Disparities in perinatal COVID-19 infection and vaccination.

The COVID-19 pandemic exposed and exacerbated persistent health inequities in perinatal populations, resulting in disparities of maternal and fetal complications. In this narrative review, we present an adapted conceptual framework of perinatal social determinants of health in the setting of the COVID-19 pandemic and use this framework to contextualize the literature regarding disparities in COVID-19 vaccination and infection. We synthesize how elements of the structural context, individual socioeconomic position, and concrete intermediary determinants influence each other and perinatal COVID-19 vaccination and infection, arguing that systemic inequities at each level contribute to observed disparities in perinatal health outcomes. From there, we identify gaps in the literature, propose mechanisms for observed disparities, and conclude with a discussion of strategies to mitigate them.

Age-Dependent Increase in Tau Phosphorylation at Serine 396 in Huntington's Disease Prefrontal Cortex.

BACKGROUND: To date, it is still controversial whether tau phosphorylation plays a role in Huntington's disease (HD), as previous studies demonstrated either no alterations or increases in phosphorylated tau (pTau) in HD postmortem brain and mouse models. OBJECTIVE: The goal of this study was to determine whether total tau and pTau levels are altered in HD. METHODS: Immunohistochemistry, cellular fractionations, and western blots were used to measure total tau and pTau levels in a large cohort of HD and control postmortem prefrontal cortex (PFC). Furthermore, western blots were performed to assess tau, and pTau levels in HD and control isogenic embryonic stem cell (ESC)-derived cortical neurons and neuronal stem cells (NSCs). Similarly, western blots were used to assess tau and pTau levels in HttQ111 and transgenic R6/2 mice. Lastly, total tau levels were assessed in HD and healthy control plasma using Quanterix Simoa assay. RESULTS: Our results revealed that, while there was no difference in total tau or pTau levels in HD PFC compared to controls, the levels of tau phosphorylated at S396 were increased in PFC samples from HD patients 60 years or older at time of death. Additionally, tau and pTau levels were not changed in HD ESC-derived cortical neurons and NSCs. Similarly, total tau or pTau levels were not altered in HttQ111 and transgenic R6/2 mice compared to wild-type littermates. Lastly, tau levels were not changed in plasma from a small cohort of HD patients compared to controls. CONCLUSIONS: Together these findings demonstrate that pTau-S396 levels increase significantly with age in HD PFC.

Mixed squamous and clear cell ovarian adenocarcinoma arising from endometriosis in a 71 year old patient.

•This 71 year old patient was diagnosed with mixed squamous and clear cell ovarian adenocarcinoma.•Patient was surgically staged with guidance from frozen section.•Patient received adjuvant treatment with carboplatin and paclitaxel for 6 cycles.

Age-dependent increase in tau phosphorylation at serine 396 in Huntington's disease pre-frontal cortex.

Background: To date, it is still controversial whether tau phosphorylation plays a role in Huntington's disease (HD), as previous studies demonstrated either no alterations or increases in phosphorylated tau (pTau) in HD post-mortem brain and mouse models. Objectives: The goal of this study was to determine whether total tau and pTau levels are altered in HD. Methods: Immunohistochemistry, cellular fractionations, and western blots were used to measure tau and pTau levels in a large cohort of HD and control post-mortem prefrontal cortex (PFC). Furthermore, western blots were performed to assess tau, and pTau levels in HD and control isogenic embryonic stem cell (ESC)-derived cortical neurons and neuronal stem cells (NSCs). Similarly, western blots were used to assess tau and pTau in Htt Q111 and transgenic R6/2 mice. Lastly, total tau levels were assessed in HD and healthy control plasma using Quanterix Simoa assay. Results: Our results revealed that, while there was no difference in tau or pTau levels in HD PFC compared to controls, tau phosphorylated at S396 levels were increased in PFC samples from HD patients 60 years or older at time of death. Additionally, tau and pTau levels were not changed in HD ESC-derived cortical neurons and NSCs. Similarly, tau or pTau levels were not altered in Htt Q111 and transgenic R6/2 mice compared to wild-type littermates. Lastly, tau levels were not changed in plasma from a small cohort of HD patients compared to controls. Conclusion: Together these findings demonstrate that pTau-S396 levels increase significantly with age in HD PFC.

Is Increasing Parity Associated with Adverse Perinatal Outcomes in Dichorionic Twin Gestations?

OBJECTIVE: Dichorionic twins have increased risk of preterm birth and hypertensive disorders of pregnancy. Grand multiparity may be associated with adverse perinatal outcomes in singleton pregnancies, although the effect of increasing parity in twins is unclear. This study aimed to elucidate whether grand multiparity leads to adverse outcomes in dichorionic twins compared with multiparity and nulliparity. STUDY DESIGN: This was a retrospective review of dichorionic twins at a single institution between January 2008 and December 2019 comparing pregnancy outcomes among grand multiparity, multiparity, and nulliparity. Primary outcome was preterm birth less than 37 weeks. Multivariable regression controlled for differing demographics, prior preterm birth, use of reproductive technologies, and hypertensive disorders of pregnancy. Chi square and Fisher's exact were used for categorical variables and Kruskal-Wallis was used for continuous variables. RESULTS: A total of 843 (60.3%) pregnancies were nulliparous, 499 (35.7%) multiparous, and 57(4.1%) grand multiparous. Univariate analysis indicated that multiparous women had lower incidence of preterm birth less than 37, 34, and 32 weeks (57 vs. 51%, p = 0.04; 19.2 vs. 14.0%, p = 0.02; 9.6 vs. 5.6%, p = 0.01) and that grand multiparous women had lower incidence of preterm birth less than 34 weeks (19.2 vs. 5.3%, p = 0.008) compared with nulliparous women. Multivariable regression confirmed multiparous women had lower odds of preterm birth less than 34 and 32 weeks compared with nulliparous women (<34 wk: odds ratio [OR] = 0.69, 95% confidence interval [CI] = 0.49-0.97, p = 0.03; <32 wk: OR = 0.48, 95% CI = 0.29-0.79, p = 0.004) and that multiparous women (OR = 0.57, 95% CI = 0.42-0.77, p = 0.0002) and grand multiparous women (OR = 0.23, 95% CI = 0.08-0.68, p = 0.0074) had lower incidence of hypertensive disorders of pregnancy when compared with nulliparous women. CONCLUSION: Grand multiparity is not associated with adverse perinatal outcomes compared with nulliparity or multiparity in dichorionic twins. Increasing parity may protect against incidence of preterm birth and hypertensive disorders of pregnancy even among grand multiparous women. KEY POINTS: · Incidence of preterm birth may decrease with increasing parity in twins.. · Hypertensive disorders of pregnancy may decrease with increasing parity in twins.. · Grand multiparity is not associated with adverse perinatal outcomes in twins..

Methicillin-resistant Staphylococcus aureus bacteremia with elevated vancomycin minimum inhibitory concentrations.

This case-control study of 25 cases with methicillin-resistant Staphylococcus aureus (MRSA) bacteremia with vancomycin minimum inhibitory concentration (MIC) ≥ 2 µg/mL and 391 controls (MIC < 2 µg/mL) characterized the clinical characteristics, treatments, and outcomes associated with elevated vancomycin MIC. Elevated vancomycin MIC was associated with baseline hemodialysis, prior MRSA colonization, and metastatic infection.

Arterial-colonic fistula secondary to colonic stent erosion into the left external iliac artery.

Self-expandable metal stent (SEMS) are widely utilized as a bridge to surgical intervention and for palliative treatment of malignant bowel obstructions. The risk of complications associated with SEMS is low in well-selected patients. Stent erosion is a rare but serious adverse event that is associated with high morbidity and mortality. Here, we report the case of a 74-year-old patient with a colonic obstruction secondary to a pelvic mass that was treated with SEMS and radiotherapy, who developed a partial thickness stent erosion and recurrent hematochezia 6 years after placement. Endoscopic retrieval was not technically feasible. During attempted surgical resection, massive hemorrhage occurred from a colonic-arterial fistula to the left external iliac artery resulting in death. While SEMS remain an effective, minimally invasive approach for the management of bowel obstructions, prolonged in-situ lifetime may confer an increased risk of serious adverse events including erosion and fistula formation.

Everybody nose: molecular and clinical characteristics of nasal colonization during active methicillin-resistant Staphylococcus aureus bloodstream infection.

BACKGROUND: Healthcare-associated infections pose a potentially fatal threat to patients worldwide and Staphylococcus aureus is one of the most common causes of healthcare-associated infections. S. aureus is a common commensal pathogen and a frequent cause of bacteremia, with studies demonstrating that nasal and blood isolates from single patients match more than 80% of the time. Here we report on a contemporary collection of colonizing isolates from those with methicillin-resistant S. aureus (MRSA) bloodstream infections to evaluate the diversity within hosts, and detail the clinical features associated with concomitant nasal colonization. METHODS: Swabs of the bilateral anterior nares were obtained from patients diagnosed with MRSA bacteremia. A single colony culture from the blood and an average of 6 colonies from the nares were evaluated for MRSA growth. For the nares cultures, we typed multiple isolates for staphylococcal protein A (spa) and derived the clonal complexes. Demographic and clinical data were obtained retrospectively from the electronic medical record system and analysed using univariate and multivariable regression models. RESULTS: Over an 11-month period, 68 patients were diagnosed with MRSA bloodstream infection, 53 were swabbed, and 37 (70%) were colonized with MRSA in the anterior nares. We performed molecular typing on 213 nasal colonies. Spa types and clonal complexes found in the blood were also detected in the nares in 95% of the cases. We also found that 11% of patients carried more than one clone of MRSA in the nares. Male sex and history of prior hospitalization within the past 90 days increased odds for MRSA colonization. CONCLUSION: The molecular epidemiological landscape of colonization in the setting of invasive disease is diverse and defining the interplay between colonization and invasive disease is critical to combating invasive MRSA disease.

Targeting Tau Mitigates Mitochondrial Fragmentation and Oxidative Stress in Amyotrophic Lateral Sclerosis.

Understanding the mechanisms underlying amyotrophic lateral sclerosis (ALS) is crucial for the development of new therapies. Previous studies have demonstrated that mitochondrial dysfunction is a key pathogenetic event in ALS. Interestingly, studies in Alzheimer's disease (AD) post-mortem brain and animal models link alterations in mitochondrial function to interactions between hyperphosphorylated tau and dynamin-related protein 1 (DRP1), the GTPase involved in mitochondrial fission. Recent evidence suggest that tau may be involved in ALS pathogenesis, therefore, we sought to determine whether hyperphosphorylated tau may lead to mitochondrial fragmentation and dysfunction in ALS and whether reducing tau may provide a novel therapeutic approach. Our findings demonstrated that pTau-S396 is mis-localized to synapses in post-mortem motor cortex (mCTX) across ALS subtypes. Additionally, the treatment with ALS synaptoneurosomes (SNs), enriched in pTau-S396, increased oxidative stress, induced mitochondrial fragmentation, and altered mitochondrial connectivity without affecting cell survival in vitro. Furthermore, pTau-S396 interacted with DRP1, and similar to pTau-S396, DRP1 accumulated in SNs across ALS subtypes, suggesting increases in mitochondrial fragmentation in ALS. As previously reported, electron microscopy revealed a significant decrease in mitochondria density and length in ALS mCTX. Lastly, reducing tau levels with QC-01-175, a selective tau degrader, prevented ALS SNs-induced mitochondrial fragmentation and oxidative stress in vitro. Collectively, our findings suggest that increases in pTau-S396 may lead to mitochondrial fragmentation and oxidative stress in ALS and decreasing tau may provide a novel strategy to mitigate mitochondrial dysfunction in ALS. pTau-S396 mis-localizes to synapses in ALS. ALS synaptoneurosomes (SNs), enriched in pTau-S396, increase oxidative stress and induce mitochondrial fragmentation in vitro. pTau-S396 interacts with the pro-fission GTPase DRP1 in ALS. Reducing tau with a selective degrader, QC-01-175, mitigates ALS SNs-induced mitochondrial fragmentation and increases in oxidative stress in vitro.

Novel genetic variants in MAPT and alterations in tau phosphorylation in amyotrophic lateral sclerosis post-mortem motor cortex and cerebrospinal fluid.

Although the molecular mechanisms underlying amyotrophic lateral sclerosis (ALS) are not yet fully understood, several studies report alterations in tau phosphorylation in both sporadic and familial ALS. Recently, we have demonstrated that phosphorylated tau at S396 (pTau-S396) is mislocalized to synapses in ALS motor cortex (mCTX) and contributes to mitochondrial dysfunction. Here, we demonstrate that while there was no overall increase in total tau, pTau-S396, and pTau-S404 in ALS post-mortem mCTX, total tau and pTau-S396 were increased in C9ORF72-ALS. Additionally, there was a significant decrease in pTau-T181 in ALS mCTX compared controls. Furthermore, we leveraged the ALS Knowledge Portal and Project MinE data sets and identified ALS-specific genetic variants across MAPT, the gene encoding tau. Lastly, assessment of cerebrospinal fluid (CSF) samples revealed a significant increase in total tau levels in bulbar-onset ALS together with a decrease in CSF pTau-T181:tau ratio in all ALS samples, as reported previously. While increases in CSF tau levels correlated with a faster disease progression as measured by the revised ALS functional rating scale (ALSFRS-R), decreases in CSF pTau-T181:tau ratio correlated with a slower disease progression, suggesting that CSF total tau and pTau-T181 ratio may serve as biomarkers of disease in ALS. Our findings highlight the potential role of pTau-T181 in ALS, as decreases in CSF pTau-T181:tau ratio may reflect the significant decrease in pTau-T181 in post-mortem mCTX. Taken together, these results indicate that tau phosphorylation is altered in ALS post-mortem mCTX as well as in CSF and, importantly, the newly described pathogenic or likely pathogenic variants identified in MAPT in this study are adjacent to T181 and S396 phosphorylation sites further highlighting the potential role of these tau functional domains in ALS.

SVA insertion in X-linked Dystonia Parkinsonism alters histone H3 acetylation associated with TAF1 gene.

X-linked Dystonia-Parkinsonism (XDP) is a neurodegenerative disease linked to an insertion of a SINE-VNTR-Alu (SVA)-type retrotransposon within an intron of TAF1. This SVA insertion induces aberrant TAF1 splicing and partial intron retention, thereby decreasing levels of the full-length transcript. Here we sought to determine if these altered transcriptional dynamics caused by the SVA are also accompanied by local changes in histone acetylation, given that these modifications influence gene expression. Because TAF1 protein may itself exhibit histone acetyltransferase activity, we also examined whether decreased TAF1 expression in XDP cell lines and post-mortem brain affects global levels of acetylated histone H3 (AcH3). The results demonstrate that total AcH3 are not altered in XDP post-mortem prefrontal cortex or cell lines. We also did not detect local differences in AcH3 associated with TAF1 exons or intronic sites flanking the SVA insertion. There was, however, a decrease in AcH3 association with the exon immediately proximal to the intronic SVA, and this decrease was normalized by CRISPR/Cas-excision of the SVA. Collectively, these data suggest that the SVA insertion alters histone status in this region, which may contribute to the dysregulation of TAF1 expression.

PathoSPOT genomic epidemiology reveals under-the-radar nosocomial outbreaks.

BACKGROUND: Whole-genome sequencing (WGS) is increasingly used to map the spread of bacterial and viral pathogens in nosocomial settings. A limiting factor for more widespread adoption of WGS for hospital infection prevention practices is the availability of standardized tools for genomic epidemiology. METHODS: We developed the Pathogen Sequencing Phylogenomic Outbreak Toolkit (PathoSPOT) to automate integration of genomic and medical record data for rapid detection and tracing of nosocomial outbreaks. To demonstrate its capabilities, we applied PathoSPOT to complete genome surveillance data of 197 MRSA bacteremia cases from two hospitals during a 2-year period. RESULTS: PathoSPOT identified 8 clonal clusters encompassing 33 patients (16.8% of cases), none of which had been recognized by standard practices. The largest cluster corresponded to a prolonged outbreak of a hospital-associated MRSA clone among 16 adults, spanning 9 wards over a period of 21 months. Analysis of precise timeline and location data with our toolkit suggested that an initial exposure event in a single ward led to infection and long-term colonization of multiple patients, followed by transmissions to other patients during recurrent hospitalizations. CONCLUSIONS: We demonstrate that PathoSPOT genomic surveillance enables the detection of complex transmission chains that are not readily apparent from epidemiological data and that contribute significantly to morbidity and mortality, enabling more effective intervention strategies.

Pediatric Patients with SARS-CoV-2 Infection: Clinical Characteristics in the United States from a Large Global Health Research Network.

Background Few reports have been published on the clinical presentation of pediatric patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We aim to shed more light on the clinical presentation of pediatric patients infected with coronavirus disease 2019 (COVID-19), and also potential risk factors for more severe clinical case presentation. Methods We used a large global health research network to gather clinical data extracted from the electronic medical records of pediatric patients aged < 18 years with confirmed SARS-CoV-2 from January 1, 2020 to May 7, 2020. Clinical symptoms at presentation, hospitalization status, associated co-morbidities, and treatments received were reviewed. Results A total of 627 patients with COVID-19 diagnosis (334 were outpatient, 293 were inpatient) were included from a total of 20 organizations across the United States. The mean age of patients was seven years, 48% were females. Inpatients were younger than outpatients (mean age of 5.6 years vs 8.2 years, p<0.001). Sixty-one percent of patients in the inpatient group were < 5 years of age vs. 44% in the outpatient group. Amongst 293 inpatients, 90% (n=265) were non-severe and 10% (n=28) were classified as severe. The percentage of patients <5 years was higher in severe inpatients vs. non-severe (71% vs 60%.) Significantly more patients with a severe illness vs. non-severe illness had a history of co-morbidity including non-congenital heart disease (50% vs 11%, p<0.001) and disease of the respiratory system (86% vs 53%, p< 0.001). Conclusion Clinicians should closely monitor young children with underlying conditions and COVID-19, as they may be more likely to be hospitalized and have a higher severity of the disease.

Neuroinflammation and histone H3 citrullination are increased in X-linked Dystonia Parkinsonism post-mortem prefrontal cortex.

Neuroinflammation plays a pathogenic role in neurodegenerative diseases and recent findings suggest that it may also be involved in X-linked Dystonia-Parkinsonism (XDP) pathogenesis. Previously, fibroblasts and neuronal stem cells derived from XDP patients demonstrated hypersensitivity to TNF-α, dysregulation in NFκB signaling, and an increase in several pro-inflammatory markers. However, the role of inflammatory processes in XDP patient brain remains unknown. Here we demonstrate that there is a significant increase in astrogliosis and microgliosis in human post-mortem XDP prefrontal cortex (PFC) compared to control. Furthermore, there is a significant increase in histone H3 citrullination (H3R2R8R17cit3) with a concomitant increase in peptidylarginine deaminase 2 (PAD2) and 4 (PAD4), the enzymes catalyzing citrullination, in XDP post-mortem PFC. While there is a significant increase in myeloperoxidase (MPO) levels in XDP PFC, neutrophil elastase (NE) levels are not altered, suggesting that MPO may be released by activated microglia or reactive astrocytes in the brain. Similarly, there was an increase in H3R2R8R17cit3, PAD2 and PAD4 levels in XDP-derived fibroblasts. Importantly, treatment of fibroblasts with Cl-amidine, a pan inhibitor of PAD enzymes, reduced histone H3 citrullination and pro-inflammatory chemokine expression, without affecting cell survival. Taken together, our results demonstrate that inflammation is increased in XDP post-mortem brain and fibroblasts and unveil a new epigenetic potential therapeutic target.

Sexual Risk Behaviors among African Americans Who Use MDMA (Molly/Ecstasy): Implications for HIV Prevention.

Numerous studies have linked sexual risk taking to recreational use of MDMA. Questions remain, however, regarding the extent and type of sexual risk behaviors that occur among MDMA users, especially African Americans who use the drug. Because the MDMA literature has historically relied on samples with little minority representation, little is known about Black MDMA users and their sexual risk taking. The primary goal of this study, therefore, was to describe patterns of sexual risk behaviors among African Americans who use MDMA. This study used survey data to identify (a) which sexual risk behaviors occurred among Black MDMA users and (b) the prevalence of each behavior. Qualitative interview data are also presented to contextualize the role that MDMA and the club/nightlife environment might play in contributing to these behaviors. Results show that sexual risk taking (e.g., sex without a condom, "hooking up," sex on MDMA, and group sex) was prevalent and that the mind-set and context in which MDMA was consumed are contributing factors. The current study adds to the limited amount of data on African Americans who use MDMA and is a step toward better understanding the link between MDMA and sexual risk taking. These data can be used to inform social workers in their efforts to prevent HIV in this population.

Lipocalin-2 is increased in amyotrophic lateral sclerosis.

BACKGROUND: The exact mechanisms underlying neuroinflammation and how they contribute to amyotrophic lateral sclerosis (ALS) pathogenesis remain unclear. One possibility is the secretion of neurotoxic factors, such as lipocalin-2 (LCN2), that lead to neuronal death. METHODS: LCN2 levels were measured in human postmortem tissue using Western blot, quantitative real time polymerase chain reaction, and immunofluorescence, and in plasma by enzyme-linked immunosorbent assay. SH-SY5Y cells were used to test the pro-inflammatory effects of LCN2. RESULTS: LCN2 is increased in ALS postmortem motor cortex, spinal cord, and plasma. Furthermore, we identified several LCN2 variants in ALS patients that may contribute to disease pathogenesis. Lastly, while LCN2 treatment caused cell death and increased pro-inflammatory markers, treatment with an anti-LCN2 antibody prevented these responses in vitro. CONCLUSIONS: LCN2 upregulation in ALS postmortem samples and plasma may be an upstream event for triggering neuroinflammation and neuronal death.

Corrigendum: Wolf-Hirschhorn Syndrome-Associated Genes Are Enriched in Motile Neural Crest Cells and Affect Craniofacial Development in Xenopus laevis.

[This corrects the article DOI: 10.3389/fphys.2019.00431.].

Cromolyn sodium delays disease onset and is neuroprotective in the SOD1G93A Mouse Model of amyotrophic lateral sclerosis.

Accumulating evidence suggests that neuroinflammatory processes are implicated in the initiation and progression of amyotrophic lateral sclerosis (ALS). Previous reports have demonstrated an increase in microgliosis and astrogliosis in the lumbar spinal cord of SOD1G93A transgenic mice before the onset of symptoms, a neuroinflammatory response which correlated with disease progression. Importantly, early stage homeostatic microglia enhanced motor neuron survival, while pro-inflammatory microglia were toxic to motor neurons in the SOD1G93A mice. Recent studies from our group have demonstrated that cromolyn sodium, an FDA approved compound, exerts neuroprotective effects in mouse models of Alzheimer's disease by altering microglial cell activation. Here, we tested the neuroprotective and anti-inflammatory effects of cromolyn sodium in the SOD1G93A mouse model of ALS. Our results indicate that cromolyn sodium treatment significantly delayed the onset of neurological symptoms, and improved deficits in PaGE performance in both male and female mice, however, there was only an effect on survival in female mice. Furthermore, there was a significant increase in motor neuron survival in the lumbar spinal cord as well as a significant decrease in the denervation of the neuromuscular junction of the tibialis anterior muscle in cromolyn treated transgenic SOD1G93A mice. Lastly, cromolyn treatment decreased the expression of pro-inflammatory cytokines/chemokines in the lumbar spinal cord and plasma and decreased mast cell degranulation in the tibialis anterior muscle of transgenic SOD1G93A mice. Together, these findings suggest that cromolyn sodium provides neuroprotection in the SOD1G93A mice by decreasing the inflammatory response.

Class I and II histone deacetylase expression is not altered in human amyotrophic lateral sclerosis: Neuropathological and positron emission tomography molecular neuroimaging evidence.

INTRODUCTION: There is an unmet need for mechanism-based biomarkers and effective disease modifying treatments in amyotrophic lateral sclerosis (ALS). Previous findings have provided evidence that histone deacetylases (HDAC) are altered in ALS, providing a rationale for testing HDAC inhibitors as a therapeutic option. METHODS: We measured class I and II HDAC protein and transcript levels together with acetylation levels of downstream substrates by using Western blotting in postmortem tissue of ALS and controls. [11 C]Martinostat, a novel HDAC positron emission tomography ligand, was also used to assess in vivo brain HDAC alterations in patients with ALS and healthy controls (HC). RESULTS: There was no significant difference in HDAC levels between patients with ALS and controls as measured by Western blotting and reverse-transcription quantitative polymerase chain reaction. Similarly, no differences were detected in [11 C]Martinostat-positron emission tomography uptake in ALS participants compared with HCs. DISCUSSION: These findings provide evidence that alterations in HDAC isoforms are not a dominant pathological feature at the bulk tissue level in ALS.