MicroRNAs: Small but Key Players in Viral Infections and Immune Responses to Viral Pathogens.

Since the discovery of microRNAs (miRNAs) in C. elegans in 1993, the field of miRNA research has grown steeply. These single-stranded non-coding RNA molecules canonically work at the post-transcriptional phase to regulate protein expression. miRNAs are known to regulate viral infection and the ensuing host immune response. Evolving research suggests miRNAs are assets in the discovery and investigation of therapeutics and diagnostics. In this review, we succinctly summarize the latest findings in (i) mechanisms underpinning miRNA regulation of viral infection, (ii) miRNA regulation of host immune response to viral pathogens, (iii) miRNA-based diagnostics and therapeutics targeting viral pathogens and challenges, and (iv) miRNA patents and the market landscape. Our findings show the differential expression of miRNA may serve as a prognostic biomarker for viral infections in regard to predicting the severity or adverse health effects associated with viral diseases. While there is huge market potential for miRNA technology, the novel approach of using miRNA mimics to enhance antiviral activity or antagonists to inhibit pro-viral miRNAs has been an ongoing research endeavor. Significant hurdles remain in terms of miRNA delivery, stability, efficacy, safety/tolerability, and specificity. Addressing these challenges may pave a path for harnessing the full potential of miRNAs in modern medicine.

Utility of Weekly Laboratory Monitoring in the Expectant Management of Hypertensive Disorders of Pregnancy.

Our retrospective cohort study evaluates the diagnostic yield of weekly laboratory surveillance in outpatient management of hypertensive disorders of pregnancy (HDP) based on patient clinical status at the time of laboratory testing. The study included 459 patients and 1,082 laboratory episodes: 356 (32.9%) episodes were performed in the setting of concerning clinical findings and 726 (67.1%) when the patient was asymptomatic. Overall, the diagnostic yield for abnormal laboratory values (n=11) was 1.0% (95% CI 0.4-1.6%) of all assessments performed and 2.4% (95% CI 1.0-3.8%) among all patients in the cohort. The prevalence of abnormal test results was higher in patients with clinical findings (2.8%, 95% CI 1.1-4.5%) compared with those who were asymptomatic (0.1%, 95% CI 0-0.2%) ( P <.01). Clinical findings suggestive of worsening disease had a 91% sensitivity (95% CI 59-100%) and a 99% (95% CI 99-100%) negative predictive value for abnormal laboratory values. Directed screening based on signs and symptoms, rather than universal weekly screening, may be a potential strategy to lower costs and reduce multiple blood draws for patients with HDP, because there is a low diagnostic yield for this practice.

Maternal Breast Milk Secretor Phenotype Does Not Affect Infant Susceptibility to Rotavirus Diarrhea.

Breast milk secretor status is associated with antibody seroconversion to oral rotavirus vaccination. Here, we were unable to detect a similar impact on risk of infant rotavirus diarrhea or vaccine efficacy through 2 years of life, underscoring limitations of immunogenicity assessment alone in evaluation of oral rotavirus vaccine response.

Masked pregnancy-associated hypertension as a predictor of adverse outcomes.

BACKGROUND: Masked hypertension has been described in nonpregnant populations as elevated blood pressure in the home setting that is not reproduced on clinical assessment. Patients with masked hypertension have a greater risk of cardiovascular morbidity than patients who have blood pressures within normal range or those with white coat hypertension. OBJECTIVE: This study aimed to determine whether masked pregnancy-associated hypertension detected on Connected Maternity Online Monitoring, a remote home blood pressure monitoring system, is associated with higher rates of hypertensive disorders of pregnancy during delivery admission and maternal and neonatal morbidities. STUDY DESIGN: This was a retrospective cohort study of all patients on Connected Maternity Online Monitoring who delivered at 6 hospitals in a single healthcare system between October 2016 and December 2020. Patients were classified as having either normal blood pressure or masked pregnancy-associated hypertension. Masked pregnancy-associated hypertension was defined as remotely detected systolic blood pressure of ≥140 mm Hg or diastolic blood pressure of ≥90 mm Hg after 20 weeks of gestation on 2 occasions before diagnosis in a clinical setting. The chi-square test and Student t test were used for demographic and outcomes comparisons. Logistic regression was used to adjust outcomes by race, insurance, and body mass index. RESULTS: A total of 2430 deliveries were included in our analysis, including 165 deliveries that met the criteria for masked pregnancy-associated hypertension. Clinically established pregnancy-associated hypertension, defined at the time of delivery, was more common in the masked pregnancy-associated hypertension group than in the normotensive group (66% vs 10%; adjusted odds ratio, 17.2; 95% confidence interval, 11.91-24.81). Patients with masked pregnancy-associated hypertension had higher rates of preeclampsia with severe features on delivery admission than normotensive patients (28% vs 2%; adjusted odds ratio, 23.35; 95% confidence interval, 14.25-38.26). Preterm delivery (16% vs 7%; adjusted odds ratio, 2.47; 95% confidence interval, 1.55-3.94), cesarean delivery(38% vs 26%; adjusted odds ratio, 1.58; 95% confidence interval, 1.13-2.23), small for gestational age (11% vs 5%; adjusted odds ratio, 2.27; 95% confidence interval, 1.31-3.94), and neonatal intensive care unit admission (8% vs 4%; adjusted odds ratio, 2.20; 95% confidence interval, 1.18-4.09) were more common among patients with masked pregnancy-associated hypertension than among normotensive patients. CONCLUSION: With more outcomes research, remote blood pressure monitoring may prove to be an important tool in identifying pregnancies at risk of complications related to masked hypertension.

Pregnancy Outcomes in Patients After Completion of the mRNA Coronavirus Disease 2019 (COVID-19) Vaccination Series Compared With Unvaccinated Patients.

OBJECTIVE: To compare frequency of perinatal death between pregnant patients who completed the mRNA coronavirus disease 2019 (COVID-19) vaccination series and unvaccinated patients. METHODS: This retrospective cohort study included 15,865 pregnant patients who delivered 16,132 newborns after 20 weeks of gestation within a large regional health system between January 1, 2021, and December 31, 2021. Patients who received two doses of mRNA vaccine (Pfizer-BioNTech [BNT162b2] or Moderna [mRNA-1273]) were included in the vaccinated group and were compared with unvaccinated patients. Exclusions included partial vaccination, viral-vector vaccine, major congenital anomalies, and higher-order multiple gestation. Our primary outcome was perinatal death, including stillbirth and neonatal death, which was evaluated by logistic regression. Unadjusted odds ratios and adjusted odds ratios (aORs) were reported, controlling for age, body mass index (BMI), diabetes, hypertension, smoking, twin gestation, and insurance status. Propensity score matching was also performed. RESULTS: A total of 15,865 patients were included in the final analysis: 2,069 in the vaccination group and 13,796 in the control group. Only 13.0% of the cohort was included in the vaccination group; however, the vaccination rate increased over the course of the study period as the vaccine became more widely available and accepted. Vaccinated patients were older, with higher rates of people of non-Black racial non-Hispanic ethnic backgrounds, people with private insurance, and those with higher BMIs. Vaccination was associated with a lower incidence of perinatal death (0.5% vaccinated group vs 0.8% unvaccinated group, aOR 0.20 0.05-0.88). Vaccination against COVID-19 was also associated with lower rates of preterm delivery (aOR 0.63, 0.48-0.82), neonates with very low birth weight (aOR 0.35, 0.15-0.84), and neonatal intensive care unit (NICU) admission (aOR 0.66, 0.52-0.85). The association between vaccination and lower rates of perinatal death was no longer significant after propensity score matching. CONCLUSION: In a large retrospective cohort study, receipt of the primary mRNA COVID-19 vaccination series was associated with a lower rate of several adverse pregnancy outcomes, including perinatal death, preterm delivery, neonates with very low birth weight, and NICU admission. Although the decreased rates of perinatal death did not remain significant after propensity score matching, there was evidence of directional benefit for vaccinated patients.

Quality Initiative to Reduce Failed Trial of Labor after Cesarean Using Calculated VBAC Success Likelihood.

OBJECTIVE: Vaginal birth after cesarean can reduce morbidity associated with multiple cesarean deliveries. Failed vaginal birth after cesarean is associated with increased maternal and neonatal morbidity. The Maternal-Fetal Medicine Units Vaginal Birth After Cesarean calculator is a validated tool to predict the likelihood of successful trial of labor after cesarean. Predicted likelihood < 60% has been associated with increased maternal and neonatal morbidity. We sought to determine if formal incorporation of calculated vaginal birth after cesarean likelihood into patient-centered counseling would reduce failed vaginal birth after cesarean. STUDY DESIGN: This is a quality improvement intervention at a single tertiary-care academic medical center, in which standardized patient counseling was implemented, facilitated by an electronic medical record template featuring patient-specific likelihood of vaginal birth after cesarean success. Term singleton pregnancies with history of one to two cesareans were included; those with contraindication to labor were excluded. Historical controls (January 2016-December 2018, n = 693) were compared with a postimplementation cohort (January 2019-April 2020, n = 328). Primary outcome was failed vaginal birth after cesarean. RESULTS: Fewer patients in the postintervention cohort had a history of an arrest disorder (PRE: 48%, 330/693 vs. POST: 40%, 130/326, p = 0.03); demographics were otherwise similar, including the proportion of patients with <60% likelihood of success (PRE: 39%, 267/693, vs. POST: 38%, 125/326). Following implementation, induction of labor in patients with a <60% likelihood of successful vaginal birth after cesarean decreased from 17% (45/267) to 5% (6/125, p < 0.01). The proportion of failed vaginal birth after cesarean decreased from 33% (107/329) to 22% (32/143, p = 0.04). Overall vaginal birth after cesarean rate did not change (PRE: 32%, 222/693, vs. POST: 34%, 111/326, p = 0.52). CONCLUSION: An intervention targeting provider counseling that included a validated vaginal birth after cesarean success likelihood was associated with decreased risk of failed trial of labor after cesarean without affecting overall vaginal birth after cesarean rate. KEY POINTS: · Labored cesarean increases maternal morbidity.. · Application of the Maternal-Fetal Medicine Units (MFMU) calculator to antenatal counseling decreased labored cesarean.. · Application of the MFMU calculator to antenatal counseling did not decrease overall vaginal birth after cesarean rate..

Preclinical efficacy and safety of novel SNAT against SARS-CoV-2 using a hamster model.

To address the unprecedented global public health crisis due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), we designed and developed a novel antiviral nano-drug, called SNAT (Smart Nano-Enabled Antiviral Therapeutic), comprised of taxoid (Tx)-decorated amino (NH2)-functionalized near-atomic size positively charged silver nanoparticles (Tx-[NH2-AgNPs]) that are stable for over 3 years. Using a hamster model, we tested the preclinical efficacy of inhaled SNAT on the body weight, virus titer, and histopathology of lungs in SARS-CoV-2-infected hamsters, including biocompatibility in human lung epithelium and dermal fibroblasts using lactase dehydrogenase (LDH) and malondialdehyde (MDA) assays. Our results showed SNAT could effectively reverse the body weight loss, reduce the virus load in oral swabs, and improve lung health in hamsters. Furthermore, LDH assay showed SNAT is noncytotoxic, and MDA assay demonstrated SNAT to be an antioxidant, potentially quenching lipid peroxidation, in both the human cells. Overall, these promising pilot preclinical findings suggest SNAT as a novel, safer antiviral drug lead against SARS-CoV-2 infection and may find applications as a platform technology against other respiratory viruses of epidemic and pandemic potential.

Detection of SARS-CoV-2 in Neonatal Autopsy Tissues and Placenta.

Severe coronavirus disease in neonates is rare. We analyzed clinical, laboratory, and autopsy findings from a neonate in the United States who was delivered at 25 weeks of gestation and died 4 days after birth; the mother had asymptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and preeclampsia. We observed severe diffuse alveolar damage and localized SARS-CoV-2 by immunohistochemistry, in situ hybridization, and electron microscopy of the lungs of the neonate. We localized SARS-CoV-2 RNA in neonatal heart and liver vascular endothelium by using in situ hybridization and detected SARS-CoV-2 RNA in neonatal and placental tissues by using reverse transcription PCR. Subgenomic reverse transcription PCR suggested viral replication in lung/airway, heart, and liver. These findings indicate that in utero SARS-CoV-2 transmission contributed to this neonatal death.

Safety-Related Outcomes of Novel mRNA COVID-19 Vaccines in Pregnancy.

OBJECTIVE: The objective of this study was to describe the safety profile and demographic data for a cohort of pregnant individuals who received an mRNA coronavirus disease 2019 (COVID-19) vaccine. STUDY DESIGN: Prospective cohort study (with exposure matching) of individuals with active pregnancy who underwent immunization with a novel mRNA COVID-19 vaccine matched 1:2 with vaccinated age-matched female nonregnant controls was carried out. The primary outcome was defined as any vaccine-related complaints as defined in the original safety data. Secondary outcomes included specific complaints, COVID-19 screening test, and positive COVID-19 test. RESULTS: Eighty-three vaccinated pregnant persons were age-matched with 166 female controls, all of whom were vaccinated between December 2020 and January, 2021. There was no difference in race or ethnicity between the groups. The mean body mass index of pregnant patients was lower than that of controls (26.1 vs. 29.2, p = 0.002). The frequency of complaints following vaccine administration was not different between pregnant and nonpregnant patients (18.1 vs. 16.9%, p = 0.201). Pregnant individuals were more likely to report fever (4.8 vs. 0.6%, p = 0.044) and gastrointestinal symptoms (4.8 vs. 0%, p = 0.012). CONCLUSIONS: Side effect profiles of COVID-19 vaccine administration at our institution were relatively similar between pregnant and nonpregnant individuals and no serious complications occurred in either group. As COVID-19 infection in pregnancy can have significant morbidity, our data support the continued use of the vaccine for pregnant patients. KEY POINTS: · Pregnant and nonpregnant women had a similar frequency of complaints.. · No serious adverse outcomes were observed in either group.. · Pregnant women were more likely to report fever and gastrointestinal side effects which may reflect gestationally mediated physiological responses to immunization..

Maternal Secretor Status Affects Oral Rotavirus Vaccine Response in Breastfed Infants in Bangladesh.

Secretor status controls mucosal histo-blood group antigen expression and is associated with susceptibility to rotavirus (RV) diarrhea, with nonsecretors less susceptible to symptomatic infection. The role of breast milk secretor status on oral live-attenuated RV vaccine response in breastfed infants has not been explored. In a monovalent G1P[8] RV vaccine (Rotarix) trial in Bangladesh, RV-specific plasma immunoglobulin A antibody seroconversion rates were higher among infants of maternal nonsecretors (39%) than infants of maternal secretors (23%; P = .001). Maternal status remained a significant predictor when correcting for infant status (P = .002). Maternal secretor status should be considered when interpreting oral RV vaccine responses in low- and middle-income settings. Clinical Trials Registration. NCT01375647.

Measures of adiposity correlate with renal filtration in young nulliparous women: An observational cohort study.

OBJECTIVE: Renal hyperfiltration, which has been documented in severe obesity and obesity-associated hypertension, can occur with hypertensive disorders of pregnancy. Identification of prepregnancy risk factors for unrecognized renal hyperfiltration could inform screening and intervention strategies to protect against pregnancy complications. In young, healthy, nulliparous women, associations between associations between measures of adiposity, insulin resistance, and renal vascular resistance were thus evaluated. METHODS: This is a secondary analysis of a prospective observational trial characterizing associations of prepregnancy and late-pregnancy maternal physiology. Seventy-nine nulligravid women aged 18-42 years without major medical conditions were assessed for percent android body fat using dual-energy X-ray absorption. Renal cortical vessel blood flow resistance index (CVRI) was determined using Doppler ultrasonography. Creatinine clearance was calculated from 24-hour urine collection. RESULTS: Renal CVRI inversely correlates with body mass index (r = -0.23, p = 0.047), percent android fat (r = -0.30, p = 0.008), and supine pulse (r = -0.44, p < 0.001). Creatinine clearance is positively associated with BMI and HOMA-IR.In regression modeling, supine pulse (r2 = 0.22, p < 0.001) and cardiac index (r2 = 0.05, p = 0.045) predict renal CVRI, whereas HOMA-IR (r2 = 0.11, p = 0.008) and cardiac output (r2 = 0.06, p = 0.039) predict creatinine clearance. Measures of adiposity are not independently predictive of either measure. CONCLUSIONS: In healthy young women, measures of adiposity and insulin resistance correlate positively with renal filtration. Preclinical manifestations of renal hyperfiltration may have implications for pregnancy outcomes.

Whipple's disease.

Whipple's disease is a rare, chronic, systemic infectious disorder with prominent intestinal manifestations. It presents with weight loss, arthralgia, diarrhea, and abdominal pain. There are different entities of infection or carriage, respectively, classical Whipple's disease, localized WD, and Isolated Neurological WD. The disease is commonly diagnosed by biopsy of lymph node or small-bowel. Histological detection within duodenal biopsies with "Periodic acid Schiff" (PAS) staining still is first choice for the diagnosis of classical Whipple's disease. PCR or immunohistochemistry can identify the agent more specifically, and DNA sequencing for Tropheryma whipplei on lymphocytes from blood and cerebrospinal fluid from PCR-positive specimens, is essential. Cell-mediated immunity in active and inactive Whipple's disease has subtle defects that might predispose some individuals to symptomatic infection with this bacillus. Successful treatment can be achieved in most of the cases by antimicrobial therapy. WD can be progressive lethal. Immune reconstitution inflammatory syndrome (IRIS) might complicate the course of treatment and in worst case end fatal.

A secondary mandibular condylar articulation and collateral effects on a Late Neolithic mandible from Bois Madame rockshelter in Arbre, Belgium.

A Neolithic Belgian mandible from Bois Madame rockshelter in Arbre presents an asymmetrical morphology resulting from a secondary, or false, articulation of the right mandibular condyle. The pathological articulation produced enlarged masseter, medial pterygoid and mylohyoid musculature on the right side as well as a flattening of the right incisal alveolus curvature. The secondary condylar articulation did not lead to pronounced asymmetry of attrition on the antimeres of the dental arcade. This is the most complete mandible from this Late Neolithic collective burial dating to the beginning of the Bronze Age circa 4000 years BP. It is possible that a fall or blow to the mental symphysis during early adolescence could have resulted in the partial intrusion of the mandibular condyle into the articulation disc of the temporomandibular joint capsule. When the affected condyle healed, a secondary, but serviceable articulation developed, producing unique stresses on the involved muscular tissue and ultimately resulted in an asymmetry of mandibular form.

Periodic Lateralized Epileptiform Discharges can Survive Anesthesia and Result in Asymmetric Drug-induced Burst Suppression.

Drug-induced burst suppression (DIBS) is bihemispheric and bisymmetric in adults and older children. However, asymmetric DIBS may occur if a pathological process is affecting one hemisphere only or both hemispheres disproportionately. The usual suspect is a destructive lesion; an irritative or epileptogenic lesion is usually not invoked to explain DIBS asymmetry. We report the case of a 66-year-old woman with new-onset seizures who was found to have a hemorrhagic cavernoma and periodic lateralized epileptiform discharges (PLEDs) in the right temporal region. After levetiracetam and before anesthetic antiepileptic drugs (AEDs) were administered, the electroencephalogram (EEG) showed continuous PLEDs over the right hemisphere with maximum voltage in the posterior temporal region. Focal electrographic seizures also occurred occasionally in the same location. Propofol resulted in bihemispheric, but not in bisymmetric, DIBS. Remnants or fragments of PLEDs that survived anesthesia increased the amplitude and complexity of the bursts in the right hemisphere leading to asymmetric DIBS. Phenytoin, lacosamide, ketamine, midazolam, and topiramate were administered at various times in the course of EEG monitoring, resulting in suppression of seizures but not of PLEDs. Ketamine and midazolam reduced the rate, amplitude, and complexity of PLEDs but only after producing substantial attenuation of all burst components. When all anesthetics were discontinued, the EEG reverted to the original preanesthesia pattern with continuous non-fragmented PLEDs. The fact that PLEDs can survive anesthesia and affect DIBS symmetry is a testament to the robustness of the neurodynamic processes underlying PLEDs.

Obstetrical Outcomes of Ultrasound Identified Uterine Fibroids in Pregnancy.

Objective We aimed to determine if fibroids in pregnancy, categorized by size, are associated with adverse obstetrical outcomes. Study Design Demographic, clinical, and delivery data were collected from charts of women with singleton gestations who delivered at >20 weeks gestation with fibroids identified at routine anatomy scan and their randomly selected age-matched controls. Largest fibroid diameter was used to categorize small fibroids (≤5 cm) and large fibroids (>5 cm). Results We included 450 patients: 264 patients with fibroids (174 small, 90 large fibroids) and 186 age-matched controls. Women with large fibroids had significantly greater blood loss than women with small fibroids and women with no fibroids (p-value <0.0001 and <0.0001 after adjusting for delivery mode). When fibroid size was compared individually, there was a significantly higher rate of primary cesarean section in both small and large fibroid groups when compared with women with no fibroids (p-values 0.044 and 0.003 after adjusting for body mass index). Conclusion Women with fibroids in pregnancy have higher rates of primary cesarean delivery and are at significant risk for increased blood loss at the time of delivery.

Fetal-Type Variants of the Posterior Cerebral Artery and Concurrent Infarction in the Major Arterial Territories of the Cerebral Hemisphere.

Fetal-type or fetal posterior cerebral artery (FPCA) is a variant of cerebrovascular anatomy in which the distal posterior cerebral artery (PCA) territory is perfused by a branch of the internal carotid artery (ICA). In the presence of FPCA, thromboembolism in the anterior circulation may result in paradoxical PCA territory infarction with or without concomitant infarction in the territories of the middle (MCA) or the anterior (ACA) cerebral artery. We describe 2 cases of FPCA and concurrent acute infarction in the PCA and ICA territories-right PCA and MCA in Patient 1 and left PCA, MCA, and ACA in Patient 2. Noninvasive angiography detected a left FPCA in both patients. While FPCA was clearly the mechanism of paradoxical infarction in Patient 2, it turned out to be an incidental finding in Patient 1 when evidence of a classic right PCA was uncovered from an old computed tomography scan image. Differences in anatomical details of the FPCA in each patient suggest that the 2 FPCAs are developmentally different. The FPCA of Patient 1 appeared to be an extension of the embryonic left posterior communicating artery (PcomA). Patient 2 had 2 PCAs on the left (PCA duplication), classic bilateral PCAs, and PcomAs, and absent left anterior choroidal artery (AchoA), suggesting developmental AchoA-to-FPCA transformation on the left. These 2 cases underscore the variable anatomy, clinical significance, and embryological origins of FPCA variants.

Postnatal craniofacial ontogeny in neandertals and modern humans.

OBJECTIVES: Neandertals and humans are closely related but differ noticeably in adult morphology. Previous work has been equivocal as to the contribution of postnatal growth and development to these differences. Due to disparate preservation, most analyses focus on specific anatomies, reconstructed fossils, or limited sample sizes. The objective of this research is to highlight the importance of postnatal growth in expressing Neandertal-human distinctions in the craniofacial skeleton, using a large and unreconstructed Neandertal sample. MATERIALS/METHODS: A resampling approach is utilized to compare relative size change in 20 craniofacial dimensions between Neandertals (n = 42) and humans (n = 262). The large number of immature Neandertal samples within and between dental stages provides the necessary variation to test for growth differences. Nested resampling using human-human comparisons assesses the likelihood of observing human-Neandertal growth differences under the null hypothesis of similar ontogenetic variation. RESULTS: Humans and Neandertals undergo comparable levels of overall size change. However, we identify growth differences for a number of traits, helping explain some of the unique features of this fossil taxon. Nested resampling shows it is unlikely that a Neandertal-like maturation would be observed in a random ontogenetic sample of humans. DISCUSSION: Growth during adolescence appears to be fundamental in the expression of some Neandertal anatomies. Neandertal upper facial and nasal breadths appear to have expanded rapidly after puberty to account for differences between preadolescents and adults, and Neandertals and humans. Mandibular growth differences may relate to anterior tooth use to process foods and paramastication during Neandertal maturation.