Simultaneous switching of two different CO2-switchable amines in the same solution.

Most CO2-responsive systems operate by using a base in water that is expected to be mostly deprotonated when under an atmosphere of air and mostly protonated under an atmosphere of CO2. This concept has led to the development of many different CO2-responsive materials such as solvents, polymers, surfactants, and solutes. As CO2-responsive materials research continues, more complex systems may be developed, including systems containing two different bases with different basicities. Understanding the influence each base has on the protonation equilibrium of the other base is important for designing systems in which effective deprotonation and protonation occur. This article presents a model that can predict the solution pH and the % protonation of two different bases at various concentrations under air and CO2. Experimental data was collected to demonstrate the successful simultaneous switching of two amines and to evaluate the accuracy of the predictive model. The simultaneous switching of two different CO2-switchable amines in the same solution was determined to be possible but only if the amine concentrations and basicities are within certain ranges, and only if the pKaH values of the two bases differ by no more than 3 units.

Cognitive remediation in residential substance use treatment: A randomized stepped-wedge trial.

ABSTRACTExecutive dysfunction is common in individuals with substance use disorder (SUD) and presents a barrier to treatment engagement. The study aimed to investigate the effectiveness of cognitive remediation (CR) for improving executive functioning and treatment retention in patients with SUD, using a stepped-wedge cluster randomized controlled trial. The sample included 527 adults enrolled across ten residential SUD treatment providers in NSW, Australia. The intervention consisted of 12 hours of CR delivered over six weeks in a group format. The comparator was treatment-as-usual (TAU). Primary outcomes included self-reported executive functioning and proportion of treatment completed (PoTC), measured as the number of days in treatment divided by the planned treatment duration. Intention-to-treat analysis did not find significant differences for self-reported executive functioning (mean difference = -2.49, 95%CI [-5.07, 0.09], p = .059) or PoTC (adjusted mean ratio = 1.09, 95%CI [0.88, 1.36], p = .442). Due to high dropout from the intention-to-treat sample (56%) a post-hoc analysis was conducted using a per-protocol approach, in which CR was associated with improved self-reported executive functioning (mean difference = -3.33, 95%CI [-6.10, -0.57], p = .019) and improved likelihood of treatment graduation (adjusted odds ratio = 2.43, 95%CI [1.43, 4.11], p < .001). More research is required to develop a CR approach that results in service-wide treatment effectiveness.

Tobacco treatment incorporating contingency management, nicotine replacement therapy, and behavioral counseling for pregnant women who use substances: a feasibility trial.

Introduction: Most pregnant women with substance use problems smoke, and few will quit during their pregnancy. Tobacco treatment is often overlooked, with the focus usually placed on other substance use. Additionally, few targeted effective treatments for this group exist. To address this, the feasibility of an intensive tobacco treatment incorporating contingency management (CM) that featured non-face-to-face delivery was examined. Methods: A single-arm pre-post design feasibility trial was conducted in three antenatal services that support women who use substances in metropolitan Australia. Participants were over the age of 15, had <33-week gestation, and smoked tobacco daily. They received financial incentives for daily carbon monoxide-verified smoking abstinence or reduction through an internet-based CM programme, nicotine replacement therapy (NRT) posted to women and partners or household members who smoked and telephone-delivered behavioral counseling from study enrolment to birth. Results: Of the 101 referrals, 46 women (46%) consented. The mean (SD) age was 31(±6) years, and the gestation period was 22(±6) weeks. Nineteen (41%) of those enrolled were retained for 12-week postpartum. Of 46 women, 32 (70%) utilized CM; 32 (70%) used NRT for ≥2 weeks; 23 (50%) attended ≥1 counseling session; and 15 (22%) received NRT for partners/household members. Fifteen (33%) were verified abstinent from tobacco at delivery after a median (IQR) period of abstinence of 65(36-128) days. All non-smokers at birth utilized NRT and financial incentives, and 9/15 (60%) utilized counseling. Four (9%) were abstinent at 12-week postpartum. Median cigarettes smoked/day reduced from baseline to delivery (10(6-20) to 1(0-6) p =< 0.001). Women who quit smoking had more education (72% vs. 33% p =< 0.02), completed more CO samples (median (IQR) 101(59-157) vs. 2(0-20) p =< 0.001), and received more incentives (median (IQR) $909($225-$1980) vs. $34($3-$64) p =< 0.001). Intervention acceptability was rated favorably by participants (9 items rated 0-10 with scores >5 considered favorable). Discussion: This study demonstrated the feasibility and acceptability of a consumer-informed, non-face-to-face intensive tobacco treatment, highlighting the potential of remotely delivered technology-based CM to reduce the health impact of tobacco smoking in high-priority populations. The intervention demonstrates scale-up potential. Future studies should extend treatment into the postpartum period, utilizing new technologies to enhance CM delivery and improve counseling provision and partner support. Clinical trial registration: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=374196, ACTRN1261800056224.

Subducting volcaniclastic-rich upper crust supplies fluids for shallow megathrust and slow slip.

Recurring slow slip along near-trench megathrust faults occurs at many subduction zones, but for unknown reasons, this process is not universal. Fluid overpressures are implicated in encouraging slow slip; however, links between slow slip, fluid content, and hydrogeology remain poorly known in natural systems. Three-dimensional seismic imaging and ocean drilling at the Hikurangi margin reveal a widespread and previously unknown fluid reservoir within the extensively hydrated (up to 47 vol % H2O) volcanic upper crust of the subducting Hikurangi Plateau large igneous province. This ~1.5 km thick volcaniclastic upper crust readily dewaters with subduction but retains half of its fluid content upon reaching regions with well-characterized slow slip. We suggest that volcaniclastic-rich upper crust at volcanic plateaus and seamounts is a major source of water that contributes to the fluid budget in subduction zones and may drive fluid overpressures along the megathrust that give rise to frequent shallow slow slip.

Protocol paper for SMART OPS: Shared decision-making Multidisciplinary Approach - a Randomised controlled Trial in the Older adult Population considering Surgery.

INTRODUCTION: The Australian population presenting with surgical pathology is becoming older, frailer and more comorbid. Shared decision-making is rapidly becoming the gold standard of care for patients considering high-risk surgery to ensure that appropriate, value-based healthcare decisions are made. Positive benefits around patient perception of decision-making in the immediacy of the decision are described in the literature. However, short-term and long-term holistic patient-centred outcomes and cost implications for the health service require further examination to better understand the full impact of shared decision-making in this population. METHODS: We propose a novel multidisciplinary shared decision-making model of care in the perioperative period for patients considering high-risk surgery in the fields of general, vascular and head and neck surgery. We assess it in a two arm prospective randomised controlled trial. Patients are randomised to either 'standard' perioperative care, or to a multidisciplinary (surgeon, anaesthetist and end-of-life care nurse practitioner or social worker) shared decision-making consultation. The primary outcome is decisional conflict prior to any surgical procedure occurring. Secondary outcomes include the patient's treatment choice, how decisional conflict changes longitudinally over the subsequent year, patient-centred outcomes including life impact and quality of life metrics, as well as morbidity and mortality. Additionally, we will report on healthcare resource use including subsequent admissions or representations to a healthcare facility up to 1 year. ETHICS AND DISSEMINATION: This study has been approved by the Hunter New England Human Research Ethics Committee (2019/ETH13349). Study findings will be presented at local and national conferences and within scientific research journals. TRIAL REGISTRATION NUMBER: ACTRN12619001543178.

A Novel, Paresthesia-Free Spinal Cord Stimulation Waveform for Chronic Neuropathic Low Back Pain: Six-Month Results of a Prospective, Single-Arm, Dose-Response Study.

OBJECTIVES: The aim of this prospective, single-blinded, dose-response study was to evaluate the safety and efficacy of a novel, paresthesia-free (subperception) spinal cord stimulation (SCS) waveform designed to target dorsal horn dendrites for the treatment of chronic neuropathic low back pain (LBP). MATERIALS AND METHODS: Twenty-seven participants with chronic neuropathic LBP were implanted with a commercial SCS system after a successful trial of SCS therapy. Devices were programmed to deliver the investigative waveform (100 Hz, 1000 µs, T9/T10 bipole) at descending stimulation perception threshold amplitudes (80%, 60%, 40%). Programs were evaluated at six, ten, and 14 weeks, after which participants selected their preferred program, with more follow-up at 26 weeks (primary outcomes). Participants were blinded to the nature of the programming. Pain score (visual analog scale [VAS]), Brief Pain Inventory (BPI), quality of life (EQ-5D-5L), and health status (36-Item Short Form [SF-36]) were measured at baseline and follow-ups. Responder rate, treatment satisfaction, clinician global impression of change, and adverse events (AEs) also were evaluated. RESULTS: Mean (± SD) baseline VAS was 72.5 ± 11.2 mm. At 26 weeks (n = 26), mean change from baseline in VAS was -51.7 mm (95% CI, -60.7 to -42.7; p < 0.001), with 76.9% of participants reporting ≥50% VAS reduction, and 46.2% reporting ≥80% VAS reduction. BPI, EQ-5D-5L, and SF-36 scores were all statistically significantly improved at 26 weeks (p < 0.001), and 100% of participants were satisfied with their treatment. There were no unanticipated AEs related to the study intervention, device, or procedures. CONCLUSIONS: This novel, paresthesia-free stimulation waveform may be a safe and effective option for patients with chronic neuropathic LBP eligible for SCS therapy and is deliverable by all current commercial SCS systems. CLINICAL TRIAL REGISTRATION: This study is registered on anzctr.org.au with identifier ACTRN12618000647235.

The relationship between pitch contours in infant-directed speech and early signs of autism in infancy.

PURPOSE: Mother-infant interactions during the first year of life are crucial to healthy infant development. The infant-directed speech (IDS), and specifically pitch contours, used by mothers during interactions are associated with infant language and social development. However, little research has examined pitch contours towards infants with socio-communication and language differences, such as those displaying early signs of autism spectrum disorder (autism). This study aimed to explore the association of infant autism signs and pitch contours used by mothers with their 12-month-old infants. METHOD: Mother-infant dyads (n = 109) were recruited from the University of Newcastle BabyLab. Parent-infant dyads completed a 15-min interaction, from which a total of 36,128 pitch contours were measured and correlated with infant autism signs. Infant autism signs were assessed via parent-report (First Year Inventory; Reznick et al., 2007). A subset of high-risk infants (admitted to a neonatal intensive care unit, n = 29) also received an observation-based assessment (Autism Detection in Early Childhood; Young & Nah, 2016). RESULTS: Mothers used fewer sinusoidal contours when they rated their infant as displaying more autism signs (rs = - .30, p = .004) and more autism-related sensory regulation issues (rs = - .31, p = .001). Mothers used fewer flat contours if their infant displayed more researcher-rated autism signs (r2 = - .39, p = .04). CONCLUSIONS: This study provides the early evidence that maternal pitch contours in IDS are related to early autism signs in infancy. If our findings are replicated in follow up studies where infants are followed to diagnosis, maternal IDS may be an important element of future early intervention protocols that focus on communication for infants with risk for autism.

Optimal cancer care pathways - the ideal versus reality for patient-centric cancer care during COVID-19.

Objectives To assess whether compliance with the nationally endorsed Optimal Care Pathways is evident in 75% of patients treated with curative intent treatment and if this compliance was impacted by the COVID-19 pandemic (hereinafter COVID-19). Methods This retrospective study included patients undergoing curative treatment with radiotherapy in head and neck (HN), breast, lung and gastrointestinal malignancies between January 2019 and June 2021 in a single NSW outer metropolitan cancer service. For care delivered within the remit of cancer services, the primary outcome measure was the proportion of patients whose treatment complied with the Optimal Care Pathways recommended time frame. Secondary outcome measures included evaluating the effect of COVID-19 on the proportion of patients being treated within the recommended time frame. Results There were n = 733 eligible patients across the five tumour streams with the majority being breast cancer patients comprising 65% (n = 479) of the cohort, followed by HN cancer patients (n = 125, 17%). None of the tumour subsites abided by the 75% compliance rate. Oesophageal cancer patients had the lowest compliance rate of 4% (P < 0.001), with a similarly low compliance rate for rectal cancer patients at 33% (P = 0.002). None of the hypothesis tests to assess for detriment in treatment time during COVID-19 were statistically significant (P > 0.05). Conclusion Despite the availability of best practice guidelines, there is limited compliance throughout all cancer subtypes, which has not been negatively influenced by COVID-19. Improved awareness of the Optimal Care Pathways, and implementation of the associated infrastructure and systems, are required to support compliance.

Health-seeking behaviour of Ethiopian caregivers when infants are unwell: a descriptive qualitative study.

OBJECTIVES: To explore the health-seeking behaviour of Ethiopian caregivers when infants are unwell. DESIGN: A qualitative descriptive approach was employed using in-depth interviews and focus group discussions. Data were collected using semistructured interview guides. SETTING: The study was conducted in East Gojjam zone, Amhara region, northwest Ethiopia. PARTICIPANTS: Participants were selected using a maximum variation purposive sampling technique across the different study groups: caregivers, community members and healthcare providers. A total of 35 respondents, 27 individuals in the focus group discussions and 8 individuals in the in-depth interviews participated in the study. METHOD: In this study, a qualitative descriptive approach was employed to explore the health-seeking behaviour of caregivers. The data were collected from July to September 2019 and conventional content analysis was applied. RESULTS: The decision to take a sick child to healthcare facilities is part of a complex care-seeking process that involves many people. Some of the critical steps in the process are caregivers recognising that the child is ill, recognising the severity of the illness and deciding to take the child to a health institution based on the recognised symptoms and illness. In Ethiopia, a significant proportion of caregivers do not seek healthcare for childhood illness, and most caregivers do not know where and when to seek care for their child. This study points out that the health-seeking behaviour of caregivers can be influenced by different contextual factors such as caregivers' disease understanding, access to health services and family pressures to seek care. CONCLUSIONS: Healthcare-seeking practice plays an important role in reducing the impact of childhood illnesses and mortality. In Ethiopia, home-based treatment practice and traditional healing methods are widely accepted. Therefore, contextual understanding of the caregivers' health-seeking is important to design contextual healthcare interventions in the study area.

Precise quantum measurement of vacuum with cold atoms.

We describe the cold-atom vacuum standards (CAVS) under development at the National Institute of Standards and Technology (NIST). The CAVS measures pressure in the ultra-high and extreme-high vacuum regimes by measuring the loss rate of sub-millikelvin sensor atoms from a magnetic trap. Ab initio quantum scattering calculations of cross sections and rate coefficients relate the density of background gas molecules or atoms to the loss rate of ultra-cold sensor atoms. The resulting measurement of pressure through the ideal gas law is traceable to the second and the kelvin, making it a primary realization of the pascal. At NIST, two versions of the CAVS have been constructed: a laboratory standard used to achieve the lowest possible uncertainties and pressures, and a portable version that is a potential replacement for the Bayard-Alpert ionization gauge. Both types of CAVSs are connected to a combined extreme-high vacuum flowmeter and dynamic expansion system to enable sensing of a known pressure of gas. In the near future, we anticipate being able to compare the laboratory scale CAVS, the portable CAVS, and the flowmeter/dynamic expansion system to validate the operation of the CAVS as both a standard and vacuum gauge.

The MOHMQuit (Midwives and Obstetricians Helping Mothers to Quit Smoking) Trial: protocol for a stepped-wedge implementation trial to improve best practice smoking cessation support in public antenatal care services.

BACKGROUND: Smoking during pregnancy is the most important preventable cause of adverse pregnancy outcomes, yet smoking cessation support (SCS) is inconsistently provided. The MOMHQUIT intervention was developed to address this evidence-practice gap, using the Behaviour Change Wheel method by mapping barriers to intervention strategies. MOHMQuit includes systems, leadership and clinician elements. This implementation trial will determine the effectiveness and cost-effectiveness of MOHMQuit in improving smoking cessation rates in pregnant women in public maternity care services in Australia; test the mechanisms of action of the intervention strategies; and examine implementation outcomes. METHODS: A stepped-wedge cluster-randomised design will be used. Implementation of MOHMQuit will include reinforcing leadership investment in SCS as a clinical priority, strengthening maternity care clinicians' knowledge, skills, confidence and attitudes towards the provision of SCS, and clinicians' documentation of guideline-recommended SCS provided during antenatal care. Approximately, 4000 women who report smoking during pregnancy will be recruited across nine sites. The intervention and its implementation will be evaluated using a mixed methods approach. The primary outcome will be 7-day point prevalence abstinence at the end of pregnancy, among pregnant smokers, verified by salivary cotinine testing. Continuous data collection from electronic medical records and telephone interviews with postpartum women will occur throughout 32 months of the trial to assess changes in cessation rates reported by women, and SCS documented by clinicians and reported by women. Data collection to assess changes in clinicians' knowledge, skills, confidence and attitudes will occur prior to and immediately after the intervention at each site, and again 6 months later. Questionnaires at 3 months following the intervention, and semi-structured interviews at 6 months with maternity service leaders will explore leaders' perceptions of acceptability, adoption, appropriateness, feasibility, adaptations and fidelity of delivery of the MOHMQuit intervention. Structural equation modelling will examine causal linkages between the strategies, mediators and outcomes. Cost-effectiveness analyses will also be undertaken. DISCUSSION: This study will provide evidence of the effectiveness of a multi-level implementation intervention to support policy decisions; and evidence regarding mechanisms of action of the intervention strategies (how the strategies effected outcomes) to support further theoretical developments in implementation science. TRIAL REGISTRATION: ACTRN12622000167763, registered February 2nd 2022.

Pharmacological targeting of glutamatergic neurons within the brainstem for weight reduction.

Food intake and body weight are tightly regulated by neurons within specific brain regions, including the brainstem, where acute activation of dorsal raphe nucleus (DRN) glutamatergic neurons expressing the glutamate transporter Vglut3 (DRNVglut3) drive a robust suppression of food intake and enhance locomotion. Activating Vglut3 neurons in DRN suppresses food intake and increases locomotion, suggesting that modulating the activity of these neurons might alter body weight. Here, we show that DRNVglut3 neurons project to the lateral hypothalamus (LHA), a canonical feeding center that also reduces food intake. Moreover, chronic DRNVglut3 activation reduces weight in both leptin-deficient (ob/ob) and leptin-resistant diet-induced obese (DIO) male mice. Molecular profiling revealed that the orexin 1 receptor (Hcrtr1) is highly enriched in DRN Vglut3 neurons, with limited expression elsewhere in the brain. Finally, an orally bioavailable, highly selective Hcrtr1 antagonist (CVN45502) significantly reduces feeding and body weight in DIO. Hcrtr1 is also co-expressed with Vglut3 in the human DRN, suggesting that there might be a similar effect in human. These results identify a potential therapy for obesity by targeting DRNVglut3 neurons while also establishing a general strategy for developing drugs for central nervous system disorders.

Effectiveness, safety and cost-effectiveness of vaporized nicotine products versus nicotine replacement therapy for tobacco smoking cessation in a low-socioeconomic status Australian population: a study protocol for a randomized controlled trial.

BACKGROUND: In Australia, tobacco smoking rates have declined but inequalities remain with significantly higher smoking prevalence among low-socioeconomic populations. Clinical trial data suggest vaporized nicotine products (VNPs) aid smoking cessation. Most VNP trials have used refillable tank systems, but newer generation (pod) devices now comprise the largest market share yet have limited clinical trial evidence on safety and effectiveness. This study evaluates the effectiveness, safety and cost-effectiveness of VNPs (pod and tank device) compared with nicotine replacement therapy ([NRT]-gum or lozenge) for smoking cessation. METHODS: This is a two-arm, open-label, superiority, parallel group, randomized controlled trial (RCT) with allocation concealment and blinded outcome assessment. The RCT is conducted at the National Drug and Alcohol Research Centre at the University of New South Wales, Sydney, Australia. Participants are people who smoke daily, are interested in quitting and receive a government pension or allowance (N = 1058). Participants will be randomized (1:1 ratio) to receive 8 weeks of free: VNPs, with pod (40 mg/mL nicotine salt) and tank device (18 mg/mL freebase nicotine) in mixed flavours; or NRT (gum or lozenge; 4 mg). All participants will receive daily text message behavioural support for 5 weeks. Assessments will be undertaken by telephone at baseline, with three follow-up calls (two check-in calls within the first month and final follow-up at 7 months post randomization) to ascertain smoking status, treatment adherence and adverse events. The primary outcome is 6-month continuous abstinence verified by carbon monoxide breath test of ≤5ppm at 7-month follow-up. Safety and cost-effectiveness of VNPs versus NRT will also be evaluated. DISCUSSION: Further data are required to strengthen certainty of evidence for VNPs aiding smoking cessation, particularly for newer generation pod devices. To our knowledge, this trial is the first to offer choice of VNPs and no comparative effectiveness trial data exists for new pod devices. If effective, the findings can inform wider implementation of VNPs to aid smoking cessation in a priority group. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12621000076875. Registered on 29 January 2021.  https://www.anzctr.org.au.

Most common principal diagnoses assigned to Australian emergency department presentations involving alcohol use: a multi-centre study.

OBJECTIVES: Alcohol is the most widely consumed psychoactive substance in Australia and the consequences of alcohol consumption have enormous personal and social impacts. This study aimed to describe the principal diagnoses of emergency department (ED) presentations involving alcohol use in the previous 12 hours at eight hospitals in Victoria and the Australian Capital Territory, Australia. METHODS: Twelve months' data (1 July 2018 - 30 June 2019) were collected from eight EDs, including demographics, ICD-10 codes, hospital location and self-reported drinking in the preceding 12 hours. The ten most common ICD-10 discharge codes were analysed based on age, sex and hospital geographic area. RESULTS: ICD codes pertaining to mental and behavioural disorders due to alcohol use accounted for the highest proportion in most EDs. Suicide ideation/attempt was in the five highest ICD codes for all but one hospital. It was the second most common alcohol-related presentation for both males and females. CONCLUSIONS: Alcohol plays a major role in a range of presentations, especially in relation to mental health and suicide. IMPLICATIONS FOR PUBLIC HEALTH: The collection of alcohol involvement in ED presentations represents a major step forward in informing the community about the burden of alcohol on their health resources.

Adapting Peer Researcher Facilitated Strategies to Recruit People Receiving Mental Health Services to a Tobacco Treatment Trial.

Introduction: One of the most challenging aspects of conducting intervention trials among people who experience severe mental illness (SMI) and who smoke tobacco, is recruitment. In our parent "QuitLink" randomized controlled trial (RCT), slower than expected peer researcher facilitated recruitment, along with the impact of COVID-19 pandemic restrictions, necessitated an adaptive recruitment response. The objectives of the present study were to: (i) describe adaptive peer researcher facilitated recruitment strategies; (ii) explore the effectiveness of these strategies; (iii) investigate whether recruitment strategies reached different subgroups of participants; and (iv) examine the costs and resources required for implementing these strategies. Finally, we offer experience-based lessons in a Peer Researcher Commentary. Methods: People were included in the RCT if they smoked at least 10 cigarettes a day and were accessing mental health support from the project's two partnering mental health organizations in Victoria, Australia. The majority of people accessing these services will have been diagnosed with SMI. Recruitment occurred over 2 years. We began with peer facilitated recruitment strategies delivered face-to-face, then replaced this with direct mail postcards followed by telephone contact. In the final 4 months of the study, we began online recruitment, broadening it to people who smoked and were accessing support or treatment (including from general practitioners) for mental health and/or alcohol or other drug problems, anywhere in the state of Victoria. Differences between recruitment strategies on key participant variables were assessed. We calculated the average cost per enrolee of the different recruitment approaches. Results: Only 109 people were recruited from a target of 382: 29 via face-to-face (March 2019 to April 2020), 66 from postcards (May 2020 to November 2020), and 14 from online (November to December 2020 and January to March 2021) strategies. Reflecting our initial focus on recruiting from supported independent living accommodation facilities, participants recruited face-to-face were significantly more likely to be living in partially or fully supported independent living (n = 29, <0.001), but the samples were otherwise similar. After the initial investment in training and equipping peer researchers, the average cost of recruitment was AU$1,182 per participant-~US$850. Face-to-face recruitment was the most expensive approach and postcard recruitment the least (AU$1,648 and AU$928 per participant). Discussion: Peer researcher facilitated recruitment into a tobacco treatment trial was difficult and expensive. Widely dispersed services and COVID-19 restrictions necessitated non-face-to-face recruitment strategies, such as direct mail postcards, which improved recruitment and may be worthy of further research. Clinical Trial Registration: The trial is registered with ANZCTR (www.anzctr.org.au): ACTRN12619000244101 prior to the accrual of the first participant and updated regularly as per registry guidelines. The trial sponsor was the University of Newcastle, NSW, Australia.

Risk factors for asthma exacerbations during pregnancy: a systematic review and meta-analysis.

BACKGROUND: Conflicting literature exists regarding the risk factors for exacerbations among pregnant women with asthma. This systematic review and meta-analysis aimed to determine risk factors for asthma exacerbations during pregnancy. METHODS: Electronic databases were searched for the following terms: (asthma or wheeze) and (pregnan* or perinat* or obstet*) and (exacerb* or flare up or morbidit* or attack*).All studies published between 2000 and 24 August 2021 were considered for inclusion if they reported at least one potential risk factor of asthma exacerbations in pregnant women with asthma. Of the 3337 references considered, 35 publications involving 429 583 pregnant women with asthma were included. Meta-analyses were conducted to determine mean difference in risk factor between exacerbation groups, or the relative risks of exacerbation with certain risk factors. Good study quality was found through the Newcastle-Ottawa Scale (median score 8, interquartile range 7-9). RESULTS: Increased maternal age (mean difference 0.62, 95% CI 0.11-1.13), obesity (relative risk 1.25, 95% CI 1.15-1.37), smoking (relative risk 1.35, 95% CI 1.04-1.75), black ethnicity (relative risk 1.62, 95% CI 1.52-1.73), multiparity (relative risk 1.31, 95% CI 1.01-1.68), depression/anxiety (relative risk 1.42, 95% CI 1.27-1.59), moderate-severe asthma (relative risk 3.44, 95% CI 2.03-5.83, versus mild) and severe asthma (relative risk 2.70, 95% CI 1.85-3.95, versus mild-moderate) were associated with an increased risk of asthma exacerbations during pregnancy. CONCLUSIONS: Future interventions aimed at reducing exacerbations in pregnancy could address the modifiable factors, such as smoking and depression/anxiety, and introduce more regular monitoring for those with nonmodifiable risk factors such as obesity and more severe asthma.

Risk factors for asthma exacerbation during pregnancy: protocol for a systematic review and meta-analysis.

BACKGROUND: Asthma is the most common medical condition to affect pregnancy. Asthma exacerbations occur in up to 45% of pregnant women and have been associated with adverse perinatal and infant outcomes. Conflicting literature exists regarding the risk factors for exacerbations, and no synthesis of the literature currently exists. Therefore, this systematic review and meta-analysis aims to determine risk factors for asthma exacerbations during pregnancy among pregnant women with asthma. METHODS: This protocol has been reported according to the Preferred Reporting Items for Systematic Review and Meta-Analysis protocols checklist. A systematic search will be conducted in the electronic MEDLINE, Embase, CINAHL and Cochrane Clinical Trials Register databases (from January 2000 onwards). Eligibility of each publication will be determined based on predefined selection criteria. Prospective cohort studies, retrospective cohort studies, case-control studies and randomised controlled trials (RCTs) will be included. Quality of included studies will be determined using the Newcastle Ottawa Scale and the Cochrane Risk of Bias tool. Pooled relative risk will be computed using random-effects meta-analyses. Heterogeneity will be assessed using the chi-squared test and the I2 parameter. Publication bias will be assessed by inspecting a funnel plot for asymmetry and with the Egger's test of analyses including ten studies or more. DISCUSSION: The results of this systematic review and meta-analysis will discuss the potential risk factors for asthma exacerbations during pregnancy. This may aid healthcare professionals in early identification of pregnant women with asthma at risk of poor outcomes, providing the opportunity to implement early interventions in order to avoid deterioration of asthma symptoms during pregnancy. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020196190.

Pathways linked to unresolved inflammation and airway remodelling characterize the transcriptome in two independent severe asthma cohorts.

BACKGROUND AND OBJECTIVE: Severe asthma (SA) is a heterogeneous disease. Transcriptomic analysis contributes to the understanding of pathogenesis necessary for developing new therapies. We sought to identify and validate mechanistic pathways of SA across two independent cohorts. METHODS: Transcriptomic profiles from U-BIOPRED and Australian NOVocastrian Asthma cohorts were examined and grouped into SA, mild/moderate asthma (MMA) and healthy controls (HCs). Differentially expressed genes (DEGs), canonical pathways and gene sets were identified as central to SA mechanisms if they were significant across both cohorts in either endobronchial biopsies or induced sputum. RESULTS: Thirty-six DEGs and four pathways were shared across cohorts linking to tissue remodelling/repair in biopsies of SA patients, including SUMOylation, NRF2 pathway and oxidative stress pathways. MMA presented a similar profile to HCs. Induced sputum demonstrated IL18R1 as a shared DEG in SA compared with healthy subjects. We identified enrichment of gene sets related to corticosteroid treatment; immune-related mechanisms; activation of CD4+ T cells, mast cells and IL18R1; and airway remodelling in SA. CONCLUSION: Our results identified differentially expressed pathways that highlight the role of CD4+ T cells, mast cells and pathways linked to ongoing airway remodelling, such as IL18R1, SUMOylation and NRF2 pathways, as likely active mechanisms in the pathogenesis of SA.