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The Children's Oncology Group Long-Term Follow-Up Guidelines provide exposure-based risks and recommendations for late effects screening of survivors of childhood cancer. Passport for Care (PFC) is a web-based clinical decision support tool for generating a personalized survivorship care plan (SCP) derived from the Guidelines and user-entered exposures. We assessed PFC clinician user practices and perceptions of PFC impact on clinic workflow, guidelines application, and survivor shared decision-making.A 35-item REDCap survey was emailed to all PFC users (n = 936) in 146 current and former PFC user clinics. Anonymous responses were permitted. Results were summarized and compared with a 2012 survey.Data were available from 148 respondents representing 64 out of 146 PFC user clinics (minimum clinic response rate 44%, excluding 49 anonymous responses). Generation of a personalized SCP was the most common application of PFC, followed by determination of surveillance recommendations and use as a survivor database. Twenty-five respondents (17%) felt data entry was a significant or insurmountable barrier to PFC application. Sixty-nine percent of respondents attributed PFC with a very high/high impact on guidelines adherence in their clinical practice, compared with 40% who attributed PFC with having a significant impact on adherence in 2012 (p .001).The survey results provide valuable insights on patterns of SCP delivery and Survivor Clinic workflow. User-perceived benefits to PFC included facilitating clinician ability to follow guidelines recommendations in clinical practice. Importantly, some barriers to resource utilization were also identified, suggesting a need for user-informed adaptations to further improve uptake.

Timely and accurate triage of upper extremity injuries is critical, but current perfusion monitoring technologies have shortcomings. These limitations are especially pronounced in patients with darker skin tones. This pilot study evaluates a Eulerian Video Magnification (EVM) algorithm combined with color channel waveform extraction to enable video-based measurement of hand and finger perfusion.Videos of 10 volunteer study participants with Fitzpatrick skin types III-VI were taken in a controlled environment during normal perfusion and tourniquet-induced ischemia. Videos were EVM processed, and red/green/blue color channel characteristics were extracted to produce waveforms. These videos were assessed by surgeons with a range of expertise in hand injuries. The videos were randomized and presented in 1 of 3 ways: unprocessed, EVM processed, and EVM with waveform output (EVM+waveform). Survey respondents indicated whether the video showed an ischemic or perfused hand or if they were unable to tell. We used group comparisons to evaluate response accuracy across video types, skin tones, and respondent groups.Of the 51 providers to whom the surveys were sent, 25 (49%) completed them. Using the Pearson χVideo-based EVM processing combined with waveform extraction from color channels improved the surgeon's ability to identify tourniquet-induced finger ischemia via video across all skin types tested.Eulerian Video Magnification with waveform extraction improved the assessment of perfusion in the distal upper extremity and has potential future applications, including triage, postsurgery vascular assessment, and telemedicine.

Study question Why is In-vitro-fertilization (IVF) an independent risk factor for placenta previa (PP). Summary answer While PP in non-assisted pregnancies is probably associated with previous cesarean deliveries (CD), in IVF it is more “sporadic”, and may complicate any index pregnancy. What is known already PP is more prevalent following IVF pregnancies as compared with unassisted pregnancies, with an increased risk of three to six-fold according to some authors. The etiology for this increased risk in IVF pregnancies in unclear, and may be related to reproductive procedures performed or to subfertility characteristics which have led to IVF. Study design, size, duration A retrospective-cohort study of deliveries with PP between 2008 and 2021. A total of 182 pregnancies were included. Participants/materials, setting, methods Placental histopathology, obstetric and neonatal outcomes were compared between IVF and unassisted pregnancies. Included, were singleton deliveries complicated by PP at gestational weeks (GA)> 24. Placental pathology was obtained utilizing the well-accepted Amsterdam criteria. Main results and the role of chance Out of 182 pregnancies which were included - 23 IVF pregnancies (IVF group) and 159 in the unassisted pregnancies (Control group). The control group was characterized by higher gravidity (p = 0.007) and parity (p Limitations, reasons for caution A major limitation was our small sample size in the IVF group. Despite a power calculation, larger study groups would have possibly allowed for the demonstration of additional differences in outcomes, including previous cesarean deliveries and placenta accreta. Moreover, this limitation prevented us from matching against possible cofounders. Wider implications of the findings While a growing proportion of pregnancies worldwide are conceived by IVF, possible iatrogenic side effects should be studied. As PP is of clinical importance, it is essential to diagnose it on time, as well as study the mechanisms and risk factors behind it, which could possibly help with its prevention. Trial registration number 0282-20-WOMC

BackgroundPerihematomal edema (PHE) volume correlates with intracerebral hemorrhage (ICH) volume and is associated with functional outcome. Minimally invasive surgery (MIS) for ICH decreases clot burden and PHE. MIS may therefore alter the time course of PHE, mitigating a critical source of secondary injury.ObjectiveTo describe a new method for the quantitative measurement of cerebral edema surrounding the evacuated hematoma cavity, termed pericavity edema (PCE), and obtain details of its time course following MIS for ICH.MethodsThe study included 48 consecutive patients presenting with ICH who underwent MIS evacuation. Preoperative and postoperative CT scans were assessed by two independent raters. Hematoma, edema, cavity, and pneumocephalus volumes were calculated using semi-automatic, threshold-guided volume segmentation software (AnalyzePro). Follow-up CT scans at variable delayed time points were available for 36 patients and were used to describe the time course of PCE.ResultsMean preoperative, postoperative, and delayed PCE were 21.0 mL (SD 15.5), 18.6 mL (SD 11.4), and 18.4 mL (SD 15.5), respectively. The percentage of ICH evacuated correlated significantly with a decrease in postoperative PCE (r=−0.46, pConclusionsWe present a detailed and accurate method for measuring PCE volume with semi-automatic, threshold-guided segmentation software in the postoperative patient with ICH. Decrease in PCE after MIS evacuation correlated with evacuation percentage, and relative PCE remained stable after minimally invasive endoscopic ICH evacuation.

OBJECTIVE 18F-fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) increases the sensitivity for preoperative detection of lymph nodes and distant metastases in endometrial cancer. The objective of this investigation was to determine the prognostic value of preoperative PET-CT compared with computed tomography (CT) alone for high-risk endometrial carcinoma. MATERIALS AND METHODS We performed a retrospective review of high-risk histology endometrial cancer from 2008 to 2015. Clinical variables including surgical procedure, preoperative imaging modality, and outcome were collected. Survival analysis was performed utilizing the Kaplan-Meier and Cox proportional hazards methodologies. RESULTS Of the 555 women treated for high-risk histology endometrial cancer, 88 (16%) had preoperative PET-CT, and 97 (17%) CT without PET available. PET-CT demonstrated positive findings in 37 women (42%) compared with 33 (30%) with preoperative CT alone. PET-CT had a positive predictive value of 96% for nodal metastasis compared with 60% for CT alone. The median follow-up time for the entire cohort was 59 months (range, 12 to 96 mo). Patients with a negative preoperative PET-CT (n=54) had a median progression-free survival (PFS) that was not reached, whereas the median PFS in the PET-CT positive group was 13 months (n=34). Women with a negative PET-CT had a longer median overall survival (OS) not yet reached compared with 34 months in the PET-CT positive cohort (hazard ratio, 2.4; P

Background & Aims: A proportion of infants and young children with inflammatory bowel diseases (IBDs) have subtypes associated with a single gene variant (monogenic IBD). We aimed to determine the prevalence of monogenic disease in a cohort of pediatric patients with IBD. Methods: We performed whole-exome sequencing analyses of blood samples from an unselected cohort of 1005 children with IBD, aged 0–18 years (median age at diagnosis, 11.96 years) at a single center in Canada and their family members (2305 samples total). Variants believed to cause IBD were validated using Sanger sequencing. Biopsies from patients were analyzed by immunofluorescence and histochemical analyses. Results: We identified 40 rare variants associated with 21 monogenic genes among 31 of the 1005 children with IBD (including 5 variants in XIAP, 3 in DOCK8, and 2 each in FOXP3, GUCY2C, and LRBA). These variants occurred in 7.8% of children younger than 6 years and 2.3% of children aged 6–18 years. Of the 17 patients with monogenic Crohn’s disease, 35% had abdominal pain, 24% had nonbloody loose stool, 18% had vomiting, 18% had weight loss, and 5% had intermittent bloody loose stool. The 14 patients with monogenic ulcerative colitis or IBD-unclassified received their diagnosis at a younger age, and their most predominant feature was bloody loose stool (78%). Features associated with monogenic IBD, compared to cases of IBD not associated with a single variant, were age of onset younger than 2 years (odds ratio [OR], 6.30; P = .020), family history of autoimmune disease (OR, 5.12; P = .002), extra-intestinal manifestations (OR, 15.36; P < .0001), and surgery (OR, 3.42; P = .042). Seventeen patients had variants in genes that could be corrected with allogeneic hematopoietic stem cell transplantation. Conclusions: In whole-exome sequencing analyses of more than 1000 children with IBD at a single center, we found that 3% had rare variants in genes previously associated with pediatric IBD. These were associated with different IBD phenotypes, and 1% of the patients had variants that could be potentially corrected with allogeneic hematopoietic stem cell transplantation. Monogenic IBD is rare, but should be considered in analysis of all patients with pediatric onset of IBD.

Inflammatory bowel disease (IBD), clinically defined as Crohn’s disease (CD), ulcerative colitis (UC), or IBD-unclassified, results in chronic inflammation of the gastrointestinal tract in genetically susceptible hosts. Pediatric onset IBD represents ≥ 25% of all IBD diagnoses and often presents with intestinal stricturing, perianal disease, and failed response to conventional treatments. NOD2 was the first and is the most replicated locus associated with adult IBD, to date. However, its role in pediatric onset IBD is not well understood. We performed whole-exome sequencing on a cohort of 1,183 patients with pediatric onset IBD (ages 0–18.5 years). We identified 92 probands with biallelic rare and low frequency NOD2 variants accounting for approximately 8% of our cohort, suggesting a Mendelian inheritance pattern of disease. Additionally, we investigated the contribution of recessive inheritance of NOD2 alleles in adult IBD patients from a large clinical population cohort. We found that recessive inheritance of NOD2 variants explains ~ 7% of cases in this adult IBD cohort, including ~ 10% of CD cases, confirming the observations from our pediatric IBD cohort. Exploration of EHR data showed that several of these adult IBD patients obtained their initial IBD diagnosis before 18 years of age, consistent with early onset disease. While it has been previously reported that carriers of more than one NOD2 risk alleles have increased susceptibility to Crohn’s Disease (CD), our data formally demonstrate that recessive inheritance of NOD2 alleles is a mechanistic driver of early onset IBD, specifically CD, likely due to loss of NOD2 protein function. Collectively, our findings show that recessive inheritance of rare and low frequency deleterious NOD2 variants account for 7–10% of CD cases and implicate NOD2 as a Mendelian disease gene for early onset Crohn’s Disease.

Purpose: This work presents unique designs for prosthetic restoration of the distal finger. We first discuss fitting a prosthetic nail in order to restore the cosmetic deficit caused by partial or complete nail injury. This concept is inspired from snap fit and lanced sheet metal technology. We also discuss new approaches to designing and fitting a full fingertip prosthetic with a special suspension and a socket for more complete cosmetic fingertip restoration. Methods: The designs utilize the compliance and higher strain level of hinges to fit the prosthesis with either the residual nail or to the distal-most aspect of the amputated fingertip. These techniques require preparation of the residual nail to match the fabricated nails well as design of a snap fit nail prosthetic. The socket and suspension design of the full fingertip prosthetic is formed with a spring shape and has an open end to allow proper molding, fit, and suspension. Results: The introduced approaches simplify the assembly steps and propose unique, cosmetically appropriate, and potentially less irritating prosthetic options compared to what has been previously used. The socket of the finger has an ability to expand and can be worn on any stump size. Conclusion: Low cost, fewer parts, ease of assembly and user friendly are the main attributes of the introduced designs. Future work to finalize these designs and trial them in humans is needed.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), a respiratory illness that can result in hospitalization or death. We used exome sequence data to investigate associations between rare genetic variants and seven COVID-19 outcomes in 586,157 individuals, including 20,952 with COVID-19. After accounting for multiple testing, we did not identify any clear associations with rare variants either exome wide or when specifically focusing on (1) 13 interferon pathway genes in which rare deleterious variants have been reported in individuals with severe COVID-19, (2) 281 genes located in susceptibility loci identified by the COVID-19 Host Genetics Initiative, or (3) 32 additional genes of immunologic relevance and/or therapeutic potential. Our analyses indicate there are no significant associations with rare protein-coding variants with detectable effect sizes at our current sample sizes. Analyses will be updated as additional data become available, and results are publicly available through the Regeneron Genetics Center COVID-19 Results Browser.

e24058 Background: Survivors of childhood cancer are at lifelong risk for late effects. The Children’s Oncology Group evidence-based guidelines provide exposure-based risks and recommendations for late effects screening. The Passport for Care (PFC) was developed in 2007 as a web-based clinical decision support tool that uses advanced algorithms to generate a personalized survivorship care plan (SCP), derived from the guidelines and user-entered exposures. Over 150 Long-Term Survivor (LTS) clinics utilize PFC, generating over 47,000 SCPs to date. Our objective was to assess PFC user practices and perceptions of PFC’s impact on clinic workflow, guideline application, and survivor shared decision-making. Methods: We designed a 35-item survey based on a 2012 PFC survey and expanded to include items related to interval website improvements. In June 2021, a REDCap™ survey was sent via email to 935 PFC users in 145 clinics: 107 active PFC clinics and 38 inactive (no data entry in the preceding 6 months). Responses were anonymous, but those who provided an email address were given a $5 gift card. Survey results were reviewed, summarized, and compared with data from 2012 using a Chi square test, when applicable. Results: There were 148 respondents of whom 104 declined anonymity, representing 64 clinics (44%): 58 of the active (54%) and 6 of the inactive clinics (16%). Respondents were largely physicians (n = 46), advanced practice providers (APPs, n = 42), and nurses (n = 49). Of the 148 respondents, 142 provided valid data for the remaining items. PFC was most often used to generate a personalized SCP (n = 131, 93%), compared with 63% in 2012. Other common uses were as a clinical database (59%) and to document late effects (51%). Seventy-one respondents (50%) used PFC to generate an SCP at entry to LTS, and 54 (38%) used PFC at every survivor visit. Most used PFC for > 75% of survivors (n = 103, 73%). Nurses (n = 89, 63%), APPs (n = 63, 44%), physicians (n = 37, 26%), and data managers (n = 13, 9%) performed data entry. Sixty-four respondents (45%) estimated requiring over 30 minutes/patient for data abstraction and entry, and 67 respondents (48%) felt data entry was a modest or significant barrier to PFC application. The majority of respondents were very or generally satisfied with PFC (87%), unchanged from previous (90%). The perceived impact of PFC on accurate application of the guidelines improved from 41% to 72% (p < 0.001), and on fostering conversations with survivors about risk for late effects and screening improved from 44% to 70% (p < 0.001). Conclusions: These results underscore the PFC’s role in increasing guidelines utilization and facilitating conversations with survivors about screening needs. The burden of data entry was a noted limitation, particularly when this responsibility fell to the physician or APP, and was further corroborated by user prioritization of ‘exposure data pre-population by treatment protocol’ for future PFC modifications.

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types., Graphical abstract, D’Antonio et al. characterize associations between GWAS signals for COVID-19 disease and eQTLs in 69 human tissues to identify causal variants and their underlying molecular mechanisms. They show that diverse symptoms and disease severity of COVID-19 are associated with variants affecting gene expression in a wide variety of tissues.

BACKGROUNDSarilumab (anti-interleukin-6 receptor-α monoclonal antibody) may attenuate the inflammatory response in Covid-19.METHODSWe performed an adaptive, phase 2/3, randomized, double-blind, placebo-controlled trial of intravenous sarilumab 200 mg or 400 mg in adults hospitalized with Covid-19. The phase 3 primary analysis population (cohort 1) was patients with critical Covid-19 receiving mechanical ventilation (MV) randomized to sarilumab 400 mg or placebo. The primary end point for phase 3 was the proportion of patients with ≥1-point improvement in clinical status from baseline to day 22.RESULTSFour-hundred fifty-seven (457) and 1365 patients were randomized and treated in phases 2 and 3, respectively. Among phase 3 critical patients receiving MV (n=289; 34.3% on corticosteroids), the proportion with ≥1-point improvement in clinical status (alive not receiving MV) at day 22 was 43.2% in sarilumab 400 mg and 35.5% in placebo (risk difference [RD] +7.5%; 95% confidence interval [CI], –7.4 to 21.3; P=0.3261), representing a relative risk improvement of 21.7%. Day 29 all-cause mortality was 36.4% in sarilumab 400 mg versus 41.9% in placebo (RD –5.5%; 95% CI, –20.2 to 8.7; relative risk reduction 13.3%). In post hoc analyses pooling phase 2 and 3 critical patients receiving MV, the hazard ratio (HR) for death in sarilumab 400 mg compared with placebo was 0.76 (95% CI, 0.51 to 1.13) overall, improving to 0.49 (95% CI, 0.25 to 0.94) in patients receiving corticosteroids at baseline.CONCLUSIONIn hospitalized patients with Covid-19 receiving MV, numerical benefits with sarilumab did not achieve statistical significance, but benefit may be greater in patients receiving corticosteroids. A larger study is required to confirm this observed numerical benefit.(ClinicalTrials.gov number, NCT04315298)

The need to identify and effectively treat COVID-19 cases at highest risk for severe disease remains critical. We identified five common genetic loci (two novel) that modulate both COVID-19 susceptibility and severity, implicating TMPRSS2, IFNAR2, CCHCR1, TCF19 and SLC6A20 as potential targets. A high genetic burden was strongly associated with increased risk of hospitalization and severe disease among COVID-19 cases, especially among individuals with few known clinical risk factors.

Summary Background Genetic data implicate IL-33 in asthma susceptibility. Itepekimab, a monoclonal antibody targeting IL-33, demonstrated clinical activity in asthma, with potential in chronic obstructive pulmonary disease (COPD). In this study we first aimed to test the hypothesis that genetic variants in the IL-33 pathway were also associated with COPD. On the basis of the strong association of IL-33 pathway genes with pulmonary diseases like asthma and COPD, we conducted this phase 2a trial to assess the safety and efficacy of itepekimab in patients with moderate-to-severe COPD on a stable regimen of triple-inhaled or double-inhaled background maintenance therapy. Methods In this two-part study, genetic analyses of loss-of-function and gain-of-function variants in the IL-33 pathway, previously associated with asthma risk, were initially characterised for COPD. We then did a double-blind, phase 2a trial comparing itepekimab with placebo in patients with moderate-to-severe COPD despite standard therapy, at 83 study sites in ten countries. Patients aged 40–75 years who were current or former smokers, had been diagnosed with COPD for at least 1 year, and were on a stable regimen of triple-inhaled or double-inhaled background maintenance therapy, were randomly assigned (1:1) to receive itepekimab 300 mg or placebo, administered as two subcutaneous injections every 2 weeks for 24–52 weeks. The primary endpoint of the phase 2a trial was annualised rate of moderate-to-severe acute exacerbations of COPD during the treatment period. The key secondary outcome was change in prebronchodilator FEV1 from baseline to weeks 16–24. Prespecified subgroup analyses were done for each of the endpoints, including by smoking status. Efficacy and safety analyses were done in all participants who received at least one dose of assigned treatment (modified intention-to-treat population). This trial is registered at ClinicalTrials.gov ( NCT03546907 ). Findings Genetic analyses demonstrated association of loss of function in IL33 with reduced COPD risk, and gain of function in IL33 and IL1RL1 variants with increased risk. Subsequent to this, in the phase 2 trial, 343 patients were randomly assigned to placebo (n=171) or itepekimab (n=172) from July 16, 2018, to Feb 19, 2020. Annualised rates of acute exacerbations of COPD were 1·61 (95% CI 1·32–1·97) in the placebo group and 1·30 (1·05–1·61) in the itepekimab group (relative risk [RR] 0·81 [95% CI 0·61–1·07], p=0·13), and least squares mean prebronchodilator FEV1 change from baseline to weeks 16–24 was 0·0 L (SD 0·02) and 0·06 L (0·02; difference 0·06 L [95% CI 0·01–0·10], p=0·024). When analysis was restricted to former smokers, treatment with itepekimab was associated with nominally significant reductions in acute exacerbations of COPD (RR 0·58 [95% CI 0·39–0·85], p=0·0061) and FEV1 improvement (least squares mean difference 0·09 L [0·02–0·15], p=0·0076) compared with placebo. Current smokers treated with itepekimab showed no treatment benefit versus placebo for exacerbations (RR 1·09 [0·74–1·61], p=0·65) or FEV1 (least squares mean difference 0·02 [−0·05 to 0·09], p=0·54). Treatment-emergent adverse events (TEAEs) occurred in 135 (78%) patients in the itepekimab group and 136 (80%) in the placebo group. The most common TEAEs were nasopharyngitis (28 [16%] in the itepekimab group vs 29 [17%] in the placebo group), bronchitis (18 [10%] vs 14 [8%]), headache (14 [8%] vs 23 [13%]), and upper respiratory tract infection (13 [8%] vs 15 [9%]). Interpretation The primary endpoint in the overall population was not met, subgroup analysis showed that itepekimab reduced exacerbation rate and improved lung function in former smokers with COPD. Two phase 3 clinical studies are ongoing to confirm the efficacy and safety profile of itepekimab in former smokers with COPD. Funding Sanofi and Regeneron Pharmaceuticals.

SARS-CoV-2 enters host cells by binding angiotensin-converting enzyme 2 (ACE2). Through a genome-wide association study, we show that a rare variant (MAF = 0.3%, odds ratio 0.60, P=4.5x10-13) that down-regulates ACE2 expression reduces risk of COVID-19 disease, providing human genetics support for the hypothesis that ACE2 levels influence COVID-19 risk. Further, we show that common genetic variants define a risk score that predicts severe disease among COVID-19 cases.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes coronavirus disease-19 (COVID-19), a respiratory illness that can result in hospitalization or death. We investigated associations between rare genetic variants and seven COVID-19 outcomes in 543,213 individuals, including 8,248 with COVID-19. After accounting for multiple testing, we did not identify any clear associations with rare variants either exome-wide or when specifically focusing on (i) 14 interferon pathway genes in which rare deleterious variants have been reported in severe COVID-19 patients; (ii) 167 genes located in COVID-19 GWAS risk loci; or (iii) 32 additional genes of immunologic relevance and/or therapeutic potential. Our analyses indicate there are no significant associations with rare protein-coding variants with detectable effect sizes at our current sample sizes. Analyses will be updated as additional data become available, with results publicly browsable athttps://rgc-covid19.regeneron.com.

Survivors of childhood cancer are at increased risk for late effects of cancer therapy, but evidence suggests that adherence to follow-up care is suboptimal. Here, we review the barriers to adherence, including those unique to childhood cancer survivors, and the rationale for distribution of a survivorship care plan. We also discuss advantages and potential limitations of delivering survivorship care plans via web-based platforms, and describe the unique features of one of these platforms, Passport for Care. A baseline survey directed toward survivors and conducted through Passport for Care found that a significant proportion of survivors are unaware of their specific health risks resulting from cancer and its treatment, and compared with their parents, are less afraid of the risks of recurrence and of cancer therapy-associated late effects (n = 528). Web-based platforms such as Passport for Care have enormous potential for improving access to health information, as well as for enhancing patient, family caregiver, and healthcare provider awareness of both risks of late effects and recommended surveillance. Results from this survey also suggest the potential utility of leveraging these tools to conduct additional research on consenting survivors.

Introduction: Perihematomal edema (PHE) impacts outcome in spontaneous intracerebral hemorrhage (ICH) and has been well defined. As minimally invasive evacuation methods are formally evaluated, the degree of edema following evacuation may differ from PHE in measurement and time course characteristics. Here we define pericavity edema (PCE) as a new entity and formally evaluate its measurement with a semi-automated threshold-guided technique. Methods: Patients (n=46) with a primary supratentorial ICH who underwent endoscopic evacuation were included in this study. AnalyzePro software was used to perform semi-automated threshold-guided volume assessment on pre and post evacuation noncontrast head CTs of the hematoma, PHE, the cavity, PCE, and pneumocephalus if present. Two raters analyzed each subject, the first twice, and intraclass correlation coefficient (ICC) values were determined to assess the inter-rater reliability. Statistical analysis was performed on the mean results to determine the change in hematoma volume, edema, cavity size, and degree of pneumocephalus. Results: ICC values for all variables were greater than 0.75, indicating good to excellent reliability. The median preoperative PHE was 18.21 cm3, while the postoperative edema was 16.2cm3. There was a mean 78.9% decrease in hematoma and a mean 76.4% increase in edema. In patients with a cavity present, the median size was 10.4cm3. Conclusions: In conclusion, PCE was successfully measured using AnalyzePro based on ICC. A mean increase in edema was shown following endoscopic evacuation, similar previous research revealing an increase in edema volume growth immediately following ICH. Further research will aim to define the time course of edema volume change following endoscopic evacuation.

The purpose of this study was to investigate the effectiveness of a resorbable alloplastic in situ hardening bone grafting material for alveolar ridge preservation in a swine model. Seven Landrace pigs were used. In each animal, the maxillary left and right deciduous second molars were extracted, and extraction sites were either grafted with a resorbable alloplastic in situ hardening bone substitute, composed of beta-tricalcium phosphate (β-TCP) granules coated with poly(lactic-co-glycolic) acid (PLGA), or left unfilled to heal spontaneously. Animals were euthanized after 12 weeks, and the bone tissue was analyzed histologically and histomorphometrically. Linear changes of ridge width were also clinically measured and analyzed. Pronounced bone regeneration was found in both experimental and control sites, with no statistically significant differences. At the experimental sites, most of the alloplastic grafting material was resorbed and remnants of the graft particles were severely decreased in size. Moreover, experimental sites showed, in a statistically nonsignificant way, less mean horizontal dimensional reduction of the alveolar ridge (7.69%) compared to the control sites (8.86%). In conclusion, the β-TCP/PLGA biomaterial performed well as a biocompatible resorbable in situ hardening bone substitute when placed in intact extraction sockets in this animal model. © 2018 Bentham Science Publishers B.V.All Rights Reserved.

Majumder et al. explore the large-scale looping architecture of the Tcrb locus early in murine thymocyte development during the generation of TCRβ diversity. They dissect novel DNA regulatory elements controlling V to D-J recombination and identify within an insulator region a distally located CTCF-containing element functioning as a tether, which facilitates looping of distal Vβ to Dβ-Jβ regions and promotes locus contraction. A second CTCF-containing element, proximal to the Dβ-Jβ region, acts as a boundary, preventing the spread of active chromatin associated with Dβ-Jβ regions. Removal of the proximal boundary element impairs the locus contraction capabilities of the tethering element., Gene regulation relies on dynamic changes in three-dimensional chromatin conformation, which are shaped by composite regulatory and architectural elements. However, mechanisms that govern such conformational switches within chromosomal domains remain unknown. We identify a novel mechanism by which cis-elements promote long-range interactions, inducing conformational changes critical for diversification of the TCRβ antigen receptor locus (Tcrb). Association between distal Vβ gene segments and the highly expressed DβJβ clusters, termed the recombination center (RC), is independent of enhancer function and recruitment of V(D)J recombinase. Instead, we find that tissue-specific folding of Tcrb relies on two distinct architectural elements located upstream of the RC. The first, a CTCF-containing element, directly tethers distal portions of the Vβ array to the RC. The second element is a chromatin barrier that protects the tether from hyperactive RC chromatin. When the second element is removed, active RC chromatin spreads upstream, forcing the tether to serve as a new barrier. Acquisition of barrier function by the CTCF element disrupts contacts between distal Vβ gene segments and significantly alters Tcrb repertoires. Our findings reveal a separation of function for RC-flanking regions, in which anchors for long-range recombination must be cordoned off from hyperactive RC landscapes by chromatin barriers.

Economic imperatives in health care financing are compelling a variety of mergers, acquisitions, integrations, and other forms of amalgamation. As hospitals merge, their pathology practices are merging. Physicians are forming clinically integrated groups, both with and without hospitals. Universities, commercial laboratories, and even insurance companies are acquiring laboratories and pathology practices. There are few standards or guidelines to help the practicing pathologist respond to such new undertakings. In the present study, we present a “how-to” guide or template to assist pathologists in evaluating proposals to amalgamate and in managing the alliance. The procedure begins with an articulation of the cons and pros, followed by a series of assessments of the cultures, the market, the organization, and operations, as well as a legal and financial assessment and human resources appraisal of each of the entities. We then outline the method for developing an organizational and operational model for the new merged entity and for performing the feasibility analysis, making a final decision, drafting a contract, and developing the business plan for the new venture.

The completion agenda is in full force at the nation's community colleges. To maximize the impact colleges can have on improving completion, colleges must organize around using student progress and outcome data to monitor and track their efforts. Unfortunately, colleges are struggling to identify relevant data and to mobilize staff to review student information that can lead to action: changes in policy and practice that improve student completion. The authors present their model for engaging educational institutions in using data to make good decisions about increasing completion.

The DNA damage response (DDR) can restrain the ability of oncogenes to cause genomic instability and drive malignant transformation. The gene encoding the histone H2AX DDR factor maps to 11q23, a region frequently altered in human cancers. Since H2ax functions as a haploinsufficient suppressor of B lineage lymphomas with c-Myc amplification and/or translocation, we determined the impact of H2ax expression on the ability of deregulated c-Myc expression to cause genomic instability and drive transformation of B cells. Neither H2ax deficiency nor haploinsufficiency affected the rate of mortality of Eμ-c-Myc mice from B lineage lymphomas with genomic deletions and amplifications. Yet H2ax functioned in a dosage-dependent manner to prevent unbalanced translocations in Eμ-c-Myc tumors, demonstrating that H2ax functions in a haploinsufficient manner to suppress allelic imbalances and limit molecular heterogeneity within and among Eμ-c-Myc lymphomas. Regardless of H2ax copy number, all Eμ-c-Myc tumors contained identical amplification of chromosome 19 sequences spanning 20 genes. Many of these genes encode proteins with tumor-promoting activities, including Cd274, which encodes the PD-L1 programmed death ligand that induces T cell apoptosis and enables cancer cells to escape immune surveillance. This amplicon was in non-malignant B and T cells and non-lymphoid cells, linked to the Eμ-c-Myc transgene, and associated with overexpression of PD-L1 on non-malignant B cells. Our data demonstrate that, in addition to deregulated c-Myc expression, non-malignant B lineage lymphocytes of Eμ-c-Myc transgenic mice may have constitutive amplification and increased expression of other tumor-promoting genes.

The heating capabilities of a water bath blood/fluid warmer, Hotline, have proven superior to those of other devices. The dry heat warmer Ranger has not previously been compared with the Hotline. We evaluated these devices in terms of flow rates and efficacy of warming. We delivered room temperature (21 degrees C) saline and 10 degrees C packed red blood cells (RBCs) by using 90 mm Hg (gravity equivalent) and 300 mm Hg bag pressure and various sizes of IV catheters. The outflow from each device was connected to an inline thermistor, and simultaneous measurements of outflow temperature and flow volume per minute were recorded. Additional data points were obtained with a roller pump that delivered flows of 1-6 L/h through each device. We calculated the effect of these flow rates and outflow temperatures on the mean body temperature (MBT) of a 70-kg patient. The Hotline and Ranger had similar flow rates at 90 and 300 mm Hg pressure infusion when studied with various sizes of IV catheters. Hotline was able to deliver warmer RBCs and saline at slower flow rates (1-4 L/h), but because changes in MBT were almost identical, there was no clinically important advantage, and almost no heat was transferred at these slower flow rates. At more rapid flow rates (>4 L/h), the Ranger warmed RBCs and saline better and produced smaller decreases in MBT than the Hotline. The use of the Hotline for rapid infusions, especially of cold RBCs, is not recommended because of low outflow temperatures and decreases in MBT that were three times larger than those seen with the Ranger.

Context.—Success in the practice of pathology demands proficiency in management, but management training for pathology residents is generally inadequate, with little agreement on an appropriate curriculum or competency assessment. Most residency training programs do not have faculty members who are interested and have expertise in management and who are dedicated to and have time available for teaching. Objective.—To develop a didactic management training program for the residents from 6 separate pathology residency programs in Southern California, with a comprehensive curriculum taught by experts in each area without undue burden on any single training program. Methods.—Faculty from the University of California–Los Angeles and the University of Southern California reviewed the literature and the management needs of practicing pathologists and devised the curriculum. Pathologist and nonpathologist speakers were identified who were working in important management positions both regionally and nationally. Seminars were presented in alternate months during a 2-year period. Sessions were videotaped, and each session was evaluated by the attendees. Results.—The curriculum consisted of 12 major topics, and seminars were delivered by 15 presenters from 6 institutions. Attendance was highest for residents in postgraduate years 2 and 3. The overall evaluation scores were exceedingly high (4.66 of a possible 5.0), and residents reported a significant increase in subject knowledge. Videotaping of presentations provided flexibility for residents who were unable to attend the seminars. Conclusion.—This program was effective and could serve as a template for other pathology residency training programs to establish curriculum content and develop resident competency. Teaching responsibilities were less burdensome when spread among several programs and when supplemented by nonpathology faculty. Electronic and audiovisual support enhanced flexibility and access to the program.

Survivors of childhood cancer are at risk of long-term adverse effects and late effects of the disease and/or its treatment. In response to national recommendations to improve evidence-based follow-up care, a web-based support system for clinical decision making, the Passport for Care (PFC), was developed for use at the point of care to produce screening recommendations individualized to the survivor. To date, the PFC has been implemented in over half of the nearly 200 clinics affiliated with the Children's Oncology Group across the USA. Most clinician users report that the PFC has been integrated into clinic workflows, and that it fosters improved conversations with survivors about the potential late effects a survivor might experience and about the screening and/or behavioural interventions recommended to improve health status. Furthermore, clinicians using the PFC have indicated that they adhered more closely to follow-up care guidelines. Perspectives on the challenges encountered and lessons learned during the development and deployment of the PFC are reviewed and contrasted with other nationwide approaches to the provision of guidance on survivor follow-up care; furthermore, the implications for the care of childhood cancer survivors are discussed.

The examination of organs and tissues macroscopically in order to establish a diagnosis and to select relevant portions for subsequent microscopic examination and special studies is fundamental to the practice of pathology. In the autopsy room, in the surgical pathology laboratory and, very often, in the operating room, gross pathology is the essential, underlying basis of morphologic diagnosis. Diagnoses on the basis of gross examination can be accurately made in as many as 90 % of specimens (Grossman IW, A primer of gross pathology, Charles C Thomas, 1972). In the remaining 10 % the skilled pathologist can be close to the diagnosis or can, at least, construct an accurate differential diagnosis that can provide guidance for subsequent studies. Sadly the numbers of pathologists with skills in macroscopic ("gross") pathology is rapidly declining, with concomitant loss in the quality of gross examinations, lower accuracy and elegance of specimen descriptions, and lack of precision in sample selection for special studies. This clearly impacts the quality of surgical pathology practice and, inevitably, the quality of patient care. The decline of gross pathology is a result of a number of factors, including a marked decrease in the numbers of autopsies which means that there are fewer opportunities for pathologists to hone gross pathology skills and to gain proficiency in handling tissues for appropriate further study. This is compounded by an increasing reliance on pathologists' assistants (PAs) for the handling, description and sampling of gross specimens, by the expanded utilization of biopsies rather than resections prior to initiating therapy and by the reliance on highly sophisticated immunopathology, molecular and genomic methods for diagnosis and even for determination of therapy. Despite these and other changes in medical and pathology practice, careful examination of the gross specimen is still the sine qua non of surgical and autopsy pathology practice.

Background. The randomized controlled Pediatric Oncology Group study 9233 tested the hypothesis that dose-intensive (DI) chemotherapy would improve event-free survival (EFS) for children ,3 years of age with newly diagnosed malignant brain tumors. Methods. Of 328 enrolled eligible patients, diagnoses were medulloblastoma (n ¼ 112), ependymoma (n ¼ 82), supratentorial primitive neuroectodermal tumor (sPNET, n ¼ 38) and other malignant brain tumors (n ¼ 96), and were randomized to 72 weeks of standard dose chemotherapy (Regimen A, n ¼ 162) or DI chemotherapy (Regimen B, n ¼ 166). Radiation therapy (RT) was recommended for patients with evidence of disease at completion of chemotherapy or who relapsed within 6 months of chemotherapy completion. Results. Distributions of EFS for Regimens A and B were not significantly different (P ¼ 0.32) with 2- and 10-year rates of 22.8%+3.3% and 15.4%+3.7%, and 27.1%+3.4% and 20.8%+3.8%, respectively. Thus, the study hypothesis was rejected. While distributions of EFS and OS were not significantly different between Regimens A and B for patients with medulloblastoma and sPNET, DI chemotherapy resulted in significantly improved EFS distribution (P ¼ .0011) (2-year EFS rates of 42.1% vs. 19.6% with SD chemotherapy), but not OS distribution, for patients with centrally confirmed ependymoma. The degree of surgical resection affected EFS, OS or both for most tumor groups. Approximately 20%, 40% and 20% of patients with medulloblastoma, ependymoma treated with DI chemotherapy, and sPNET, respectively appear to have been cured without RT. Of 11 toxic deaths on study, 10 occurred on the DI chemotherapy arm. Conclusions. Prolonged dose-intensive chemotherapy given to infants with malignant brain tumors resulted in increased EFS only for patients with ependymoma.

Approximately 12,000 children in the United States are diagnosed with cancer each year, and roughly 75% of these patients become long-term survivors. The Passport for Care was developed to support these survivors and their health care providers.

The observation that neuroectodermal differentiation imparts a worse prognosis to the Ewing family of tumors has been suggested by some studies and refuted by others. To assess whether the diagnosis of Ewing's sarcoma versus peripheral primitive neuroectodermal tumor (PNET) affects prognosis, we analyzed tumors from 63 analogously treated pediatric and young adult patients from the National Cancer Institute and St Jude Children's Research Hospital and retrospectively compared the results with clinical outcomes. The tumors were assessed using standard light microscopy and immunohistochemical stains for neuron-specific enolase, CD57, S100 protein, neurofilament protein, and synaptophysin with or without antigen retrieval. Ultrastructural evaluation was also performed in 39 tumors. Classification was performed using Kiel criteria as well as a modified classification. Kaplan-Meier analyses, with Mantel-Haenzel evaluation of the significance of the differences, were performed separately for localized or metastatic tumors. Using the Kiel classification on a subset of 60 cases, 39 tumors qualified as PNET and 21 as Ewing's sarcoma. Using the modified classification on a subset of 61 cases, 14 were classified as PNET, 21 as atypical Ewing's sarcoma, and 26 as Ewing's sarcoma. The addition of electron microscopy to the diagnostic armamentarium significantly increased the likelihood of identifying PNET. No significant differences in event-free or overall survival were seen using either the modified or Kiel classification, regardless of the ancillary diagnostic techniques employed. In this exploratory analysis, neuroectodermal differentiation did not play a role in clinical outcome. Confirmation of this finding will require a larger, separate study of similarly treated patients, and it may not apply to older patients.

OBJECTIVE—To evaluate the feasibility of anatomical correction based on morphological and echocardiographic findings in patients and preserved hearts with discordant atrioventricular connections. DESIGN—A retrospective study with clinicomorphological correlations to assess potential contraindications for anatomical correction in the setting of discordant atrioventricular connections. SETTING—A tertiary referral centre for congenital heart disease. MATERIAL—25 specimens and 53 patients unified by presence of discordant atrioventricular connections. METHODS—The potential contraindications for anatomical correction were first evaluated on the basis of morphological findings in all 25 specimens with discordant atrioventricular connections collected in the department museum, including study of the major coronary arterial patterns in 20. These contraindications were then sought in a population of 53 patients examined echocardiographically between January 1992 and October 1997. RESULTS—At least one lesion was discovered that might have contraindicated anatomical correction in 14 of the specimens and in 16 of the patients. The most common lesions that might militate against the anatomical approach were severe Ebstein's malformation or straddling and overriding of the tricuspid valve, each when combined with hypoplasia of the morphologically right ventricle. Other potential contraindications were atrioventricular septal defect with common atrioventricular junction, and obstruction of the left ventricular outlet combined with a restrictive ventricular septal defect, although these may be overcome with increasing experience and expertise. CONCLUSIONS—According to the morphological and echocardiographic findings, at least 10 hearts and 37 patients would have produced no anatomical problems for the type of surgical correction in which the morphologically left ventricle is restored its rightful role as the systemic pumping chamber. Keywords: atrioventricular discordant connections; congenitally corrected transposition; double switch operation

Between 1986 and 1990, the Pediatric Oncology Group conducted a study in which 198 children younger than 3 years of age with malignant brain tumors were treated with prolonged postoperative chemotherapy in an effort to delay irradiation and reduce long-term neurotoxicity. Children younger than 2 years of age received 24 months of chemotherapy followed by irradiation, and those between 2 and 3 years of age received 12 months of chemotherapy plus irradiation. Chemotherapy was given in 28-day cycles (AAB, AAB), with cycle A = vincristine (0.065 mg/kg) intravenously on days 1 and 8 and cyclophosphamide (65 mg/kg) intravenously on day 1, and cycle B = cisplatinum (4 mg/kg) intravenously on day 1 and etoposide (6.5 mg/kg) intravenously on days 3 and 4. Five of the 198 children developed second malignancies, with a cumulative risk at 8 years of 11.3% (95% confidence interval [CI], 0-39%). Four of the five second malignancies occurred in children younger than 2 years of age at diagnosis, with a cumulative risk at 8 years of 18.9% (CI, 0-70%). Initial diagnoses were choroid plexus carcinoma (2 children), ependymoma (1 child), desmoplastic infantile ganglioglioma (2 children), and medulloblastoma (1 child). Duration from diagnosis of initial tumor to second malignancy was 33, 35, 57, 66, and 92 months. Three children younger than 2 years of age developed lymphoproliferative disease, that is, myelodysplastic syndrome (2 children), both with monosomy 7 deletions, and acute myelogenous leukemia (1 child), after 24 to 26 cycles of chemotherapy, including 8 cycles of etoposide. Two of 3 received craniospinal irradiation (2,560/3,840 cGy) and (3,520/5,320 cGy). Time to second malignancy was 7 years 8 months, 4 years 9 months, and 2 years 9 months. Two children developed solid tumors, at 5 years 6 months and 2 years 11 months, respectively, after initiation of treatment. A sarcoma developed after 26 cycles of chemotherapy and no irradiation, and a meningioma developed after 12 cycles of chemotherapy and local craniospinal irradiation. Potential causative factors for this high rate of secondary malignancies include prolonged use of alkylating agents and etoposide with or without irradiation.

Horowitz describes how Web technology can offer a relatively painless way to extend the life of legacy systems, which are, by definition, both fragile and valuable. The Web can give aging applications a modern graphical interface, deliver them to employees' desktops regardless of platform, and grant access to databases distributed across the enterprise.

PURPOSE This late effects study was designed to determine if survivors of Ewing's sarcoma family tumors (ESFT) had adverse outcomes in employment, marital status, fertility, and functional status when compared to sibling controls. SUBJECTS AND METHODS Eighty-nine survivors (case subjects) of ESFT treated at the National Cancer Institute between 1965 and 1992 and 97 sibling controls completed a questionnaire probing aspects of quality of life. The answers from case subjects were compared to pooled and matched sibling controls for all key variables. Odds ratios (OR) and p values from pooled analyses are presented. RESULTS Although case subjects and controls did not differ in educational achievement, case subjects were less likely to be employed full-time (OR 0.4, p < 0.01), to be married (OR 0.2, p < 0.01), and to have children (OR 0.3, p < 0.01). Their most common treatment-related difficulties included permanent hair and skin changes (43%), lung problems (18%), neurologic problems (14%), visual difficulties (10%), second malignancy (7%), and amputation (5%). Functional status, measured by Karnofsky performance scale, was also adversely affected in case subjects. Case subjects did not differ from sibling controls in health care insurance status or in utilization of health services. CONCLUSIONS Important aspects of life such as employment, marital status, fertility, and functional status are affected in survivors of ESFT. More studies are needed to better define the health status of adult survivors of pediatric cancer and the impact of cancer in adolescence on psychosocial development.

Over the past 5 years, we have been engaged in a cross-sectional evaluation of risk factors for higher asthma severity in adolescents aged 13-18. All recruitment takes place through public and private schools. The sample from which our current findings are derived includes 151 adolescents covering a wide spectrum of asthma severity and socioeconomic status (SES) and representing both African American and Caucasians. An asthma severity instrument has been developed and validated for the purpose of this study. This yields an asthma severity score which is a continuous variable. Female gender and the number of positive skin tests are the best independent correlates to the asthma severity score. Among the 18 aeroallergens used in the study, the American cockroach Periplaneta americana is the only one that relates to the asthma severity score in a stepwise regression model. The two other cockroaches, German and oriental, as well as the dust mites Dermatophagoides farinae and Dermatophagoides pteronyssinus, correlate with the asthma severity only in simple regression analysis. The relationship between asthma severity and cockroach sensitivity is strongest within the lowest-income per family member quartile. This is consistent with the additional observations that (1) significantly higher rates of sensitization for cockroaches are observed in the lowest-income quartile subjects and (2) higher levels of the cockroach allergen Bla g 1 are found in their homes. Preliminary analysis suggests that ethnic background may interact with environmental exposure in that, within the lowest-income quartile, Caucasians have lower sensitization rates to cockroaches and other allergens compared to African Americans. Within the Caucasian population, income does not appear to influence sensitization rates. The treatment that adolescents with asthma receive for their respiratory disease is characterized by an overall low rate of prescribed inhaled corticosteroids (37% in the moderately severe and severe groups). This inadequacy in treatment is accentuated by SES: 28% of adolescents in the highest and 6% in the lowest-income quartile are prescribed these medications. Our findings are consistent with the hypothesis that the higher asthma morbidity and mortality observed in the African American population is related to higher exposure and sensitization to allergens such as those from cockroaches that are more prevalent in lower SES environments. It is possible that genetic factors contribute to the higher degree of sensitization. In addition, individuals of low SES are subjected to inadequate medical management of their asthma.

Using pharmacologic agents, we explored the mechanism by which a potent neuropeptide, substance P, induces the secretion of histamine from human skin mast cells and compared their effects on substance P-induced histamine release to the secretion activated by anti-IgE. Histamine release from human cutaneous mast cells induced by substance P was inhibited by the Ge-protein inhibitor pertussis toxin that, in turn, did not affect the IgE-mediated secretion. Similarly to anti-IgE, two activators of protein kinase C, tetradecanoylphorbol acetate (TPA) and bryostatin 1, significantly inhibited the substance P-induced response. In contrast, drugs that enhance intracellular levels of cAMP, an inhibitor of protein kinases, genistein, and a protease inhibitor, AEBSF, did not affect substance P-induced histamine secretion, whereas these compounds significantly reduced the response initiated by anti-IgE. Our data demonstrate that substance P activates human cutaneous mast cells by acting on G proteins and protein kinase C. Our results also suggest that the biochemical pathways underlying mast cell activation by substance P and anti-IgE are to a great extent unrelated.