Important Changes Research Articles

Effect of a short course of parenteral treprostinil therapy on right heart structure and function in pulmonary arterial hypertension

Abstract Background Pulmonary arterial hypertension (PAH) is characterized by an increase in pulmonary vascular resistance, leading to increased afterload and right-sided heart failure. It is important to routinely assess disease progression and treatment response, with echocardiography an increasingly recognized important component of risk assessment. Parenteral prostacyclin therapy has been shown to be associated with improvements in right-sided cardiac structure and function, which are prognostic in PAH. Purpose To describe changes in right-sided cardiac structural and functional parameters after a short course of parenteral treprostinil. Methods The EXPEDITE trial (NCT03497689) was a 16-week open-label study of WHO Functional Class (FC) II or III patients with PAH designed to assess short-term (expedited) induction therapy with parenteral treprostinil over 2-8 weeks, to facilitate transition to comparable doses of oral treprostinil. The subset of patients in the per-protocol population that had clinical and/or echocardiographic data available at both baseline (prior to initiation of parenteral treprostinil) and end of induction (2-8 weeks) were included for analysis. Changes in each parameter were analyzed using the non-parametric Wilcoxon signed-rank test. Results In the per-protocol population of EXPEDITE (n=29), the median age was 56 years, 62% were female, and 79% were white. At baseline, 52% were classified as WHO FC II and 48% WHO FC III. Patients were on either no (n=6, 21%), 1 (n=11, 38%), or 2 (n=12, 41%) background PAH therapies. The end of the parenteral treprostinil induction period occurred at Week 2 (n=1), Week 4 (n=5), or Week 8 (n=23); the median (interquartile range) parenteral treprostinil dose achieved was 23.8 (20, 39.3) ng/kg/min. Median changes from baseline to the end of the parenteral treprostinil induction period for this analysis are shown in Table 1. There were directional changes for most measures of right-sided cardiac structure and function that reflected overall improvement; two key markers of cardiac function, cardiac output and NT-proBNP significantly improved. Conclusions In this trial of expedited parenteral treprostinil induction, we saw favorable directional trends in changes in right heart structure and function that were achieved in 8 weeks or less, including some statistically-significant parameters known to have prognostic value in PAH. The relatively rapid improvements we observed in this small cohort may signal important changes in risk status, and support treatment guidelines emphasizing importance of early improvement in the first 3-6 months following treatment. Furthermore, changes in cardiac structure and function often occur before other clinically-evident indicators of disease progression, and early response to treatment has been shown to impact long-term outcomes in patients with PAH. Larger studies with short-term serial right heart imaging assessment to confirm findings are warranted.Table 1

Relationship between myocardial strain, coronary microvascular dysfunction, and myocardial extracellular volume in patients with type 2 diabetes: a cross-sectional CMR study

Abstract Background Patients with diabetes often develop heart failure with preserved ejection and often demonstrate early indications of myocardial dysfunction by decreased strain, notably the global longitudinal (GLS). The underlying myocardial phenotypical changes in patients with diabetes are coronary microvascular dysfunction and myocardial interstitial fibrosis. The relation of these to strain-indicators of early systolic dysfunction is not established. Purpose We hypothesized that coronary microvascular function and interstitial fibrosis contribute to the subclinical myocardial dysfunction seen in patients with diabetes. Method With gadolinium contrast and adenosine-stress magnetic resonance imaging, we determined myocardial blood flow (MBF) and perfusion ratio (MPR) and extracellular volume (ECV; an imaging biomarker of diffuse fibrosis) in 211 patients with type 2 diabetes without macrovascular coronary artery disease and 25 control subjects. Left ventricular (LV) function was determined from its ejection fraction and 3D feature tracking of GLS, circumferential (GCS), and radial strains (GRS). Results Without a significant age- or sex-differences to control subjects, patients (median age 57 years [IQR 50, 67], 70% males) had a median diabetes duration of 12 [IQR 6, 18] years. LV ejection fraction was normal and similar to controls. Compared to control subjects (GLS -13.9±2.0%), GLS, GCS and GRS were reduced in the total diabetes cohort, and GLS was reduced also in the subgroup of patients without any diabetes complications (total -11.6±3.0%; without-complications -12.3±2.6%). GLS, but not GCS or GRS or LVEF, was associated with albuminuria (b (95%CI) 1.09 (0.22-1.96)) and autonomic neuropathy (b (95%CI) 1.43 (0.54-2.31)). Independently of ECV, a 10% increase in MBF at adenosine-stress and MPR was associated with improved GLS in uni- and multivariable regression analyses. A 10% increase in ECV was associated with a decrease in GLS in univariable and multivariable regression analysis, but this was abolished when adjusted for MPR. GLS showed a moderate ability to discriminate a significantly lowered myocardial blood flow at stress defined as <1.49 mL/min/g (AUC 0.72, GLS threshold -11.5%; sensitivity 75% and specificity 53%) and myocardial perfusion ratio defined as as <2.1 (AUC 0.73, GLS threshold -10.8% resulted in a sensitivity of 71% and a specificity of 70%). GLS had a poor ability to predict increased extracellular volume defined as > 31% (AUC 0.60, GLS threshold -13.5 resulted in a sensitivity of 72% and a specificity of 34%). Conclusion Of the two important phenotypical changes seen with type 2 diabetes, microvascular dysfunction and fibrosis, coronary microvacular dysfunction demonstrates the more important relation to early systolic compromise as determined from the left ventricle global longitudinal strain.Associations of Systolic parametersROC curve

Degenerative or rheumatic: after all, what is the most prevalent etiology of mitral regurgitation in developing countries?

Abstract Introduction Mitral regurgitation (MR) is the most prevalent valve disease in Europe, mostly degenerative. In Brazil, on the other hand, there are few recent epidemiological data and previous studies show a higher prevalence of rheumatic disease. However, a change in the epidemiological profile of valve disease has recently been observed, largely due to the increase in life expectancy and decrease in the incidence of rheumatic fever. This study aims to evaluate patients with MR in a tertiary hospital in Brazil, emphasizing the etiological analysis. Methods Patients with moderate or severe MR on echocardiogram performed between 07/01/2018 and 06/30/2020 in a Brazilian Cardiology hospital were retrospectively evaluated, including 2,017 cases. Clinical data (age, sex, symptoms and comorbidities) were analyzed, in addition to complementary tests, such as electrocardiogram and echocardiogram. Results A total of 2,017 cases were included, of which 1,966 (97.5%) had severe MR. The mean age was 65 years and 52% were female. In this cohort, 924 patients (45.8%) had primary MR, while 1093 (54.2%) had secondary causes. Among the primary etiologies (N=1093), degenerative was the most prevalent, responding to 51.3% (n=474), followed by rheumatic disease, present in 34.5% of the patients (n=319). The other primary etiologies observed were calcific (94 patients = 4.7%), infective endocarditis (15 patients = 0.7%) and congenital (10 patients = 0.5%). In the comparative analysis between degenerative and rheumatic MR, a statistically significant difference was observed in age and gender. Patients diagnosed with rheumatic MR were younger - mean age: 58 years (standard deviation 49-68) compared to 67 years in patients with degenerative mitral disease (standard deviation 58-76 years). Most patients with rheumatic disease were female (N=255, 79.9%), with percentages almost twice as high as those observed in degenerative MR (N=192 - 40.5%). Secondary causes (N=1,093) were composed of dilated etiology in 859 patients (78.6%), ischemic (140 patients - 12.8%) and atrial functional (55 patients - 5%). Conclusion In agreement with the current epidemiological change in valvular heart disease, we could also observe an important change in the etiology of MR in Brazil, with a reduction in the burden of rheumatic disease and greater expressiveness of mitral prolapse.

Repositioning Construct Validity Theory: From Nomological Networks to Pragmatic Theories and Their Evaluation by Explanatory Means

In this article, I argue for a number of important changes to the conceptual foundations of construct validity theory. I begin by suggesting that construct validity theorists should shift their attention from the validation of constructs to the process of evaluating scientific theories. This shift in focus is facilitated by distinguishing construct validation (understood as theory evaluation) from test validation, thereby freeing it from its long-standing focus on psychological measurement. In repositioning construct validity theory in this way, researchers should jettison the outmoded but superficially popular notion that theories are nomological networks in favor of a more plausible pragmatic view of their natures, such as the idea that theories are explanatorily coherent networks. Consistent with this shift in understanding the nature of theories, my recommendation is that construct validation should embrace an explanationist perspective on the theory evaluation process to complement its focus on hypothetico-deductive theory testing. On this view, abductive research methods have an important role to play. The revisionist perspective on construct validity proposed here is discussed in light of relevant developments in scientific methodology and is applied to an influential account of the validation process that has shaped research practice.

Hypothetical impact of the Mexican front-of-pack labeling on intake of critical nutrients and energy

BackgroundSince 2020 in Mexico, front-of-pack warning labels (FOPWL) have been implemented in processed products. Evidence supports warning labels allow consumers to identify unhealthy products. We aimed to evaluate the hypothetical impact of the FOPWL regulation on the Mexican population’s intake of critical nutrients and energy, based on the replacement of food and beverages using 4 hypothetical scenarios which represented the phases of the regulation.MethodsDietary data were collected using a standardized 24-h dietary recall from the 2016 Mexican National Health and Nutrition Survey (n = 4184). To evaluate the hypothetical impact of FOPWL, the nutritional content of critical nutrients in processed products was evaluated according to the Mexican Official Standard 051 (NOM-051). Then, we replaced products with several warning labels (WL) with those with a fewer number of them or with non-processed food. For the replacement, 4 hypothetical scenarios were established: scenario 1: the current consumption of the Mexican Population, scenario 2: the replacement during the first phase of the norm, scenario 3: the replacement in the second phase and scenario 4: the replacement in the last phase. We estimated the means, confidence intervals (CI 95%), and the mean percentage change of energy, saturated fat, trans-fat, added sugars, and sodium intake during the second, third, and the fourth scenarios.ResultsAccording to the norm, in the second scenario, the majority of the products presented a label for energy (52.6%) whereas in the third (56.4%) and fourth (61.2%) scenarios were for sodium. In contrast, trans-fat was the least labeled nutrient in all the scenarios (from 2.1 to 4.1%). In the fourth scenario, we observed a reduction of the intake of energy intake to 15.4% as well as saturated fat (− 20%, CI 95% − 18.4; − 21.6), trans-fat (− 8.2%, CI 95% − 6.4; − 10.1) and sodium (− 12.7%, CI 95% − 11.3; − 14.1). The most important reduction was observed for added sugars intake (until − 54.1%, CI 95% − 51; − 57.1).ConclusionsFOPWL could be an effective strategy to decrease energy consumption and nutrients of concern. If consumers use the FOPWL, it would be an important change in critical nutrients intake. These results support that FOPWL might help the Mexican population to choose healthier nutrition alternatives.

Abstract 15296: Incidence and Predictive Factors for Left Ventricular Dysfunction After Transcatheter Device Closure of Patent Ductus Arteriosus in Extremely Low Birth Weight Infants

Background: Left ventricular (LV) dysfunction is a known complication after ligation or device closure of patent ductus arteriosus (PDA). Recently, an increasing number of premature and extremely low birth weight (ELBW) infants undergo transcatheter device closure of PDAs. Afterload sensitivity of the immature myocardium may be expected to result in important changes in LV ejection fraction (EF) post-procedure. Aim: To evaluate incidence and magnitude of LV dysfunction after device closure of PDA in ELBW infants. Methods: Subjects undergoing PDA device closure from 2020-2022 who were ELBW (<1 kg) and extremely premature (gestational age <29 weeks) at birth were included. A single cardiologist reviewed each pre- and post-intervention echocardiogram and calculated LVEF. Mildly depressed function was defined as an LVEF <53%, moderately depressed as LVEF <40% and severely depressed as LVEF <30%. Results: There were 62 subjects who met inclusion criteria. Mean gestational age and birth weight were 24.8 weeks and 646 g, respectively. Mean age and weight at intervention were 7.9 weeks and 1718 g, respectively. All patients had normal LVEF pre-procedure (mean LVEF 68%) with a significant decline post-procedure to 60% (p<0.001) (Figure). Post-procedure, 80.6% of subjects maintained normal LVEF. Of 12 subjects who developed depressed function, 83% (n=10) had mildly depressed function and 17% (n=2) had moderately depressed function. There was no significant difference in post-procedure LV dysfunction in relation to pre-procedural PDA size, left atrial dilation, or LV dilation on univariate analysis. All subjects recovered function without additional inotropic support with a median time to observed normal LVEF of 5 days. Conclusions: LV dysfunction develops in 19% of ELBW infants undergoing PDA device occlusion, is usually mild in severity, and normalizes in all subjects. The size of PDA or degree of left heart dilation does not predict LV dysfunction in this population.

Variability in Minimal Clinically Important Difference Calculation and Reporting in the Otolaryngology Literature.

Best practices for calculation of the minimal clinically important difference (MCID) of outcome measures include the use of complementary methodologies (broadly classified as anchor-based and distribution-based) and reporting of the MCID's predictive ability. We sought to determine MCID calculation and reporting patterns within the otolaryngology literature. A systematic search strategy of Embase, PubMed, and Web of Science databases was developed and implemented to identify studies reporting the determination of an MCID for an outcome measure. Studies specifically within the otolaryngology literature (defined as journals classified as "otorhinolaryngology" in the Journal Citation Reports database) were included. All those journals were additionally searched for relevant articles. There were 35 articles that met the inclusion criteria. Of these studies, 88.6% reported MCID of a patient-reported outcome measure and the remainder were for objective outcome measurements. Anchor-based methods were used by 82.9% of studies and distribution-based methods were used by 68.6% of studies. Of all studies, 31.4% utilized anchor-based methods alone, 17.1% utilized distribution-based methods alone, and 51.4% used both methods. Only 25.7% of studies reported the sensitivity (median: 60.8%, range: 40.5%-86.7%) and specificity (median: 80.4%, range: 63.5%-88.0%) of the MCID to detect patients experiencing clinically important change. Deviation from best practices in MCID calculation and reporting exists within the otolaryngology literature, with almost half of all studies only using one method of MCID calculation and almost three-quarters not reporting the predictive ability (sensitivity/specificity) of the calculated MCID. When predictive ability is reported, however, MCIDs appear to be more specific than sensitive. NA Laryngoscope, 134:2059-2069, 2024.

Changes in fungal taxonomy: mycological rationale and clinical implications.

Numerous fungal species of medical importance have been recently subjected to and will likely continue to undergo nomenclatural changes as a result of the application of molecular approaches to fungal classification together with abandonment of dual nomenclature. Here, we summarize those changes affecting key groups of fungi of medical importance, explaining the mycological (taxonomic) rationale that underpinned the changes and the clinical relevance/importance (where such exists) of the key nomenclatural revisions. Potential mechanisms to mitigate unnecessary taxonomic instability are suggested, together with approaches to raise awareness of important changes to minimize potential clinical confusion.

Ecological Constraints and Drivers for Human Dispersals and Adaptations in the Late Pleistocene and Early Holocene Environments of the East Siberian Arctic

Starting roughly 50,000 years ago, the Arctic region of East Siberia remained continuously populated by groups of anatomically modern humans including the most uncomfortable episodes in the development of the late Quaternary environment; for some of them, human presence in the area became ephemeral. At present, archaeological fossil records allow for distinguishing three main stages in human occupation of the area: Early (~50 to ~29 ka, MIS 3), middle (~29 to ~11.7 ka, MIS 2), and late (from 11.7 to ~8 ka). For most of the time, they the populated open landscapes of the Mammoth Steppe, which declined at the onset of the Holocene. Human settlement of the Arctic was driven by various abiotic and biotic factors and thus archaeologically visible cardinal cultural and technological changes correspond to the most important paleoclimatic and habitat changes in the late Pleistocene and early Holocene. Successful peopling of the Arctic was largely facilitated by the adoption of critically important innovations such as sewing technology based on the use of the eyed bone needle and the manufacture of long shafts and pointed implements made of mammoth tusks. Mammoth exploitation is seen in mass accumulations of mammoths formed by hunting. An obvious connection between archaeological materials and such accumulations is observed in the archaeological record. In the lithic technology, the early stage is presented by archaic-looking flake industries. Starting the LGM, the wedge-core based-microblade technology known as the Beringian microblade tradition spread widely following the shrinkage of the mammoth range. At the late stage, starting at the Holocene boundary, microprismatic blade technology occurs. In all stages, the complex social behavior of the ancient Arctic settlers is revealed. The long-distance transport of products, knowledge, and genes occurs due to the introduction of the land transportation system. Initial human settlement of this region is associated with carriers of the West Eurasian genome who became replaced by the population with East Asian ancestry constantly moving North under the pressure of climate change.

Protection of Women Victims of Sexual Violence in Indonesia in Perspectives of the 1945 Constitution After the Amendment

Background: After the 1998 reform, the amendments to the 1945 Constitution which were carried out, have brought about changes in the Indonesian state administration, the recognition, respect and protection of Human Rights (HAM) has become an important change clause in the NRI constitution. Several legal instruments related to protecting women from sexual violence, the latest legal product being Law Number 12 of 2022 concerning Criminal Acts of Sexual Violence, demonstrate this commitment. Objective: The aim of this research is to analyze legal norms in various court decisions regarding the protection of women victims of sexual violence in Indonesia. Next, to look for a comprehensive concept of protection for women victims of sexual violence in national legal policies in Indonesia. Theoretical framework: This article will discuss and analyze the changes brought about by the 1945 Constitution after the amendments, especially regarding the protection of women against sexual violence. The extent to which the amendments to the 1945 Constitution have changed regarding the protection of women victims of sexual violence. There are contradictions regarding the condition of national criminal law regarding protective legal norms and sexual violence. This research proposes that there should be synchronization and harmonization efforts in national criminal law policies, in line with the 1945 Constitution which has been amended to ensure that the protection of women victims of sexual violence can be strategic and effective in Indonesia. In general, it provides benefits to help Indonesia carry out legal arrangements or reforms related to national criminal policies in line with the 1945 Constitution. Method: In this research, normative legal research methods are used to solve the legal problems being faced. This research to use several statutory approaches, a conceptual approach, a historical approach, a comparative approach and an analytical approach.

Epidemiological, clinical, and economic burden of myocardial infarction patients in Iran during the COVID-19 pandemic

BackgroundTo define changes in AMI case rates, patient demographics, cardiovascular comorbidities, treatment approaches, in-hospital outcomes, and the economic burden of COVID-19 during the pandemic. MethodsWe conducted a multicenter, observational survey with selected hospitals from three medical universities in Tehran city. A data collection tool consisting of three parts. The first part included socio-demographic information, and the second part included clinical information, major complications, and in-hospital mortality. Finally, the third part was related to the direct medical costs generated by AMI in COVID-19 and non-COVID-19 patients. The study cohort comprised 4,560 hospitalizations for AMI (2,935 for STEMI [64%] and 1,625 for NSTEMI [36%]). ResultsOf those hospitalized for AMI, 1,864 (76.6 %) and 1,659 (78 %) were male before the COVID-19 outbreak and during the COVID-19 era, respectively. The length of stay (LOS), was significantly lower during the COVID-19 pandemic era (4.27 ± 3.63 vs 5.24 ± 5.17, p = 0.00). Results showed that there were no significant differences in terms of patient risk factors across periods. A total of 2,126 AMIs were registered during the COVID-19 era, with a 12.65 % reduction (95 % CI 1.5–25.1) compared with the equivalent time in 2019 (P = 0.179). The risk of in-hospital mortality rate for AMI patients increased from 4.9 % in 2019 to 7.0 % in the COVID-19 era (OR = 1.42; 95 % CI 1.11–1.82; P = 0.004). Major complications were registered in 9.7 % of cases in 2020, which is higher than the rate of 6.6 % reported in 2019 (OR = 1.46, 95 % CI 1.11–1.82; P = 0.000). Total costs in hospitalized AMI-COVID patients averaged $188 more than in AMI patients (P = 0.020). ConclusionThis cross-sectional study found important changes in AMI hospitalization rates, worse outcomes, and higher costs during the COVID-19 periods. Future studies are recommended to examine the long-term outcomes of hospitalized AMI patients during the COVID-19 era.

Preserving Change Information in Multi-temporal Choropleth Maps Through an Extended Data Classification Method

ABSTRACT Diverse user requirements has led to an increasing availability of multi-temporal data, the analysis of which often requires visualization, e.g. in multi-temporal choropleth maps. However, if using standard data classification methods for the creation of these maps, problems arise: significant changes can be lost by data classification (change loss) or non-significant changes can be emphasized (change exaggeration). In this paper, an extended method for data classification is presented, which can reduce these effects as far as possible. In the first step, class differences are set for important or necessary changes. The actual data classification considers these class differences in the context of a sweep line algorithm, whose optimal solution is determined with the help of a measure called Preservation of Change Classes (POCC). By assigning weights during computation of this measure, different tasks or change analyses (e.g. emphasize only highly significant changes) can be processed.

Mapping Chemo-Resistance Profiles of Pediatric Acute Leukemia through Integration of Ex-Vivo Drug Screens with Molecular Data

Introduction While novel approaches for treatment of acute lymphoblastic leukemia (ALL) in children have resulted in significant improvements in survival rates, survivors are faced with potentially life-long challenges as a result of the highly toxic treatment and the outcome for patients who relapse remains poor. The current risk-adapted treatment for ALL in children includes multiple drugs administered sequentially or in combination, with little variation in timing or intensity. Factors that affect varying treatment response between patients and cellular mechanisms that underly response to individual drugs are still under exploration. In this study, we investigate the relationship between ex-vivo drug resistance, transcriptomes, epigenomes and clinical outcome, with the aim of better understanding underlying determinants of treatment response. Methods Pediatric patients diagnosed with B-ALL between 1992 and 2008 in the Nordic countries were included in the study (n = 598). For these patients, ex-vivo drug response to ten clinically used drugs was determined using the fluorometric microculture cytotoxicity assay (FMCA). Clinical data, including follow-up information (overall survival and relapse free survival) was available for all patients. Additionally, DNA-methylation (450K array, n = 383) and gene expression profiling (RNA-seq, n = 119) was performed on a subset of diagnostic patient samples. The patients were stratified into low, medium and high resistance groups based on ex-vivo drug response. The low and high resistance groups were compared with regard to differentially methylated CpG sites or expressed genes associated with individual drug response profiles. Results Overall survival was significantly lower for patients with higher ex-vivo drug resistance to dexamethasone, doxorubicin and thioguanine compared to patients that displayed sensitivity to these drugs (p < 0.05). Similarly, relapse free survival was significantly lower for patients with ex-vivo resistance to cytarabine, dexamethasone, doxorubicin, prednisolone and thioguanine (p < 0.05). After adjusting for sex and risk group, according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) protocol, in a Cox proportional hazards model, higher hazard ratios for relapse were observed in the highly resistant group across all drugs. We identified distinct DNA methylation and gene expression patterns in patients with low and high resistance, indicating the presence of predetermined molecular resistance fates. These resistance patterns included 665 genes that were differentially expressed (absolute log2FC > 1, Benjamini-Hochberg adjusted p value < 0.05) and 1 422 CpG sites with differential methylation status (absolute mean β-value difference > 0.2, Benjamini-Hochberg adjusted p value < 0.05) in resistant compared to sensitive groups, for one or multiple drugs. With the aim of identifying the genes with the largest impact on drug resistance, we selected the most differentially expressed genes and the genes with the largest difference in methylation status between resistant and sensitive samples. Among these, we identified ~20 putative genes of interest for future studies into resistance mechanisms based on potential functional prioritization. Conclusion Our findings confirm that drug response profiles are associated with outcome in pediatric ALL, reflecting response in vivo. We show molecular evidence for differentiating low- and high-resistant types based on diagnostic gene expression and DNA methylation profiles, suggesting contribution of certain molecular signatures to drug response. Our data integrating molecular data with drug response profiles may help identifying such changes of importance in drug resistance mechanisms.

Dynamic Modelling for Cancer-Associated Venous Thromboembolism

Background: Cancer-associated venous thromboembolism (VTE) is an important source of morbidity and mortality. Current risk prediction models for thrombosis are handicapped by static applicability (i.e. one-time evaluation prior to the first cycle of chemotherapy). We hypothesized that event forecasting using time series modelling could account for important changes in clinical state, variations in treatment and aspects of cancer progression over time. Methods: The cohort consisted of adult patients with a solid tumor enrolled in the MSK-IMPACT study between 2014 and 2019. VTE was defined as any symptomatic or asymptomatic pulmonary embolus or lower extremity deep vein thrombosis. We derived time series mixed-effects logistic regression models in order to predict cancer-associated VTE events using baseline patient characteristics (cancer type, time from diagnosis and age) along with time-dependent covariates including total white blood cell count, hemoglobin, platelet count, albumin, creatinine and parenteral chemotherapy type. Time-periods of one month were used and models were fitted to predict the presence or absence of a VTE episode in the following period (time = t+1) based on predictor values in the current period (time = t). The laboratory test result ascribed to a given period could be either the last value in the interval or the mean of all interval-specific values (both approaches tested). Missing laboratory results were imputed using the previously known value when available. Differences in laboratory values between periods t-1 and t were included as predictors in the initial model along with indicators of missingness (see Figure for flow of information between time-period cells). We hypothesized that absence of laboratory testing for a time-period would be a marker of stable medical state and hence associated with a lower risk of VTE. A previously defined training set comprising 80% of the cohort was used and different modelling approaches were evaluated using 5-fold cross-validation. The final selected model was evaluated in a separate dedicated validation set including the remaining 20% of the cohort. Results: The original cohort included 35,391 patients, from which 26,075 individuals with no cancer-associated VTE episode before observation start and sufficient laboratory test information could be included in the analysis, comprising 276,579 months of observation and 1,463 VTE events. The initial logistic regression model including all available predictors was fitted on the training set, revealing associations between predictors and VTE risk largely consistent with data reported by other groups (see Table). After adjusting for multiple comparisons, significant predictors of cancer-associated VTE identified included albumin, cell count result missingness (decreased risk for missing value), treatment with a platinum analogue (increased risk), hemoglobin, white blood cell count, breast cancer (decreased risk) and high-grade glioma (increased risk). Based on model metrics and prior knowledge from published literature, the set of covariates selected for inclusion in the final model consisted of cell counts along with the corresponding missingness indicator, platelet count change over time, albumin and chemotherapy types. The c-index for the final model using 5-fold cross-validation in the training set was 0.77 (95% CI = 0.75-0.80), compared to 0.77 (95% CI = 0.74-0.79) in the validation set. The latter corresponded to a specificity of 0.83 (95% CI = 0.79-0.86) when fixing sensitivity at 50%. Conclusions: A simple mixed-effects logistic regression time series model demonstrated promising potential to estimate the risk of cancer-associated VTE on a dynamic basis using routine laboratory test results and chemotherapy prescription data widely available in most electronic health record systems. Validation of this dynamic VTE risk model has the potential to optimize outpatient thromboprophylaxis during periods of high thrombotic risk.

Times of crisis and new entrepreneurial opportunities in highly regulated environments: the case of mRNA-biotechs during COVID-19 pandemic

PurposeCrises, such as COVID-19 pandemic, are critical events that provoke important changes in organizational practices, regulations and actors' roles. The pharmaceutical sector has been strongly affected because of the urgency to produce drugs that are effective and safe. However, the validation process and regulations are historically restrictive in this sector. This study aims to study how biotechnology firms, small companies lacking resources, have undertaken strategic actions during crisis time to induce important changes to their advantage within such a highly regulated environment.Design/methodology/approachInterviews were conducted with 21 managers in four mRNA-based biotechnology firms.FindingsResults showed that rhetorical strategies and institutional actions are used in order to manage change opportunities. Media attention, greater openness of state agencies and public willingness to accept new ways of treatment illustrated this opportunity of change in favor of biotechnology firms.Originality/valueHighly regulated environments tend to be unfavorable to smaller firms with limited resources to overcome these constraints. The authors show that times of crisis can reverse this assumption through the provision of new opportunities as long as the smaller firms skillfully use strategic actions to exploit the institutional changes at play.

Assessment of the Roles of Magnesium and Zinc in Clinical Disorders.

The ability and facility of magnesium (Mg2+) and zinc (Zn2+) to interact with phosphate ions confer them the characteristics of essential trace elements. Trace elements are extremely necessary for the basic nucleic acid chemistry of cells of all known living organisms. More than 300 enzymes require zinc and magnesium ions for their catalytic actions, including all the enzymes involved in the synthesis of ATP. In addition, enzymes such as isomerases, oxidoreductases, lyases, transferases, ligases and hydrolases that use other nucleotides to synthesize DNA and RNA require magnesium and zinc. These nucleotides may trigger oxidative damage or important changes against free radicals. In the same way, nucleotides may play an important role in the pathophysiology of degenerative diseases, including in some clinical disorders, where vascular risk factors, oxidative stress and inflammation work to destabilize the patients` homeostatic equilibrium. Indeed, reduced levels of zinc and magnesium may lead to inadequate amount of antioxidant enzymes, and thus, acts as an important contributing factor for the induction of oxidative stress leading to cellular or tissue dysfunction. Hence, the development of zinc or magnesium enzyme inhibitors could be a novel opportunity for the treatment of some human disorders. Therefore, the objective of the present work was to assess the clinical benefits of zinc and magnesium in human health and their effects in some clinical disorders.

Comparative Pharmacokinetics of Intravenous Enrofloxacin in One- Six- And Twelve-Month-Old Sheep.

Enrofloxacin (ENR) is a fluoroquinolone antibiotic approved for use in sheep of all ages. The body composition and metabolic capability change with age. These changes may alter the pharmacokinetics of drugs and thus their effect. Therefore, the pharmacokinetics of drugs need to be established in target- age animals. To determine the pharmacokinetics of ENR and its active metabolite, ciprofloxacin (CIP), following a single intravenous administration of ENR at a dose of 10 mg/kg in different ages of sheep. The study was carried out in the one-, six- and twelve-month age period of the sheep. A single dose of 10 mg/kg ENR was administered intravenously through the jugular vein to sheep in all age periods. ENR and CIP plasma concentrations were determined using HPLC-UV and analyzed using a non-compartmental method. ENR was detected in the plasma until 36 h in one-month-old and up to 24 h in other ages. CIP was detected in the plasma up to 24 h in all age groups. The t1/2ʎz and Vdss were significantly higher in one-month-old sheep than in six and twelve-months old sheep. There was no difference in ClT and AUC values in different age groups. AUC0-∞CIP/AUC0-∞ENR ratios were higher in one-month-old than in six- and twelve-months sheep. The most important pharmacokinetic changes associated with aging in sheep are decreased Vdss and t1/2ʎz of ENR and the low ratio metabolizing of ENR to CIP. Pharmacokinetic/pharmacodynamic data showed that ENR after IV administration of 10 mg/kg dose provided the optimal AUC0-24/MIC90 ratios for E. coli, P. multocida and Mycoplasma spp. (>125) with MIC of 0.37 µg/mL and for S. aureus (>30) with MIC of 0.5 µg/mL in all ages of sheep.

Climate change, costs, or jobs: How policymakers frame state clean energy laws

Renewable portfolio standard (RPS) laws are among the most important climate change policies, requiring a minimum percentage of electricity from clean energy sources. From 2015–2022 in the U.S., eleven states enacted 100 % RPS laws and seven others strengthened their targets. This study examines the issue framing behind these recent RPS laws, which reflects and affects the political context surrounding the policies, people's views, and support among stakeholders. Through coding of policy documents, the study evaluates how policymakers have framed the policies, differences in framing between states with 100 % and non-100 % RPS targets, and variation in framing connected with political party and partisan votes. Surprisingly, given recommendations in the literature to downplay climate issues and emphasize economics, lawmakers predominantly framed 100 % clean energy laws based on climate change. Policymakers that adopted non-100 % RPS laws utilized less climate framing and garnered more Republican Party legislator votes. The results indicate a distinction in framing between more modest and ambitious climate policies, raising a question about the applicability of recommendations urging minimization of climate messaging to transformative climate and clean energy policy efforts. Depending on political conditions, climate framing may be effective for ambitious energy approaches.

Chronic kidney disease prevalence in asymptomatic patients with risk factors—usefulness of serum cystatin C: a cross-sectional study

Abstract Background: Chronic kidney disease is recognized as a worldwide public health problem, particularly within an increasing prevalence of obesity, diabetes mellitus, and hypertension. This disease affects more than 13% of the world's population and is increasing. Further biochemical assessment with new biomarkers, such as serum cystatin C (CysC), would improve patient care and disease control. The aim of this study was to detect chronic kidney disease (CKD) in asymptomatic subjects with risk factors and evaluate CysC as early biomarker of renal damage and accurate test to estimation glomerular filtration (GF). Methods: This observational analytic and cross-sectional design included 195 patients of both sexes. A full clinical evaluation included height, weight, waist circumference, body mass index (BMI), blood pressure (BP), and family history of disease. Renal function was evaluated through serum creatinine (SCrea), serum CysC, urinary albumin, and urinary creatinine. GF was calculated using CKD-EPI creatinine (CKD-EPI Crea) and CKD-EPI creatinine-cystatin C equations (CKD-EPI Crea-CysC). Results: Renal injury showed 24% of patients with albuminuria; 18% of them were categorized as A2 and 6% as A3. Therefore, 73% had no progression risk (baseline risk), 20% moderate risk, and 7% high risk. Among analyzed groups, significant differences were found in BMI, BP, Screa, CysC, CKD-EPI Crea, and CKD-EPI Crea-CysC. Overweight population was analyzed by assessing CysC and calculating CKD-EPI Crea-CysC, showing an important change with respect to the general population. Conclusion: Combined CysC and Crea measurement provides incremental improvement in predicting measured GF.

Religious Buildings in Early al-Andalus: Origins, Consolidation and Prevalence in Urban Contexts

The arrival of Islam to the Iberian Peninsula at the beginning of the 8th c. brought important changes to the urbanism of cities which contributed to turn the previous late-antique realities into medieval Islamic settlements. Among all the transformations that took place, the introduction of mosques and the reconfiguration of cities’ religioscapes is one of the most relevant. The processes through which the earliest mosques were first inserted in urban landscapes in al-Andalus are unclear, since so far there are no remains that can be undoubtedly dated before the Umayyad period. From that moment on, and alongside the Umayyad organization of the Andalusi state, the founding of mosques becomes clearer and traceable, and their urban, religious and political roles more evident. This contribution seeks to identify how and why mosques appeared in the Iberian Peninsula, how they (re)configured religious spaces in cities, and how they contributed to consolidate their significance through specific written and architectural narratives. This topic will be explored also seeking for parallels and connections in the Bilād al-Shām region.