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Background Bone fractures are important clinical events for both patients and professionals. Active treatment options are limited for delayed unions and for nonunions; surgery is common but not entirely risk-free. This report describes three cases of delayed union successfully treated with herbal decoction. Participants Three patients had trapezoid and 3rd metacarpal bone fractures, 2nd, and 5th metatarsal bone fractures, respectively. All three patients were diagnosed with delayed union by an independent orthopedic surgeon based on computed tomography (CT) scan/radiographic imaging and fracture duration without a healing process. Patients took herbal decoction, Jeopgol-tang, with individually added herbs based on symptom manifestations, twice daily for 56, 85 and 91 days with no additional interventions except for a splint that they had been wearing since fracture diagnosis. Outcomes Improvement of delayed union was evaluated using radiographic imaging or CT during treatment with Jeopgol-tang. Results After taking herbal medicine, callus and bony bridging were confirmed on follow-up imagings and the patients described their experience with pain reduction at an interview after recovery. Conclusions This case series suggests that the herbal decoction Jeopgol-tang warrants further investigation to establish its role as a complementary and integrative medicine treatment option for delayed unions., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Epidemiologic evidence suggests that environmental factors acting as endocrine disrupting chemicals (EDCs) are associated with mammographic breast density and the risk of breast cancer. Exposure to EDCs during puberty, a period of rapid breast development, may affect susceptibility to breast carcinogenesis., Methods: In a cohort of 366 Chilean adolescents from the Growth and Obesity Cohort Study, we evaluated the relation between urinary concentrations of 15 suspected EDC biomarkers across three pubertal time points (Tanner breast stage 1 (B1), 4 (B4), and 1-year post-menarche) and breast fibroglandular volume (FGV; percent FGV [%FGV] and absolute FGV [aFGV]) and total breast volume (tBV) at 2-years post-menarche. We used linear mixed models to test differences in creatinine-corrected EDC biomarker concentrations at B4 and 1-year post-menarche compared to B1 and calculated intraclass correlation coefficients (ICC) of EDC concentrations across time points to appraise the consistency of measurements. We fit multivariable generalized estimating equations (GEEs) to evaluate windows of susceptibility for the association between log 10 -transformed EDCs and log 10 -transformed breast outcomes. GEEs were adjusted for age, body fat percentage, total caloric intake, and maternal education., Results: Urinary EDC biomarker concentrations highly varied across pubertal time points (ICC range 0.01-0.30). For 12 EDCs, biomarker concentrations decreased over time. Triclosan measured at 1-year post-menarche was inversely associated with %FGV at 2-years post-menarche (β = -0.025, 95 % confidence interval = -0.041, -0.008). Mono(2-ethyl-5-carboxypentyl) phthalate and the sum of di(2-ethylhexyl) phthalate metabolite concentrations at B4 were positively associated with aFGV and tBV at 2-years post-menarche. No measured phenols were associated with aFGV and tBV, while no measured parabens were associated with %FGV and aFGV., Conclusions: Our study suggests relatively high variability in EDC biomarker concentrations across the peripubertal time period. We also found evidence to suggest that there may be pubertal windows of susceptibility to select EDCs for the association with adolescent breast density., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Prebiotic and probiotic supplementation and yogurt consumption (a probiotic food) alter gut microbial diversity, which may influence colorectal carcinogenesis. This systematic review evaluates the existing literature on the effect of these nutritional supplements and yogurt consumption on colorectal neoplasia incidence among adults. We systematically identified ten randomized controlled trials and observational studies in adults age ≥ 18 without baseline gastrointestinal disease. Prebiotics included inulin, fructooligosaccharides, galactooligosaccharides, xylooligosaccharides, isomaltooligosaccharides, and β-glucans. Probiotics included bacterial strains of Lactobacillus, Bifidobacterium, Saccharomyces, Streptococcus, Enterococcus, Bacillus, Pediococcus, Leuconostoc, and Escherichia coli. Synbiotic supplements, a mixture of both prebiotic and probiotic supplements, and yogurt, a commonly consumed dietary source of live microbes, were also included. We defined colorectal neoplasia as colorectal adenomas, sessile serrated polyps, and colorectal cancer (CRC). Overall, findings suggest a moderate decrease in risk of adenoma and CRC for high levels of yogurt consumption compared to low or no consumption. Prebiotic supplementation was not associated with colorectal neoplasia risk. There was some evidence that probiotic supplementation may be associated with lower risk of adenomas but not with CRC incidence. Higher yogurt consumption may be associated with lower incidence of colorectal neoplasia. We found little evidence to suggest that prebiotic or probiotic supplements are associated with significant decreases in CRC occurrence.

The gut microbiome has been linked to breast cancer via immune, inflammatory, and hormonal mechanisms. We examined the relation between adolescent breast density and gut microbial composition and function in a cohort of Chilean girls. This cross-sectional study included 218 female participants in the Growth and Obesity Cohort Study who were 2 years post-menarche. We measured absolute breast fibroglandular volume (aFGV) and derived percent FGV (%FGV) using dual energy X-ray absorptiometry. All participants provided a fecal sample. The gut microbiome was characterized using 16S ribosomal RNA sequencing of the V3-V4 hypervariable region. We examined alpha diversity and beta diversity across terciles of %FGV and aFGV. We used MaAsLin2 for multivariable general linear modeling to assess differential taxa and predicted metabolic pathway abundance (MetaCyc) between %FGV and aFGV terciles. All models were adjusted for potential confounding variables and corrected for multiple comparisons. The mean %FGV and aFGV was 49.5% and 217.0 cm 3 , respectively, among study participants. Similar median alpha diversity levels were found across %FGV and aFGV terciles when measured by the Shannon diversity index (%FGV T1: 4.0, T2: 3.9, T3: 4.1; aFGV T1: 4.0, T2: 4.0, T3: 4.1). %FGV was associated with differences in beta diversity ( R 2 = 0.012, p =0.02). No genera were differentially abundant when comparing %FGV nor aFGV terciles after adjusting for potential confounders (q > 0.56 for all genera). We found no associations between predicted MetaCyc pathway abundance and %FGV and aFGV. Overall, breast density measured at 2 years post-menarche was not associated with composition and predicted function of the gut microbiome among adolescent Chilean girls., Competing Interests: Author JH is employed by Leidos, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Yoon, Jacobs, Hoehner, Pereira, Gana, Corvalán and Michels.)

Consumption of prebiotic inulin has been found to increase calcium absorption, which may protect against gut diseases such as colorectal cancer. This dietary relation may be modulated by compositional changes in the gut microbiota; however, no human study has addressed this hypothesis. We determined the feasibility of a randomized crossover trial to evaluate the effect of three interventions (combined calcium and inulin supplementation, calcium supplementation alone, and inulin supplementation alone) on the intestinal microbiota composition and function. We conducted a 16-week pilot study in 12 healthy adults who consumed the three interventions in a random sequence. Participants provided fecal and blood samples before and after each intervention. Each intervention period lasted four weeks and was flanked by one-week washout periods. 16S ribosomal RNA sequencing and quantification of short chain fatty acids (SCFA) was determined in fecal samples. Systemic lipopolysaccharide binding protein (LBP) was quantified in serum. Of the 12 individuals assigned to an intervention sequence, seven completed the study. Reasons for dropout included time ( n = 3), gastrointestinal discomfort ( n = 1), and moving ( n = 1). Overall, participants reported positive attitudes towards the protocol ( n = 9) but were unsatisfied by the practicalities of supplement consumption (44%) and experienced digestive discomfort (56%). We found no appreciable differences in microbial composition, SCFA concentration, nor LBP concentrations when comparing intervention periods. In conclusion, an intervention study using a randomized crossover design with calcium and a prebiotic fiber is feasible. Improvements of our study design include using a lower dose prebiotic fiber supplement and a larger sample size.

Background: Venous thromboembolism (VTE) is rare among young women and is often presumed to occur in the setting of a genetic predisposition or during the use of estrogen-containing combined hormonal contraceptive or to have an unknown cause. This study aims to describe the distribution of VTE risk factors among women with a confirmed VTE., Methods: We identified all women aged 15-46 years with a VTE diagnosis at Columbia University Medical Center from 2005 to 2012 using medical center databases. We then reviewed all electronic medical records to validate the diagnoses and identify risk factors associated with each confirmed case., Results: We identified 315 cases and confirmed 186 (59%). The proportion of unconfirmed cases increased over time. Forty percent of confirmed cases were associated with hormonal contraceptives or pregnancy. Ninety-five percent of confirmed cases had identifiable major risk factors including a personal history, family history, malignancy or other predisposing illness, recent long-haul travel, trauma, hospitalization, and obesity; many had multiple simultaneous risk factors. None of the confirmed cases was associated with a previously known genetic predisposition, but in 10 confirmed cases a genetic predisposition was identified during evaluation. In only 10 of the 186 confirmed cases could we not identify any acquired risk factor, and only 2 of those 10 women had a genetic predisposition., Conclusions: Many reproductive age women experiencing a VTE have risk factors unique to this group, and most have multiple risk factors, confirming that this is a multifactorial disease. The large proportion of unconfirmed cases suggests the need for great caution in using administrative databases for research due to poor diagnostic specificity and due to lack of information about additional risk factors.

Background: Endometrial cancer is the most common gynecologic cancer in the United States. Statins have demonstrated anti-cancer effects in other tumor types, such as the breast and lung cancers., Aim: The objective of our study was to determine the association between statin use and endometrial cancer survival in a nationally-representative elderly population with endometrial cancer in the U.S., Methods: We employed the linked Surveillance, Epidemiology and End Results registries and Medicare claims files to collect data from 2987 patients who were diagnosed with endometrial cancer between 2007 and 2009 and who received a hysterectomy. The association between statin use and overall survival was examined using Cox regression models adjusting for follow-up time, age, race, neighborhood income, cancer stage, tumor grade, hysterectomy type, chemotherapy, radiation, impaired glucose tolerance, obesity, dyslipidemia and diabetes., Results: The mortality rate was lower in statin users compared to non-users for both type I (4.6 vs. 5.7 deaths/100 person-years, p=0.08) and type II (11.2 vs. 16.5 deaths/100 person-years, p=0.01) cancer types. However, after adjustment for the time from surgery to statin use and confounding, statin use after a hysterectomy was not significantly associated with a reduction in hazard of death for both type I (hazard ratio [HR] 0.92, 95%CI 0.70,1.2) and type II (HR=0.92, 95%CI 0.65, 1.29, p=0.62) endometrial cancer patients., Conclusion: Accounting for all confounders and biases considered, statin use on or after a hysterectomy was not associated with survival in those with type I or type II disease., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: The purpose of this study was to compare 2-dimensional (2D) and 3D magnetic resonance cholangiopancreatography (MRCP) for image quality and diagnostic performance in the evaluation of pathologically verified intraductal papillary mucinous neoplasm (IPMN) of the pancreas., Materials and Methods: In this institutional review board-approved retrospective review, 21 patients (14 women and 7 men; mean age, 69 years; range, 43-93 years) who underwent 2D and 3D MRCPs on a 1.5-T system for pathologically confirmed IPMN were studied. Two-dimensional MRCP protocol included multiplanar thin- and thick-slab single-shot fast spin-echo imaging, coronal single-shot fast spin-echo, and transverse T2-weighted fast spin-echo imaging. Three-dimensional MRCP was performed using a fast-recovery fast spin-echo sequence with single-volume acquisition and maximum intensity projection reconstructions. Using a 5-point scale, 2 readers independently evaluated MRCPs for (1) image quality, (2) visualization of the pancreatic duct (PD), and (3) visualization of the cystic lesions. Intraductal papillary mucinous neoplasm's morphological features (septa, mural nodules, and duct communication) were also graded similarly to predict benignity or malignancy. Surgical and pathological data served as reference standard. A pancreatic surgeon reviewed the 21 MRCPs to determine the usefulness of 3D MRCP compared with that of 2D MRCP for surgical planning., Results: Of the 21 IPMNs, 11 were side-branch IPMNs and 10 were main-duct-lesions IPMNs with side-branch involvement. A statistically significant improvement in image quality and visualization of the PD and cystic lesion was demonstrated with 3D MRCP in comparison with that demonstrated with 2D MRCP (P < or = 0.002). The morphological details of IPMN were also identified, with higher confidence with 3D MRCP in comparison with that using 2D MRCP. Two-dimensional and 3D MRCPs performed similarly for predicting benign and malignant lesions, with sensitivity ranging from 50.0% to 66.7% and specificity ranging from 86.7% to 93.3%. The pancreatic surgeon preferred 3D to 2D MRCP for surgical evaluation and planning in 14 of 21 cases., Conclusion: Compared with 2D MRCP, 3D MRCP provides better image quality, offers superior evaluation of the PD and morphological details of IPMN, and is preferred for surgical planning.

Objective: In recent years, radial imaging has been advocated for improved visualization of the acetabular labrum in magnetic resonance arthrography of the hip. The purpose of this study was to investigate whether radial imaging demonstrates labral tears not visible on standard imaging planes., Methods: Fifty-four consecutive magnetic resonance (MR) arthrograms of the hip that included radial imaging over 2 years were retrospectively analyzed by two radiologists. Standard imaging planes and radial imaging were reviewed for identification of labral tears in four specific areas of the labrum: anterosuperior, posterosuperior, anteroinferior, and posteroinferior. The standard imaging sequences include fat-saturated spin-echo T1-weighted images in the coronal and oblique axial planes, non-fat-saturated T1-weighted images in the coronal and sagittal planes, and T2-weighted sequence in the axial plane. Radial imaging was performed as previously described using fat-saturated T1-weighted sequences., Results: Using standard imaging planes, 50 anterosuperior, 31 posterosuperior, 10 anteroinferior, and 9 posteroinferior labral tears were detected in 54 MR arthrograms of the hip. Using radial sequences alone, 44 anterosuperior, 25 posterosuperior, 9 anteroinferior, and 5 posteroinferior labral tears were detected. In all four areas of the labrum, the radial imaging did not show any labral tear not seen on standard imaging planes., Discussion: In MR arthrography of the hip, radial imaging did not reveal any additional labral tears. Standard imaging planes sufficiently demonstrate all acetabular labral tears.

Introduction: Statistics and a good understanding of numbers are important professional tools for doctors in order to understand and communicate risk estimates., Materials and Methods: In this questionnaire survey carried out among 129 specialist trainees the ability to calculate and compare risk values (Relative Risk Reduction, Absolute Risk Reduction, Number Needed to Treat and a combination of these) was examined along with the general understanding of numbers in relation to probabilities., Results: The survey showed that 69% of the participants were able to calculate a risk reduction accurately. Answers from the respondents did not depend on whether information was given as absolute or relative risk reductions. 13% of the participants were able to correctly estimate the risk of a false positive answer in connection with screening., Conclusion: The trainee doctors demonstrated a surprisingly poor ability to make basic probability calculations and a poor understanding of screening results. A thorough understanding of risk measures as well as basic probabilities is a prerequisite for good objective patient information. This survey indicates that there is considerable room for improvement in these areas.

Purpose: To retrospectively analyze magnetic resonance (MR) arthrographic findings in patients with clinical cam-type femoroacetabular impingement., Materials and Methods: This study was approved by the institutional review board, and informed consent was waived. Study was compliant with the Health Insurance Portability and Accountability Act. Forty-two MR arthrograms obtained in 40 patients with clinical femoroacetabular impingement were analyzed retrospectively by two radiologists. Quantitative analysis by using alpha angle measurement was performed to assess anterosuperior femoral head-neck morphology. Presence of labral tears, articular cartilage lesions, paralabral cysts, os acetabuli, and synovial herniation pits was recorded. Presence of the typical triad of anterosuperior labral tear, anterosuperior cartilage lesion, and abnormal alpha angle was recorded. Surgical comparison was available for 11 patients., Results: At imaging, in 40 patients (22 male, 18 female) with a mean age of 36.5 years, 39 of 42 hips (93%) had an abnormal alpha angle, with a mean angle of 69.7 degrees ; 40 of 42 (95%) had an anterosuperior cartilage abnormality; and 42 of 42 (100%) had an anterosuperior labral tear. Thirty-seven of 42 hips (88%) had the triad. Six had paralabral cysts, 17 had an os acetabuli, and two had synovial herniation pits. Surgical comparison for 11 hips led to confirmation of all labral and cartilage abnormalities seen at imaging., Conclusion: MR arthrography demonstrated a triad of abnormal head-neck morphology, anterosuperior cartilage abnormality, and anterosuperior labral abnormality in 37 of 42 patients with cam-type femoroacetabular impingement.

Purpose: To evaluate the use of a redundant system in improving quality of care in the trauma setting by examining a subset of our quality assurance program., Materials and Methods: Five hundred thirty-one consecutive abdominal and pelvic CT reports obtained in patients with trauma at a level I trauma center from August 22, 1999, to August 21, 2000, were retrospectively reviewed. Each case was initially interpreted by a board-certified or board-eligible radiologist during evaluation in the emergency department and was subsequently reviewed by a subspecialty abdominal imaging radiologist as part of a quality assurance program. Nineteen cases were excluded because available information was incomplete, resulting in 512 cases in the current study. Cases with discordant interpretations were followed up to discern care change., Results: Of the 512 trauma cases, 153 (29.9%) showed discordant readings. Review of patient records demonstrated changes in patient care in 12 (7.8%) cases. Three (2.0%) cases were reviewed from the morbidity and mortality records of the Department of Trauma Surgery as a direct result of misinterpretations. Six (4%) cases involved additional diagnostic imaging for reevaluation; in four of these six cases the quality assurance reader's interpretation was confirmed, while in the other two, the initial interpretations were favored., Conclusion: Findings suggest that discordant radiologic interpretations most often do not result in a change in patient care and outcome. The quality assurance program did, however, identify and lead to changes in care in a number of cases by providing clinically important additional findings.

The c-Raf-1 kinase is converted into an oncoprotein by functional inactivation of its NH2-terminal regulatory domain and into a dominant-interfering protein by mutations that eliminate catalytic activity. This report describes a systematic charged residue-to-alanine scanning mutagenesis of the ATP-binding subdomain of the c-raf-1 gene. Two temperature-sensitive mutations were found, which were then used to construct both conditionally active and conditionally dominant-defective alleles. Stable cell lines overexpressing both types of mutants were isolated, and their phenotypes were examined. Ectopic expression of Raf-1 activity in quiescent cells was not sufficient to elicit S-phase entry, but the Raf signal could be efficiently complemented by the progression factor insulin-like growth factor I. The results point to a function of Raf-1 in the platelet-derived growth factor and epidermal growth factor pathways, leading to the establishment of competence for cell cycle entry. Ectopic expression of the dominant-defective activity in quiescent cells efficiently blocked entry into S phase. Effects of the dominant-defective protein could be detected minutes after the shift to the restrictive conditions and resulted in the rapid down-regulation of the mitogen-activated protein kinase pathway. Taken together, the phenotypes of the conditionally active and conditionally dominant-defective mutants point to a critical function of Raf-1 at very early times during exit from G0 and entry into G1.

Here we investigate the role of the Raf-1 kinase in transformation by the v-abl oncogene. Raf-1 can activate a transforming signalling cascade comprising the consecutive activation of Mek and extracellular-signal-regulated kinases (Erks). In v-abl-transformed cells the endogenous Raf-1 protein was phosphorylated on tyrosine and displayed high constitutive kinase activity. The activities of the Erks were constitutively elevated in both v-raf- and v-abl-transformed cells. In both cell types the activities of Raf-1 and v-raf were almost completely suppressed after activation of the cyclic AMP-dependent kinase (protein kinase A [PKA]), whereas the v-abl kinase was not affected. Raf inhibition substantially diminished the activities of Erks in v-raf-transformed cells but not in v-abl-transformed cells, indicating that v-abl can activate Erks by a Raf-1-independent pathway. PKA activation induced apoptosis in v-abl-transformed cells while reverting v-raf transformation without severe cytopathic effects. Overexpression of Raf-1 in v-abl-transformed cells partially protected the cells from apoptosis induced by PKA activation. In contrast to PKA activators, a Mek inhibitor did not induce apoptosis. The diverse biological responses correlated with the status of c-myc gene expression. v-abl-transformed cells featured high constitutive levels of expression of c-myc, which were not reduced following PKA activation. Myc activation has been previously shown to be essential for transformation by oncogenic Abl proteins. Using estrogen-regulated c-myc and temperature-sensitive Raf-1 mutants, we found that Raf-1 activation could protect cells from c-myc-induced apoptosis. In conclusion, these results suggest (i) that Raf-1 participates in v-abl transformation via an Erk-independent pathway by providing a survival signal which complements c-myc in transformation, and (ii) that cAMP agonists might become useful for the treatment of malignancies where abl oncogenes are involved, such as chronic myeloid leukemias.