Prevalence of depression in hypertensive patients and its associated factors in India: A systematic review and meta-analysis.

BACKGROUND: Hypertension is a prevalent health challenge in India, with a bidirectional link to depression. Recognizing the prevalence of depression among hypertensive patients and associated factors are important for better health outcomes. METHODS: A comprehensive search was conducted in PubMed, Embase, Scopus, and Google Scholar databases to identify relevant studies. R software was used for analysis, employing a random effects model with a 95% confidence interval. Subgroup analyses were done to explore sources of heterogeneity within the included studies. RESULTS: The prevalence of depression among hypertensive patients in India was 39.8% (95% CI: 28.6; 52.1). Despite a higher prevalence observed in South region (44.7%) compared to North (26.9%), the difference was not significant (p=0.39). Studies utilizing different assessment scales and varying sample sizes yielded similar prevalence. However, a temporal trend analysis indicated a higher prevalence in studies published between 2020 and 2023 (52.6%) compared to those published between 2016 and 2019 (35.5%) (p=0.03). Major factors associated with depression included lower socioeconomic status, low education level, female gender, uncontrolled hypertension, and COVID-19 related factors. CONCLUSIONS: A significant proportion of hypertensive patients suffer from depression. Therefore, screening for depression in hypertensive patients is essential to improve hypertension management in India.

Prognosis of MGMT -Positive Gene in Patients with Brain Tumors of Grade III and Grade IV.

Sumit GoyalObjective To evaluate MGMT gene positivity is associated with better survival in patients diagnosed with brain tumor World Health Organization (WHO) grades III and IV Material and Methods Single-institute restrospective study. A total of 80 patients were enrolled, all underwent surgery either total or subtotal excision of the tumor and MGMT gene testing on tumor tissue by RT-PCR. All received adjuvant radiation (60 Gy/30 fractions, 5 fractions/week) with concurrent temozolomide (75 mg/m 2 ), followed by 12 cycles of adjuvant temozolomide (150 mg/m 2 1st cycle followed by 200 mg/m 2 ) with regular follow-up. Results A total of 80 patients, 75 underwent subtotal excision, 27 were WHO grade III vs. 48 WHO grade IV. Five underwent total excision 1 was WHO grade III vs. 4 WHO grade IV. The median PFS and OS in five patients in total excision in grade III patient was 9.0 and 20 compared with Grade IV, where the median PFS and OS was 8.8 and 17.8 months. Out of 75 patients in the subtotal group median PFS and OS, respectively, in Grade III group was 9.1 and 19.3 and, WHO grade IV with median PFS of 8.8 and OS of 18.8. Conclusion MGMT gene positivity is a prognostic factor in grade III and IV brain tumor.

Fungal thalamic abscess caused by Rhinocladiella mackenziei in an immunocompetent patient.

Cerebral phaeohyphomycosis (CP) stands as an exceedingly uncommon yet severe type of fungal infection affecting the central nervous system, attributable to dematiaceous fungi. Despite the patient's immune status, CP is associated with grave prognosis. In the present study, authors describe the first case of left thalamic fungal abscess due to Rhinocladiella mackenziei in an immunocompetent 39-year-old male patient in Jaipur, Rajasthan. Early diagnosis by direct microscopy of aspirated pus and extensive management with surgical excision and prolonged antifungal coverage showed favourable outcome. The present case is one of the few cases documented globally who has survived.

Characterization of novel polysulfide polymer coated fly ash and its application in mitigating diffusion of contaminants.

Fly ash consists of a considerable amount of hazardous elements with high mobility, posing substantial environmental risks during storage in surface impoundments and landfills. This hinders its efficient reuse in construction or material industries. To enhance the versatility of fly ash applications, a novel surface modification technique, termed SuMo, has been developed to create a hydrophobic polysulfide polymer coating on the surface of fly ash particles. The physicochemical properties of SuMo fly ash samples were examined using atomic force microscopy (AFM), environmental scanning electron microscopy (ESEM), thermal gravimetric analysis (TGA), Fourier Transform Infrared spectroscopy (FTIR), and leaching of hazardous elements was tested under practical environmental conditions (pH 4-12) based on the EPA's leaching environmental assessment framework (LEAF). The successful coating of polysulfide polymer on fly ash surface was verified through an increased percentage of C, S, and O in elemental mapping, coupled with the identification of S-O, CO, and C-H functional groups consistent with the chemical structure of polysulfide polymer. While the SuMo fly ash particles maintained their spherical shape, they exhibited increased surface roughness, robust hydrophobicity, and thermal stability up to 250 °C. Notably, owing to the coating's resilience against water leaching, the SuMo fly ash demonstrated a substantial reduction (up to 60-fold) in leachate concentrations of multiple concerning elements, including B, Be, Ba, Mn, Zn, As, Cr, Hg, etc., under various pH conditions compared to the uncoated fly ash. Furthermore, the polysulphide polymer coating effectively prevented Hg volatilization from fly ash below 163 °C. This study highlights the efficacy of the developed polysulfide polymer coating in mitigating the diffusion of hazardous elements from fly ash, thereby enhancing its potential reutilization in material, construction, and agriculture industries.

Regional sources of NH3, SO2 and CO in the Third Pole.

The Third Pole (TP) is a high mountain region in the world, and is well-known for its pristine environment, but recent development activities in the region have degraded its air quality. Here, we investigate the spatial and temporal changes of the air pollutants ammonia (NH3), sulphur dioxide (SO2) and carbon monoxide (CO) in TP, and reveal their sources using satellite measurements and emission inventory. We observe a clear seasonal cycle of NH3 in TP, with high values in summer and low values in winter. The intense agriculture activities in the southern TP are the cause of high NH3 (6-8 × 1016 molec./cm2) there. Similarly, CO shows a distinct seasonal cycle with high values in spring in the southeast TP due to biomass burning. In addition, the eastern boundary of TP in the Sichuan and Qinghai provinces also show high values of CO (about 1.5 × 1018 mol/cm2), primarily owing to the industrial activities. There is no seasonal cycle found for SO2 distribution in TP, but relatively high values (8-10 mg/m2) are observed in its eastern boundary. The high-altitude pristine regions of inner TP are also getting polluted because of increased human activities in and around TP, as we estimate positive trends in CO (0.5-1.5 × 1016 mol/cm2/yr) there. In addition, positive trends are also found in NH3 (0.025 × 1016 molec./cm2/yr) during 2008-2020 in most regions of TP and SO2 (about 0.25-0.75 mg/m2/yr) in the Sichuan and Qinghai region during 2000-2020. As revealed by the emission inventory, there are high anthropogenic emissions of NH3, SO2 and CO within TP. There are emissions of pollutants from energy sectors, oil and refinery, agriculture waste burning and manure management within TP. These anthropogenic activities accelerate the ongoing development in TP, but severely erode its environment.

Effect of residue and weed management practices on weed flora, yield, energetics, carbon footprint, economics and soil quality of zero tillage wheat.

A two-year field study was conducted during Rabi 2018-2019 and 2019-20 to find out the influence of different residue and weed management practices on weed dynamics, growth, yield, energetics, carbon footprint, economics and soil properties in zero-tilled sown wheat at Research Farm, AICRP-Weed management, SKUAST-Jammu. The experiment with four rice residue management practices and four weed management practices was conducted in a Strip-Plot Design and replicated thrice. The results showed that residue retention treatments recorded lower weed density, biomass and higher wheat growth, yield attributes and yields of wheat as compared to no residue treatment. The magnitude of increase in wheat grain yield was 17.55, 16.98 and 7.41% when treated with 125% recommended dose of nitrogen + residue + waste decomposer (RDN + R + WD), 125% RDN + R, and 100% RDN + R, respectively, compared to no residue treatment. Further, all three herbicidal treatments decreased weed density and biomass than weedy treatments. Consequently, a reduction of 29.30, 28.00, and 25.70% in grain yield were observed in control as compared to sulfosulfuron + carfentrazone, clodinafop-propargyl + metasulfuron, and clodinafop-propargyl + metribuzin, respectively. Moreover, 125% RDN + R + WD obtained significantly higher energy output (137860 MJ ha-1) and carbon output (4522 kg CE/ha), but 100% RDN had significantly higher net energy (101802 MJ ha-1), energy use efficiency (7.66), energy productivity (0.23 kg MJ-1), energy profitability (6.66 kg MJ-1), carbon efficiency (7.66), and less carbon footprint (7.66) as compared to other treatments. Despite this, treatments with 125% RDN + R + WD and 125% RDN + R provided 17.58 and 16.96% higher gross returns, and 24.45% and 23.17% net outcomes, respectively, than that of control. However, compared to the control, sulfosulfuron + carfentrazone showed considerably higher energy output (140492 MJ ha-1), net energy (104778 MJ ha-1), energy usage efficiency (4.70), energy productivity (0.14 kg MJ-1), energy profitability (3.70 kg MJ-1), carbon output (4624 kg CE ha-1), carbon efficiency (4.71), and lower carbon footprint (0.27). Furthermore, sulfosulfuron + carfentrazone, clodinafop-propargyl + metasulfuron, and clodinafop-propargyl + metribuzin recorded 29.29% and 38.42%, 27.99%, and 36.91%, 25.69% and 34.32% higher gross returns and net returns over control treatment, respectively. All three herbicides showed higher gross returns, net returns, and benefit cost ratio over control. The soil nutrient status was not significantly affected either by residue or weed management practices. Therefore, based on present study it can be concluded that rice residue retention with 25% additional nitrogen and weed management by clodinafop-propargyl + metasulfuron herbicide found suitable for zero tillage wheat.

Nature to Nurture: Chitosan nanopowder a natural carbohydrate polymer choice of egg parasitoid, Trichogramma Japonicum Ashmead.

Chitosan is a naturally occurring linear biopolymer made of partially deacetylated acetyl and N-acetyl glucosamine. Its biocompatible physiochemical and biochemical properties are unmatched. Chitosan is transformed to nanopowder for use in agriculture and associated industries as nanocarriers for existing agrochemicals, ensuring the delayed release of chemicals with better solubility. Chitosan nanopowder applied to leaves or soil can activate a plant's natural defences against insects and pathogens. These studies were carried out because there is a potential for toxicological risk linked with products created utilizing nanotechnology, such as chitosan nanopowder, and therefore researchers felt the need to investigate this. The egg parasitoides Trichogramma Japonicum Ashmead was used as a low-cost biomarker to determine the potential toxicity of chitosan nanopowder. This study looked into the possibility that the adult stage of the egg parasitoids, Trichogramma Japonicum Ashmead might be negatively impacted by chitosan nanopowder (80-100 nm). Unpaired t-test statistical analysis has been carried out. According to the statistical analysis, host eggs exposed to chitosan nanopowder showed noticeably greater parasitization than the control group. As a natural supply of carbohydrate polymers chitosan nanopowder promotes the parasitization of T. Japonicum. The findings showed that T. Japonicum favoured chitosan nanopowder. Through Y dual choice, eight-arm multiple choice, and no-choice olfactometer experiments, as well as images from a stereozoom microscope and a scanning electron microscope (SEM), the data was thoroughly supported. Future agricultural applications of chitosan nanopowder will benefit from a deeper understanding of our findings.

A gradual increase of aerosol pollution in the Third Pole during the past four decades: Implication for regional climate change.

We analyse the long-term (1980-2020) changes in aerosols over the Third Pole (TP) and assess the changes in radiative forcing (RF) using satellite, ground-based and reanalysis data. The annual mean aerosol optical depth (AOD) varies from 0.06 to 0.24, with the highest values of around 0.2 in the north and southwest TP, which are dominated by dust from Taklimakan and Thar deserts, respectively. However, Organic Carbon (OC), Black Carbon (BC) and sulphate aerosols have significant contributions to the total AOD in the south and east TP. High amounts of dust are observed in spring and summer, but BC in winter. Trajectory analysis reveals that the air mass originated from East and South Asia carries BC and OC, whereas the air from South Asia, Central Asia and Middle East brings dust to TP. Significant positive trends in AOD is found in TP, with high values of about 0.002/yr in the eastern and southern TP. There is a gradual increase in BC and OC concentrations during 1980-2020, but the change from 2000 is phenomenal. The RF at the top of the atmosphere varies from -10 to 2 W/m2 in TP, and high positive RF of about 2 W/m2 is estimated in Pamir, Karakoram and Nyainquentanglha mountains, where the massive glacier mass exists. The RF has increased in much of TP during recent decades (2001-2020) with respect to previous decades (1981-2000), which can be due to the rise in BC and dust during the latter period. Therefore, the positive trend in BC and its associated change in RF can amplify the regional warming, and thus, the melting of glaciers or ice in TP. This is a great concern as it is directly connected to the water security of many South Asian countries.

Effect of resveratrol and combination of resveratrol and donepezil on the expression of microglial cells and astrocytes in Wistar albino rats of colchicine-induced Alzheimer's disease.

Aim: The goal was to evaluate the effect of resveratrol (RS) and combination therapy of RS and donepezil (DPZ), on the numerical expression of microglial cells and astrocytes, in the frontal cortex, regions of the hippocampus in colchicine-induced Alzheimer's disease (AD) model. Methods: The study involved male albino Wistar rats of three months, age and consisted of 6 groups, with six animals each. The immunohistochemical staining with mouse monoclonal anti-human CD 68 and mouse monoclonal anti-GFAP was performed to assess the number of microglial cells and astrocytes, respectively. Results: AD group showed an increase in the number of microglia, and the numbers declined in the treatment groups, RS 10, RS 20, RS10/10 and DPZ + RS (p < 0.001). Astrocyte count was increased in the treatment groups in contrast to the AD group (p < 0.05). The DPZ + RS combination group revealed substantial elevation in the number of astrocytes and decreased microglial number among all the groups (p < 0.001). Conclusion: RS administration has diminished the microglial number and elevated the number of astrocytes. The elevated reactive astrocytes have decreased the microglial population. However, the limitation of our study is utilizing the colchicine for the induction of neurodegeneration. Using the transgenic models of AD may give a better insight into the pathogenesis and effect of RS. Another limitation of this study is the administration of RS and DPZ through different routes. The prospects of this research include studying the probiotic nature of RS and the effect of RS in other neurodegenerative disorders.

Endocytosis of GABA receptor: Signaling in nervous system.

GABA (ᵞ-aminobutyric acid), is the principal neurotransmitter known for its inhibitory role in chemical synapses. Being localized primarily in the central nervous system (CNS) it maintains a balance between excitatory (regulated by another neurotransmitter, glutamate) and inhibitory impulses. GABA acts by binding to their specific receptors GABAA and GABAB when released into the post-synaptic nerve terminal. Both of these receptors are responsible for fast and slow inhibition of neurotransmission, respectively. GABAA is a ligand-gated ionopore receptor which opens the Cl- ion channel and decreases the resting potential of the membrane resulting into inhibition of the synapse. On the other hand, GABAB is a metabotropic receptor which increases the K+ ion levels preventing Ca+ ion release inhibiting the release of other neurotransmitters into the presynaptic membrane. The internalization and trafficking of these receptors is also conducted through distinct pathways and mechanism, discussed in detail in the chapter. Without the desired levels of GABA in the body, the psychological and neurological states of brain get hard to maintain. Various neurodegenerative diseases/disorders have been associated to low levels of GABA, such as anxiety, mood disorders, fear, schizophrenia, hungtington's chorea, seizures, epilepsy, etc. The allosteric sites present on GABA receptors have been proved to be potent drug targets to pacify the pathological states of these brain related disorders to an extent. Further in depth studies focussing on the subtypes of GABA receptors and their comprehensive mechanism are required to explore new drug targets and therapeutic avenues for effectual management of GABA related neurological diseases.

Mid-term outcome of arthroscopic TightRope fixation of displaced lateral end clavicular fractures: Average follow-up of 6.1 years.

PURPOSE: Various surgical modalities are available to treat Neer types 2 and 5 unstable fractures of lateral end clavicle but none of them are standardized. Arthroscopic fixation of the displaced lateral end clavicle fractures provides good short-term results but mid- to long-term outcomes are not available. The purpose of this study was to show the mid- to long-term radiological and functional outcomes of these fractures treated arthroscopically by a TightRope device, and to show the complications associated with this procedure. METHODS: A retrospective study was conducted over 2 years from January 2014 to December 2015 with a minimum 5-year follow-up. Active patients aged 18-50 years with acute (less than 3 weeks) displaced fracture of lateral end of the clavicle, with a minimum 5-year follow-up were included in the study. Patients with associated fractures of the proximal humerus, glenoid, scapula and acromioclavicular joint injuries were excluded from the study along with open fractures and neurovascular injuries. The outcomes were assessed by objective (complications and radiographic examination) and subjective criteria (quick disabilities of the arm, shoulder and hand score, the Constant-Murley score and the visual pain analogue scale). The data were analyzed by SPSS version 21.0. RESULTS: Totally, 42 patients were operated during the study period and 37 were available with a minimum 5-year follow-up. Thirty were male and 7 were female with a mean age of 29.5 years and a mean follow-up of 6.1 years. The mean quick disabilities of the arm, shoulder and hand score was 68.2 ± 4.6 preoperatively and 1.27 ± 2.32 at final follow-up (p < 0.001); the mean visual pain analogue scale score was 6.85 ± 2.2 preoperatively and 0.86 ± 1.60 at final follow-up (p < 0.001). The average Constant-Murley score was 93.38 ± 3.25 at the end of the follow-up. There were 2 fixation failures, with established non-union and 3 patients developed radiographic acromioclavicular joint arthritis. CONCLUSIONS: Arthroscopic TightRope fixation of displaced lateral end clavicular fractures provides good radiological and functional outcomes at mid- to long-term follow-up. With the low complication rates and high patient satisfaction, this technique can be considered as a primary option in the surgical treatment of these fractures.

Clonal KEAP1 mutations with loss of heterozygosity share reduced immunotherapy efficacy and low immune cell infiltration in lung adenocarcinoma.

BACKGROUND: KEAP1 mutations have been associated with reduced survival in lung adenocarcinoma (LUAD) patients treated with immune checkpoint inhibitors (ICIs), particularly in the presence of STK11/KRAS alterations. We hypothesized that, beyond co-occurring genomic events, clonality prediction may help identify deleterious KEAP1 mutations and their counterparts with retained sensitivity to ICIs. PATIENTS AND METHODS: Beta-binomial modelling of sequencing read counts was used to infer KEAP1 clonal inactivation by combined somatic mutation and loss of heterozygosity (KEAP1 C-LOH) versus partial inactivation [KEAP1 clonal diploid-subclonal (KEAP1 CD-SC)] in the Memorial Sloan Kettering Cancer Center (MSK) MetTropism cohort (N = 2550). Clonality/LOH prediction was compared to a streamlined clinical classifier that relies on variant allele frequencies (VAFs) and tumor purity (TP) (VAF/TP ratio). The impact of this classification on survival outcomes was tested in two independent cohorts of LUAD patients treated with immunotherapy (MSK/Rome N = 237; DFCI N = 461). Immune-related features were studied by exploiting RNA-sequencing data (TCGA) and multiplexed immunofluorescence (DFCI mIF cohort). RESULTS: Clonality/LOH inference in the MSK MetTropism cohort overlapped with a clinical classification model defined by the VAF/TP ratio. In the ICI-treated MSK/Rome discovery cohort, predicted KEAP1 C-LOH mutations were associated with shorter progression-free survival (PFS) and overall survival (OS) compared to KEAP1 wild-type cases (PFS log-rank P = 0.001; OS log-rank P < 0.001). Similar results were obtained in the DFCI validation cohort (PFS log-rank P = 0.006; OS log-rank P = 0.014). In both cohorts, we did not observe any significant difference in survival outcomes when comparing KEAP1 CD-SC and wild-type tumors. Immune deconvolution and multiplexed immunofluorescence revealed that KEAP1 C-LOH and KEAP1 CD-SC differed for immune-related features. CONCLUSIONS: KEAP1 C-LOH mutations are associated with an immune-excluded phenotype and worse clinical outcomes among advanced LUAD patients treated with ICIs. By contrast, survival outcomes of patients whose tumors harbored KEAP1 CD-SC mutations were similar to those with KEAP1 wild-type LUADs.

Comparison of treatment modalities for single-sided deafness in paediatric patients.

OBJECTIVE: Children with single-sided deafness often receive inconsistent clinical recommendations because there is currently no clear best practice in paediatric single-sided deafness. This systematic review of the literature aimed to compare commonly used treatments and attempted to support the use of a particular treatment modality. METHOD: This was a comprehensive literature review from 1 January 2000 to 22 February 2022; the study compared the outcomes of bone conduction devices and cochlear implantation in paediatric patients with single-sided deafness. RESULTS: Fifteen studies consisting of 202 patients were examined. Variables including speech reception in quiet and noise, as well as quality of life measures were compared. Both cochlear implantation and bone-anchored hearing aids demonstrated benefits in sound perception. Quality of life measures improved with both modalities. CONCLUSION: Although both bone-anchored hearing aids and cochlear implantation appear to provide significant improvements, additional research with more direct comparisons is needed to provide more decisive results.

Entropy generation minimization of higher-order endothermic/exothermic chemical reaction with activation energy on MHD mixed convective flow over a stretching surface.

The present investigation aims to analyze higher-order endothermic/exothermic chemical reactions with activation energy by considering thermophoresis and Brownian motion effects on MHD mixed convective flow across a vertical stretching surface. The influence of velocity slip, thermal slip, and concentration slip along with an inclined external magnetic field is also considered. The governing coupled non-linear partial differential equations are transformed into ordinary differential equations using similarity transformation. The resulting system of non-linear ODEs is solved by the Newton Raphson shooting technique using the RK-4 algorithm. The impact of various physical parameters discovered in the problem viz. endothermic/exothermic reaction variable, thermophoresis parameter, activation energy parameter, Brownian motion parameter, chemical reaction parameter have been analyzed on velocity profile, temperature profile, and concentration profile. The effects of these parameters on skin-friction coefficient, Nusselt number, and Sherwood number are displayed in tabular form as well as surface plots. The impact of various physical parameters that appeared in the entropy generation is shown using surface and contour plots. The numerical findings are in good agreement with the previously published results. It is observed that an increment in thermophoresis and Brownian motion parameters results in a declination of entropy profiles, whereas an increment in Bejan number profiles is observed. A small region near the surface exhibits an inclination in concentration profiles with an increase in the order of the chemical reaction. In contrast, the opposite effect is analyzed near the boundary layer. Also, the contour and surface plots are displayed to portray real-world applications in industrial and technical processes and the physical depiction of flow characteristics that arise in the current study.

Dissecting the clinicopathologic, genomic, and immunophenotypic correlates of KRASG12D-mutated non-small-cell lung cancer.

BACKGROUND: Allele-specific KRAS inhibitors are an emerging class of cancer therapies. KRAS-mutant (KRASMUT) non-small-cell lung cancers (NSCLCs) exhibit heterogeneous outcomes, driven by differences in underlying biology shaped by co-mutations. In contrast to KRASG12C NSCLC, KRASG12D NSCLC is associated with low/never-smoking status and is largely uncharacterized. PATIENTS AND METHODS: Clinicopathologic and genomic information were collected from patients with NSCLCs harboring a KRAS mutation at the Dana-Farber Cancer Institute (DFCI), Memorial Sloan Kettering Cancer Center, MD Anderson Cancer Center, and Imperial College of London. Multiplexed immunofluorescence for CK7, programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), Foxp3, and CD8 was carried out on a subset of samples with available tissue at the DFCI. Clinical outcomes to PD-(L)1 inhibition ± chemotherapy were analyzed according to KRAS mutation subtype. RESULTS: Of 2327 patients with KRAS-mutated (KRASMUT) NSCLC, 15% (n = 354) harbored KRASG12D. Compared to KRASnon-G12D NSCLC, KRASG12D NSCLC had a lower pack-year (py) smoking history (median 22.5 py versus 30.0 py, P < 0.0001) and was enriched in never smokers (22% versus 5%, P < 0.0001). KRASG12D had lower PD-L1 tumor proportion score (TPS) (median 1% versus 5%, P < 0.01) and lower tumor mutation burden (TMB) compared to KRASnon-G12D (median 8.4 versus 9.9 mt/Mb, P < 0.0001). Of the samples which underwent multiplexed immunofluorescence, KRASG12D had lower intratumoral and total CD8+PD1+ T cells (P < 0.05). Among 850 patients with advanced KRASMUT NSCLC who received PD-(L)1-based therapies, KRASG12D was associated with a worse objective response rate (ORR) (15.8% versus 28.4%, P = 0.03), progression-free survival (PFS) [hazard ratio (HR) 1.51, 95% confidence interval (CI) 1.45-2.00, P = 0.003], and overall survival (OS; HR 1.45, 1.05-1.99, P = 0.02) to PD-(L)1 inhibition alone but not to chemo-immunotherapy combinations [ORR 30.6% versus 35.7%, P = 0.51; PFS HR 1.28 (95%CI 0.92-1.77), P = 0.13; OS HR 1.36 (95%CI 0.95-1.96), P = 0.09] compared to KRASnon-G12D. CONCLUSIONS: KRASG12D lung cancers harbor distinct clinical, genomic, and immunologic features compared to other KRAS-mutated lung cancers and worse outcomes to PD-(L)1 blockade. Drug development for KRASG12D lung cancers will have to take these differences into account.

Salubrious effects of ulinastatin and quercetin alone or in combination in endothelial dysfunction and vascular dementia.

BACKGROUND: Vascular dementia is the second most prevalent form of dementia. Hypertension is the leading risk factor for endothelial dysfunction and the progression of dementia that is of vascular origin. This study investigates the role of ulinastatin (UTI) and quercetin alone as well as in combination in hypertension-induced endothelial dysfunction and vascular dementia (VaD). METHOD: Two-kidney one-clip (2K1C) renovascular model was set up to induce hypertension in the Albino Wistar rats (males). Rats were assessed for mean arterial blood pressure, behavioral function (Morris water maze, attention set-shifting tests), vascular endothelial function, and biochemical levels (aortic superoxide anion and serum nitrite/nitrate), as well as brains' thiobarbituric acid reactive species-TBARS, reduced glutathione-GSH, interleukin-6, 10, tumor necrosis factor-TNF-α and acetylcholinesterase-AChE). UTI (10,000 U/kg, ip) and quercetin (60 mg/kg) were used alone and in combination for treatment. Donepezil (0.5 mg/kg) was used as a positive control. RESULTS: 2K1C rats showed impairment in learning, memory, executive functioning, and reversal learning. These rats further showed endothelial dysfunction as well as an increase in mean arterial blood pressure, brains' oxidative stress, inflammation, and AChE-activity. Treatment with UTI and quercetin alone as well in combination significantly attenuated the 2K1C model induced impairments in the behavioural, biochemical, and endothelial parameters. CONCLUSION: 2K1C renovascular hypertension-induced impairment in behavioural, biochemical, and endothelial parameters were attenuated by the treatment with UTI and quercetin alone as well as in combination. Therefore, the utility of these agents might be studied further to understand their full potential in hypertension-induced VaD.

Neurobehavioral and neurobiochemical effect of atomoxetine and N-acetylcysteine in streptozotocin diabetes induced endothelial dysfunction and related dementia.

Metabolic conditions like diabetes, is a major risk factor for the development of dementia of vascular origin. This study investigates the efficacy of atomoxetine (ATX) and N-acetylcysteine (NAC) in streptozotocin (STZ) diabetes induced vascular endothelium dysfunction and related dementia. Single dose STZ (50 mg/kg i.p) was administered to Albino Wistar rats (male, 200-250 g) by dissolving in citrate buffer. Morris water maze (MWM) and attentional set shifting tests (ASST) were used to assess the spatial learning, memory, reversal learning, and executive functioning in animals. Body weight, serum glucose, serum nitrite/nitrate, vascular endothelial function, aortic superoxide anion, brains' oxidative markers (thiobarbituric acid reactive species-TBARS, reduced glutathione-GSH, superoxide dismutase-SOD, and catalase-CAT), inflammatory markers (IL-6, IL-10, TNF-α, and myeloperoxidase-MPO), acetylcholinesterase activity-AChE and histopathological changes were also assessed. Atomoxetine - ATX (2 mg kg-1/ 4 mg kg-1) and N-acetylcysteine- NAC (250 mg kg-1/ 500 mg kg-1) were used alone as well as in combination, as the treatment drugs. Donepezil (0.5 mg kg-1) was used as a positive control. STZ administered rats showed increase in serum glucose levels and decrease in body weight. Rats administered with STZ also showed reduction in learning, memory, reversal learning, executive functioning, impairment in endothelial function, increase in brains' oxidative stress, inflammation, AChE activity and histopathological changes. Administration of ATX and NAC in two different doses as well as in combination, significantly attenuated the STZ induced diabetes induced impairments in the behavioral, endothelial, biochemical parameters and histopathological changes. Co-treatment of ATX and NAC was better in comparison to the doses when given alone. Hence, STZ administration caused diabetes induced dementia of vascular origin which was attenuated by the administration of ATX and NAC. Therefore, these agents may be studied further for the assessment of their full potential in diabetes induced dementia of vascular origin conditions.