Systematic Review of Kangaroo Care Duration's Impact in Neonatal Intensive Care Units on Infant-Maternal Health.

Kangaroo care (KC), skin-to-skin contact between infants and caregivers, is encouraged in neonatal intensive care units (NICUs) to support health through improved weight, growth, and infant-maternal attachment while reducing the incidence of sepsis and infant pain. However, the optimal duration and frequency of KC to maximize health outcomes is unknown. Given parents' time stressors, identifying optimal KC time is critical. A literature review was undertaken on May 28, 2021 via querying the PubMed database from January 1, 1995, to May 28, 2021, regarding KC and NICUs with 442 results. Eleven studies met the eligibility criteria of (1) comparative KC between infants and adult caregivers in NICUs as a randomized controlled trial, (2) peer-reviewed articles in English, (3) study subjects ≥5, (4) health outcomes, and (5) KC sessions >1. Infant physical growth parameters, infant neurodevelopment, infant stress via salivary cortisol levels, and breastfeeding outcomes appear to increase with KC as compared with standard care (SC) without KC. Improvements were observed with longer KC duration, 2 h/d as compared with 1 h/d, for neurodevelopment and breastfeeding outcomes, but no greater improvement with longer KC duration was shown for reducing infant stress through salivary cortisol levels. Regarding maternal stress, the influence of KC duration showed mixed Parental Stressor Score: NICU scores. Further study on the impact of KC duration and frequency on health outcomes and dose-response relationship would help determine how much and how frequent KC is needed to improve specific health outcomes for infants and their mothers. KEY POINTS: · Data on kangaroo care duration's health impacts is lacking.. · Establishing dose-response for kangaroo care is needed.. · Kangaroo care for longer improves some but not all outcomes..

Estrogen Signaling and Portopulmonary Hypertension: The Pulmonary Vascular Complications of Liver Disease Study (PVCLD2).

BACKGROUND AND AIMS: Portopulmonary hypertension (POPH) was previously associated with a single-nucleotide polymorphism (SNP) rs7175922 in aromatase (cytochrome P450 family 19 subfamily A member 1 [CYP19A1]). We sought to determine whether genetic variants and metabolites in the estrogen signaling pathway are associated with POPH. APPROACH AND RESULTS: We performed a multicenter case-control study. POPH patients had mean pulmonary artery pressure >25 mm Hg, pulmonary vascular resistance >240 dyn-sec/cm-5 , and pulmonary artery wedge pressure ≤15 mm Hg without another cause of pulmonary hypertension. Controls had advanced liver disease, right ventricular (RV) systolic pressure <40 mm Hg, and normal RV function by echocardiography. We genotyped three SNPs in CYP19A1 and CYP1B1 using TaqMan and imputed SNPs in estrogen receptor 1 using genome-wide markers. Estrogen metabolites were measured in blood and urine samples. There were 37 patients with POPH and 290 controls. Mean age was 57 years, and 36% were female. The risk allele A in rs7175922 (CYP19A1) was significantly associated with higher levels of estradiol (P = 0.02) and an increased risk of POPH (odds ratio [OR], 2.36; 95% confidence interval [CI], 1.12-4.91; P = 0.02) whereas other SNPs were not. Lower urinary 2-hydroxyestrogen/16-α-hydroxyestrone (OR per 1-ln decrease = 2.04; 95% CI, 1.16-3.57; P = 0.01), lower plasma levels of dehydroepiandrosterone-sulfate (OR per 1-ln decrease = 2.38; 95% CI, 1.56-3.85; P < 0.001), and higher plasma levels of 16-α-hydroxyestradiol (OR per 1-ln increase = 2.16; 95% CI, 1.61-2.98; P < 0.001) were associated with POPH. CONCLUSIONS: Genetic variation in aromatase and changes in estrogen metabolites were associated with POPH.

Analysis of Electronic Residency Application Service (ERAS) Data Can Improve House Staff Diversity.

BACKGROUND: Training diverse house staff, including those who are underrepresented in medicine, is vital to provide high-quality patient care for the communities that we serve. In 2018, the Accreditation Council for Graduate Medical Education announced new common program requirements for systematic efforts to recruit and retain a diverse workforce. However, questions remain about how to implement such efforts. MATERIALS AND METHODS: Electronic Residency Application Service (ERAS) data from eight residency programs spanning two recruitment cycles (2017-2018, 2018-2019) was reviewed. The number of candidates at each stage in the process (applicant, invited to interview, interviewed, and matched) was examined by self-identified race or ethnicity. These data were presented to residency program directors at our Graduate Medical Education committee meeting before the next recruitment cycle. Data were analyzed following the 2019-20 residency match. Odds ratios and Pearson's chi-squared test were used to assess statistical significance. RESULTS: A total of 10,445 and 10,982 medical students applied to our 8 core residency programs in 2017 and 2018, respectively. Medical students who applied and self-identified as Asian, Black or African American, and Hispanic or Latino or Spanish origin had lower odds of being invited to interview than those who self-identified as White. After data presentation, the odds of inviting Black or African American applicants to interview increased significantly. The odds of attending an interview once invited were the same across groups. CONCLUSIONS: Sharing ERAS data patterns with residency program directors was associated with a significant year over year change in interviewee diversity. Structured analysis of institutional ERAS data can provide insight into the resident selection process and may be a useful tool to improve house staff diversity.

Bone Morphogenetic Protein 9 Is a Mechanistic Biomarker of Portopulmonary Hypertension.

RATIONALE: BMP9 (bone morphogenetic protein 9) is a circulating endothelial quiescence factor with protective effects in pulmonary arterial hypertension (PAH). Loss-of-function mutations in BMP9, its receptors, and downstream effectors have been reported in heritable PAH. OBJECTIVES: To determine how an acquired deficiency of BMP9 signaling might contribute to PAH. METHODS: Plasma levels of BMP9 and antagonist soluble endoglin were measured in group 1 PAH, group 2 and 3 pulmonary hypertension (PH), and in patients with severe liver disease without PAH. MEASUREMENTS AND MAIN RESULTS: BMP9 levels were markedly lower in portopulmonary hypertension (PoPH) versus healthy control subjects, or other etiologies of PAH or PH; distinguished PoPH from patients with liver disease without PAH; and were an independent predictor of transplant-free survival. BMP9 levels were decreased in mice with PH associated with CCl4-induced portal hypertension and liver cirrhosis, but were normal in other rodent models of PH. Administration of ALK1-Fc, a BMP9 ligand trap consisting of the activin receptor-like kinase-1 extracellular domain, exacerbated PH and pulmonary vascular remodeling in mice treated with hypoxia versus hypoxia alone. CONCLUSIONS: BMP9 is a sensitive and specific biomarker of PoPH, predicting transplant-free survival and the presence of PAH in liver disease. In rodent models, acquired deficiency of BMP9 signaling can predispose to or exacerbate PH, providing a possible mechanistic link between PoPH and heritable PAH. These findings describe a novel experimental model of severe PH that provides insight into the synergy between pulmonary vascular injury and diminished BMP9 signaling in the pathogenesis of PAH.

Lower DHEA-S levels predict disease and worse outcomes in post-menopausal women with idiopathic, connective tissue disease- and congenital heart disease-associated pulmonary arterial hypertension.

High oestradiol (E2) and low dehydroepiandrosterone-sulfate (DHEA-S) levels are risk factors for pulmonary arterial hypertension (PAH) in men, but whether sex hormones are related to PAH in women is unknown.Post-menopausal women aged ≥55 years with PAH were matched by age and body mass index to women without cardiovascular disease. Plasma sex hormone levels were measured by immunoassay.Lower levels of DHEA-S (p<0.001) and higher levels of E2 (p=0.02) were associated with PAH. In PAH cases (n=112), lower DHEA-S levels were associated with worse haemodynamics (all p<0.01) and more right ventricular dilatation and dysfunction (both p=0.001). Lower DHEA-S levels were associated with shorter 6-min walking distance (6MWD) (p=0.01) and worse functional class (p=0.004). Each Ln(1 µg·dL-1) decrease in DHEA-S was associated with a doubling in the risk of death (hazard ratio 2.0, 95% CI 1.5-2.7; p<0.001). Higher levels of E2 were associated with shorter 6MWD (p=0.03) and worse functional class (p=0.01).High E2 and low DHEA-S levels are associated with the risk and severity of PAH in post-menopausal women. Hormonal modulation should be studied as a treatment strategy in PAH.

Laryngeal Mask Airway for Surfactant Administration in Neonates: A Randomized, Controlled Trial.

OBJECTIVE: To determine if preterm infants with moderate respiratory distress syndrome on continuous positive airway pressure (CPAP) who received surfactant via a laryngeal mask airway (LMA) would have a decreased rate of intubation and mechanical ventilation compared with those on CPAP who did not receive surfactant. STUDY DESIGN: In this prospective, multicenter, randomized controlled trial, 103 premature infants 280/7-356/7 weeks gestation, ≥1250 g and ≤36 hours old on CPAP requiring fraction of inspired oxygen 0.30-0.40 were assigned to receive surfactant administered through an LMA then placed back on CPAP (LMA group) or maintained on CPAP with no surfactant administered (control group). The primary outcome was treatment failure necessitating intubation and mechanical ventilation in the first 7 days of life. RESULTS: Surfactant administration through an LMA (n = 50) significantly decreased the rate of intubation and mechanical ventilation compared with controls (n = 53): 38% vs 64%, respectively, OR 0.30 (95% CI 0.13, 0.70), P = .006, number needed to treat: 4). There were no serious adverse events associated with placement of the LMA or surfactant administration. CONCLUSIONS: In premature neonates with moderate respiratory distress syndrome, surfactant administered through an LMA decreased the rate of intubation and mechanical ventilation. This intervention may have significant impact on clinical care in both high and low resource settings. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01116921.

Mesenchymal stem cells in the pathogenesis and treatment of bronchopulmonary dysplasia: a clinical review.

Advances in neonatal medicine have led to increased survival of infants born at the limits of viability, resulting in an increased incidence of bronchopulmonary dysplasia (BPD). BPD is a chronic lung disease of premature infants characterized by the arrest of alveolarization, fibroblast activation, and inflammation. BPD leads to significant morbidity and mortality in the neonatal period and is one of the leading causes of chronic lung disease in children. The past decade has brought a surge of trials investigating cellular therapies for the treatment of pulmonary diseases. Mesenchymal stem cells (MSCs) are of particular interest because of their ease of isolation, low immunogenicity, and anti-inflammatory and reparative properties. Clinical trials of MSCs have demonstrated short-term safety and tolerability; however, studies have also shown populations of MSCs with adverse pro-inflammatory and myofibroblastic characteristics. Cell-based therapies may represent the next breakthrough therapy for the treatment of BPD, however, there remain barriers to implementation as well as gaps in knowledge of the role of endogenous MSCs in the pathogenesis of BPD. Concurrent high-quality basic science, translational, and clinical studies investigating the fundamental pathophysiology underlying BPD, therapeutic mechanisms of exogenous MSCs, and logistics of translating cellular therapies will be important areas of future research.

Higher Estradiol and Lower Dehydroepiandrosterone-Sulfate Levels Are Associated with Pulmonary Arterial Hypertension in Men.

RATIONALE: Recent studies have focused on the role of female sex and estradiol (E2) in pulmonary arterial hypertension (PAH), but it is not known whether sex hormones are risk factors for PAH in men. OBJECTIVES: We performed a case-control study to determine whether hormone levels (E2, dehydroepiandrosterone-sulfate [DHEA-S], and testosterone) are associated with PAH in men. METHODS: Plasma sex hormone levels in men with idiopathic, heritable, or connective tissue disease-associated PAH were compared with those from age- and body mass index-matched men without clinical cardiovascular disease. MEASUREMENTS AND MAIN RESULTS: There were 23 cases with PAH (70% had idiopathic PAH, 65% were functional class III/IV) and 67 control subjects. Higher E2 and E2/testosterone levels were associated with the risk of PAH (odds ratio per 1 ln[E2:testosterone], 6.0; 95% confidence interval, 2.2-16.4; P = 0.001), whereas higher levels of DHEA-S were associated with a reduced risk (odds ratio per 1 ln[DHEA-S], 0.1; 95% confidence interval, 0.0-0.3; P = 0.001). E2 and DHEA-S levels were strong predictors of case status (C statistic for both, 0.82) but testosterone was not (C statistic, 0.53). Higher levels of E2 were associated with shorter 6-minute-walk distances (P = 0.03), whereas higher levels of DHEA-S were associated with lower right atrial pressure (P = 0.02) and pulmonary vascular resistance (P = 0.01) in men with PAH. CONCLUSIONS: Higher levels of E2 and lower levels of DHEA-S were associated with PAH in men. Sex-based differences in sex hormone processing and signaling may contribute to unique phenotypes in pulmonary vascular disease.

Effect of Warfarin Treatment on Survival of Patients With Pulmonary Arterial Hypertension (PAH) in the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL).

BACKGROUND: Long-term anticoagulation is recommended in idiopathic pulmonary arterial hypertension (IPAH). In contrast, limited data support anticoagulation in pulmonary arterial hypertension (PAH) associated with systemic sclerosis (SSc-PAH). We assessed the effect of warfarin anticoagulation on survival in IPAH and SSc-PAH patients enrolled in Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL), a longitudinal registry of group I PAH. METHODS AND RESULTS: Patients who initiated warfarin on study (n=187) were matched 1:1 with patients never on warfarin, by enrollment site, etiology, and diagnosis status. Descriptive analyses were conducted to compare warfarin users and nonusers by etiology. Survival analyses with and without risk adjustment were performed from the time of warfarin initiation or a corresponding quarterly update in matched pairs to avoid immortal time bias. Time-varying covariate models were used as sensitivity analyses. Mean warfarin treatment was 1 year; mean international normalized ratios were 1.9 (IPAH) and 2.0 (SSc-PAH). Two-thirds of patients initiating warfarin discontinued treatment before the last study assessment. There was no survival difference with warfarin in IPAH patients (adjusted hazard ratio, 1.37; P=0.21) or in SSc-PAH patients (adjusted hazard ratio, 1.60; P=0.15) in comparison with matched controls. However, SSc-PAH patients receiving warfarin within the previous year (hazard ratio, 1.57; P=0.031) or any time postbaseline (hazard ratio, 1.49; P=0.046) had increased mortality in comparison with warfarin-naïve patients. CONCLUSIONS: No significant survival advantage was observed in IPAH patients who started warfarin. In SSc-PAH patients, long-term warfarin was associated with poorer survival than in patients not receiving warfarin, even after adjusting for confounders. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00370214.

Influenza A virus uses intercellular connections to spread to neighboring cells.

UNLABELLED: In the extracellular environment, cell-free virions seek out naive host cells over long distances and between organisms. This is the primary mechanism of spread for most viruses. Here we provide evidence for an alternative pathway previously undescribed for orthomyxoviruses, whereby the spread of influenza A virus (IAV) infectious cores to neighboring cells can occur within intercellular connections. The formation of these connections requires actin dynamics and is enhanced by viral infection. Connected cells have contiguous membranes, and the core infectious viral machinery (RNP and polymerase) was present inside the intercellular connections. A live-cell movie of green fluorescent protein (GFP)-tagged NS1 of IAV shows viral protein moving from one cell to another through an intercellular connection. The movement of tagged protein was saltatory but overall traveled only in one direction. Infectious virus cores can move from one cell to another without budding and release of cell-free virions, as evidenced by the finding that whereas a neuraminidase inhibitor alone did not inhibit the development of IAV microplaques, the presence of a neuraminidase inhibitor together with drugs inhibiting actin dynamics or the microtubule stabilizer paclitaxel (originally named taxol) precluded microplaque formation. Similar results were also observed with parainfluenza virus 5 (PIV5), a paramyxovirus, when neutralizing antibody was used to block spread by cell-free virions. Intercellular spread of infectious core particles was unaffected or enhanced in the presence of nocodazole for IAV but inhibited for PIV5. The intercellular connections have a core of filamentous actin, which hints toward transport of virus particles through the use of a myosin motor. IMPORTANCE: Here we describe a new method by which influenza A virus (IAV) spreads from cell to cell: IAV uses intracellular connections. The formation of these connections requires actin dynamics and is enhanced by viral infection and the absence of microtubules. Connected cells appeared to have contiguous membranes, and the core infectious viral machinery (RNP and polymerase) was present inside the intercellular connections. Infectious virus cores can move from one cell to another without budding and release of cell-free virions. Similar results were also observed with parainfluenza virus 5 (PIV5).

Current practice of neonatal resuscitation documentation in North America: a multi-center retrospective chart review.

BACKGROUND: To determine the comprehensiveness of neonatal resuscitation documentation and to determine the association of various patient, provider and institutional factors with completeness of neonatal documentation. METHODS: Multi-center retrospective chart review of a sequential sample of very low birth weight infants born in 2013. The description of resuscitation in each infant's record was evaluated for the presence of 29 Resuscitation Data Items and assigned a Number of items documented per record. Covariates associated with this Assessment were identified. RESULTS: Charts of 263 infants were reviewed. The mean gestational age was 28.4 weeks, and the mean birth weight 1050 g. Of the infants, 69 % were singletons, and 74 % were delivered by Cesarean section. A mean of 13.2 (SD 3.5) of the 29 Resuscitation Data Items were registered for each birth. Items most frequently present were; review of obstetric history (98 %), Apgar scores (96 %), oxygen use (77 %), suctioning (71 %), and stimulation (62 %). In our model adjusted for measured covariates, the institution was significantly associated with documentation. CONCLUSIONS: Neonatal resuscitation documentation is not standardized and has significant variation. Variation in documentation was mostly dependent on institutional factors, not infant or provider characteristics. Understanding this variation may lead to efforts to standardize documentation of neonatal resuscitation.

The amphipathic helix of influenza A virus M2 protein is required for filamentous bud formation and scission of filamentous and spherical particles.

Influenza virus assembles and buds at the infected-cell plasma membrane. This involves extrusion of the plasma membrane followed by scission of the bud, resulting in severing the nascent virion from its former host. The influenza virus M2 ion channel protein contains in its cytoplasmic tail a membrane-proximal amphipathic helix that facilitates the scission process and is also required for filamentous particle formation. Mutation of five conserved hydrophobic residues to alanines within the amphipathic helix (M2 five-point mutant, or 5PM) reduced scission and also filament formation, whereas single mutations had no apparent phenotype. Here, we show that any two of these five residues mutated together to alanines result in virus debilitated for growth and filament formation in a manner similar to 5PM. Growth kinetics of the M2 mutants are approximately 2 logs lower than the wild-type level, and plaque diameter was significantly reduced. When the 5PM and a representative double mutant (I51A-Y52A) were introduced into A/WSN/33 M2, a strain that produces spherical particles, similar debilitation in viral growth occurred. Electron microscopy showed that with the 5PM and the I51A-Y52A A/Udorn/72 and WSN viruses, scission failed, and emerging virus particles exhibited a "beads-on-a-string" morphology. The major spike glycoprotein hemagglutinin is localized within lipid rafts in virus-infected cells, whereas M2 is associated at the periphery of rafts. Mutant M2s were more widely dispersed, and their abundance at the raft periphery was reduced, suggesting that the M2 amphipathic helix is required for proper localization in the host membrane and that this has implications for budding and scission.

The impact of left ventricular hypertrophy on survival in candidates for liver transplantation.

Left ventricular hypertrophy (LVH) occurs in 12% to 30% of patients with cirrhosis; however, its prognostic significance is not well studied. We assessed the association of LVH with survival in patients undergoing a liver transplantation (LT) evaluation. We performed a multicenter cohort study of patients undergoing an evaluation for LT. LVH was defined with transthoracic echocardiography. The outcome of interest was all-cause mortality. LVH was present in 138 of 485 patients (28%). Patients with LVH were older, more likely to be male and African American, and were more likely to have hypertension. Three hundred forty-five patients did not undergo transplantation (212 declined, and 133 were waiting): 36 of 110 patients with LVH (33%) died, whereas 57 of 235 patients without LVH (24%) died (P = 0.23). After LT, 8 of 28 patients with LVH (29%) died over the course of 3 years, whereas 9 of 112 patients without LVH (8%) died (P = 0.007). This finding was independent of conventional risk factors for LVH, and all deaths for patients with LVH occurred within 9 months of LT. No clinical or demographic characteristics were associated with mortality among LVH patients. In conclusion, the presence of LVH is associated with an early increase in mortality after LT, and this is independent of conventional risk factors for LVH. Further studies are needed to confirm these findings and identify factors associated with mortality after transplantation to improve outcomes.

Comparison of laryngeal mask airway and endotracheal tube placement in neonates.

OBJECTIVE: We hypothesize that the time, number of attempts, and physiologic stability of placement of an LMA would be superior compared to ETT. STUDY DESIGN: Videotape and physiologic parameters of LMA (n = 36) and ETT (n = 31) placement procedures for infants 28-36 weeks gestation were reviewed. RESULTS: Duration of attempts (32 vs 66 s, p < 0.001) and mean total airway insertion time (88 vs 153 s, p = 0.06) was shorter for LMA compared to ETT. Mean number of attempts for successful placement was fewer for LMA (1.5 vs 1.9, p = 0.11). Physiologic parameters remained near baseline in both groups despite very different degrees of premedication. CONCLUSION: Placement of an LMA required less time and fewer number of attempts compared to ETT. Physiologic stability of an LMA was maintained without the use of an analgesic and muscle relaxant. Use of an LMA is a favorable alternative to ETT placement for surfactant delivery in neonates. TRIAL REGISTRATION: NCT01116921.

Novel FOXF1 mutations in sporadic and familial cases of alveolar capillary dysplasia with misaligned pulmonary veins imply a role for its DNA binding domain.

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare and lethal developmental disorder of the lung defined by a constellation of characteristic histopathological features. Nonpulmonary anomalies involving organs of gastrointestinal, cardiovascular, and genitourinary systems have been identified in approximately 80% of patients with ACD/MPV. We have collected DNA and pathological samples from more than 90 infants with ACD/MPV and their family members. Since the publication of our initial report of four point mutations and 10 deletions, we have identified an additional 38 novel nonsynonymous mutations of FOXF1 (nine nonsense, seven frameshift, one inframe deletion, 20 missense, and one no stop). This report represents an up to date list of all known FOXF1 mutations to the best of our knowledge. Majority of the cases are sporadic. We report four familial cases of which three show maternal inheritance, consistent with paternal imprinting of the gene. Twenty five mutations (60%) are located within the putative DNA-binding domain, indicating its plausible role in FOXF1 function. Five mutations map to the second exon. We identified two additional genic and eight genomic deletions upstream to FOXF1. These results corroborate and extend our previous observations and further establish involvement of FOXF1 in ACD/MPV and lung organogenesis.

Comparison of Laryngeal Mask Airway and Endotracheal Tube Placement in Neonates.

Objective: We hypothesize that the time, number of attempts and physiologic stability of placement of an LMA would be superior compared to ETT. Study Design: Videotape and physiologic parameters of LMA (n = 36) and ETT (n = 31) placement procedures for infants 28-36 weeks gestation were reviewed. Results: Duration of attempts (32 vs 66 sec, p < 0.001) and mean total procedure time (88 vs 153 sec, p = 0.06) was shorter for LMA compared to ETT. Mean number of attempts for successful placement was fewer for LMA (1.5 vs 1.9, p = 0.11). Physiologic parameters remained near baseline in both groups despite very different degrees of premedication. Conclusion: Placement of an LMA required less time and fewer number of attempts compared to ETT. Physiologic stability of an LMA was maintained without the use of an analgesic and muscle relaxant. Use of an LMA is a favorable alternative to ETT placement for surfactant delivery in neonates. Trial registration: NCT01116921.

Surfactant delivery strategies to prevent bronchopulmonary dysplasia.

Bronchopulmonary dysplasia (BPD) is one of the most devastating morbidities of preterm infants. Antenatal factors like growth restriction and inflammation are risk factors for its development. Use of oxygen and positive pressure ventilation, which are often necessary to treat respiratory distress syndrome (RDS), increase the risk for development of BPD. Continuous positive airway pressure (CPAP) as primary respiratory support allows for avoidance of positive pressure ventilation in many cases but may lead to a delay of surfactant administration which is a proven therapy for RDS. Several alternative surfactant delivery strategies, including nebulization of surfactant, pharyngeal instillation of surfactant, delivery of surfactant via supraglottic airway device or surfactant delivery via a thin endotracheal catheter have been described which allow for the benefit of surfactant therapy while on CPAP. This review reports available data and discusses the existing evidence of their value in preventing BPD as well as further research directions.

Alternative routes of surfactant application - An update.

Non-invasive modes of respiratory support have been shown to be the preferable way of primary respiratory support of preterm infants with respiratory distress syndrome (RDS). The avoidance of invasive mechanical ventilation can be beneficial for preterm infants in reduction of morbidity and even mortality. However, it is well-established that some infants managed with non-invasive respiratory support from the outset have symptomatic RDS to a degree that warrants surfactant administration. Infants for whom non-invasive respiratory support ultimately fails are prone to adverse outcomes, occurring at a frequency on par with the group intubated primarily. This raises the question how to combine non-invasive respiratory support with surfactant therapy. Several methods of less or minimally invasive surfactant therapy have been developed to address the dilemma between avoidance of mechanical ventilation and administration of surfactant. This paper describes the different methods of less invasive surfactant application, reports the existing evidence from clinical studies, discusses the limitations of each of the methods and the open and future research questions.

Preventing lost-to-follow up diagnostic imaging in ambulatory care: evaluation of an electronic notification tool.

OBJECTIVE: Missed or cancelled imaging tests may be invisible to the ordering clinician and result in diagnostic delay. We developed an outpatient results notification tool (ORNT) to alert physicians of patients' missed radiology studies. DESIGN: Randomised controlled evaluation of a quality improvement intervention. SETTING: 23 primary care and subspecialty ambulatory clinics at an urban academic medical centre. PARTICIPANTS: 276 physicians randomised to intervention or usual care. MAIN OUTCOME MEASURE: 90-day test completion of missed imaging tests. RESULTS: We included 3675 radiology tests in our analysis: 1769 ordered in the intervention group and 1906 in the usual care group. A higher per cent of studies were completed for intervention compared with usual care groups in CT (20.7% vs 15.3%, p=0.06), general radiology (19.6% vs 12.0%, p=0.02) and, in aggregate, across all modalities (18.1% vs 16.1%, p=0.03). In the multivariable regression model adjusting for sex, age and insurance type and accounting for clustering with random effects at the level of the physician, the intervention group had a 36% greater odds of test completion than the usual care group (OR: 1.36 (1.097-1.682), p=0.005). In the Cox regression model, patients in the intervention group were 1.32 times more likely to complete their test in a timely fashion (HR: 1.32 (1.10-1.58), p=0.003). CONCLUSIONS: An electronic alert that notified the responsible clinician of a missed imaging test ordered in an ambulatory clinic reduced the number of incomplete tests at 90 days. Further study of the obstacles to completing recommended diagnostic testing may allow for the development of better tools to support busy clinicians and their patients and reduce the risk of diagnostic delays.