Systemic inflammation, enteropathogenic E. Coli, and micronutrient insufficiencies in the first trimester as possible predictors of preterm birth in rural Bangladesh: a prospective study.

BACKGROUND: An incomplete understanding of preterm birth is especially concerning for low-middle income countries, where preterm birth has poorer prognoses. While systemic proinflammatory processes are a reportedly normal component of gestation, excessive inflammation has been demonstrated as a risk factor for preterm birth. There is minimal research on the impact of excessive maternal inflammation in the first trimester on the risk of preterm birth in low-middle income countries specifically. METHODS: Pregnant women were enrolled at the rural Bangladesh site of the National Institute of Child Health Global Network Maternal Newborn Health Registry. Serum samples were collected to measure concentrations of the inflammatory markers C-reactive protein (CRP) and Alpha-1-acid glycoprotein (AGP), and stool samples were collected and analyzed for enteropathogens. We examined associations of maternal markers in the first-trimester with preterm birth using logistic regression models. CRP and AGP were primarily modeled with a composite inflammation predictor. RESULTS: Out of 376 singleton births analyzed, 12.5% were preterm. First trimester inflammation was observed in 58.8% of all births, and was significantly associated with increased odds of preterm birth (adjusted odds ratio [aOR] = 2.23; 95% confidence interval [CI]: 1.03, 5.16), independent of anemia. Maternal vitamin B12 insufficiency (aOR = 3.33; 95% CI: 1.29, 8.21) and maternal anemia (aOR = 2.56; 95% CI: 1.26, 5.17) were also associated with higher odds of preterm birth. Atypical enteropathogenic E. coli detection showed a significant association with elevated AGP levels and was significantly associated with preterm birth (odds ratio [OR] = 2.36; 95% CI: 1.21, 4.57), but not associated with CRP. CONCLUSIONS: Inflammation, anemia, and vitamin B12 insufficiency in the first trimester were significantly associated with preterm birth in our cohort from rural Bangladesh. Inflammation and anemia were independent predictors of premature birth in this low-middle income setting where inflammation during gestation was widespread. Further research is needed to identify if infections such as enteropathogenic E. coli are a cause of inflammation in the first trimester, and if intervention for infection would decrease preterm birth.

Repressed Ang 1-7 in COVID-19 Is Inversely Associated with Inflammation and Coagulation.

The coronavirus SARS-CoV-2 infects host cells by binding to the angiotensin-converting enzyme 2 (ACE2) receptor, which belongs to an anti-inflammatory, anti-thrombotic counter-regulatory arm of the renin-angiotensin system (RAS). ACE2 dysfunction and RAS dysregulation has been explored as a driving force in acute respiratory distress syndrome (ARDS), but data from COVID-19 patients has been inconsistent and inconclusive. We sought to identify disruptions of the classical (ACE)/angiotensin (Ang) II/Ang II type-1 receptor (AT1R) and the counter-regulatory ACE2/Ang 1-7/Mas Receptor (MasR) pathways in patients with COVID-19 and correlate these with severity of infection and markers of inflammation and coagulation. Ang II and Ang 1-7 levels in plasma were measured by enzyme-linked immunosorbent assay (ELISA) for 230 patients, 166 of whom were SARS-CoV-2+. Ang 1-7 was repressed in COVID-19 patients compared to that in SARS-CoV-2 negative outpatient controls. Since the control cohort was less sick than the SARS-CoV-2+ group, this association between decreased Ang 1-7 and COVID-19 cannot be attributed to COVID-19 specifically as opposed to critical illness more generally. Multivariable logistic regression analyses demonstrated that every 10-pg/mL increase in plasma Ang 1-7 was associated with a 3% reduction in the odds of hospitalization (adjusted odds ratio [AOR] 0.97, confidence interval [CI] 0.95 to 0.99) and a 3% reduction in odds of requiring oxygen supplementation (AOR 0.97, CI 0.95 to 0.99) and/or ventilation (AOR 0.97, CI 0.94 to 0.99). Ang 1-7 was also inversely associated with pro-inflammatory cytokines and d-dimer in this patient cohort, suggesting that reduced activity in this protective counter-regulatory arm of the RAS contributes to the hyper-immune response and diffuse coagulation activation documented in COVID-19. IMPORTANCE Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a unique disease, COVID-19, which ranges in severity from asymptomatic to causing severe respiratory failure and death. Viral transmission throughout the world continues at a high rate despite the development and widespread use of effective vaccines. For those patients who contract COVID-19 and become severely ill, few therapeutic options have been shown to provide benefits and mortality rates are high. Additionally, the pathophysiology underlying COVID-19 disease presentation, progression, and severity is incompletely understood. The significance of our research is in confirming the role of renin-angiotensin system dysfunction in COVID-19 pathogenesis in a large cohort of patients with diverse disease severity and outcomes. Additionally, to our knowledge, this is the first study to pair angiotensin peptide levels with inflammatory and thrombotic markers. These data support the role of ongoing clinical trials examining renin-angiotensin system-targeted therapeutics for the treatment of COVID-19.

U-Shaped Association between Maternal Hemoglobin and Low Birth Weight in Rural Bangladesh.

Low birth weight (LBW) is associated with a higher risk of neonatal mortality and the development of adult-onset chronic disease. Understanding the ongoing contribution of maternal hemoglobin (Hgb) levels to the incidence of LBW in South Asia is crucial to achieve the World Health Assembly global nutrition target of a 30% reduction in LBW by 2025. We enrolled pregnant women from the rural Tangail District of Bangladesh in a Maternal Newborn Health Registry established under The Global Network for Women's and Children's Health Research. We measured the Hgb of pregnant women at enrollment and birth weights of all infants born after 20 weeks gestation. Using logistic regression to adjust for multiple potential confounders, we estimated the association between maternal Hgb and the risk of LBW. We obtained Hgb measurements and birth weights from 1,665 mother-child dyads between July 2019 and April 2020. Using trimester-specific cutoffs for anemia, 48.3% of the women were anemic and the mean (±SD) Hgb level was 10.6 (±1.24) g/dL. We identified a U-shaped relationship where the highest risk of LBW was seen at very low (< 7.0 g/dL, OR = 2.00, 95% CI = 0.43-7.01, P = 0.31) and high (> 13.0 g/dL, OR = 2.17, 95% CI = 1.01-4.38, P = 0.036) Hgb levels. The mechanisms underlying this U-shaped association may include decreased plasma expansion during pregnancy and/or iron dysregulation resulting in placental disease. Further research is needed to explain the observed U-shaped relationship, to guide iron supplementation in pregnancy and to minimize the risk of LBW outcomes.

IL-13 is a driver of COVID-19 severity.

Immune dysregulation is characteristic of the more severe stages of SARS-CoV-2 infection. Understanding the mechanisms by which the immune system contributes to COVID-19 severity may open new avenues to treatment. Here, we report that elevated IL-13 was associated with the need for mechanical ventilation in 2 independent patient cohorts. In addition, patients who acquired COVID-19 while prescribed Dupilumab, a mAb that blocks IL-13 and IL-4 signaling, had less severe disease. In SARS-CoV-2-infected mice, IL-13 neutralization reduced death and disease severity without affecting viral load, demonstrating an immunopathogenic role for this cytokine. Following anti-IL-13 treatment in infected mice, hyaluronan synthase 1 (Has1) was the most downregulated gene, and accumulation of the hyaluronan (HA) polysaccharide was decreased in the lung. In patients with COVID-19, HA was increased in the lungs and plasma. Blockade of the HA receptor, CD44, reduced mortality in infected mice, supporting the importance of HA as a pathogenic mediator. Finally, HA was directly induced in the lungs of mice by administration of IL-13, indicating a new role for IL-13 in lung disease. Understanding the role of IL-13 and HA has important implications for therapy of COVID-19 and, potentially, other pulmonary diseases. IL-13 levels were elevated in patients with severe COVID-19. In a mouse model of the disease, IL-13 neutralization reduced the disease and decreased lung HA deposition. Administration of IL-13-induced HA in the lung. Blockade of the HA receptor CD44 prevented mortality, highlighting a potentially novel mechanism for IL-13-mediated HA synthesis in pulmonary pathology.

Diverse Humoral Immune Responses in Younger and Older Adult COVID-19 Patients.

We sought to discover links between antibody responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and patient clinical variables, cytokine profiles, and antibodies to endemic coronaviruses. Serum samples from 30 patients of younger (26 to 39 years) and older (69 to 83 years) age groups and with varying clinical severities ranging from outpatient to mechanically ventilated were collected and used to probe a novel multi-coronavirus protein microarray. This microarray contained variable-length overlapping fragments of SARS-CoV-2 spike (S), envelope (E), membrane (M), nucleocapsid (N), and open reading frame (ORF) proteins created through in vitro transcription and translation (IVTT). The array also contained SARS-CoV, Middle East respiratory syndrome coronavirus (MERS-CoV), human coronavirus OC43 (HCoV-OC43), and HCoV-NL63 proteins. IgG antibody responses to specific epitopes within the S1 protein region spanning amino acids (aa) 500 to 650 and within the N protein region spanning aa 201 to 300 were found to be significantly higher in older patients and further significantly elevated in those older patients who were ventilated. Additionally, there was a noticeable overlap between antigenic regions and known mutation locations in selected emerging SARS-CoV-2 variants of current clinical consequence (B.1.1.7, B1.351, P.1, CAL20.C, and B.1.526). Moreover, the older age group displayed more consistent correlations of antibody reactivity with systemic cytokine and chemokine responses than the younger adult group. A subset of patients, however, had little or no response to SARS-CoV-2 antigens and disproportionately severe clinical outcomes. Further characterization of these slow-low-responding individuals with cytokine analysis revealed significantly higher interleukin-10 (IL-10), IL-15, and interferon gamma-induced protein 10 (IP-10) levels and lower epidermal growth factor (EGF) and soluble CD40 ligand (sCD40L) levels than those of seroreactive patients in the cohort. IMPORTANCE As numerous viral variants continue to emerge in the coronavirus disease 2019 (COVID-19) pandemic, determining antibody reactivity to SARS-CoV-2 epitopes becomes essential in discerning changes in the immune response to infection over time. This study enabled us to identify specific areas of antigenicity within the SARS-CoV-2 proteome, allowing us to detect correlations of epitopes with clinical metadata and immunological signals to gain holistic insight into SARS-CoV-2 infection. This work also emphasized the risk of mutation accumulation in viral variants and the potential for evasion of the adaptive immune responses in the event of reinfection. We additionally highlighted the correlation of antigenicity between structural proteins of SARS-CoV-2 and endemic HCoVs, raising the possibility of cross-protection between homologous lineages. Finally, we identified a subset of patients with minimal antibody reactivity to SARS-CoV-2 infection, prompting discussion of the potential consequences of this alternative immune response.

Predictable fabrication of pre-made alginate hydrogel microtubes for stem cell aggregation using needle-in-needle devices.

Alginate hydrogels in microtubular structures have great potential to advance three-dimensional (3D) culture, organoid formation, tissue engineering, and cell therapy. To address the need of fabricating consistent, stable hydrogel microtubes for efficient large organoid generation in a simple and quick manner, we have designed needle-in-needle devices to fabricate alginate hydrogel microtubes without any dead volume of the cell-alginate mixture and demonstrated the feasibility of injecting and culturing embryoid bodies in these pre-made hydrogel microtubes. We further used a reverse engineering approach to find out the optimal flow rates and alginate concentration for fabricating pre-made hydrogel microtubes with desired diameter using particular sets of needle-in-needle devices. We established the relationship of the alginate flow rate with diameter and wall thickness of the microtube using mathematic modeling. It offers a way to determine the flow rate for making microtubes with the desired dimension. Additionally, we evaluated the effect of CaCl2concentration on the diameter as well as stem cell viability. At last, we demonstrated the capacity of fabricating hydrogel microtubes of varying diameters using three sets of needle-in-needle devices and evaluated stem cell growth in these hydrogel microtubes. It provides a new avenue to accessible, repeatable, scalable, and easy to use pre-made 'off-the-shelf' hydrogel microtubes for 3D cell culture including, but not limiting to stem cells.

IL-13 is a driver of COVID-19 severity.

Immune dysregulation is characteristic of the more severe stages of SARS-CoV-2 infection. Understanding the mechanisms by which the immune system contributes to COVID-19 severity may open new avenues to treatment. Here we report that elevated interleukin-13 (IL-13) was associated with the need for mechanical ventilation in two independent patient cohorts. In addition, patients who acquired COVID-19 while prescribed Dupilumab had less severe disease. In SARS-CoV-2 infected mice, IL-13 neutralization reduced death and disease severity without affecting viral load, demonstrating an immunopathogenic role for this cytokine. Following anti-IL-13 treatment in infected mice, in the lung, hyaluronan synthase 1 (Has1) was the most downregulated gene and hyaluronan accumulation was decreased. Blockade of the hyaluronan receptor, CD44, reduced mortality in infected mice, supporting the importance of hyaluronan as a pathogenic mediator, and indicating a new role for IL-13 in lung disease. Understanding the role of IL-13 and hyaluronan has important implications for therapy of COVID-19 and potentially other pulmonary diseases.

IgG Antibodies against SARS-CoV-2 Correlate with Days from Symptom Onset, Viral Load and IL-10.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in a pandemic of the respiratory disease coronavirus disease 2019 (COVID-19). Antibody testing is essential to identify persons exposed to the virus and potentially in predicting disease immunity. 183 COVID-19 patients (68 of whom required mechanical ventilation) and 41 controls were tested for plasma IgG, IgA and IgM against the SARS-CoV-2 S1, S2, receptor binding domain (RBD) and N proteins using the MILLIPLEX® SARS-CoV-2 Antigen Panel. Plasma cytokines were concurrently measured using the MILLIPLEX® MAP Human Cytokine/Chemokine/Growth Factor Panel A. As expected the 183 COVID-19 positive patients had high levels of IgG, IgA and IgM anti-SARS-CoV-2 antibodies against each of the viral proteins. Sensitivity of anti-S1 IgG increased from 60% to 93% one week after symptom onset. S1-IgG and S1-IgA had specificities of 98% compared to the 41 COVID-19 negative patients. The 68 ventilated COVID-19 positive patients had higher antibody levels than the 115 COVID-19 positive patients who were not ventilated. IgG antibody levels against S1 protein had the strongest positive correlation to days from symptom onset. There were no statistically significant differences in IgG, IgA and IgM antibodies against S1 based on age. We found that patients with the highest levels of anti-SARS-CoV-2 antibodies had the lowest viral load in the nasopharynx. Finally there was a correlation of high plasma IL-10 with low anti-SARS-CoV-2 antibodies. Anti-SARS-CoV-2 antibody levels, as measured by a novel antigen panel, increased within days after symptom onset, achieving > 90% sensitivity and specificity within one week, and were highest in patients who required mechanical ventilation. Antibody levels were inversely associated with viral load but did not differ as a function of age. The correlation of high IL-10 with low antibody response suggests a potentially suppressive role of this cytokine in the humoral immune response in COVID-19.

Immediate and short term effects of values-based interventions on paranoia.

BACKGROUND AND OBJECTIVES: Paranoia is a common, distressing, and persistent experience that can negatively impact on health, wellbeing, and functioning. This study examined the immediate and short term (2-weeks) effects of two values-based interventions, versus a non-values control, on paranoia, as well as the moderating effect of self-esteem. METHODS: 171 non-clinical adults were randomised to a value-affirmation and goals task (VAG: clarifying and reflecting on core values and setting value-based goals) (n = 57), a value-affirmation task (VA: clarifying and reflecting on core values without setting value-based goals) (n = 57), or a non-affirmation control task (NAC) (n = 57). Paranoia was assessed at baseline (T1), post-intervention (T2), and two weeks post-intervention (T3). Self-esteem was measured at baseline. RESULTS: VAG participants had significantly lower state paranoia scores at T3 than VA (d = .34) and NAC (d = .31) participants. This effect was moderated by trait self-esteem: At follow-up, the differential effect of condition on state paranoia was greatest amongst those with low self-esteem, with the VAG condition being most beneficial for participants with low self-esteem and the VA condition being least beneficial. LIMITATIONS: Without a goals only control group it is possible that the benefits of VAG over VA were attributable to setting and achieving goals. Use of a nonclinical sample limits generalisability to clinical groups. CONCLUSIONS: The findings suggest that focusing on a deeply held value and setting goals in line with that value reduced paranoia. This intervention may be most beneficial for individuals with low self-esteem.

Home treatment teams: what should they do? A qualitative study of patient opinions.

BACKGROUND: Home treatment teams (HTTs) have limited evidence of altering hospital admissions. There is no consensus on what HTTs "do", and a considerable lack of data on whether they deliver patient-relevant meaningful care. The Royal College of Psychiatrists has recently established the Home Treatment Accreditation Scheme (HTAS) to institute a quality standard for HTTs, though it is unclear whether such accreditation could of itself measure effective care. AIMS: To explore opinions of HTT service users on the care they received to guide future research and service provision. METHOD: Ten ex-HTT patients were interviewed on the care they had received, using thematic analysis of semi-structured interviews. RESULTS: Positive aspects of HTT intervention included a rapid, accessible and crisis-focused approach, though changing staff and appointment times were considered unhelpful. Proposals were made for greater psycho-and occupational-therapeutic inputs to manage long-term care, and for provision of peer-support within HTTs. CONCLUSIONS: HTTs were valued but service users' focus was on goals notably different to factors generally assayed by existing research. There is a severe lack of longitudinal clinical and patient-centred outcome data. HTAS provides a potential vehicle through which this could be addressed.