors elicit antineoplastic effect through activation of various apoptotic pathways and promoting cell cycle arrest at various phases. Due to their promising chemo preventive action and low cytotoxicity against normal host cells, bioactive substances like flavonoids, alkaloids, and polyphenolic compounds from plants have recently gained importance. Even though all bioactive compounds mentioned have an HDAC inhibitory action, some of them have a direct effect and others enhance the effects of the standard well known HDAC inhibitors. In this review, the action of plant derived compounds against histone deacetylases in a variety of in vitro cancer cell lines and in vivo animal models are articulated.

Oncolytic DNX-2401 virotherapy plus pembrolizumab in recurrent glioblastoma: a phase 1/2 trial.

Immune-mediated anti-tumoral responses, elicited by oncolytic viruses and augmented with checkpoint inhibition, may be an effective treatment approach for glioblastoma. Here in this multicenter phase 1/2 study we evaluated the combination of intratumoral delivery of oncolytic virus DNX-2401 followed by intravenous anti-PD-1 antibody pembrolizumab in recurrent glioblastoma, first in a dose-escalation and then in a dose-expansion phase, in 49 patients. The primary endpoints were overall safety and objective response rate. The primary safety endpoint was met, whereas the primary efficacy endpoint was not met. There were no dose-limiting toxicities, and full dose combined treatment was well tolerated. The objective response rate was 10.4% (90% confidence interval (CI) 4.2-20.7%), which was not statistically greater than the prespecified control rate of 5%. The secondary endpoint of overall survival at 12 months was 52.7% (95% CI 40.1-69.2%), which was statistically greater than the prespecified control rate of 20%. Median overall survival was 12.5 months (10.7-13.5 months). Objective responses led to longer survival (hazard ratio 0.20, 95% CI 0.05-0.87). A total of 56.2% (95% CI 41.1-70.5%) of patients had a clinical benefit defined as stable disease or better. Three patients completed treatment with durable responses and remain alive at 45, 48 and 60 months. Exploratory mutational, gene-expression and immunophenotypic analyses revealed that the balance between immune cell infiltration and expression of checkpoint inhibitors may potentially inform on response to treatment and mechanisms of resistance. Overall, the combination of intratumoral DNX-2401 followed by pembrolizumab was safe with notable survival benefit in select patients (ClinicalTrials.gov registration: NCT02798406).

Immunotherapy May Improve Tumor Sensitivity to Palliative Chemotherapy in Platinum Resistant Ovarian Cancer.

Ovarian cancer is the second most common gynecologic cancer in the US and ranks among the top 10 causes of female cancer-related deaths. Platinum-resistant disease carries a particularly poor prognosis and leaves patients with limited remaining therapeutic options. Patients with platinum-resistant disease have significantly lower response rates to additional chemotherapy, with estimates as low as 10%-25%. We hypothesize that in patients with platinum-resistant ovarian cancer, treatment with immunotherapy followed by cytotoxic chemotherapy with antiangiogenic therapy results in prolonged survival without compromising quality of life. Our experience of 3 patients with recurrent, metastatic platinum-resistant ovarian cancer treated with immunotherapy followed by anti-angiogenic treatment plus chemotherapy resulted in progression-free survival durations significantly above previously published averages. Further studies evaluating the role of immunotherapy followed by chemotherapy in combination with drugs targeting angiogenesis are needed and may provide a long-sought after breakthrough for advancing survival in platinum-resistant ovarian cancer.

Endoscopy-Assisted Microneurosurgery for Sella and Optic Foramen Invading Anterior Cranial Fossa Base Meningiomas.

BACKGROUND: Anterior skull base meningioma produces symptoms as a result of mass effect and neurovascular compression. The bony anatomy of the anterior skull base is complex and houses the critical cranial nerves and vessels. Traditional microscopic approaches remove these tumors effectively but require extensive brain retraction and bone drilling. Endoscope assistance offers the advantages of a smaller incision, less brain retraction, and bone drilling. The most significant advantage of endoscope-assisted microneurosurgery for lesions invading the sella and optic foramen is the complete resection of the sellar and foraminal components frequently responsible for recurrence. OBJECTIVE: In this report, we describe the technique of endoscope-assisted microneurosurgical resection of anterior skull base meningiomas invading the sella and foramen. METHODS: We present 10 cases and 3 case examples of endoscope-assisted microneurosurgery for meningiomas invading the sella and optic foramen. This report presents the operating room setup and surgical details to resect sellar and foraminal tumors. The surgical procedure is presented as a video. RESULTS: Endoscope-assisted microneurosurgery yielded excellent clinical and radiologic results and no recurrence at the last follow-up of meningiomas invading the sella and optic foramen. The present article discusses the challenges faced with endoscope-assisted microneurosurgery, techniques, and challenges in the procedure. CONCLUSIONS: Endoscope assistance enables complete tumor excision under vision with less retraction and bone drilling in anterior cranial fossa meningioma, invading the chiasmatic sulcus, optic foramen, and sella. The mixed use of microscope and endoscope makes it safer and saves time and is like bringing out the best of both worlds.

The influence of tumor topography on the surgical outcome of craniopharyngiomas.

OBJECTIVE: Various topographical classifications for craniopharyngioma have been proposed based on their relationship with optic chiasm and the third ventricular floor. There is a paucity of literature evaluating the surgical outcome based on tumor topography. This study aims to compare the surgical outcomes of retrochiasmatic craniopharyngiomas (RCPs) and nonretrochiasmatic craniopharyngiomas (non-RCPs). METHODS: This retrospective study includes newly diagnosed patients with craniopharyngioma who underwent surgery between January 2000 and December 2015. Clinical features, the extent of resection (EOR), surgical outcomes, tumor recurrence, and progression-free survival (PFS) of craniopharyngiomas were compared with respect to their relationship to the optic chiasm and third ventricular floor. RESULTS: The authors identified RCPs in 104 and non-RCPs in 33 patients. RCPs were significantly larger and more associated with hydrocephalus than were non-RCPs (p < 0.001) at the time of diagnosis. Puget grade 2 hypothalamic involvement was more frequent with RCPs. EOR and PFS following either subtotal resection (p = 0.07) or gross-total resection (p = 0.7) were comparable between RCPs and non-RCPs. There was no significant difference in the postoperative visual outcome. Resection of RCPs resulted in higher postoperative hypopituitarism (64% vs 42%, p = 0.01) and hypothalamic dysfunction (18% vs 3%, p = 0.02). Location of the tumor, either retrochiasmatic (HR 0.5; 95% CI 0.14-2.2; p = 0.4) or nonretrochiasmatic (HR 1.3; 95% CI 0.3-5.5; p = 0.6), did not show association with recurrence. RCPs with extra- and intraventricular components (type 3b) had a higher incidence of postoperative hypothalamic morbidities (p = 0.01) and tumor recurrence (36% vs 19%; p = 0.05) during follow-up than the extraventricular (type 3a) RCP. Between prechiasmatic and infrachiasmatic/intrasellar craniopharyngiomas, EOR (p = 0.7), postoperative diabetes insipidus (p = 0.4), endocrinological outcome (p = 0.7), and recurrence (p = 0.1) were comparable. The patients with complex multicompartmental tumors had a lower rate of gross-total resection (25%, p = 0.02) and a higher incidence of tumor recurrence (75%, p = 0.004) than the rest. CONCLUSIONS: The tumor topography can influence the postoperative outcome. RCPs can be associated with a higher incidence of hypopituitarism and hypothalamic morbidities postoperatively. The influence of topography on EOR and tumor recurrence is controversial. However, this study did not find a significant difference in EOR and tumor recurrence between RCPs and non-RCPs. PFS and overall mortality are also comparable.

Development and validation of an integrative pan-solid tumor predictor of PD-1/PD-L1 blockade benefit.

BACKGROUND: Anti-PD-1 and PD-L1 (collectively PD-[L]1) therapies are approved for many advanced solid tumors. Biomarkers beyond PD-L1 immunohistochemistry, microsatellite instability, and tumor mutation burden (TMB) may improve benefit prediction. METHODS: Using treatment data and genomic and transcriptomic tumor tissue profiling from an observational trial (NCT03061305), we developed Immunotherapy Response Score (IRS), a pan-tumor predictive model of PD-(L)1 benefit. IRS real-world progression free survival (rwPFS) and overall survival (OS) prediction was validated in an independent cohort of trial patients. RESULTS: Here, by Cox modeling, we develop IRS-which combines TMB with CD274, PDCD1, ADAM12 and TOP2A quantitative expression-to predict pembrolizumab rwPFS (648 patients; 26 tumor types; IRS-High or -Low groups). In the 248 patient validation cohort (248 patients; 24 tumor types; non-pembrolizumab PD-[L]1 monotherapy treatment), median rwPFS and OS are significantly longer in IRS-High vs. IRS-Low patients (rwPFS adjusted hazard ratio [aHR] 0.52, p = 0.003; OS aHR 0.49, p = 0.005); TMB alone does not significantly predict PD-(L)1 rwPFS nor OS. In 146 patients treated with systemic therapy prior to pembrolizumab monotherapy, pembrolizumab rwPFS is only significantly longer than immediately preceding therapy rwPFS in IRS-High patients (interaction test p = 0.001). In propensity matched lung cancer patients treated with first-line pembrolizumab monotherapy or pembrolizumab+chemotherapy, monotherapy rwPFS is significantly shorter in IRS-Low patients, but is not significantly different in IRS-High patients. Across 24,463 molecularly-evaluable trial patients, 7.6% of patients outside of monotherapy PD-(L)1 approved tumor types are IRS-High/TMB-Low. CONCLUSIONS: The validated, predictive, pan-tumor IRS model can expand PD-(L)1 monotherapy benefit outside currently approved indications.

Therapies activating the immune system (checkpoint inhibitors) have revolutionized the treatment of patients with advanced cancer, however new molecular tests may better identify patients who could benefit. Using treatment data and clinical molecular test results, we report the development and validation of Immunotherapy Response Score (IRS) to predict checkpoint inhibitor benefit. Across patients with more than 20 advanced cancer types, IRS better predicted checkpoint inhibitor benefit than currently available tests. Data from >20,000 patients showed that IRS identifies ~8% of patients with advanced cancer who may dramatically benefit from checkpoint inhibitors but would not receive them today based on currently available tests. Our approach may help clinicians to decide which patients should receive checkpoint inhibitors to treat their disease.

Multicenter Phase II Clinical Trial of Gemcitabine and Cisplatin as Neoadjuvant Chemotherapy for Patients With High-Grade Upper Tract Urothelial Carcinoma.

PURPOSE: Neoadjuvant chemotherapy (NAC) has proven survival benefits for patients with invasive urothelial carcinoma of the bladder, yet its role for upper tract urothelial carcinoma (UTUC) remains undefined. We conducted a multicenter, single-arm, phase II trial of NAC with gemcitabine and split-dose cisplatin (GC) for patients with high-risk UTUC before extirpative surgery to evaluate response, survival, and tolerability. METHODS: Eligible patients with defined criteria for high-risk localized UTUC received four cycles of split-dose GC before surgical resection and lymph node dissection. The primary study end point was rate of pathologic response (defined as < ypT2N0). Secondary end points included progression-free survival (PFS), overall survival (OS), and safety and tolerability. RESULTS: Among 57 patients evaluated, 36 (63%) demonstrated pathologic response (95% CI, 49 to 76). A complete pathologic response (ypT0N0) was noted in 11 patients (19%). Fifty-one patients (89%) tolerated at least three complete cycles of split-dose GC, 27 patients (47%) tolerated four complete cycles, and all patients proceeded to surgery. With a median follow up of 3.1 years, 2- and 5-year PFS rates were 89% (95% CI, 81 to 98) and 72% (95% CI, 59 to 87), while 2- and 5-year OS rates were 93% (95% CI, 86 to 100) and 79% (95% CI, 67 to 94), respectively. Pathologic complete and partial responses were associated with improved PFS and OS compared with nonresponders (≥ ypT2N any; 2-year PFS 100% and 95% v 76%, P < .001; 2-year OS 100% and 100% v 80%, P < .001). CONCLUSION: NAC with split-dose GC for high-risk UTUC is a well-tolerated, effective therapy demonstrating evidence of pathologic response that is associated with favorable survival outcomes. Given that these survival outcomes are superior to historical series, these data support the use of NAC as a standard of care for high-risk UTUC, and split-dose GC is a viable option for NAC.

Pseudomonas-specific 16S rRNA insect gut-microbiome profiling using next-generation sequencing.

We present a detailed protocol for Pseudomonas-specific 16S rRNA gut-microbiome profiling of brown planthopper (BPH) populations collected across changing climates and geographical locations using next-generation sequencing. We provide a technique for comparative analysis of Pseudomonas species structure and composition across BPH populations. Additionally, using qPCR we quantify the titers of Pseudomonas species in BPH. This protocol can be adopted for analyzing microbiome dynamics and monitoring populations of other pests, a crucial aspect for understanding their biodiversity, speciation, and adaptations. For complete details on the use and execution of this protocol, please refer to Gupta et al. (2022).1.

Systematic scoping review of papilledema in vestibular schwannoma without hydrocephalus.

BACKGROUND: Vestibular schwannoma is a common pathology encountered by neurosurgeons worldwide. Often vestibular schwannoma presents with obstructive hydrocephalus. Papilledema is present in 8% of the patients with vestibular schwannoma, primarily due to obstructive hydrocephalus. Hyperproteinorrhachia is believed to be responsible for papilledema in the absence of hydrocephalus in vestibular schwannoma. However, there is a paucity of literature on the mechanism of papilledema in vestibular schwannoma patients with hydrocephalus. OBJECTIVE: The aim of this study was to conduct a scoping review of scientific literature on papilledema in vestibular schwannoma patients without hydrocephalus. METHODS: Design: This was a systematic scoping review and critical appraisal. Literature Search from PubMed was done following PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews) and Joanna Briggs Institute guidelines for conducting and reporting scoping reviews. RESULTS: A total of seven studies, including eight patients, were identified for inclusion in the review. The studies were heterogeneous in terms of reporting for various variables. All the included studies were case reports, with the earliest publication in 1954 and the latest publication in 2020. The mean age of the patients in the included studies was 35 years, with a minimum age of 20 years and maximum age of 64 years. Approximately 62.5% were females, and 37.5% were males in the included study. Only three studies have studied cerebrospinal fluid (CSF) proteins levels in these patients. CONCLUSIONS: There is paucity in literature and a lack of evidence to conclusively state hyperproteinorrhachia as an antecedent to the development of papilledema in vestibular schwannoma patients without hydrocephalus. Younger age and female gender are risk factors for developing papilledema in the absence of hydrocephalus in vestibular schwannoma patients. Brainstem compression due to the large size of vestibular schwannoma can still have a patent aqueduct of Sylvius and no obstruction to CSF flow. The development of papilledema in vestibular schwannoma is a complex interplay of multiple factors that must be studied comprehensively for complete understanding.

Epigenetic Diversity Underlying Seasonal and Annual Variations in Brown Planthopper (BPH) Populations as Revealed by Methylation- sensitive Restriction Assay.

Background: The brown planthopper (BPH) is a monophagous sap-sucking insect pest of rice that is responsible for massive yield loss. BPH populations, even when genetically homogenous, can display a vast range of phenotypes, and the development of effective pest-management strategies requires a good understanding of what generates this phenotypic variation. One potential source could be epigenetic differences. Methods: With this premise, we explored epigenetic diversity, structure and differentiation in field populations of BPH collected across the rice-growing seasons over a period of two consecutive years. Using a modified methylation-sensitive restriction assay (MSRA) and CpG island amplification-representational difference analysis, site-specific cytosine methylation of five stress-responsive genes (CYP6AY1, CYP6ER1, Carboxylesterase, Endoglucanase, Tf2-transposon) was estimated, for identifying methylation-based epiallelic markers and epigenetic variation across BPH populations. Results: Using a cost-effective and rapid protocol, our study, for the first time, revealed the epigenetic component of phenotypic variations in the wild populations of BPH. Besides, results showed that morphologically indistinguishable populations of BPH can be epigenetically distinct. Conclusion: Screening field-collected BPH populations revealed the presence of previously unreported epigenetic polymorphisms and provided a platform for future studies aimed at investigating their significance for BPH. Furthermore, these findings can form the basis for understanding the contribution(s) of DNA methylation in providing phenotypic plasticity to BPH.

Routine Application of Lung Ultrasonography in Respiratory Care: Knowledge, Perceptions, and Barriers to Instigate.

Background: Lung Ultrasound (LUS) had proved to be beneficial in detecting respiratory disorders at the bedside. Understanding the important role of Respiratory Therapists (RTs) in the critical care, we aimed to assess their knowledge, perceived relevance of LUS to clinical practice, current skill gaps, and barriers to practice. Methods: A cross-sectional, nationwide survey conducted among the RTs working in the Kingdom of Saudi Arabia. The validated questionnaire included 4 sections; the demographics, knowledge and perceptions, applicability and self-reported proficiency, and barriers to the use of LUS by RTs. Results: A total of 256 RTs across different regions of Saudi Arabia participated in this survey. 71.9% of them were males, and 46.1% of the participants were having <5 years of working experience. Only (18.1%) of the participants used LUS in their clinical practice, and (43%) of them had never received any training. 66% of the participants perceived LUS as an effective tool in the RT practice and immensely valuable in their daily practice (70%). A large proportion of RTs perceived LUS to be ineffective in calculating the lung score (50.4%), assessing the diaphragm (40.2%), and detecting pulmonary edema (38.3%). Calculating lung score has a lower mean score of 2.55 on both skills, and identifying its applicability to clinical practice with a mean score of 2.71 than other indications. Lack of training and curriculum (154/256; 60.2%) remains the top barrier that prevented RTs from using LUS in their clinical practice. Conclusion: While many RTs in Saudi Arabia perceived LUS as an effective tool in the RT practice, considerable competence gap exist, indicating the need for LUS training. There is a need for incorporating LUS into the curriculum of RT schools and promoting competency-based training for the current RT workforce to help improve patient care.

Analysis of Prognostic Factors, Extent of Resection, and Long-Term Outcome of Craniopharyngioma in Adults and Children.

Introduction: Surgical management of craniopharyngioma is debatable and still lacks clear guidelines. Long-term complications are attributed to radical resection of the tumor. Extent of resection may not be the only factor which determines the functional outcome, because studies have reported hypothalamic and visual morbidities even with conservative resection. In this article, we analyze the extent of resection, long-term outcome, and various prognostic factors in adults and children. Materials and Methods: Newly diagnosed cases of craniopharyngioma operated between 2001 and 2013 were reviewed retrospectively. PFS and OS were calculated. Predictors of various outcome parameters were analyzed. Results: Of 140 patients, 41% were children and 59% were adults. Postoperatively, vision has improved in 63% and worsened in 12%. GTR was achieved in 66%. The median follow-up was 67 months. PFS at 5 and 10 years was 95% and 41.5%, respectively. OS at 5 and 10 years was 92.6% and 89.5%, respectively. Symptoms of raised ICP and hypothalamic involvement, extensive calcifications, tumor size >5 cm, and multi-compartmental tumors were associated with presence of residual tumor. Regression analysis showed symptoms of hypothalamic involvement, size of the tumor > 5 cm, and hydrocephalus predicted postoperative hypothalamic morbidities. No significant difference was found in postoperative visual, endocrinological, hypothalamic, and functional outcomes between GTR and STR. Conclusion: Conservative resection should be carried out in patients with preoperative hypothalamic symptoms and imaging evidence of extensive hypothalamic involvement. Size of the tumor and invasiveness are the other factors should be considered before radical excision of craniopharyngiomas.