High-Sensitivity Cardiac Troponin I Enhances Preeclampsia Prediction Beyond Maternal Factors and the sFlt-1/PlGF Ratio.

BACKGROUND: Preeclampsia shares numerous risk factors with cardiovascular diseases. Here, we aimed to assess the potential utility of high-sensitivity cardiac troponin I (hs-cTnI) values during pregnancy in predicting preeclampsia occurrence. METHODS: This study measured hs-cTnI levels in 3721 blood samples of 2245 pregnant women from 4 international, prospective cohorts. Three analytical approaches were used: (1) a cross-sectional analysis of all women using a single blood sample, (2) a longitudinal analysis of hs-cTnI trajectories in women with multiple samples, and (3) analyses of prediction models incorporating hs-cTnI, maternal factors, and the sFlt-1 (soluble fms-like tyrosine kinase 1)/PlGF (placental growth factor) ratio. RESULTS: Women with hs-cTnI levels in the upper quarter had higher odds ratios for preeclampsia occurrence compared with women with levels in the lower quarter. Associations were driven by preterm preeclampsia (odds ratio, 5.78 [95% CI, 2.73-12.26]) and remained significant when using hs-cTnI as a continuous variable adjusted for confounders. Between-trimester hs-cTnI trajectories were independent of subsequent preeclampsia occurrence. A prediction model incorporating a practical hs-cTnI level of detection cutoff (≥1.9 pg/mL) alongside maternal factors provided comparable performance with the sFlt-1/PlGF ratio. A comprehensive model including sFlt-1/PlGF, maternal factors, and hs-cTnI provided added value (cross-validated area under the receiver operator characteristic, 0.78 [95% CI, 0.73-0.82]) above the sFlt-1/PlGF ratio alone (cross-validated area under the receiver operator characteristic, 0.70 [95% CI, 0.65-0.76]; P=0.027). As assessed by likelihood ratio tests, the addition of hs-cTnI to each prediction model significantly improved the respective prediction model not incorporating hs-cTnI, particularly for preterm preeclampsia. Net reclassification improvement analyses indicated that incorporating hs-cTnI improved risk prediction predominantly by correctly reclassifying women with subsequent preeclampsia occurrence. CONCLUSIONS: These exploratory findings uncover a potential role for hs-cTnI as a complementary biomarker in the prediction of preeclampsia. After validation in prospective studies, hs-cTnI, alongside maternal factors, may either be considered as a substitute for angiogenic biomarkers in health care systems where they are sparce or unavailable, or as an enhancement to established prediction models using angiogenic markers.

Outcomes of Patients with Gastrointestinal Stromal Tumors in the Past Decade.

BACKGROUND: Gastrointestinal stromal tumors (GISTs) are rare mesenchymal neoplasms of the gastrointestinal tract (GIT) that represent approximately 1 to 2 percent of primary gastrointestinal (GI) cancers. Owing to their rarity, very little is known about their overall epidemiology, and the prognostic factors of their pathology. The current study aimed to evaluate the independent determinants of mortality in patients diagnosed with GISTs over the past decade. METHODS: Our study comprised 2374 patients diagnosed with GISTs from 2000 to 2017 from the Surveillance, Epidemiology, and End Results (SEER) database. We analyzed the baseline characteristics, and overall mortality (OM), as well as the cancer-specific mortality (CSM) of GISTs. Variables with a p value < 0.01 in the univariate Cox regression were incorporated into the multivariate Cox model, to determine the independent prognostic factors. RESULTS: Multivariate Cox proportional hazard regression analyses of factors affecting the all-cause mortality and GIST-related mortality among US patients between 2010 and 2017 revealed a higher overall mortality in non-Hispanic Black patients (HR = 1.516, 95% CI 1.172-1.961, p = 0.002), patients aged 80+ (HR = 9.783, 95% CI 4.185-22.868, p = 0), followed by those aged 60-79 (HR = 3.408, 95% CI 1.488-7.807, p = 0.004); male patients (HR = 1.795, 95% CI 1.461-2.206, p < 0.001); patients with advanced disease with distant metastasis (HR = 3.865, 95% CI 2.977-5.019, p < 0.001), followed by cases with regional involvement via both direct extension and lymph node involvement (HR = 3.853, 95% CI 1.551-9.57, p = 0.004); and widowed patients (HR = 1.975, 95% CI 1.494-2.61, p < 0.001), followed by single patients (HR = 1.53, 95% CI 1.154-2.028, p = 0.003). The highest CSM was observed in the same groups, except widowed patients and patients aged 60-79. The highest CSM was also observed among patients that underwent chemotherapy (HR = 1.687, 95% CI 1.19-2.392, p = 0.003). CONCLUSION: In this updated study on the outcomes of patients with GISTs, we found that non-Hispanic Black patients, male patients, and patients older than 60 years have a higher mortality with GISTs. Furthermore, patients who have received chemotherapy have a higher GIST-specific mortality, and married patients have a lower mortality. However, we do not know to what extent these independent prognostic factors interact with each other to influence mortality. This study paves the way for future studies addressing these interactions. The results of this study may help treating clinicians to identify patient populations associated with a dismal prognosis, as those may require closer follow-up and more intensive therapy; furthermore, with married patients having a better survival rate, we hope to encourage clinicians to involve family members of the affected patients early in the disease course, as the social support might impact the prognosis.

Proportion of thyroid cancer and other cancers in the democratic republic of Congo.

BACKGROUND: Cancer diagnosis is increasing around the world and in the Democratic Republic of the Congo (DRC). The proportion of thyroid cancer has increased over the past three decades. There are very few studies on cancer epidemiology, and in particular on thyroid cancer in the DRC. AIM: To establish the most recent proportion of thyroid cancer in the DRC compared to other cancers. METHODS: This is a retrospective and descriptive study of 6106 consecutive cancer cases listed in the pathological registers of 4 Laboratories in the city of Kinshasa. This study included all cancer cases recorded in the registers between 2005 and 2019. RESULTS: From a sample of 6106 patients, including all cancer types, 68.3% cases were female and 31.7% were male. Breast and cervical cancer were the most common types of cancer in women and, prostate and skin cancer were the most common types in men. Thyroid cancer was sixth in proportion in women and eleventh in men compared to all cancers. Papillary carcinoma was the most common of thyroid cancers. Rare cancers such as anaplastic and medullary thyroid carcinomas had a proportion of 7% and 2%, respectively. CONCLUSION: Newer diagnostic tools led to a surge in cancer diagnoses in the DRC. Thyroid cancer has more than doubled its proportion over the last several decades in the country.

New Perspectives on Long COVID Syndrome: The Development of Unusually Delayed and Recurring Pericarditis After a Primary SARS-CoV-2 Infection.

Since the start of the COVID-19 pandemic in early 2020, pericarditis has been identified as a COVID-19 complication. We report a case where the development of pericarditis was unusually delayed after the initial COVID infection. The reported onset of pericarditis and pericardial effusion is anywhere from a few days to a few months after infection. Our case surmises that a latent complication of COVID-19 can manifest more than one year after the initial infection. A forty-three-year-old male with a past medical history of SARS-CoV-2 infection in September 2020 presented in September 2021 and January 2022 with recurrent sharp chest pain and shortness of breath. During both admissions, he was diagnosed with acute pericarditis, and his workup was significant for elevations in D-dimer and CRP as well as pericardial and pleural effusions. Recurring pericardial symptoms and persistent elevations in D-dimer and CRP point toward a COVID etiology, particularly in the absence of other factors associated with pericarditis. Our case highlights the importance of recognizing this latent complication one year after the initial infection and how the symptoms can persist beyond the one-year period.

Tuning the Catalytic Activity of a Metal-Organic Framework Derived Copper and Nitrogen Co-Doped Carbon Composite for Oxygen Reduction Reaction.

An efficient non-noble metal catalyst for the oxygen reduction reaction (ORR) is of great importance for the fabrication of cost-effective fuel cells. Nitrogen-doped carbons with various transition metal co-dopants have emerged as attractive candidates to replace the expensive platinum catalysts. Here we report the preparation of various copper- and nitrogen-doped carbon materials as highly efficient ORR catalysts by pyrolyzing porphyrin based metal organic frameworks and investigate the effects of air impurities during the thermal carbonization process. Our results indicate that the introduction of air impurities can significantly improve ORR activity in nitrogen-doped carbon and the addition of copper co-dopant further enhances the ORR activity to exceed that of platinum. Systematic structural characterization and electrochemical studies demonstrate that the air-impurity-treated samples show considerably higher surface area and electron transfer numbers, suggesting that the partial etching of the carbon by air leads to increased porosity and accessibility to highly active ORR sites. Our study represents the first example of using air or oxygen impurities to tailor the ORR activity of metal and nitrogen co-doped carbon materials and open up a new avenue to engineer the catalytic activity of these materials.

Integrated Care and the Evolution of the Multidisciplinary Team.

The primary care medical home continues to adapt by applying new research to population health approaches to care. With the discovery that life experiences trigger a chain of biologic events linked to chronic illnesses, the role of patient-centered multidisciplinary care teams becomes of paramount importance. Subsequently, mental health professionals are being incorporated into the primary care setting, using their skills in nontraditional models to customize care for each patient. This "integration" of primary care and unique mental health services engenders opportunity for enhanced clinical care, professional workforce development and support, more effective population health initiatives, and informed health care policy.

Beginning the Work of Integration: An Investigation of Primary Care Physicians' Attitudes Toward Psychiatry.

OBJECTIVE: The authors sought to better understand the attitudes of primary care physicians toward psychiatrists in order to assess their receptivity for further psychiatric education. METHODS: A survey about attitudes toward psychiatrists in comparison to other specialties was distributed among four family medicine residency programs at Southern Illinois University. RESULTS: Respondents rated psychiatry lower than other specialties in the areas measured. However, family medicine physicians expressed a desire to work with psychiatrists and receive further education in psychiatry. CONCLUSION: Favorable attitudes toward psychiatrists and education in psychiatry suggest the potential for additional family medicine training in psychiatry.

Kaposi's Sarcoma-Associated Herpesvirus Viral Interferon Regulatory Factor 4 (vIRF4) Perturbs the G1-S Cell Cycle Progression via Deregulation of the cyclin D1 Gene.

Kaposi's sarcoma-associated herpesvirus (KSHV) infection modulates the host cell cycle to create an environment optimal for its viral-DNA replication during the lytic life cycle. We report here that KSHV vIRF4 targets the ß-catenin/CBP cofactor and blocks its occupancy on the cyclin D1 promoter, suppressing the G1-S cell cycle progression and enhancing KSHV replication. This shows that KSHV vIRF4 suppresses host G1-S transition, possibly providing an intracellular milieu favorable for its replication.

Use of ranolazine in the prevention and treatment of postoperative atrial fibrillation in patients undergoing cardiac surgery.

OBJECTIVE: To determine the evidence for use of ranolazine for treatment and prevention of postoperative atrial fibrillation (POAF) in patients undergoing cardiac surgery. DATA SOURCES: A literature search of MEDLINE (1946 to January 2014) was conducted, using the search terms ranolazine, atrial fibrillation, and cardiac surgery. A search of reference citations was conducted to identify additional references. STUDY SELECTION AND DATA EXTRACTION: Clinical trials investigating the use of ranolazine for POAF were included in the review. DATA SYNTHESIS: Three clinical trials were reviewed; 2 trials, 1 retrospective and 1 prospective, compared ranolazine with amiodarone or usual care for prevention of POAF and demonstrated a significant decrease in the incidence of POAF without increasing the incidence of postoperative complications. A third prospective trial used ranolazine in combination with amiodarone for the treatment of POAF and demonstrated a significant reduction in the time required to convert patients from atrial fibrillation to normal sinus rhythm compared with amiodarone alone. CONCLUSIONS: In these current small trials, ranolazine appears to be a safe and efficacious therapeutic alternative for the treatment and prevention of POAF in patients undergoing cardiac surgery. However, larger randomized controlled trials are needed before ranolazine should be considered for the treatment or prevention of POAF. It is an attractive option compared with current treatments for this indication-primarily ß-blockers and amiodarone-because ranolazine has minimal effects on heart rate and blood pressure.

Kaposi's sarcoma-associated herpesvirus viral interferon regulatory factor 4 (vIRF4) targets expression of cellular IRF4 and the Myc gene to facilitate lytic replication.

Besides an essential transcriptional factor for B cell development and function, cellular interferon regulatory factor 4 (c-IRF4) directly regulates expression of the c-Myc gene, which is not only associated with various B cell lymphomas but also required for herpesvirus latency and pathogenesis. Kaposi's sarcoma-associated herpesvirus (KSHV), the etiological agent of Kaposi's sarcoma and primary effusion lymphoma, has developed a unique mechanism to deregulate host antiviral innate immunity and growth control by incorporating four viral homologs (vIRF1 to -4) of cellular IRFs into its genome. Previous studies have shown that several KSHV latent proteins, including vIRF3, vFLIP, and LANA, target the expression, function, and stability of c-Myc to establish and maintain viral latency. Here we report that the KSHV vIRF4 lytic protein robustly suppresses expression of c-IRF4 and c-Myc, reshaping host gene expression profiles to facilitate viral lytic replication. Genomewide gene expression analysis revealed that KSHV vIRF4 grossly affects host gene expression by upregulating and downregulating 118 genes and 166 genes, respectively, by at least 2-fold. Remarkably, vIRF4 suppressed c-Myc expression by 11-fold, which was directed primarily by the deregulation of c-IRF4 expression. Real-time quantitative PCR (RT-qPCR), single-molecule in situ hybridization, and chromatin immunoprecipitation assays showed that vIRF4 not only reduces c-IRF4 expression but also competes with c-IRF4 for binding to the specific promoter region of the c-Myc gene, resulting in drastic suppression of c-Myc expression. Consequently, the loss of vIRF4 function in the suppression of c-IRF4 and c-Myc expression ultimately led to a reduction of KSHV lytic replication capacity. These results indicate that the KSHV vIRF4 lytic protein comprehensively targets the expression and function of c-IRF4 to downregulate c-Myc expression, generating a favorable environment for viral lytic replication. Finally, this study further reinforces the important role of the c-Myc gene in KSHV lytic replication and latency.

MR imaging quantitative analysis of fetal Chiari II malformations and associated open neural tube defects: balanced SSFP versus half-Fourier RARE and interobserver reliability.

PURPOSE: To evaluate bSSFP (balanced steady state free precession) and half-Fourier RARE (rapid acceleration with relaxation enhancement) MRI sequences in their ability to demonstrate fetal anatomic landmarks, quantify the degree of cerebellar herniation in Chiari II malformations and level and length of the associated open neural tube defects, as well as evaluate interobserver reliability of these measurements. MATERIALS AND METHODS: Two independent observers retrospectively reviewed MRIs of 37 fetuses with Chiari II malformations and associated open neural tube defects (mean gestational age: 27 weeks 2 days). Comparison of bSSFP and RARE included: (i) Ability to confidently identify anatomic landmarks of the posterior fossa and spine; (ii) Measurements of the foramen magnum, cerebellar tonsillar herniation length, intervertebral disc space level of tonsillar herniation, open neural tube defect length, and disc space start and end level of the open neural tube defect; (iii) Observed conspicuity of anatomic landmarks. RESULTS: There was no significant difference in assessment of cerebellar tonsillar herniation or open neural tube defect level between bSSFP and RARE for either observer. Intervertebral discs were more conspicuous on bSSFP while cerebellar tonsils were more conspicuous on RARE (P < 0.05). Interobserver reliability was strong for both sequences in assessing the foramen magnum (r = 0.95, 0.94), tonsillar herniation length (r = 0.93, 0.95), and open neural tube defect length (r = 0.97, 0.96). CONCLUSION: Despite improved conspicuity of the intervertebral discs with bSSFP and cerebellar tonsils with RARE, there is no significant difference in measurement of hindbrain herniation or open neural tube defect level; interobserver reliability is excellent for both sequences.

Bilateral inhibition of HAUSP deubiquitinase by a viral interferon regulatory factor protein.

Herpesvirus-associated ubiquitin-specific protease (HAUSP) regulates the stability of p53 and the p53-binding protein MDM2, implicating HAUSP as a therapeutic target for tuning p53-mediated antitumor activity. Here we report the structural analysis of HAUSP with Kaposi's sarcoma-associated herpesvirus viral interferon (IFN) regulatory factor 4 (vIRF4) and the discovery of two vIRF4-derived peptides, vif1 and vif2, as potent and selective HAUSP antagonists. This analysis reveals a bilateral belt-type interaction that results in inhibition of HAUSP. The vif1 peptide binds the HAUSP TRAF domain, competitively blocking substrate binding, whereas the vif2 peptide binds both the HAUSP TRAF and catalytic domains, robustly suppressing its deubiquitination activity. Peptide treatments comprehensively blocked HAUSP, leading to p53-dependent cell-cycle arrest and apoptosis in culture and to tumor regression in xenograft mouse model. Thus, the virus has developed a unique strategy to target the HAUSP-MDM2-p53 pathway, and these virus-derived short peptides represent biologically active HAUSP antagonists.

Immune evasion by Kaposi's sarcoma-associated herpesvirus.

Persistent viral infections are often associated with serious diseases, primarily by altering functions of the host immune system. The hallmark of Kaposi's sarcoma-associated herpesvirus (KSHV) infection is the establishment of a life-long persistent infection, which leads to several clinical, epidemiological and infectious diseases, such as Kaposi's sarcoma, a plasmablastic variant of multicentric Castleman's disease, and primary effusion lymphoma. To sustain an efficient life-long persistency, KSHV dedicates a large portion of its genome to encoding immunomodulatory proteins that antagonize the immune system of its host. In this article, we highlight the strategies KSHV uses to evade, escape and survive its battle against the host's immune system.

When autophagy meets viruses: a double-edged sword with functions in defense and offense.

Autophagy is a ubiquitous catabolic process that ensures organism's well-being by sequestering a wide array of undesired intracellular constituents into double-membrane vesicles termed autophagosomes for lysosomal degradation. Interest in autophagy research has recently gained momentum as it is increasingly being recognized to play fundamental roles in diverse aspects of human pathophysiology including virus infection and its subsequent complications. This review discusses recent advances in autophagy studies with respect to virus infection and pathogenesis. A growing body of evidence suggests that the autophagy pathway and/or autophagy genes play pleiotropic functions in the host's intrinsic, innate, and adaptive immune response against viruses. However, some viruses have evolved to encode virulence factors that evade or counteract the execution of autophagy. Furthermore, certain viruses are equipped to enhance autophagy or exploit the autophagy machinery for their replication and pathogenesis. A comprehensive understanding of the roles of autophagy pathway and autophagy genes during viral infection may enable the discovery of novel antiviral drug targets.

Epigenetic analysis of KSHV latent and lytic genomes.

Epigenetic modifications of the herpesviral genome play a key role in the transcriptional control of latent and lytic genes during a productive viral lifecycle. In this study, we describe for the first time a comprehensive genome-wide ChIP-on-Chip analysis of the chromatin associated with the Kaposi's sarcoma-associated herpesvirus (KSHV) genome during latency and lytic reactivation. Depending on the gene expression class, different combinations of activating [acetylated H3 (AcH3) and H3K4me3] and repressive [H3K9me3 and H3K27me3] histone modifications are associated with the viral latent genome, which changes upon reactivation in a manner that is correlated with their expression. Specifically, both the activating marks co-localize on the KSHV latent genome, as do the repressive marks. However, the activating and repressive histone modifications are mutually exclusive of each other on the bulk of the latent KSHV genome. The genomic region encoding the IE genes ORF50 and ORF48 possesses the features of a bivalent chromatin structure characterized by the concomitant presence of the activating H3K4me3 and the repressive H3K27me3 marks during latency, which rapidly changes upon reactivation with increasing AcH3 and H3K4me3 marks and decreasing H3K27me3. Furthermore, EZH2, the H3K27me3 histone methyltransferase of the Polycomb group proteins (PcG), colocalizes with the H3K27me3 mark on the entire KSHV genome during latency, whereas RTA-mediated reactivation induces EZH2 dissociation from the genomic regions encoding IE and E genes concurrent with decreasing H3K27me3 level and increasing IE/E lytic gene expression. Moreover, either the inhibition of EZH2 expression by a small molecule inhibitor DZNep and RNAi knockdown, or the expression of H3K27me3-specific histone demethylases apparently induced the KSHV lytic gene expression cascade. These data indicate that histone modifications associated with the KSHV latent genome are involved in the regulation of latency and ultimately in the control of the temporal and sequential expression of the lytic gene cascade. In addition, the PcG proteins play a critical role in the control of KSHV latency by maintaining a reversible heterochromatin on the KSHV lytic genes. Thus, the regulation of the spatial and temporal association of the PcG proteins with the KSHV genome may be crucial for propagating the KSHV lifecycle.

An objective structured clinical examination to evaluate health historian competencies.

BACKGROUND: Post-donation information events in the blood-collection process account for the majority of errors reported to the FDA. An eight-station objective structured clinical examination (OSCE) based on information reported after donation was developed as a competency examination for health historians. STUDY DESIGN AND METHODS: The OSCE measured two individual skill components: history-taking technique (HXE) and ability to record and interpret a medical history (HXI). Donor historians at the Hoxworth Blood Center, University of Cincinnati Medical Center, were examined (n = 56). RESULTS: In general, staff performance was acceptable, but several areas for improvement were identified. Of particular concern were the deferrals associated with the malaria scenarios. The overall reliability score was greater than 0.8 for the total OSCE and HXI. Using the cut score of 0.9, or 90 percent, 10 subjects would not have passed the exam based on the HXE score and one person would not have demonstrated competency based on the HXI score. CONCLUSION: An OSCE is a reliable, valid, and practical method for assessing continued competency in health historians. This form of competency assessment and subsequent retraining may reduce the incidence of errors in information reported after donation and should be further studied as a suitable national standard for assessing competency.