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Objectives: To evaluate the reliability of a novel segmentation-based volume rendering approach for quantification of benign central airway obstruction (BCAO). Design: A retrospective single-center cohort study. Setting: Data were ascertained using electronic health records at a tertiary academic medical center in the United States. Participants and inclusion: Patients with airway stenosis located within the trachea on two-dimensional (2D) computed tomography (CT) imaging and documentation of suspected benign etiology were included. Four readers with varying expertise in quantifying tracheal stenosis severity were selected to manually segment each CT using a volume rendering approach with the available free tools in the medical imaging viewing software OsiriX (Bernex, Switzerland). Three expert thoracic radiologists were recruited to quantify the same CTs using traditional subjective methods on a continuous and categorical scale. Outcome measures: The interrater reliability for continuous variables was calculated by the intraclass correlation coefficient (ICC) using a two-way mixed model with 95% confidence intervals (CI). Results: Thirty-eight patients met the inclusion criteria, and fifty CT scans were selected for measurement. The most common etiology of BCAO was iatrogenic in 22 patients (58%). There was an even distribution of chest and neck CT imaging within our cohort. The average ICC across all four readers for the volume rendering approach was 0.88 (95% CI, 0.84 to 0.93), suggesting good to excellent agreement. The average ICC for thoracic radiologists for subjective methods on the continuous scale was 0.38 (95% CI, 0.20 to 0.55), suggesting poor to fair agreement. The kappa for the categorical approach was 0.26, suggesting a slight to fair agreement amongst the raters. Conclusion: In this retrospective cohort study, agreement was good to excellent for raters with varying expertise in airway cross-sectional imaging using a novel segmentation-based volume rendering approach to quantify BCAO. This proposed measurement outperformed our expert thoracic radiologists using conventional subjective grading methods. [ABSTRACT FROM AUTHOR]

Background: Communal traits, such as empathy, warmth, and consensus-building, are not highly valued in the medical hierarchy. Devaluing communal traits is potentially harmful for two reasons. First, data suggest that patients may prefer when physicians show communal traits. Second, if female physicians are more likely to be perceived as communal, devaluing communal traits may increase the gender inequity already prevalent in medicine. We test for both these effects. Materials and Methods: This study analyzed 22,431 Press Ganey outpatient surveys assessing 480 physicians collected from 2016 to 2017 at a large tertiary hospital. The surveys asked patients to provide qualitative comments and quantitative Likert-scale ratings assessing physician effectiveness. We coded whether patients described physicians with "communal" language using a validated word scale derived from previous work. We used multivariate logistic regressions to assess whether (1) patients were more likely to describe female physicians using communal language and (2) patients gave higher quantitative ratings to physicians they described with communal language, when controlling for physician, patient, and comment characteristics. Results: Female physicians had higher odds of being described with communal language than male physicians (odds ratio 1.29, 95% confidence interval 1.18–1.40, p < 0.001). In addition, patients gave higher quantitative ratings to physicians they described with communal language. These results were robust to inclusion of controls. Conclusions: Female physicians are more likely to be perceived as communal. Being perceived as communal is associated with higher quantitative ratings, including likelihood to recommend. Our study indicates a need to reevaluate what types of behaviors academic hospitals reward in their physicians. [ABSTRACT FROM AUTHOR]

Antithymocyte globulin (ATG) is used as prophylaxis against graft-versus-host disease (GVHD). Current dosing regimens for ATG are empiric and weight-based, and do not account for patient-specific factors. Furthermore, the target of ATG, recipient T cells post-cytotoxic chemotherapy, is not a function of recipient weight. We hypothesized the recipient peripheral blood absolute lymphocyte count (ALC) on the day of ATG administration would interact with the dose of ATG administered to predict transplantation outcomes. We retrospectively analyzed 135 patients who received ATG for GVHD prophylaxis for unrelated allogeneic hematopoietic cell transplantation at 3 different doses: 10 mg/kg, 7.5 mg/kg, and 5 mg/kg. There was no difference in 2-year overall survival (OS) among ATG dosing groups; however, deaths from infectious complications were significantly higher with higher doses of ATG (3.7% versus 19% versus 26.7%; P  = .02). Severity of chronic GVHD was lower with higher doses of ATG (28% versus 24% versus 4%; P  = .03). In multivariate analysis, the median peripheral blood ALC on day of ATG administration and the total amount of ATG interacted to predict OS (hazard ratio, .09; P  = .03). For low recipient ALC (10th percentile, or .56 × 10 2 /µL), a higher total ATG dose was associated with a greater risk of death, whereas for high recipient ALC (90th percentile, or 24.96 × 10 2 /µL), a higher ATG dose was associated with a lower risk of death. Our findings suggest that the interaction between ATG and its target, the recipient lymphocyte, could represent a new paradigm for ATG dosing. [ABSTRACT FROM AUTHOR]

Objectives KRAS mutations are the most commonly found mutations in patients with non-small cell lung cancer (NSCLC) adenocarcinoma histology. The clinical implications of KRAS mutations in patients with advanced NSCLC are not well defined. We sought to determine if there is a correlation between KRAS mutation status, response to cytotoxic chemotherapy, and survival in patients with metastatic or recurrent NSCLC. Materials and methods Patients with metastatic or recurrent NSCLC and tumor mutation analyses were analyzed for response to conventional chemotherapy. The presence or absence of tumor mutations was assessed with the SNaPshot assay, which detects >40 somatic mutations in eight genes, including KRAS . ALK fluorescence in-situ hybridization analysis was done separately. Associations between KRAS mutation status and response to chemotherapy and survival were assessed. Results We identified 80 patients with metastatic or recurrent NSCLC and a KRAS activating mutation, and we compared these patients to 70 patients who were pan negative (no detectable mutation by the SNaPshot assay and ALK negative). Patients with KRAS -mutant advanced NSCLC demonstrated a significantly shorter progression-free survival in response to first line chemotherapy (4.5 months versus 5.7 months, p = 0.008) compared to pan-mutation negative patients. Overall survival was also significantly shorter in patients with KRAS -mutant advanced NSCLC compared to patients without KRAS activating mutations (8.8 months versus 13.5 months, p = 0.038). Conclusions Within this single institution retrospective analysis, patients with advanced NSCLC and a KRAS activating mutation exhibited inferior responses to cytotoxic chemotherapy and decreased survival compared to patients with advanced NSCLC and no KRAS mutation. [ABSTRACT FROM AUTHOR]

A case study of a 40-yr-old woman with lupus with anticoagulant positivity and end-stage renal disease status after right-sided kidney transplantation complicated by retroperitoneal hematoma and lumbar plexopathy presented with recurrent right medial thigh intramuscular (IM) hematomas. Topics include Ultrasound-guided aspiration was offered for persistent or worsening symptoms; and examination significant for right medial thigh ecchymosis with 5/5 strength and preserved reflexes and sensation.

Identifying coronary artery progenitors and their developmental pathways could inspire novel regenerative treatments for heart disease. Multiple sources of coronary vessels have been proposed, including the sinus venosus (SV), endocardium and proepicardium, but their relative contributions to the coronary circulation and the molecular mechanisms regulating their development are poorly understood. We created an ApjCreER mouse line as a lineage-tracing tool to map SV-derived vessels onto the heart and compared the resulting lineage pattern with endocardial and proepicardial contributions to the coronary circulation. The data showed a striking compartmentalization to coronary development. ApjCreER-traced vessels contributed to a large number of arteries, capillaries and veins on the dorsal and lateral sides of the heart. By contrast, untraced vessels predominated in the midline of the ventral aspect and ventricular septum, which are vessel populations primarily derived from the endocardium. The proepicardium gave rise to a smaller fraction of vessels spaced relatively uniformly throughout the ventricular walls. Dorsal (SV-derived) and ventral (endocardialderived) coronary vessels developed in response to different growth signals. The absence of VEGFC, which is expressed in the epicardium, dramatically inhibited dorsal and lateral coronary growth but left vessels on the ventral side unaffected. We propose that complementary SV-derived and endocardial-derived migratory routes unite to form the coronary vasculature and that the former requires VEGFC, revealing its role as a tissue-specific mediator of blood endothelial development. [ABSTRACT FROM AUTHOR]

Obstructive sleep apnea (OSA) is common in autism spectrum disorder (ASD). Children with OSA can present with a range of symptoms including loud snoring, excessive daytime sleepiness, and changes in cognitive function. Some of these symptoms can overlap with and exacerbate symptoms of ASD, potentially delaying OSA diagnosis in children with both conditions. The primary objective of this study was to assess between-group difference in OSA symptomatology and age at OSA diagnosis in children with and without ASD. A retrospective chart review was conducted on 166 pediatric patients (<18 years) with OSA undergoing adenotonsillectomy at a single academic institution between 2019 and 2021. The control group consisted of 91 patients (54.9% male) without ASD. The ASD group included 75 patients (88.0% male). Autism severity was scored on a 1–4 scale using a novel methodology. Statistical analyses included Wilcoxon rank sum tests for continuous variables, chi-squared tests for categorical variables, and multivariable analyses as needed. There was a significant between-group difference in total number of reported OSA symptoms (p < 0.001), with more symptoms reported in patients with ASD. Within the ASD group, lower autism severity was associated with an increased number of reported OSA symptoms (p = 0.006). There was not a significant between-group difference in age at OSA diagnosis (p = 0.999); however, lower autism severity was associated with an increased age at diagnosis (p = 0.002). These findings suggest that OSA may present with a higher symptom burden in children with ASD, particularly for children with lower ASD severity, who often experience delays in OSA diagnosis. These findings and their clinical implications merit further explanation. [ABSTRACT FROM AUTHOR]

Background: There is a need for biomarkers that improve accuracy compared with current demographic risk indices to detect individuals at the highest lung cancer risk. Improved risk determination will enable more effective lung cancer screening and better stratification of lung nodules into high or low-risk category. We previously reported discovery of a biomarker for lung cancer risk characterized by increased prevalence of TP53 somatic mutations in airway epithelial cells (AEC). Here we present results from a validation study in an independent retrospective case–control cohort. Methods: Targeted next generation sequencing was used to identify mutations within three TP53 exons spanning 193 base pairs in AEC genomic DNA. Results: TP53 mutation prevalence was associated with cancer status (P < 0.001). The lung cancer detection receiver operator characteristic (ROC) area under the curve (AUC) for the TP53 biomarker was 0.845 (95% confidence limits 0.749–0.942). In contrast, TP53 mutation prevalence was not significantly associated with age or smoking pack-years. The combination of TP53 mutation prevalence with PLCOM2012 risk score had an ROC AUC of 0.916 (0.846–0.986) and this was significantly higher than that for either factor alone (P < 0.03). Conclusions: These results support the validity of the TP53 mutation prevalence biomarker and justify taking additional steps to assess this biomarker in AEC specimens from a prospective cohort and in matched nasal brushing specimens as a potential non-invasive surrogate specimen. [ABSTRACT FROM AUTHOR]

Coronary arteries (CAs) stem from the aorta at 2 highly stereotyped locations, deviations from which can cause myocardial ischemia and death. CA stems form during embryogenesis when peritruncal blood vessels encircle the cardiac outflow tract and invade the aorta, but the underlying patterning mechanisms are poorly understood. Here, using murine models, we demonstrated that VEGF-C-deficient hearts have severely hypoplastic peritruncal vessels, resulting in delayed and abnormally positioned CA stems. We observed that VEGF-C is widely expressed in the outflow tract, while cardiomyocytes develop specifically within the aorta at stem sites where they surround maturing CAs in both mouse and human hearts. Mice heterozygous for islet 1 (Isl1) exhibited decreased aortic cardiomyocytes and abnormally low CA stems. In hearts with outflow tract rotation defects, misplaced stems were associated with shifted aortic cardiomyocytes, and myocardium induced ectopic connections with the pulmonary artery in culture. These data support a model in which CA stem development first requires VEGF-C to stimulate vessel growth around the outflow tract. Then, aortic cardiomyocytes facilitate interactions between peritruncal vessels and the aorta. Derangement of either step can lead to mispatterned CA stems. Studying this niche for cardiomyocyte development, and its relationship with CAs, has the potential to identify methods for stimulating vascular regrowth as a treatment for cardiovascular disease. [ABSTRACT FROM AUTHOR]

Background: Electromagnetic navigational bronchoscopy has been the dominant bronchoscopic technology for targeting small peripheral lesions and now includes digital tomosynthesis-electromagnetic navigational bronchoscopy (DT-ENB), allowing near-real-time intraprocedural nodule visualization. Shape-sensing robotic-assisted bronchoscopy (ssRAB), with improved catheter stability and articulation, recently became available. Although the diagnostic performance of these two methods seems higher than that of legacy systems, data remain limited. We sought to compare the diagnostic yield of these two novel platforms after their introduction at our institution.Research Question: Does the diagnostic yield of ssRAB differ significantly from that of DT-ENB in patients undergoing biopsy of peripheral pulmonary lesions (PPLs)?Study Design and Methods: This retrospective comparative cohort study analyzed prospectively collected data on consecutive procedures performed with DT-ENB and ssRAB in their first 6 months of use at our institution. Biopsies were considered diagnostic if histopathologic analysis revealed malignancy or specific benign features that readily explained the presence of a PPL. Nonspecific inflammation, normal lung or airway, and atypia not diagnostic of malignancy were considered nondiagnostic.Results: SSRAB was used to biopsy 143 PPLs in 133 patients and DT-ENB was used to biopsy 197 PPLs in 170 patients. Diagnostic yield was 77% for ssRAB (110/143 PPLs) and 80% (158/197 PPLs) for DT-ENB (OR, 0.8; 95% CI, 0.5-1.4; P = .4). Median lesion diameters were 17 and 19 mm, respectively. No difference in diagnostic yield was found after adjustment for lesion size, bronchus sign, peripheral vs middle third location, and sex. Pneumothorax complicated 1.5% of ssRAB and 1.8% of DT-ENB procedures (P = .86).Interpretation: SSRAB and DT-ENB showed comparable diagnostic yields and safety profiles in this comparative cohort study. [ABSTRACT FROM AUTHOR]

BACKGROUND: The focal adhesion kinase (FAK) is a non-receptor tyrosine kinase linked to tumor growth, invasion, and metastasis. FAK is overexpressed and associated with prognosis in many cancers, but its prognostic value in small-cell lung carcinoma (SCLC) is unknown and was the focus of this study. METHODS: Total FAK expression was analyzed via immunohistochemistry in tissue microarrays consisting of formalin-fixed, paraffin-embedded SCLC specimens from 85 patients. FAK staining scores were tested for correlations with pathological characteristics and clinical outcomes. Phospho-paxillin was also tested in 35 of the 85 specimens to evaluate whether FAK expression was associated with downstream signaling. RESULTS: Specific FAK expression was localized to the cytoplasm of 78/85 (92%) SCLCs. FAK expression was scored low in 11 (13%), moderate in 17 (20%), and high in 50 (59%) SCLCs. FAK staining scores treated as continuous variables did not correlate with SCLC disease stage, response to therapy, recurrence/progression-free survival, or overall survival. Moreover, total FAK expression did not correlate with phospho-paxillin Tyr118 expression. CONCLUSIONS: Total FAK is strongly expressed in a majority of SCLC tumors. However, the expression evaluated via immunohistochemistry is not a prognostic factor in patients with SCLC. Cancer 2012;. © 2011 American Cancer Society. [ABSTRACT FROM AUTHOR]

Simon's two-stage designs are very popular for phase II clinical trials. A literature review revealed that the inference procedures used with Simon's designs almost always ignore the actual sampling plan used. Reported P-values, point estimates and confidence intervals for the response rate are not usually adjusted for the design's adaptiveness. In addition, we found that the actual sample size for the second stage is often different from that planned. We present here a method for inferences using both the planned and the actual sample sizes. The conventional and the preferred inference procedures usually yield similar P-values and confidence intervals for the response rate. The conventional inference, however, may contradict the result of the corresponding hypothesis testing. Copyright © 2007 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Abstract: Semiquantitative analysis mode in inductively coupled plasma mass spectrometry (ICP-MS) has been popularly used for fast screening purposes. Although the benefit of it has been studied by many researchers, its performance of application in real-world routine analyses has not been reported. In this study, we evaluated the reliability of semiquantitative analysis mode through inter-laboratory comparison using two different ICP-MS systems with one multi-element calibration standard. The suitability of semiquantitative analysis mode in routine analysis laboratory was demonstrated by evaluating its application in different laboratories and in real production laboratory practices. Twenty one elements were measured, namely, Be, B, Al, Ti, V, Cr, Mn, Co, Ni, Cu, Zn, As, Sr, Mo, Ag, Cd, Sn, Sb, Ba, Tl, and Pb in various fresh water reference samples. Good results concerning accuracy (relative percentage error within 10%) and reproducibility (relative standard deviation lower than 5%) were obtained in more than 90% analyzed samples at concentrations equal to or greater than 10 times the detection limit (DL). Semiquantitative analysis mode also enabled the determination of elements that are not present in the calibration standard. The results demonstrated the potential of semiquantitative analysis mode as a reliable approach in routine laboratory determination of simple matrices, where high throughput and cost-effectiveness are desired, as well as in emergency situations where speed of analysis is critical and quite often limited sample information is available. [Copyright &y& Elsevier]

Objectives: Umbilical artery (UA) Doppler indices are surrogate measures of placental function, most commonly used to assess fetal wellbeing in pregnancies with fetal growth restriction. Fetuses with trisomy 21 (t21) are reported to have elevated UA Doppler indices, but reference percentiles are currently lacking for this population. We hypothesized that gestational age-specific values of UA Doppler indices in pregnancies complicated by t21 will be elevated compared to established percentiles based on euploid pregnancies. We aimed to assess UA Doppler indices longitudinally in fetuses with t21 in order to demonstrate Doppler patterns across gestation in this population, compare them with euploid fetuses, and investigate their association with pregnancy outcomes. Methods: We conducted a retrospective cohort study of singleton pregnancies with confirmed fetal t21 who underwent UA Doppler surveillance antenatally from January 2012 to August 2019. UA Doppler indices, including systolic/diastolic (S/D) ratio, pulsatility index (PI), and resistance index (RI) were extracted from ultrasound reports or directly from ultrasound images. UA S/D, PI, and RI percentiles by gestational week were created from available observations from our cohort via a data-driven approach using a generalized additive model. A secondary analysis was run to statistically compare t21 values to established percentiles based on observations from a historical population of euploid fetuses. Results: UA Doppler measurements from 86 t21 fetuses and 130 euploid fetuses were included in our analysis. Median (IQR) maternal age in t21 pregnancies and euploid pregnancies were 35 years (29–38) and 30 years (27–33), respectively. As in euploid fetuses, we found a negative association between Doppler indices and gestational age in the t21 fetuses. Maternal tobacco use, obesity, or chronic hypertension had no significant effect on UA Doppler indices. As hypothesized, values for UA S/D ratio, PI, and RI at the 2.5th, 5th, 10th, 25th, 50th, 75th, 90th, 95th, and 97.5th percentiles by gestational week were significantly higher in t21 fetuses compared to euploid fetuses (p<.001). Overall, 55.8% (48/86) of the t21 fetuses demonstrated at least one Doppler value above the 95th percentile for gestational age based on euploid reference standard. At birth, eight (9.3%) of the t21 fetuses were small for gestational age. When these pregnancies were removed from analysis, UA Doppler indices remained significantly higher than established percentiles at each week of gestation (p < .001). Only three pregnancies ended in fetal demise in the t21 population, two of which had persistently elevated Dopplers above the 95th percentile per established reference percentiles. Conclusions: At each week of gestation, UA Doppler indices in t21 fetuses were significantly higher than established percentiles from a euploid population. Reference intervals based on euploid fetuses may therefore not be appropriate for antenatal surveillance of fetuses with t21. Prospective studies are needed to investigate the role and impact of serial UA Doppler velocimetry in the surveillance of pregnancies complicated by fetal t21. [ABSTRACT FROM AUTHOR]

A critical question in biology is how new traits evolve, but studying this in wild animals remains challenging. Here, we probe the genetic basis of trait gain in sea robin fish, which have evolved specialized leg-like appendages for locomotion and digging along the ocean floor. We use genome sequencing, transcriptional profiling, and interspecific hybrid analysis to explore the molecular and developmental basis of leg formation. We identified the ancient, conserved transcription factor tbx3a as a major determinant of sensory leg development. Genome editing confirms that tbx3a is required for normal leg formation in sea robins, and for formation of enlarged central nervous system lobes, sensory papillae, and adult digging behavior. Our study establishes sea robins as a model organism for studying the evolution of major trait gain and illustrates how ancient developmental control genes can underlie novel organ formation. [Display omitted] • Sea robins are fish that walk and probe substrate with leg-like structures • Transcriptomics identifies ancient genes controlling leg formation from fins • Genome editing of tbx3a disrupts legs, nervous system structures, and behavior • Analysis of sea robin hybrids reveals genes underlying trait differences Herbert et al. determine that ancient genes involved in limb formation play a key role in the development of new leg-like appendages with unique sensory functions in sea robin fish. [ABSTRACT FROM AUTHOR]

A substantial body of epidemiologic literature addresses risks associated with occupational radiation exposure but comparing results between studies is often difficult as different statistical models are commonly used. It is unclear whether different methods produce similar results for estimates of radiation risk when applied to the same data. The goal of this study was to compare the radiation risk estimates for leukemia other than chronic lymphocytic leukemia (non-CLL) and ischemic heart disease (IHD) produced by both Cox and Poisson regression models for time-dependent dose-response analyses of occupational exposure. For brevity, this methods paper presents the results from one cohort, the Nuclear Power Plant workers (NPP), though the evaluation considered five cohorts of varying size and exposure as part of the Million Worker Study. Cox Proportional Hazards models, with age as the underlying timescale for hazard, were conducted using three computer software programs: SAS, R, and Epicure. Doses lagged 2 years for non-CLL and 10 years for ischemic heart disease were treated as time-dependent exposures at the annual level and were examined both in categories and as a continuous term. Hazard ratios (HR) and 95% confidence intervals (CI) were reported for each model in SAS and R, while the Peanuts program of Epicure was utilized to produce Excess Relative Risk (ERR) estimates and 95% CI. All models were adjusted for gender and year of birth. Four piece-wise exponential Poisson models (log-linear regression for rate) were developed with varying cutpoints for age strata from very fine to broad categories using both R and the Amfit program in Epicure for ERR estimates. Comparable estimates of risk (both RR and ERR) were observed from Cox and Poisson models, regardless of software utilized, as long as appropriately narrow categories of age were utilized to control the confounding of age in Poisson models. The ERR estimates produced in Epicure tended to agree very closely with the HR or RR estimates, and the statistical software program used had no impact to risk estimates for the same model. As computational power is no longer the burden today as it has been in the past, the results of this evaluation support the use of the Cox proportional hazards or the ungrouped Poisson approach to analyzing time-dependent dose-response relationships to ensure that maximum control over the confounding of age is achieved in studies of mortality for cohorts occupationally exposed to radiation. [ABSTRACT FROM AUTHOR]

Background Objectives Methods Results Conclusions High‐frequency ultrasound (HFUS) can safely and efficiently visualize cutaneous tumour characteristics including depth.We aimed to evaluate its accuracy in measuring melanoma depth against the gold standard, histopathology, for treatment planning.A review of publications was conducted in March 2023 through five electronic databases. Thirty‐six included articles studied patients who received HFUS (≥10 MHz) measurements, melanoma biopsy or excision, and reported a tumour depth correlation coefficient between HFUS and histopathology. We analysed correlation coefficients between HFUS and histopathology, measured tumour depths and shed light on reasons for mismeasurements. Additionally, we identified the reporting of critical metrics including, lesion characteristics, melanoma subtype, type of correlation coefficient, 95% confidence intervals for Pearson coefficients and sample size.The most common tumour imaged was superficial spreading melanoma on the trunk and extremities, followed by head/face. Maximum ultrasound frequencies ranged from 13 MHz to 100 MHz with participants ranging from 5 to 264. Histopathology and HFUS correlation coefficients ranged from 0.417 to 0.997 (median: 0.94, mean: 0.89 and SD: 0.13). Lower frequency probes (10–20 MHz) were less accurate in assessing melanoma thickness, with a cumulative mean correlation coefficient of 0.87 compared to 0.94 (20–25 MHz) and 0.98 (≥70 MHz). Studies demonstrated higher sonographic accuracy in melanomas >0.75 mm.Additionally, ultrasound may report increased melanoma depth compared to histopathology for reasons including lymphocytic infiltration, presence of a nevus and shrinkage during specimen processing. Furthermore, we found a gap in the reporting of details such as fundamental characteristics of lesion populations. Specifically, 86% (31 out of 36) of the studies failed to report one or more critical metrics, such as mean, median or range of lesion depths.HFUS may serve as a supplementary tool for preoperative melanoma assessment, with increased accuracy in thicker tumours. Frequencies <20 MHz are less reliable in assessing depth. Frequencies ≥70 MHz demonstrate stronger correlations to histopathology. Higher ultrasound accuracy was seen for melanomas with Breslow depth >0.75 mm. [ABSTRACT FROM AUTHOR]

Introduction: Achalasia among children often fails endoscopic management (e.g., dilation, botulinum toxin). Laparoscopic esophagocardiomyotomy (L-ECM) is a standard intervention to relieve obstruction but can induce gastroesophageal reflux (GER). Concurrent anterior fundoplication (A-fundo) has been evaluated in randomized trials among adults, demonstrating mixed results on controlling postoperative GER without exacerbating dysphagia. Furthermore, evidence for the best approach among children remains sparse. We hypothesized that, among children undergoing L-ECM without mucosal violation, routine A-fundo would not improve postoperative GER control while exacerbating dysphagia. Materials and Methods: Observational data of 47 consecutive achalasia patients ≤18 years who received L-ECM (2002–2023) at a single academic institution were collected. Patient records were culled for demographics, achalasia characteristics, and outcomes. Two L-ECM groups were identified: with or without A-fundo. Patients were screened for postoperative dysphagia (additional procedures) and GER (new antireflux medications). Univariate independence testing was conducted to identify statistically significant variables. Results: Among 47 patients undergoing L-ECM, 28 (59.6%) received concurrent A-fundo. Compared with patients undergoing L-ECM alone, patients with L-ECM/A-fundo had significantly longer hospital stays (P < .01) without statistically different rates of postoperative dysphagia (P = .81) or GER (P = .51). Five children (10.6%) experienced mucosal injury with L-ECM: 4 recognized intraoperatively received A-Fundo without subsequent leak; 1 mucosal injury was missed and did not receive A-Fundo, which subsequently leaked. Conclusion: In this largest observation of pediatric achalasia patients, A-fundo appeared clinically insignificant when determining contributors to control GER or exacerbate postoperative dysphagia. A-fundo should not be routinely adopted in children having L-ECM for achalasia without further multicenter analysis but appears beneficial in cases having inadvertent mucosal violation. [ABSTRACT FROM AUTHOR]

Large community cohorts are useful for lung cancer research, allowing for the analysis of risk factors and development of predictive models. A robust methodology for (1) identifying lung cancer and pulmonary nodules diagnoses as well as (2) associating multimodal longitudinal data with these events from electronic health record (EHRs) is needed to optimally curate cohorts at scale. In this study, we leveraged (1) SNOMED concepts to develop ICD-based decision rules for building a cohort that captured lung cancer and pulmonary nodules and (2) clinical knowledge to define time windows for collecting longitudinal imaging and clinical concepts. We curated three cohorts with clinical data and repeated imaging for subjects with pulmonary nodules from our Vanderbilt University Medical Center. Our approach achieved an estimated sensitivity 0.930 (95% CI: [0.879, 0.969]), specificity of 0.996 (95% CI: [0.989, 1.00]), positive predictive value of 0.979 (95% CI: [0.959, 1.000]), and negative predictive value of 0.987 (95% CI: [0.976, 0.994]) for distinguishing lung cancer from subjects with SPNs. This work represents a general strategy for high-throughput curation of multi-modal longitudinal cohorts at risk for lung cancer from routinely collected EHRs. [ABSTRACT FROM AUTHOR]

Background: A systems-level approach to smoking cessation treatment may optimize healthcare provider adherence to guidelines. Institutions such as the Veterans Health Administration (VHA) are unique in their systematic approach, but comparisons of provider behavior in different healthcare systems are limited.Methods: We surveyed general medicine providers and specialists in a large academic health center (AHC) and its affiliated VHA in the Mid-South in 2017 to determine the cross-sectional association of healthcare system in which the provider practiced (exposure: AHC versus VHA) with self-reported provision of evidence-based smoking cessation treatment (delivery of counseling plus smoking cessation medication or referral) at least once in the past 12 months (composite outcome). Multivariable logistic regression with adjustment for specialty was performed in 2017-2019.Results: Of 625 healthcare providers surveyed, 407 (65%) responded, and 366 (59%) were analyzed. Most respondents practiced at the AHC (273[75%] vs VHA 93[25%]) and were general internists (215[59%]); pulmonologists (39[11%]); hematologists/oncologists (69[19%]); and gynecologists (43[12%]). Most respondents (328[90%]) reported the primary outcome. The adjusted odds of evidence-based smoking cessation treatment were higher among VHA vs. AHC healthcare providers (aOR = 4.3; 95% CI 1.3-14.4; p = .02). Health systems differed by provision of individual treatment components, including smoking cessation medication use (98% VHA vs. 90% AHC, p = 0.02) and referral to smoking cessation services (91% VHA vs. 65% AHC p = 0.001).Conclusions: VHA healthcare providers were significantly more likely to provide evidence-based smoking cessation treatment compared to AHC healthcare providers. Healthcare systems' prioritization of and investment in smoking cessation treatment is critical to improving providers' adherence to guidelines. [ABSTRACT FROM AUTHOR]

Background: Haploidentical bone marrow transplant (haplo‐BMT) offers near universal donor availability as a curative modality for individuals with severe sickle cell disease (SCD). However, the required intense immunodepletion is associated with increased infectious complications. A paucity of data exists on immune reconstitution following haplo‐BMT for SCD. Methods: A multi‐institution learning collaborative was developed in the context of a phase II clinical trial of a non‐myeloablative, related haplo‐BMT with post‐transplant cyclophosphamide for SCD. We report results from a cohort of 23 patients for whom immune reconstitution data up to one year were available. Results: Median age was 14.8 years. Out of 23, 18 participants received pre‐conditioning with azathioprine, hydroxyurea, and hypertransfusions. 70% (16/23) of participants had multiple indications for haplo‐BMT. We observed excellent immune reconstitution of CD4, CD8, CD19, and CD56 cellular subsets by 6 months post transplant. Engraftment rate and event‐free survival in this cohort were 100% and 96%, respectively. 70% (16/23) of patients had at least one viral reactivation or infection, including CMV 35% (8/23), HHV‐6 22% (5/23), and polyoma virus 17% (4/23), with no cases of post‐transplant lymphoproliferative disease. Conclusion: Further prospective studies are needed to better characterize immune reconstitution and the immunologic basis for increased viral reactivation following haplo‐BMT with post‐transplant cyclophosphamide for SCD. [ABSTRACT FROM AUTHOR]

Background: Robotic-assisted bronchoscopy has recently emerged as an alternative to electromagnetic navigational bronchoscopy for the evaluation of peripheral pulmonary lesions. While robotic-assisted bronchoscopy is proposed to have several advantages, such as an easier learning curve, it is unclear if it has comparable diagnostic utility as electromagnetic navigational bronchoscopy. Methods: Robotic versus Electromagnetic bronchoscopy for pulmonary LesIon AssessmeNT (RELIANT) is an investigator-initiated, single-center, open label, noninferiority, cluster randomized controlled trial conducted in two operating rooms at Vanderbilt University Medical Center. Each operating room (OR) is assigned to either robotic-assisted or electromagnetic navigational bronchoscopy each morning, with each OR day considered one cluster. All patients undergoing diagnostic bronchoscopy for evaluation of a peripheral pulmonary lesion in one of the two operating rooms are eligible. Schedulers, patients, and proceduralists are blinded to daily group allocations until randomization is revealed for each operating room each morning. The primary endpoint is the diagnostic yield defined as the proportion of cases yielding lesional tissue. Secondary and safety endpoints include procedure duration and procedural complications. Enrolment began on March 6, 2023, and will continue until 202 clusters have been accrued, with expected enrolment of approximately 400 patients by the time of completion in March of 2024. Discussion: RELIANT is a pragmatic randomized controlled trial that will compare the diagnostic yield of the two most commonly used bronchoscopic approaches for sampling peripheral pulmonary lesions. This will be the first known cluster randomized pragmatic trial in the interventional pulmonology field and the first randomized controlled trial of robotic-assisted bronchoscopy. Trial registration: ClinicalTrials.gov registration (NCT05705544) on January 30, 2023. [ABSTRACT FROM AUTHOR]

Triple negative breast cancers (TNBC) are aggressive tumors, with high rates of metastatic spread and targeted therapies are critically needed. We aimed to assess the prognostic and predictive value of a 3q 19-gene signature identified previously from lung cancer in a collection of 4,801 breast tumor gene expression data. The 3q gene signature had a strong association with features of aggressiveness such as high grade, hormone receptor negativity, presence of a basal-like or TNBC phenotype and reduced distant metastasis free survival. The 3q gene signature was strongly associated with lung metastasis only in TNBC (P < 0.0001, Hazard ratio (HR) 1.44, 95% confidence interval (CI), 1.31-1.60), significantly associated with brain but not bone metastasis regardless of TNBC status. The association of one 3q driver gene FXR1 with distant metastasis in TNBC (P = 0.01) was further validated by immunohistochemistry. In addition, the 3q gene signature was associated with better response to neoadjuvant chemotherapy in TNBC (P < 0.0001) but not in non-TNBC patients. Our study suggests that the 3q gene signature is a novel prognostic marker for lung and/or brain metastasis and a predictive marker for the response to neoadjuvant chemotherapy in TNBC, implying a potential role for 3q genes in the mechanism of organ-specific metastasis. [ABSTRACT FROM AUTHOR]

Biliary atresia (BA) is a rare obstructive cholangiopathy that presents in early infancy. The Kasai portoenterostomy (PE) improves survival with the native liver. Epidural analgesia is an appealing option to control pain in this fragile patient population, yet its safety, efficacy, and potential benefits remain unproven. Patients undergoing PE for BA between 2001 and 2016 at a single institution were identified by ICD codes. Preoperative laboratories, procedure details, and recovery outcomes were reviewed retrospectively. Outcomes of interest were need for postoperative mechanical ventilation, pain scores, normalized opioid administration, return of bowel function, and length of hospital stay after PE. Of 47 infants undergoing PE for BA, 25 received epidural analgesia, and 22 did not. Infants with epidurals received less systemic opioids over the first 96 h postoperatively than those without (P < 0.001). Epidurals were associated with lower pain scores between 6 and 30 h postoperatively (P = 0.01 to 0.04), during which the highest median 6-h interval pain score was 0.2 (IQR 0-1.3) for patients with epidurals yet 2.1 (IQR 1.2-3.3) for patients without. Patients with epidurals (88%, n = 22) were more commonly extubated before leaving the operating room than those without (59%, n = 13; P = 0.02). No significant difference was observed in time to first bowel movement (P = 0.48) or first oral feed (P = 0.81). However, infants with epidurals had shorter hospital stays after PE than those without (6 d [IQR 5-7] versus 8 d [IQR 6.3-11], P = 0.01). No major complications were associated with epidural catheters. Epidural analgesia in patients undergoing PE for BA appears safe and effectively controls pain while minimizing the need for systemic opioids. Reduced need for mechanical ventilation postoperatively and shortened hospital stays serve as further evidence for using epidurals to enhance recovery after PE. [ABSTRACT FROM AUTHOR]

Distantly related species entering similar biological niches often adapt by evolving similar morphological and physiological characters. How much genomic molecular convergence (particularly of highly constrained coding sequence) contributes to convergent phenotypic evolution, such as echolocation in bats and whales, is a long-standing fundamental question. Like others, we find that convergent amino acid substitutions are not more abundant in echolocating mammals compared to their outgroups. However, we also ask a more informative question about the genomic distribution of convergent substitutions by devising a test to determine which, if any, of more than 4,000 tissue-affecting gene sets is most statistically enriched with convergent substitutions. We find that the gene set most overrepresented (q-value = 2.2e-3) with convergent substitutions in echolocators, affecting 18 genes, regulates development of the cochlear ganglion, a structure with empirically supported relevance to echolocation. Conversely, when comparing to nonecholocating outgroups, no significant gene set enrichment exists. For aquatic and high-altitude mammals, our analysis highlights 15 and 16 genes from the gene sets most affected by molecular convergence which regulate skin and lung physiology, respectively. Importantly, our test requires that the most convergence-enriched set cannot also be enriched for divergent substitutions, such as in the pattern produced by inactivated vision genes in subterranean mammals. Showing a clear role for adaptive protein-coding molecular convergence, we discover nearly 2,600 convergent positions, highlight 77 of them in 3 organs, and provide code to investigate other clades across the tree of life. [ABSTRACT FROM AUTHOR]

BACKGROUND Low cardiac output syndrome is a transient constellation of signs and symptoms that indicate the heart's inability to supply sufficient oxygen to tissues and end-organs to meet metabolic demand. Because the term lacks a standard clinical definition, the bedside diagnosis of this syndrome can be difficult. OBJECTIVE To evaluate concordance among pediatric cardiac intensive care unit nurses in their identification of low cardiac output syndrome in pediatric patients after cardiac surgery. METHODS An anonymous survey was distributed to 69 pediatric cardiac intensive care unit nurses. The survey described 10 randomly selected patients aged 6 months or younger who had undergone corrective or palliative cardiac surgery at a freestanding children's hospital in a tertiary academic center. For each patient, data were presented corresponding to 5 time points (0, 6, 12, 18, and 24 hours postoperatively). The respondent was asked to indicate whether the patient had low cardiac output syndrome (yes or no) at each time point on the basis of the data presented. RESULTS The response rate was 46% (32 of 69 nurses). The overall Fleiss k value was 0.30, indicating fair agreement among raters. When the results were analyzed by years of experience, agreement remained only slight to fair. CONCLUSIONS Regardless of years of experience, nurses have difficulty agreeing on the presence of low cardiac output syndrome. Further research is needed to determine whether the development of objective guidelines could improve recognition and facilitate communication between the pediatric cardiac intensive care unit nurse and the medical team. [ABSTRACT FROM AUTHOR]

Highlights • Extracorporeal photopheresis is used to treat chronic graft-versus-host disease. • In a highly pretreated cohort, 62% of patients responded to this treatment. • Treatment was associated with a meaningful decrease in prednisone dose. • Overall, global severity and body surface area redness decreased with treatment. • Response was not associated with frequency of regulatory T cells. Abstract Extracorporeal photopheresis (ECP) is an accepted treatment for chronic graft-versus-host disease (cGVHD); however, the mechanism of action is unclear. We conducted a prospective multicenter clinical trial to assess ECP response rates using the 2005 National Institutes of Health (NIH) consensus criteria and to assess the relationship between regulatory T cells (Tregs) and treatment response (NCT01324908). Eighty-three patients with any NIH subtype of cGVHD were enrolled, irrespective of number of prior lines of treatment, and 6 were subsequently excluded because of the absence of follow-up from cancer relapse, infection, or study withdrawal. Study outcomes were provider-assessed response and formal response by 2005 NIH criteria. Peripheral blood samples were collected at prespecified study visits and were analyzed by flow cytometry for Tregs. In a heavily pretreated cohort of patients, with a median of 2 prior lines of therapy, 62.3% of patients had a provider-assessed response to ECP and 43.5% had response by NIH criteria. These assessments showed only a slight agreement (kappa statistic,.09). In a logistic regression model that included previously identified risk factors such as bilirubin, platelet count, and time from transplant to study entry, no clinical factors were associated with the provider's response assessment. Furthermore, there was no significant difference in percentage of Tregs in blood leukocytes at study entry and completion or in overall change in Treg frequency between ECP responders and nonresponders. ECP was associated with a clinically significant decrease in median prednisone dose (.36 to.14 mg/kg, P <.001) from study entry to last visit and a significant decrease in global severity of cGVHD and total body surface area with erythematous rash. Overall, ECP was able to deliver response using NIH response criteria in a highly pretreated cohort with moderate and severe cGVHD independent of most previous risk factors for adverse outcomes of cGVHD. [ABSTRACT FROM AUTHOR]

Chronic graft-versus-host disease (cGVHD) is a severe complication in long-term survivors of allogeneic hematopoietic stem cell transplantation. This disease is challenging to manage clinically due to a lack of validated tools to quantitatively measure skin sclerosis. The current gold standard for measuring skin sclerosis is the NIH Skin Score which has only moderate agreement among clinicians and experts. To more accurately assess skin sclerosis in cGVHD, the Myoton and durometer devices can be used to directly measure biomechanical parameters of the skin. However, the reproducibility of these devices is not known in patients with cGVHD. To determine this reproducibility, three observers independently measured 10 anatomic sites in each of seven patients with sclerotic cGVHD using the Myoton and durometer. Clinical reproducibility was measured by mean pairwise differences (U-statistic) and intraclass correlation coefficients (ICCs) with 95% confidence intervals (CIs). Mean pairwise differences, expressed in true physical units, were used to report typical errors for each anatomic site and device. Mean pairwise differences were less than 11% of the average overall values for all five Myoton parameters and durometer hardness. These were lower for Myoton creep (4.1%), relaxation time (4.7%), and frequency (5.1%) than decrement (9.0%), stiffness (10.4%), and durometer hardness (9.0%). Myoton parameters creep, relaxation time, and frequency showed promise for capturing skin biomechanics more accurately than Myoton stiffness, decrement, or durometer hardness. Mean pairwise differences trended highest in the shin and volar forearm and lowest in the dorsal forearm. The interobserver ICC for overall (averaged across all measured body sites of a patient) creep (0.94; 95% CI 0.87–1.00), relaxation time (0.96; 95% CI 0.90–1.00), and frequency (0.95; 95% CI 0.88–1.00), trended higher than that for decrement (0.43; 95% CI 0.00–0.88), stiffness (0.92; 95% CI 0.81–1.00), and durometer hardness (0.82; 95% CI 0.61–1.00). Similar trends were observed in healthy participants. These findings can help clinicians design better studies to assess therapeutic response to new cGVHD treatments and support the interpretation of future measurements. [ABSTRACT FROM AUTHOR]

Simple Summary: Lung cancer remains one of the deadliest cancers, with the worst survival rate. Cells from the airway lining of patients at high risk for lung cancer differentially express proteins that may serve as biomarkers for early detection of lung cancer. Previously, we identified candidate proteins in patients at high risk for lung cancer. In the present study, we validated several proteins in an independent cohort of 179 patients. Patients without lung cancer were stratified at low and high risk using an established risk model. Several proteins were found to be significantly overexpressed in the normal airways of individuals at high risk for lung cancer compared to the low-risk group. Our goal is to deliver a signature of risk that may provide the basis for lung cancer risk assessment and possibly novel future prevention strategies. A major challenge in lung cancer prevention and cure hinges on identifying the at-risk population that ultimately develops lung cancer. Previously, we reported proteomic alterations in the cytologically normal bronchial epithelial cells collected from the bronchial brushings of individuals at risk for lung cancer. The purpose of this study is to validate, in an independent cohort, a selected list of 55 candidate proteins associated with risk for lung cancer with sensitive targeted proteomics using selected reaction monitoring (SRM). Bronchial brushings collected from individuals at low and high risk for developing lung cancer as well as patients with lung cancer, from both a subset of the original cohort (batch 1: n = 10 per group) and an independent cohort of 149 individuals (batch 2: low risk (n = 32), high risk (n = 34), and lung cancer (n = 83)), were analyzed using multiplexed SRM assays. ALDH3A1 and AKR1B10 were found to be consistently overexpressed in the high-risk group in both batch 1 and batch 2 brushing specimens as well as in the biopsies of batch 1. Validation of highly discriminatory proteins and metabolic enzymes by SRM in a larger independent cohort supported their use to identify patients at high risk for developing lung cancer. [ABSTRACT FROM AUTHOR]

Introduction: Venetoclax is utilized with low-dose cytarabine or a hypomethylating agent for the treatment of acute myeloid leukemia. Clinical trials report a risk of tumor lysis syndrome and the package insert recommends a venetoclax dose ramp-up at the initiation. The purpose of this study was to evaluate the risk of tumor lysis syndrome in a large population of patients with acute myeloid leukemia outside of a clinical trial and evaluate the incidence of hospital-acquired complications during inpatient ramp-up. Methods: We performed a retrospective study of adult patients with acute myeloid leukemia receiving venetoclax with a hypomethylating agent or low-dose cytarabine. The primary outcome was the incidence of tumor lysis syndrome. Secondary outcomes included risk factors for tumor lysis syndrome, length of admission, and incidence of hospital-acquired complications. Results: One hundred thirteen patients were included. Although all patients were given some form of prophylaxis, the incidence of tumor lysis syndrome was 8.8%. All were laboratory tumor lysis syndrome; one with hyperuricemia, nine with hypocalcemia, and ten with hyperphosphatemia. Six patients received sevelamer. Tumor lysis syndrome was resolved in all cases. No clinical tumor lysis syndrome occurred. Hepatic dysfunction, tumor lysis syndrome high-risk stratification, higher baseline white blood cell count, and lactate dehydrogenase levels were more common in the tumor lysis syndrome group. Hospital-acquired complications reached 13% in those directly admitted for dose ramp-up. Conclusions: Tumor lysis syndrome was uncommon and manifested as minor lab abnormalities. White blood cell count continues to be an indicator of risk for tumor lysis syndrome. Those who present with an elevated white blood cell or are otherwise at high risk for tumor lysis syndrome should be admitted for ramp-up. Otherwise, initiation and monitoring of venetoclax are feasible in the outpatient setting. [ABSTRACT FROM AUTHOR]

A deep learning model (LCP CNN) for the stratification of indeterminate pulmonary nodules (IPNs) demonstrated better discrimination than commonly used clinical prediction models. However, the LCP CNN score is based on a single timepoint that ignores longitudinal information when prior imaging studies are available. Clinically, IPNs are often followed over time and temporal trends in nodule size or morphology inform management. In this study we investigated whether the change in LCP CNN scores over time was different between benign and malignant nodules. This study used a prospective-specimen collection, retrospective-blinded-evaluation (PRoBE) design. Subjects with incidentally or screening detected IPNs 6–30 mm in diameter with at least 3 consecutive CT scans prior to diagnosis (slice thickness ≤ 1.5 mm) with the same nodule present were included. Disease outcome was adjudicated by biopsy-proven malignancy, biopsy-proven benign disease and absence of growth on at least 2-year imaging follow-up. Lung nodules were analyzed using the Optellum LCP CNN model. Investigators performing image analysis were blinded to all clinical data. The LCP CNN score was determined for 48 benign and 32 malignant nodules. There was no significant difference in the initial LCP CNN score between benign and malignant nodules. Overall, the LCP CNN scores of benign nodules remained relatively stable over time while that of malignant nodules continued to increase over time. The difference in these two trends was statistically significant. We also developed a joint model that incorporates longitudinal LCP CNN scores to predict future probability of cancer. Malignant and benign nodules appear to have distinctive trends in LCP CNN score over time. This suggests that longitudinal modeling may improve radiomic prediction of lung cancer over current models. Additional studies are needed to validate these early findings. [ABSTRACT FROM AUTHOR]

Background: The COVID-19 pandemic has presented significant safety concerns for healthcare providers, especially those performing aerosol-generating procedures. Several surgical societies issued early warnings that aerosols generated during minimally invasive surgery (MIS) could harbor infectious quantities of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). This study tested the hypothesis that MIS-aerosols contain SARS-CoV-2.Methods: To evaluate SARS-CoV-2 presence in aerosols emitted during intracavitary MIS, children <18 years who required emergent MIS and were discovered to be SARS-CoV-2-positive were enrolled. Swabs were obtained from the port in-line with a filtered smoke evacuation system, the tubing adjacent to this port, the fluid collection chamber and filter, and the distal endotracheal tube (ETT). All swabs were analyzed for SARS-CoV-2 using quantitative reverse-transcription polymerase chain reaction. To evaluate viral distribution in tissues, fluorescence in situ hybridization for SARS-CoV-2 was performed on resected specimens. Outcomes were recorded, and participating healthcare workers were tracked for SARS-CoV-2 conversion.Results: From July 1, 2020, to June 30, 2021, 11 children requiring emergent MIS were discovered preoperatively to be SARS-CoV-2 positive (median age: 14 years [5-17]). SARS-CoV-2 was detected only in ETT swabs and not in surgical aerosols or specimens. Median operative time was 56.5 minutes (IQR: 46-66), and postoperative stay was 21.2 hours (IQR: 1.97-57.57). No complications or viral eruption were recorded, and none of 63 healthcare workers tested positive for SARS-CoV-2 within 6 weeks.Discussion: SARS-CoV-2 was detected only in ETT secretions and not in surgical aerosols or specimens among a pediatric cohort of asymptomatic patients having emergent MIS. [ABSTRACT FROM AUTHOR]

FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) is a somatic mutation associated with poor outcome when treated with chemotherapy alone. In children, hematopoietic stem cell transplantation (HSCT) is recommended, but very limited data on outcome are reported. We determined the outcome of 29 children with FLT3/ITD–positive acute myelogenous leukemia (AML) who underwent allogeneic HSCT in 4 pediatric centers. Eleven patients (38%) received matched related donor hematopoietic stem cells and 18 (62%) received alternative donors. Eighteen patients (62%) received total body irradiation (TBI)–based regimens. No patients experienced transplantation-related mortality. Eleven patients (38%) experienced relapsed disease. The cumulative incidence of relapse at 2 years was 34.7% (95% confidence interval [CI], 20.4% to 54.9%). Two-year disease-free survival (DFS) and overall survival (OS) were 65.3% (95% CI, 45.1% to 79.6%) and 82.2% (95% CI, 58.5% to 91.3%), respectively. There was no difference in the DFS of patients who received transplants from related donors versus the DFS of those who received transplants from alternative donors (hazard ratio [HR], 2.64; 95% CI, .79 to 8.76; P = .10), using univariate analysis. Patients with higher FLT3/ITD ratio at diagnosis had significantly worse DFS (HR, 1.42; 95% CI, 1.04 to 1.93; P = .03). The use of TBI in the preparative regimen was associated with superior DFS (HR, .29; 95% CI, .08 to .99; P = .04) and OS (HR, .07; 95% CI, .01 to .62; P = .002). We conclude that allogeneic HSCT improves DFS and OS in children with FLT3/ITD–positive AML compared with what has been reported in those treated with chemotherapy alone. [ABSTRACT FROM AUTHOR]

Crizotinib, a selective tyrosine kinase inhibitor (TKI), shows marked activity in patients whose lung cancers harbor fusions in the gene encoding anaplastic lymphoma receptor tyrosine kinase (ALK), but its efficacy is limited by variable primary responses and acquired resistance. In work arising from the clinical observation of a patient with ALK fusion-positive lung cancer who had an exceptional response to an insulin-like growth factor 1 receptor (IGF-1R)-specific antibody, we define a therapeutic synergism between ALK and IGF-1R inhibitors. Similar to IGF-1R, ALK fusion proteins bind to the adaptor insulin receptor substrate 1 (IRS-1), and IRS-1 knockdown enhances the antitumor effects of ALK inhibitors. In models of ALK TKI resistance, the IGF-1R pathway is activated, and combined ALK and IGF-1R inhibition improves therapeutic efficacy. Consistent with this finding, the levels of IGF-1R and IRS-1 are increased in biopsy samples from patients progressing on crizotinib monotherapy. Collectively these data support a role for the IGF-1R-IRS-1 pathway in both ALK TKI-sensitive and ALK TKI-resistant states and provide a biological rationale for further clinical development of dual ALK and IGF-1R inhibitors. [ABSTRACT FROM AUTHOR]

Abstract: The optimal healthcare model for follow-up of allogeneic hematopoietic stem cell transplantation (HSCT) recipients after day 100 is not clear. We previously demonstrated that longitudinal follow-up at the transplant center using a multidisciplinary approach is associated with superior survival. Recent data suggest that increased distance from the transplant center is associated with inferior survival. A dedicated long-term transplant clinic (LTTC) was established in 2006 at our center. We hypothesized that geographic distance would not be associated with inferior outcome if patients are followed in the LTTC. We studied 299 consecutive patients who underwent HSCT and established care in an LTTC. The median distance from the transplant center was 118 miles (range, 1 to 1591). The 75th percentile (170 miles) was used as the cut-off to analyze the impact of distance from the center on outcome (219 patients ≤75th percentile; 80 patients >75th percentile). The 2 groups were balanced for pretransplant characteristics. In multivariate analyses adjusted for donor type, Center for International Blood and Marrow Transplant Research risk, and transplant regimen intensity, distance from transplant center did not impact outcome. Our study suggests that geographic distance from the transplant center is not associated with inferior outcome when follow-up care is delivered via a dedicated LTTC incorporating well-coordinated multidisciplinary care. [Copyright &y& Elsevier]

The aim of the Million Person Study of Low-Dose Health Effects (MPS) is to examine the level of radiation risk for chronic exposures received gradually over time and not acutely as was the case for the Japanese atomic bomb survivors. Nuclear power plant (NPP) workers comprise nearly 15 percent of the MPS. Leukemia, selected cancers, Parkinson's disease, ischemic heart disease (IHD) and other causes of death are evaluated. The U.S. Nuclear Regulatory Commission's Radiation Exposure Information and Reporting System (REIRS) and the Landauer, Inc. dosimetry databases identified 135,193 NPP workers first monitored 1957–1984. Annual personal dose equivalents [Hp(10)] were available for each worker. Radiation records from all places of employment were sought. Vital status was determined through 2011. Mean absorbed doses to red bone marrow (RBM), esophagus, lung, colon, brain and heart were estimated by adjusting the recorded Hp(10) for each worker by scaling factors, accounting for exposure geometry and energy of the incident gamma radiation. Standardized mortality ratios (SMR) were calculated. Radiation risks were estimated using Cox proportional hazards models. Nearly 50% of workers were employed for more than 20 years. The mean duration of follow-up was 30.2 y. Overall, 29,124 total deaths occurred, 296 from leukemia other than chronic lymphocytic leukemia (CLL), 3382 from lung cancer, 140 from Parkinson's disease and 5410 from IHD. The mean dose to RBM was 37.9 mGy (maximum 1.0 Gy; percent >100 mGy was 9.2%), 43.2 mGy to lung, 43.7 mGy to colon, 33.2 mGy to brain, and 43.9 mGy to heart. The SMRs (95% CI) were 1.06 (0.94; 1.19) for leukemia other than CLL, 1.10 (1.07; 1.14) for lung cancer, 0.90 (0.76; 1.06) for Parkinson's disease, and 0.80 (0.78; 0.82) for IHD. The excess relative risk (ERR) per 100 mGy for leukemia other than CLL was 0.15 (90% CI −0.001; 0.31). For all solid cancers the ERR per 100 mGy (95% CI) was 0.01 (–0.03; 0.05), for lung cancer −0.04 (–0.11; 0.02), for Parkinson's disease 0.24 (–0.02; 0.50), and for IHD −0.01 (–0.06; 0.04). Prolonged exposure to radiation increased the risk of leukemia other than CLL among NPP workers. There was little evidence for a radiation association for all solid cancers, lung cancer or ischemic heart disease. Increased precision will be forthcoming as the different cohorts within the MPS are combined, such as industrial radiographers and medical radiation workers who were assembled and evaluated in like manner. [ABSTRACT FROM AUTHOR]

Approximately 235,000 military personnel participated at one of 230 U.S. atmospheric nuclear weapons tests from 1945 through 1962. At the Nevada Test Site (NTS), the atomic veterans participated in military maneuvers, observed nuclear weapons tests, or provided technical support. At the Pacific Proving Ground (PPG), they served aboard ships or were stationed on islands during or after nuclear weapons tests. Participants at seven test series, previously studied with high-quality dosimetry and personnel records, and the first test at TRINITY formed the cohort of 114,270 male military participants traced for vital status from 1945 through 2010. Dose reconstructions were based on Nuclear Test Personnel Review records, Department of Defense. Standardized mortality ratios (SMR) and Cox and Poisson regression models were used in the analysis. Most atomic veterans were enlisted men, served in the Navy at the PPG, and were born before 1930. Vital status was determined for 96.8% of the veterans; 60% had died. Enlisted men had significantly high all-causes mortality SMR (1.06); officers had significantly low all-causes mortality SMR (0.71). The pattern of risk over time showed a diminution of the 'healthy soldier effect': the all-causes mortality SMR after 50 years of follow-up was 1.00. The healthy soldier effect for all cancers also diminished over time. The all-cancer SMR was significantly high after 50 years (SMR 1.10) primarily from smoking-related cancers, attributed in part to the availability of cigarettes in military rations. The highest SMR was for mesothelioma (SMR 1.56) which was correlated with asbestos exposure in naval ships. Prostate cancer was significantly high (SMR 1.13). Ischemic heart disease was significantly low (SMR 0.84). Estimated mean doses varied by organ were low; e.g., the mean red bone marrow dose was 6 mGy (maximum 108 mGy). Internal cohort dose–response analyses provided no evidence for increasing trends with radiation dose for leukemia (excluding chronic lymphocytic leukemia (CLL)) [ERR (95% CI) per 100 mGy −0.37 (−1.08, 0.33); n = 710], CLL, myelodysplastic syndrome, multiple myeloma, ischemic heart disease, or cancers of the lung, prostate, breast, and brain. No statistically significant radiation associations were observed among 114,270 nuclear weapons test participants followed for up to 65 years. The 95% confidence limits were narrow and excluded mortality risks per unit dose that are two to four times higher than those reported in other investigations. Significantly elevated SMRs were seen for mesothelioma and asbestosis, attributed to asbestos exposure aboard ships. [ABSTRACT FROM AUTHOR]

Background: 18F-fluorodeoxyglucose (FDG) PET/CT is recommended for evaluation of intermediate-risk indeterminate pulmonary nodules (IPNs). While highly sensitive, the specificity of FDG remains suboptimal for differentiating malignant from benign nodules, particularly in areas where fungal lung diseases are prevalent. Thus, a cancer-specific imaging probe is greatly needed. In this study, we tested the hypothesis that a PET radiotracer (S)-4-(3-[18F]-fluoropropyl)-L-glutamic acid (FSPG) improves the diagnostic accuracy of IPNs compared to 18F-FDG PET/CT. Methods: This study was conducted at a major academic medical center and an affiliated VA medical center. Twenty-six patients with newly discovered IPNs 7-30mm diameter or newly diagnosed lung cancer completed serial PET/CT scans utilizing 18F-FDG and 18F-FSPG, without intervening treatment of the lesion. The scans were independently reviewed by two dual-trained diagnostic radiology and nuclear medicine physicians. Characteristics evaluated included quantitative SUVmax values of the pulmonary nodules and metastases. Results: A total of 17 out of 26 patients had cancer and 9 had benign lesions. 18F-FSPG was negative in 6 of 9 benign lesions compared to 7 of 9 with 18F-FDG. 18F-FSPG and 18F-FDG were positive in 14 of 17 and 12 of 17 malignant lesions, respectively. 18F-FSPG detected brain and intracardiac metastases missed by 18F-FDG PET in one case, while 18F-FDG detected a metastasis to the kidney missed by 18F-FSPG. Conclusion: In this pilot study, there was no significant difference in overall diagnostic accuracy between 18F-FSPG and 18F-FDG for the evaluation of IPNs and staging of lung cancer. Additional studies will be needed to determine the clinical utility of this tracer in the management of IPNs and lung cancer. [ABSTRACT FROM AUTHOR]

The uterosacral ligaments (USLs) are key support structures of the uterus and upper vagina. Previously, we have shown that HOXA11 is necessary for the development of the USLs, is deficient in women with pelvic organ prolapse (POP) and regulates expression of extracellular matrix (ECM) proteins. Here we sought to determine if HOXA11 regulates cell proliferation in the USLs in women. Like others, we have found that, there is decreased cellularity in prolapsed USLs compared to USLs in women with normal pelvic support. We have also demonstrated that HOXA11 promotes cell proliferation in murine fibroblasts and primary human USL cells in vitro. These findings support a relationship between HOXA11 expression, rates of proliferation and phenotypic abnormalities in the USL. Based on these findings, we sought to determine if HOXA11 regulates p53, a tumor suppressor gene which controls progression through the cell cycle and regulates ECM genes. We have demonstrated that expression of HOXA11 represses expression of p53, suggesting a mechanism by which HOXA11 regulates of the morphology and integrity of the USLs. A better understanding of the influence of these genes on the homeostasis of the ECM and interactions with each other may prove beneficial in defining the underlying etiologies of the development of POP and aid in the development of new treatment options for women with this disorder. [ABSTRACT FROM AUTHOR]

Pelvic organ prolapse (POP) is a common, debilitating disorder affecting millions of women. Uterosacral ligaments (USLs) are the main supportive structures of the uterus and vagina and are often attenuated in women with POP. Although the mechanical strength of USLs is known to be dependent on collagen synthesis and catabolism and the degradation protein MMP2 has been implicated in POP, the molecular mechanisms involved in the development of POP are currently unknown. Homeobox (HOX) genes are transcriptional regulators that orchestrate embryonic development of the urogenital tract. We demonstrated here that HOXA11 was essential for organogenesis of the USL by showing that USLs were absent in Hoxa11-null mice. We compared expression of HOXA11, collagen type I, collagen type III, MMP2, and MMP9 in USLs of women with and without POP. Expression of HOXA11 and both collagens was dramatically decreased while MMP2 was increased in women with POP. Constitutive expression of Hoxa11 in murine fibroblasts resulted in significantly increased expression of collagen type III and decreased expression of MMP2. These results identified HOXA11 as an essential gene for the development of the USL and suggested that women with POP might have weakened connective tissue due to changes in a signaling pathway involving HOXA11, collagen type III, and MMP2. [ABSTRACT FROM AUTHOR]

The mortality rate triples for the 50% of patients diagnosed with new-onset post-transplant diabetes mellitus (PTDM) after HLA-identical allogeneic hematopoietic cell transplant (HCT) (Griffith, BBMT 2011). Haploidentical HCT (haplo-HCT) with post-transplant cyclophosphamide (PTCY) is increasingly utilized for patients with hematological disorders but without a conventional HLA-matched donor; however, the effects of PTDM after haplo-HCT is unknown. We examined the incidence, outcomes, and risk factors for PTDM in patients undergoing haplo-HCT. Patients receiving haplo-HCT with PTCY at Vanderbilt-Ingram Cancer Center (n= 65) were retrospectively analyzed for PTDM diagnosis (defined as a random blood glucose ≥200 mg/dL). Exclusion criteria included non-haplo-HCTs, second HCT, or pre-existing diabetes mellitus. The primary outcome was the incidence of new-onset PTDM by day 100. Secondary outcomes included: cumulative incidence (CI) of grades 2-4 graft-versus-host disease (GVHD), time to systemic steroids, PTDM risk factors, overall survival (OS), disease free survival (DFS), and non-relapse mortality (NRM). PTDM was diagnosed in 14 (21.5%) patients at a median of 18 days after haplo-HCT (range, 8-72 days). Hyperglycemia preceded grade 2-4 GVHD and steroids in 12 (85.7%) patents. Clinical characteristics including ablative conditioning and GVHD did not predict PTDM development (Table 1). OS was decreased in the PTDM group (Figure 1). Among haplo-HCT recipients with cancer (n= 41) DFS was lower and the CI of relapse was increased in PTDM patients (Figure 1). Similar to HLA-identical transplants, PTDM occurs frequently, precedes alloreactivity, and leads to inferior survival following haplo-HCT. Interestingly, glucose metabolism appears to be associated with relapse risk. Prophylaxis/treatment of PTDM may improve outcomes after conventional and haplo-HCT. [ABSTRACT FROM AUTHOR]

Abstract: A series of amino analogs of 1,3-dihydro-1-phenyl-3-[[3-(trifluoromethyl)phenyl]imino]-2H-indol-2-one (1) were synthesized to improve aqueous solubility, while retaining high affinity for the human galanin Gal3 receptor. A very potent analog (9e, 1,3-dihydro-1-[3-(2-pyrrolidinylethoxy)phenyl]-3-[[3-(trifluoromethyl)phenyl]imino]-2H-indol-2-one, K i =5nM) shows good selectivity and solubility of 48μg/mL at pH 7.4. [Copyright &y& Elsevier]

Purpose: Although concurrent chemoradiotherapy can now achieve demonstrated long-term survival in patients with locally advanced non–small-cell lung cancer (LANSCLC), it is difficult to predict which patients will benefit most from this therapeutic approach. Studies have suggested that local control, and the response to therapy, may be linked to improved survival; however, detailed analysis of the impact of tumor response to chemoradiotherapy on survival has not been thoroughly reported. Therefore, we sought to determine the impact of the response rate on survival for patients who were treated with combined modality therapy for LANSCLC. Methods and Materials: We reviewed the data from 116 patients enrolled between 1994 and 1997 in three trials investigating paclitaxel-based concurrent chemoradiotherapy for LANSCLC. Tumor size measurements were assessed immediately before and 2 months after completion of combined modality therapy to determine the response and to calculate the percentage of decrease in tumor size. Results: Patients with a response (complete or partial) had an improved 4-year overall survival rate compared with patients with no response (stable or progressive disease; 21.1% vs. 3.3%, p <0.0001) in the 109 assessable patients. Progression-free survival also improved significantly with response. An analysis of the percentage of decrease in tumor size vs. survival was performed (n = 74) using Cox proportion model analysis. After combined modality therapy, a 20%, 40%, 60%, 80%, and 100% decrease in tumor size conferred a 39%, 63%, 78%, 86%, and 92% reduction in risk of death compared with a 0% decrease in tumor size (p <0.0001). Conclusion: The response by conventional response criteria correlated strongly with improved overall survival and progression-free survival and an increasing percentage of decrease in tumor size resulted in a reduction in the risk of death. Additional investigation of the degree of response as a factor predictive of improved therapeutic efficacy, translating into improved survival, is warranted. [Copyright &y& Elsevier]

Abstract: The capillary electrophoresis (CE) method combined with a sequential extraction was applied to determine the distribution of Fe, Zn, Cu, Mn and Cd in urban ambient air PM2.5 samples. PM2.5 was collected on Teflon filters with dichotomous sampler, and the modified extraction procedure following the BCR leaching procedure was used to chemically fractionate metals into “easily exchangeable” with water, “acid extractable” with 0.11mol/l acetic acid, “reducible” with 0.1mol/l hydroxylamine hydrochloride acidified to pH 2.0 with nitric acid, and “oxidisable” with oxidation by 8.8mol/l hydrogen peroxide (H2O2) followed by extraction with 1.0mol/l ammonium acetate. Based on the obtained results it was concluded that the application of the studied methodology provides chemical fractionation data that reflect the general sources and potential health hazards of the studied metals. [Copyright &y& Elsevier]

Background: Several advanced bronchoscopy platforms are currently available, but the clinical data supporting their use vary. Electromagnetic navigation bronchoscopy (ENB) remains the dominant technology; it is limited by its reliance on preoperative computed tomography, which only approximates patient anatomy during the procedure. Recently, ENB was enhanced with the (1) addition of digital tomosynthesis-based navigation correction, (2) improvements in planning algorithms, and (3) continuous real-time guidance (Illumisite™; Medtronic, Minneapolis, MN, USA). There are currently no clinical data on the diagnostic yield and safety profile of this system. Objectives: The primary objective of this study is to describe the diagnostic yield of the first 100 pulmonary parenchymal lesions sampled using the multimodality navigation bronchoscopy (MNB) platform. The secondary objective is to describe safety. Methods: In this single-center prospective observational study, a database was maintained to track patient, procedural, and outcome data for the first 100 consecutive lesions sampled using the MNB platform at an academic quaternary referral center. Descriptive statistics and univariate and multivariate analyses are reported. Results: The overall diagnostic yield of samples acquired was 79% (79/100). In the cohort where digital tomosynthesis was used, the diagnostic yield was 83% (69/83). Sensitivity for malignancy was 71% (52/73). Overall complication rates were low: pneumothorax (n = 3, 3%) and bleeding requiring intervention (n = 2, 2%). There were no procedural-related hospital admissions. Conclusions: The MNB system performed favorably. Platform superiority cannot be established without future prospective and comparative studies. [ABSTRACT FROM AUTHOR]

This work continues an evaluation of a previously developed capillary electrophoresis (CE) method to determine the distribution of Fe, Zn, Cu, Mn, and Cd in airborne particulate matter (PM) after sequential extraction. A three-stage extraction procedure following the BCR protocol was used to chemically fractionate metals between (F1) “exchangeable water and acid-extractable” (0.11 M acetic acid), (F2) “reducible” (0.1 M hydroxylamine hydrochloride acidified to pH 2.0 with nitric acid) and (F3) “oxidizable” (1.0 M ammonium acetate extraction after oxidation by 8.8 M hydrogen peroxide) PM fractions. The reliability and applicability of the developed procedure were tested using NIST 1648 Urban Air Particulate Matter. Small-scale extractions (10 mg mass in 1 ml extractant) have been used. The work has been focused on (i) the optimization of CE experimental conditions for sensitivity measuring trace metals in the BCR extractants and (ii) speeding up BCR extraction by finding a set of sonication conditions giving recoveries similar to conventional extraction for the metals of interest. The CE method was validated with respect to linearity, detection limits, precision, and accuracy. Detection limits were at low-μg/l (μg/g) and mid-μg/l (tens of μg/g) levels using electrokinetic and pressure injection modes, respectively. The efficiency of the accelerated BCR extraction method using an ultrasonic bath was evaluated, for each metal in each fraction, as a percent recovery of the conventional method. With the exception of iron (45.0 and 55.2%, respectively, in F1 and F2 fractions), the results attempted from ultrasonic extraction for all metals were reasonably comparable with those obtained using the conventional BCR procedure. The optimized procedure was found to be precise (typically R.S.D.<10%) for all metals in all fractions. Detailed fraction-specific concentration data are presented, based on six replicates, for Fe, Zn, Cu, Mn, and Cd in NIST 1648 PM using both accelerated and conventional BCR extraction. Taking into account that the overall extraction time was reduced from 48 to 2 h, the proposed analytical methodology provides a promising approach to obtain information about origin, mode of occurrence, and/or potential bioavailability of metals in airborne particulate matter with a much shorter operating time. [Copyright &y& Elsevier]

• Programmed necroptosis is increased in MDS as suggested by increased RIPK1 in erythroid precursors. • Programmed necroptosis contributes to ineffective hematopoiesis in MDS. • Inhibiting RIPK1 improves erythroid colony-forming ability of human MDS. Myelodysplastic syndrome (MDS) is characterized by persistent cytopenias and evidence of morphologic dysplasia in the bone marrow (BM). Excessive hematopoietic programmed cell death (PCD) and inflammation have been observed in the bone marrow of patients with MDS, and are thought to play a significant role in the pathogenesis of the disease. Necroptosis is a major pathway of PCD that incites inflammation; however, the role of necroptosis in human MDS has not been extensively investigated. To assess PCD status in newly diagnosed MDS, we performed immunofluorescence staining with computational image analysis of formalin-fixed, paraffin-embedded BM core biopsies using cleaved caspase-3 (apoptosis marker) and necroptosis markers (receptor-interacting serine/threonine-protein kinase 1 [RIPK1], phospho-mixed lineage kinase domain-like protein [pMLKL]). Patients with MDS, but not controls without MDS or patients with de novo acute myeloid leukemia, had significantly increased expression of RIPK1 and pMLKL but not cleaved caspase-3, which was most evident in morphologically low-grade MDS (<5% BM blasts) and in MDS with low International Prognostic Scoring System risk score. RIPK1 expression highly correlated with the distribution of CD71+ erythroid precursors but not with CD34+ blast cells. We found that necroptosis is upregulated in early/low-grade MDS relative to control participants, warranting further study to define the role of necroptosis in the pathogenesis of MDS and as a potential biomarker for the diagnosis of low-grade MDS. [Display omitted] [ABSTRACT FROM AUTHOR]