Capnography waveforms: basic interpretation in neonatal intensive care.

End-tidal capnography can provide useful clinical information displayed on the ventilator screen or bedside monitor. It is important that clinicians can assess and utilise this information to assist in identifying underlying complications and pulmonary pathology. Sudden change or loss of the CO2 waveform can act as a safety measure in alerting clinicians of a dislodged or blocked endotracheal tube, considering the concurrent flow and volume waveforms. Visual pattern recognition by the clinicians of commonly seen waveform traces may act as an adjunct to other modes of ventilatory monitoring techniques. Waveforms traces can aid clinical management, help identify cases of ventilation asynchrony between the infant and the ventilator. We present some common clinical scenarios where tidal capnography can be useful in the timely identification of pulmonary complication and for practical troubleshooting at the cot-side.

Faecal microbial transfer and complex carbohydrates mediate protection against COPD.

OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is a major cause of global illness and death, most commonly caused by cigarette smoke. The mechanisms of pathogenesis remain poorly understood, limiting the development of effective therapies. The gastrointestinal microbiome has been implicated in chronic lung diseases via the gut-lung axis, but its role is unclear. DESIGN: Using an in vivo mouse model of cigarette smoke (CS)-induced COPD and faecal microbial transfer (FMT), we characterised the faecal microbiota using metagenomics, proteomics and metabolomics. Findings were correlated with airway and systemic inflammation, lung and gut histopathology and lung function. Complex carbohydrates were assessed in mice using a high resistant starch diet, and in 16 patients with COPD using a randomised, double-blind, placebo-controlled pilot study of inulin supplementation. RESULTS: FMT alleviated hallmark features of COPD (inflammation, alveolar destruction, impaired lung function), gastrointestinal pathology and systemic immune changes. Protective effects were additive to smoking cessation, and transfer of CS-associated microbiota after antibiotic-induced microbiome depletion was sufficient to increase lung inflammation while suppressing colonic immunity in the absence of CS exposure. Disease features correlated with the relative abundance of Muribaculaceae, Desulfovibrionaceae and Lachnospiraceae family members. Proteomics and metabolomics identified downregulation of glucose and starch metabolism in CS-associated microbiota, and supplementation of mice or human patients with complex carbohydrates improved disease outcomes. CONCLUSION: The gut microbiome contributes to COPD pathogenesis and can be targeted therapeutically.

Monitoring persistent pulmonary hypertension of the newborn using the arterial to end tidal carbon dioxide gradient.

Persistent pulmonary hypertension of the newborn (PPHN) can be monitored theoretically by the difference of the partial pressure of arterial (PaCO2) to end-tidal CO2 (EtCO2). We aimed to test the hypothesis that the PaCO2-EtCO2 gradient in infants with PPHN would be higher compared to infants without PPHN. Prospective, observational study of term-born ventilated infants with echocardiographically-confirmed PPHN with right-to-left shunting and term-born control infants without respiratory disease. The PaCO2-EtCO2 gradient was calculated as the difference between the PaCO2 measured from indwelling arterial sample lines and EtCO2 measured by continuous Microstream sidestream capnography. Twenty infants (9 with PPHN and 11 controls) were studied with a median (IQR) gestational age of 39.5 (38.7-40.4) weeks, a birthweight of 3.56 (3.15-3.93) kg and a birthweight z-score of 0.03 (- 0.91 to 1.08). The PaCO2-EtCO2 gradient was larger in the infants with PPHN compared to those without PPHN after adjusting for differences in the mean airway pressure and fraction of inspired oxygen (adjusted p = 0.037). In the infants with PPHN the median PaCO2-EtCO2 gradient decreased from 10.7 mmHg during the acute illness to 3.3 mmHg pre-extubation. The median difference in the gradient was significantly higher in infants with PPHN (6.2 mmHg) compared to infants without PPHN (-3.2 mmHg, p = 0.022). The PaCO2-EtCO2 gradient was higher in infants with PPHN compared to term born infants without PPHN and decreased over the first week of life in infants with PPHN. The gradient might be utilised to monitor the evolution and resolution of PPHN.

Sex differences in preterm respiratory morbidity: A recent whole-population study.

AIM: To determine whether there were differences between male and female infants in respiratory morbidity in a whole population of extremely preterm infants, including infants born below 24 weeks of gestation. METHODS: Retrospective whole-population study of all infants <28 weeks of gestation admitted to a neonatal unit in England from 2014 to 2019. Bronchopulmonary dysplasia (BPD) development was defined as any respiratory support at 36 weeks postmenstrual age. RESULTS: The 11 844 infants had a median (IQR) gestational age of 26.0 (24.9-27.1) weeks and a birth weight of 0.81 (0.67-0.96) kg. The duration of invasive ventilation was longer in male compared to female infants who were born at 24-27 completed weeks of gestation (p < 0.001), but not significantly different between male and female infants born at 22 and 23 weeks of gestation (p = 0.446). The incidence of BPD was higher in male compared to female infants born at 24-27 weeks of gestation (p < 0.001) but not different between male and female infants born at 22 and 23 weeks of gestation (p = 0.148). CONCLUSION: Respiratory morbidity was more pronounced in male compared to female extremely preterms, only in gestations 24-27 completed weeks. Male predominance was absent in infants born below 24 weeks of gestation.

Risk assessment of survival and morbidity of infants born at <24 completed weeks of gestation.

BACKGROUND: Infants born at the threshold of viability have a high risk of mortality and morbidity. The British Association of Perinatal Medicine (BAPM) provided updated guidance in 2019 advising a risk-based approach to balancing decisions about active versus redirected care at birth. AIMS: To determine survival and morbidity of infants born between 22 and 24 completed weeks of gestation. To develop a scoring system to categorise infants at birth according to risk for mortality or severe adverse outcome. METHODS: A retrospective, single centre observational study of infants who received neonatal care from 2011 to 2021. Data were collected on mortality, morbidity and two-year neurodevelopmental outcomes. Each infant was risk categorised utilising the proposed tools in the BAPM (2019) framework. A composite adverse score for either dying or surviving with severe impairment was created. RESULTS: Four infants born at 22 weeks, 49 at 23 weeks and 105 at 24 weeks of gestation were included. The mortality rate was 23.4 %. Following risk categorisation there were 8 (5.1 %) extremely high risk, 44 (27.8 %) high risk and 106 (67.1 %) moderate risk infants. The rate of dying or surviving with severe impairment for extremely high risk, high risk and moderate risk were 100 %, 88.9 % and 53 % respectively. The proportions with the composite adverse outcome differed significantly according to the risk category (p < 0.001). CONCLUSIONS: When applying a scoring system to risk categorise infants at birth, high rates of dying or surviving with severe impairment were found in infants born at 22 or 23 weeks of gestation.

Permissive hypercapnia and oxygenation impairment in premature ventilated infants.

AIM: In permissive hypercapnia high levels of carbon dioxide (CO2) are tolerated in ventilated preterm infants to minimise lung injury, but hypercapnia could directly impair oxygenation. We aimed to quantify the association of elevated CO2 with oxygenation impairment in preterm infants by measuring the right-to-left shunt and the ventilation/perfusion (VA/Q) ratio. METHODS: Pre-existing datasets from preterm infants during the acute phase of respiratory distress syndrome or with evolving or established bronchopulmonary dysplasia were analysed. Non-invasive paired measurements of the fraction of inspired oxygen (FIO2) and transcutaneous oxygen saturation (SpO2) were used to calculate the degree of right-to-left shunt, right shift of the FIO2 versus SpO2 curve and the VA/Q. RESULTS: A total of 75 infants (43 male) with a median (IQR) gestational age of 26.4 (24.7-27.7) weeks were studied at 7 (2-31) days. Thirty-six infants (48 %) had an arterial partial pressure of CO2 (PaCO2) above 6 kPa. The PaCO2 was independently associated with the right shift of the curve [adjusted p < 0.001, unstandardised coefficient; 2.26, 95 % CI: 1.51-2.95] and the right-to-left shunt [adjusted p = 0.016, unstandardised coefficient; 1.86, 95 % CI: 0.36-3.36] after adjusting for confounders. An increase of the PaCO2 from 5 to 8 kPa, corresponded to a right shift of the curve of 20.2 kPa or a decrease in the VA/Q from 0.66 to 0.24. CONCLUSIONS: Increased carbon dioxide levels were significantly associated with impaired oxygenation in preterm infants with respiratory distress syndrome or bronchopulmonary dysplasia.

A surge in serum mucosal cytokines associated with seroconversion in children at risk for type 1 diabetes.

AIMS/INTRODUCTION: Autoantibodies to pancreatic islet antigens identify young children at high risk of type 1 diabetes. On a background of genetic susceptibility, islet autoimmunity is thought to be driven by environmental factors, of which enteric viruses are prime candidates. We sought evidence for enteric pathology in children genetically at-risk for type 1 diabetes followed from birth who had developed islet autoantibodies ("seroconverted"), by measuring mucosa-associated cytokines in their sera. MATERIALS AND METHODS: Sera were collected 3 monthly from birth from children with a first-degree type 1 diabetes relative, in the Environmental Determinants of Islet Autoimmunity (ENDIA) study. Children who seroconverted were matched for sex, age, and sample availability with seronegative children. Luminex xMap technology was used to measure serum cytokines. RESULTS: Of eight children who seroconverted, for whom serum samples were available at least 6 months before and after seroconversion, the serum concentrations of mucosa-associated cytokines IL-21, IL-22, IL-25, and IL-10, the Th17-related cytokines IL-17F and IL-23, as well as IL-33, IFN-γ, and IL-4, peaked from a low baseline in seven around the time of seroconversion and in one preceding seroconversion. These changes were not detected in eight sex- and age-matched seronegative controls, or in a separate cohort of 11 unmatched seronegative children. CONCLUSIONS: In a cohort of children at risk for type 1 diabetes followed from birth, a transient, systemic increase in mucosa-associated cytokines around the time of seroconversion lends support to the view that mucosal infection, e.g., by an enteric virus, may drive the development of islet autoimmunity.

Ventilatory response to added dead space in infants exposed to second-hand smoke in pregnancy.

Maternal cigarette smoking in pregnancy can adversely affect infant respiratory control. In utero nicotine exposure has been shown to blunt the infant ventilatory response to hypercapnia, which could increase the risk of sudden infant death syndrome. The potential impact of maternal second-hand smoke exposure, however, has not yet been determined. The aim of this study was to assess ventilatory response to added dead-space (inducing hypercapnia) in infants with second-hand smoke exposure during pregnancy, in infants whose mothers smoked and in controls (non-smoke exposed). Infants breathed through a face mask and specialised "tube-breathing" circuit, incorporating a dead space of 4.4 ml/kg body weight. The maximum minute ventilation (MMV) during added dead space breathing was determined and the time taken to achieve 63% of the MMV calculated (the time constant (TC) of the response). Infants were studied on the postnatal ward prior to discharge home. Thirty infants (ten in each group) were studied with a median gestational age of 39 [range 37-41] weeks, birthweight of 3.1 [2.2-4.0] kg, and postnatal age of 33 (21-62) h. The infants whose mothers had second-hand smoke exposure (median TC 42 s, p = 0.001), and the infants of cigarette smoking mothers (median TC 37 s, p = 0.002) had longer time constants than the controls (median TC 29 s). There was no significant difference between the TC of the infants whose mothers had second-hand smoke exposure and those whose mothers smoked (p = 0.112).    Conclusion: Second-hand smoke exposure during pregnancy was associated with a delayed newborn ventilatory response. What is Known: • Maternal cigarette smoking in pregnancy can adversely affect infant respiratory control. • The potential impact of maternal second-hand smoke exposure, however, has not yet been determined. What is New: • We have assessed the ventilatory response to added dead-space (inducing hypercapnia) in newborns with second-hand smoke exposure during pregnancy, in infants whose mothers smoked, and in controls (non-smoke exposed). • Maternal second-hand smoke exposure, as well as maternal smoking, during pregnancy was associated with a delayed newborn ventilatory response.

Falling from new heights: Traumatic fracture burden and resource utilization after border wall height increase.

BACKGROUND: San Diego County hospitals commonly care for patients injured by falls from the United States-Mexico border. From 2018 to 2019, the height of >400 miles of an existing border wall was raised. Prior work has demonstrated a 5-fold increase in traumatic border wall fall injuries after barrier expansion. We aimed to examine the impact of a barrier height increase on fracture burden and resource use. METHODS: We performed a retrospective review of patients admitted to a level 1 trauma center from 2016 to 2021 with lower extremity or pelvic fractures sustained from a border wall fall. We defined the pre-wall group as patients admitted from 2016 to 2018 and the post-wall group as those admitted from 2019 to 2021. We collected demographic and treatment data, hospital charges, weight-bearing status at discharge, and follow-up. RESULTS: A total of 320 patients (pre-wall: 45; post-wall: 275) were admitted with 951 lower extremity fractures (pre-wall: 101; post-wall: 850) due to border wall fall. Hospital resources were utilized to a greater extent post-wall: a 537% increase in hospital days, a 776% increase in intensive care unit days, and a 468% increase in operative procedures. Overall, 86% of patients were non-weight-bearing on at least 1 lower extremity at discharge; 82% were lost to follow-up. CONCLUSION: Traumatic lower extremity fractures sustained from border wall fall rapidly rose after the wall height increase. Hospital resources were used to a greater extent. Patients were frequently discharged with weight-bearing limitations and rarely received scheduled follow-up care. Policymakers should consider the costs of caring for border fall patients, and access to follow-up should be expanded.

ERS International Congress 2022: highlights from the Paediatrics Assembly.

This review has been prepared by the Early Career Members and Chairs of the European Respiratory Society (ERS) Assembly 7: Paediatrics. We here summarise the highlights of the advances in paediatric respiratory research presented at the ERS International Congress 2022. The eight scientific groups of this Assembly cover a wide range of research areas, including respiratory physiology and sleep, asthma and allergy, cystic fibrosis (CF), respiratory infection and immunology, neonatology and intensive care, respiratory epidemiology, bronchology, and lung and airway developmental biology. Specifically, we report on abstracts presented at the congress on the effect of high altitude on sleep, sleep disorders, the hypoxic challenge test, and measurements of ventilation inhomogeneity. We discuss prevention of preschool wheeze and asthma, and new asthma medications. In children with CF, we describe how to monitor the effect of CF transmembrane conductance regulator modulator therapy. We present respiratory manifestations and chronic lung disease associated with common variable immunodeficiency. Furthermore, we discuss how to monitor respiratory function in neonatal and paediatric intensive care units. In respiratory epidemiology, we present the latest news from population-based and clinical cohort studies. We also focus on innovative and interventional procedures for the paediatric airway, such as cryotherapy. Finally, we stress the importance of better understanding the molecular mechanisms underlying normal and abnormal lung development.

Pathophysiology of gas exchange impairment in extreme prematurity: Insights from combining volumetric capnography and measurements of ventilation/perfusion ratio.

Background: Infants born extremely preterm often suffer from respiratory disease and are invasively ventilated. We aimed to test the hypothesis that gas exchange in ventilated extremely preterm infants occurs both at the level of the alveoli and via mixing of fresh deadspace gas in the airways. Methods: We measured the normalised slopes of phase II and phase III of volumetric capnography and related them with non-invasive measurements of ventilation to perfusion ratio (VA/Q) and right-to-left shunt in ventilated extremely preterm infants studied at one week of life. Cardiac right-to-left shunt was excluded by concurrent echocardiography. Results: We studied 25 infants (15 male) with a median (range) gestational age of 26.0 (22.9-27.9) weeks and birth weight of 795 (515-1,165) grams. The median (IQR) VA/Q was 0.52 (0.46-0.56) and shunt was 8 (2-13) %. The median (IQR) normalised slope of phase II was 99.6 (82.7-116.1) mmHg and of phase III was 24.6 (16.9-35.0) mmHg. The VA/Q was significantly related to the normalised slope of phase III (ρ = -0.573, p = 0.016) but not to the slope of phase II (ρ = 0.045, p = 0.770). The right-to-left shunt was not independently associated with either the slope of phase II or the slope of phase III after adjusting for confounding parameters. Conclusions: Abnormal gas exchange in ventilated extremely preterm infants was associated with lung disease at the alveolar level. Abnormal gas exchange at the level of the airways was not associated with quantified indices of gas exchange impairment.

Functional morphometry: non-invasive estimation of the alveolar surface area in extremely preterm infants.

BACKGROUND: The main pathophysiologic characteristic of chronic respiratory disease following extremely premature birth is arrested alveolar growth, which translates to a smaller alveolar surface area (SA). We aimed to use non-invasive measurements to estimate the SA in extremely preterm infants. METHODS: Paired measurements of the fraction of inspired oxygen and transcutaneous oxygen saturation were used to calculate the ventilation/perfusion ratio, which was translated to SA using Fick's law of diffusion. The SA was then adjusted using volumetric capnography. RESULTS: Thirty infants with a median (range) gestational age of 26.3 (22.9-27.9) weeks were studied. The median (range) adjusted SA was 647.9 (316.4-902.7) cm2. The adjusted SA was lower in the infants who required home oxygen [637.7 (323.5-837.5) cm2] compared to those who did not [799.1 (444.2-902.7) cm2, p = 0.016]. In predicting the need for supplemental home oxygen, the adjusted SA had an area under the receiver operator characteristic curve of 0.815 (p = 0.017). An adjusted SA ≥688.6 cm2 had 86% sensitivity and 77% specificity in predicting the need for supplemental home oxygen. CONCLUSIONS: The alveolar surface area can be estimated non-invasively in extremely preterm infants. The adjusted alveolar surface area has the potential to predict the subsequent need for discharge home on supplemental oxygen. IMPACT: We describe a novel biomarker of respiratory disease following extremely preterm birth. The adjusted alveolar surface area index was derived by non-invasive measurements of the ventilation/perfusion ratio and adjusted by concurrent measurements of volumetric capnography. The adjusted alveolar surface area was markedly reduced in extremely preterm infants studied at 7 days of life and could predict the need for discharge home on supplemental oxygen. This method could be used at the bedside to estimate the alveolar surface area and provide an index of the severity of lung disease, and assist in monitoring, clinical management and prognosis.

Protocol for a nested case-control study design for omics investigations in the Environmental Determinants of Islet Autoimmunity cohort.

Background: The Environmental Determinants of Islet Autoimmunity (ENDIA) pregnancy-birth cohort investigates the developmental origins of type 1 diabetes (T1D), with recruitment between 2013 and 2019. ENDIA is the first study in the world with comprehensive data and biospecimen collection during pregnancy, at birth and through childhood from at-risk children who have a first-degree relative with T1D. Environmental exposures are thought to drive the progression to clinical T1D, with pancreatic islet autoimmunity (IA) developing in genetically susceptible individuals. The exposures and key molecular mechanisms driving this progression are unknown. Persistent IA is the primary outcome of ENDIA; defined as a positive antibody for at least one of IAA, GAD, ZnT8 or IA2 on two consecutive occasions and signifies high risk of clinical T1D.Method: A nested case-control (NCC) study design with 54 cases and 161 matched controls aims to investigate associations between persistent IA and longitudinal omics exposures in ENDIA. The NCC study will analyse samples obtained from ENDIA children who have either developed persistent IA or progressed to clinical T1D (cases) and matched control children at risk of developing persistent IA. Control children were matched on sex and age, with all four autoantibodies absent within a defined window of the case's onset date. Cases seroconverted at a median of 1.37 years (IQR 0.95, 2.56). Longitudinal omics data generated from approximately 16,000 samples of different biospecimen types, will enable evaluation of changes from pregnancy through childhood.Conclusions: This paper describes the ENDIA NCC study, omics platform design considerations and planned univariate and multivariate analyses for its longitudinal data. Methodologies for multivariate omics analysis with longitudinal data are discovery-focused and data driven. There is currently no single multivariate method tailored specifically for the longitudinal omics data that the ENDIA NCC study will generate and therefore omics analysis results will require either cross validation or independent validation.KEY MESSAGESThe ENDIA nested case-control study will utilize longitudinal omics data on approximately 16,000 samples from 190 unique children at risk of type 1 diabetes (T1D), including 54 who have developed islet autoimmunity (IA), followed during pregnancy, at birth and during early childhood, enabling the developmental origins of T1D to be explored.

Some effects of detection dogs on passenger behavior at border control ports.

Detection dogs are used at border controls as an antecedent intervention to deter the smuggling of contraband. However, there is little research that has explored how the presence of dogs might affect passenger behavior. We observed passengers' behavior at a port when there was an officer alone, an officer with a dog, and an officer with a dog wearing a florescent yellow jacket with "police" written on it for increased salience. We measured eye contact, vocal-verbal interactions, facial expressions, and nonvocal verbal gestures toward the officer and dog, and changes in passenger direction. Passengers looked, talked, and had the highest frequencies of positive facial expressions when the dog was not wearing a jacket. However, passengers looked toward the dog the quickest and had the highest frequency of negative facial expressions and gestures when the dog was wearing a jacket. We discuss how these findings might inform antecedent interventions to address undesirable behavior such as smuggling.

Circulating biomarkers during progression to type 1 diabetes: A systematic review.

Aim: Progression to type 1 diabetes (T1D) is defined in stages and clinical disease is preceded by a period of silent autoimmunity. Improved prediction of the risk and rate of progression to T1D is needed to reduce the prevalence of diabetic ketoacidosis at presentation as well as for staging participants for clinical trials. This systematic review evaluates novel circulating biomarkers associated with future progression to T1D. Methods: PubMed, Ovid, and EBSCO databases were used to identify a comprehensive list of articles. The eligibility criteria included observational studies that evaluated the usefulness of circulating markers in predicting T1D progression in at-risk subjects <20 years old. Results: Twenty-six studies were identified, seventeen were cohort studies and ten were case control studies. From the 26 studies, 5 found evidence for protein and lipid dysregulation, 11 identified molecular markers while 12 reported on changes in immune parameters during progression to T1D. An increased risk of T1D progression was associated with the presence of altered gene expression, immune markers including regulatory T cell dysfunction and higher short-lived effector CD8+ T cells in progressors. Discussion: Several circulating biomarkers are dysregulated before T1D diagnosis and may be useful in predicting either the risk or rate of progression to T1D. Further studies are required to validate these biomarkers and assess their predictive accuracy before translation into broader use. Systematic review registration: https://www.crd.york.ac.uk/prospero, identifier (CRD42020166830).

Respiratory function monitoring during early resuscitation and prediction of outcomes in prematurely born infants.

OBJECTIVES: Over the last decade, there has been increased use of end-tidal carbon dioxide (ETCO2) and oxygen saturation (SpO2) monitoring during resuscitation of prematurely born infants in the delivery suite. Our objectives were to test the hypotheses that low end-tidal carbon dioxide (ETCO2) levels, low oxygen saturations (SpO2) and high expiratory tidal volumes (VTE) during the early stages of resuscitation would be associated with adverse outcomes in preterm infants. METHODS: Respiratory recordings made in the first 10 min of resuscitation in the delivery suite of 60 infants, median GA 27 (interquartile range 25-29) weeks were analysed. The results were compared of infants who did or did not die or did or did not develop intracerebral haemorrhage (ICH) or bronchopulmonary dysplasia (BPD). RESULTS: Twenty-five infants (42%) developed an ICH and 23 (47%) BPD; 11 (18%) died. ETCO2 at approximately 5 min after birth was lower in infants who developed an ICH, this remained significant after adjusting for gestational age, coagulopathy and chorioamnionitis (p=0.03). ETCO2 levels were lower in infants who developed ICH or died compared to those that survived without ICH, which remained significant after adjustment for gestational age, Apgar score at 10 min, chorioamnionitis and coagulopathy (p=0.004). SpO2 at approximately 5 min was lower in the infants who died compared to those who survived which remained significant after adjusting for the 5-min Apgar score and chorioamnionitis (p=0.021). CONCLUSIONS: ETCO2 and SpO2 levels during early resuscitation in the delivery suite were associated with adverse outcomes.

Islet-specific CD8+ T cells gain effector function in the gut lymphoid tissues via bystander activation not molecular mimicry.

Type 1 diabetes (T1D) is caused by aberrant activation of autoreactive T cells specific for the islet beta cells. How islet-specific T cells evade tolerance to become effector T cells is unknown, but it is believed that an altered gut microbiota plays a role. Possible mechanisms include bystander activation of autoreactive T cells in the gut or "molecular mimicry" from cross-reactivity between gut microbiota-derived peptides and islet-derived epitopes. To investigate these mechanisms, we use two islet-specific CD8+ T cell clones and the non-obese diabetic mouse model of type 1 diabetes. Both insulin-specific G9C8 cells and IGRP-specific 8.3 cells underwent early activation and proliferation in the pancreatic draining lymph nodes but not in the Peyer's patches or mesenteric lymph nodes. Mutation of the endogenous epitope for G9C8 cells abolished their CD69 upregulation and proliferation, ruling out G9C8 cell activation by a gut microbiota derived peptide and molecular mimicry. However, previously activated islet-specific effector memory cells but not naïve cells migrated into the Peyer's patches where they increased their cytotoxic function. Oral delivery of butyrate, a microbiota derived anti-inflammatory metabolite, reduced IGRP-specific cytotoxic function. Thus, while initial activation of islet-specific CD8+ T cells occurred in the pancreatic lymph nodes, activated cells trafficked through the gut lymphoid tissues where they gained additional effector function via non-specific bystander activation influenced by the gut microbiota.

Multi-omic interactions in the gut of children at the onset of islet autoimmunity.

BACKGROUND: The gastrointestinal ecosystem is a highly complex environment with a profound influence on human health. Inflammation in the gut, linked to an altered gut microbiome, has been associated with the development of multiple human conditions including type 1 diabetes (T1D). Viruses infecting the gastrointestinal tract, especially enteroviruses, are also thought to play an important role in T1D pathogenesis possibly via overlapping mechanisms. However, it is not known whether the microbiome and virome act together or which risk factor may be of greater importance at the time when islet autoimmunity is initiated. RESULTS: Here, we apply an integrative approach to combine comprehensive fecal virome, microbiome, and metaproteome data sampled before and at the onset of islet autoimmunity in 40 children at increased risk of T1D. We show strong age-related effects, with microbial and metaproteome diversity increasing with age while host antibody number and abundance declined with age. Mastadenovirus, which has been associated with a reduced risk of T1D, was associated with profound changes in the metaproteome indicating a functional shift in the microbiota. Multi-omic factor analysis modeling revealed a cluster of proteins associated with carbohydrate transport from the genus Faecalibacterium were associated with islet autoimmunity. CONCLUSIONS: These findings demonstrate the interrelatedness of the gut microbiota, metaproteome and virome in young children. We show a functional remodeling of the gut microbiota accompanies both islet autoimmunity and viral infection with a switch in function in Faecalibacterium occurring at the onset of islet autoimmunity. Video Abstract.

Cost-Effectiveness of Arthroscopic Partial Meniscectomy and Physical Therapy for Degenerative Meniscal Tear.

OBJECTIVE: We examined the cost-effectiveness of treatment strategies for concomitant meniscal tear and knee osteoarthritis (OA) involving arthroscopic partial meniscectomy surgery and physical therapy (PT). METHODS: We used the Osteoarthritis Policy Model, a validated Monte Carlo microsimulation, to compare three strategies, 1) PT-only, 2) immediate surgery, and 3) PT + optional surgery, for participants whose pain persists following initial PT. We modeled a cohort with baseline meniscal tear, OA, and demographics from the Meniscal Tear in Osteoarthritis Research (MeTeOR) trial of arthroscopic partial meniscectomy versus PT. We estimated risks and costs of arthroscopic partial meniscectomy complications and accounted for heightened OA progression post surgery using published data. We estimated surgery use rates and treatment efficacies using MeTeOR data. We considered a 5-year time horizon, discounted costs, and quality-adjusted life-years (QALYs) 3% per year and conducted sensitivity analyses. We report incremental cost-effectiveness ratios. RESULTS: Relative to PT-only, PT + optional surgery added 0.0651 QALY and $2,010 over 5 years (incremental cost-effectiveness ratio = $30,900 per QALY). Relative to PT + optional surgery, immediate surgery added 0.0065 QALY and $3080 (incremental cost-effectiveness ratio = $473,800 per QALY). Incremental cost-effectiveness ratios were sensitive to optional surgery efficacy in the PT + optional surgery strategy. In the probabilistic sensitivity analysis, PT + optional surgery was cost-effective in 51% of simulations at willingness-to-pay thresholds of both $50,000 per QALY and $100,000 per QALY. CONCLUSION: First-line arthroscopic partial meniscectomy has a prohibitively high incremental cost-effectiveness ratio. Under base case assumptions, second-line arthroscopic partial meniscectomy offered to participants with persistent pain following initial PT is cost-effective at willingness-to-pay thresholds between $31,000 and $473,000 per QALY. Our analyses suggest that arthroscopic partial meniscectomy can be a high-value treatment option for patients with meniscal tear and OA when performed following an initial PT course and should remain a covered treatment option.

Diaphragmatic electromyography during a spontaneous breathing trial to predict extubation failure in preterm infants.

BACKGROUND: Premature attempts at extubation and prolonged episodes of ventilatory support in preterm infants have adverse outcomes. The aim of this study was to determine whether measuring the electrical activity of the diaphragm during a spontaneous breathing trial (SBT) could predict extubation failure in preterm infants. METHODS: When infants were ready for extubation, the electrical activity of the diaphragm was measured by transcutaneous electromyography (EMG) before and during a SBT when the infants were on endotracheal continuous positive airway pressure. RESULTS: Forty-eight infants were recruited (median (IQR) gestational age of 27.2 (25.6-30.4) weeks). Three infants did not pass the SBT and 13 failed extubation. The amplitude of the EMG increased during the SBT [2.3 (1.5-4.2) versus 3.5 (2.1-5.3) µV; p < 0.001]. In the whole cohort, postmenstrual age (PMA) was the strongest predictor for extubation failure (area under the curve (AUC) 0.77). In infants of gestational age <29 weeks, the percentage change of the EMG predicted extubation failure with an AUC of 0.74 while PMA was not associated with the outcome of extubation. CONCLUSIONS: In all preterm infants, PMA was the strongest predictor of extubation failure; in those born <29 weeks of gestation, diaphragmatic electromyography during an SBT was the best predictor of extubation failure. IMPACT: Composite assessments of readiness for extubation may be beneficial in the preterm population. Diaphragmatic electromyography measured by surface electrodes is a non-invasive technique to assess the electrical activity of the diaphragm. Postmenstrual age was the strongest predictor of extubation outcome in preterm infants. The change in diaphragmatic activity during a spontaneous breathing trial in extremely prematurely born infants can predict subsequent extubation failure with moderate sensitivity and specificity.