Data-driven predictions of the time remaining until critical global warming thresholds are reached.

Leveraging artificial neural networks (ANNs) trained on climate model output, we use the spatial pattern of historical temperature observations to predict the time until critical global warming thresholds are reached. Although no observations are used during the training, validation, or testing, the ANNs accurately predict the timing of historical global warming from maps of historical annual temperature. The central estimate for the 1.5 °C global warming threshold is between 2033 and 2035, including a ±1σ range of 2028 to 2039 in the Intermediate (SSP2-4.5) climate forcing scenario, consistent with previous assessments. However, our data-driven approach also suggests a substantial probability of exceeding the 2 °C threshold even in the Low (SSP1-2.6) climate forcing scenario. While there are limitations to our approach, our results suggest a higher likelihood of reaching 2 °C in the Low scenario than indicated in some previous assessments-though the possibility that 2 °C could be avoided is not ruled out. Explainable AI methods reveal that the ANNs focus on particular geographic regions to predict the time until the global threshold is reached. Our framework provides a unique, data-driven approach for quantifying the signal of climate change in historical observations and for constraining the uncertainty in climate model projections. Given the substantial existing evidence of accelerating risks to natural and human systems at 1.5 °C and 2 °C, our results provide further evidence for high-impact climate change over the next three decades.

Potential for perceived failure of stratospheric aerosol injection deployment.

As anthropogenic activities warm the Earth, the fundamental solution of reducing greenhouse gas emissions remains elusive. Given this mitigation gap, global warming may lead to intolerable climate changes as adaptive capacity is exceeded. Thus, there is emerging interest in solar radiation modification, which is the process of deliberately increasing Earth's albedo to cool the planet. Stratospheric aerosol injection (SAI)-the theoretical deployment of particles in the stratosphere to enhance reflection of incoming solar radiation-is one strategy to slow, pause, or reverse global warming. If SAI is ever pursued, it will likely be for a specific aim, such as affording time to implement mitigation strategies, lessening extremes, or reducing the odds of reaching a biogeophysical tipping point. Using an ensemble climate model experiment that simulates the deployment of SAI in the context of an intermediate greenhouse gas trajectory, we quantified the probability that internal climate variability masks the effectiveness of SAI deployment on regional temperatures. We found that while global temperature was stabilized, substantial land areas continued to experience warming. For example, in the SAI scenario we explored, up to 55% of the global population experienced rising temperatures over the decade following SAI deployment and large areas exhibited high probability of extremely hot years. These conditions could cause SAI to be perceived as a failure. Countries with the largest economies experienced some of the largest probabilities of this perceived failure. The potential for perceived failure could therefore have major implications for policy decisions in the years immediately following SAI deployment.

Internal variability and forcing influence model-satellite differences in the rate of tropical tropospheric warming.

Climate-model simulations exhibit approximately two times more tropical tropospheric warming than satellite observations since 1979. The causes of this difference are not fully understood and are poorly quantified. Here, we apply machine learning to relate the patterns of surface-temperature change to the forced and unforced components of tropical tropospheric warming. This approach allows us to disentangle the forced and unforced change in the model-simulated temperature of the midtroposphere (TMT). In applying the climate-model-trained machine-learning framework to observations, we estimate that external forcing has produced a tropical TMT trend of 0.25 ± 0.08 K⋅decade-1 between 1979 and 2014, but internal variability has offset this warming by 0.07 ± 0.07 K⋅decade-1. Using the Community Earth System Model version 2 (CESM2) large ensemble, we also find that a discontinuity in the variability of prescribed biomass-burning aerosol emissions artificially enhances simulated tropical TMT change by 0.04 K⋅decade-1. The magnitude of this aerosol-forcing bias will vary across climate models, but since the latest generation of climate models all use the same emissions dataset, the bias may systematically enhance climate-model trends over the satellite era. Our results indicate that internal variability and forcing uncertainties largely explain differences in satellite-versus-model warming and are important considerations when evaluating climate models.

Learning outcomes from a systematic review workshop series for junior doctors.

BACKGROUND: Systematic reviews provide the highest level of evidence about a topic. Ten-week workshops in conducting systematic reviews were held with hospital doctors in 2019 and 2020. AIM: This study analysed participants' feedback about the systematic review workshops to improve how we teach clinicians about conducting systematic reviews. METHODS: Attendees completed a post-workshop survey (with multiple-choice and free-text items) to assess knowledge and skills gained. We compared the responses of senior and junior doctors. We used descriptive statistics for the quantitative data and compared groups using Χ2 testing. Qualitative data were analysed using conceptual content analysis. RESULTS: Of 81 attendees, 52% completed the survey. Of those, 69% had no prior experience with systematic reviews, 93% reported increased knowledge and ability to conduct research and 69% reported increased ability to conduct systematic reviews. More senior than junior clinicians reported gaining knowledge about writing and publishing (37% vs 11%, P = 0.047) and making greater use of skills gained to conduct research (56% vs 23%, P = 0.029). Five themes were identified: learning through course structure; learning through course organisation; teaching style; flexible learning; and suggestions for progression and improvement. Respondents suggested running the workshops during protected teaching time, more time for some sessions, conducting the workshop series more often and making clinicians aware of the workshop series at hospital orientation. CONCLUSION: The skills learnt from the systematic review workshop series impacted not only participants' research knowledge and skills, and plans to conduct future research, but also facilitated looking up medical literature in daily clinical work, supporting evidence-based clinical practice.

Adjuvant chemotherapy following chemoradiotherapy as primary treatment for locally advanced cervical cancer versus chemoradiotherapy alone (OUTBACK): an international, open-label, randomised, phase 3 trial.

BACKGROUND: Standard treatment for locally advanced cervical cancer is chemoradiotherapy, but many patients relapse and die of metastatic disease. We aimed to determine the effects on survival of adjuvant chemotherapy after chemoradiotherapy. METHODS: The OUTBACK trial was a multicentre, open-label, randomised, phase 3 trial done in 157 hospitals in Australia, China, Canada, New Zealand, Saudi Arabia, Singapore, and the USA. Eligible participants were aged 18 year or older with histologically confirmed squamous cell carcinoma, adenosquamous cell carcinoma, or adenocarcinoma of the cervix (FIGO 2008 stage IB1 disease with nodal involvement, or stage IB2, II, IIIB, or IVA disease), Eastern Cooperative Oncology Group performance status 0-2, and adequate bone marrow and organ function. Participants were randomly assigned centrally (1:1) using a minimisation approach and stratified by pelvic or common iliac nodal involvement, requirement for extended-field radiotherapy, FIGO 2008 stage, age, and site to receive standard cisplatin-based chemoradiotherapy (40 mg/m2 cisplatin intravenously once-a-week for 5 weeks, during radiotherapy with 45·0-50·4 Gy external beam radiotherapy delivered in fractions of 1·8 Gy to the whole pelvis plus brachytherapy; chemoradiotherapy only group) or standard cisplatin-based chemoradiotherapy followed by adjuvant chemotherapy with four cycles of carboplatin (area under the receiver operator curve 5) and paclitaxel (155 mg/m2) given intravenously on day 1 of a 21 day cycle (adjuvant chemotherapy group). The primary endpoint was overall survival at 5 years, analysed in the intention-to-treat population (ie, all eligible patients who were randomly assigned). Safety was assessed in all patients in the chemoradiotherapy only group who started chemoradiotherapy and all patients in the adjuvant chemotherapy group who received at least one dose of adjuvant chemotherapy. The OUTBACK trial is registered with ClinicalTrials.gov, NCT01414608, and the Australia New Zealand Clinical Trial Registry, ACTRN12610000732088. FINDINGS: Between April 15, 2011, and June 26, 2017, 926 patients were enrolled and randomly assigned to the chemoradiotherapy only group (n=461) or the adjuvant chemotherapy group (n=465), of whom 919 were eligible (456 in the chemoradiotherapy only group and 463 in the adjuvant chemotherapy group; median age 46 years [IQR 37 to 55]; 663 [72%] were White, 121 [13%] were Black or African American, 53 [6%] were Asian, 24 [3%] were Aboriginal or Pacific islander, and 57 [6%] were other races) and included in the analysis. As of data cutoff (April 12, 2021), median follow-up was 60 months (IQR 45 to 65). 5-year overall survival was 72% (95% CI 67 to 76) in the adjuvant chemotherapy group (105 deaths) and 71% (66 to 75) in the chemoradiotherapy only group (116 deaths; difference 1% [95% CI -6 to 7]; hazard ratio 0·90 [95% CI 0·70 to 1·17]; p=0·81). In the safety population, the most common clinically significant grade 3-4 adverse events were decreased neutrophils (71 [20%] in the adjuvant chemotherapy group vs 34 [8%] in the chemoradiotherapy only group), and anaemia (66 [18%] vs 34 [8%]). Serious adverse events occurred in 107 (30%) in the adjuvant chemotherapy group versus 98 (22%) in the chemoradiotherapy only group, most commonly due to infectious complications. There were no treatment-related deaths. INTERPRETATION: Adjuvant carboplatin and paclitaxel chemotherapy given after standard cisplatin-based chemoradiotherapy for unselected locally advanced cervical cancer increased short-term toxicity and did not improve overall survival; therefore, it should not be given in this setting. FUNDING: National Health and Medical Research Council and National Cancer Institute.

Hypoxia-Inducible Factor-1α in SM22α-Expressing Cells Modulates Alveolarization.

Worldwide, the incidence of both preterm births and chronic lung disease of infancy, or bronchopulmonary dysplasia, remains high. Infants with bronchopulmonary dysplasia have larger and fewer alveoli, a lung pathology that can persist into adulthood. Although recent data point to a role for hypoxia-inducible factor-1α (HIF-1α) in mediating pulmonary angiogenesis and alveolarization, the cell-specific role of HIF-1α remains incompletely understood. Thus, we hypothesized that HIF-1α, in a distinct subset of mesenchymal cells, mediates postnatal alveolarization. To test the hypothesis, we generated mice with a cell-specific deletion of HIF-1α by crossing SM22α promoter-driven Cre mice with HIF-1αflox/flox mice (SM22α-HIF-1α-/-), determined SM-22α-expressing cell identity using single-cell RNA sequencing, and interrogated samples from preterm infants. Deletion of HIF-1α in SM22α-expressing cells had no effect on lung structure at day 3 of life. However, at 8 days, there were fewer and larger alveoli, a difference that persisted into adulthood. Microvascular density, elastin organization, and peripheral branching of the lung vasculature were decreased in SM22α-HIF-1α-/- mice, compared with control mice. Single-cell RNA sequencing demonstrated that three mesenchymal cell subtypes express SM22α: myofibroblasts, airway smooth muscle cells, and vascular smooth muscle cells. Pulmonary vascular smooth muscle cells from SM22α-HIF-1α-/- mice had decreased angiopoietin-2 expression and, in coculture experiments, a diminished capacity to promote angiogenesis that was rescued by angiopoietin-2. Angiopoietin-2 expression in tracheal aspirates of preterm infants was inversely correlated with overall mechanical ventilation time, a marker of disease severity. We conclude that SM22α-specific HIF-1α expression drives peripheral angiogenesis and alveolarization in the lung, perhaps by promoting angiopoietin-2 expression.

Loss of prolyl hydroxylase 1 and 2 in SM22α-expressing cells prevents Hypoxia-Induced pulmonary hypertension.

Pulmonary arterial hypertension (PAH) is a disease characterized by increased vasoconstriction and vascular remodeling. Pulmonary artery smooth muscle cells (PASMCs) highly express the transcription factor hypoxia-inducible factor-1α (HIF-1α), yet the role of PASMC HIF-1α in the development of PAH remains controversial. To study the role of SMC HIF-1α in the pulmonary vascular response to acute and chronic hypoxia, we used a gain-of-function strategy to stabilize HIF-1α in PASMC by generating mice lacking prolyl hydroxylase domain (PHD) 1 and 2 in SM22α-expressing cells. This strategy increased HIF-1α expression and transcriptional activity under conditions of normoxia and hypoxia. Acute hypoxia increased right ventricular systolic pressure (RVSP) in control, but not in SM22α-PHD1/2-/- mice. Chronic hypoxia increased RVSP and vascular remodeling more in control SM22α-PHD1/2+/+ than in SM22α-PHD1/2-/- mice. In vitro studies demonstrated increased contractility and myosin light chain phosphorylation in isolated PHD1/2+/+ compared with PHD1/2-/- PASMC under both normoxic and hypoxic conditions. After chronic hypoxia, there was more p27 and less vascular remodeling in SM22α-PHD1/2-/- compared with SM22α-PHD1/2+/+ mice. Hypoxia increased p27 in PASMC isolated from control patients, but not in cells from patients with idiopathic pulmonary arterial hypertension (IPAH). These findings highlight an SM22α-expressing cell-specific role for HIF-1α in the inhibition of pulmonary vasoconstriction and vascular remodeling. Modulating HIF-1α expression in PASMC may represent a promising preventative and therapeutic strategy for patients with PAH.NEW & NOTEWORTHY In a mouse model wherein hypoxia-inducible factor 1 alpha (HIF-1α) is stabilized in vascular smooth muscle cells, we found that HIF-1α regulates vasoconstriction by limiting phosphorylation of myosin light chain and regulates vascular remodeling through p27 induction. These findings highlight a cell-specific role for HIF-1α in the inhibition of pulmonary vasoconstriction and vascular remodeling.

Prevalence of palliative radiotherapy abstracts presented at the annual scientific meetings of the Canadian Association of Radiation Oncology: 2003-2021.

PURPOSE: Approximately half of all radiotherapy (RT) is delivered with palliative intent. Clinical research in palliative RT aims to manage symptoms, improve quality of life (QoL), evaluate supportive care, and determine optimal dose-fractionation schedules. Our aim was to describe the prevalence of palliative research at the Canadian Association of Radiation Oncology (CARO) Annual Scientific Meeting (ASM) over time and compare this analysis to previously published work which evaluated the years 1992-2002. METHODS: Published abstracts (2003-2021) were independently reviewed by two authors who categorized each as curative-intent; palliative-intent; pertaining to both populations; or neither. Abstracts were considered palliative if they described incurable malignancy and interventions primarily for symptom control or QoL. Type of study, primary, site treated, and symptoms palliated were recorded. Descriptive and summary statistics were calculated including one-way ANOVA test for trend. RESULTS: Three hundred thirty-nine out of 4566 abstracts (7.4%, range 2.4-13.9% per year) were classified as palliative. 7.7% (26/339) described phase I-III trials. The main primary site was the lung (39/339) and the most common metastatic site was the bone (34.2%). QoL, symptom and toxicity outcomes were reported in 31.6% (107/339), 37.8% (128/339) and 17.7% (60/339), respectively. The most common symptom investigated was pain (38/339). The proportion of abstracts classified as curative, palliative or reporting toxicity endpoints demonstrated significant change over time (all p<0.0001). CONCLUSION: While proportion of palliative themed abstracts has increased with time, there remains a significant gap before equivalence with the prevalence of palliative RT in clinical practice is achieved.

Clinical features associated with epilepsy occurrence, resolution, and drug resistance in children with cerebral palsy: A population-based study.

AIM: To investigate clinicoradiological features associated with epilepsy, its resolution, and drug resistance in children with cerebral palsy (CP). METHOD: Data were gathered from the New South Wales/Australian Capital Territory CP Register, encompassing children with CP born between 2003 and 2015 (n = 1916). Clinical features and the severity of impairments were compared among three groups: children with current epilepsy (n = 604), those with resolved epilepsy by age 5 years (n = 109), and those without epilepsy (n = 1203). Additionally, a subset of the registry cohort attending Children's Hospital Westmead (n = 256) was analysed to compare epilepsy and treatment characteristics between drug-responsive (n = 83) and drug-resistant groups (n = 147) using logistic regression and hierarchical cluster analysis. RESULTS: Manual Ability Classification System levels IV and V, intellectual impairment, and vision impairment were found to be associated with epilepsy in children with CP on multivariable analysis (p < 0.01). Moderate to severe intellectual impairment and bilateral spastic CP were independent positive and negative predictors of epilepsy persistence at the age of 5 years respectively (p < 0.05). Microcephaly and multiple seizure types were predictors of drug-resistant epilepsy (area under the receiver operating characteristic curve of 0.83; 95% confidence interval 0.77-0.9). Children with a known genetic cause (14%) and CP epilepsy surgery group (4.3%) formed specific clinical subgroups in CP epilepsy. INTERPRETATION: Our study highlights important clinical associations of epilepsy, its resolution, and treatment response in children with CP, providing valuable knowledge to aid in counselling families and identifying distinct prognostic groups for effective medical surveillance and optimal treatment.

A natural history study of autosomal dominant GUCY2D-associated cone-rod dystrophy.

PURPOSE: To describe the natural history of autosomal dominant (AD) GUCY2D-associated cone-rod dystrophies (CRDs), and evaluate associated structural and functional biomarkers. METHODS: Retrospective analysis was conducted on 16 patients with AD GUCY2D-CRDs across two sites. Assessments included central macular thickness (CMT) and length of disruption to the ellipsoid zone (EZ) via optical coherence tomography (OCT), electroretinography (ERG) parameters, best corrected visual acuity (BCVA), and fundus autofluorescence (FAF). RESULTS: At first visit, with a mean age of 30 years (range 5-70 years), 12 patients had a BCVA below Australian driving standard (LogMAR ≥ 0.3 bilaterally), and 1 patient was legally blind (LogMAR ≥ 1). Longitudinal analysis demonstrated a deterioration of LogMAR by - 0.019 per year (p < 0.001). This accompanied a reduction in CMT of - 1.4 µm per year (p < 0.0001), lengthened EZ disruption by 42 µm per year (p = < 0.0001) and increased area of FAF by 0.05 mm2 per year (p = 0.027). Similarly, cone function decreased with increasing age, as demonstrated by decreasing b-wave amplitude of the light-adapted 30 Hz flicker and fused flicker (p = 0.005 and p = 0.018, respectively). Reduction in CMT and increased EZ disruption on OCT were associated with functional changes including poorer BCVA and decreased cone function on ERG. CONCLUSION: We have described the natural long-term decline in vision and cone function associated with mutations in GUCY2D and identified a set of functional and structural biomarkers that may be useful as outcome parameters for future therapeutic clinical trials.

Patterns of parental online health information-seeking behaviour.

AIM: This study aimed to understand parents' online health information-seeking behaviour and the potential influence of this on their relationship with their child's physician. METHODS: A survey regarding parental online health information-seeking behaviour was administered to parents of children aged under 18 years admitted to an Australian tertiary paediatric hospital, paediatric hospital ward and paediatric clinic, and in their social media networks. Responses were presented as frequencies and percentages. Associations between parents' trust in their child's doctor and survey responses were analysed using χ2 tests. RESULTS: In all, 300 surveys were completed. Most parents (89%) reported searching for online health information when their child was sick. Some (31%) followed online health information instead of going to the doctor. Parents who trusted their child's doctor were more likely to follow the doctor instead of online health information when it contained conflicting advice. Most parents (91%) wanted health-care professionals' help in searching for online health information. CONCLUSION: Almost all parents search for online health information, but most do not act on it. Parents' trust in their child's doctor influences how parents use online health information. Thus, clinicians could recommend trustworthy websites with information that complements their advice to ensure parents access reliable online health information.

Does pre-school developmental assessment agree with later intellectual assessment? A retrospective cohort study.

AIM: This study sought to assess the association between early developmental assessment of toddlers with idiopathic global developmental delay (GDD) and their later intelligence test scores. METHODS: Toddlers with idiopathic GDD attending a community clinic over a 6-year period were assessed initially using the Griffiths Mental Development Scales - Extended Revised version (GMDS-ER) and later completing formal intelligence testing using the Stanford-Binet Intelligence Scale - 5th Edition (SB5) at age 4-6 years. Spearman's correlation was used to assess the association of quotient scores across the tools. The composite quotient (GQ) and the subscale quotients of GMDS-ER were correlated with the full-scale IQ (FSIQ), verbal and non-verbal IQ scores from the SB5. RESULTS: Thirty of 153 children assessed at the clinic were eligible for the study. The correlation between GMDS-ER GQ and later SB5 FSIQ was strong (r = 0.86, P < 0.001). The subscales' associations were moderate to strong (0.48-0.71). Eighty-six percent (86%) of children with delay on GMDS-ER GQ were found later to be in the impaired category based on the FSIQ of the SB5. CONCLUSION: There was a strong association between toddlers' early developmental quotients and later IQ scores for children with idiopathic GDD, though agreement between early GDD diagnoses and later intellectual disability is not absolute. Individualised care is needed around prognostic advice and recommendations to caregivers and families in the early years, so they may effectively plan for interventions, supports and later reassessment to optimise their child's development and learning.

SM22α cell-specific HIF stabilization mitigates hyperoxia-induced neonatal lung injury.

Though survival rates for preterm infants are improving, the incidence of chronic lung disease of infancy, or bronchopulmonary dysplasia (BPD), remains high. Histologically, BPD is characterized by larger and fewer alveoli. Hypoxia-inducible factors (HIFs) may be protective in the context of hyperoxia-induced lung injury, but the cell-specific effects of HIF expression in neonatal lung injury remain unknown. Thus, we sought to determine whether HIF stabilization in SM22α-expressing cells can limit hyperoxia-induced neonatal lung injury. We generated SM22α-specific HIF-1α-stabilized mice (SM22α-PHD1/2-/- mice) by cross-breeding SM22α-promotor-driven Cre recombinase mice with prolyl hydroxylase PHD1flox/flox and PHD2flox/flox mice. Neonatal mice were randomized to 21% O2 (normoxia) or 80% O2 (hyperoxia) exposure for 14 days. For the hyperoxia recovery studies, neonatal mice were recovered from normoxia for an additional 10 wk. SM22α-specific HIF-1α stabilization mitigated hyperoxia-induced lung injury and preserved microvessel density compared with control mice for both neonates and adults. In SM22α-PHD1/2-/- mice, pulmonary artery endothelial cells (PAECs) were more proliferative and pulmonary arteries expressed more collagen IV compared with control mice, even under hyperoxic conditions. Angiopoietin-2 (Ang2) mRNA expression in pulmonary artery smooth muscle cells (PASMC) was greater in SM22α-PHD1/2-/- compared with control mice in both normoxia and hyperoxia. Pulmonary endothelial cells (PECs) cocultured with PASMC isolated from SM22α-PHD1/2-/- mice formed more tubes and branches with greater tube length compared with PEC cocultured with PASMC isolated from SM22α-PHD1/2+/+ mice. Addition of Ang2 recombinant protein further augmented tube formation for both PHD1/2+/+ and PHD1/2-/- PASMC. Cell-specific deletion of PHD1 and 2 selectively increases HIF-1α expression in SM22α-expressing cells and protects neonatal lung development despite prolonged hyperoxia exposure. HIF stabilization in SM22α-expressing cells preserved endothelial cell proliferation, microvascular density, increased angiopoietin-2 expression, and lung structure, suggesting a role for cell-specific HIF-1α stabilization to prevent neonatal lung injury.

Chemokines, soluble PD-L1, and immune cell hyporesponsiveness are distinct features of SARS-CoV-2 critical illness.

Critically ill patients manifest many of the same immune features seen in coronavirus disease 2019 (COVID-19), including both "cytokine storm" and "immune suppression." However, direct comparisons of molecular and cellular profiles between contemporaneously enrolled critically ill patients with and without severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) are limited. We sought to identify immune signatures specifically enriched in critically ill patients with COVID-19 compared with patients without COVID-19. We enrolled a multisite prospective cohort of patients admitted under suspicion for COVID-19, who were then determined to be SARS-CoV-2-positive (n = 204) or -negative (n = 122). SARS-CoV-2-positive patients had higher plasma levels of CXCL10, sPD-L1, IFN-γ, CCL26, C-reactive protein (CRP), and TNF-α relative to SARS-CoV-2-negative patients adjusting for demographics and severity of illness (Bonferroni P value < 0.05). In contrast, the levels of IL-6, IL-8, IL-10, and IL-17A were not significantly different between the two groups. In SARS-CoV-2-positive patients, higher plasma levels of sPD-L1 and TNF-α were associated with fewer ventilator-free days (VFDs) and higher mortality rates (Bonferroni P value < 0.05). Lymphocyte chemoattractants such as CCL17 were associated with more severe respiratory failure in SARS-CoV-2-positive patients, but less severe respiratory failure in SARS-CoV-2-negative patients (P value for interaction < 0.01). Circulating T cells and monocytes from SARS-CoV-2-positive subjects were hyporesponsive to in vitro stimulation compared with SARS-CoV-2-negative subjects. Critically ill SARS-CoV-2-positive patients exhibit an immune signature of high interferon-induced lymphocyte chemoattractants (e.g., CXCL10 and CCL17) and immune cell hyporesponsiveness when directly compared with SARS-CoV-2-negative patients. This suggests a specific role for T-cell migration coupled with an immune-checkpoint regulatory response in COVID-19-related critical illness.

FGF21 outperforms GDF15 as a diagnostic biomarker of mitochondrial disease in children.

Several studies have shown serum fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) levels are elevated in patients with mitochondrial disease (MD) where myopathy is a feature. In this study we investigated the utility of FGF21 and GDF15 as biomarkers for MD in a phenotypically and genotypically diverse pediatric cohort with suspected MD against a panel of healthy controls and non-mitochondrial disease controls with some overlapping clinical features. Serum was collected from 56 children with MD, 104 children with non-mitochondrial disease (27 neuromuscular, 26 cardiac, 21 hepatic, 30 renal) and 30 pediatric controls. Serum FGF21 and GDF15 concentrations were measured using ELISA, and their ability to detect MD was determined. Median FGF21 and GDF15 serum concentrations were elevated 17-fold and 3-fold respectively in pediatric MD patients compared to the healthy control group. Non-mitochondrial disease controls had elevated serum GDF15 concentrations while FGF21 concentrations were in the normal range. Elevation of GDF15 in a range of non-mitochondrial pediatric disorders limits its use as a MD biomarker. FGF21 was elevated in MD patients with a spectrum of clinical phenotypes, including those without myopathy. Serum FGF21 had an area under the receiver operating characteristic curve of 0.87, indicating good ability to discriminate between pediatric MD and healthy and non-mitochondrial disease controls. Triaging of pediatric MD patients by clinical phenotyping and serum FGF21 testing, followed by massively parallel sequencing, may enable more rapid diagnosis of pediatric MD.

Living with presbyopia: experiences from a virtual roundtable dialogue among impacted individuals and healthcare professionals.

BACKGROUND: Presbyopia is a common progressive vision disorder characterised by an inability to focus on near objects. The emergence of newer treatment options in addition to spectacles or contact lenses highlights the importance of assessing patient/user preferences. METHODS: People with presbyopia and healthcare professionals (HCPs) took part in a moderated, structured discussion of specific questions on a virtual advisory-board platform. The objective was to better understand unmet needs and the experience of living with the condition. Closed and open questions were included. RESULTS: Nine individuals (age 40 to 70 years) with presbyopia participated, from Australia, China, France, Italy, Ireland, Japan and the US. One ophthalmologist and one optometrist represented the perspective of HCPs. Over two weeks, 621 posts were entered on the platform. There was widespread agreement that the often stated association between age and presbyopia was unfortunate. Some participants had developed presbyopia at 30-45 years of age. What is more, the association with age was seen as implying a natural process, reducing the incentive to treat. Instead there was a call for an action-oriented view of presbyopia as a condition which may be effectively treated in the future. All participants experienced dealing with presbyopia as burdensome, affecting quality of life to varying degrees. When considering new treatments, convenience was the most important factor. The option to administer drops when needed was considered favourable, but short-acting treatments may not reduce inconvenience compared with spectacles. Participants viewed a therapy that targets the underlying cause of the condition favourably compared with symptomatic treatment. Side effects would severely reduce the appeal of drops. For clinical trials in presbyopia, patient-reported outcomes should be mandatory and need adequately to capture quality of life. Studies in presbyopia must be designed to minimise the inconvenience to participants in order to counter the risk of high drop-out rates. CONCLUSIONS: The interactive format provided insights into living with presbyopia, particularly the negative impact on quality of life, subjects' openness to new therapies, and the need to move away from considering the condition an unavoidable and intractable consequence of ageing.

The term presbyopia describes the difficulty to focus the eyes on things nearby, due to stiffening of the eye lens. The condition often considered something which worsens with increasing age. Many people cope with presbyopia by wearing reading glasses or bifocals, but alternative treatments are being developed. This publication reports from a moderated discussion among people with presbyopia and healthcare professionals specialising in eye health. People with presbyopia strongly felt that it should not be seen as an inevitable effect of middle age, but as something which may be treated medically. They felt that reading glasses, bifocals and monovision lenses were a daily burden and did not fit with how they wanted to live their lives. When discussing possible medical treatments, the option to use drops instead of glasses to improve eye sight appealed to the participants, particularly if the drops acted on the mechanism behind the stiffened lens with effect over many weeks or months. Convenience was the key benefit the participants would look for when considering a new treatment. Importantly, drops must not have any undesirable effects such as burning. The roundtable discussion showed the need for both healthcare professionals and those living with presbyopia to take the condition seriously with an an action-oriented view towards better therapies in the future.

An analysis of social marketing practice: Factors associated with success.

This paper aims to identify factors that contribute to the success of current social marketing practices. These factors include setting clear behavior change objectives and segmentation that informs communication and messaging strategies. Other factors include rigorous research (consumer research, formative research, literature review), pre-testing of interventions, developing a partnership approach, using planning methodologies/theories, and monitoring and evaluation. These success factors could be used for policymakers, governments, agencies and social marketers delivering interventions focussed on healthy lives and well-being. The examples given in this study illustrate how these factors can be achieved, providing a focus for discussion and emulation.

Maternal autoimmunity and inflammation are associated with childhood tics and obsessive-compulsive disorder: Transcriptomic data show common enriched innate immune pathways.

Although genetic variation is a major risk factor of neurodevelopmental disorders, environmental factors during pregnancy and early life are also important in disease expression. Animal models demonstrate that maternal inflammation causes fetal neuroinflammation and neurodevelopmental deficits, and brain transcriptomics of neurodevelopmental disorders in humans show upregulated differentially expressed genes are enriched in immune pathways. We prospectively recruited 200 sequentially referred children with tic disorders/obsessive-compulsive disorder (OCD), 100 autoimmune neurological controls, and 100 age-matched healthy controls. A structured interview captured the maternal and family history of autoimmune disease and other pro-inflammatory states. Maternal blood and published Tourette brain transcriptomes were analysed for overlapping enriched pathways. Mothers of children with tics/OCD had a higher rate of autoimmune disease compared with mothers of children with autoimmune neurological conditions (p = 0.054), and mothers of healthy controls (p = 0.0004). Autoimmunity was similarly elevated in first- and second-degree maternal relatives of children with tics/OCD (p < 0.0001 and p = 0.014 respectively). Other pro-inflammatory states were also more common in mothers of children with tics/OCD than controls (p < 0.0001). Upregulated differentially expressed genes in maternal autoimmune disease and Tourette brain transcriptomes were commonly enriched in innate immune processes. Pro-inflammatory states, including autoimmune disease, are more common in the mothers and families of children with tics/OCD. Exploratory transcriptome analysis indicates innate immune signalling may link maternal inflammation and childhood tics/OCD. Targeting inflammation may represent preventative strategies in pregnancy and treatment opportunities for children with neurodevelopmental disorders.

An exploration of factors associated with food protein-induced enterocolitis syndrome: Birth, infant feeding and food triggers.

BACKGROUND: Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergic disorder with a well-characterized phenotype, but limited understanding of factors associated with food cross-reactivity, severity and tolerance. METHODS: A retrospective cohort study spanning 20 years on children with acute FPIES from a single paediatric tertiary centre in New South Wales, Australia, focusing on identifying food trigger co-associations and factors associated with reaction severity, multiple trigger FPIES and/or tolerance was performed. RESULTS: A total of 168 individuals with 329 recorded FPIES episodes between 1997 and 2017 were included. 49% were male. The median age at first reaction was 5 months, and median age at diagnosis was 9 months. 73% experienced at least one severe FPIES reaction. Rice (45%), cow's milk (30%) and soya (13%) were the most common triggers. Rice or cow's milk FPIES was strongly associated with increased odds of having multiple trigger FPIES. The odds of having multiple food FPIES and severe reactions were slightly decreased with vaginal delivery. No factors were associated with increased risk of severe reactions. Infants with rice and grains FPIES outgrew their reactions at an earlier age, compared to those with fish FPIES. CONCLUSIONS: Rice remains the most common trigger in Australia with co-associations between rice/oats and cow's milk/soya observed. This suggests that taxonomically related foods may share similar protein structure and trigger similar mechanisms of antigen recognition. Vaginal delivery may have a mild protective effect on the development of multiple FPIES and severe reactions. No other features from birth or infant-feeding history influenced outcomes in FPIES.

Comparison of host endothelial, epithelial and inflammatory response in ICU patients with and without COVID-19: a prospective observational cohort study.

BACKGROUND: Analyses of blood biomarkers involved in the host response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral infection can reveal distinct biological pathways and inform development and testing of therapeutics for COVID-19. Our objective was to evaluate host endothelial, epithelial and inflammatory biomarkers in COVID-19. METHODS: We prospectively enrolled 171 ICU patients, including 78 (46%) patients positive and 93 (54%) negative for SARS-CoV-2 infection from April to September, 2020. We compared 22 plasma biomarkers in blood collected within 24 h and 3 days after ICU admission. RESULTS: In critically ill COVID-19 and non-COVID-19 patients, the most common ICU admission diagnoses were respiratory failure or pneumonia, followed by sepsis and other diagnoses. Similar proportions of patients in both groups received invasive mechanical ventilation at the time of study enrollment. COVID-19 and non-COVID-19 patients had similar rates of acute respiratory distress syndrome, severe acute kidney injury, and in-hospital mortality. While concentrations of interleukin 6 and 8 were not different between groups, markers of epithelial cell injury (soluble receptor for advanced glycation end products, sRAGE) and acute phase proteins (serum amyloid A, SAA) were significantly higher in COVID-19 compared to non-COVID-19, adjusting for demographics and APACHE III scores. In contrast, angiopoietin 2:1 (Ang-2:1 ratio) and soluble tumor necrosis factor receptor 1 (sTNFR-1), markers of endothelial dysfunction and inflammation, were significantly lower in COVID-19 (p < 0.002). Ang-2:1 ratio and SAA were associated with mortality only in non-COVID-19 patients. CONCLUSIONS: These studies demonstrate that, unlike other well-studied causes of critical illness, endothelial dysfunction may not be characteristic of severe COVID-19 early after ICU admission. Pathways resulting in elaboration of acute phase proteins and inducing epithelial cell injury may be promising targets for therapeutics in COVID-19.