Aspirin for preeclampsia prevention in low- and middle-income countries: mind the gaps.

Preeclampsia is a syndrome that continues to be a major contributor to maternal and neonatal mortality, especially in low-income countries. Low-dose aspirin reduces the risk of preeclampsia, but the mechanism is still unknown. Risk factors to identify women at risk of preeclampsia are based on clinical characteristics. Women identified as high-risk would benefit from aspirin treatment initiated, preferably at the end of the first trimester. Current efforts have largely focused on developing screening algorithms that incorporate clinical risk factors, maternal biomarkers, and uterine artery Doppler evaluated in the first trimester. However, most studies on preeclampsia are conducted in high-income settings, raising uncertainties about whether the information gained can be totally applied in low-resource settings. In low- and middle-income countries, lack of adequate antenatal care and late commencement of antenatal care visits pose significant challenges for both screening for preeclampsia and initiating aspirin treatment. Furthermore, the preventive effect of first-trimester screening based on algorithms and subsequent aspirin treatment is primarily seen for preterm preeclampsia, and reviews indicate minimal or no impact on reducing the risk of term preeclampsia. The lack of evidence regarding the effectiveness of aspirin in preventing term preeclampsia is a crucial concern, as 75% of women will develop this subtype of the syndrome. Regarding adverse outcomes, low-dose aspirin has been linked to a possible higher risk of postpartum hemorrhage, a condition as deadly as preeclampsia in many low- and middle-income countries. The increased risk of postpartum hemorrhage among women in low-income settings should be taken into consideration when discussing which pregnant women would benefit from the use of aspirin and the ideal aspirin dosage for preventing preeclampsia. In addition, women's adherence to aspirin during pregnancy is crucial for determining its effectiveness and complications, an aspect often overlooked in trials. In this review, we analyze the knowledge gaps that must be addressed to safely increase low-dose aspirin use in low- and middle-income countries, and we propose directions for future research.

Hypoglycemia Unawareness and Recurrent Severe Hypoglycemia in an Individual With Type 1 Diabetes Mellitus on Insulin.

Background/Objective: Hypoglycemia unawareness is a complication of recurrent hypoglycemia that can complicate diabetes management and impact quality of life. We present the case of an individual with type 1 diabetes with hypoglycemia unawareness and recurrent severe hypoglycemia requiring emergency intervention. Case Report: A 55-year-old man with type 1 diabetes was referred for hypoglycemia unawareness and recurrent hypoglycemia with seizures. Over the prior 4 years he had >400 paramedic responses with 56 hospitalizations. Blood glucose levels ranged between 0.7 and 2.4 mmol/L during these episodes and presenting Hemoglobin A1c (HbA1c) was 4.6% (28 mmol/mol). He was taking insulin glargine daily and aspart with meals via insulin pens with no alternative etiology for his hypoglycemia was identified. The patient expressed difficulty with self-management, social instability, and limited appointment attendance. He was provided a continuous glucose monitor, educational support, and glycemic targets were broadened. After 6 months, HbA1c was 4.6% (28 mmol/mol) and he had 65 paramedic responses. A multidisciplinary team was organized for biweekly follow-up, community outreach, remote technological support, and psychological counseling. After 2 years, the patient had 2 emergency responses and HbA1c was 7.2% (55.2 mmol/mol). Discussion: Permissive hyperglycemia, educational interventions, and continuous glucose monitoring are validated strategies for prevention of hypoglycemia. Limiting hypoglycemia is crucial to restore hypoglycemia awareness, and in severe cases may require high intensity follow-up, community outreach, and psychosocial support. Conclusion: Hypoglycemia unawareness can complicate hypoglycemia prevention. Severe refractory cases are often multifaceted and may warrant a multidisciplinary approach to identify and target patient-specific needs.

Enhanced Hydrogen Bonding by Urea Functionalization Tunes the Stability and Biological Properties of Peptide Amphiphiles.

Self-assembled nanostructures such as those formed by peptide amphiphiles (PAs) are of great interest in biological and pharmacological applications. Herein, a simple and widely applicable chemical modification, a urea motif, was included in the PA's molecular structure to stabilize the nanostructures by virtue of intermolecular hydrogen bonds. Since the amino acid residue nearest to the lipid tail is the most relevant for stability, we decided to include the urea modification at that position. We prepared four groups of molecules (13 PAs in all), with varying levels of intermolecular cohesion, using amino acids with distinct ß-sheet promoting potential and/or containing hydrophobic tails of distinct lengths. Each subset contained one urea-modified PA and nonmodified PAs, all with the same peptide sequence. The varied responses of these PAs to variations in pH, temperature, counterions, and biologically related proteins were examined using microscopic, X-ray, spectrometric techniques, and molecular simulations. We found that the urea group contributes to the stabilization of the morphology and internal arrangement of the assemblies against environmental stimuli for all peptide sequences. In addition, microbiological and biological studies were performed with the cationic PAs. These assays reveal that the addition of urea linkages affects the PA-cell membrane interaction, showing the potential to increase the selectivity toward bacteria. Our data indicate that the urea motif can be used to tune the stability of a wide range of PA nanostructures, allowing flexibility on the biomaterial's design and opening a myriad of options for clinical therapies.

Experiences of Motivational Interviewing in Virtual Health-care Visits for Adults With Type 2 Diabetes Mellitus: A Qualitative Analysis.

OBJECTIVES: The purpose of this qualitative study is to identify barriers minimizing the effectiveness of motivational interviewing during virtual clinic encounters for individuals with type 2 diabetes based on the capability, opportunity, motivation, and behaviour (COM-B) model. METHODS: One-on-one semistructured interviews were conducted from March to June 2023, with 17 adults with type 2 diabetes (64.7% female; median age 69 years, range 47 to 83 years) followed at St. Michael's Hospital (Toronto, Canada). Themes from transcribed interviews were identified through descriptive analysis using a grounded theory approach. RESULTS: The following main themes were identified: 1) face-to-face appointments strengthen provider-patient rapport and collaboration; 2) virtual encounters reduce patient accountability and hinder health-seeking behaviour; and 3) individuals with physical disabilities and/or low technological proficiency experience decreased provider accessibility. Protective factors that can mitigate these negative impacts include establishing rapport during in-person appointments before transitioning to virtual appointments and incorporating a video component during virtual encounters. CONCLUSIONS: Several barriers of virtual appointments currently limit the effectiveness of motivational interviewing for individuals with type 2 diabetes and make it difficult to provide person-centred care, especially by phone. However, there are protective factors that help to maintain healthy lifestyle behaviours, even after transitioning to virtual settings, and are areas for optimization moving forward.

Mathematical Modeling of Alpha-Tocopherol Early Degradation Kinetics to Predict the Shelf-Life of Bulk Oils.

The kinetics of lipid oxidation includes a lag phase followed by an exponential increase in oxidation products, which cause rancidity. Current models focus on the slope of this exponential curve for shelf-life estimation, which still requires the measurement of full oxidation kinetics. In this paper, we analyzed the formation of lipid oxidation products in stripped soybean oil containing different levels of α-tocopherol. The lag phases of lipid hydroperoxides and headspace hexanal formation were found to have a strong positive correlation with the α-tocopherol depletion time. We propose that the kinetics of antioxidant (α-tocopherol) depletion occur during the lag phase and could serve as an early shelf-life indicator. Our results showed that α-tocopherol degradation can be described by Weibull kinetics over a wide range of initial concentrations. Furthermore, we conducted in silico investigations using Monte Carlo simulations to critically evaluate the feasibility and sensitivity of the shelf-life prediction using early antioxidant degradation kinetics. Our results revealed that the shelf life of soybean oil may be accurately predicted as early as 20% of the overall shelf life. This innovative approach provides a more efficient and faster assessment of shelf life, ultimately reducing waste and enhancing product quality.

Disruption of the Mouse Blood-Brain Barrier by Small Extracellular Vesicles from Hypoxic Human Placentas.

Cerebrovascular complications, including cerebral edema and ischemic and hemorrhagic stroke, constitute the leading cause of maternal mortality associated with preeclampsia. The underlying mechanisms of these cerebrovascular complications remain unclear. However, they are linked to placental dysfunction and blood-brain barrier (BBB) disruption. Nevertheless, the connection between these two distant organs is still being determined. Increasing evidence suggests that the placenta releases signaling molecules, including extracellular vesicles, into maternal circulation. Extracellular vesicles are categorized according to their size, with small extracellular vesicles (sEVs smaller than 200 nm in diameter) considered critical signaling particles in both physiological and pathological conditions. In preeclampsia, there is an increased number of circulating sEVs in maternal circulation, the signaling function of which is not well understood. Placental sEVs released in preeclampsia or from normal pregnancy placentas exposed to hypoxia induce brain endothelial dysfunction and disruption of the BBB. In this protocol, we assess whether sEVs isolated from placental explants cultured under hypoxic conditions (modeling one aspect of preeclampsia) disrupt the BBB in vivo.

Predictive model for a second hip fracture occurrence using natural language processing and machine learning on electronic health records.

Hip fractures (HFx) are associated with a higher morbidity and mortality rates, leading to a significant reduction in life quality and in limitation of patient´s mobility. The present study aimed to obtain real-world evidence on the clinical characteristics of patients with an initial and a second hip fracture (HFx) and develop a predictive model for second HFx using artificial intelligence. Electronic health records from one hospital centre in Spain from January 2011 to December 2019 were analysed using EHRead® technology, based on natural language processing and machine learning. A total of 1,960 patients with HFx were finally included during the study period after meeting all inclusion and exclusion criteria. From this total, 1835 (93.6%) patients were included in the HFx subgroup, while 124 (6.4%) were admitted to the second HFx (2HFx) subgroup. The mean age of the participants was 84 years and 75.5% were female. Most of comorbidities were more frequently identified in the HFx group, including hypertension (72.0% vs. 67.2%), cognitive impairment (33.0% vs. 31.2%), diabetes mellitus (28.7% vs. 24.8%), heart failure (27.6% vs. 22.4%) and chronic kidney disease (26.9% vs. 16.0%). Based on clinical criteria, 26 features were selected as potential prediction factors. From there, 16 demographics and clinical characteristics such as comorbidities, medications, measures of disabilities for ambulation and type of refracture were selected for development of a competitive risk model. Specifically, those predictors with different associated risk ratios, sorted from higher to lower risk relevance were visual deficit, malnutrition, walking assistance, hypothyroidism, female sex, osteoporosis treatment, pertrochanteric fracture, dementia, age at index, osteoporosis, renal failure, stroke, COPD, heart disease, anaemia, and asthma. This model showed good performance (dependent AUC: 0.69; apparent performance: 0.75) and could help the identification of patients with higher risk of developing a second HFx, allowing preventive measures. This study expands the current available information of HFx patients in Spain and identifies factors that exhibit potential in predicting a second HFx among older patients.

Sarcopenic Obesity in Community-Dwelling Spanish Adults Older than 65 Years.

Sarcopenic obesity (SO) is diagnosed when sarcopenia and obesity coexist in patients. The objective of this study was to determine the prevalence of SO under different diagnostic criteria in community-dwelling Spanish adults aged over 65 years residing in Valencia (Spain). The research was conducted as an observational and cross-sectional study with a sample size of 202 subjects. To diagnose sarcopenia, we used the tests proposed by the European Working Group on Sarcopenia in Older People in 2019 (EWGSOP2): SARC-F, grip strength, sit-to-stand, gait speed, Appendicular Skeletal Muscle Mass (ASMM), and Short Physical Performance Battery (SPPB). For obesity diagnosis, we used body mass index (BMI), waist circumference (WC), total body fat percentage (%TBF), and tricipital skinfold (TS). The prevalence of SO was 16.5% in women and 29% in men, according to any of the diagnostic criteria used to determine obesity. A higher proportion of SO was observed as age increased in both groups, although no significant differences were found. Most values obtained in tests related to SO diagnosis were worse in the group affected by the disease; however, there were two exceptions related to the amount of ASMM. In total, 18.8% of the participants presented SO according to any diagnostic criteria related to obesity. Our results suggest significant differences in the number of SO cases depending on diagnostic criteria used to determine the participants' obesity. BMI, WC, and TBF% were shown as principal variables to be included in obesity diagnosis within the SO construct. These findings underscore the need to unify criteria to standardize the diagnosis of SO in the global population.

Probing optical anapoles with fast electron beams.

Optical anapoles are intriguing charge-current distributions characterized by a strong suppression of electromagnetic radiation. They originate from the destructive interference of the radiation produced by electric and toroidal multipoles. Although anapoles in dielectric structures have been probed and mapped with a combination of near- and far-field optical techniques, their excitation using fast electron beams has not been explored so far. Here, we theoretically and experimentally analyze the excitation of optical anapoles in tungsten disulfide (WS2) nanodisks using Electron Energy Loss Spectroscopy (EELS) in Scanning Transmission Electron Microscopy (STEM). We observe prominent dips in the electron energy loss spectra and associate them with the excitation of optical anapoles and anapole-exciton hybrids. We are able to map the anapoles excited in the WS2 nanodisks with subnanometer resolution and find that their excitation can be controlled by placing the electron beam at different positions on the nanodisk. Considering current research on the anapole phenomenon, we envision EELS in STEM to become a useful tool for accessing optical anapoles appearing in a variety of dielectric nanoresonators.

Long Term Veno-Pulmonary Arterial Extracorporeal Membrane Oxygenation as Bridge To Lung Transplantation And Its Challenges: A Case Report.

We present a case of a patient with acute respiratory distress syndrome due to severe acute respiratory syndrome coronavirus 2 infection who underwent an extracorporeal membrane oxygenation (ECMO) run of 8 months with various configuration changes, including off-label use of cannulas. The patient eventually underwent successful double lung transplantation after a follow-up of 17 months, demonstrating the successful application of a hybrid approach and careful monitoring in the face of supply shortages during the pandemic. This case highlights the challenges faced by ECMO and transplantation centers during the pandemic and the importance of careful communication and planning to optimize patient outcomes.

Reduced Brain Cortex Angiogenesis in the Offspring of the Preeclampsia-Like Syndrome.

BACKGROUND: Children from pregnancies affected by preeclampsia have an increased risk of cognitive and behavioral alterations via unknown pathophysiology. We tested the hypothesis that preeclampsia generated reduced brain cortex angiogenesis in the offspring. METHODS: The preeclampsia-like syndrome (PELS) mouse model was generated by administering the nitric oxide inhibitor NG-nitroarginine methyl ester hydrochloride. Confirmatory experiments were done using 2 additional PELS models. While in vitro analysis used mice and human brain endothelial cells exposed to serum of postnatal day 5 pups or umbilical plasma from preeclamptic pregnancies, respectively. RESULTS: We report significant reduction in the area occupied by blood vessels in the motor and somatosensory brain cortex of offspring (postnatal day 5) from PELS compared with uncomplicated control offspring. These data were confirmed using 2 additional PELS models. Furthermore, circulating levels of critical proangiogenic factors, VEGF (vascular endothelial growth factor), and PlGF (placental growth factor) were lower in postnatal day 5 PELS. Also we found lower VEGF receptor 2 (KDR [kinase insert domain-containing receptor]) levels in mice and human endothelial cells exposed to the serum of postnatal day 5 PELS or fetal plasma of preeclamptic pregnancies, respectively. These changes were associated with lower in vitro angiogenic capacity, diminished cell migration, larger F-actin filaments, lower number of filopodia, and lower protein levels of F-actin polymerization regulators in brain endothelial cells exposed to serum or fetal plasma of offspring from preeclampsia. CONCLUSIONS: Offspring from preeclampsia exhibited diminished brain cortex angiogenesis, associated with lower circulating VEGF/PlGF/KDR protein levels, impaired brain endothelial migration, and dysfunctional assembly of F-actin filaments. These alterations may predispose to structural and functional alterations in long-term brain development.

Maternal and Fetal Expression of ATP-Binding Cassette and Solute Carrier Transporters Involved in the Brain Disposition of Drugs.

Evidence from preclinical and clinical studies demonstrate that pregnancy is a physiological state capable of modifying drug disposition. Factors including increased hepatic metabolism and renal excretion are responsible for impacting disposition, and the role of membrane transporters expressed in biological barriers, including the placental- and blood-brain barriers, has received considerable attention. In this regard, the brain disposition of drugs in the mother and fetus has been the subject of studies attempting to characterize the mechanisms by which pregnancy could alter the expression of ATP-binding cassette (ABC) and solute carrier (SLC) transporters. This chapter will summarize findings of the influence of pregnancy on the maternal and fetal expression of ABC and SLC transporters in the brain and the consequences of such changes on the disposition of therapeutic drugs.

Language Impairment in Children of Mothers with Gestational Diabetes, Preeclampsia, and Preterm Delivery: Current Hypothesis and Potential Underlying Mechanisms : Language Impartment and Pregnancy Complications.

Many conditions may impair or delay language development, including socioeconomic status, parent's education, or intrauterine environment. Accordingly, increasing evidence has described that pregnancy complications, including gestational diabetes mellitus (GDM), preeclampsia, and preterm delivery, are associated with the offspring's impaired neurodevelopment. Since language is one of the high brain functions, alterations in this function are another sign of neurodevelopment impairment. How these maternal conditions may generate language impairment has yet to be entirely understood. However, since language development requires adequate structural formation and function/connectivity of the brain, these processes must be affected by alterations in maternal conditions. However, the underlying mechanisms of these structural alterations are largely unknown. This manuscript critically analyzes the literature focused on the risk of developing language impairment in children of mothers with GDM, preeclampsia, and preterm delivery. Furthermore, we highlight potential underlying molecular mechanisms associated with these alterations, such as neuroinflammatory and metabolic and cerebrovascular alterations.

COVID-19 on Pregnancy Outcomes, Mental Health and Placenta: Focus in Latin America.

The COVID-19 pandemic has impacted many aspects of health and society worldwide. One vulnerable group that faced SARS-CoV-2 infection is pregnant women, who were considered to have potentiated risk factors. In physiological pregnancy, maternal systems have several changes and adaptations to support fetal development. These changes involve regulations of cardiovascular, respiratory, and immunologic systems, among others, which SARS-CoV-2 could severely alter. Furthermore, the systemic effects of viral infection could be associated with placental dysfunction and adverse pregnancy outcomes, which have been studied from the start of the pandemic to date. Additionally, pregnancy is a condition of more significant mental health vulnerability, especially when faced with highly stressful situations. In this chapter, we have collected information on the effect of COVID-19 on maternal mortality, the SARS-CoV-2 infection rate in pregnancy, and the impact on pregnancy outcomes, maternal mental health, and placental function, with a particular focus on studies that consider the Latin American population.

The Placental Function Beyond Pregnancy: Insights from Latin America.

Currently, more than 100,000 papers had been published studying the placenta in both physiological and pathological contexts. However, relevant health conditions affecting placental function, mostly found in low-income countries, should be evaluated deeper. This review will raise some - of what we think necessary - points of discussion regarding challenging topics not fully understood, including the paternal versus maternal contribution on placental genes imprinting, placenta-brain communication, and some environmental conditions affecting the placenta. The discussions are parts of an international effort to fulfil some gaps observed in this area, and Latin-American research groups currently evaluate that.

Modulation of the activation of endothelial nitric oxide synthase and nitrosative stress biomarkers by aspirin triggered lipoxins: A possible mechanism of action of aspirin in the antiphospholipid syndrome.

PROBLEM: Antiphospholipid syndrome (APS) is characterized by the clinical manifestation of vascular thrombosis (VT) or pregnancy morbidity (PM) and antiphospholipid antibodies (aPL) that can modify the nitric oxide production. Low-dose aspirin is used in the prevention and treatment of diverse alterations of pregnancy. One of the mechanisms of action of aspirin is to induce the production of aspirin-triggered-lipoxins (ATL). The aim of this study was to evaluate the modulatory effect of ATL over the activation of endothelial nitric oxide synthase (eNOS) and nitrosative stress biomarkers induced by aPL. METHODS: We used polyclonal IgG and sera from women with aPL and PM/VT or VT only, and from women with PM only and positive for non-criteria aPL (SN-OAPS). In these sera, biomarkers of nitrosative stress (nitrites and nitrotyrosine) were measured. The protein expression of nitrotyrosine and the phosphorylation of eNOS (at Ser1177) were estimated in human umbilical vein endothelial cells (HUVECs) stimulated with polyclonal IgG with or without ATL. RESULTS: Women with SN-OAPS showed increased circulating levels of nitrites and nitrotyrosine. Likewise, polyclonal IgG from either SN-OAPS or VT patients stimulated nitrotyrosine expression in HUVECs. ATL decreased the nitrotyrosine expression induced by polyclonal IgG from the SN-OAPS group. ATL also recovered the reduced eNOS phosphorylation at Ser1177 in HUVECs stimulated with polyclonal IgG from women with PM/VT or SN-OAPS. CONCLUSIONS: Increased nitrosative stress present in serum of women with SN-OAPS is associated with IgG-mediated impaired endothelial NO synthesis in endothelial cells. ATL prevent these cellular changes.

Stability and Reversible Oxidation of Sub-Nanometric Cu5 Metal Clusters: Integrated Experimental Study and Theoretical Modeling.

Sub-nanometer metal clusters have special physical and chemical properties, significantly different from those of nanoparticles. However, there is a major concern about their thermal stability and susceptibility to oxidation. In situ X-ray Absorption spectroscopy and Near Ambient Pressure X-ray Photoelectron spectroscopy results reveal that supported Cu5 clusters are resistant to irreversible oxidation at least up to 773 K, even in the presence of 0.15 mbar of oxygen. These experimental findings can be formally described by a theoretical model which combines dispersion-corrected DFT and first principles thermochemistry revealing that most of the adsorbed O2 molecules are transformed into superoxo and peroxo species by an interplay of collective charge transfer within the network of Cu atoms and large amplitude "breathing" motions. A chemical phase diagram for Cu oxidation states of the Cu5 -oxygen system is presented, clearly different from the already known bulk and nano-structured chemistry of Cu.

Preeclampsia association of placental nucleotide variations in eNOS, VEGFA, and FLT-1 genes in Latin American pregnant women.

INTRODUCTION: Preeclampsia is a leading cause of maternal and fetal morbidity in low- and middle-income countries, including those in Latin America. Placental vascular alterations are crucial in the pathophysiology of preeclampsia and few studies have evaluated nucleotide variations on genes associated with vascular regulation in the human placenta. This study aimed to evaluate whether placental nucleotide variations on eNOS, VEGFA, and FLT-1 genes are more frequently associated with preeclampsia in the Latin American population. METHODS: This case-control study included placental tissue from 88 controls and 82 cases that were genotyped through Taqman probes for eNOS, VEGFA, and FLT-1 genes. The intergroup comparisons were analyzed with the Mann-Whitney U test. Genotype and allele frequencies were compared by the X2 test. The association between the nucleotide variants with preeclampsia was evaluated through logistic regression analysis. RESULTS: A significant association was observed for VEGFA SNV rs2010963 (OR 1.95; CI 95% 1.13-3.37), after adjusting for population substructure. The allele combination T, G, G, C, C, C (rs2070744, rs1799983, rs2010963, rs3025039, rs699947 and rs4769613 respectively), showed a negative association with preeclampsia (OR 0.08; CI 95% 0.01-0.93). DISCUSSION: Placental SNV rs2010963 in the VEGFA gene was a risk factor for preeclampsia, while the allele combination T, G, G, C, C, C may represent potential protective factors for preeclampsia within Latin American women.

Adenosine promoted angiogenesis mediated by the release of small extracellular vesicles from human endothelial progenitor cells.

Endothelial progenitor cells (EPCs) are stem cells mainly derived from bone marrow; from where they migrate to repair and regenerate damaged tissues. eEPCs have been classified into two sub-populations, early (eEPC) and late EPCs (lEPC), depending on maturation stages in vitro. In addition, eEPC release endocrine mediators, including small extracellular vesicles (sEVs), which in turn may enhance the eEPC-mediated wound healing properties. Nevertheless, adenosine contributes to angiogenesis by recruiting eEPC at the injury site. However, whether ARs may enhance the secretome of eEPC, including sEVs, is unknown. Therefore, we aimed to investigate whether AR activation increase the release of sEVs in eEPC, which in turn has paracrine effects on recipient endothelial cells. Results shown that 5'-N-ethylcarboxamidoadenosine (NECA), a non-selective agonist, increase both the protein levels of the vascular endothelial growth factor (VEGF), and the number of sEVs released to the conditioned medium (CM) in primary culture of eEPC. Importantly, CM and EVs harvested from NECA-stimulated eEPC promote in vitro angiogenesis, without changes in cell proliferation, in recipient ECV-304 endothelial cells. This constitutes the first evidence showing that adenosine enhances sEVs release from eEPC, which has pro-angiogenic capacity on recipient endothelial cells.