Natural killer cells and innate lymphoid cells but not NKT cells are mature in their cytokine production at birth.

Early life is a time of increased susceptibility to infectious diseases and development of allergy. Innate lymphocytes are crucial components of the initiation and regulation of immune responses at mucosal surfaces, but functional differences in innate lymphocytes early in life are not fully described. We aimed to characterize the abundance and function of different innate lymphocyte cell populations in cord blood in comparison to that of adults. Blood was collected from adult donors and umbilical vessels at birth. Multicolor flow cytometry panels were used to identify and characterize lymphocyte populations and their capacity to produce hallmark cytokines. Lymphocytes were more abundant in cord blood compared to adults, however, mucosal-associated invariant T cells and natural killer T (NKT)-like cells, were far less abundant. The capacity of NKT-like cells to produce cytokines and their expression of the cytotoxic granule protein granzyme B and the marker of terminal differentiation CD57 were much lower in cord blood than in adults. In contrast, natural killer (NK) cells were as abundant in cord blood as in adults, they could produce IFNγ, and their expression of granzyme B was not significantly different from that of adult NK cells, although CD57 expression was lower. All innate lymphoid cell (ILC) subsets were more abundant in cord blood, and ILC1 and ILC2 were capable of production of IFNγ and IL-13, respectively. In conclusion, different innate lymphoid cells differ in both abundance and function in peripheral blood at birth and with important implications for immunity in early life.

Cancer of the esophagus and esophagogastric junction-Major changes in the American Joint Committee on Cancer eighth edition cancer staging manual.

Answer questions and earn CME/CNE New to the eighth edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual for epithelial cancers of the esophagus and esophagogastric junction are separate, temporally related cancer classifications: 1) before treatment decision (clinical); 2) after esophagectomy alone (pathologic); and 3) after preresection therapy followed by esophagectomy (postneoadjuvant pathologic). The addition of clinical and postneoadjuvant pathologic stage groupings was driven by a lack of correspondence of survival, and thus prognosis, between both clinical and postneoadjuvant pathologic cancer categories (facts about the cancer) and pathologic categories. This was revealed by a machine-learning analysis of 6-continent data from the Worldwide Esophageal Cancer Collaboration, with consensus of the AJCC Upper GI Expert Panel. Survival is markedly affected by histopathologic cell type (squamous cell carcinoma and adenocarcinoma) in clinically and pathologically staged patients, requiring separate stage grouping for each cell type. However, postneoadjuvant pathologic stage groups are identical. For the future, more refined and granular data are needed. This requires: 1) more accurate clinical staging; 2) innovative solutions to pathologic staging challenges in endoscopically resected cancers; 3) integration of genomics into staging; and 4) precision cancer care with targeted therapy. It is the responsibility of the oncology team to accurately determine and record registry data, which requires eliminating both common errors and those related to incompleteness and inconsistency. Despite the new complexity of eighth edition staging of cancers of the esophagus and esophagogastric junction, these key concepts and new directions will facilitate precision cancer care. CA Cancer J Clin 2017;67:304-317. © 2017 American Cancer Society.

Adjuvant Therapy After Neoadjuvant Therapy for Esophageal Cancer: Who Needs It?

OBJECTIVE: We hypothesized that, on average, patients do not benefit from additional adjuvant therapy after neoadjuvant therapy for locally advanced esophageal cancer, although subsets of patients might. Therefore, we sought to identify profiles of patients predicted to receive the most survival benefit or greatest detriment from adding adjuvant therapy. BACKGROUND: Although neoadjuvant therapy has become the treatment of choice for locally advanced esophageal cancer, the value of adding adjuvant therapy is unknown. METHODS: From 1970 to 2014, 22,123 patients were treated for esophageal cancer at 33 centers on 6 continents (Worldwide Esophageal Cancer Collaboration), of whom 7731 with adenocarcinoma or squamous cell carcinoma received neoadjuvant therapy; 1348 received additional adjuvant therapy. Random forests for survival and virtual-twin analyses were performed for all-cause mortality. RESULTS: Patients received a small survival benefit from adjuvant therapy (3.2±10 months over the subsequent 10 years for adenocarcinoma, 1.8±11 for squamous cell carcinoma). Consistent benefit occurred in ypT3-4 patients without nodal involvement and those with ypN2-3 disease. The small subset of patients receiving most benefit had high nodal burden, ypT4, and positive margins. Patients with ypT1-2N0 cancers had either no benefit or a detriment in survival. CONCLUSIONS: Adjuvant therapy after neoadjuvant therapy has value primarily for patients with more advanced esophageal cancer. Because the benefit is often small, patients considering adjuvant therapy should be counseled on benefits versus morbidity. In addition, given that the overall benefit was meaningful in a small number of patients, emerging modalities such as immunotherapy may hold more promise in the adjuvant setting.

I21: an advanced high-resolution resonant inelastic X-ray scattering beamline at Diamond Light Source.

The I21 beamline at Diamond Light Source is dedicated to advanced resonant inelastic X-ray scattering (RIXS) for probing charge, orbital, spin and lattice excitations in materials across condensed matter physics, applied sciences and chemistry. Both the beamline and the RIXS spectrometer employ divergent variable-line-spacing gratings covering a broad energy range of 280-3000 eV. A combined energy resolution of ∼35 meV (16 meV) is readily achieved at 930 eV (530 eV) owing to the optimized optics and the mechanics. Considerable efforts have been paid to the design of the entire beamline, particularly the implementation of the collection mirrors, to maximize the X-ray photon throughput. The continuous rotation of the spectrometer over 150° under ultra high vacuum and a cryogenic manipulator with six degrees of freedom allow accurate mappings of low-energy excitations from solid state materials in momentum space. Most importantly, the facility features a unique combination of the high energy resolution and the high photon throughput vital for advanced RIXS applications. Together with its stability and user friendliness, I21 has become one of the most sought after RIXS beamlines in the world.

Value of Lymphadenectomy in Patients Receiving Neoadjuvant Therapy for Esophageal Adenocarcinoma.

OBJECTIVE: The aim of this study was to assess the effect on survival of extent of lymphadenectomy during esophagectomy for patients undergoing multimodality (neoadjuvant) therapy for adenocarcinoma of the esophagus and esophagogastric junction using Worldwide Esophageal Cancer Collaboration data. SUMMARY BACKGROUND DATA: Previous worldwide data demonstrated that optimum lymphadenectomy during esophagectomy alone for esophageal cancer provides accurate staging and maximum survival. However, for patients undergoing neoadjuvant therapy for locally advanced adenocarcinoma, its value is unclear, leading to wide practice variability. METHODS: A total of 3859 patients with adenocarcinoma of the esophagus or esophagogastric junction received neoadjuvant therapy. The endpoint was all-cause mortality, reported as gain or loss of lifetime within 10 years. Lifetime predicted for each regional lymph node resected used quantile survival random forest methodology. RESULTS: Across all post-neoadjuvant ypTNM cancer categories, some degree of lymphadenectomy was associated with longer lifetime, but in a nonlinear fashion. For patients with ypN0 cancers, there was a modest gain in lifetime up to 25 lymph nodes resected and an incremental loss in lifetime as >25 were resected. For patients with ypN+ cancers, there was a robust gain in lifetime up to 30 lymph nodes resected and then an incremental loss in lifetime. CONCLUSIONS: Worldwide data for adenocarcinoma of the esophagus and esophagogastric junction demonstrate that lymphadenectomy during esophagectomy is a valuable component of neoadjuvant therapy. Survival is maximized when an optimum range of nodes is resected.

Changes in esophageal physiology after paraesophageal hernia repair and Collis gastroplasty.

BACKGROUND: The surgical approach and technique for paraesophageal hernia (PEH) repair is much debated. The changes in the esophageal physiology after PEH repair with a concomitant Collis gastroplasty (PEH-CG) are not clearly known. The aim of this study was to determine the changes in high resolution esophageal manometry (HREM) and esophageal pH testing after PEH-CG. METHODS: Retrospective analysis of all patients who underwent PEH-CG at our institution between 2006 and 2013 was performed. Patients had esophageal pH testing, HREM, barium swallow and an upper endoscopy before and after PEH-CG. RESULTS: A total of 182 patients underwent PEH-CG during the study period. Majority of patients had Nissen fundoplication (176, 96.7%) with Toupet in 6 (3.3%). Basal lower esophageal sphincter pressure (LESP) was lower after fundoplication (20.3 mmHg ± 11.3 vs. 25.8 mmHg ± 15.6, p < 0.001), whereas residual LESP was noted to be higher after fundoplication (7.7 mmHg ± 4.9 vs. 6.1 mmHg ± 6.7, p < 0.009). There were no significant changes in the esophageal motility patterns. There was an improvement in total pH and upright pH but not supine pH post PEH-CG. Normalization of total acid exposure after fundoplication was noted in 31 (59.6%) of the 52 patients who had abnormal total acid exposure prior to fundoplication. CONCLUSIONS: Objective clinical assessment in patients undergoing PEH-CG demonstrates an effective operation for this complex problem. There was an increase in residual LESP but interestingly, decrease in basal LESP. Additionally, there was an improvement in esophageal acid exposure afterwards. These findings will facilitate future management of PEH.

Antibody glycosylation in pregnancy and in newborns: biological roles and implications.

PURPOSE OF REVIEW: Glycosylation patterns have the potential to affect the function of antibody, antibody half-life and transplacental transfer from mother to foetus. Here, we review recent advances in our understanding of how glycosylation patterns of antibodies may be altered during pregnancy, vaccination and infection. RECENT FINDINGS: During pregnancy, there is preferential transplacental transfer of natural killer (NK) cell-activating antibodies that are galactosylated and sialylated, against both bacterial and viral antigens. Markers of NK cell function are also associated with a higher abundance of galactosylation and sialylation in respiratory syncytial virus-specific IgG, compared with total IgG, in infants up to 7 months of age which may suggest a role for NK-cell activating antibodies as important mediators of immunity during early infancy. Differential glycosylation patterns have been observed in some respiratory conditions, as increased nongalactosylated antibodies have been associated with the development of chronic inflammatory bronchopulmonary dysplasia (BPD) in preterm infants. Glycosylation patterns in children appear age-dependent, which could modulate the effector function of IgG. The clinical relevance of these findings needs to be established. SUMMARY: Glycosylation plays a key role in mediating antibody function. Glycosylation patterns associated with positive outcomes from infection in mothers and infants could inform the design of the next generation of vaccines for use in pregnancy and infancy. SDC VIDEO LINK:: http://links.lww.com/COID/A29.

Esophageal dysmotility and other preoperative factors associated with acid suppressive therapy after fundoplication.

Background and aims: Acid suppressive therapy (AST) is frequently used after fundoplication. Prior studies show that most patients requiring AST after fundoplication have normal esophageal acid exposure and therefore do not need AST. Our aim was to determine the indications for AST use following fundoplication and the associated factors.Methods: Retrospective analysis of patients who underwent fundoplication at our institution between 2006 and 2013 with pre and postoperative esophageal physiologic studies was performed. Demographic data, symptoms, and findings on high resolution manometry, esophageal pH monitoring and upper endoscopy were collected.Results: Three hundred and thirty-nine patients were included with a median follow up time of 12.8[2.6, 47.7] months. Mean age was 59.6 ± 13.3 years and 71.4% were women. Of those, 39.5% went on AST following fundoplication with a median time to AST use of 15.7[2.8, 36.1] months. The most common reason for AST use was heartburn. Only 29% of patients had objective evidence of acid reflux. Preoperative factors associated with AST use following fundoplication were male gender (HR1.6, p = 0.019), esophageal dysmotility (HR1.7, p = 0.004), proton pump inhibitor use (HR2.3, p < 0.001) and prior history of fundoplication (HR1.8, p = 0.006). In those with paraesophageal hernia repair with Collis gastroplasty (N = 182), esophageal dysmotility (HR1.7, p = 0.047) and NSAID use (HR1.9, p = 0.023) were associated with AST use postoperatively.Discussion: AST use is common after fundoplication. Male gender, preoperative esophageal dysmotility, proton pump inhibitor use and redo fundoplication were associated with AST use following fundoplication. In those undergoing combined Collis gastroplasty, preoperative NSAID use and esophageal dysmotility predicted AST use.

How to select patients for antireflux surgery? The ICARUS guidelines (international consensus regarding preoperative examinations and clinical characteristics assessment to select adult patients for antireflux surgery).

OBJECTIVE: Antireflux surgery can be proposed in patients with GORD, especially when proton pump inhibitor (PPI) use leads to incomplete symptom improvement. However, to date, international consensus guidelines on the clinical criteria and additional technical examinations used in patient selection for antireflux surgery are lacking. We aimed at generating key recommendations in the selection of patients for antireflux surgery. DESIGN: We included 35 international experts (gastroenterologists, surgeons and physiologists) in a Delphi process and developed 37 statements that were revised by the Consensus Group, to start the Delphi process. Three voting rounds followed where each statement was presented with the evidence summary. The panel indicated the degree of agreement for the statement. When 80% of the Consensus Group agreed (A+/A) with a statement, this was defined as consensus. All votes were mutually anonymous. RESULTS: Patients with heartburn with a satisfactory response to PPIs, patients with a hiatal hernia (HH), patients with oesophagitis Los Angeles (LA) grade B or higher and patients with Barrett's oesophagus are good candidates for antireflux surgery. An endoscopy prior to antireflux surgery is mandatory and a barium swallow should be performed in patients with suspicion of a HH or short oesophagus. Oesophageal manometry is mandatory to rule out major motility disorders. Finally, oesophageal pH (±impedance) monitoring of PPI is mandatory to select patients for antireflux surgery, if endoscopy is negative for unequivocal reflux oesophagitis. CONCLUSION: With the ICARUS guidelines, we generated key recommendations for selection of patients for antireflux surgery.

Macrophage Exosomes Induce Placental Inflammatory Cytokines: A Novel Mode of Maternal-Placental Messaging.

During pregnancy, the placenta forms the interface between mother and fetus. Highly controlled regulation of trans-placental trafficking is therefore essential for the healthy development of the growing fetus. Extracellular vesicle-mediated transfer of protein and nucleic acids from the human placenta into the maternal circulation is well documented; the possibility that this trafficking is bi-directional has not yet been explored but could affect placental function and impact on the fetus.We hypothesized that the ability of the placenta to respond to maternal inflammatory signals is mediated by the interaction of maternal immune cell exosomes with placental trophoblast. Utilizing the BeWo cell line and whole placental explants, we demonstrated that the human placenta internalizes macrophage-derived exosomes in a time- and dose-dependent manner. This uptake was via clathrin-dependent endocytosis. Furthermore, macrophage exosomes induced release of proinflammatory cytokines by the placenta. Taken together, our data demonstrates that exosomes are actively transported into the human placenta and that exosomes from activated immune cells modulate placental cytokine production. This represents a novel mechanism by which immune cells can signal to the placental unit, potentially facilitating responses to maternal inflammation and infection, and thereby preventing harm to the fetus.

Revisiting out-of-pocket requirements: trends in spending, financial access barriers, and policy in ten high-income countries.

BACKGROUND: Countries rely on out-of-pocket (OOP) spending to different degrees and employ varying techniques. The article examines trends in OOP spending in ten high-income countries since 2000, and analyzes their relationship to self-assessed barriers to accessing health care services. The countries are Australia, Canada, France, Germany, the Netherlands, New Zealand, Norway, Sweden, Switzerland, the United Kingdom, and the United States. METHODS: Data from three sources are employed: OECD statistics, the Commonwealth Fund survey of individuals in each of ten countries, and country-specific documents on health care policies. Based on trends in OOP spending, we divide the ten countries into three groups and analyze both trends and access barriers accordingly. As part of this effort, we propose a conceptual model for understanding the key components of OOP spending. RESULTS: There is a great deal of variation in aggregate OOP spending per capita spending but there has been convergence over time, with the lowest-spending countries continuing to show growth and the highest spending countries showing stability. Both the level of aggregate OOP spending and changes in spending affect perceived access barriers, although there is not a perfect correspondence between the two. CONCLUSIONS: There is a need for better understanding the root causes of OOP spending. This will require data collection that is broken down into OOP resulting from cost sharing and OOP resulting from direct payments (due to underinsurance and lacking benefits). Moreover, data should be disaggregated by consumer groups (e.g. income-level or health status). Only then can we better link the data to specific policies and suggest effective solutions to policy makers.

Geographic Differences in Temporal Incidence Trends of Hepatitis C Virus Infection Among People Who Inject Drugs: The InC3 Collaboration.

BACKGROUND: We determined temporal trends (1985-2011) in hepatitis C virus (HCV) incidence and associated behavioral exposures for people who inject drugs (PWID) from the United States (Boston, Baltimore, and San Francisco), Canada (Montreal), the Netherlands (Amsterdam), and Australia (Sydney and Melbourne). METHODS: Using population-based cohort data from HCV-negative PWID, we calculated overall and within-city HCV incidence trends, HCV rates by study enrollment period (1985-2011), and temporal trends in exposure behaviors. Poisson regression models estimated trends in HCV incidence over calendar-time. Survival models identified risk factors for HCV incidence across cities and estimated independent effects of city and calendar period on HCV infection risk. RESULTS: Among 1391 initially HCV-negative participants followed prospectively (1644.5 person-years of observation [PYO]), 371 HCV incident infections resulted in an overall incidence of 22.6 per 100 PYO (95% confidence interval [CI], 20.4-25.0). Incidence was highest and remained elevated in Baltimore (32.6/100 PYO), San Francisco (24.7/100 PYO), and Montreal (23.5/100 PYO), lowest in Melbourne and Amsterdam (7.5/100 PYO and 13.1/100 PYO, respectively), and moderate (21.4/100 PYO) in Sydney. Higher rates of syringe and equipment sharing and lower prevalence of opioid agonist therapy were associated with HCV incidence in cities with the highest incidence. Risk for infection dropped by 18% for every 3-year increase in calendar-time (adjusted hazard ratio, 0.8 [95% CI, .8-.9]) in the multivariable model. CONCLUSIONS: Differences in prevention strategies and injecting contexts may explain the ongoing high HCV incidence in these North American cities and emphasize the need for scale-up of opioid agonist therapy and increased coverage of needle and syringe programs in North America.

Esophageal Cancer: Associations With (pN+) Lymph Node Metastases.

OBJECTIVES: To identify the associations of lymph node metastases (pN+), number of positive nodes, and pN subclassification with cancer, treatment, patient, geographic, and institutional variables, and to recommend extent of lymphadenectomy needed to accurately detect pN+ for esophageal cancer. SUMMARY BACKGROUND DATA: Limited data and traditional analytic techniques have precluded identifying intricate associations of pN+ with other cancer, treatment, and patient characteristics. METHODS: Data on 5806 esophagectomy patients from the Worldwide Esophageal Cancer Collaboration were analyzed by Random Forest machine learning techniques. RESULTS: pN+, number of positive nodes, and pN subclassification were associated with increasing depth of cancer invasion (pT), increasing cancer length, decreasing cancer differentiation (G), and more regional lymph nodes resected. Lymphadenectomy necessary to accurately detect pN+ is 60 for shorter, well-differentiated cancers (<2.5 cm) and 20 for longer, poorly differentiated ones. CONCLUSIONS: In esophageal cancer, pN+, increasing number of positive nodes, and increasing pN classification are associated with deeper invading, longer, and poorly differentiated cancers. Consequently, if the goal of lymphadenectomy is to accurately define pN+ status of such cancers, few nodes need to be removed. Conversely, superficial, shorter, and well-differentiated cancers require a more extensive lymphadenectomy to accurately define pN+ status.

Effectiveness of a Home-Based Eccentric-Exercise Program on the Torque-Angle Relationship of the Shoulder External Rotators: A Pilot Study.

CONTEXT: The role of the rotator cuff is to provide dynamic stability to the glenohumeral joint. Human and animal studies have identified sarcomerogenesis as an outcome of eccentric training indicated by more torque generation with the muscle in a lengthened position. OBJECTIVE: The authors hypothesized that a home-based eccentric-exercise program could increase the shoulder external rotators' eccentric strength at terminal internal rotation (IR). DESIGN: Prospective case series. SETTING: Clinical laboratory and home exercising. PARTICIPANTS: 10 healthy subjects (age 30 ± 10 y). INTERVENTION: All participants performed 2 eccentric exercises targeting the posterior shoulder for 6 wk using a home-based intervention program using side-lying external rotation (ER) and horizontal abduction. MAIN OUTCOME MEASURES: Dynamic eccentric shoulder strength measured at 60°/s through a 100° arc divided into 4 equal 25° arcs (ER 50-25°, ER 25-0°, IR 0-25°, IR 25-50°) to measure angular impulse to represent the work performed. In addition, isometric shoulder ER was measured at 5 points throughout the arc of motion (45° IR, 30° IR, 15° IR, 0°, and 15° ER). Comparison of isometric and dynamic strength from pre- to posttesting was evaluated with a repeated-measure ANOVA using time and arc or positions as within factors. RESULTS: The isometric force measures revealed no significant differences between the 5 positions (P = .56). Analysis of the dynamic eccentric data revealed a significant difference between arcs (P = .02). The percentage-change score of the arc of IR 25-50° was found to be significantly greater than that of the arc of IR 0-25° (P = .007). CONCLUSION: After eccentric training the only arc of motion that had a positive improvement in the capacity to absorb eccentric loads was the arc of motion that represented eccentric contractions at the longest muscle length.

Changing Diagnostic Methods and Increased Detection of Verotoxigenic Escherichia coli, Ireland.

The recent paradigm shift in infectious disease diagnosis from culture-based to molecular-based approaches is exemplified in the findings of a national study assessing the detection of verotoxigenic Escherichia coli infections in Ireland. The methodologic changes have been accompanied by a dramatic increase in detections of non-O157 verotoxigenic E. coli serotypes.

ypN0: Does It Matter How You Get There? Nodal Downstaging in Esophageal Cancer.

BACKGROUND: ypN0 following induction treatment for advanced esophageal cancer improves survival. Importance of how ypN0 is achieved is unknown. This study evaluates survival in "natural" N0 (cN0/ypN0) and "downstaged" N0 (cN+/ypN0) patients. METHODS: Among patients treated with induction treatment and surgery, 83 CT scans were retrieved in digital format and re-evaluated by a radiologist, blinded to pathological nodal status: 28 natural N0, 37 downstaged N0, and 18 ypN+. Impact of N0 classification on survival and associations with survival were identified. RESULTS: Survival varied with ypN: 3-year survival was 84 % for natural N0 patients, 59 % for downstaged N0, and 20 % for ypN+ (p < .001). Compared with natural N0 patients, risk of cancer mortality was 3.8 for downstaged N0 and 7.6 for ypN+ (p = .01). Survival was also stratified by ypT: compared with ypT0 natural N0, who had the best survival, intermediate survival was seen in ypT+ natural N0 [hazard ratio (HR), 1.3] and ypT0 downstaged N0 (HR, 1.8), and poor survival in ypT+ downstaged N0 (HR, 9.5) and ypN+ (HR, 12.0) (p = .026). CONCLUSIONS: Natural N0 and downstaged N0 patients are different clinical entities: downstaging cN+ with induction treatment producing downstaged N0 improves survival only if there is concomitant primary cancer downstaging to ypT0. Intermediate survival is seen in downstaged N0 patients with complete tumor response. Natural N0 patients experience intermediate survival with incomplete response (ypT+). Complete response in natural N0 patients produces the best survival. Means of obtaining ypN0 status matters and requires a complete response for downstaged N0 patients to benefit from induction treatment.

North Carolina Macular Dystrophy Is Caused by Dysregulation of the Retinal Transcription Factor PRDM13.

PURPOSE: To identify specific mutations causing North Carolina macular dystrophy (NCMD). DESIGN: Whole-genome sequencing coupled with reverse transcription polymerase chain reaction (RT-PCR) analysis of gene expression in human retinal cells. PARTICIPANTS: A total of 141 members of 12 families with NCMD and 261 unrelated control individuals. METHODS: Genome sequencing was performed on 8 affected individuals from 3 families affected with chromosome 6-linked NCMD (MCDR1) and 2 individuals affected with chromosome 5-linked NCMD (MCDR3). Variants observed in the MCDR1 locus with frequencies <1% in published databases were confirmed using Sanger sequencing. Confirmed variants absent from all published databases were sought in 8 additional MCDR1 families and 261 controls. The RT-PCR analysis of selected genes was performed in stem cell-derived human retinal cells. MAIN OUTCOME MEASURES: Co-segregation of rare genetic variants with disease phenotype. RESULTS: Five sequenced individuals with MCDR1-linked NCMD shared a haplotype of 14 rare variants spanning 1 Mb of the disease-causing allele. One of these variants (V1) was absent from all published databases and all 261 controls, but was found in 5 additional NCMD kindreds. This variant lies in a DNase 1 hypersensitivity site (DHS) upstream of both the PRDM13 and CCNC genes. Sanger sequencing of 1 kb centered on V1 was performed in the remaining 4 NCMD probands, and 2 additional novel single nucleotide variants (V2 in 3 families and V3 in 1 family) were identified in the DHS within 134 bp of the location of V1. A complete duplication of the PRDM13 gene was also discovered in a single family (V4). The RT-PCR analysis of PRDM13 expression in developing retinal cells revealed marked developmental regulation. Next-generation sequencing of 2 individuals with MCDR3-linked NCMD revealed a 900-kb duplication that included the entire IRX1 gene (V5). The 5 mutations V1 to V5 segregated perfectly in the 102 affected and 39 unaffected members of the 12 NCMD families. CONCLUSIONS: We identified 5 rare mutations, each capable of arresting human macular development. Four of these strongly implicate the involvement of PRDM13 in macular development, whereas the pathophysiologic mechanism of the fifth remains unknown but may involve the developmental dysregulation of IRX1.

The Association of Central-Line-Associated Bloodstream Infections With Central-Line Utilization Rate and Maintenance Bundle Compliance Among Types of PICUs.

OBJECTIVE: Central-line-associated bloodstream infections comprise 25% of device-associated infections. Compared with other units, PICUs demonstrate a higher central-line-associated bloodstream infections prevalence. Prior studies have not investigated the association of central-line-associated bloodstream infections prevalence, central-line utilization, or maintenance bundle compliance between specific types of PICUs. DESIGN: This study analyzed monthly aggregate data regarding central-line-associated bloodstream infections prevalence, central-line utilization, and maintenance bundle compliance between three types of PICUs: 1) PICUs that do not care for cardiac patients (PICU); 2) PICUs that provide care for cardiac and noncardiac patients (C/PICU); or 3) designated cardiac ICUs (CICU). SETTING: The included units submitted data as part of The Children's Hospital Association PICU central-line-associated bloodstream infections collaborative from January 1, 2011, to December 31, 2013. PATIENTS: Patients admitted to PICUs in collaborative institutions. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The overall central-line-associated bloodstream infections prevalence was low (1.37 central-line-associated bloodstream infections events/1,000 central-line days) and decreased over the time of the study. Central-line-associated bloodstream infections prevalence was not related to the type of PICU although C/PICU tended to have a higher central-line-associated bloodstream infections prevalence (p = 0.055). CICU demonstrated a significantly higher central-line utilization ratio (p < 0.001). However, when examined on a unit level, central-line utilization was not related to the central-line-associated bloodstream infections prevalence. The central-line maintenance bundle compliance rate was not associated with central line-associated bloodstream infections prevalence in this unit-level investigation. Neither utilization rate nor compliance rate changed significantly over time in any of the types of units. CONCLUSIONS: Although this unit-level analysis did not demonstrate an association between central-line-associated bloodstream infections prevalence and central-line utilization and maintenance bundle compliance, optimization of both should continue, further decreasing central-line-associated bloodstream infections prevalence. In addition, investigation of patient-specific factors may aid in further central-line-associated bloodstream infections eradication.

The association between graduated driver licensing laws and travel behaviors among adolescents: an analysis of US National Household Travel Surveys.

BACKGROUND: Young novice drivers have crash rates higher than any other age group. To address this problem, graduated driver licensing (GDL) laws have been implemented in the United States to require an extended learner permit phase, and create night time driving or passenger restrictions for adolescent drivers. GDL allows adolescents to gain experience driving under low-risk conditions with the aim of reducing crashes. The restricted driving might increase riding with parents or on buses, which might be safer, or walking or biking, which might be more dangerous. We examined whether GDL increases non-driver travels, and whether it reduces total travels combining drivers and non-drivers. METHODS: We used data from the US National Household Travel Survey for the years 1995-1996, 2001-2002, and 2008-2009 to estimate the adjusted ratio for the number of trips and trip kilometers made by persons exposed to a GDL law, compared with those not exposed. RESULTS: Adolescents aged 16 years had fewer trips and kilometers as drivers when exposed to a GDL law: ratio 0.84 (95 % confidence interval (CI) 0.71, 1.00) for trips; 0.79 (0.63, 0.98) for kilometers. For adolescents aged 17 years, the trip ratio was 0.94 (0.83, 1.07) and the kilometers ratio 0.80 (0.63, 1.03). There was little association between GDL laws and trips or kilometers traveled by other methods: ratio 1.03 for trips and 1.00 for kilometers for age 16 years, 0.94 for trips and 1.07 for kilometers for age 17. CONCLUSIONS: If these associations are causal, GDL laws reduced driving kilometers by about 20 % for 16 and 17 year olds, and reduced the number of driving trips by 16 % among 16 year olds. GDL laws showed little relationship with trips by other methods.

Recommendations for clinical staging (cTNM) of cancer of the esophagus and esophagogastric junction for the 8th edition AJCC/UICC staging manuals.

We report analytic and consensus processes that produced recommendations for clinical stage groups (cTNM) of esophageal and esophagogastric junction cancer for the AJCC/UICC cancer staging manuals, 8th edition. The Worldwide Esophageal Cancer Collaboration (WECC) provided data on 22,123 clinically staged patients with epithelial esophageal cancers. Risk-adjusted survival for each patient was developed using random survival forest analysis from which (1) data-driven clinical stage groups were identified wherein survival decreased monotonically and was distinctive between and homogeneous within groups and (2) data-driven anatomic clinical stage groups based only on cTNM. The AJCC Upper GI Task Force, by smoothing, simplifying, expanding, and assessing clinical applicability, produced (3) consensus clinical stage groups. Compared with pTNM, cTNM survival was "pinched," with poorer survival for early cStage groups and better survival for advanced ones. Histologic grade was distinctive for data-driven grouping of cT2N0M0 squamous cell carcinoma (SCC) and cT1-2N0M0 adenocarcinoma, but consensus removed it. Grouping was different by histopathologic cell type. For SCC, cN0-1 was distinctive for cT3 but not cT1-2, and consensus removed cT4 subclassification and added subgroups 0, IVA, and IVB. For adenocarcinoma, N0-1 was distinctive for cT1-2 but not cT3-4a, cStage II subgrouping was necessary (T1N1M0 [IIA] and T2N0M0 [IIB]), advanced cancers cT3-4aN0-1M0 plus cT2N1M0 comprised cStage III, and consensus added subgroups 0, IVA, and IVB. Treatment decisions require accurate cStage, which differs from pStage. Understaging and overstaging are problematic, and additional factors, such as grade, may facilitate treatment decisions and prognostication until clinical staging techniques are uniformly applied and improved.