Current perception and barriers to implementing lung ultrasound in Canadian neonatal intensive care units: a national survey.

Despite the growing body of literature supporting the use of point-of-care lung ultrasound (POC-LU) in neonates, its adoption in Canadian neonatal intensive care units (NICUs) remains limited. This study aimed to identify healthcare providers' perceptions and barriers to implementing POC-LU in Canadian NICUs. We conducted an electronic survey targeting neonatologists, neonatal fellows, neonatal nurse practitioners, and registered respiratory therapists in 20 Canadian NICUs. The survey comprised a 28-item questionnaire divided into four sections: (1) participants' demographics and availability of POC-LU equipment, (2) experience and interest in POC-LU learning, (3) perception of POC-LU as a diagnostic tool, and (4) barriers to POC-LU implementation in NICUs. A total of 194 participants completed the survey, with neonatologists comprising the majority (45%). Nearly half of the participants (48%) reported prior experience with POC-LU. The most prevalent indications for POC-LU use were diagnosis of pleural effusion (90%), pneumothorax (87%), and respiratory distress syndrome (76%). Participants identified the primary barrier to POC-LU adoption as the lack of trained providers available for both training and clinical integration. Notably, most respondents (87%) expressed keen interest in learning neonatal POC-LU. A subgroup analysis based on the responses collected from NICU-directors of 12 institutions yielded results consistent with those of the overall participant pool.     Conclusion: This survey underscores the perceived importance of POC-LU among NICU healthcare providers. A Canadian consensus is required to facilitate the development of widespread training programs as well as standardized clinical practice guideline for its implementation. What is Known: • In recent years, point-of-care lung ultrasound (POC-LU) has emerged as an important tool in neonatology, revolutionizing the assessment and management of critically ill infants. However, its adoption in Canadian Neonatal Intensive Care Units remains limited. What is New: • Most Canadian healthcare providers showed high level of interest in learning POC-LU techniques. Additionally, POC-LU was perceived as a useful tool for diagnosis and guiding intervention in various neonatal respiratory diseases. Nonetheless, the lack of expertise emerged as the primary barrier to its adoption and practice across different groups of participants regardless of their clinical experience level.

Sex-Based Differences in the Sonographic Characterization of Diaphragm Thickness in Preterm Infants With Bronchopulmonary Dysplasia at Term Corrected Age: A Secondary Analysis of a Prospective Study.

OBJECTIVE: To determine the sex-specific diaphragm thickness in infants with bronchopulmonary dysplasia (BPD) as well as in healthy term and near-term infants. METHODS: We performed a secondary analysis of an observational study to compare the sonographic diaphragm thickness at end expiration (DTexp) in female and male infants. The study included infants with BPD and healthy near-term and term infants. To account for differences in anthropometric measurements, we calculated the DTexp as a ratio of body surface area (BSA). Statistical analysis was performed using R statistical software. RESULTS: Of the 111 infants included, 54 (48.6%) were female. There were no significant differences in mean (SD) birth gestation [26.2 (2.1) vs 26.3 (2.1) weeks] and mean study age [38.0 (2.0) vs 37.4 (1.1) weeks] of male vs female infants with BPD. The mean (SD) DTexp [1.5 (0.4) mm vs 1.2 (0.3) mm, P = .02] and DTexp/BSA [8.3 (2.3) mm/m2 vs 6.7 (1.6) mm/m2, P < .01] were significantly thicker in female than male infants with BPD. In contrast, there were no significant differences in DTexp between sexes [1.5 (0.4) mm vs 1.5 (0.3) mm, P = .89] within the healthy control group. Moreover, there were no differences in inspiratory diaphragm thickness, diaphragm thickness fraction, or excursion between males and females in the BPD or healthy groups. CONCLUSIONS: Male infants with BPD exhibit thinner diaphragm thickness compared with female infants. Its implication on higher rates of BPD in preterm males is unclear, but this finding highlights the need for further investigation.

Variations in Site-Specific Costs for Infants Born Extremely Preterm in Canadian Neonatal Intensive Care Units.

OBJECTIVE: To quantify site-specific costs and their association with survival without major morbidity (SWMM) in Canada for neonates <28 weeks of gestation admitted to large tertiary neonatal intensive care units. METHODS: We conducted a retrospective analysis of infants born at <28 weeks of gestation and admitted to Canadian Neonatal Network sites from 2010 through 2021. Sites that cared for at least 50 eligible infants by gestational age in weeks over the study period were included. Using a validated costing algorithm that assessed physician, nursing, respiratory therapy, diagnostic imaging, transfusions, procedural, medication, and certain indirect costs, we calculated site and resource-specific costs in 2017 Canadian dollars (CAD) and evaluated their relationship with SWMM. RESULTS: Seven sites with 8180 (range 841-1605) eligible neonates with a mean (SD) gestation of 25.4 [1.3] weeks were included. Survival to discharge or transfer was 85.3% with a mean (SD) length of stay of 75 (46) days. The mean (SD) total and daily costs per neonate varied between $94 992 ($60 283) and $174 438 ($130 501) CAD and $1833 ($916) to $2307 ($1281) CAD, respectively. Between sites, there was no relationship between costs and SWMM. CONCLUSIONS: There was marked variation in costs and SWMM between sites in Canada with universal health care. The lack of concordance between both outcomes and costs among sites may provide possibilities for outcomes improvement and cost containment.

Surfactant delivery via thin catheter in preterm infants: A systematic review and meta-analysis.

OBJECTIVE: Surfactant administration via a thin catheter (STC) is an alternative to surfactant administration post endotracheal intubation in preterm infants with respiratory distress syndrome (RDS); however, the benefits particularly in infants <29 weeks' gestation and the neurodevelopmental outcomes remain unclear. Thus, our objective was to systematically review and meta-analyze the efficacy and safety of STC compared to intubation for surfactant or nasal continuous positive airway pressure (nCPAP) in preterm infants with RDS. METHODS: Medical databases were searched until December 2022 for randomized controlled trials (RCTs) assessing STC compared to controls that included intubation for surfactant or nCPAP in preterm infants with RDS. The primary outcome was bronchopulmonary dysplasia (BPD) at 36 weeks gestation in survivors. Subgroup analysis was conducted comparing STC to controls in infants < 29 weeks' gestation. The Cochrane risk of bias (ROB) tool was used and certainty of evidence (CoE) was rated according to GRADE. RESULTS: Twenty-six RCTs of 3349 preterm infants, in which half of the studies had low risk of bias, were included. STC decreased the risk of BPD in survivors compared to controls (17 RCTs; N = 2408; relative risk (RR) = 0.66; 95% confidence interval (CI) 0.51 to 0.85; number needed to treat for an additional beneficial outcome (NNTB) = 13; CoE: moderate). In infants < 29 weeks' gestation, STC significantly reduced the risk of BPD compared to controls (6 RCTs, N = 980; RR 0.63; 95% CI 0.47 to 0.85; NNTB = 8; CoE: moderate). CONCLUSIONS: Compared to controls, STC may be a more efficacious and safe method of surfactant delivery in preterm infants with RDS, including infants < 29 weeks' gestation.

A comparison of tertiary level NICU costs for infants born <1250 g supplemented with human versus bovine milk-based fortifiers.

BACKGROUND: Human milk-based fortifiers (HMBF) are more costly than bovine milk-based fortifiers (BMBF); but, the efficacy of human or bovine fortification for infants born <1250 g has yet to be fully elucidated. Our objective was to determine the effect of fortifier source on tertiary neonatal costs. METHODS: Costs associated with tertiary neonatal care, including direct and indirect hospital expenditures, feed-related costs and physician billing were analysed retrospectively for participants of OptiMoM (NCT02137473), a blinded RCT comparing fortifier type for babies born <1250 g. A generalized linear model of cost according to fortifier type was created. RESULTS: Mean [95% confidence interval] daily costs per patient, adjusted for birth gestation and weight, was significantly greater in the human than the BMBF group ($3,452 [$3,186 - $3,740] Canadian dollars (CAD) versus $2,451 [$2,257 - $2,662] CAD) respectively, p < 0.0001). CONCLUSION: HMBF usage entails additional costs on NICU stay that should be considered with implementation.

Accuracy of lung and diaphragm ultrasound in predicting successful extubation in extremely preterm infants: A prospective observational study.

OBJECTIVE: Chest ultrasound has emerged as a promising tool in predicting extubation readiness in adults and children, yet its utility in preterm infants is lacking. Our aim was to assess the utility of lung ultrasound severity score (LUSS) and diaphragmatic function in predicting extubation readiness in extremely preterm infants. STUDY DESIGN: In this prospective cohort study, preterm infants < 28 weeks gestational age (GA) who received invasive mechanical ventilation for ≥12 h were enrolled. Chest ultrasound was performed before extubation. The primary outcome was lung ultrasound accuracy for predicting successful extubation at 3 days. Descriptive statistics and logistic regression were done using SPSS version 22. RESULTS: We enrolled 45 infants, of whom 36 (80%) were successfully extubated. GA and postmenstrual age (PMA) at extubation were significantly higher in the successful group. The LUSS was significantly lower in the successful group compared to failed group (11.9 ± 3.2 vs. 19.1 ± 3.1 p < 0.001). The two groups had no statistically significant difference in diaphragmatic excursion or diaphragmatic thickness fraction. Logistic regression analysis controlling for GA and PMA at extubation showed LUSS was an independent predictor for successful extubation (odd ratio 0.46, 95% confidence interval [0.23-0.9], p = 0.02). The area under the receiver operating characteristic curve was 0.95 (p ˂ 0.001) for LUSS, and a cut-off value of ≥15 had 95% sensitivity and 85% specificity in detecting extubation failure. CONCLUSION: In extremely preterm infants, lung ultrasound has good accuracy for predicting successful extubation. However, diaphragmatic measurements were not reliable predictors.

Diaphragmatic Thickness and Excursion in Preterm Infants With Bronchopulmonary Dysplasia Compared With Term or Near Term Infants: A Prospective Observational Study.

BACKGROUND: Diaphragmatic atrophy associated with mechanical ventilation is reported in pediatric and adult patients, but a similar association has not been described in preterm infants with bronchopulmonary dysplasia (BPD). RESEARCH QUESTION: Does BPD impact the diaphragm thickness (DT) and diaphragm excursion (DE) in infants born before 32 weeks' gestation compared with healthy late preterm or term infants? STUDY DESIGN AND METHODS: In this prospective observational case-control study, DT at end of expiration (DTexp), DT at end of inspiration (DTins), DT fraction (DTF), and DE (DE) were assessed using bedside ultrasound. Two groups were compared: infants with BPD (patients) and healthy, postmenstrual age-matched infants (control participants). To account for variations in body size between groups, diaphragmatic measurements were expressed as a ratio of body surface area (BSA). Statistical analyses were conducted using SAS software version 9.4 (SAS Institute, Inc.). RESULTS: We enrolled 111 infants, including 56 preterm infants with BPD (mean ± SD study age, 37.7 ± 1.7 weeks) and 55 healthy control participants (mean ± SD study age, 38.1 ± 1.5 weeks). DTexp and DTexp to BSA ratio were significantly lower in the BPD group compared with the healthy control group (mean ± SD, 1.3 ± 0.4 mm vs 1.5 ± 0.4 mm [P = .01] and 7.1 ± 1.4 mm/m2 vs 7.8 ± 1.8 mm/m2 [P = .03]). DTF and DE were significantly higher in the BPD group vs the healthy control group (mean ± SD, 61.8 ± 26.0 vs 43.3 ± 19.7 [P < .01] and 6.0 ± 1.7 mm vs 4.4 ± 1.6 mm [P < .01], respectively). INTERPRETATION: In infants with BPD, DTexp was significantly lower, whereas DTF and DE were significantly higher, compared with healthy, age-matched control participants. Future studies are required and should focus on describing the evolution of diaphragmatic dimensions in preterm infants with and without BPD. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT04941963; URL: www. CLINICALTRIALS: gov.

The Trend in Costs of Tertiary-Level Neonatal Intensive Care for Neonates Born Preterm at 220/7-286/7 Weeks of Gestation from 2010 to 2019 in Canada.

OBJECTIVE: To describe the trend in costs over 10 years for tertiary-level neonatal care of infants born 220/7-286/7 weeks of gestation during an ongoing Canadian national quality improvement project. STUDY DESIGN: Clinical characteristics, outcomes, and third-party payor costs for the tertiary neonatal care of infants born 220/7-286/7 weeks of gestation between the years 2010 and 2019 were analyzed from the Canadian Neonatal Network database. Costs were estimated using resource use data from the Canadian Neonatal Network and cost inputs from hospitals, physician billing, and administrative databases in Ontario, Canada. Cost estimates were adjusted to 2017 Canadian dollars (CAD). A generalized linear mixed-effects model with gamma regression was used to estimate trends in costs. RESULTS: Between 2010 and 2019, the number of infants born <24 weeks of gestation increased from 4.4% to 7.7%. The average length of stay increased from 68 days to 75 days. Unadjusted average ± SD total costs per neonate were $120 717 ± $93 062 CAD in 2010 and $132 774 ± $93 161 CAD in 2019. After adjustment for year, center, and gestation, total costs and length of stay increased significantly, by $13 612 CAD (P < .01) and 8.1 days (P < .01) over 10 years, respectively; whereas costs accounting for LOS remained stable. CONCLUSIONS: The total costs and length of stay for infants 220/7-286/7 weeks of gestation have increased over the past decade in Canada during an ongoing national quality improvement initiative; however, there was an increase in the number and survival of neonates at the age of periviability.

Therapeutic Drug Monitoring of Moxifloxacin to Guide Treatment of Mycoplasma hominis Meningitis in an Extremely Preterm Infant.

Mycoplasma hominis (M hominis) is a rare cause of neonatal bacterial meningitis. Treatment can be challenging because of M hominis' intrinsic antibiotic resistance and the difficulty in accessing antimicrobial susceptibility testing. In this report, we describe an extremely preterm male infant with seizures who had a subsequent diagnosis of M hominis meningitis. Because of severity of illness, doxycycline (4 mg/kg IV every 24 hours) and moxifloxacin (5 mg/kg IV every 24 hours) were started empirically. Repeat cerebrospinal fluid cultures were negative and showed decreasing pleiocytosis. Given the concentration-dependent killing of moxifloxacin and concern for endovascular infection from a concomitant cerebral venous sinus thrombosis, serum concentrations of moxifloxacin were obtained to estimate pharmacokinetic and pharmacodynamic parameters. These were compared to the targets described in other case reports of M hominis meningitis. The maximum serum concentration (Cmax) was 2.5 mg/L, volume of distribution was 2.2 L/kg, clearance was 0.18 L/kg/hr, terminal half-life was 8.6 hours, and area-under-the-concentration-time curve (AUC) was 28.1 mg•hr/L. Using the range of minimum inhibitory concentrations (MICs) reported in the literature, the estimated Cmax/MIC for this patient was 21 to 158 (target Cmax/MIC: >10) and AUC/MIC was 234 to 1757 (target AUC/MIC: ≥100). Doxycycline and moxifloxacin were continued for 6 weeks. No adverse events to moxifloxacin or doxycycline were observed in the NICU. This report describes the successful treatment of M hominis neonatal meningitis and adds to the knowledge of pharmacokinetic and pharmacodynamic parameters of moxifloxacin in neonates. Additional data will help to confirm the role for routine therapeutic drug monitoring of moxifloxacin in neonates.

Steroids for the Management of Neonates With Meconium Aspiration Syndrome: A Systematic Review and Meta-analysis.

BACKGROUND: Steroids are a potential treatment for pulmonary inflammation in meconium aspiration syndrome (MAS). OBJECTIVE: To assess the efficacy and safety of steroids for the management of neonates with MAS. DESIGN: Systematic review and meta-analysis of randomized controlled trials (RCT). DATA SOURCES AND SELECTION CRITERIA: A systematic search of PubMed, Embase, Cochrane, and CINAHL was performed from database inception to May 2020 for trials assessing the efficacy of steroids (inhaled/systemic or both) in neonates with MAS. The primary outcome was in-hospital mortality, with secondary outcomes being length of hospital stay and duration of oxygen support. RESULTS: Nine RCTs (758 neonates) were included. Overall, steroids did not decrease in-hospital mortality (RR: 0.59; 95% CI 0.28 to 1.23; I2 = 0%; GRADE: low) nor had any effect on the secondary outcomes. CONCLUSIONS: There is low quality of evidence that the administration of steroids is not associated with a reduction in mortality in infants with MAS. Further well-designed studies with low bias are needed to draw conclusions.

Home Management of Childhood Asthma Exacerbations.

INTRODUCTION: Effective home management of childhood asthma by caregivers requires education along with a written asthma action plan (AAP), which should outline clear instructions for treatment during exacerbations. However, a large number of asthma exacerbations continue to be managed in the emergency department (ED) and in hospitals, particularly in Canada. The objective of this study was to assess caregiver management of acute asthma at home following the 2015 Global Initiative for Asthma (GINA) guidelines and to identify factors that may be associated with deviations from these guidelines. METHODS: 122 caregivers of children, aged 3-17 years, with physician diagnosed asthma, completed a paper-based questionnaire. Correct caregiver management (defined according to the GINA guidelines) of acute asthma as well as their use of an AAP were assessed. RESULTS: Out of all caregivers, 74.6% incorrectly treated their child's asthma exacerbation in a home setting. Among those who used an AAP, we observed significantly more ED visits (0.9 ± 1.2 versus 0.5 ± 0.9, p = 0.04) and hospitalizations (0.2 ± 0.4 versus 0.0 ± 0.0, p = 0.02) when compared to non-AAP users in the past 1 year. CONCLUSIONS: Caregivers of children with asthma in Canada may still lack skills for proper home management of asthma exacerbations. We found a higher number of ED visits and hospitalizations in those using an AAP compared to those who did not use an AAP. These data suggest that current AAPs may not be sufficient for home asthma management.

Identification and differentiation of PDX1 ß-cell progenitors within the human pancreatic epithelium.

AIM: To minimize the expansion of pancreatic mesenchymal cells in vitro and confirm that ß-cell progenitors reside within the pancreatic epithelium. METHODS: Due to mesenchymal stem cell (MSC) expansion and overgrowth, progenitor cells within the pancreatic epithelium cannot be characterized in vitro, though ß-cell dedifferentiation and expansion of MSC intermediates via epithelial-mesenchymal transition (EMT) may generate ß-cell progenitors. Pancreatic epithelial cells from endocrine and non-endocrine tissue were expanded and differentiated in a novel pancreatic epithelial expansion medium supplemented with growth factors known to support epithelial cell growth (dexamethasone, epidermal growth factor, 3,5,3'-triiodo-l-thyronine, bovine brain extract). Cells were also infected with a single and dual lentiviral reporter prior to cell differentiation. Enhanced green fluorescent protein was controlled by the rat Insulin 1 promoter and the monomeric red fluorescent protein was controlled by the mouse PDX1 promoter. In combination with lentiviral tracing, cells expanded and differentiated in the pancreatic medium were characterized by flow cytometry (BD fluorescence activated cell sorting), immunostaining and real-time polymerase chain reaction (PCR) (7900HT Fast Realtime PCR System). RESULTS: In the presence of 10% serum MSCs rapidly expand in vitro while the epithelial cell population declines. The percentage of vimentin(+) cells increased from 22% ± 5.83% to 80.43% ± 3.24% (14 d) and 99.00% ± 0.0% (21 d), and the percentage of epithelial cells decreased from 74.71% ± 8.34% to 26.57% ± 9.75% (14 d) and 4.00% ± 1.53% (21 d), P < 0.01 for all time points. Our novel pancreatic epithelial expansion medium preserved the epithelial cell phenotype and minimized epithelial cell dedifferentiation and EMT. Cells expanded in our epithelial medium contained significantly less mesenchymal cells (vimentin(+)) compared to controls (44.87% ± 4.93% vs 95.67% ± 1.36%; P < 0.01). During cell differentiation lentiviral reporting demonstrated that, PDX1(+) and insulin(+) cells were localized within adherent epithelial cell aggregates compared to controls. Compared to starting islets differentiated cells had at least two fold higher gene expression of PDX1, insulin, PAX4 and RFX (P < 0.05). CONCLUSION: PDX1(+) cells were confined to adherent epithelial cell aggregates and not vimentin(+) cells (mesenchymal), suggesting that EMT is not a mechanism for generating pancreatic progenitor cells.

Bioengineering a highly vascularized matrix for the ectopic transplantation of islets.

Islet transplantation is a promising treatment for Type 1 diabetes; however limitations of the intra-portal site and poor revascularization of islets must be overcome. We hypothesize that engineering a highly vascularized collagen-based construct will allow islet graft survival and function in alternative sites. In this study, we developed such a collagen-based biomaterial. Neonatal porcine islets (NPIs) were embedded in collagen matrices crosslinked with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide and N-hydroxysuccinimide containing combinations of chondroitin-6-sulfate, chitosan, and laminin, and compared with controls cultured in standard media. Islets were examined for insulin secretory activity after 24 h and 4 d and for apoptotic cell death and matrix integrity after 7 d in vitro. These same NPI/collagen constructs were transplanted subcutaneously in immunoincompetent B6.Rag-/- mice and then assessed for islet survival and vascularization. At all time points assessed during in vitro culture there were no significant differences in insulin secretory activity between control islets and those embedded in the collagen constructs, indicating that the collagen matrix had no adverse effect on islet function. Less cell death was observed in the matrix with all co-polymers compared with the other matrices tested. Immunohistochemical analysis of the grafts post-transplant confirmed the presence of intact insulin-positive islets; grafts were also shown to be vascularized by von Willebrand factor staining. This study demonstrates that a collagen, chondroitin-6-sulfate, chitosan, and laminin matrix supports islet function in vitro and moreover allows islet survival and vascularization post-transplantation; therefore, this bio-engineered vascularized construct is capable of supporting islet survival.

Human mesenchymal stem cells protect human islets from pro-inflammatory cytokines.

Transplantation of human islets is an attractive alternative to daily insulin injections for patients with type 1 diabetes. However, the majority of islet recipients lose graft function within five years. Inflammation is a primary contributor to graft loss, and inhibiting pro-inflammatory cytokine activity can reverse inflammation mediated dysfunction of islet grafts. As mesenchymal stem cells (MSCs) possess numerous immunoregulatory properties, we hypothesized that MSCs could protect human islets from pro-inflammatory cytokines. Five hundred human islets were co-cultured with 0.5 or 1.0 × 10(6) human MSCs derived from bone marrow or pancreas for 24 hours followed by 48 hour exposure to interferon-γ, tumor necrosis factor-α and interleukin 1ß. Controls include islets cultured alone (± cytokines) and with human dermal fibroblasts (± cytokines). For all conditions, glucose stimulated insulin secretion (GSIS), total islet cellular insulin content, islet ß cell apoptosis, and potential cytoprotective factors secreted in the culture media were determined. Cytokine exposure disrupted human islet GSIS based on stimulation index and percentage insulin secretion. Conversely, culture with 1.0 × 10(6) bMSCs preserved GSIS from cytokine treated islets. Protective effects were not observed with fibroblasts, indicating that preservation of human islet GSIS after exposure to pro-inflammatory cytokines is MSC dependent. Islet ß cell apoptosis was observed in the presence of cytokines; however, culture of bMSCs with islets prevented ß cell apoptosis after cytokine treatment. Hepatocyte growth factor (HGF) as well as matrix metalloproteinases 2 and 9 were also identified as putative secreted cytoprotective factors; however, other secreted factors likely play a role in protection. This study, therefore, demonstrates that MSCs may be beneficial for islet engraftment by promoting cell survival and reduced inflammation.

Comprehensive analysis of missense variations in the BRCT domain of BRCA1 by structural and functional assays.

Genetic screening of the breast and ovarian cancer susceptibility gene BRCA1 has uncovered a large number of variants of uncertain clinical significance. Here, we use biochemical and cell-based transcriptional assays to assess the structural and functional defects associated with a large set of 117 distinct BRCA1 missense variants within the essential BRCT domain of the BRCA1 protein that have been documented in individuals with a family history of breast or ovarian cancer. In the first method, we used limited proteolysis to assess the protein folding stability of each of the mutants compared with the wild-type. In the second method, we used a phosphopeptide pull-down assay to assess the ability of each of the variants to specifically interact with a peptide containing a pSer-X-X-Phe motif, a known functional target of the BRCA1 BRCT domain. Finally, we used transcriptional assays to assess the ability of each BRCT variant to act as a transcriptional activation domain in human cells. Through a correlation of the assay results with available family history and clinical data, we define limits to predict the disease risk associated with each variant. Forty-two of the variants show little effect on function and are likely to represent variants with little or no clinical significance; 50 display a clear functional effect and are likely to represent pathogenic variants; and the remaining 25 variants display intermediate activities. The excellent agreement between the structure/function effects of these mutations and available clinical data supports the notion that functional and structure information can be useful in the development of models to assess cancer risk.