Levels of evidence and grades of recommendation supporting European society for medical oncology clinical practice guidelines

Background:The European Society for Medical Oncology(ESMO)guidelines are among the most comprehensive and widely used clinical practice guidelines(CPGs)globally.However,the level of scientific evidence supporting ESMO CPG recommendations has not been systematically investigated.This study assessed ESMO CPG levels of evidence(LOE)and grades of recommendations(GOR),as well as their trends over time across various cancer settings.Methods:We manually extracted every recommendation with the Infectious Diseases Society of America(IDSA)classification from each CPG.We examined the distribution of LOE and GOR in all available ESMO CPG guidelines across different topics and cancer types.Results:Among the 1,823 recommendations in the current CPG,30%were classified as LOEⅠ,and 43%were classified as GOR A.Overall,there was a slight decrease in LOEⅠ(−2%)and an increase in the proportion of GOR A(+1%)in the current CPG compared to previous versions.The proportion of GOR A recommendations based on higher levels of evidence such as randomized trials(LOEⅠ–Ⅱ)shows a decrease(71%vs.63%,p=0.009)while recommendations based on lower levels of evidence(LOEⅢ–Ⅴ)show an increase(29%vs.37%,p=0.01)between previous and current version.In the current versions,the highest proportion of LOEⅠ(42%)was found in recommendations related to pharmacotherapy,while the highest proportion of GOR A recommendations was found in the areas of pathology(50%)and diagnostic(50%)recommendations.Significant variability in LOEⅠand GOR A recommendations and their changes over time was observed across different cancer types.Conclusion:One-third of the current ESMO CPG recommendations are supported by the highest level of evidence.More well-designed randomized clinical trials are needed to increase the proportion of LOEⅠand GOR A recommendations,ultimately leading to improved outcomes for cancer patients.

Probing the Gamma-Ray Emission Region of Five TeV Flat Spectrum Radio Quasars

The location ofγ-ray emission of blazars remains a contested topic,inspiring the development of numerous investigative techniques to address this issue.In this work,we analyzed Fermiγ-ray light curves in the GeV and MeV bands,employing the discrete cross-correlation function method to discern time lags between the two bands.For 4C+21.35,Ton 599,B21420+32,and PKS 1510-089,we identified a time lag spanning several days,while for PKS 1441+25,the time lag was not statistically found.The results imply that the soft photons necessary for inverse Compton scattering predominantly originate from the dusty torus in the first four sources,whereas for PKS1441+25,they seem to be sourced mainly from the broad-line region.Further analysis of the opacity(τγγ)and the GeV spectra study supports the conclusion that the location of the dissipation region must be beyond the BLR to avoid significant absorption.Notably,for PKS 1441+25,the emission region is also posited to lie outside yet proximate to the BLR.The parameters of describing the emission region were obtained by fitting broadband spectral energy distribution with contemporaneous observation data.Our findings suggest that for the five TeV FSRQs,during Te V flaring events,the jet appears to maintain an equilibrium between the energy density of the magnetic field and that of the particles for all investigated sources,with the exceptions of 4C+21.35 and PKS1441+25.In terms of the overall jet power,particle energy is the dominant contributor,and the observed blazar radiation cannot be solely attributed to the magnetic field,except in the case of 4C+21.35.Consequently,magnetic reconnection is unlikely to be the primary mechanism behind particle acceleration in these systems.

The Impact of Finerenone on Changes in Pulse Wave Velocity, Arterial Pressure and Heart Related Deaths in Hemodialysis Patients—Study Perspective

The description in the abstract lacks clear logic and a comprehensive summary of this study, so please revise and improve it according to the design theme and main content of this study, and describe it in the order of (research background), purpose/aim, method, results and conclusions. The introduction of the abstract and preface is rather lengthy, but the summary of the whole study and the presentation of the research background are not perfect (mainly because the logic of the context is not clear and orderly), so it will appear a bit messy. Hope to be able to modify (this has been mentioned in the preliminary opinion). Cardiovascular events (CVE) pose a significant threat to individuals with end-stage renal disease (ESRD), yet these patients are often excluded from cardiovascular clinical trials, leaving prognostic factors associated with CVE in ESRD patients largely unexplored. Recent human studies have demonstrated elevated circulating aldosterone levels in ESRD patients, correlating with left ventricular hypertrophy. Additionally, animal models have shown improvements in uremic cardiomyopathy with spironolactone therapy, prompting interest in assessing the efficacy of spironolactone or eplerenone in reducing mortality and improving cardiovascular function in dialysis patients. Clinicians have historically been cautious about prescribing mineralocorticoid receptor antagonists (MRAs) to congestive heart failure patients with chronic kidney disease (CKD) due to hyperkalemia risk. However, the emergence of finerenone, a novel MR antagonist with a favorable safety profile and lower hyperkalemia risk, has renewed interest in MRA therapy in this population. Heart disease, including coronary artery disease, hypertension, and left ventricular failure, is alarmingly prevalent in dialysis patients, contributing significantly to elevated mortality rates compared to the general population. Arterial stiffness, as indicated by pulse wave velocity (PWV), progressively worsens with advancing CKD stages, peaking in severity among ESRD patients undergoing dialysis. High PWV serves as a crucial risk stratification tool in ESRD. Elevated NT-proBNP and BNP levels in ESRD patients are well-documented, with significant associations observed between baseline peptide concentrations and cardiovascular morbidity and mortality. By incorporating finerenone into our study, we aim to investigate its potential benefits in reducing arterial stiffness, lowering blood pressure, and ultimately mitigating heart-related mortality among hemodialysis patients. This study holds substantial implications for hypertension and cardiovascular risk management in this vulnerable patient population. Eligible participants must have been on chronic hemodialysis for at least three months, with ACE inhibitors or angiotensin receptor blockers included in their therapy at maximum tolerable doses. Serum potassium levels 5.7 mmol/L, left ventricular ejection fraction 50%, and PWV higher than age-estimated values are also prerequisites for study entry. Randomized allocation will be conducted using a permuted block design, stratified by center, with allocation communicated via signed study forms during initial examinations. All steps of this research will be conducted in accordance with the principles of the Helsinki Declaration.

Size matters:analyzing bank profitability and efficiency under the Basel III framework

The latest regulatory framework,which has been introduced globally in the form of Basel III,and its implementation in the legislation of the member states of the Euro-pean Union has generated much interest in the impact of regulation on the efficiency and profitability of banks.This study aims to examine the impact of the introduction of two major regulatory changes(Basel II and Basel III)on bank performance,in terms of bank size and bank-specific and macroeconomic variables.A two-stage empirical anal-ysis was conducted on a sample of 433 European commercial banks over the 2006–2015 period.In the first stage,relative efficiency was calculated using non-parametric data envelopment analysis.In the second stage,the generalized method of moments was used to examine the impact of bank-specific and macroeconomic variables as well as regulation on bank performance,that is,profitability and efficiency.Consider-ing bank size,the results show a diverse impact of regulation on bank performance.Regarding large-and medium-sized banks,regulation positively affects both efficiency and profitability,whereas,for small banks,it negatively affects performance.The results suggest that larger banks have skillfully adapted to the new regulatory environment.In contrast,small banks have problems with profitability and efficiency because the new regulatory framework has imposed additional administrative and regulatory burdens.This could result in future failure or mergers with larger banks,resulting in a higher concentration in the banking sector and increased systemic risk.Our results strongly suggest that regulation should not be implemented equally for all banks;that is,on a one size fits all terms.A distinction between small and large banks when introducing new regulatory frameworks should be made if a reasonable level of competition is to be preserved.

Panhypopituitarism caused by a suprasellar germinoma: A case report

BACKGROUND Suprasellar germinomas are rare intracranial tumors frequently associated with permanent endocrine disorders.We present the clinical picture,treatment,and complications of suprasellar germinoma at pediatric age which,besides being lifethreatening,has lifelong endocrinological consequences.CASE SUMMARY A 12-year-old female patient was presented having had intensive headaches for three weeks and visual disturbances for six months.An ophthalmological examination revealed bilateral papilledema and a marked loss of vision.Emergency brain magnetic resonance imaging(MRI)showed a suprasellar tumor,involving the infundibulum and the optic chiasm,extending to the third ventricle.Laboratory tests confirmed decreased levels of thyroxine,cortisol,gonadotropins,and insulin-like growth factor 1.Maximal tumor reduction was performed,and immunohistopathology established the diagnosis of suprasellar germinoma.MRI of the spine and cerebrospinal fluid cytology confirmed the localized disease.Adjuvant chemotherapy and radiotherapy were performed according to the SIOP CNS GCT II protocol.A post-treatment MRI showed no residual tumor,but pituitary function had not recovered.Three and a half years after the end of the treatment,the patient is in a complete remission,requiring hormonal replacement therapy,continuous education,and psychological support.CONCLUSION This complex case highlights the importance of timely diagnosis,a multidisciplinary approach,and close follow-up in children with suprasellar germinomas.

Parenteral iron therapy in children with iron deficiency anemia

Iron deficiency anemia(IDA)continues to be a global public health problem.Oral iron is the universally accepted first-line therapy,and most children have a prompt and favorable response to oral formulations.In subsets of children who fail to respond due to intolerance,poor adherence,or inadequate intestinal absorption,parenteral iron is indicated.Despite numerous studies in adults with IDA of diverse etiologies,pediatric studies on parenteral iron use are very limited.Although mostly retrospective and small,these studies have documented the efficacy and safety profile of intravenous iron formulations.In this editorial the author comments on the most important published data and underscores the need to seriously consider parenteral iron use in children unresponsive to oral therapy.

Comparative Analysis of PSO Algorithms for PID Controller Tuning

The active magnetic bearing（AMB）suspends the rotating shaft and maintains it in levitated position by applying controlled electromagnetic forces on the rotor in radial and axial directions.Although the development of various control methods is rapid,PID control strategy is still the most widely used control strategy in many applications,including AMBs.In order to tune PID controller,a particle swarm optimization（PSO）method is applied.Therefore,a comparative analysis of particle swarm optimization（PSO）algorithms is carried out,where two PSO algorithms,namely（1）PSO with linearly decreasing inertia weight（LDW-PSO）,and（2）PSO algorithm with constriction factor approach（CFA-PSO）,are independently tested for different PID structures.The computer simulations are carried out with the aim of minimizing the objective function defined as the integral of time multiplied by the absolute value of error（ITAE）.In order to validate the performance of the analyzed PSO algorithms,one-axis and two-axis radial rotor/active magnetic bearing systems are examined.The results show that PSO algorithms are effective and easily implemented methods,providing stable convergence and good computational efficiency of different PID structures for the rotor/AMB systems.Moreover,the PSO algorithms prove to be easily used for controller tuning in case of both SISO and MIMO system,which consider the system delay and the interference among the horizontal and vertical rotor axes.

Experimental determination of mechanical properties and short-time creep of AISI 304 stainless steel at elevated temperatures

The high temperature properties of AISI 304 stainless steel were studied. Basic data about the employed experimental equipment, testing procedures, and specimen geometry were given. The experimental setup was used to obtain stress-strain diagrams from tensile tests at room temperature as well as several elevated temperatures. Furthermore, the specimens were subjected to short-time creep tests at various temperatures. Stress levels for creep testing were established as a percentage of yield stress. The results indicate that at lowered temperatures and lower stress levels, AISI 304 stainless steel can be used as a sufficiently creep resistant material.

Behavior of HSLA A709 Steel under Different Environmental Conditions

According to the requirement of the knowledge of material mechanical properties in structure design procedure,the paper considered experimentally obtained data regarding the high-strength low-alloy A 709 Gr50 steel.In that way,ultimate tensile strength and 0.2 offset yield strength at both lowered and elevated temperatures were presented and analyzed.The effect of temperature exerted on both of the mentioned strengths was presented.Creep responses for selected temperatures and selected stress levels were also considered.All of the tests are related to the uniaxial tensile tests and were performed in the laboratory of the Department for Engineering Mechanics at the Faculty of Engineering Rijeka.

Behavior of AISI 316L Steel Subjected to Uniaxial State of Stress at Elevated Temperatures

This paper presents an experimental investigation on an AISI 316L stainless steel regarding mechanical properties and short uniaxial creep tests at elevated temperatures. The short time creep tests were carried out under different but constant stresses. The obtained data of ultimate tensile strength, yield strength, creep curves and effects of elevated temperatures on mechanical properties were presented. For a selected rheological model, material parameters were obtained. As a justification, such rheological model is implemented in the finite element procedure for an uniaxially stressed specimen in selected environmental conditions.

Dynamic expression of ATF3 as a novel tool to study activation and migration of endogenous spinal stem cells and their role in neural repair

One of the major problems of modern neurobiology is how to replace dead or damaged neurons in the human brain or spinal cord after injury or as a consequence of neurodegenerative dis- eases. In fact, because adult mammalian neurons are post-mi- totic cells that cannot divide to replace dead cells, loss due to lesion or disease is permanent. Furthermore, surviving neurons have modest capacity to regenerate their damaged axons and re-establish functional connections. Thus, a gradual neurode- generative scenario with certain similarities in stroke, brain or spinal cord injuries and neurological diseases like Alzheimer＇s disease is produced. These conditions represent the major disease burden of the modern world in terms of mortality, dis- ability, productivity loss and health-care costs （World Health Organization, 2008）. While much effort has been directed to understand the molecular and cellular mechanisms involved in the pathology of these diseases to set new effective treatments, many neuroprotective and regenerative approaches, although showing positive results in preclinical studies, have so far failed to provide strong benefit to patients.

GLOBAL SOLUTION TO 1D MODEL OF A COMPRESSIBLE VISCOUS MICROPOLAR HEAT-CONDUCTING FLUID WITH A FREE BOUNDARY

In this paper we consider the nonstationary 1D flow of the compressible viscous and heat-conducting micropolar fluid, assuming that it is in the thermodynamically sense perfect and polytropic. The fluid is between a static solid wall and a free boundary connected to a vacuum state. We take the homogeneous boundary conditions for velocity, microrotation and heat flux on the solid border and that the normal stress, heat flux and microrotation are equal to zero on the free boundary. The proof of the global existence of the solution is based on a limit procedure. We define the finite difference approximate equations system and construct the sequence of approximate solutions that converges to the solution of our problem globally in time.

Monodelphis domestica: a new source of mammalian primary neurons in vitro

In vi t ro mode ls have tremendously revolutionized cell biology and biomedical research,reducing the need for in vivo experiments,as well as offering the simplified models for easier investigations at molecular and cellular level(for example genetic manipulations,electrophysiological measurements,drug screening etc.).However,the major challenge is to develop long-surviving in vitro preparations of post-mitotic cells such as neurons or cardiocytes.To overcome the problem of neuronal inability to proliferate,the immortalized cell lines derived from neuronal tumors have been prepared.Such secondary neuronal cultures are restricted to neuroblastoma-like cells,but their biological relevance is often questionable due to genetic drift and lack of mature,differentiated neuronal phenotypes,which makes primary cultures the better choice.Mammalian central nervous system(CNS)in vitro primary cell cultures are mostly prepared from the late embryonic or early postnatal mice and rats.Other mammalian species have been less used,meaning that inter-species diversity is not sufficiently investigated and that the additional comparative analyses are required to avoid misinterpretations in translating the knowledge to humans(Bonfanti and Peretto,2011).

Effect of clonidine on the cutaneous silent period during spinal anesthesia

AIM To investigate the effect of clonidine on the cutaneous silent period(CSP) during spinal anesthesia. METHODS A total of 67 adult patients were included in this randomized, prospective, single-center, double-blind trial. They did not have neurological disorders and were scheduled for inguinal hernia repair surgery. This trial was registered on ClinicalTrials.gov(NTC03121261). The patients were randomized into two groups with regards to the intrathecally administered solution:(1) 15 mg of 0.5% levobupivacaine with 50 μg of 0.015% clonidine, or(2) 15 mg of 0.5% levobupivacaine alone. There were 34 patients in the levobupivacaine-clonidine(LC) group and 33 patients in the levobupivacaine(L) group. CSP and its latency were measured four times: prior to the subarachnoid block(SAB), after motor block regression to the 0 level of the Bromage scale, with ongoing sensory blockade, and both 6 and 24 h after SAB.RESULTS Only data from 30 patients in each group were analyzed. There were no significant differences between the groups investigated preoperatively and after 24 h. The CSP of the L group at the time point when the Bromage scale was 0 was 44.8 ± 8.1 ms, while in the LC group it measured 40.2 ± 3.8 ms(P = 0.007). The latency in the L group at the time point when the Bromage scale was 0 was 130.3 ± 10.2 ms, and in the LC group it was 144.7 ± 8.3 ms(P < 0.001). The CSP of the L group after 6 h was 59.6 ± 9.8 ms, while in the LC group it was 44.5 ± 5.0 ms(P < 0.001). The latency in the L group after 6 h was 110.4 ± 10.6 ms, while in LC group it was 132.3 ± 9.7 ms(P < 0.001).CONCLUSION Intrathecal addition of clonidine to levobupivacaine for SAB in comparison with levobupivacaine alone resultsin a diminished inhibitory tonus and shortened CSP.

Noninvasive markers of liver steatosis and fibrosis after liver transplantation-Where do we stand?

In the last two decades,advances in immunosuppressive regimens have led to fewer complications of acute rejection crisis and consequently improved shortterm graft and patient survival.In parallel with this great success,long-term posttransplantation complications have become a focus of interest of doctors engaged in transplant medicine.Metabolic syndrome(MetS)and its individual components,namely,obesity,dyslipidemia,diabetes,and hypertension,often develop in the post-transplant setting and are associated with immunosuppressive therapy.Nonalcoholic fatty liver disease(NAFLD)is closely related to MetS and its individual components and is the liver manifestation of MetS.Therefore,it is not surprising that MetS and its individual components are associated with recurrent or“de novo”NAFLD after liver transplantation(LT).Fibrosis of the graft is one of the main determinants of overall morbidity and mortality in the post-LT period.In the assessment of post-LT steatosis and fibrosis,we have biochemical markers,imaging methods and liver biopsy.Because of the significant economic burden of post-LT steatosis and fibrosis and its potential consequences,there is an unmet need for noninvasive methods that are efficient and cost-effective.Biochemical scores can overestimate fibrosis and are not a good method for fibrosis evaluation in liver transplant recipients due to frequent post-LT thrombocytopenia.Transient elastography with controlled attenuation parameter is a promising noninvasive method for steatosis and fibrosis.In this review,we will specifically focus on the evaluation of steatosis and fibrosis in the post-LT setting in the context of de novo or recurrent NAFLD.

New Finite Elements in Shear Stress Analysis of Saint Venant′s Torsional Loaded Beam Structures

Recent engineering design as well as material processing on the optimization procedure are based and computeroriented. Finite element stress and sensitivity analysis are the most important things in such modern determinationof optimal solution. According to high computer capacity finite element continuum discretization and load applicationindependent of the coming fields become unlimited. This paper deals with the development of a new finite elementsgeneration used in shear stress analysis caused by S.Venant′s torsional load and bending with shear. Their stiffnessmatrices and load vectors on the basis of their geometrical properties are derived. For justification of new finiteelements application some examples are presented.

Ocular hypertension secondary to obesity: cortisol, the missing piece of the pathophysiological puzzle?

Dear Editor,Obesity has nowadays become a global public health challenge due to its rapidly growing prevalence and interconnection with a wide spectrum of comorbidities.

Significance of Experimental Data in the Design of Structures Made from 1.4057 Steel

This paper presents experimentally-obtained data which can be of importance in the design procedure of engineering components made of 1.4057 （X 17CrNil 6-2; AISI 431） steel. In this manner, uniaxialy tests related to determine material mechanical properties and short-time creep behavior were performed. Based on the mentioned tests, ultimate tensile strength, 0.2 offset yield strength and modulus of elasticity at low and elevated temperatures were determined. Also, creep behavior of considered steel was tested for selected temperatures and selected stress levels. According to experimentally determined Charpy impact energy an assessment of fracture toughness was made.

Liver disease in the era of COVID-19: Is the worst yet to come?

The global social,economic and political crises related to coronavirus disease 2019(COVID-19)presumably had more indirect than direct negative impacts on health systems.Drastic lifestyle changes,social isolation and distancing,and individual and global financial crises resulted in robust populations forfeiting healthy habits and seeking comfort in alcoholic beverages,drugs and unhealthy diets.The inevitable consequences are increases in the incidence of nonalcoholic fatty liver disease,viral hepatitis,acute alcoholic hepatitis,liver cirrhosis decompensation and ultimately liver-related mortality.The inaccessibility of regular clinical and sonographic monitoring systems has caused difficulties in the treatment of patients with chronic liver disease(CLD)and has prevented prompt hepatocellular carcinoma detection and treatment.A dramatic reduction in the number of liver donors and the transformation of numerous transplantation centers into COVID-19 units drastically decreased the rate of orthotopic liver transplantation.The indirect,unavoidable effects of the COVID-19 pandemic in the following years have yet to be determined.Substantial efforts in the management of patients with liver disease in order to overcome the inevitable COVID-19-related morbidity and mortality that will follow have yet to be initiated.Several questions regarding the impact of the COVID-19 pandemic on liver disease remain.The most important question for general CLD patients is:How will the modification of clinical practice during this pandemic affect the outcomes of CLD patients?This article reviews the influence of COVID-19 on patients with liver disease during the pandemic,with particular emphasis on the disease course associated with pandemic resolution.