Risk of cardiovascular events following intermittent and continuous androgen deprivation therapy in patients with nonmetastatic prostate cancer.

BACKGROUND: Intermittent androgen deprivation therapy (iADT) alleviates some side effects of continuous (c) ADT in patients with prostate cancer (PC), but its relative impact on ADT-associated comorbidities is uncertain. We assessed real-world use of iADT and cADT and associated risk of cardiovascular and endocrine/metabolic events in patients with nonmetastatic (nm) PC. METHODS: This retrospective longitudinal cohort study included patients with nmPC initiating systemic ADT with gonadotropin-releasing hormone agonists (goserelin, histrelin, leuprolide, and triptorelin) or antagonists (degarelix) in the US Surveillance, Epidemiology and End Results-Medicare database (2010-2017), who had ≥ 36 months of continuous insurance coverage, unless death occurred, and did not receive chemotherapy or next-generation hormonal therapies during follow-up (through 2019). Risk of major adverse cardiovascular events (MACE [myocardial infarction, stroke, cardiomyopathy/heart failure, pulmonary embolism, ischemic heart disease, all-cause mortality]) and endocrine/metabolic events (diabetes, hypercholesterolemia, bone fractures, and osteoporosis) were examined between cohorts. Inverse probability of treatment-weighted Cox regression models estimated adjusted hazard ratios (HRs) of the outcomes. RESULTS: Of 10,655 eligible patients, 2,095 (19.7%) received iADT and 8,560 (80.3%) cADT. Median follow-up was 43.9 and 48.4 months and median ADT duration (excluding iADT gaps) was 22.0 and 13.5 months for the iADT and cADT cohorts, respectively. Patients receiving cADT had a lower risk of MACE vs. iADT (HR 0.90; 95% confidence interval [CI] 0.83-0.96). No difference in risk of endocrine/metabolic events was observed (HR 0.97; 95% CI 0.92-1.03). Subgroup analysis found that the difference in MACE was maintained in patients with a history of cardiovascular disease (HR 0.90; 95% CI 0.83-0.98) and eliminated in patients without (HR 0.94; 95% CI 0.82-1.08). CONCLUSIONS: Patients with nmPC who received cADT had a lower risk of MACE and similar risk of endocrine/metabolic events vs. those who received iADT. Further research assessing both regimens is needed to inform treatment decisions.

Implications of Delayed Testosterone Recovery in Patients with Prostate Cancer.

To assess the clinical impact of delayed testosterone recovery (TR) following the discontinuation of medical androgen deprivation therapy (ADT), a retrospective, longitudinal analysis was conducted in adult males with prostate cancer using the Optum® de-identified Electronic Health Record data set and Optum® Enriched Oncology Data (2010-2021). Of 3875 patients who initiated and discontinued ADT, 1553 received one or more testosterone-level tests within the 12 mo following discontinuation and were included in this study. These 1553 patients were categorized into two cohorts: 25% as TR (testosterone levels >280 ng/dl at any test within 12 mo following ADT discontinuation) and 75% as non-TR. At baseline, non-TR patients were older, had lower testosterone levels, and were more likely to have diabetes, hyperlipidemia, and hypertension, but less likely to have sexual dysfunction. After adjustment for baseline characteristics, the TR cohort had a lower risk of new-onset diabetes (hazard ratio [HR] 0.47; 95% confidence interval [CI] 0.27-0.79), trended toward a lower risk of new-onset depression (HR 0.58; 95% CI 0.33-1.02), and had a higher likelihood of seeking treatment for sexual dysfunction (HR 1.33; 95% CI 0.99-1.78) versus the non-TR cohort. These findings support monitoring testosterone levels after ADT discontinuation to manage potential long-term comorbidities in patients with prostate cancer. Patient summary: This real-world analysis of males with prostate cancer who were treated with medical androgen deprivation therapy (ADT) found that most patients did not have their testosterone level checked in the 12 mo after stopping ADT. Of those who did, 75% did not achieve normal testosterone levels (>280 ng/dl), and these patients were more likely to experience new-onset diabetes than those who achieved normal testosterone levels. These results suggest that to ensure effective clinical decision-making, physicians should check patients' testosterone levels after stopping ADT.

A quad DC source switched three-phase multilevel DC-link inverter topology.

The concept of an isolated DC source cascaded multilevel inverter finds good solutions for generating quality output voltage for low-medium power applications. It shapes the output voltage from three levels into a number of steps closer to a sinusoidal shape using small DC sources or batteries. Several advantages have been sighted like lower voltage stress and bearing noise, and lesser THD. However, a common issue in the MLIs is the total components required which increase with the rise in voltage levels. This paper proposes a three-phase MLI design having several isolated quad voltage source modules including an H-Bridge inverter. The design suggested claims reduced switching components for current conduction paths showing improved output quality. The operational features of the suggested MLI have been analyzed using Matlab/Simulink software, furthermore, an experimental module is constructed for demonstrating the effectiveness of the simulated results.

Hybrid optimized feature selection and deep learning based COVID-19 disease prediction.

The COVID-19 virus has affected many people around the globe with several issues. Moreover, it causes a worldwide pandemic, and it makes more than one million deaths. Countries around the globe had to announce a complete lockdown when the corona virus causes the community to spread. In real-time, Polymerase Chain Reaction (RT-PCR) test is conducted to detect COVID-19, which is not effective and sensitive. Hence, this research presents the proposed Caviar-MFFO-assisted Deep LSTM scheme for COVID-19 detection. In this research, the COVID-19 cases data is utilized to process the COVID-19 detection. This method extracts the various technical indicators that improve the efficiency of COVID-19 detection. Moreover, the significant features fit for COVID-19 detection are selected using proposed mayfly with fruit fly optimization (MFFO). In addition, COVID-19 is detected by Deep Long Short Term Memory (Deep LSTM), and the Conditional Autoregressive Value at Risk MFFO (Caviar-MFFO) is modeled to train the weight of Deep LSTM. The experimental analysis reveals that the proposed Caviar-MFFO assisted Deep LSTM method provided efficient performance based on the Mean Squared Error (MSE) and Root Mean Squared Error (RMSE), and achieved the recovered cases with the minimal values of 1.438 and 1.199, whereas the developed model achieved the death cases with the values of 4.582 and 2.140 for MSE and RMSE. In addition, 6.127 and 2.475 are achieved by the developed model based on infected cases.

A novel nucleoside rescue metabolic pathway may be responsible for therapeutic effect of orally administered cordycepin.

Although adenosine and its analogues have been assessed in the past as potential drug candidates due to the important role of adenosine in physiology, only little is known about their absorption following oral administration. In this work, we have studied the oral absorption and disposition pathways of cordycepin, an adenosine analogue. In vitro biopharmaceutical properties and in vivo oral absorption and disposition of cordycepin were assessed in rats. Despite the fact that numerous studies showed efficacy following oral dosing of cordycepin, we found that intact cordycepin was not absorbed following oral administration to rats. However, 3'-deoxyinosine, a metabolite of cordycepin previously considered to be inactive, was absorbed into the systemic blood circulation. Further investigation was performed to study the conversion of 3'-deoxyinosine to cordycepin 5'-triphosphate in vitro using macrophage-like RAW264.7 cells. It demonstrated that cordycepin 5'-triphosphate, the active metabolite of cordycepin, can be formed not only from cordycepin, but also from 3'-deoxyinosine. The novel nucleoside rescue metabolic pathway proposed in this study could be responsible for therapeutic effects of adenosine and other analogues of adenosine following oral administration. These findings may have importance in understanding the physiology and pathophysiology associated with adenosine, as well as drug discovery and development utilising adenosine analogues.

Sustained Neurotrophin Release from Protein Nanoparticles Mediated by Matrix Metalloproteinases Induces the Alignment and Differentiation of Nerve Cells.

The spatial and temporal availability of cytokines, and the microenvironments this creates, is critical to tissue development and homeostasis. Creating concentration gradients in vitro using soluble proteins is challenging as they do not provide a self-sustainable source. To mimic the sustained cytokine secretion seen in vivo from the extracellular matrix (ECM), we encapsulated a cargo protein into insect virus-derived proteins to form nanoparticle co-crystals and studied the release of this cargo protein mediated by matrix metalloproteinase-2 (MMP-2) and MMP-8. Specifically, when nerve growth factor (NGF), a neurotrophin, was encapsulated into nanoparticles, its release was promoted by MMPs secreted by a PC12 neuronal cell line. When these NGF nanoparticles were spotted onto a cover slip to create a uniform circular field, movement and alignment of PC12 cells via their extended axons along the periphery of the NGF nanoparticle field was observed. Neural cell differentiation was confirmed by the expression of specific markers of tau, neurofilament, and GAP-43. Connections between the extended axons and the growth cones were also observed, and expression of connexin 43 was consistent with the formation of gap junctions. Extensions and connection of very fine filopodia occurred between growth cones. Our studies indicate that crystalline protein nanoparticles can be utilized to generate a highly stable cytokine gradient microenvironment that regulates the alignment and differentiation of nerve cells. This technique greatly simplifies the creation of protein concentration gradients and may lead to therapies for neuronal injuries and disease.

Accuracy Enhanced Lung Cancer Prognosis for Improving Patient Survivability Using Proposed Gaussian Classifier System.

Statistical classifier and good accuracy is an essential part of the research in medical data mining. Accurate prediction of lung cancer is an essential step for making effective clinical decisions. After identifying the lung cancer, minimum scopes are available in the medications for patient living in the world. Hemoglobin level and TNM stage wise patients survival period has to be varied. Some group of people survival period is minimal and another group of people survival time is lengthy. This study is aimed to develop a prediction model with new clinical variables to predict lung cancer patients. It's based on revised 8th edition study of TNM in lung cancer. These new attributes are collected from SEER databases, Indian cancer hospitals and research centers. The collected new attributes are classified using supervised machine learning algorithms of linear regression, Naïve Bayes classifier and proposed algorithms of Gaussian K-Base NB classifier. In particular, for TNM stage 1 group of people with normal hemoglobin level (NHBL), that group of lung cancer patient quality of life is highly enhanced. Which proved by using supervised machine learning algorithms. The proposed algorithm classified the database in terms of with respect to tumor size and HB level and the results are confirmed in the R environment. The continuous attribute classification method to prove first level of TNM in lung cancer patient along with standard hemoglobin has to be maintained that the people survivability rate is higher than the smaller level of hemoglobin people survival rate. The Gaussian K-Base NB classifier is more effective than the existing machine learning algorithms for lung cancer prediction model. The proposed classification accuracy has measured using ROC methods.

The polyadenylation inhibitor cordycepin reduces pain, inflammation and joint pathology in rodent models of osteoarthritis.

Clinically, osteoarthritis (OA) pain is significantly associated with synovial inflammation. Identification of the mechanisms driving inflammation could reveal new targets to relieve this prevalent pain state. Herein, a role of polyadenylation in OA synovial samples was investigated, and the potential of the polyadenylation inhibitor cordycepin (3' deoxyadenosine) to inhibit inflammation as well as to reduce pain and structural OA progression were studied. Joint tissues from people with OA with high or low grade inflammation and non-arthritic post-mortem controls were analysed for the polyadenylation factor CPSF4 and inflammatory markers. Effects of cordycepin on pain behavior and joint pathology were studied in models of OA (intra-articular injection of monosodium iodoacetate in rats and surgical destabilisation of the medial meniscus in mice). Human monocyte-derived macrophages and a mouse macrophage cell line were used to determine effects of cordycepin on nuclear localisation of the inflammatory transcription factor NFĸB and polyadenylation factors (WDR33 and CPSF4). CPSF4 and NFκB expression were increased in synovia from OA patients with high grade inflammation. Cordycepin reduced pain behaviour, synovial inflammation and joint pathology in both OA models. Stimulation of macrophages induced nuclear localisation of NFĸB and polyadenylation factors, effects inhibited by cordycepin. Knockdown of polyadenylation factors also prevented nuclear localisation of NFĸB. The increased expression of polyadenylation factors in OA synovia indicates a new target for analgesia treatments. This is supported by the finding that polyadenylation factors are required for inflammation in macrophages and by the fact that the polyadenylation inhibitor cordycepin attenuates pain and pathology in models of OA.

Use of Transcranial Doppler in Patients with Severe Traumatic Brain Injuries.

Severe traumatic brain injuries (TBI) are associated with a high rate of mortality and disability. Transcranial Doppler (TCD) sonography permits a noninvasive measurement of cerebral blood flow. The purpose of this study is to determine the usefulness of TCD in patients with severe TBI. TCD was performed, from April 2008 to April 2013, on 255 patients with severe TBI, defined as a Glasgow Coma Scale score of ≤8 on admission. TCD was performed on hospital days 1, 2, 3, and 7. Hypoperfusion was defined by having two out of three of the following: 1) mean velocity (Vm) of the middle cerebral artery <35 cm/sec, 2) diastolic velocity (Vd) of the middle cerebral artery <20 cm/sec, or 3) pulsatility index (PI) of >1.4. Vasospasm was defined by the following: Vm of the middle cerebral artery >120 cm/sec and/or a Lindegaard index (LI) >3. One hundred fourteen (45%) had normal measurements. Of these, 92 (80.7%) had a good outcome, 6 (5.3%) had moderate disability, and 16 (14%) died, 4 from brain death. Seventy-two patients (28%) had hypoperfusion and 71 (98.6%) died, 65 from brain death, and 1 patient survived with moderate disability. Sixty-nine patients (27%) had vasospasm, 31 (44.9%) had a good outcome, 16 (23.2%) had severe disability, and 22 (31.9%) died, 13 from brain death. The vasospasm was detected on hospital day 1 in 8 patients, on day 2 in 23 patients, on day 3 in 22 patients, and on day 7 in 16 patients. Patients with normal measurements can be expected to survive. Patients with hypoperfusion have a poor prognosis. Patients with vasospasm have a high incidence of mortality and severe disability. TCD is useful in determining early prognosis.

The role of acid-base imbalance in statin-induced myotoxicity.

Disturbances in acid-base balance, such as acidosis and alkalosis, have potential to alter the pharmacologic and toxicologic outcomes of statin therapy. Statins are commonly prescribed for elderly patients who have multiple comorbidities such as diabetes mellitus, cardiovascular, and renal diseases. These patients are at risk of developing acid-base imbalance. In the present study, the effect of disturbances in acid-base balance on the interconversion of simvastatin and pravastatin between lactone and hydroxy acid forms have been investigated in physiological buffers, human plasma, and cell culture medium over pH ranging from 6.8-7.8. The effects of such interconversion on cellular uptake and myotoxicity of statins were assessed in vitro using C2C12 skeletal muscle cells under conditions relevant to acidosis, alkalosis, and physiological pH. Results indicate that the conversion of the lactone forms of simvastatin and pravastatin to the corresponding hydroxy acid is strongly pH dependent. At physiological and alkaline pH, substantial proportions of simvastatin lactone (SVL; ∼87% and 99%, respectively) and pravastatin lactone (PVL; ∼98% and 99%, respectively) were converted to the active hydroxy acid forms after 24 hours of incubation at 37°C. At acidic pH, conversion occurs to a lower extent, resulting in greater proportion of statin remaining in the more lipophilic lactone form. However, pH alteration did not influence the conversion of the hydroxy acid forms of simvastatin and pravastatin to the corresponding lactones. Furthermore, acidosis has been shown to hinder the metabolism of the lactone form of statins by inhibiting hepatic microsomal enzyme activities. Lipophilic SVL was found to be more cytotoxic to undifferentiated and differentiated skeletal muscle cells compared with more hydrophilic simvastatin hydroxy acid, PVL, and pravastatin hydroxy acid. Enhanced cytotoxicity of statins was observed under acidic conditions and is attributed to increased cellular uptake of the more lipophilic lactone or unionized hydroxy acid form. Consequently, our results suggest that comorbidities associated with acid-base imbalance can play a substantial role in the development and potentiation of statin-induced myotoxicity.

Geriatric Trauma Patients With Cervical Spine Fractures due to Ground Level Fall: Five Years Experience in a Level One Trauma Center.

BACKGROUND: It has been found that significantly different clinical outcomes occur in trauma patients with different mechanisms of injury. Ground level falls (GLF) are usually considered "minor trauma" with less injury occurred in general. However, it is not uncommon that geriatric trauma patients sustain cervical spine (C-spine) fractures with other associated injuries due to GLF or less. The aim of this study is to determine the injury patterns and the roles of clinical risk factors in these geriatric trauma patients. METHODS: Data were reviewed from the institutional trauma registry of our local level 1 trauma center. All patients had sustained C-spine fracture(s). Basic clinical characteristics, the distribution of C-spine fracture(s), and mechanism of injury in geriatric patients (65 years or older) were compared with those less than 65 years old. Furthermore, different clinical variables including age, gender, Glasgow coma scale (GCS), blood alcohol level, and co-existing injuries were analyzed by multivariate logistic regression in geriatric trauma patients due to GLF and internally validated by random bootstrapping technique. RESULTS: From 2006 - 2010, a total of 12,805 trauma patients were included in trauma registry, of which 726 (5.67%) had sustained C-spine fracture(s). Among all C-spine fracture patients, 19.15% (139/726) were geriatric patients. Of these geriatric patients 27.34% (38/139) and 53.96% (75/139) had C1 and C2 fractures compared with 13.63% (80/587) and 21.98% (129/587) in young trauma patients (P < 0.001). Of geriatric trauma patients 13.67% (19/139) and 18.71% (26/139) had C6 and C7 fractures compared with 32.03% (188/587) and 41.40% (243/587) in younger ones separately (P < 0.001). Furthermore, 53.96% (75/139) geriatric patients had sustained C-spine fractures due to GLF with more upper C-spine fractures (C1 and C2). Only 3.2% of those had positive blood alcohol levels compared with 52.9% of younger patients (P < 0.001). In addition, 6.34% of geriatric patients due to GLF had intracranial pathology (ICP) which was one of the most common co-injuries with C-spine fractures. Logistic regression analysis showed the adjusted odds ratios of 1.17 (age) and 91.57 (male) in geriatric GLF patients to predict this co-injury pattern of C-spine fracture and ICP. CONCLUSION: Geriatric patients tend to sustain more upper C-spine fractures than non-geriatric patients regardless of the mechanisms. GLF or less not only can cause isolated C-spines fracture(s) but also lead to other significant injuries with ICP as the most common one in geriatric patients. Advanced age and male are two risk factors that can predict this co-injury pattern. In addition, it seems that alcohol plays no role in the cause of GLF in geriatric trauma patients.

Neutrino mass hierarchy and octant determination with atmospheric neutrinos.

The recent discovery by the Daya-Bay and RENO experiments, that θ(13) is nonzero and relatively large, significantly impacts existing experiments and the planning of future facilities. In many scenarios, the nonzero value of θ(13) implies that θ(23) is likely to be different from π/4. Additionally, large detectors will be sensitive to matter effects on the oscillations of atmospheric neutrinos, making it possible to determine the neutrino mass hierarchy and the octant of θ(23). We show that a 50 kT magnetized liquid argon neutrino detector can ascertain the mass hierarchy with a significance larger than 4σ with moderate exposure times, and the octant at the level of 2-3σ with greater exposure.

Large matter effects in numu-->nutau oscillations.

We show that matter effects change the numu-->nutau oscillation probability by as much as 70% for certain ranges of energies and path lengths. Consequently, the numu-->nutau survival probability also undergoes large changes. A proper understanding of numu survival rates must consider matter effects in Pmutau as well as Pmue. We comment on (a) how these matter effects may be observed and the sign of Delta31 determined in atmospheric neutrino measurements and at neutrino factories, and (b) how they lead to heightened sensitivity for small theta13.