A novel stoploss mutation CYB5R3 c.906A>G(p.*302Trpext*42) involved in the pathogenesis of hereditary methemoglobinemia.

Recessive congenital methemoglobinemia (RCM) is a hereditary autosomal disorder with an extremely low incidence rate. Here, we report a case of methemoglobinemia type I in a patient with congenital persistent cyanosis. The condition was attributed to a novel compound heterozygous mutation in CYB5R3, characterized by elevated methemoglobin levels (13.4 % of total hemoglobin) and undetectable NADH cytochrome b5 reductase (CYB5R3) activity. Whole-exome sequencing (WES) revealed two heterozygous mutations in CYB5R3: a previously reported pathogenic missense mutation c.611G>A(p.Cys204Tyr) inherited from the father, and a novel stop codon mutation c.906A>G(p.*302Trpext*42) from the mother, the latter mutation assessed as likely pathogenic according to ACMG guidelines. In cells overexpressing the CYB5R3 c.906A>G mutant construct, the CYB5R3 mRNA level was significantly lower than in cells overexpressing the wild-type (WT) CYB5R3 construct. However, there was no significant difference in protein expression levels between the mutant and WT constructs. Notably, an additional protein band of approximately 55 kDa was detected in the mutant cells. Immunofluorescence localization showed that, compared to wild-type CYB5R3, the subcellular localization of the CYB5R3 p.*302Trpext*42 mutant protein did not show significant changes and remained distributed in the endoplasmic reticulum and mitochondria. However, the c.906A>G(p.*302Trpext*42) mutation resulted in increased intracellular reactive oxygen species (ROS) levels and decreased NAD+/NADH ratio, suggesting impaired CYB5R3 function and implicating this novel mutation as likely pathogenic.

Exposición a temperaturas extremas y su efecto en la gestación en un departamento de Colombia / Exposure to extreme temperatures and its effect on pregnancy in a department of Colombia

Introducción: Diversas investigaciones han establecido la relación entre temperatura y duración del embarazo, la exposición a temperaturas altas durante el embarazo plantea interrogantes en especial el papel que esta juega frente a los partos prematuros y partos de bajo peso, es indispensable determinar si las temperaturas altas o bajas tienen un comportamiento protector o de riesgo sobre el feto durante la gestación en regiones tropicales. Objetivo: describir la relación entre la exposición a temperaturas altas y bajas durante el embarazo y su efecto en la edad gestacional y peso al momento del parto en los recién nacidos del departamento del Guaviare-Colombia. Metodología: Estudio tipo observacional, analítico, retrospectivo de corte transversal que busco determinar la relación entre exposición a temperaturas altas y bajas durante el embarazo y su efecto en la edad gestacional y peso al momento del parto en los recién nacidos, el universo estuvo conformado por 10.137 nacidos vivos, de los cuales 9.932 cumplieron los criterios de inclusión. Se determinó Odds Ratio para estimar la asociación entre las variables. Resultados: Dentro de la semana de retraso 3 el estar expuesto a temperaturas máximas percentil 90 es un factor protector para la ganancia ponderal de peso OR < 1, la exposición a temperaturas mínimas percentil 10 se asoció como factor protector para el parto prematuro en la semana de retraso 1 y 2 OR < 1.Conclusión: A pesar del beneficio de las altas y bajas temperaturas durante el embarazo en la ganancia ponderal de peso y disminución del parto prematuro, es recomendable prevenir la exposición a temperaturas extremas durante el periodo de gestación[AU]

Introduction: Various investigations have established the relationship between temperature and duration of pregnancy. Exposure to high temperatures during pregnancy raises questions, especially the role it plays in premature births and low-weight births. It is essential to determine whether high temperatures or low have a protective or risky behavior on the fetus during pregnancy in tropical regions.Objective: to describe the relationship between exposure to high and low temperatures during pregnancy and its effect on gestational age and weight at the time of delivery in newborns in the department of Guaviare-Colombia.Methodology:Observational, analytical, retrospective cross-sectional study that sought to determine the relationship between exposure to high and low temperatures during pregnancy and its effect on gestational age and weight at the time of delivery in newborns. The universe was made up of 10,137 births. alive, of which 9,932 met the inclusion criteria. Odds Ratio was determined to estimate the association between the variables.Results:Within the 3rd week of delay, being exposed to maximum temperatures at the 90th percentile is a protective factor for weight gain OR < 1, exposure to minimum temperatures at the 10th percentile was associated as a protective factor for premature birth in the week. of delay 1 and 2 OR < 1. Conclusion: Despite the benefit of high and low temperatures during pregnancy in weight gain and reduction in premature birth, it is advisable to prevent exposure to extreme temperatures during the gestation period[AU]

Introdução: Várias investigações estabeleceram a relação entre temperatura e duração da gravidez. A exposição a altas temperaturas durante a gravidez levanta questões, especialmente o papel que desempenha nos partos prematuros e nos nascimentos de baixo peso. É essencial determinar se as temperaturas altas ou baixas têm um comportamento protetor ou de risco para o feto durante a gravidez em regiões tropicais. Objetivo:descrever a relação entre a exposição a altas e baixas temperaturas durante a gravidez e seu efeito na idade gestacional e no peso no momento do parto em recém-nascidos no departamento de Guaviare-Colômbia. Metodologia: Estudo observacional, analítico, retrospectivo e transversal que buscou determinar a relação entre a exposição a altas e baixas temperaturas durante a gravidez e seu efeito na idade gestacional e no peso no momento do parto em recém-nascidos. O universo foi composto por 10.137 nascimentos. vivos, dos quais 9.932 preencheram os critérios de inclusão. O Odds Ratio foi determinado para estimar a associação entre as variáveis. Resultados:Na 3ª semana de atraso, a exposição a temperaturas máximas no percentil 90 é fator de proteção para ganho de peso OR < 1, a exposição a temperaturas mínimas no percentil 10 foi associada como fator de proteção para parto prematuro na semana. de atraso 1 e 2 OR < 1.Conclusão:Apesar do benefício das altas e baixas temperaturas durante a gravidez no ganho de peso e redução do parto prematuro, é aconselhável evitar a exposição a temperaturas extremas durante o período de gestação[AU]

Formación docente para la educación inclusiva en instituciones públicas del Quindío / Teacher training for inclusive education in public institutions of Quindío

La formación docente es esencial dentro del proceso de educación inclusiva permitiendo responder a la diversidad de los estudiantes a partir de estrategias que promuevan su aprendizaje y participación. Este estudio analiza la formación en inclusión de 253 docentes de instituciones públicas mediante el Cuestionario de Valoración Docente de la Inclusión Educativa (CEFI-R). Los resultados indican niveles bajos de formación en las dimensiones concepciones, apoyos y metodologías. Lo que sugiere que no existe una preparación integral del profesorado para la inclusión y los planes de formación deben abordar desde aspectos conceptuales hasta la implementación de ajustes en el aula. (AU)

Teacher training is essential within the inclusive education process, allowing students to respond to diversity through strategies that promote their learning and participation. This study analyzes the inclusion training of 253 teachers in public institutions, through the Cuestionario de Valoración Docente de la Inclusión Educativa (CEFI-R). The results indicate low levels of training in the conceptual dimensions, supports and methodologies. This suggests that there is no comprehensive preparation of teachers for inclusion and training plans should address conceptual aspects to the implementation of adjustments in the classroom. (AU)

Formación docente para la educación inclusiva en instituciones públicas del Quindío / Teacher training for inclusive education in public institutions of Quindío

La formación docente es esencial dentro del proceso de educación inclusiva permitiendo responder a la diversidad de los estudiantes a partir de estrategias que promuevan su aprendizaje y participación. Este estudio analiza la formación en inclusión de 253 docentes de instituciones públicas mediante el Cuestionario de Valoración Docente de la Inclusión Educativa (CEFI-R). Los resultados indican niveles bajos de formación en las dimensiones concepciones, apoyos y metodologías. Lo que sugiere que no existe una preparación integral del profesorado para la inclusión y los planes de formación deben abordar desde aspectos conceptuales hasta la implementación de ajustes en el aula. (AU)

Teacher training is essential within the inclusive education process, allowing students to respond to diversity through strategies that promote their learning and participation. This study analyzes the inclusion training of 253 teachers in public institutions, through the Cuestionario de Valoración Docente de la Inclusión Educativa (CEFI-R). The results indicate low levels of training in the conceptual dimensions, supports and methodologies. This suggests that there is no comprehensive preparation of teachers for inclusion and training plans should address conceptual aspects to the implementation of adjustments in the classroom. (AU)

The Significance of Right-Sided Precordial ECG Leads (V3R and V4R) in Assessing Right Ventricular Dysfunction: A Single Center Cross-Sectional Study.

BACKGROUND: Right ventricular systolic dysfunction is associated with poor prognosis and increased mortality rates. Our objective was to investigate ECG changes in patients with this condition, focusing on the right-sided precordial leads. METHODS: In this cross-sectional study, 60 patients with right ventricular dysfunction were included from April 2020 to April 2021. Cardiac structure and function were assessed using 2D transthoracic echocardiography. Standard 12-lead electrocardiograms and right-sided precordial ECGs (V3R-V4R) were obtained and analyzed for QRS complex configuration, ST-segment elevation, and T-wave morphology. RESULTS: In our study, the majority were male (70.0%) with a mean age of 58.76 years. The most common initial diagnoses were pulmonary thromboembolism (43.3%), chronic obstructive pulmonary disease (26.7%), and pulmonary hypertension (25.0%). The predominant ECG finding in the right-sided precordial leads (V3R, V4R) was a deep negative T wave (90.0%). Patients with severe right ventricular systolic dysfunction often exhibited a qR pattern (41.2%), whereas those with nonsevere dysfunction showed rS and QS patterns (55.8%). Approximately 41.0% of severe RV dysfunction cases had ST segment depression in the right-sided precordial leads, and 28.0% of patients displayed signs of right atrial abnormality. CONCLUSION: The study found that qR, rS, and QS patterns were more prevalent in V3R and V4R leads among patients with severe and nonsevere right ventricular systolic dysfunction. The most common ECG feature observed was deep T-wave inversion in these leads. The study recommends using right-sided precordial leads in all patients with RV systolic dysfunction for early detection and risk stratification.

Prevalence of non-Hodgkin lymphoma patients at high-risk of failure after CAR T-cell therapy eligible for bridging radiation therapy.

Background and purpose: The aim of this study was to determine the prevalence of patients with relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL) meeting high-risk criteria for early relapse after CD19 CAR T-cell therapy (CART) who have disease encompassable in a standard radiation therapy (RT) plan (defined as <5 malignant lesions) and may benefit from bridging RT prior to CD19 CART. Materials and methods: This is a single-center, retrospective study of patients with R/R NHL who received CD19 CART from 2018 to 2022. Eligible patients had pre-apheresis radiologic studies available. All patients were classified by number of lesions and history of high-risk disease criteria: bulky disease ≥10 cm, ≥1 extranodal (EN) sites, LDH ≥normal, or ≥1 lesion with SUVmax ≥10. Results: A total of 81 patients with R/R NHL were evaluated. Based on our definition, 40 (49%) patients would have been eligible for bridging RT, including 38 patients who met high-risk criteria: 31 with ≥1 EN site, 19 had ≥1 lesion with SUVmax ≥10, 16 with bulky disease, and 3 with elevated LDH. At 3 months after CART, ORRs in high-risk patients with <5 lesions, ≥5 lesions, and no lesions on pre-apheresis studies were 76% (CR 69%, PR 7%), 70% (CR 60%, PR 10%), and 80% (CR 80%), respectively. Conclusion: Approximately 47% (38/81) of patients were classified as at high risk of relapse after CART with disease encompassable in a standard radiation plan and eligible for bridging RT studies.

Free energy landscape of the PI3Kα C-terminal activation.

The gene PIK3CA, encoding the catalytic subunit p110α of PI3Kα, is the second most frequently mutated gene in cancer, with the highest frequency oncogenic mutants occurring in the C-terminus of the kinase domain. The C-terminus has a dual function in regulating the kinase, playing a putative auto-inhibitory role for kinase activity and being absolutely essential for binding to the cell membrane. However, the molecular mechanisms by which these C-terminal oncogenic mutations cause PI3Kα overactivation remain unclear. To understand how a spectrum of C-terminal mutations of PI3Kα alter kinase activity compared to the WT, we perform unbiased and biased Molecular Dynamics simulations of several C-terminal mutants and report the free energy landscapes for the C-terminal "closed-to-open" transition in the WT, H1047R, G1049R, M1043L and N1068KLKR mutants. Results are consistent with HDX-MS experimental data and provide a molecular explanation why H1047R and G1049R reorient the C-terminus with a different mechanism compared to the WT and M1043L and N1068KLKR mutants. Moreover, we show that in the H1047R mutant, the cavity, where the allosteric ligands STX-478 and RLY-2608 bind, is more accessible contrary to the WT. This study provides insights into the molecular mechanisms underlying activation of oncogenic PI3Kα by C-terminal mutations and represents a valuable resource for continued efforts in the development of mutant selective inhibitors as therapeutics.

Prognostic Impact of Surgical Margin Status on Overall Survival of Patients with Early Breast Cancer: A Retrospective Analysis from the Department for Women's Medicine at Charité - University Hospital Berlin.

Introduction: The impact of surgical margins on the prognosis of early breast cancer remains uncertain, particularly in the context of modern treatment approaches. This study aimed to investigate whether involved margins after surgery for early breast cancer affect overall survival. Methods: We conducted a retrospective analysis of 3767 patients who underwent surgery for primary breast cancer or carcinoma in situ between 2006 and 2022 at Charité - University Hospital Berlin. Survival analysis based on margin status and a subsequent multivariate Cox regression analysis were conducted. Results: With a median follow-up of 72.2 months, clear margins were achieved in 81.4% of patients (n = 3068) after primary surgery, while 16.2% (n = 610) required re-excision. Only 2.4% of patients (n = 89) had definitively involved margins. Margin involvement was more common in hormone receptor-positive disease, lobular subtype, carcinoma in situ, or locally advanced tumors, but less frequent in patients with previous neoadjuvant chemotherapy or triple-negative breast cancer. The Kaplan-Meier survival curves showed a significant separation with worse outcomes for patients with definitive R1 resections. However, the multivariate Cox regression analysis detected no statistically significant difference in overall survival based on margin status. Breast conserving surgery (HR 0.66; 95% CI 0.54-0.81) and HER2 overexpression (HR 0.65; 95% CI 0.48-0.89) were associated with improved survival. Conclusion: Patients who underwent breast-conserving surgery in our study demonstrated favorable outcomes compared to patients after mastectomy. Although margin status did not significantly affect overall survival, larger multicenter studies are needed to evaluate the prognostic implications of margin involvement in breast cancer treatment in different tumor stages, tumor subtypes and local and systemic treatments.

Two-step synthesis of enantiomerically pure morphans from (R)-carvone.

Enantiomerically pure 4-hydroxymorphan-7-ones were prepared in two steps from the natural product (R)-carvone. At first, the isopropenyl moiety of (R)-carvone was converted into the epoxide 7. A Domino reaction consisting of epoxide opening with primary amines followed by intramolecular conjugate addition of the resulting secondary amines at the α,ß-unsaturated ketone established the morphan scaffold. This novel morphan synthesis allowed the modification of the bicyclic system at three positions resulting in 26 diverse morphans. Various primary amines led to morphans 8‒13 with different N-substituents. Acylation or water elimination followed by hydrogenation led to esters 15 and 16 or the morphan 18 without a hydroxy moiety. The benzylidenemorphans 25a and 26a were prepared by condensation of the ketones 11a and 12a with benzaldehyde. Finally, the α-methylene ketone of 11a and 12a was exploited to obtain indolomorphans, quinolinomorphans, pyrimidinomorphans and pyrazolomorphans. Affinity of the novel morphans at opioid receptors MOR, DOR and KOR could not be detected. However, the indolomorphan 19 and the quinolinomorphan 22 showed nanomolar σ1 receptor affinity (Ki = 58 nM and 20 nM).

A Causal Mediation Approach to Account for Interaction of Treatment and Intercurrent Events: Using Hypothetical Strategy.

Hypothetical strategy is a common strategy for handling intercurrent events (IEs). No current guideline or study considers treatment-IE interaction to target the estimand in any one IE-handling strategy. Based on the hypothetical strategy, we aimed to (1) assess the performance of three estimators with different considerations for the treatment-IE interaction in a simulation and (2) compare the estimation of these estimators in a real trial. Simulation data were generalized based on realistic clinical trials of Alzheimer's disease. The estimand of interest was the effect of treatment with no IE occurring under the hypothetical strategy. Three estimators, namely, G-estimation with and without interaction and IE-ignored estimation, were compared in scenarios where the treatment-IE interaction effect was set as -50% to 50% of the main effect. Bias was the key performance measure. The real case was derived from a randomized trial of methadone maintenance treatment. Only G-estimation with interaction exhibited unbiased estimations regardless of the existence, direction or magnitude of the treatment-IE interaction in those scenarios. Neglecting the interaction and ignoring the IE would introduce a bias as large as 0.093 and 0.241 (true value, -1.561) if the interaction effect existed. In the real case, compared with G-estimation with interaction, G-estimation without interaction and IE-ignored estimation increased the estimand of interest by 33.55% and 34.36%, respectively. This study highlights the importance of considering treatment-IE interaction in the estimand framework. In practice, it would be better to include the interaction in the estimator by default.

Robotic surgery: bibliometric analysis, continental distribution, and co-words analysis from 2001 to 2023.

The project aimed to conduct an up-to-date and comprehensive bibliometric analysis of robotic surgery to provide a detailed and holistic understanding of the field. Three strategies were employed in the data analysis i.e. search terms were explored in (A) the title, abstract, and keywords and (B) only in the title of the documents. In 3rd part we analyzed the top 100 most cited papers. Vosviewer and R Studio were utilized for detailed bibliometric and network analyses. Strategy one identified 38,469 publications, and strategy two identified 6451 publications from 2001 to 2023. The top authors, universities, countries, sponsors, and sources based on the number of publications were identified for both strategies. The top 100 most cited papers were analyzed, providing the annual number of publications and various citation metrics. Top authors (by number of publications, total citations, h-index, g-index, and m-index), universities, and countries within these highly cited papers, along with their co-authorship networks and dynamics, were examined. Co-words analysis of the top 100 most cited papers revealed the primary focus of these documents across 25 categories. This comprehensive bibliometric analysis of robotic surgery highlighted significant contributions and collaborations in the field, emphasizing the importance of global and collaborative efforts in advancing robotic surgery research.

Multicenter, multivendor validation of liver quantitative susceptibility mapping in patients with iron overload at 1.5 T and 3 T.

PURPOSE: To evaluate the repeatability and reproducibility of QSM of the liver via single breath-hold chemical shift-encoded MRI at both 1.5 T and 3 T in a multicenter, multivendor study in subjects with iron overload. METHODS: This prospective study included four academic medical centers with three different MRI vendors at 1.5 T and 3 T. Subjects with known or suspected liver iron overload underwent multi-echo spoiled gradient-recalled-echo scans at each field strength. A subset received repeatability testing at either 1.5 T or 3 T. Susceptibility and R 2 * $$ {\mathrm{R}}_2^{\ast } $$ maps were reconstructed from the multi-echo images and analyzed at a single center. QSM-measured susceptibility was compared with R 2 * $$ {\mathrm{R}}_2^{\ast } $$ and a commercial R2-based liver iron concentration method across centers and field strengths using linear regression and F-tests on the intercept and slope. Field-strength reproducibility and test/retest repeatability were evaluated using Bland-Altman analysis. RESULTS: A total of 155/80 data sets (test/retest) were available at 1.5 T, and 159/70 data sets (test/retest) were available at 3 T. Calibrations across sites were reproducible, with some variability (e.g., susceptibility slope with liver iron concentration ranged from 0.102 to 0.123 g/[mg · $$ \cdotp $$ ppm] across centers at 1.5 T). Field strength reproducibility was good (concordance correlation coefficient = 0.862), and test/retest repeatability was excellent (intraclass correlation coefficient = 0.951). CONCLUSION: QSM as an imaging biomarker of liver iron overload is feasible and repeatable across centers and MR vendors. It may be complementary with R 2 * $$ {\mathrm{R}}_2^{\ast } $$ as they are obtained from the same acquisition. Although good reproducibility was observed, liver QSM may benefit from standardization of acquisition parameters. Overall, QSM is a promising method for liver iron quantification.

The Legal Framework for Public-Private Partnerships in Drug R&D.

Public-private partnerships in drug R&D have great potential for driving innovation. They can bridge between excellent fundamental research and development and commercialization of innovative medicines to address unmet needs for the therapy of severe diseases in the interest of public health and human welfare. Therefore, public-private partnerships in drug R&D are promoted and publicly funded by governments and the European Commission. Nonetheless, they need to comply with legal requirements, particularly stemming from State aid law and competition law. Those requirements do not only protect a fair competition, but rather also further open information exchange as well as fair sharing of risks and fair participation in gains and results with the goal of having a successful collaboration and increasing the chance of successful commercialization of pharmaceutical innovations.

Schisandra chinensis lignans improve insulin resistance by targeting TLR4 and activating IRS-1/PI3K/AKT and NF-κB signaling pathways.

Schisandra chinensis, a traditional Chinese medicine, has been widely applied in China to treat diabetes and its complications. The aim of this study was to discover the active compounds and explain related molecular mechanism contributing to the anti-diabetic effect of Schisandra chinensis. Herein, the therapeutic effects of Schisandra chinensis extracts on type 2 diabetes mellitus (T2DM) were firstly confirmed in vivo. Subsequently, various lignans were isolated from Schisandra chinensis and tested for hypoglycemic activity in palmitic acid-induced insulin-resistant HepG2 (IR-HepG2) cells. Among these lignans, R-biar-(7S,8R)-6,7,8,9-tetrahydro-1,2,3,12,13,14-hexamethoxy-7,8-dimethyl-7-dibenzo [a, c] cyclooctenol (compound 2) and Gomisin A (compound 4) were identified significantly increased the glucose consumption in IR-HepG2 cells. Meanwhile, compounds 2 and 4 activated the insulin receptor substrate-1 (IRS-1)/phosphoinositide 3-kinase (PI3K)/Ak strain transforming (AKT) pathway, which regulates glucose transporter 2 (GLUT2) and glucose-6-phosphatase (G6Pase), essential for gluconeogenesis and glucose uptake. These compounds also inhibited the nuclear factor-κB (NF-κB) signaling pathway, reducing interleukin-6 (IL-6) levels. Importantly, the hypoglycemic effects of compounds 2 and 4 were diminished after Toll-like receptor 4 (TLR4) knockdown. Cellular thermal shift assays confirmed increased TLR4 protein stability upon treatment with these compounds, indicating direct binding to TLR4. Furthermore, TLR4 knockdown reversed the effects of compounds 2 and 4 on the NF-κB and IRS-1/PI3K/AKT pathways. Taken together, compounds 2 and 4 alleviate IR by targeting TLR4, thereby modulating the NF-κB and IRS-1/PI3K/AKT pathways. These findings suggest that compounds 2 and 4 could be developed as therapeutic agents for T2DM.

Identification of a novel B cell epitope of ASFV pCP312R recognized using a monoclonal antibody.

African swine fever (ASF) is an acute and devastating infectious disease that has caused significant economic losses to the global pig industry since it was first discovered and reported. African swine fever virus (ASFV) has a large genome encoding more than 160 proteins. The biological characteristics and functions of its various proteins still remain unclear; therefore, the efficacy of specific drugs and vaccines against ASFV remains limited. ASFV pCP312R is an important ASFV protein that exhibits good immunogenicity. In this study, five monoclonal antibodies (mAbs) targeting pCP312R were successfully prepared. Confocal microscopy observations showed that pCP312R was located in the viral factory at the late stage of ASFV infection, and was co-located with p30 and pK205R. These results suggested that pCP312R might be involved in ASFV assembly. Neutralization tests revealed that pCP312R mAb could not neutralize ASFV. Next, we identified the B cell epitopes of one of the most immunogenic mAbs and found a novel epitope of pCP312R, 72TIPPSTDEEVIR83, which was conserved in different pCP312R strains. Overall, five ASFV pCP312R monoclonal antibodies were prepared, and the antigenic epitope of one strain was identified in this study, laying a foundation for further studies on ASFV pCP312R function and facilitating serological diagnosis vaccine development for ASFV.

Air pollution, sustainable development, and corporate R&D: Evidence from emerging countries.

This paper studies the adverse effect of air pollution on corporate research and development (R&D) and how sustainable development moderates this negative impact in emerging market economies (EMEs). Using a sample of 18 EMEs' firm-level data, the empirical results show that firms substantially reduce R&D expenses in the face of increasing air pollution, and this adverse effect becomes less pronounced with higher levels of sustainable development. Our analyses suggest that air pollution negatively affects R&D by increasing firms' difficulties in hiring highly skilled people or raising operation and production costs. Furthermore, we divide our sample firms into two groups according to some institutional quality factors related to sustainable development. The negative impact of air pollution on R&D is lower in countries with higher levels of institutional quality. Based on our research, to attract more R&D investment, EMEs should not only make an effort to manage air pollution but also invest more in human capital and improve their institutional quality to amplify the impact of their efforts.

The pharmaceutical productivity gap - incremental decline in R&D efficiency despite transient improvements.

Rising research and development costs, currently exceeding $3.5 billion per novel drug, reflect a five-decade decline in pharmaceutical R&D efficiency. While recent reports suggest a potential turnaround, this review offers a systems-level analysis to explore whether this marks a structural shift or transient reversal. We analyzed financial data from the 200 largest pharmaceutical firms, novel drug approvals, and more than 80000 clinical trials between 2012 and 2023. Our analysis revealed that despite recent stabilization, the pharmaceutical industry continues to face challenges, particularly due to elevated late-stage clinical attrition, suggesting that a sustained turnaround in R&D efficiency remains elusive.

Evaluation of Mean Plasma Glucose Levels Using HbA1C in Patients With Severe Eating Disorders.

OBJECTIVE: Hypoglycemia causes significant morbidity and mortality in patients with severe eating disorders. We measured average glycemic levels using hemoglobin A1C (HbA1C) in patients hospitalized for extreme anorexia nervosa (AN) and avoidant restrictive food intake disorder (ARFID). METHODS: This was a prospective, single-center cohort study conducted in an inpatient medical stabilization unit. Clinical outcomes were compared using paired t-tests. Additional analysis comparing clinical variables between undetectable and detectable HbA1c used two-sample t-tests. RESULTS: The study cohort consisted of 148 individuals, 90% female, average age of 31 years, average admit body mass index of 12.5 kg/m2, and mean percentage ideal body weight of 60.1%. Diagnoses included AN-restricting (54%), AN-binge purge (39%), and ARFID (7%). HbA1C and fructosamine levels decreased from admission to discharge. Serum glucose levels increased significantly from admission to discharge. Mean HbA1C was 4.7% on admission and 4.3% on discharge. DISCUSSION: This study evaluated mean blood glucose levels using HbA1C in patients with extreme forms of AN and ARFID. Given the concern for morbidity and mortality from hypoglycemia in this population, which can be overlooked on a single point-of-care glucose measurement, HbA1C is a valuable laboratory measure of glycemic status in patients with extreme forms of eating disorders.

The Bioenergetics of Traumatic Brain Injury and its Long-Term Impact for Brain Plasticity and Function.

Mitochondria provide the energy to keep cells alive and functioning and they have the capacity to influence highly complex molecular events. Mitochondria are essential to maintain cellular energy homeostasis that determines the course of neurological disorders, including traumatic brain injury (TBI). Various aspects of mitochondria metabolism such as autophagy can have long-term consequences for brain function and plasticity. In turn, mitochondria bioenergetics can impinge on molecular events associated with epigenetic modifications of DNA, which can extend cellular memory for a long time. Mitochondrial dysfunction leads to pathological manifestations such as oxidative stress, inflammation, and calcium imbalance that threaten brain plasticity and function. Hence, targeting mitochondrial function may have great potential to lessen the outcomes of TBI.

Tangzu granule alleviate neuroinflammation in diabetic peripheral neuropathy by suppressing pyroptosis through P2X7R /NLRP3 signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Diabetic peripheral neuropathy (DPN) is a common complication of diabetes mellitus, mainly manifested as paresthesia. Tangzu granule (TZG) is derived from famous traditional Chinese medicine decoctions and optimized by long-term temporary practice. TZG has good efficacy in improving numbness, pain and pruritus of the lower extremities of DPN patients. However, the overall regulatory mechanisms underlying its effects on DPN remain unclear. AIM OF THE STUDY: This study aims to explore the potential mechanism of TZG for treating DPN. MATERIALS AND METHODS: Sprague-Dawley (SD) rats were used to establish an in vivo model of DPN with streptozotocin (STZ) injection and high-fat diet (HFD) feeding. Additionally, sciatic glial RSC96 cells were induced with high glucose in vitro. SD rats in intervention group received TZG treatment for 12 weeks. After 12 weeks of treatment, sciatic nerve function was evaluated by intelligent hot plate meter and neuro electrophysiology detector. The morphological changes of sciatic nerve cells were observed by hematoxylin-eosin staining and transmission electron microscope. IL-1ß, IL-18 inflammatory cytokines, pyroptosis and P2X7R/NLRP3 signaling pathway were observed by Western blotting, immunofluorescence staining and ELISA. RESULTS: TZG improved nerve conduction velocity and sciatic neuropathy rational structural changes in DPN rats. It also inhibited RSC96 inflammatory response and cell death that induced by high glucose. This may be related to TZG inhibiting P2X7R, decreasing the activation of NLRP3 inflammasomes, down-regulating the levels of pyroptosis proteins such as caspase-1, cleaved caspase-1, gasdermin D (GSDMD), and GSDMD-N, and inhibiting the release of interleuki (IL)-18 and IL-1ß inflammatory cytokines. CONCLUSIONS: TZG inhibited pyroptosis through P2X7R/NLRP3 signaling pathway, alleviated neuroinflammation, and showed protective effect in the treatment of DPN.