Smad4 restricts injury-provoked biliary proliferation and carcinogenesis.

Cholangiocarcinoma (CCA) is a deadly and heterogeneous type of cancer characterized by a spectrum of epidemiologic associations as well as genetic and epigenetic alterations. We seek to understand how these features inter-relate in the earliest phase of cancer development and through the course of disease progression. For this, we studied murine models of liver injury integrating the most commonly occurring gene mutations of CCA - including Kras, Tp53, Arid1a and Smad4 - as well as murine hepatobiliary cancer models and derived primary cell lines based on these mutations. Among commonly mutated genes in CCA, we found that Smad4 functions uniquely to restrict reactive cholangiocyte expansion to liver injury through restraint of the proliferative response. Inactivation of Smad4 accelerates carcinogenesis, provoking pre-neoplastic biliary lesions and CCA development in an injury setting. Expression analyses of Smad4-perturbed reactive cholangiocytes and CCA lines demonstrated shared enriched pathways, including cell-cycle regulation, MYC signaling and oxidative phosphorylation, suggesting that Smad4 may act via these mechanisms to regulate cholangiocyte proliferation and progression to CCA. Overall, we showed that TGFß/SMAD4 signaling serves as a critical barrier restraining cholangiocyte expansion and malignant transformation in states of biliary injury.

Analysis of risk factors for early crestal bone loss in osseointegrated, submerged implants prior to restoration.

BACKGROUND: Evidence on the etiology behind bone loss around submerged, prosthetically nonloaded implants is still limited. The long-term stability and success of implants with early crestal bone loss (ECBL), especially when placed as two-stage implants, is uncertain. Hence, the aim of this retrospective study is to analyze the potential patient-level, tooth- and implant-related factors for ECBL around osseointegrated, submerged implants, before restoration as compared with healthy implants with no bone loss. METHODS: Retrospective data were collected from patient electronic health records between 2015 and 2022. Control sites included healthy implants with no bone loss and test sites included implants with ECBL, both of which were submerged. Patient, tooth and implant level data were collected. ECBL was assessed using periapical radiographs obtained during implant placement and second-stage surgeries. Generalized estimating equation logistic regression models were used to account for multiple implants within patients. RESULTS: The total number of implants included in the study was 200 from 120 patients. Lack of supportive periodontal therapy (SPT) was shown to have nearly five-times higher risk of developing ECBL and was statistically significant (p < 0.05). Guided bone regeneration (GBR) procedures before implant placement had a protective effect with an odds ratio of 0.29 (p < 0.05). CONCLUSIONS: Lack of SPT was significantly associated with ECBL, while sites that received GBR procedures prior to implant placement were less likely to exhibit ECBL. Our results underscore the importance of periodontal treatment and SPT for peri-implant health, even when the implants are submerged and unrestored.

Visual exogenous and endogenous attention and visual memory in preschool children who stutter.

PURPOSE: Attention develops gradually from infancy to the preschool years and beyond. Exogenous attention, consisting of automatic responses to salient stimuli, develops in infancy, whereas endogenous attention, or voluntary attention, begins to develop later, in the preschool years. The purpose of this study was to examine (a) exogenous and endogenous attention in young children who stutter (CWS) and children who do not stutter (CWNS) through two conditions of a visual sustained selective attention task, and (b) visual short-term memory (STM) between groups within the context of this task. METHOD: 42 CWS and 42 CWNS, ages 3;0-5;5 (years;months), were pair-matched in age, gender (31 males, 11 females per group), and socioeconomic status. Children completed a visual tracking task (Track-It Task; Fisher et al., 2013) requiring sustained selective attention and engaging exogenous and endogenous processes. Following each item, children were asked to recall the item they had tracked, as a memory check. RESULTS: The CWS group demonstrated significantly less accuracy in overall tracking and visual memory for the tracked stimuli, compared to the CWNS group. Across groups, the children performed better in sustained selective attention when the target stimuli were more salient (the condition tapping both exogenous and endogenous attention) than when stimuli were less so (the condition tapping primarily endogenous processes). CONCLUSIONS: Relative to peers, preschool-age CWS, as a group, display weaknesses in visual sustained selective attention and visual STM.

Ridge Augmentation Comparing a Cancellous Block Allograft to an Osteoinductive Demineralized Bone Matrix Allograft: A Randomized, Controlled, Blinded Clinical Trial.

Twenty-six patients with a horizontal ridge defect were entered into this 4-month randomized, controlled, blinded clinical trial to compare a cancellous block allograft to a demineralized bone matrix (DBM) allograft for ridge augmentation. Six patients were excluded from the study, leaving 20 for data interpretation. Both groups had a xenograft overlay and a collagen membrane. For the Block group there was a significant gain of 4.8 ± 1.9 mm (P = .00002; 95% confidence interval [CI]: 3.49 to 6.21), while the DBM group gained 4.6 ± 2.4 mm (P = .0002; 95% CI: 2.88 to 6.36). Vertical change was minimal for both groups (P > .05). The Block group had a mean of 40% vital bone while the DBM group had 35%.

Adaptive Information Processing Theory: Origins, Principles, Applications, and Evidence.

This paper describes the origins, principles, applications, and evidence related to Adaptive Information Processing (AIP) theory. AIP theory provides the theoretical underpinning of Eye Movement Desensitization and Reprocessing (EMDR) therapy. AIP theory was developed to explain the observed results of EMDR therapy delivered to individuals experiencing trauma and PTSD. The AIP model hypothesizes that maladaptively stored memories of trauma create obstacles to rational processing of information, which occurs in the prefrontal cortex area of the brain. Bilateral stimulation, through eye movements or other mechanisms, is hypothesized to remove the obstacles and permit complete processing of the memory, leading to a reduction in trauma symptoms. EMDR therapy, with the AIP model as rationale, has been effectively used in the treatment of PTSD. Evidence in support of AIP theory is emerging as some promising results have been shown in studies that rely on measuring various types of physiological changes that occur during EMDR therapy.

Word learning from context in school-age children: relations with language ability and executive function.

Purpose: Although school-age children learn most new word meanings from surrounding context, the joint roles of language ability and executive function (EF) in the word learning process remain unclear. This study examined children's acquisition of word meanings from context in relation to oral language ability and three EF skills (working memory, inhibitory control, and cognitive flexibility). Method: Typically developing school-age children completed measures of language and EF, then read and listened to short stories containing unfamiliar target words. A multiple-choice pretest-posttest measure assessed children's target word knowledge gains. Results: Regression analyses showed that language and cognitive flexibility were both related to word knowledge gains; each skill assumed greater importance among children with relative weakness in the other skill. Conclusion: Language ability and cognitive flexibility may each play a direct role in contextual word learning among school-age children, with children naturally relying on one skill if the other is weaker.

A Comparison of the Effect of Barrier Membranes on Clinical and Histologic Hard and Soft Tissue Healing with Ridge Preservation.

Twenty patients completed this randomized, controlled, blinded clinical trial comparing ridge preservation with a bioabsorbable polylactic acid membrane (PLA group) compared to an acellular dermal matrix membrane guided bone regeneration (ADMG group). An intrasocket corticocancellous allograft plus a facial overlay xenograft was used for both groups. Final crestal ridge width was significantly greater for the ADMG group (P < .05). Soft tissue thickness, conversely, was thicker for the PLA group. Vertical ridge height change increased significantly for the midbuccal site of the ADMG group. Histologic evaluation showed high percentages of vital bone for both groups.

Outcomes after bloodstream infection in hospitalized pediatric hematology/oncology and stem cell transplant patients.

BACKGROUND: Pediatric hematology/oncology (PHO) patients receiving therapy or undergoing hematopoietic stem cell transplantation (HSCT) often require a central line and are at risk for bloodstream infections (BSI). There are limited data describing outcomes of BSI in PHO and HSCT patients. METHODS: This is a multicenter (n = 17) retrospective analysis of outcomes of patients who developed a BSI. Centers involved participated in a quality improvement collaborative referred to as the Childhood Cancer and Blood Disorder Network within the Children's Hospital Association. The main outcome measures were all-cause mortality at 3, 10, and 30 days after positive culture date; transfer to the intensive care unit (ICU) within 48 hours of positive culture; and central line removal within seven days of the positive blood culture. RESULTS: Nine hundred fifty-seven BSI were included in the analysis. Three hundred fifty-four BSI (37%) were associated with at least one adverse outcome. All-cause mortality was 1% (n = 9), 3% (n = 26), and 6% (n = 57) at 3, 10, and 30 days after BSI, respectively. In the 165 BSI (17%) associated with admission to the ICU, the median ICU stay was four days (IQR 2-10). Twenty-one percent of all infections (n = 203) were associated with central line removal within seven days of positive blood culture. CONCLUSIONS: BSI in PHO and HSCT patients are associated with adverse outcomes. These data will assist in defining the impact of BSI in this population and demonstrate the need for quality improvement and research efforts to decrease them.

The Effect of Platform-Switching Plus Laser Grooving on Peri-implant Hard and Soft Tissue Level: A Randomized, Controlled, Blinded Clinical Trial.

Twenty patients were randomly assigned to receive either a platform-switched or platform-matched implant to replace a single maxillary anterior tooth. Primary outcome variables were the implant interproximal bone loss, facial recession, and papilla fill at 12 months. The platform-switched group showed crestal bone loss of 0.1 ± 0.3 (mesial) and 0 mm (distal) while the platform-matched group showed losses of 0.6 ± 0.5 mm (mesial) and 0.7 ± 0.7 mm (distal) (P < .05). Facial recessions for the platform-switched and platform-matched groups were 0.1 ± 0.3 mm and 0.4 ± 0.8 mm, respectively.

Ridge Preservation Comparing the Clinical and Histologic Healing of Membrane vs No-Membrane Approach to Buccal Overlay Grafting.

Twenty-four patients completed this randomized, controlled, blinded clinical trial comparing ridge preservation with a membrane (acellular dermal matrix graft [ADMG]) vs no membrane on buccal overlay graft technique. An intrasocket corticocancellous allograft with a facial overlay xenograft was used for both groups, and an ADMG was used as a membrane with guided bone regeneration in the ADMG group (control group). In the No Membrane group (test group), ADMG was used to cover only the occlusal surface for graft containment, with no membrane on the buccal overlay graft. Final crestal ridge width and vertical ridge height had no significant difference between groups (P > .05). Facial contour was preserved for the ADMG group compared to No Membrane group. Histologic examination showed a high percentage of vital bone for both groups with no significant difference between groups.

Ridge Augmentation Comparing an Allograft Plus Autogenous Bone Chips to an Osteoinductive Demineralized Bone Matrix: A Clinical and Histologic Study in Humans.

PURPOSE: The primary aim of this randomized, controlled, blinded, clinical trial was to compare a mix of particulate allograft and harvested autogenous particles (Autogenous) to an osteoinductive demineralized bone matrix (DBM) allograft on clinical and histologic outcomes for horizontal ridge augmentation procedure. MATERIALS AND METHODS: Fourteen patients with a horizontal ridge defect with at least 1 adjacent tooth were entered into this study. The test group of 7 subjects received corticocancellous particulate allograft (Mineross) mixed with autogenous bone chips (70:30) harvested using a bone scraper (SafeScraper TWIST). Seven subjects in the control group received DBM (Optecure-CCC). Both groups had a corticocancellous particulate allograft overlay and an acellular dermis membrane (ADMG) (AlloDerm GBR) to cover the grafts. RESULTS: For the Autogenous group, there was a gain of 3.5 ± 1.4 mm while the DBM group gained 3.8 ± 1.6 mm (P < 0.05). Vertical change was minimal for both groups (P > 0.05). The Autogenous group had a mean of 35% vital bone while the DBM had 39% (P > 0.05). CONCLUSIONS: Both treatments provided similar gain of ridge width and minimal loss of ridge height. The autogenous bone chips did not provide any additional benefit when compared with allograft alone that had lot verified osteoinductive activity.

Caregivers' Perceptions of Their Child's Language Disorder: Alignment between Caregivers and Speech-Language Pathologists.

Caregivers' perceptions regarding their child's language disorder may influence caregivers' involvement in therapy as well as daily home interactions, thus impacting developmental outcomes. However, little is known about the alignment between caregivers' perceptions of their child's language disorder and those of speech-language pathologists (SLPs), nor of factors that might relate to alignment between caregivers and SLPs. This study addressed three aims: (1) to characterize caregivers' perceptions regarding children's quality of communicative interactions, competence in communicative abilities, and outcomes of communicative improvement; (2) to measure alignment between caregivers' and SLPs' perceptions; and (3) to explore caregiver- and child-level factors that might relate to alignment. Caregivers and SLPs of 3- to 4-year-old children currently receiving treatment for language disorders completed questionnaires to assess perceptions along with two caregiver factors (maternal education and self-efficacy) and child language disorder severity. Caregivers' perceptions were more positive and more variable than those of SLPs. However, caregivers and SLPs agreed in rating perceptions of present and future outcomes higher than either quality or competence. Maternal education, caregiver's self-efficacy, and children's language disorder severity were not related to alignment between caregivers and SLPs. Given the variability in caregivers' perceptions, future research should explore the role of perceptions in children's language intervention outcomes.

Kras and Tp53 Mutations Cause Cholangiocyte- and Hepatocyte-Derived Cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (iCCA) is a primary liver cancer epidemiologically linked with liver injury, which has poorly understood incipient stages and lacks early diagnostics and effective therapies. While iCCA is conventionally thought to arise from the biliary tract, studies have suggested that both hepatocytes and biliary cells (cholangiocytes) may give rise to iCCA. Consistent with the plasticity of these cell lineages, primary liver carcinomas exhibit a phenotypic range from hepatocellular carcinoma (HCC) to iCCA, with intermediates along this spectrum. Here, we generated mouse models to examine the consequence of targeting mutant Kras and Tp53, common alterations in human iCCA, to different adult liver cell types. Selective induction of these mutations in the SOX9+ population, predominantly consisting of mature cholangiocytes, resulted in iCCA emerging from premalignant biliary intraepithelial neoplasia (BilIN). In contrast, adult hepatocytes were relatively refractory to these mutations and formed rare HCC. In this context, injury accelerated hepatocyte-derived tumorigenesis and promoted a phenotypic switch to iCCA. BilIN precursor lesions were absent in the hepatocyte-derived iCCA models, pointing toward distinct and direct emergence of a malignant cholangiocytic phenotype from injured, oncogenically primed hepatocytes. Tp53 loss enhanced the reprogramming of hepatocytes to cholangiocytes, which may represent a mechanism facilitating formation of hepatocyte-derived iCCA. Overall, our work shows iCCA driven by Kras and Tp53 may originate from both mature cholangiocytes and hepatocytes, and factors such as chronic liver injury and underlying genetic mutations determine the path of progression and resulting cancer phenotype.Significance: The histopathogenesis of biliary tract cancer, driven by Tp53 and Kras mutations, can be differentially impacted by the cell of origin within the mature liver as well by major epidemiologic risk factors. Cancer Res; 78(16); 4445-51. ©2018 AACR.

Reduction in Rate of Nosocomial Respiratory Virus Infections in a Children's Hospital Associated With Enhanced Isolation Precautions.

OBJECTIVE To determine whether the use of enhanced isolation precautions (droplet and contact precautions) for inpatients with respiratory tract viral infections is associated with a reduction in rate of nosocomial viral respiratory infections. DESIGN Quasi-experimental study with the rate of nosocomial respiratory virus infection as the primary dependent variable and rate of nosocomial Clostridium difficile infection as a nonequivalent dependent variable comparator. SETTING Cohen Children's Medical Center of NY, a tertiary-care children's hospital attached to a large general hospital. INTERVENTION During years 1 and 2 (July 2012 through June 2014), the Centers for Disease Control and Prevention/Healthcare Infection Control Practices Advisory Committee's recommended isolation precautions for inpatients with selected respiratory virus infections were in effect. Enhanced isolation precautions were in effect during years 3 and 4 (July, 2014 through June, 2016), except for influenza, for which enhanced precautions were in effect during year 4 only. RESULTS During the period of enhanced isolation precautions, the rate of nosocomial respiratory virus infections with any of 4 virus categories decreased 39% from 0.827 per 1,000 hospital days prior to enhanced precautions to 0.508 per 1,000 hospital days (P<.0013). Excluding rhinovirus/enterovirus infections, the rates decreased 58% from 0.317 per 1,000 hospital days to 0.134 per 1,000 hospital days during enhanced precautions (P<.0014). During these periods, no significant change was detected in the rate of nosocomial C. difficile infection. CONCLUSIONS Enhanced isolation precautions for inpatients with respiratory virus infections were associated with a reduction in the rate of nosocomial respiratory virus infections. Infect Control Hosp Epidemiol 2018;39:152-156.

Ridge Preservation Comparing a Nonresorbable PTFE Membrane to a Resorbable Collagen Membrane: A Clinical and Histologic Study in Humans.

PURPOSE: The primary aim of this randomized, controlled, blinded clinical trial was to compare the effect of a resorbable collagen membrane (CM group) versus a nonresorbable high-density polytetrafluoroethylene membrane (PTFE group) on the clinical and histologic outcomes of a ridge preservation procedure. MATERIALS AND METHODS: All 24 sites received an intrasocket cancellous allograft and a buccal overlay bovine derived xenograft. RESULTS: The change in horizontal crestal ridge width was -1.4 ± 1.2 mm for the CM group, whereas the PTFE group lost -2.2 ± 1.5 mm, which was not statistically significant between groups (P > 0.05). Vertical ridge height change was -1.2 ± 1.5 for the CM group, whereas the PTFE group lost -0.5 ± 1.6, which was not significantly different between groups (P > 0.05). The percent vital bone was similar and not significantly different between groups. Primary closure was not obtained and the exposed membrane portion over the socket opening healed with keratinized tissue. CONCLUSION: The choice of a resorbable versus a nonresorbable barrier membrane did not affect the clinical or the histologic outcome of ridge preservation treatment.

Semantic-syntactic partial word knowledge growth through reading.

PURPOSE: Incidental reading provides a powerful opportunity for partial word knowledge growth in the school-age years. The extent to which children of differing language abilities can use reading experiences to glean partial knowledge of words is not well understood. The purpose of this study was to compare semantic-syntactic partial word knowledge growth of children with higher language skills (HL group; overall language standard scores of 85 or higher) to that of children with relatively lower language skills (LL group; overall receptive or expressive standard score below 85). METHOD: Thirty-two children, 16 per group, silently read stories containing unfamiliar nouns and verbs 3 times over a 1-week period. Semantic-syntactic partial word knowledge growth was assessed after each reading and 2-3 days later to assess retention. RESULTS: Over time, both groups showed significant partial word knowledge growth, with the HL group showing significantly more growth. In addition, both groups retained knowledge several days later. CONCLUSION: Regardless of language skill level, children benefit from multiple exposures to unfamiliar words in reading in their development and retention of semantic-syntactic partial word knowledge growth.

Canadian Association of Radiologists consensus guidelines for the prevention of contrast-induced nephropathy: update 2012.

PURPOSE: Contrast-induced acute kidney injury or contrast-induced nephropathy (CIN) is a significant complication of intravascular contrast medium (CM). These guidelines are intended as a practical approach to risk stratification and prevention. The major risk factor that predicts CIN is pre-existing chronic kidney disease. METHODS: Members of the committee represent radiologists and nephrologists across Canada. The previous guidelines were reviewed, and an in-depth up-to-date literature review was carried out. RESULTS: A serum creatinine level (SCr) should be obtained, and an estimated glomerular filtration rate (eGFR) should be calculated within 6 months in the outpatient who is stable and within 1 week for inpatients and patients who are not stable. Patients with an eGFR of ≥ 60 mL/min have an extremely low risk of CIN. The risk of CIN after intra-arterial CM administration appears be at least twice that after intravenous administration. Fluid volume loading remains the single most important measure, and hydration regimens that use sodium bicarbonate or normal saline solution should be considered for all patients with GFR < 60 mL/min who receive intra-arterial contrast and when GFR < 45 mL/min in patients who receive intravenous contrast. Patients are most at risk for CIN when eGFR < 30 mL/min. Additional preventative measures include the following: avoid dehydration, avoid CM when appropriate, minimize CM volume and frequency, avoid high osmolar CM, and discontinue nephrotoxic medications 48 hours before administration of CM.

The mysterious organ. Spectrum of focal lesions within the splenic parenchyma: cross-sectional imaging with emphasis on magnetic resonance imaging.

Incidental splenic lesions are frequently encountered at imaging performed for unrelated causes. Splenic cysts, hemangiomas, and lymphomatous involvement are the most frequently encountered entities. Computed tomography and sonography are commonly used for initial evaluation with magnetic resonance imaging reserved as a useful problem-solving tool for characterizing atypical and uncommon lesions. The value of magnetic resonance imaging lies in classifying these lesions as either benign or malignant by virtue of their signal-intensity characteristics on T1- and T2-weighted imaging and optimal depiction of internal hemorrhage. Dynamic contrast-enhanced sequences may improve the evaluation of focal splenic lesions and allow characterization of cysts, smaller hemangiomas, and hamartomas. Any atypical or unexplained imaging feature related to an incidental splenic lesion requires additional evaluation and/or follow-up. Occasionally, biopsy or splenectomy may be required for definitive assessment given that some of tumours may demonstrate uncertain biologic behavior.

Platelet-rich plasma-assisted guided bone regeneration for ridge augmentation: a randomized, controlled clinical trial.

BACKGROUND: Platelet-rich plasma (PRP) contains a number of biologically active growth factors, and previous studies have reported conflicting ridge augmentation results. The primary aim of this randomized, controlled, masked, clinical trial was to determine if PRP combined with a rapidly resorbing cancellous allograft would enhance the regenerative result compared with an allograft without PRP. METHODS: Thirty-two patients with an edentulous ridge defect were sequentially entered into the study; four were excluded from data analysis. Fourteen patients received a cancellous allograft (CAN group) and the other 14 received a cancellous allograft mixed with PRP (PRP group). All 28 grafted sites were covered with a resorbable polylactide membrane. After elevation of a full-thickness flap, horizontal ridge dimensions were measured with a digital caliper at the crest and 5 mm apical to the crest. Vertical ridge dimensions were measured from a tooth-supported stent. All sites were reentered at 4 months, and a trephine core was obtained for histologic analysis before implant placement. RESULTS: The crestal ridge width for the CAN group had a mean gain of 2.0 ± 1.2 mm, whereas the PRP group gained 2.9 ± 1.0, and the difference was statistically significant between groups (P <0.05). The percent vital bone was 36% ± 14% for the CAN group compared with 51% ± 15% for the PRP group and was statistically significant between groups (P <0.05). Loss of augmented ridge width was 34% ± 17% for the CAN group and 28% ± 17% for the PRP group (P >0.05). CONCLUSION: These clinical and histologic findings suggest that PRP enhanced bone regeneration and resulted in increased horizontal bone gain and percentage vital bone.

Mucinous neoplasms of the appendix: a current comprehensive clinicopathologic and imaging review.

Mucinous neoplasms of the appendix are a heterogeneous group of neoplasms ranging from simple mucoceles to complex pseudomyxoma peritonei. Considerable controversy exists on their pathologic classification and nomenclature. Clear understanding of the histopathologic diversity of these neoplasms helps in establishing proper communication between the radiologist, the pathologist and the surgeon. In this article, we present a brief discussion of the current taxonomy and nomenclature of mucinous neoplasms of the appendix followed by a review of their imaging features. Important points including the significance of identifying extra-appendiceal mucin at imaging, the new classification of pseudomyxoma peritonei into low- and high-grade varieties and the significance of simultaneous ovarian and appendiceal neoplasms are highlighted.