Biological and pathological mechanisms leading to the birth of a small vulnerable newborn.

The pathway to a thriving newborn begins before conception and continues in utero with a healthy placenta and the right balance of nutrients and growth factors that are timed and sequenced alongside hormonal suppression of labour until a mature infant is ready for birth. Optimal nutrition that includes adequate quantities of quality protein, energy, essential fats, and an extensive range of vitamins and minerals not only supports fetal growth but could also prevent preterm birth by supporting the immune system and alleviating oxidative stress. Infection, illness, undernourishment, and harmful environmental exposures can alter this trajectory leading to an infant who is too small due to either poor growth during pregnancy or preterm birth. Systemic inflammation suppresses fetal growth by interfering with growth hormone and its regulation of insulin-like growth factors. Evidence supports the prevention and treatment of several maternal infections during pregnancy to improve newborn health. However, microbes, such as Ureaplasma species, which are able to ascend the cervix and cause membrane rupture and chorioamnionitis, require new strategies for detection and treatment. The surge in fetal cortisol late in pregnancy is essential to parturition at the right time, but acute or chronically high maternal cortisol levels caused by psychological or physical stress could also trigger labour onset prematurely. In every pathway to the small vulnerable newborn, there is a possibility to modify the course of pregnancy by supporting improved nutrition, protection against infection, holistic maternal wellness, and healthy environments.

Neuropilin-1 is uniquely expressed on small syncytiotrophoblast extracellular vesicles but not on medium/large vesicles from preeclampsia and normal placentae.

Preeclampsia (PE) is a multisystem progressive hypertensive disorder unique to human pregnancy. The placenta is fundamental to its pathogenesis and releases placental factors as well as extracellular vesicles (small and medium/large syncytiotrophoblast extracellular vesicles (STB-EVs)) as a response to syncytiotrophoblast stress such as tissue factor and plasminogen activator inhibitors 1. Neuropilin 1 (NRP-1) is an anti-angiogenic factor involved in development, angiogenesis, arteriogenesis, and vascular permeability. NRP-1 acts as a co-receptor for growth factors such as vascular endothelial growth factor (VEGF), placenta growth factor (PLGF), and epidermal growth factor (EGF). Given the documented pro and anti-angiogenic roles of STB-EVs, we hypothesized that 1) STB-EVs might express NRP-1; and 2) the expression of NRP-1 might differ between normal and preeclampsia STB-EVs. METHODS: We isolated STB-EVs (both small and medium/large) from PE and NP placentae using the physiologic ex vivo dual lobe perfusion model. The enriched STB-EVs were characterized by Western blot, transmission electron microscopy (TEM), and nanoparticle tracking analysis (NTA) according to the international society of extracellular vesicles (ISEV) guidelines. We assessed for NRP-1 expression with Western blot (placenta and STB-EVs) and immunohistochemistry (placenta). We performed co-expression analysis for placenta alkaline phosphatase (PLAP - a known STB-EV marker) and NRP-1 with immunoprecipitation followed by Western blot. RESULTS: We confirmed NRP-1 expression in NP and PE placenta. We showed that NRP-1 Expression was limited to small syncytiotrophoblast membrane extracellular vesicles (S STB-EVs) but not medium/large STB-EVs and that NRP-1 is co-expressed with PLAP. CONCLUSION: Neuropilin-1 is uniquely expressed on small syncytiotrophoblast extracellular vesicles but not on medium/large vesicles from preeclampsia and normal placentae.

Preeclampsia and syncytiotrophoblast membrane extracellular vesicles (STB-EVs).

Preeclampsia (PE) is a hypertensive complication of pregnancy that affects 2-8% of women worldwide and is one of the leading causes of maternal deaths and premature birth. PE can occur early in pregnancy (<34 weeks gestation) or late in pregnancy (>34 weeks gestation). Whilst the placenta is clearly implicated in early onset PE (EOPE), late onset PE (LOPE) is less clear with some believing the disease is entirely maternal whilst others believe that there is an interplay between maternal systems and the placenta. In both types of PE, the syncytiotrophoblast (STB), the layer of the placenta in direct contact with maternal blood, is stressed. In EOPE, the STB is oxidatively stressed in early pregnancy (leading to PE later in gestation- the two-stage model) whilst in LOPE the STB is stressed because of villous overcrowding and senescence later in pregnancy. It is this stress that perturbs maternal systems leading to the clinical manifestations of PE. Whilst some of the molecular species driving this stress have been identified, none completely explain the multisystem nature of PE. Syncytiotrophoblast membrane vesicles (STB-EVs) are a potential contributor to this multisystem disorder. STB-EVs are released into the maternal circulation in increasing amounts with advancing gestational age, and this release is further exacerbated with stress. There are good in vitro evidence that STB-EVs are taken up by macrophages and liver cells with additional evidence supporting endothelial cell uptake. STB-EV targeting remains in the early stages of discovery. In this review, we highlight the role of STB-EVs in PE. In relation to current research, we discuss different protocols for ex vivo isolation of STB-EVs, as well as specific issues involving tissue preparation, isolation (some of which may be unique to STB-EVs), and methods for their analysis. We suggest potential solutions for these challenges.

Glycosylated Siglec-6 expression in syncytiotrophoblast-derived extracellular vesicles from preeclampsia placentas.

INTRODUCTION: Preeclampsia (PE) is associated with an exaggerated maternal systemic inflammatory response. Throughout gestation, the placenta releases extracellular vesicles through the syncytiotrophoblast layer (STB) into the maternal circulation and this is increased in PE. Expression of Siglec-6, a transmembrane receptor of molecular weight 50 KDa, is upregulated in PE placental tissue. METHODS: Here we investigated respective abundance of Siglec-6 in PE -and normal pregnancy- (NP) derived placental lysates (PL) and syncytiotrophoblast-derived extracellular vesicles (STBEV). STBEV from PE and NP placentas were isolated through dual-lobe placental perfusion and serial ultracentrifugation. Siglec-6 was characterized by immunohistochemistry, immunoblotting, mass spectrometry (MS), and deglycosylation. RESULTS: Immunoblotting revealed the expected Siglec-6 (50 KDa) band present in both PE and NP PL, however an additional heavier band was observed at 70 KDa only in PE PL, but not in NP. When interrogating STBEV we saw an absence of the expected 50 KDa band but the 70 KDa was present predominantly only in the PE STBEV. Deglycosylation of PL and STBEV from PE showed that the 70 KDa and the 50 KDa bands were reduced to 48 KDa, suggesting glycosylation. Both 48 KDa and 70 KDa bands were subjected to MS, confirming Siglec-6 expression in both. DISCUSSION: Our data shows that the inability to detect Siglec-6 in circulation might be due to the placenta secreting STBEV carrying a modified glycosylated form of Siglec-6 with a 70 KDa molecular weight, significantly and uniquely upregulated in PE STBEV.

Telemedicine in Cardiology: Enhancing Access to Care and Improving Patient Outcomes.

Telemedicine has gained significant recognition, particularly since the COVID-19 pandemic. However, its roots date back to its significant role during major epidemic outbreaks such as severe acute respiratory syndrome (SARS), H1N1 and H7N9 influenza, and Middle East respiratory syndrome (MERS), where alternate means of accessing healthcare were adopted to combat the outbreak while limiting the spread of the virus. In Sub-Saharan Africa, telemedicine has supported healthcare delivery, patient and professional health education, disease prevention, and surveillance, starting with its first adoption in Ethiopia in 1980. In the United States, telemedicine has significantly impacted cardiology, particularly at-home monitoring programs, which have proven highly effective for patients with abnormal heart rhythms. Devices such as Holter monitors, blood pressure monitors, and implantable cardioverter-defibrillators have reduced mortality rates and hospital readmissions while improving healthcare efficiency by saving healthcare costs. However, the COVID-19 pandemic accelerated the adoption of telemedicine, as evidenced by a dramatic increase in telemedicine visits at institutions like New York University (NYU) Langone Health during and post-COVID-19 pandemic. In addition, telemedicine has also facilitated cardiac rehabilitation and improved access to specialized cardiology care in rural and underserved areas, reducing disparities in cardiovascular health outcomes. As technology advances, telemedicine is poised to play an increasingly significant role in cardiology and healthcare at large, enhancing patient management, healthcare efficiency, and cost reduction. This review underscores the significance of telemedicine in cardiology, its challenges, and future directions.

Olanzapine-induced cardiomyopathy: A mimicker of obesity cardiomyopathy?

Olanzapine, an atypical antipsychotic medication, has gained prominence in the treatment of schizophrenia and related psychotic disorders due to its effectiveness and perceived safety profile. However, emerging evidence suggests a potential link between olanzapine use and adverse cardiovascular effects, including cardiomyopathy. This narrative review explores the mechanisms, clinical implications, and management strategies associated with olanzapine-induced cardiomyopathy. A comprehensive review of the literature was conducted to investigate the relationship between olanzapine and cardiomyopathy. The search included epidemiological studies, clinical case reports, and mechanistic research focusing on the pathophysiology of olanzapine-induced cardiomyopathy. The review also examined treatment strategies for managing this potential complication. Olanzapine-induced cardiomyopathy is hypothesized to be associated with metabolic disturbances and receptor antagonism. The metabolic effects of olanzapine, such as weight gain, insulin resistance, and dyslipidemia, share similarities with obesity-related cardiomyopathy. Additionally, olanzapine's antagonism of certain receptors may contribute to cardiovascular stress. The review highlighted that patients with new-onset heart failure and significant weight gain while on olanzapine should be closely monitored for signs of cardiomyopathy. Early detection and prompt withdrawal of olanzapine, along with initiation of goal-directed medical therapy, are crucial for mitigating this potentially life-threatening condition. The relationship between olanzapine and cardiomyopathy is complex and not yet fully understood. However, the potential for significant cardiovascular risk necessitates vigilance among healthcare providers. Early identification and management of olanzapine-induced cardiomyopathy can improve patient outcomes. Further research is needed to elucidate the precise mechanisms behind this adverse effect and to develop optimized treatment strategies for patients requiring antipsychotic therapy.

MicroRNA analysis of medium/large placenta extracellular vesicles in normal and preeclampsia pregnancies.

Background: Preeclampsia (PE) is a hypertensive disorder of pregnancy, affecting 2%-8% of pregnancies worldwide, and is the leading cause of adverse maternal and fetal outcomes. The disease is characterized by oxidative and cellular stress and widespread endothelial dysfunction. While the precise mechanisms are not entirely understood, the pathogenesis of PE is closely linked to placental dysfunction and, to some extent, syncytiotrophoblast extracellular vesicle release (STB-EVs). These vesicles can be divided into the less well-studied medium/large EVs (220-1,000 nm) released in response to stress and small EVs (<220 nm) released as a component of intercellular communication. The previously described production of m/lSTB-EVs in response to cellular stress combined with the overwhelming occurrence of cellular and oxidative stress in PE prompted us to evaluate the microRNAome of PE m/lSTB-EVs. We hypothesized that the microRNAome profile of m/lSTB-EVs is different in PE compared to normal pregnancy (NP), which might permit the identification of potential circulating biomarkers not previously described in PE. Methods/study design: We performed small RNA sequencing on medium/large STB-EVs isolated from PE and NP placentae using dual-lobe ex vivo perfusion. The sequencing data was bioinformatically analyzed to identify differentially regulated microRNAs. Identified microRNAs were validated with quantitative PCR analysis. We completed our analysis by performing an in-silico prediction of STB-EV mechanistic pathways. Results: We identified significant differences between PE and NP in the STB-EVs micro ribonucleic acid (microRNA) profiles. We verified the differential expression of hsa-miR-193b-5p, hsa-miR-324-5p, hsa-miR-652-3p, hsa-miR-3196, hsa-miR-9-5p, hsa-miR-421, and hsa-miR-210-3p in the medium/large STB-EVs. We also confirmed the differential abundance of hsa-miR-9-5p in maternal serum extracellular vesicles (S EVs). In addition, we integrated the results of these microRNAs into the previously published messenger RNA (mRNA) data to better understand the relationship between these biomolecules. Conclusions: We identified a differentially regulated micro-RNA, hsa-miR-9-5p, that may have biomarker potential and uncovered mechanistic pathways that may be important in the pathophysiology of PE.

Adult-onset Still's disease complicated by macrophage activation syndrome.

Key Clinical Message: Young patients with persistent rash and fevers despite antibiotic treatment should be evaluated for non-infectious etiologies. In our patient's case, these findings led to a diagnosis of MAS, which ultimately affected how she was managed. Abstract: Adult-onset Still's disease (AOSD) is a rare, often difficult to diagnose autoimmune disease that typically presents as a rash, unresolving fevers and joint pains capable of mimicking a number of autoimmune diseases. Here, we present the case of a young postpartum woman whose clinical presentation, which included a pruritic maculopapular rash that evolved to include a flagellate component, and serological studies, chief among them cytopenias and a Ferritin >15,000 nm/mL) allowed us to make an early diagnosis of AOSD complicated by macrophage activation syndrome. We discuss the treatment for AOSD complicated by MAS with Hydrocortisone and Anakinra, the final discharge regimen prescribed for our patient, and report on her state 3 months post-hospitalization, which was favorable. Our case is unique because we ultimately believe that pregnancy itself triggered her ASOD, because of how the quality of the flagellate component of her rash allowed us to narrow the differential diagnosis, and because of how the significant cytopenias and significant liver dysfunction alerted us to the possibility of MAS.

Wheel of misfortune: A unique case of MRSA pyomyositis of the adductor muscle group from blunt unicycle trauma.

In patients with infectious symptoms and severe muscle pain, it is crucial to consider pyomyositis as a significant potential cause. A normal complete blood count should not exclude this possibility early in the course. Early advanced imaging modalities and blood cultures are crucial in narrowing the differential. Methicillin resistant Staphylococcus aureus is increasingly implicated.

A cross-sectional analysis of syncytiotrophoblast membrane extracellular vesicles-derived transcriptomic biomarkers in early-onset preeclampsia.

Background: Preeclampsia (PE) is a pregnancy-specific hypertensive disorder affecting 2%-8% of pregnancies worldwide. Biomarker(s) for the disorder exists, but while these have excellent negative predictive value, their positive predictive value is poor. Extracellular vesicles released by the placenta into the maternal circulation, syncytiotrophoblast membrane extracellular vesicles (STB-EVs), have been identified as being involved in PE with the potential to act as liquid biopsies. Objective: The objective of this study was to identify the difference in the transcriptome of placenta and STB-EVs between preeclampsia and normal pregnancy (NP) and mechanistic pathways. Methods/study design: We performed RNA-sequencing on placental tissue, medium/large and small STB-EVs from PE (n = 6) and NP (n = 6), followed by bioinformatic analysis to identify targets that could be used in the future for EV-based diagnostic tests for preeclampsia. Some of the identified biomarkers were validated with real-time polymerase chain reactions. Results: Our analysis identified a difference in the transcriptomic STB-EV cargo between PE and NP. We then identified and verified the differential expression of FLNB, COL17A1, SLC45A4, LEP, HTRA4, PAPP-A2, EBI3, HSD17B1, FSTL3, INHBA, SIGLEC6, and CGB3. Our analysis also identified interesting mechanistic processes via an in silico prediction of STB-EV-based mechanistic pathways. Conclusions: In this study, using comprehensive profiling of differentially expressed/carried genes of three linked sample subtypes in PE, we identified potential biomarkers and mechanistic gene pathways that may be important in the pathophysiology of PE and could be further explored in future studies.

Twitter Sentiment Analysis of Long COVID Syndrome.

Background Long COVID syndrome originated as a patient phrased terminology which was initially used to describe a group of vague symptoms that persisted after recovering from COVID-19. However, it has moved from a patient lingo to a recognized pathological entity which refers to a group of symptoms that lasts weeks or months after the COVID-19 illness. The novelty of this condition, the inadequacy of research on long COVID syndrome, and its origin as a patient-coined terminology necessitated exploring the disease's sentiments and conversations by analyzing publicly available tweets. Method Tweets were extracted using the Twarc2 tool for tweets in the English language with the keywords (long COVID syndrome, long COVID, post-COVID syndrome, post-acute sequelae of SARS-CoV-2, long-term COVID, long haulers, and chronic COVID syndrome) between March 25, 2022, and April 1, 2022. The analyses included frequency of the keywords, sentiment analysis, and topic modeling to identify and explore discussion topics over time. A natural language approach and the latent Dirichlet allocation algorithm were used to determine the most shared tweet topics, categorize clusters, and identify themes based on keyword analysis. Results The search yielded 62,232 tweets. The tweets were reduced to 10,670 tweets after removing the duplicates. The vast majority of the tweets originated from the United States of America (38%), United Kingdom (30%), and Canada (13%), with the most common hashtags being #longcovid (36%) and #covid (6.36%), and the most frequently used word being people (1.05%). The top three emotions detected by our analysis were trust (11.68%), fear (11.26%), and sadness (9.76%). The sentiment analysis results showed that people have comparable levels of positivity (19.90%) and negativity (18.39%) towards long COVID. Conclusions Our analysis revealed comparable sentiments about long COVID syndrome, albeit slightly positive. Most tweets connoted trust (positive), fear (negative), and sadness (negative). These emotions were linked with concerns about the infection, pandemic, chronic disability, and governmental policies. We believe this study would be important in guiding information dissemination and governmental policy implementation necessary in tackling long COVID syndrome.

COVID-19 in Africa: An Explorative Cross-Sectional Analysis of Twenty-One African Countries From January to June 2020.

INTRODUCTION:  Africa has surprisingly recorded better gains in containing the coronavirus spread than countries with the better health indices, such as the USA and UK. The low rate of coronavirus disease 2019 (COVID-19) cases and death in Africa represents a puzzle with different biological and social theories such as low COVID-19 testing capacity, substantial young population, few old people, favourable climate, genetic admixture, infectious disease antibodies, and sound community health care systems proposed. We aimed to understand the COVID-19 preventive measures in a group of twenty-one systematically selected African countries that may explain the low burden of COVID-19 in Africa. METHODS: Data (COVID-19, health, socioeconomic, and demographics indices) of twenty-one systemically selected African countries were retrieved from the various official country and multilateral organization sources such as Worldbank, and the United nations development Programme (UNDP). The extracted data were analyzed in three large groups: international travel restrictions, physical and social distancing, and movement restrictions (lockdown measures; curfews, partial or/and national lockdowns). Data cleaning, analysis (including Pearson correlation), and visualization were done with Microsoft Excel and Graph Pad Prism version 9 (https://www.graphpad.com/). RESULT: Southern Africa had the greatest number of cases and deaths within the period studied compared to East Africa, which was the least COVID-19 affected sub-region (in terms of COVID-19 cases and deaths). We observed that coronary artery disease death rate was highly correlated with COVID-19 death density (number of COVID-19 deaths/total population) and similarly observed a correlation between the number of cases and deaths and number of in-country arrivals, pandemic preparedness (health security index), COVID-19 containment, and health index (not correlated with deaths). Finally, we noted that the most effective preventive strategy was the 'use of a face mask'. CONCLUSION: Africa had fewer COVID-19 cases and COVID-19 related deaths. Our data shows that the rapidity and stringency of COVID-19 preventive measures and government policies, and the low level of tourism in Africa compared to other countries (i.e., low COVID-19 seeding rate) may have been contributory to these favorable statistics. We hope these findings impact how the preparedness for pandemics can be enhanced to decrease the burden of preventable deaths and morbidity.

Emotional Analysis of Tweets About Clinically Extremely Vulnerable COVID-19 Groups.

Background Clinically extremely vulnerable (CEV) individuals have a significantly higher risk of morbidity and mortality from coronavirus disease 2019 (COVID-19). This high risk is due to predispositions such as chronic obstructive pulmonary disease (COPD), diabetes mellitus, hypertension, smoking, or extreme age (≥75). The initial COVID-19 preventive measures (use of face masks, social distancing, social bubbles) and vaccine allocation prioritized this group of vulnerable individuals to ensure their continued protection. However, as countries start relaxing the lockdown measures to help prevent socio-economic collapse, the impact of this relaxation on CEVs is once again brought to light. In this study, we set out to understand the impact of policy changes on the lives of CEVs by analyzing Twitter data with the hashtag #highriskcovid used by many high-risk individuals to tweet about and express their opinions and feelings. Methodology Tweets were extracted from the Twitter API between March 01, 2022, and April 21, 2022, using the Twarc2 tool. Extracted tweets were in English and included the hashtag #highriskcovid. We evaluated the most frequently used words and hashtags by calculating term frequency-inverse document frequency, and the location of tweets using the tidygeocoder package (method = osm). We also evaluated the sentiments and emotions depicted by these tweets using the National Research Council sentiment lexicon of the Syuzhet package. Finally, we used the latent Dirichlet allocation algorithm to determine relevant high-risk COVID-19 themes. Results The vast majority of the tweets originated from the United States (64%), Canada (22%), and the United Kingdom (4%). The most common hashtags were #highriskcovid (25.5%), #covid (6.82%), #immunocompromised (4.93%), #covidisnotover (4.0%), and #Maskup (1.40%), and the most frequently used words were immunocompromised (1.64%), people (1.4%), disabled (0.97%), maskup (0.85%), and eugenics (0.85%). The tweets were more negative (19.27%) than positive, and the most expressed negative emotions were fear (13.62%) and sadness (12.47%). At the same time, trust was the most expressed positive emotion and was used in relation to belief in masks, policies, and health workers to help. Finally, we detected frequently co-tweeted words such asmass and disaster, deadly and disabling, high and risk, public and health, immunocompromised and people, mass and disaster, and deadly and disabling. Conclusions The study provides evidence regarding the concerns and fears of high-risk COVID-19 groups as expressed via social media. It is imperative that further policies be implemented to specifically protect the health and mental wellness of high-risk individuals (for example, incorporating sentiment analyses of high-risk COVID-19 individuals such as this paper to inform the evaluation of already implemented preventive measures and policies). In addition, considerable work needs to be done to educate the public on high-risk individuals.

Syncytiotrophoblast Extracellular Vesicles From Late-Onset Preeclampsia Placentae Suppress Pro-Inflammatory Immune Response in THP-1 Macrophages.

Syncytiotrophoblast derived Extracellular Vesicles (STBEV) from normal pregnancy (NP) have previously been shown to interact with circulating monocytes and B cells and induce pro-inflammatory cytokine release. Early-onset preeclampsia (EOPE) is associated with an exacerbated inflammatory response, yet there is little data regarding late-onset PE (LOPE) and immune function. Here, using a macrophage/monocyte cell line THP-1, we investigated the inflammatory potential of STBEV, comprising medium/large-STBEV (>200nm) and small-STBEV (<200nm), isolated from LOPE (n=6) and normal (NP) (n=6) placentae via dual-lobe ex-vivo placental perfusion and differential centrifugation. THP-1 cells bound and internalised STBEV isolated from NP and LOPE placentae, as revealed by flow cytometry, confocal microscopy, and ELISA. STBEV-treated THP-1 cells were examined for cytokine gene expression by RT-qPCR and the cell culture media examined for secreted cytokines/chemokines. As expected, NP medium/large-STBEV significantly upregulated the transcriptional expression of TNF-α, IL-10, IL-6, IL-12, IL-8 and TGF-ß compared to PE medium/large-STBEV. However, there was no significant difference in the small STBEV population between the two groups, although in general, NP small STBEVs slightly upregulated the same cytokines. In contrast, LOPE STBEV (medium and large) did not induce pro-inflammatory responses by differentiated THP-1 macrophages. This decreased effect of LOPE STBEV was echoed in cytokine/chemokine release. Our results appear to suggest that STBEV from LOPE placentae do not have a major immune-modulatory effect on macrophages. In contrast, NP STBEV caused THP-1 cells to release pro-inflammatory cytokines. Thus, syncytiotrophoblast extracellular vesicles from LOPE dampen immune functions of THP-1 macrophages, suggesting an alternative mechanism leading to the pro-inflammatory environment observed in LOPE.