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Background and Objective: Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors improve progression-free survival when combined with endocrine therapies in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. However, the comparative cost effectiveness of utilizing three US Food and Drug Administration-approved CDK4/6 inhibitors is unknown. Therefore, we aimed to evaluate the cost effectiveness of individual CDK4/6 inhibitors (palbociclib, ribociclib, abemaciclib) with letrozole versus letrozole monotherapy in the first-line treatment of hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer in the USA. Methods: We constructed a Markov-based decision-analytic model to evaluate the cost effectiveness of CDK4/6 inhibitors plus endocrine therapies over a 40-year lifetime from a third-party payer perspective. The model incorporated health states (progression-free disease, progressive disease, and death), major adverse events (neutropenia), and cancer-specific and all-cause mortality. Using clinical efficacy and quality-of-life scores (utility) data from clinical trials, we estimated quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios using Medicare charges reported in US dollars per 2022 valuation and a discount rate of 3% applied to costs and outcomes. We performed deterministic and probabilistic sensitivity analyses to evaluate parametric and decision uncertainty. Results: Compared to letrozole, the model estimated an increase of 5.72, 5.87, and 6.39 in QALYs and costs of $799,178, $788,168, and $741,102 in combining palbociclib, ribociclib, and abemaciclib plus letrozole, respectively. Palbociclib or ribociclib plus letrozole were dominated by abemaciclib plus letrozole. Compared with letrozole, abemaciclib plus letrozole resulted in an incremental cost-effectiveness ratio of $457,538 per QALY with an incremental cost of $553,621 and an incremental QALY gain of 1.21. The results were sensitive to the cost of abemaciclib, disease progression utility, and patients' age. Conclusions: At a willingness to pay of $100,000/QALY gained, our model predicts that combining CDK4/6 inhibitors plus letrozole is not cost effective with a marginal increase in QALYs at a high cost. Lowering the cost of these drugs or identifying patients who can receive maximal benefit from CDK4/6 inhibitors would improve the value of this regimen in patients. [ABSTRACT FROM AUTHOR]

Silver nanoparticles (AgNPs) are noteworthy used nanomaterials in a wide array of fields, particularly in the agricultural sector. Plants play a multifarious role in the ecosystem and provide a source of food for mankind. The responsibility of the scientific community is to recognize the deleterious impact of AgNPs (1–100 nm in size) on critical crop growth and development of plants, which is required for the assessment of environmental threats to plant, human, and animal health. The continued use of AgNPs in agriculture areas may have negative effects on plant biochemical and physiological responses. The current context focused mainly on AgNPs uptake, transport, and accumulation on crop plants and summarizes different levels of phytotoxicity of AgNPs on plant functions and focused on mechanisms of phytotoxicity employed by AgNPs. Moreover, some tolerance mechanisms and various survival strategies developed by plants under AgNPs toxicity are discussed. This background provides comprehensive information necessary to facilitate profound understanding of the toxic impacts of AgNPs on crop plants. [ABSTRACT FROM AUTHOR]

Lateritic bauxite are the products of intense sub-aerial weathering of rocks. It is characterized by a particular enrichment of aluminium-hydroxide minerals such as gibbsite, boehmite and diaspore. Bauxite ore is the result of weathering of various parent rocks such as khondalite, Deccan trap basalt, granite gneiss, charnockite, etc. The two types of lateritic bauxite deposits are located in India viz high level and low level (coastal), situated in the regions namely Eastern ghat, Western ghat, central India, Gujarat, and in union territory Jammu. There are distinct geological variations in the mode of occurrence and ore body configuration. The geological, chemico-mineralogical and petrological characteristics are varying in deposits from region to region. The Eastern ghat and west coast bauxite is dominant in gibbsite minerals however, the central Indian bauxite is mixed gibbsitic boehmite and at places diasporic in nature. For the present study, representative samples of bauxite have been collected from Indian deposits. The samples were characterized for chemical composition, mineralogy and petrography. The bond work index tests have been performed on bauxite samples by standard procedure. The bond work index of ore indicates how much energy is required to grind the ore and it is a very significant property from a plant point of view. The laboratory results show that the eastern ghat bauxite is soft (BWI-10 kwh/mt) as compared to Central Indian bauxite (16 kwh/mt). The studies indicate that the base rock/parent rock, geological formation, mineralogy, etc. play an important role in the hardness of bauxite. In the present paper, details of the Bond work index of various bauxite are specified and factors responsible for the hardness of the ore is being highlighted. [ABSTRACT FROM AUTHOR]

Early diagnosis of Alzheimer's disease plays a pivotal role in patient care and clinical trials. In this study, we have developed a new approach based on 3D deep convolutional neural networks to accurately differentiate mild Alzheimer's disease dementia from mild cognitive impairment and cognitively normal individuals using structural MRIs. For comparison, we have built a reference model based on the volumes and thickness of previously reported brain regions that are known to be implicated in disease progression. We validate both models on an internal held-out cohort from The Alzheimer's Disease Neuroimaging Initiative (ADNI) and on an external independent cohort from The National Alzheimer's Coordinating Center (NACC). The deep-learning model is accurate, achieved an area-under-the-curve (AUC) of 85.12 when distinguishing between cognitive normal subjects and subjects with either MCI or mild Alzheimer's dementia. In the more challenging task of detecting MCI, it achieves an AUC of 62.45. It is also significantly faster than the volume/thickness model in which the volumes and thickness need to be extracted beforehand. The model can also be used to forecast progression: subjects with mild cognitive impairment misclassified as having mild Alzheimer's disease dementia by the model were faster to progress to dementia over time. An analysis of the features learned by the proposed model shows that it relies on a wide range of regions associated with Alzheimer's disease. These findings suggest that deep neural networks can automatically learn to identify imaging biomarkers that are predictive of Alzheimer's disease, and leverage them to achieve accurate early detection of the disease. [ABSTRACT FROM AUTHOR]

Background and Objective: Cholinesterase inhibitors (ChEIs) are used as first-line pharmacotherapy to manage dementia. However, there are limited data regarding their relative safety. This study evaluated the risk of serious adverse events (SAEs) associated with individual ChEIs in older adults with dementia and also examined sex-based and dose-based effects on this risk. Methods: This was a retrospective cohort study using 2013–2015 US Medicare claims data involving Parts A, B, and D. Patients aged ≥ 65 years with a dementia diagnosis and incident use of the ChEIs, namely donepezil, galantamine, or rivastigmine, were included. The primary outcome of interest was SAEs defined as emergency department visits, inpatient hospitalizations, or death within 6 months of ChEI initiation. Multivariable Cox proportional hazards regression with propensity score (PS) as a covariate and inverse probability of treatment weighting generated using generalized boosted models was used to assess the risk of SAEs across individual ChEIs. Results: The study included 767,684 older adults with dementia who were incident new users of ChEIs (donepezil 79.42%, rivastigmine 17.67%, galantamine 2.91%). SAEs were observed in 15.5% of the cohort within 6 months of ChEI prescription. Cox regression model with PS as covariate found that patients prescribed rivastigmine (adjusted hazard ratio [aHR] 1.12; 95% CI 1.03–1.33) and galantamine (aHR 1.51; 95% CI 1.24–1.84) were at increased risk of SAEs compared with patients on donepezil. Stratified analyses revealed that rivastigmine was associated with an 18% increased risk for SAEs in females (aHR 1.18; 95% CI 1.06–1.31), and galantamine was associated with a 71% increased risk in males (aHR 1.71; 95% CI 1.17–2.51) compared with donepezil. High and recommended index doses of rivastigmine and galantamine were associated with an increased risk of SAEs compared with donepezil. The findings were consistent in sensitivity analyses. Conclusion: The study found that the risk of SAEs varied across individual ChEIs, with sex and dose moderating these effects. Therefore, these moderating effects should be carefully considered in personalizing dementia care. [ABSTRACT FROM AUTHOR]

Background: Acetylcholinesterase inhibitors (AChEIs) have been associated with an increased risk of starting antimuscarinic treatment to treat overactive bladder (OAB)—an example of a prescribing cascade. Limited comparative data exist regarding the prescribing cascade of antimuscarinics across individual AChEIs in older adults with dementia. Objective: This study examined the association between individual AChEI use and antimuscarinic cascade in older adults with dementia. Methods: We conducted a new user retrospective cohort study from January 2005 to December 2018 using data from the TriNetX electronic medical record database, a federated electronic medical records network in the US. The cohort included patients 65 years or older with a diagnosis of dementia using AChEIs (donepezil, galantamine, or rivastigmine). Individual AChEIs were identified with index dates from 1 January 2006 to 31 June 2018, with a 1-year washout period. The study excluded patients with any antimuscarinic use and OAB diagnosis 1 year before the AChEI index date. The primary outcome of interest was the prescription of antimuscarinics within 6 months of the AChEI index date. A Cox proportional hazard model was used to assess the association between individual incident AChEI use and antimuscarinic prescribing cascade after controlling for several covariates. Results: The study included 47,059 older adults with dementia who were incident users of AChEIs. Most of these patients were initiated with donepezil (83.1%), followed by rivastigmine (12.3%) and galantamine (4.6%). Overall, 8.16% of the study cohort had incident OAB diagnosis or antimuscarinic prescription. Antimuscarinics were initiated by 1725 (3.7%) older adults with dementia within 6 months of AChEI prescription, and cascade varied widely across individual agents—donepezil (3.9%), rivastigmine (2.6%), and galantamine (2.9%). Cox proportional hazard analyses revealed that donepezil users had an increased risk of receiving antimuscarinics (adjusted hazard ratio 1.55, 95% confidence interval 1.31–1.83) compared with rivastigmine. The findings were consistent in sensitivity analyses. Conclusion: This study found that donepezil use is more likely to lead to antimuscarinic cascade than rivastigmine. Future studies are needed to determine the potential consequences of this cascade in dementia. [ABSTRACT FROM AUTHOR]

Monolayer transition metal dichalcogenides (TMD) have numerous potential applications in ultrathin electronics and photonics. The exposure of TMD-based devices to light generates photo-carriers resulting in an enhanced conductivity, which can be effectively used, e.g., in photodetectors. If the photo-enhanced conductivity persists after removal of the irradiation, the effect is known as persistent photoconductivity (PPC). Here we show that ultraviolet light (λ = 365 nm) exposure induces an extremely long-living giant PPC (GPPC) in monolayer MoS2 (ML-MoS2) field-effect transistors (FET) with a time constant of ~30 days. Furthermore, this effect leads to a large enhancement of the conductivity up to a factor of 107. In contrast to previous studies in which the origin of the PPC was attributed to extrinsic reasons such as trapped charges in the substrate or adsorbates, we show that the GPPC arises mainly from the intrinsic properties of ML-MoS2 such as lattice defects that induce a large number of localized states in the forbidden gap. This finding is supported by a detailed experimental and theoretical study of the electric transport in TMD based FETs as well as by characterization of ML-MoS2 with scanning tunneling spectroscopy, high-resolution transmission electron microscopy, and photoluminescence measurements. The obtained results provide a basis for the defect-based engineering of the electronic and optical properties of TMDs for device applications. [ABSTRACT FROM AUTHOR]

There is currently no therapy to limit the development of cardiac fibrosis and consequent heart failure. We have recently shown that cardiac fibrosis post-myocardial infarction (MI) can be regulated by resident cardiac cells with a fibrogenic signature and identified by the expression of PW1 (Peg3). Here we identify αV-integrin (CD51) as an essential regulator of cardiac PW1+ cells fibrogenic behavior. We used transcriptomic and proteomic approaches to identify specific cell-surface markers for cardiac PW1+ cells and found that αV-integrin (CD51) was expressed in almost all cardiac PW1+ cells (93% ± 1%), predominantly as the αVβ1 complex. αV-integrin is a subunit member of the integrin family of cell adhesion receptors and was found to activate complex of latent transforming growth factor beta (TGFβ at the surface of cardiac PW1+ cells. Pharmacological inhibition of αV-integrin reduced the profibrotic action of cardiac PW1+CD51+ cells and was associated with improved cardiac function and animal survival following MI coupled with a reduced infarct size and fibrotic lesion. These data identify a targetable pathway that regulates cardiac fibrosis in response to an ischemic injury and demonstrate that pharmacological inhibition of αV-integrin could reduce pathological outcomes following cardiac ischemia. [ABSTRACT FROM AUTHOR]

Lateritic bauxite are the products of intense subareal weathering of rocks. It is characterised by a particular enrichment of aluminium-hydroxide minerals such as gibbsite, boehmite and diaspore. Based on geological occurrences, bauxite is classified as lateritic, karstic, tikhvin type and about 86% deposits of the world are lateritic bauxite deposits. They typically are in stable areas of plateaux, where they had sufficient geological time to form and were protected from erosion. India is endowed about 3896 million tons of bauxite resources and Maharashtra state constitutes about 5 % of the total assets. The medium to high grade lateritic bauxite occurrences are located in western Maharashtra which spread up in two distinct belts, viz. high level and low-level coastal areas. The coastal bauxite deposits in Raigad, Ratnagiri and Sindhudurg districts are located at altitude varying between 50 to 350 m above mean sea level (msl), while high level bauxite deposits of Kolhapur, Satara and Sangli districts occur on the plateaus with an elevation 900 to 1300 m above msl. Most of the laterite of the western Maharashtra overlies the Deccan Trap basalt, except in some part of coastal areas, it either caps the Kaladgi sandstone or overlie the Dharwar pebble beds. The lateritic bauxite deposits of the western Maharashtra have been studied with reference to its geology, chemico-mineralogy and petrological characteristics. Field studies indicate the following successive stages developed during in-situ weathering: Deccan trap basalt (parent rock) → weathered basalt → saprolite/lithomargic clay → bauxite → duricrust (ferruginous, aluminous laterites). The geological, physical and chemico-mineralogical characteristics of the bauxite and laterite located in two belts is distinguished from one another. For the present study, two bauxite deposits namely Ringewadi and Velas located in Kolhapur (high-level) and Raigad (coastal) district of western Maharashtra respectively have been selected. The representative samples of bauxite, laterite, saprolite, parent rock have been collected. In present paper, comparative study has been done and the geological, geomorphological, geochemical, mineralogical, petrographic and physical characteristics of low level (coastal) and high-level lateritic bauxite deposits are highlighted. [ABSTRACT FROM AUTHOR]

"SL was partially supported by NSF DMS-2009752, NSF NRT-HDR-1922658, and Leon Lowenstein Foundation." now reads: "SL was supported by Alzheimer's Association grant AARG-NTF-21-848627, and received partial support from NSF DMS-2009752, NSF NRT-HDR-1922658, and the Leon Lowenstein Foundation." Correction to: I Scientific Reports i https://doi.org/10.1038/s41598-022-20674-x, published online 17 October 2022 The original version of this Article contained an error in the Acknowledgements section. [Extracted from the article]

The expression and stabilization of recombinant proteins is fundamental to basic and applied biology. Here we have engineered a thermostable protein nanoparticle (tES) to improve both expression and stabilization of recombinant proteins using this technology. tES provides steric accommodation and charge complementation to green fluorescent protein (GFPuv), horseradish peroxidase (HRPc), and Renilla luciferase (rLuc), improving the yields of functional in vitro folding by ~100-fold. Encapsulated enzymes retain the ability to metabolize small-molecule substrates, presumably via four 4.5-nm pores present in the tES shell. GFPuv exhibits no spectral shifts in fluorescence compared to a nonencapsulated control. Thermolabile proteins internalized by tES are resistant to thermal, organic, chaotropic, and proteolytic denaturation and can be released from the tES assembly with mild pH titration followed by proteolysis. [ABSTRACT FROM AUTHOR]

Background: There is a growing interest in measuring cerebral autoregulation in patients with acute brain injury. Non-invasive finger photo-plethysmography (Finapres) is the method of choice to relate arterial blood pressure to changes in cerebral blood flow. Among acutely ill patients, however, peripheral vasoconstriction often limits the use of Finapres requiring direct intravascular blood pressure measurement. We evaluated how these two different forms of blood pressure monitoring affect the parameters of dynamic cerebral autoregulation (DCA).Methods: We performed 37 simultaneous recordings of BP and cerebral blood flow velocity in 15 patients with acute brain injury. DCA was estimated in the frequency domain using transfer function analysis to calculate phase shift, gain, and coherence. In addition the mean velocity index (Mx) was calculated for assessment of DCA in the time domain.Results: The mean patient age was 58.1 ± 15.9 years, 80 % (n = 12) were women. We found good inter-method agreement between Finapres and direct intravascular measurement using Bland-Altman and correlation analyses. Finapres gives higher values for the efficiency of dynamic CA compared with values derived from radial artery catheter, as indicated by biases in the phase (26.3 ± 11.6° vs. 21.7 ± 10.5°, p = 0.001) and Mx (0.571 ± 0.137 vs. 0.649 ± 0.128, p < 0.001). Gain in the low frequency range did not significantly differ between the two arterial blood pressure methods. The average coherence between CBFV and ABP was higher when BP was measured with arterial catheter for frequencies above 0.05 Hz (0.8 vs. 0.73, p < 0.001).Conclusion: Overall, both methods yield similar results and can be used for the assessment of DCA. However, there was a small but significant difference for both mean Mx and phase shift, which would need to be adjusted for during monitoring of patients when using both methods. When available, invasive arterial blood pressure monitoring may improve accuracy and thus should be the preferred method for DCA assessment in the ICU. [ABSTRACT FROM AUTHOR]

The development of green experimental processes for the synthesis of nanoparticles is a need in the field of nanotechnology. The synthesis of silver nanoparticles was achieved using Bacillus cereus supernatant and 1 mM silver nitrate. 100 mM glucose was found to quicken the rate of reaction of silver nanoparticles synthesis. UV-visible spectrophotometric analysis was carried out to assess the synthesis of silver nanoparticles. The synthesized silver nanoparticles were further characterized by using Nanoparticle Tracking Analyzer (NTA), Transmission Electron Microscope and Energy Dispersive X-ray spectra. These silver nanoparticles showed enhanced quorum quenching activity against Staphylococcus aureus biofilm and prevention of biofilm formation which can be seen under inverted microscope (40 X). The synergistic effect of silver nanoparticles along with antibiotics in biofilm quenching was found to be effective. In the near future, silver nanoparticles could be used in the treatment of infections caused by highly antibiotic resistant biofilm. [ABSTRACT FROM AUTHOR]

Rudimentary gallbladder is a rare congenital anomaly. We present a case of an 18-year-old boy who was referred to us for surgical management of choledochal cyst. Clinical assessment and correlation of various investigations raised the possibility of rudimentary gallbladder rather than choledochal cyst. Laparoscopy evaluation confirmed the same and simple removal of the hypoplastic gallbladder cured him of his symptoms. Awareness of rare anomalies of the gallbladder and correlation of various imaging modalities aids in accurate diagnosis, thus avoiding major exploration. [ABSTRACT FROM AUTHOR]