A RGS7-CaMKII complex drives myocyte-intrinsic and myocyte-extrinsic mechanisms of chemotherapy-induced cardiotoxicity.

Dose-limiting cardiotoxicity remains a major limitation in the clinical use of cancer chemotherapeutics. Here, we describe a role for Regulator of G protein Signaling 7 (RGS7) in chemotherapy-dependent heart damage, the demonstration for a functional role of RGS7 outside of the nervous system and retina. Though expressed at low levels basally, we observed robust up-regulation of RGS7 in the human and murine myocardium following chemotherapy exposure. In ventricular cardiomyocytes (VCM), RGS7 forms a complex with Ca2+/calmodulin-dependent protein kinase (CaMKII) supported by key residues (K412 and P391) in the RGS domain of RGS7. In VCM treated with chemotherapeutic drugs, RGS7 facilitates CaMKII oxidation and phosphorylation and CaMKII-dependent oxidative stress, mitochondrial dysfunction, and apoptosis. Cardiac-specific RGS7 knockdown protected the heart against chemotherapy-dependent oxidative stress, fibrosis, and myocyte loss and improved left ventricular function in mice treated with doxorubicin. Conversely, RGS7 overexpression induced fibrosis, reactive oxygen species generation, and cell death in the murine myocardium that were mitigated following CaMKII inhibition. RGS7 also drives production and release of the cardiokine neuregulin-1, which facilitates paracrine communication between VCM and neighboring vascular endothelial cells (EC), a maladaptive mechanism contributing to VCM dysfunction in the failing heart. Importantly, while RGS7 was both necessary and sufficient to facilitate chemotherapy-dependent cytotoxicity in VCM, RGS7 is dispensable for the cancer-killing actions of these same drugs. These selective myocyte-intrinsic and myocyte-extrinsic actions of RGS7 in heart identify RGS7 as an attractive therapeutic target in the mitigation of chemotherapy-driven cardiotoxicity.

Cardiac RGS7 and RGS11 drive TGFß1-dependent liver damage following chemotherapy exposure.

Off target damage to vital organ systems is an unfortunate side effect of cancer chemotherapy and remains a major limitation to the use of these essential drugs in the clinic. Despite decades of research, the mechanisms conferring susceptibility to chemotherapy driven cardiotoxicity and hepatotoxicity remain unclear. In the livers of patients with a history of chemotherapy, we observed a twofold increase in expression of G protein regulator RGS7 and a corresponding decrease in fellow R7 family member RGS11. Knockdown of RGS7 via introduction of RGS7 shRNA via tail vein injection decreased doxorubicin-induced hepatic collagen and lipid deposition, glycogen accumulation, and elevations in ALT, AST, and triglycerides by approximately 50%. Surprisingly, a similar result could be achieved via introduction of RGS7 shRNA directly to the myocardium without impacting RGS7 levels in the liver directly. Indeed, doxorubicin-treated cardiomyocytes secrete the endocrine factors transforming growth factor ß1 (TGFß1) and TGFß superfamily binding protein follistatin-related protein 1 (FSTL1). Importantly, RGS7 overexpression in the heart was sufficient to recapitulate the impacts of doxorubicin on the liver and inhibition of TGFß1 signaling with the receptor blocker GW788388 ameliorated the effect of cardiac RGS7 overexpression on hepatic fibrosis, steatosis, oxidative stress, and cell death as well as the resultant elevation in liver enzymes. Together these data demonstrate that RGS7 controls both the release of TGFß1 from the heart and the profibrotic and pro-oxidant actions of TGFß1 in the liver and emphasize the functional significance of endocrine cardiokine signaling in the pathogenesis of chemotherapy drive multiorgan damage.

A reversed-phase ultra-fast liquid chromatography-photodiode array detector (RP-UFLC-PDA) method for simultaneous estimation of ayapanin and umbelliferone in Ayapana triplinervis Vahl.

A rapid validated ultra-fast liquid chromatography-photodiode array detector (UFLC-PDA) method was developed to identify and quantify ayapanin (AY) and umbelliferone (UM) simultaneously in Ayapana triplinervis Vahl methanolic extract. The method was validated for linearity, limit of detection (LOD; 3:1σ/S), limit of quantification (LOQ; 10:1σ/S), precision, accuracy, specificity and robustness. The response was linear with a good correlation between concentration and mean peak area through a correlation coefficient of 0.9996, y = 7025.7x - 2269.8 and 0.9997, y = y = 16,262x - 946 with LOD of 6.256 ± 0.52 and 3.325 ± 0.36, and LOQ of 18.838 ± 0.18 and 8.870 ± 0.85 for AY (0.67% w/w) and UM (0.18% w/w), respectively. The relative standard deviation (%) of precision and recovery of AY and UM was <2.0%. The proposed method was simple, accurate, specific, precise and reproducible.

Optimized piperine-phospholipid complex with enhanced bioavailability and hepatoprotective activity.

Piper species is one of the most widely consumed spices for culinary purposes. Piperine (PIP) present in Piper species has a wide range of therapeutic activity including hepatoprotection. However, the major biological limitation of PIP is its low bioavailability after oral administration. Purpose of the study was to prepare an optimized and adequately characterized PIP-phospholipid complex (PPC) as a delivery system to overcome these limitations and to investigate the pharmacokinetics and hepato-protectivity of the formulation in the animal model. Response surface methodology was adopted to optimize the process parameters for PPC preparation. FT-IR, DTA, PXRD, SEM, molecular docking etc. were used for characterization. Solubility, log P, dissolution efficiency and in vivo pharmacokinetics were also investigated. PPC showed enhanced hepatoprotective potential as compared to pure PIP at the same dose level (25 and 50 mg/kg). PPC restored the levels of serum marker and antioxidant enzymes. PPC also increased the bioavailability of PIP in rat serum by 10.40-fold in comparison with pure PIP at the same dose level and enhanced the elimination half-life (t1/2 el) from 0.477 ± 1.76 to 9.80 ± 1.98 h. Results concluded that PPC enhanced the hepatoprotection of PIP which may be due to the improved bioavailability and pharmacokinetics of PIP in rats.

UPLC-QTOF-MS analysis of a carbonic anhydrase-inhibiting extract and fractions of Luffa acutangula (L.) Roxb (ridge gourd).

INTRODUCTION: Luffa acutangula (L.) Roxb, commonly known as ridge gourd (cucurbitaceae), is a common vegetable cultivated in India. It is also a well-used medicinal plant in Indian traditional medicine. OBJECTIVES: To analyse the phenolics content of the most potent carbonic anhydrase-inhibiting fraction from an extract of L. acutangula. MATERIALS AND METHODS: An aqueous ethanol extract of dried fruits of L. acutangula was successively fractionated into petroleum ether, dichloromethane and ethyl acetate. The extract and subsequent fractions were assessed for carbonic anhydrase-inhibitory activity and the enzyme inhibition kinetics were determined for the most active fraction. Total phenolic and flavonoid content of the extract and subsequent fractions were determined spectrophotometrically. Ultra-performance liquid chromatography-quadrupole/time-of-flight mass spectrometry (UPLC-QTOF-MS) analysis was used to tentatively identify the major phenolics in the most active fraction. RESULTS: The concentration of total phenolics and total flavonoids in the extract and each fraction thereof correlated with the level of carbonic anhydrase inhibition activity. The ethyl acetate fraction of the aqueous ethanol extract of L. acutangula had the highest carbonic anhydrase inhibition activity. The enzyme kinetics analysis indicated a mixed mode of inhibition. UPLC-QTOF-MS analysis of the ethyl acetate fraction indicated a number of phenolic acids, hydroxycoumarins, flavones, flavanones, and flavonoids. CONCLUSION: The correlation of total phenolic content with carbonic anhydrase inhibition suggested further research that might confirm that phenolic compounds of L. acutangula offer potential therapeutic benefits against carbonic anhydrase-related disorders.

Enhanced bioavailability and hepatoprotectivity of optimized ursolic acid-phospholipid complex.

OBJECTIVE: To prepare and characterize an optimized phospholipid complex of Ursolic acid (UA) to overcome the poor pharmacokinetic properties and to investigate the impact of the complex on hepatoprotective activity and bioavailability in animal model. SIGNIFICANCE: UA is a potential phytoconstituent obtained from several plant sources, which has been explored for its diverse pharmacological activities including hepatoprotection. Its major limitation is poor absorption, rapid elimination, and hence low bioavailability after administration. METHODS: Response surface methodology was adopted to formulate an optimized (UA) complex. The complex was characterized by differential thermal analysis (DTA), Fourier transform-Infrared Spectroscopy, Powder X ray Diffraction, molecular docking, etc. The physico-chemical profile (solubility, oil/water partition coefficient) and in vitro dissolution profile was estimated. The formulation was then used to study hepatoprotective activity and bioavailability in animal models. RESULTS: Results showed that the phospholipid complex of UA has enhanced the hepatoprotective potential as compared to pure UA at the same dose level. The complex restored the levels of serum hepatic marker enzymes with respect to untreated group and increased the relative bioavailability of UA in rat plasma by 8.49-fold in comparison with pure compound at the same dose level. It enhanced the elimination half-life (t1/2 el) from 0.69 ± 1.76 to 8.28 ± 1.98 h. CONCLUSION: Complexation of UA with phospholipid markedly enhanced the hepatoprotective potential of UA by improving its bioavailability and pharmacokinetic parameters. Novelty statement The present article deals with rational optimization of the formulation parameters for phospholipid complex of ursolic acid by Response Surface Methodology analysis, characterizing the formulation by in silico approach apart from conventional instrumental techniques, and evaluating the in vitro dissolution, pharmacokinetics, and hepatoprotective activity of the complex in animals. Novelty statement The present article deals with rational optimization of the formulation parameters for phospholipid complex of ursolic acid by Response Surface Methodology analysis, characterizing the formulation by in silico approach apart from conventional instrumental techniques, and evaluating the in vitro dissolution, pharmacokinetics, and hepatoprotective activity of the complex in animals.

What Degree of Radiological Compression Predicts Cauda Equina Syndrome: A Retrospective Study at a National Tertiary Centre.

OBJECTIVE: Cauda Equina Syndrome (CES) is diagnosed both clinically and radiologically. However, it's unclear if a specific degree of cauda equina compression (CEC) on imaging can confirm the diagnosis. This study aimed to identify an optimal percentage of prolapse to canal ratio (PCR) on MRI that correlates with CEC, facilitating reliable decision-making for CES symptoms. METHODS: A single-center retrospective case series analysis was conducted from 2020 to 2021. Sixty-one patients who underwent emergency lumbar discectomy within 48 hours of presentation were included, divided into a CES group and a disc prolapse (DP) group. CES cases were identified using ICD-10 code G83.4. PCR was calculated by dividing the width of the disc herniation by the total width of the spinal canal at the level of the herniation on single mid-sagittal T2 MRI scans, using the IC Measure software on Windows. RESULTS: CES most frequently occurred at the L4/5 level (37/61). The median PCR in CES cases was 76.19% (66.67 - 85.71), significantly higher than in DP cases, 48.08% (31.33 - 55.56) (p<0.001). A PCR threshold of 40% maximized sensitivity at 100% but had a specificity of 45%. Conversely, a threshold of 75% maximized specificity at 100% with a sensitivity of 50%. The optimal PCR, determined by the Youden index, was 66%, yielding a sensitivity of 75% and specificity of 97%, with an area under the curve (AUC) of 0.923. CONCLUSIONS: Simple radiological measurements of PCR can potentially triage CES patients and guide their management. Future studies should correlate PCR with clinical signs and symptoms for a comprehensive assessment.

Clinicosocial determinants of hospital stay following cervical decompression: A public healthcare perspective and machine learning model.

OBJECTIVE: Post-operative length of hospital stay (LOS) is a valuable measure for monitoring quality of care provision, patient recovery, and guiding hospital resource management. But the impact of patient ethnicity, socio-economic deprivation as measured by the indices of multiple deprivation (IMD), and pre-existing health conditions on LOS post-anterior cervical decompression and fusion (ACDF) is under-researched in public healthcare settings. METHODS: From 2013 to 2023, a retrospective study at a single center reviewed all ACDF procedures. We analyzed 14 non-clinical predictors-including demographics, comorbidities, and socio-economic status-to forecast a categorized LOS: short (≤2 days), medium (2-3 days), or long (>3 days). Three machine learning (ML) models were developed and assessed for their prediction reliability. RESULTS: 2033 ACDF patients were analyzed; 79.44 % had a LOS ≤ 2 days. Significant predictors of LOS included patient sex (HR:0.81[0.74-0.88], p < 0.005), IMD decile (HR:1.38[1.24-1.53], p < 0.005), smoking (HR:1.24[1.12-1.38], p < 0.005), DM (HR:0.70[0.59-0.84], p < 0.005), and COPD (HR:0.66, p = 0.01). Asian patients had the highest mean LOS (p = 0.003). Testing on 407 patients, the XGBoost model achieved 80.95 % accuracy, 71.52 % sensitivity, 85.76 % specificity, 71.52 % positive predictive value, and a micro F1 score of 0.715. This model is available at: https://acdflos.streamlit.app. CONCLUSIONS: Utilizing non-clinical pre-operative parameters such as patient ethnicity, socio-economic deprivation index, and baseline comorbidities, our ML model effectively predicts postoperative LOS for patient undergoing ACDF surgeries. Yet, as the healthcare landscape evolves, such tools will require further refinement to integrate peri and post-operative variables, ensuring a holistic decision support tool.

Combining LC-MS/MS profiles with network pharmacology to predict molecular mechanisms of the hyperlipidemic activity of Lagenaria siceraria stand.

ETHNOPHARMACOLOGICAL RELEVANCE: Lagenaria siceraria Stand. (Family: Cucurbitaceae), popularly known as bottle gourd, is traditionally used in Ayurvedic medicine as a food plant, especially in hypertension and obesity. AIM OF THE STUDY: Investigations were undertaken to assign novel lead combinations from this common food plant to multi-molecular modes of actions in the complex disease networks of obesity and hypertension. LC-MS/MS based metabolite screening, in-vivo high fat diet induced hyperlipidemia animal study and network pharmacology explorations of the mechanism of action for lipid lowering effects including a neighbourhood community approach for molecular combinations were performed. MATERIAL AND METHODS: Major chemical constituents of the fruits of LS (LSFE) were analysed by HPLC-DAD-MS/MS-QTOF. Wistar albino rats (n = 36), divided into 6 groups (n = 6) received either no treatment or a high-fat diet along with LSFE or Atorvastatin. Lipid profiles and biochemical parameters were evaluated. In silico cross-validated network analyses using different databases and Cytospace were applied. RESULTS: Profiling of LSFE revealed 18 major constituents: phenolic acids like p-Coumaric acid and Ferulic acid, the monolignolconferyl alcohol, the flavonoid glycosides hesperidin and apigenin-7-glucoside. Hyperlipidemic animals treated with LSFE (200 mg/kg, 400 mg/kg, 600 mg/kg) showed a significant improvement of their lipid profiles after 30 days of treatment. Network pharmacology analyses for the major 18 compounds revealed enrichment of the insulin and the ErbB signalling pathway. Novel target node combinations (e.g. AKR1C1, AGXT) including their connection to different pathways were identified in silico. CONCLUSIONS: The combined in vivo and bioinformatics analyses propose that lead compounds of LSFE act in combination on relevant targets of hyperlipidemia. Perturbations of the IRS→Akt→Foxo1 cascade are predicted which suggest further clinical investigation towards development of safe natural alternative to manage hyperlipidemia.

Development and Validation of the Chronic Subdural HematOma Referral oUtcome Prediction Using Statistics (CHORUS) Score: A Retrospective Study at a National Tertiary Center.

BACKGROUND: Chronic subdural hematoma (CSDH) is a common neurosurgical condition with an increasing rate of patient referrals. CSDH referral decision-making is a subjective clinical process, and our aim was to develop a simple scoring system capable of acting as a decision support tool aiding referral triage. METHODS: A single tertiary center retrospective case series analysis of all CSDH patient referrals from 2015 to 2020 was conducted. Ten independent variables used in the referral process were analyzed to predict the binary outcome of either accepting or rejecting the CSDH referral. Following feature selection analysis, a multivariable scoring system was developed and evaluated. RESULTS: 1500 patient referrals were included. Stepwise multivariable logistic and least absolute shrinkage and selection operator regression identified age <85 years, the presence of headaches, dementia, motor weakness, radiological midline shift, a reasonable premorbid quality of life, and a large sized hematoma to be statistically significant predictors of CSDH referral acceptance (P <0.04). These variables derived a scoring system ranging from -9 to 6 with an optimal cut-off for referral acceptance at any score >1 (P <0.0001). This scoring system demonstrated optimal calibration (brier score loss = 0.0552), with a score >1 predicting referral acceptance with an area under the curve of 0.899 (0.876-0.922), a sensitivity of 83.838% (76.587-91.089), and a specificity of 96.000% (94.080-97.920). CONCLUSIONS: Certain patient specific clinical and radiological characteristics can predict the acceptance or rejection of a CSDH referral. Considering the precision of this scoring system, it has the potential for effectively triaging CSDH referrals.

Natural language processing for the automated detection of intra-operative elements in lumbar spine surgery.

Background: The aim of this study was to develop natural language processing (NLP) algorithms to conduct automated identification of incidental durotomy, wound drains, and the use of sutures or skin clips for wound closure, in free text operative notes of patients following lumbar surgery. Methods: A single-centre retrospective case series analysis was conducted between January 2015 and June 2022, analysing operative notes of patients aged >18 years who underwent a primary lumbar discectomy and/or decompression at any lumbar level. Extreme gradient-boosting NLP algorithms were developed and assessed on five performance metrics: accuracy, area under receiver-operating curve (AUC), positive predictive value (PPV), specificity, and Brier score. Results: A total of 942 patients were used in the training set and 235 patients, in the testing set. The average age of the cohort was 53.900 ± 16.153 years, with a female predominance of 616 patients (52.3%). The models achieved an aggregate accuracy of >91%, a specificity of >91%, a PPV of >84%, an AUC of >0.933, and a Brier score loss of ≤0.082. The decision curve analysis also revealed that these NLP algorithms possessed great clinical net benefit at all possible threshold probabilities. Global and local model interpretation analyses further highlighted relevant clinically useful features (words) important in classifying the presence of each entity appropriately. Conclusions: These NLP algorithms can help monitor surgical performance and complications in an automated fashion by identifying and classifying the presence of various intra-operative elements in lumbar spine surgery.

Determining the risk of spinal pathology progression in neurofibromatosis type 1 patients - a national tertiary neurofibromatosis type 1 centre study.

BACKGROUND: Neurofibromatosis type 1 (NF1) gives rise to a variety of spinal pathologies that include dural ectasia (DE), vertebral malalignments (VMA), spinal deformities (SD), syrinx, meningoceles, spinal nerve root tumours (SNRT), and spinal plexiform tumours (SPT). The relationship between these and the progression of these pathologies has not been explored before in detail and this paper aims to address this. METHODS: Data was retrospectively collected from adult NF1 multi-disciplinary team meetings from 2016 to 2022 involving a total of 593 patients with 20 distinct predictor variables. Data were analyzed utilizing; Chi-Square tests, binary logistic regression, and Kaplan-Meier analysis. RESULTS: SNRT (19.9%), SD (18.6%), and (17.7%) of VMA had the highest rates of progression. SD was significantly associated (p < 0.02) with the presence and progression of all spinal pathologies except for SPT. Statistically significant predictors of SD progression included the presence of DVA, VMA, syrinx, meningocele, and SNRT. Kaplan-Meier analysis revealed no statistically significant difference between the times to progression for SD (85 days), SNRT (1196 days), and VMA (2243 days). CONCLUSION: This paper explores for the first time in detail, the progression of various spinal pathologies in NF1. The presence and progression of SD is a key factor that correlated with the progression of different spinal pathologies. Early identification of SD may help support clinical decision-making and guide radiological follow-up protocols and treatment.

RGS7-ATF3-Tip60 Complex Promotes Hepatic Steatosis and Fibrosis by Directly Inducing TNFα.

Aims: The pathophysiological mechanism(s) underlying non-alcoholic fatty liver disease (NAFLD) have yet to be fully delineated and only a single drug, peroxisome proliferator-activated receptor (PPAR) α/γ agonist saroglitazar, has been approved. Here, we sought to investigate the role of Regulator of G Protein Signaling 7 (RGS7) in hyperlipidemia-dependent hepatic dysfunction. Results: RGS7 is elevated in the livers of NAFLD patients, particularly those with severe hepatic damage, pronounced insulin resistance, and high inflammation. In the liver, RGS7 forms a unique complex with transcription factor ATF3 and histone acetyltransferase Tip60, which is implicated in NAFLD. The removal of domains is necessary for ATF3/Tip60 binding compromises RGS7-dependent reactive oxygen species generation and cell death. Hepatic RGS7 knockdown (KD) prevented ATF3/Tip60 induction, and it provided protection against fibrotic remodeling and inflammation in high-fat diet-fed mice translating to improvements in liver function. Hyperlipidemia-dependent oxidative stress and metabolic dysfunction were largely reversed in RGS7 KD mice. Interestingly, saroglitazar failed to prevent RGS7/ATF3 upregulation but it did partially restore Tip60 levels. RGS7 drives the release of particularly tumor necrosis factor α (TNFα) from isolated hepatocytes, stellate cells and its depletion reverses steatosis, oxidative stress by direct TNFα exposure. Conversely, RGS7 overexpression in the liver is sufficient to trigger oxidative stress in hepatocytes that can be mitigated via TNFα inhibition. Innovation: We discovered a novel non-canonical function for an R7RGS protein, which usually functions to regulate G protein coupled receptor (GPCR) signaling. This is the first demonstration for a functional role of RGS7 outside the retina and central nervous system. Conclusion: RGS7 represents a potential novel target for the amelioration of NAFLD. Antioxid. Redox Signal. 38, 137-159.

Quantification and Standardization of Andrographolide in Andrographis Paniculata Samples by Validated RP-HPLC and HPTLC Methods.

Andrographis paniculata (family Acanthaceae) is known as Kalmegh, one of the traditionally used important medicinal plant contains several biologically active phytochemical including andrographolide. A. paniculata is broadly used by healthcare practitioners in India and also used in different traditional medicinal system. In this study, the leaves of A. paniculata were collected from West Medinipur, East Medinipur, South 24 Parganas, Purulia and Hooghly district of West Bengal, India. This study aiming towards validation and development of a simple, precise and reproducible reverse-phase high-performance liquid chromatography (RP-HPLC) and high-performance thin layer chromatography (HPTLC) methods for quantification of andrographolide in A. paniculata extracts. The validated RP-HPLC and HPTLC study confirmed that different concentrations of andrographolide content present in the plant samples, which are collected from above different districts of West Bengal, India. The amounts of andrographolide were found to be 2.71% (w/w), 3.19% (w/w), 1.83% (w/w), 1.73% (w/w) and 2.94% (w/w) in RP-HPLC study and 2.13% (w/w), 2.51% (w/w), 1.01% (w/w), 1.25% (w/w) and 2.15% (w/w) in HPTLC study. This precise, reproducible, accurate and specific method can be used for the quantification of andrographolide in kalmegh, as per the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines recommendations.

Temporal trends in neurosurgical volume and length of stay in a public healthcare system: A decade in review with a focus on the COVID-19 pandemic.

Background: Over the past decade, neurosurgical interventions have experienced changes in operative frequency and postoperative length of stay (LOS), with the recent COVID-19 pandemic significantly impacting these metrics. Evaluating these trends in a tertiary National Health Service center provides insights into the impact of surgical practices and health policy on LOS and is essential for optimizing healthcare management decisions. Methods: This was a single tertiary center retrospective case series analysis of neurosurgical procedures from 2012 to 2022. Factors including procedure type, admission urgency, and LOS were extracted from a prospectively maintained database. Six subspecialties were analyzed: Spine, Neuro-oncology, Skull base (SB), Functional, Cerebrospinal fluid (CSF), and Peripheral nerve (PN). Mann-Kendall temporal trend test and exploratory data analysis were performed. Results: 19,237 elective and day case operations were analyzed. Of the 6 sub-specialties, spine, neuro-oncology, SB, and CSF procedures all showed a significant trend toward decreasing frequency. A shift toward day case over elective procedures was evident, especially in spine (P < 0.001), SB (tau = 0.733, P = 0.0042), functional (tau = 0.156, P = 0.0016), and PN surgeries (P < 0.005). Over the last decade, decreasing LOS was observed for neuro-oncology (tau = -0.648, P = 0.0077), SB (tau = -0.382, P = 0.012), and functional operations, a trend which remained consistent during the COVID-19 pandemic (P = 0.01). Spine remained constant across the decade while PN demonstrated a trend toward increasing LOS. Conclusion: Most subspecialties demonstrate a decreasing LOS coupled with a shift toward day case procedures, potentially attributable to improvements in surgical techniques, less invasive approaches, and increased pressure on beds. Setting up extra dedicated day case theaters could help deal with the backlog of procedures, particularly with regard to the impact of COVID-19.

Predicting neurosurgical referral outcomes in patients with chronic subdural hematomas using machine learning algorithms - A multi-center feasibility study.

Background: Chronic subdural hematoma (CSDH) incidence and referral rates to neurosurgery are increasing. Accurate and automated evidence-based referral decision-support tools that can triage referrals are required. Our objective was to explore the feasibility of machine learning (ML) algorithms in predicting the outcome of a CSDH referral made to neurosurgery and to examine their reliability on external validation. Methods: Multicenter retrospective case series conducted from 2015 to 2020, analyzing all CSDH patient referrals at two neurosurgical centers in the United Kingdom. 10 independent predictor variables were analyzed to predict the binary outcome of either accepting (for surgical treatment) or rejecting the CSDH referral with the aim of conservative management. 5 ML algorithms were developed and externally tested to determine the most reliable model for deployment. Results: 1500 referrals in the internal cohort were analyzed, with 70% being rejected referrals. On a holdout set of 450 patients, the artificial neural network demonstrated an accuracy of 96.222% (94.444-97.778), an area under the receiver operating curve (AUC) of 0.951 (0.927-0.973) and a brier score loss of 0.037 (0.022-0.056). On a 1713 external validation patient cohort, the model demonstrated an AUC of 0.896 (0.878-0.912) and an accuracy of 92.294% (90.952-93.520). This model is publicly deployed: https://medmlanalytics.com/neural-analysis-model/. Conclusion: ML models can accurately predict referral outcomes and can potentially be used in clinical practice as CSDH referral decision making support tools. The growing demand in healthcare, combined with increasing digitization of health records raises the opportunity for ML algorithms to be used for decision making in complex clinical scenarios.

RGS11-CaMKII complex mediated redox control attenuates chemotherapy-induced cardiac fibrosis.

Dose limiting cardiotoxicity remains a major limiting factor in the clinical use of several cancer chemotherapeutics including anthracyclines and the antimetabolite 5-fluorouracil (5-FU). Prior work has demonstrated that chemotherapeutics increase expression of R7 family regulator of G protein signaling (RGS) protein-binding partner Gß5, which drives myocyte cytotoxicity. However, though several R7 family members are expressed in heart, the exact role of each protein in chemotherapy driven heart damage remains unclear. Here, we demonstrate that RGS11, downregulated in the human heart following chemotherapy exposure, possesses potent anti-apoptotic actions, in direct opposition to the actions of fellow R7 family member RGS6. RGS11 forms a direct complex with the apoptotic kinase CaMKII and stress responsive transcription factor ATF3 and acts to counterbalance the ability of CaMKII and ATF3 to trigger oxidative stress, mitochondrial dysfunction, cell death, and release of the cardiokine neuregulin-1 (NRG1), which mediates pathological intercommunication between myocytes and endothelial cells. Doxorubicin triggers RGS11 depletion in the murine myocardium, and cardiac-specific OE of RGS11 decreases doxorubicin-induced fibrosis, myocyte hypertrophy, apoptosis, oxidative stress, and cell loss and aids in the maintenance of left ventricular function. Conversely, RGS11 knockdown in heart promotes cardiac fibrosis associated with CaMKII activation and ATF3/NRG1 induction. Indeed, inhibition of CaMKII largely prevents the fibrotic remodeling resulting from cardiac RGS11 depletion underscoring the functional importance of the RGS11-CaMKII interaction in the pathogenesis of cardiac fibrosis. These data describe an entirely new role for RGS11 in heart and identify RGS11 as a potential new target for amelioration of chemotherapy-induced cardiotoxicity.

Withania somnifera (L.) Dunal - Modern perspectives of an ancient Rasayana from Ayurveda.

ETHNOPHARMACOLOGICAL RELEVANCE: Withania somnifera (L.) Dunal, commonly known as Ashwagandha, is an important medicinal plant that has been used in Ayurvedic and indigenous medicine for more than 3000 years. According to Charaka Samhita, Susruta Samhita and other ancient texts, Ashwagandha is known as Balya (increases strength), Brusya (sexual performance enhancer), vajikari (spermatogenic), Kamarupini (libido-enhancing), Pustida (nourishing). AIM OF THE REVIEW: This review article documented and critically assessed W. somnifera regarding its ethnopharmacology, traditional use, botanical description, phytochemicals present, pharmacological activities, clinical trials, and marketed formulations. MATERIALS AND METHODS: The sources of information used in the study are traditional Ayurvedic books like Charaka Samhita, Susruta Samhita, Astanga Hridaya etc, government reports, dissertations, books, research articles and databases like Science-Direct, SciFinder, Web of Science, PubMed, Wiley Online Library, and ACS Publications on Ashwagandha and Withania somnifera (L.) Dunal. RESULTS: Traditional uses of Ashwagandha in Ayurveda are very prominent in several texts where formulations with various dosage forms have been mentioned in Charaka Samhita, Susruta Samhita, Astanga Hridaya, different nighantus etc. The drugs were identified based on their composition containing Ashwagandha as one of the major ingredients and their medicinal uses. Phytochemical studies on W. somnifera revealed the presence of important chemical constituents such as flavonoids, phenolic acids, alkaloids, saponins, tannins, and withanolides. The phytochemicals showed various pharmacological activities like anti-cancer, immunomodulatory, cardioprotective, neuroprotective, anti-aging, anti-stress/adaptogenic and anti-diabetic. Various clinical trials show that the plant extract and its bioactive compounds are used in the prevention and treatment of many diseases, such as arthritis, impotence, amnesia, anxiety, cancer, neurodegenerative and cardiovascular diseases, and others. CONCLUSIONS: Pharmacological data reviewed here revealed that W. somnifera is a potential source for the treatment of a wide range of diseases especially anxiety and other CNS disorders. From its ancient use to its modern application it has been proven to be non-toxic and effective clinically for human health and wellness. W. somnifera based herbal formulation has been marketed in the form of supplement, extract, capsule, powder etc. This review will be helpful to correlate the mechanism of action with the phytochemical profile of this well-known plant from Ayurveda.

Synergistic effect of ursolic acid and piperine in CCl4 induced hepatotoxicity.

BACKGROUND: Ursolic acid (UA) is a potent plant-based hepatoprotective agent having poor bioavailability, which hampers its therapeutic efficacy. The present study tries to overcome this limitation by combining it with piperine (PIP), a proven bioenhancer and hepatoprotective agent. METHODS: The type of interaction (synergism, addition, or antagonism) resulting between UA and PIP was analyzed and quantified by isobologram and combination index analysis. The hepatoprotective activity of UA and PIP was evaluated by measuring the level of hepatic marker enzymes. Pharmacokinetic analysis was carried out to ascertain the improvement of bioavailability. RESULTS: The combinations significantly decrease the enzyme levels, which indicate better hepatoprotective activity compared to single drugs. The relative oral bioavailability of UA was increased about tenfold (from AUC0-t =12.78 ± 2.59 µg/h/ml to 125.15 ± 1.84 µg/h/ml) along with the improvement of plasma concentration and elimination half-life. CONCLUSIONS: The findings indicated that the combination of PIP and UA is an effective strategy in enhancing the bioavailability and hepatoprotective potential of UA.KEY MESSAGESUrsolic acid in a combination with piperine provides a synergistic hepatoprotective effect in carbon tetrachloride induced liver damage in rats.Piperine improves the pharmacokinetic properties of ursolic acid when given in combination.Piperine improves the relative oral bioavailability of ursolic acid by tenfold when combined together.

A Tunable Palette of Molecular Rotors Allows Multicolor, Ratiometric Fluorescence Imaging and Direct Mapping of Mitochondrial Heterogeneity.

Environment-sensitive molecular probes offer the potential for a comprehensive mapping of the complex cellular milieu. We present here a radically new strategy of multiplexing highly sensitive, spectrally tuned fluorescent dyes for sensing cellular microenvironment. To achieve this multicolor, ratiometric cellular imaging, we first developed a series of highly sensitive, tunable molecular rotors for mitochondrial imaging, with emission wavelengths spanning the visible spectrum. These fluorogenic merocyanine dyes are all sensitive to solvent viscosity despite distinctive photophysical features. Our results show that merocyanine dyes can show a rotor-like behavior despite significant changes to the conventional donor-acceptor or push-pull scaffolds, thereby revealing conserved features of rotor dye chemistry. Developing closely related but spectrally separated dyes that have distinct response functions allows us to do ″two-color, two-dye″ imaging of the mitochondrial microenvironment. Our results with multidye, combinatorial imaging provide a direct visualization of the intrinsic heterogeneity of the mitochondrial microenvironment. The overall mitochondrial microenvironment (including contributions from local membrane order) as reported through two-color fluorescence ″ratio″ changes of multiplexed rotor dyes shows dynamic heterogeneity with distinct spatiotemporal signatures that evolve over time and respond to chemical perturbations. Our results offer a powerful illustration of how multiplexed dye imaging allows the quantitative imaging of mitochondrial membrane order and cellular microenvironment.