Dung biomass smoke exposure impairs resolution of inflammatory responses to influenza infection.

Epidemiological studies associate biomass smoke with an increased risk for respiratory infections in children and adults in the developing world, with 500,000 premature deaths each year attributed to biomass smoke-related acute respiratory infections including infections caused by respiratory viruses. Animal dung is a biomass fuel of particular concern because it generates more toxic compounds per amount burned than wood, and is a fuel of last resort for the poorest households. Currently, there is little biological evidence on the effects of dung biomass smoke exposure on immune responses to respiratory viral infections. Here, we investigated the impact of dung biomass exposure on respiratory infection using a mouse model of dung biomass smoke and cultured primary human small airway epithelial cells (SAECs). Mice infected with influenza A virus (IAV) after dung biomass smoke exposure had increased mortality, lung inflammation and virus mRNA levels, and suppressed expression of innate anti-viral mediators compared to air exposed mice. Importantly, there was still significant tissue inflammation 14 days after infection in dung biomass smoke-exposed mice even after inflammation had resolved in air-exposed mice. Dung biomass smoke exposure also suppressed the production of anti-viral cytokines and interferons in cultured SAECs treated with poly(I:C) or IAV. This study shows that dung biomass smoke exposure impairs the immune response to respiratory viruses and contributes to biomass smoke-related susceptibility to respiratory viral infections, likely due to a failure to resolve the inflammatory effects of biomass smoke exposure.

Diminished seroconversion following a single SARS-COV-2 vaccine in ocrelizumab-treated relapsing-remitting multiple sclerosis patients.

BACKGROUND: Despite impressive efficacy in immunocompetent individuals, the immunogenicity of a single dose of COVID-19 vaccine in B-cell-deplete patients remains unknown. OBJECTIVES: We aimed to quantify real-world vaccine immunogenicity in ocrelizumab recipients. METHODS: We measured post-vaccination SARS-COV-2 immunoglobulin G (IgG) in ocrelizumab recipients using a highly sensitive Luminex assay. RESULTS: 44.1% of patients had detectable SARS-COV-2-IgG 21+ days after one vaccine dose, regardless of vaccine type (AZD1222 vs BNT162b2, odds ratio (OR) = 0.62, 95% confidence interval (CI) = 0.157-2.32, p = 0.72). B-cell count strongly predicted seroconversion (ß1 = 12.38, 95% CI = 4.59-20.16, p = 0.0029), but undetectable B-cells did not preclude it. The second vaccine seroconverted 53% of the patients who had not already responded to dose 1. CONCLUSION: Humoral response after one COVID-19 vaccine dose is lower than expected in CD20-deplete patients.

The self-fulfilling prophecy of pulmonary fibrosis: a selective inspection of pathological signalling loops.

Pulmonary fibrosis is a devastating, progressive disease and carries a prognosis worse than most cancers. Despite ongoing research, the mechanisms that underlie disease pathogenesis remain only partially understood. However, the self-perpetuating nature of pulmonary fibrosis has led several researchers to propose the existence of pathological signalling loops. According to this hypothesis, the normal wound-healing process becomes corrupted and results in the progressive accumulation of scar tissue in the lung. In addition, several negative regulators of pulmonary fibrosis are downregulated and, therefore, are no longer capable of inhibiting these feed-forward loops. The combination of pathological signalling loops and loss of a checks and balances system ultimately culminates in a process of unregulated scar formation. This review details specific signalling pathways demonstrated to play a role in the pathogenesis of pulmonary fibrosis. The evidence of detrimental signalling loops is elucidated with regard to epithelial cell injury, cellular senescence and the activation of developmental and ageing pathways. We demonstrate where these loops intersect each other, as well as common mediators that may drive these responses and how the loss of pro-resolving mediators may contribute to the propagation of disease. By focusing on the overlapping signalling mediators among the many pro-fibrotic pathways, it is our hope that the pulmonary fibrosis community will be better equipped to design future trials that incorporate the redundant nature of these pathways as we move towards finding a cure for this unrelenting disease.

A double dilemma: treatment of stage IV fetal twin-twin transfusion syndrome in the setting of maternal recurrent venous thromoembolism: a case report.

BACKGROUND: Fetal conditions can pose significant challenges in the management of pregnancies complicated by pre-existing maternal medical conditions. CASE PRESENTATION: We report a case of a 34-year-old woman with Stage IV Twin Twin Transfusion syndrome in the presence of maternal recurrent complex venous thromboembolic disease. Following a previous pregnancy loss, complicated by a third episode of thromboembolic disease, an inferior vena cava filter was placed. One month later, a pregnancy was confirmed and subsequently identified as a monochorionic twin pregnancy. Twin-Twin Transfusion syndrome was identified at 18 weeks' gestation and progressed rapidly to Quintero Stage IV. In consultation with a multi-disciplinary international team, fetoscopic laser photocoagulation was performed. The pregnancy progressed to delivery of female infants at 33 weeks gestation, who have achieved all developmental milestones at 2 years of age. CONCLUSIONS: We describe the multi-disciplinary effort to optimise the maternal condition to allow fetoscopic laser photocoagulation and continued management of the maternal and fetal conditions to a successful pregnancy outcome.

Psychodynamic therapy for non-compliance: a case report.

OBJECTIVES: This paper outlines the use of psychodynamic psychotherapy as an adjunct to treatment as usual for addressing challenging behaviours in a patient with schizophrenia under the care of a community mental health team (CMHT) in South Australia. METHODS: Ms P suffered from schizophrenia and demonstrated challenging behaviours in the context of being administered depot medication under a community treatment order (CTO). Multiple attempts at addressing non-compliance and consistently disruptive behaviour through conventional methods had failed. Consequently, the novel approach of fortnightly psychodynamic psychotherapy sessions was trialled for 5 months, augmenting treatment as usual. RESULTS: Psychodynamic psychotherapy proved effective for this patient. With treatment, she showed an improved compliance and overall engagement. Additionally, consequent to regularly receiving medication, her mental state improved and hospitalisations decreased. CONCLUSIONS: Further research could lead to a better understanding of how and in what contexts, psychodynamic therapy and psychodynamic thinking can be utilised in the public health system.

Cigarette smoke dampens antiviral signaling in small airway epithelial cells by disrupting TLR3 cleavage.

Cigarette smokers and people exposed to second-hand smoke are at an increased risk for pulmonary viral infections, and yet the mechanism responsible for this heightened susceptibility is not understood. To understand the effect of cigarette smoke on susceptibility to viral infection, we used an air-liquid interface culture system and exposed primary human small airway epithelial cells (SAEC) to whole cigarette smoke, followed by treatment with the viral mimetic polyinosinic polycytidylic acid (poly I:C) or influenza A virus (IAV). We found that prior smoke exposure strongly inhibited production of proinflammatory (interleukin-6 and interleukin-8) and antiviral [interferon-γ-induced protein 10 (IP-10) and interferons] mediators in SAECs in response to poly I:C and IAV infection. Impaired antiviral responses corresponded to increased infection with IAV. This was associated with a decrease in phosphorylation of the key antiviral transcription factor interferon response factor 3 (IRF3). Here, we found that cigarette smoke exposure inhibited activation of Toll-like receptor 3 (TLR3) by impairing TLR3 cleavage, which was required for downstream phosphorylation of IRF3 and production of IP-10. These results identify a novel mechanism by which cigarette smoke exposure impairs antiviral responses in lung epithelial cells, which may contribute to increased susceptibility to respiratory infections.

Endogenous ligands of the aryl hydrocarbon receptor regulate lung dendritic cell function.

The aryl hydrocarbon receptor (AhR) is a transcription factor that has been extensively studied as a regulator of toxicant metabolism. However, recent evidence indicates that the AhR also plays an important role in immunity. We hypothesized that the AhR is a novel, immune regulator of T helper type 2 (Th2) -mediated allergic airway disease. Here, we report that AhR-deficient mice develop increased allergic responses to the model allergen ovalbumin (OVA), which are driven in part by increased dendritic cell (DC) functional activation. AhR knockout (AhR(-/-) ) mice sensitized and challenged with OVA develop an increased inflammatory response in the lung compared with wild-type controls, with greater numbers of inflammatory eosinophils and neutrophils, greater T-cell proliferation, greater production of Th2 cytokines, and higher levels of OVA-specific IgE and IgG1. Lung DCs from AhR(-/-) mice stimulated antigen-specific proliferation and Th2 cytokine production by naive T cells in vitro. Additionally, AhR(-/-) DCs produced higher levels of tumour necrosis factor-α and interleukin-6, which promote Th2 differentiation, and expressed higher cell surface levels of stimulatory MHC Class II and CD86 molecules. Overall, loss of the AhR was associated with enhanced T-cell activation by pulmonary DCs and heightened pro-inflammatory allergic responses. This suggests that endogenous AhR ligands are involved in the normal regulation of Th2-mediated immunity in the lung via a DC-dependent mechanism. Therefore, the AhR may represent an important target for therapeutic intervention in allergic airways inflammation.

Dung biomass smoke activates inflammatory signaling pathways in human small airway epithelial cells.

Animal dung is a biomass fuel burned by vulnerable populations who cannot afford cleaner sources of energy, such as wood and gas, for cooking and heating their homes. Exposure to biomass smoke is the leading environmental risk for mortality, with over 4,000,000 deaths each year worldwide attributed to indoor air pollution from biomass smoke. Biomass smoke inhalation is epidemiologically associated with pulmonary diseases, including chronic obstructive pulmonary disease (COPD), lung cancer, and respiratory infections, especially in low and middle-income countries. Yet, few studies have examined the mechanisms of dung biomass smoke-induced inflammatory responses in human lung cells. Here, we tested the hypothesis that dung biomass smoke causes inflammatory responses in human lung cells through signaling pathways involved in acute and chronic lung inflammation. Primary human small airway epithelial cells (SAECs) were exposed to dung smoke at the air-liquid interface using a newly developed, automated, and reproducible dung biomass smoke generation system. The examination of inflammatory signaling showed that dung biomass smoke increased the production of several proinflammatory cytokines and enzymes in SAECs through activation of the activator protein (AP)-1 and arylhydrocarbon receptor (AhR) but not nuclear factor-κB (NF-κB) pathways. We propose that the inflammatory responses of lung cells exposed to dung biomass smoke contribute to the development of respiratory diseases.

Managing novel orally administered anticoagulants in patients undergoing urogynaecological surgery.

The use of novel orally administered anticoagulant agents (NOACs) provides new challenges to clinicians in the perioperative care of patients undergoing urogynaecological surgery. We aimed to assess evidence for managing patients taking NOACs before and after urogynaecological surgery. We conducted a literature search in CINAHL, MEDLINE, CENTRAL, Cochrane Library and PubMed for original research articles in the English language on this topic. However, despite initially identifying 556 articles, no articles pertained to the use of NOACs in urogynaecological surgery. We subsequently reviewed national and international guidance on managing patients prescribed NOACs and created a concise guideline to aid urogynaecologists in the perioperative care of these patients. Consensus is needed on perioperative optimisation of anticoagulation in urogynaecological patients using NOACs.

Perinatal outcomes of reduced fetal movements: a cohort study.

BACKGROUND: The perception of reduced fetal movement (RFM) is an important marker of fetal wellbeing and is associated with poor perinatal outcome (such as intra-uterine death). METHODS: We conducted a prospective study of women presenting with RFM over 28 weeks' gestation to a tertiary-level maternity hospital. We examined pregnancy outcomes and compared them to a retrospectively collected control group delivering contemporaneously. RESULTS: In total, 275 presentations were analysed in the RFM group, with 264 in the control group. Women with RFM were more likely to be nulliparous (p = 0.002) and have an induction of labour (p = 0.0011). 26.5 % (n = 73) of cases were admitted following presentation with RFM, and 79.4 % (n = 58) delivered on primary presentation. Overall, 15.2 % (n = 42) women were induced for RFM specifically. CONCLUSION: This prospective study shows the increased burden of care required by those with RFM, including increased neonatal unit admission rates, increased induction rates and higher surveillance demands, demonstrating the need for increased attention to this area of practice.

Inhibition of transglutaminase 2, a novel target for pulmonary fibrosis, by two small electrophilic molecules.

Idiopathic pulmonary fibrosis (IPF) is characterized by progressive fibrotic destruction of normal lung architecture. Due to a lack of effective treatment options, new treatment approaches are needed. We previously identified transglutaminase (TG)2, a multifunctional protein expressed by human lung fibroblasts (HLFs), as a positive driver of fibrosis. TG2 catalyzes crosslinking of extracellular matrix proteins, enhances cell binding to fibronectin and integrin, and promotes fibronectin expression. We investigated whether the small electrophilic molecules 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO) and 15-deoxy-delta-12,14-prostaglandin J2 (15d-PGJ2) inhibit the expression and profibrotic functions of TG2. CDDO and 15d-PGJ2 reduced expression of TG2 mRNA and protein in primary HLFs from control donors and donors with IPF. CDDO and 15d-PGJ2 also decreased the in vitro profibrotic effector functions of HLFs including collagen gel contraction and cell migration. The decrease in TG2 expression did not occur through activation of the peroxisome proliferator activated receptor γ or generation of reactive oxidative species. CDDO and 15d-PGJ2 inhibited the extracellular signal-regulated kinase pathway, resulting in the suppression of TG2 expression. This is the first study to show that small electrophilic compounds inhibit the expression and profibrotic effector functions of TG2, a key promoter of fibrosis. These studies identify new and important antifibrotic activities of these two small molecules, which could lead to new treatments for fibrotic lung disease.

The importance of collaboration in maternal medicine: A retrospective descriptive study of a maternal multidisciplinary team meeting.

OBJECTIVE: In the present study we aimed to review the evolution and function of the maternal medicine multidisciplinary team (MMMDT) meeting of a maternal medicine service of a tertiary level stand-alone maternity hospital. METHODS: We conducted a retrospective descriptive study of all minutes of MMMDT meetings from 2014 to 2020, with the aim of evaluating meeting characteristics and patient demographics. RESULTS: There were 575 multidisciplinary team (MDT) discussions of 486 women during 43 meetings in the 7 year period. On average, 13 (range 3-23; SD = 5.28) women were discussed at each meeting, attended by 17 (range: 11-27; SD = 4.26) attendees. There were 18 women discussed during successive pregnancies. When analyzing the 2017-2020 data, preconceptual discussions made up 7.3% (n = 42) of patients discussed, with 5.7% (n = 33) being postnatal. The mean maternal age was 32.5 years (range 15-48 years) and women were most likely to be discussed in the mid-trimester period (21-24 weeks gestation). The top five primary specialities involved were hematology, neurology, rheumatology, neurosurgery and gastroenterology; however, 22 specialities were represented overall when classified by the primary medical condition. When examining the MDT input, hematology input was required in 144 patients (25.0%), radiology in 161 (28.0%) patients, and 117 in anesthesiology (20.3%). When examining the number of teams required to manage the patient, 80 women required the input of three specialities, with 16 women requiring the input of four specialities. CONCLUSION: We demonstrate the value and role of the MDT in the management of complex patients, providing a forum to discuss care in all phases of the obstetric journey.

Exploring a Potential Interaction Between the Effect of Specific Maternal Smoking Patterns and Comorbid Antenatal Depression in Causing Postpartum Depression.

Purpose: To explore a potential interaction between the effect of specific maternal smoking patterns and the presence of antenatal depression, as independent exposures, in causing postpartum depression (PPD). Methods: This case-control study of participants with singleton term births (N = 51220) was based on data from the 2017-2018 Pregnancy Risk Assessment Monitoring System. Multivariable log-binomial regression models examined the main effects of smoking patterns and self-reported symptoms of antenatal depression on the risk of PPD on the adjusted risk ratio (aRR) scale and tested a two-way interaction adjusting for covariates selected in a directed acyclic graph (DAG). The interaction effects were measured on the additive scale using relative excess risk due to interaction (RERI), the attributable proportion of interaction (AP), and the synergy index (SI). Causal effects were defined in a counterfactual framework. The E-value quantified the potential impact of unobserved/unknown covariates, conditional on observed covariates. Results: Among 6841 women in the sample who self-reported PPD, 35.7% also reported symptoms of antenatal depression. Out of 3921 (7.7%) women who reported smoking during pregnancy, 32.6% smoked at high intensity (≥10 cigarettes/day) in all three trimesters and 36.6% had symptoms of antenatal depression. The main effect of PPD was the strongest for women who smoked at high intensity throughout pregnancy (aRR 1.65; 95% CI: 1.63, 1.68). A synergistic interaction was detected, and the effect of all maternal smoking patterns was augmented, particularly in late pregnancy for Increasers and Reducers. Conclusion: Strong associations and interaction effects between maternal smoking patterns and co-occurring antenatal depression support smoking prevention and cessation interventions during pregnancy to lower the likelihood of PPD.

Splenic vein rupture in pregnancy: A case report and systematic review of the literature.

Splenic vein aneurysm (SVA) rupture is a rare clinical entity, with few case reports detailing its occurrence during pregnancy. We describe a case of a SVA rupture and present a systematic review of the literature in relation to splenic vein rupture, with or without aneurysm. Our case was of a 30-year-old woman, Para 4 at 37 weeks' gestation who presented with significant abdominal pain and subsequent maternal collapse. Massive intra-abdominal hemorrhage was identified, with splenic vessel rupture suspected. A splenectomy and partial pancreatectomy were performed along with massive blood product transfusion. There was both maternal and fetal survival with no long-term sequelae at follow-up. Histological examination of the spleen and its vessels noted a SVA rupture. In a subsequent systematic review of the literature, we identified 10 cases of splenic vein rupture with only two previously documented cases of SVA rupture in pregnancy. Maternal and fetal survival has only been reported in two cases of splenic vein rupture, with ours being a third.

Follow-up and outcomes of patients with a pregnancy of unknown location: A comparison of two prediction models.

BACKGROUND: The time period while delineating the final diagnosis following presentation with a pregnancy of unknown location (PUL) can be an anxious time, as well as being time and resource intensive. Prediction models have been utilised in order to tailor counselling, frame expectations and plan care. OBJECTIVES: We aimed to review diagnoses of PUL in our population and assess the value of two prediction models. STUDY DESIGN: We reviewed all 394 PUL diagnoses over a three year period in a tertiary level maternity hospital. We then retrospectively applied the M1 and M6NP models to assess their accuracy when compared to the final diagnosis. RESULTS: PUL comprises of 2.9% (394/13401) of attendances in our unit, requiring 752 scans and 1613 separate blood tests. Just under one in ten women (9.9%, n = 39) presenting with a PUL had a viable pregnancy at discharge, however of the remainder, only 18.0% (n = 83) required medical or surgical treatment for a PUL. The M1 model was more successful at predicting an ectopic pregnancy than the M6NP, with the latter over-predicting viable pregnancies (33.4%, n = 77). CONCLUSIONS: We demonstrate that the management of women with a PUL could be stratified through the application of outcome prediction models, having positive results for framing expectations and potentially reducing this resource-intensive diagnosis.

Factors influencing medical students' decision to pursue a career in obstetrics and gynaecology.

INTRODUCTION: The career intentions of medical students can exert influence on service provision and medical staffing in the health services. It is vital for a specialty's development and sustainability that it has a constant stream of trainees into it annually. An appreciation of how a specialty is viewed by medical students can be used as an opportunity for early intervention in order to improve perception of the specialty and reduce future workforce problems, such as retention and attrition within obstetrics and gynaecology (O&G). We aimed to analyse positive and negative factors of the specialty of O&G as perceived by medical students in order to gain insight into changes that need to be made to improve recruitment and retention into the specialty. METHODS: A 70-item structured questionnaire consisting of demographic information and 5-point Likert scale questions relating to O&G was administered to final year medical students in the Republic of Ireland. Data were analysed with descriptive statistics, logistic regression, and odds ratios as appropriate. RESULTS: Of 195 medical students approached, 134 completed the questionnaire, a response rate of 68.7%. The majority were female (55.2%, n = 74) and 76.1% of respondents (n = 102) were Direct Entry Medicine students, with the remainder Graduate Entry Medicine students. 30.8% (n = 41) of students who responded scored 6 or more on a 10-point Likert scale when asked about their likelihood of considering a career in O&G. Students' clerkship experience factored heavily into their perception of the specialty and was more likely to be positive if they experienced direct consultant engagement and the opportunity for hands-on experience. Lifestyle factors, litigation and media were found to be deterrents to considering the specialty after graduation. CONCLUSIONS: This study demonstrates the importance of good clerkship experience in fostering an interest amongst undergraduates in O&G. Educators and those working within the specialty should showcase the strengths of the specialty during undergraduate education, and work on ameliorating deterrents to ultimately provide a structured approach to improving recruitment into O&G.

Benefits of a collaborative approach to service evaluation in urgent care.

Collaboration and service evaluation are essential enablers for improving models of health and social care. Significant benefits can be achieved when they are combined to form a collaborative service evaluation, particularly when such collaboration involves different clinical professions. This article uses the NHS 111 Wales service to explore a simple example of collaborative service evaluation and to discuss the benefits and challenges identified. While the tabletop exercises described were expected to focus solely on compliance data and the reasons for non-compliance, broader learning was identified for all parties involved. It became clear that there was a lack of shared understanding of each service, and that there were opportunities for education and opportunities to develop new national pathways. It is hoped that readers may be able to compare, learn and possibly replicate the collaborative approach used in their practice settings to achieve similar outcomes.

Synthesis of three asymmetric N-confused tetraarylporphyrins.

Two monosubstituted and one tetrasubstituted N-confused porphyrins (1-3) were prepared in ca. 3-5% yields using a [2 + 2] synthesis. The monosubstituted porphyrins have carbomethoxy (1) or nitro (2) substituents on one of the meso-phenyl groups, while the meso-phenyl groups of the third NCP (3) are substituted with nitro, bromo, and methyl groups in an AB(2)C pattern. The specific regiochemistry of the aryl rings around the macrocycle in each porphyrin was definitively determined using a combination of 1D ((1)H and (13)C) and 2D (gHMBC, gHSQC and ROESY) NMR spectroscopy. The absorption spectra of 1-3 in CH(2)Cl(2) are similar to those of N-confused tetraphenylporphyrin (NCTPP) but have Soret and Q bands that are shifted to lower energies with smaller extinction coefficients in comparison to those for NCTPP.

A novel strategy to reduce the immunogenicity of biological therapies.

Biological therapies, even humanized mAbs, may induce antiglobulin responses that impair efficacy. We tested a novel strategy to induce tolerance to a therapeutic mAb. Twenty patients with relapsing-remitting multiple sclerosis received an initial cycle of alemtuzumab (Campath-1H), up to 120 mg over 5 d, preceded by 500 mg SM3. This Ab differs from alemtuzumab by a single point mutation and is designed not to bind to cells. Twelve months later, they received a second cycle of alemtuzumab, up to 72 mg over 3 d. One month after that, 4 of 19 (21%) patients had detectable serum anti-alemtuzumab Abs compared with 145 of 197 (74%) patients who received two cycles of alemtuzumab without SM3 in the phase 2 CAMMS223 trial (p < 0.001). The efficacy and safety profile of alemtuzumab was unaffected by SM3 pretreatment. Long-lasting "high-zone" tolerance to a biological therapy may be induced by pretreatment with a high i.v. dose of a drug variant, altered to reduce target-binding.

Induction of labor: reviewing the past to improve the future.

BACKGROUND: Women undergoing induction of labor should be empowered with accurate information. OBJECTIVE: This study aimed to examine the characteristics of and indications for induction of labor and delivery outcomes to help inform practice and counseling. STUDY DESIGN: We conducted a retrospective cohort study of all singleton pregnancies undergoing induction of labor over a 3-month period in a tertiary-level hospital in the Republic of Ireland. Data were obtained from paper and electronic registries. Descriptive and inferential statistics were performed on data collected. RESULTS: There were 1084 women delivered, with an induction rate of 46.0% (n=499). Primiparous women were more likely to be induced compared with multiparous women (51.4%; n=254/494 vs 41.5%; n=245/590; P<.001), and were more likely to be induced for postmaturity (30.7%; n=78/254 vs 23.6%; 58/245; P≤.001). More than half (50.3%; 251/399) were induced before 40 weeks' gestation, irrespective of parity. Multiparous women and those induced for maternal medical indications had a shorter overall time to delivery interval (21.7 hours [standard deviation, 13.0] vs 13.8 hours [standard deviation, 11.2]; P<.001 and 18.3 hours [standard deviation, 12.7] vs 14.7 hours [standard deviation, 12.4]; P<.01). CONCLUSION: Information on induction of labor can aid in the guidance and education of women undergoing the process, educate clinicians for appropriate counseling, and facilitate shared decision-making.