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Objectives To examine the efficacy of weekly and bi-weekly heat training to maintain heat acclimatization (HAz) and heat acclimation (HA) for 8 weeks in aerobically trained athletes. Design Randomized, between-group. Methods Twenty-four males (mean [m ± standard deviation [sd]; (age, 34 ± 12 y; body mass, 72.6 ± 8.8 kg, VO2peak, 57.7 ± 6.8 mL·kg-1·min-1) completed five trials (baseline, following HAz, following HA (HAz + HA), four weeks into heat training [HTWK4], and eight weeks into HT [HTWK8] that involved 60 min of steady-state exercise (59.1 ± 1.8% vVO2peak) in an environmental laboratory (wet bulb globe temperature [WBGT], 29.6 ± 1.4 °C) on a motorized treadmill. Throughout exercise, heart rate (HR) and rectal temperature (Trec) were recorded. Following HAz + HA, participants were assigned to three groups: control group (HT0), once per week heat training (HT1), and twice per week heat training (HT2). HT involved heated exercise (WBGT, 33.3 ± 1.3 °C) to achieve hyperthermia (38.5-39.75 °C) for 60 min. Repeated measures ANOVAs were used to determine differences. Results HAz + HA resulted in significant improvements in HR (p Conclusions Bi-weekly HT provided clear evidence for the ability to maintain physiological adaptions for 8 weeks following HA.

Objectives To assess the effects of hydration status and ice-water dousing on physiological and performance parameters. Design Randomized, crossover. Methods Twelve athletes (mean[M] ± standard deviation[SD]; age, 20 ± 1 years; height, 174 ± 8 cm; body mass, 72.1 ± 11.0 kg; VO2max 53.9 ± 7.3 mL⋅kg−1⋅min−1) completed four trials (euhydrated without dousing, hypohydrated without dousing, euhydrated with dousing, and hypohydrated with dousing), which involved intermittent treadmill running (five 15-minute bouts) in the heat (M ± SD; ambient temperature, 34.7 ± 2.1 °C; relative humidity, 46 ± 3%; wet-bulb globe temperature, 28.0 ± 0.4 °C). Participants also completed four cognitive, power, agility, reaction time, and repeated sprint performance tests throughout each trial. Heart rate (HR) and rectal temperature (Trec) were measured continuously. Repeated measures ANOVAs were performed to assess differences between physiological and performance variables. Alpha was set at ≤0.05, a priori. Data are reported as mean difference ± standard error (MD ± SE). Results HR was significantly lower in euhydrated trials compared to hypohydrated trials, irrespective of dousing (8 ± 2 bpm; p = 0.001). Dousing did not significantly impact HR (p = 0.455) and there was no interaction between hydration and dousing (p = 0.893). Trec was significantly lower in euhydrated trials compared to hypohydrated trials (0.39 ± 0.05 °C, p Conclusions Athletes should aim to maintain euhydration during exercise in the heat for improved physiological function and cooling with ice-water dousing elicits additional performance benefits.

Interventional radiology is a constantly evolving specialty overlapping with multiple other specialties, including cardiology, vascular surgery, orthopedic surgery, urology, and minimally invasive surgery. Unique ergonomic considerations for interventional radiology include utilization of intraoperative viewing monitors and personal radiation protection equipment. Work-related injuries are common in interventional radiologists,1 often leading to pain while performing procedures or during time away from work. This review article aims to identify the ergonomic challenges related to interventional radiology and provide background, guidelines, and specific recommendations for prevention of musculoskeletal injury.

Background Rare diseases (RDs) affect a small number of people within a population. About 5000 to 8000 distinct RDs have been identified, with an estimated 6% to 8% of people worldwide suffering from an RD. Approximately 75% of RDs affect children. Frequently, these conditions are heterogeneous; many are progressive. Regulatory incentives have increased orphan drug designations and approvals. Objective To develop emerging good practices for RD outcomes research addressing the challenges inherent in identifying, selecting, developing, adapting, and implementing patient-reported outcome (PRO) and observer-reported outcome (ObsRO) assessments for use in RD clinical trials. Good Practices for Outcomes Research This report outlines the challenges and potential solutions in determining clinical outcomes for RD trials. It follows the US Food and Drug Administration Roadmap to Patient-Focused Outcome Measurement in Clinical Trials. The Roadmap consists of three columns: 1) Understanding the Disease or Condition, 2) Conceptualizing Treatment Benefit, and 3) Selecting/Developing the Outcome Measure. Challenges in column 1 include factors such as incomplete natural history data and heterogeneity of disease presentation and patient experience. Solutions include using several information sources, for example, clinical experts and patient advocacy groups, to construct the condition’s natural history and understand treatment patterns. Challenges in column 2 include understanding and measuring treatment benefit from the patient’s perspective, especially given challenges in defining the context of use such as variations in age or disease severity/progression. Solutions include focusing on common symptoms across patient subgroups, identifying short-term outcomes, and using multiple types of COA instruments to measure the same constructs. Challenges in column 3 center around the small patient population and heterogeneity of the condition or study sample. Few disease-specific instruments for RDs exist. Strategies include adapting existing instruments developed for a similar condition or that contain symptoms of importance to the RD patient population, or using a generic instrument validated for the context of use. Conclusions This report provides state-of-the-art solutions to patient-reported outcome (PRO) and observer-reported outcome (ObsRO) assessments challenges in clinical trials of patients with RDs. These recommended solutions are both pragmatic and creative and posed with clear recognition of the global regulatory context used in RD clinical development programs.

Background Little is known about which materials and techniques general dentists (GDs) use during endodontic procedures. The objectives were to quantify GDs’ use of specific endodontic tools, quantify inappropriate use, and ascertain whether inappropriate use is associated with GDs’ practice characteristics. Methods GDs in The National Dental Practice-Based Research Network reported in a questionnaire materials and techniques they use during endodontic procedures. Results Among eligible GDs, 1,490 (87%) participated. Most (93%; n = 1,383) used sodium hypochlorite to irrigate. The most commonly used sealers were zinc oxide eugenol (43%) and resin (40%), followed by calcium hydroxide (26%). Most (62%; n = 920) used a compaction obturation technique; 36% (n = 534) used a carrier-based method. Most (96%; n = 1,423) used gutta-percha as a filler; 5% used paste fillers. Few used irrigants (n = 46), techniques (n = 49), or fillers (n = 10) that investigators classified as inappropriate. Conclusions GDs use a broad range of endodontic techniques and materials, often adapting to newer technologies as they become available. Few GDs use tools that the investigators classified as inappropriate. Practical Implications GDs use many types of endodontic techniques and materials, but only a small percentage of them are inappropriate.

Magnesium reduction of MCl5 (M = Nb or Ta) in the presence of R2S (R = Me or nBu) affords the complexes [M2Cl4(R2S)2(?-Cl)2(?-R2S)]. The X-ray structures of those complexes where M = Nb or Ta, R = nBu2S, and of a new polymorph of [Ta2Cl4(Me2S)2(?-Cl)2(?-Me2S)], show that they have confacial bi-octahedral structures with Mdouble bond; length as m-dashM double bonds. The reactions of [Nb2Cl4(R2S)2(?-Cl)2(?-R2S)] with MeSCH2CH2SMe, MeSeCH2CH2SeMe or MeSeCH2CH2CH2SeMe produce the edge-linked dimers [Nb2Cl4(MeSCH2CH2SMe)2(?-Cl)2] and [Nb2Cl4{MeSe(CH2)nSeMe}2(?-Cl)2], all with Mdouble bond; length as m-dashM double bonds (M26+). The tantalum diselenoether complex, [Ta2Cl4(MeSeCH2CH2SeMe)2(?-Cl)2], is similar. Two “dimer of dimers”, [{Nb2Cl4(?-Cl)2(?-Me2S)}2(?-MeSeCH2CH2CH2SeMe)2] and [{Ta2Cl4(?-Cl)2(?-Me2S)}2(?-nBuSeCH2CH2CH2SenBu)2], containing confacial bi-octahedra linked by diselenoether bridges, were obtained as minor by-products and were identified via their X-ray crystal structures. Under similar conditions the xylyl-linked diselenoether, o-C6H4(CH2SeMe)2, gave a complex mixture of products, including [Ta2Cl4{o-C6H4(CH2SeMe)2}2(?-Se)2]. The complexes were characterised by microanalysis, IR and UV–visible spectroscopy. X-ray crystal structures are reported for [Nb2Cl6(nBu2S)3], [Ta2Cl6(nBu2S)3], [Ta2Cl8(Me2S)2], [Ta2Cl6(Me2S)3], [Ta2Cl4{o-C6H4(CH2SeMe)2}2(Se)2], [{Ta2Cl6(Me2S)(nBuSeCH2CH2CH2SenBu)}2] and [Ta2Cl4(Me2S)4(S)2].

This article reviews work up until mid-2014 on the synthesis and properties of transition metal complexes containing the heavier Group 15 Sb(III) and Bi(III) ligands, of general formula ER3 (E = Sb or Bi; R = alkyl, aryl etc, and may include a pendant donor group such as amine or ether) and ER(3-n)Xn (E = Sb or Bi; R is an organic substituent such as alkyl, aryl, etc.; X is an electronegative substituent such as halide; n = 0-3) in which these ligands function as a donor to a transition metal fragment, while simultaneously participating as an acceptor to another electronegative group such as an anionic or metal-coordinated halide, or an amine, ether, etc., leading to Sb/Bi centres bearing more than eight valence electrons ('hypervalent'). The Lewis acid properties of the halostibines and halobismuthines, ER(3-n)Xn, are also reviewed.

Introduction A preliminary study done by a National Dental Practice-Based Research Network precursor observed that 44% of general dentists (GDs) reported always using a rubber dam (RD) during root canal treatment (RCT). This full-scale study quantified the use of all isolation techniques, including RD use. Methods Network practitioners completed a questionnaire about isolation techniques used during RCT. Network enrollment questionnaire data provided practitioner characteristics. Results One thousand four hundred ninety of 1716 eligible GDs participated (87%); 697 (47%) reported always using an RD. This percentage varied by tooth type. These GDs were more likely to always use an RD, do not own a private practice, perform less than 10 RCTs/month, and have postgraduate training. Conclusions Most GDs do not use an RD all the time. Ironically, RDs are used more frequently by GDs who do not perform molar RCT. RD use varies with tooth type and certain dentist, practice, and patient characteristics.

A series of cold cathode field emission points to be used for electron impact ionization of background gas in Penning trap mass spectrometry applications have been fabricated by electrochemically etching tungsten rod in a NaOH solution. A new variation of the drop-off etching method that can produce tips with tip radii down to 10 nm is described. We present the results of studies in which the parameters used in the etching process were varied, and the geometry and operation of the resulting tips was investigated by imaging them with a scanning electron microscope and by operating them in field emission mode. Finally, the use of these tips in a Penning trap mass spectrometry application is described.

Background Chimeric antigen receptor (CAR) T cell therapy is FDA-approved for the treatment of refractory or multiple-relapsed CD19+ B-NHL. Despite its ability to induce rapid and durable responses, it carries the risk of significant toxicities including cytokine release syndrome (CRS) and reversible encephalopathy. There have been reports of bone marrow failure after engineered-T cell receptor cellular immunotherapy, however, no such reports exist for CAR-T cells. Here, we report persistent cytopenias after T cell therapy (PCTT) following axicabtagene ciloleucel (axi-cel) infusion. Methods A retrospective analysis of all patients who were treated with commercial axi-cel at the University of Miami/Sylvester Cancer Center was conducted through 10/12/18. PCTT was defined as patients who were alive at 30 days after axi-cel infusion and did not have ANC>500cells/mL without growth factor support. Results Fifteen patients with CD19+ relapse or refractory B-NHL were identified who received commercial axi-cel, but of those 15 patients, 13 were evaluable (one died from cerebral edema on day +7 and the other has not reached the day +30 benchmark yet). Six of the 13 evaluable patients (46%) fulfilled the criterion for PCTT. None of the 6 patients recovered ANC by day +42. Platelets of 50,000/mL or less on the first day of lymphodepleting chemotherapy was found to be a significant predictor for PCTT (p=0.01) in 5 of 6 PCTT patients. We did not find any other predictive associations with factors such as bulky disease, CRP, ferritin, LDH, ANC, or hemoglobin. It was observed that 4 of 6 (66.7%) patients with PCTT developed CRS of at least grade 2 the day after CAR-T infusion requiring tocilizumab infusion as opposed to only 1 of 7 (14.3%) who did not develop PCTT. Conclusions Low platelet count at the first day of lymphodepleting chemotherapy may be an indicator of low stem cell reserve and a predictor for PCTT after axi-cel. In addition, early onset of at least grade 2 CRS may contribute to PCTT after axi-cel. Notably, 5 of 6 patients who went on to develop PCTT would have been excluded from participation in the ZUMA-1 registration trial.

Self-monitoring is an important clinical technique used in cognitive-behavioral therapy. It is frequently used for homework assignments in the context of comprehensive treatments. A description of self-monitoring and practical considerations is presented, followed by an examination of self-monitoring as a means to facilitate collaborative empiricism in therapy. It may foster collaboration between therapist and client in collecting and reviewing essential data, inform treatment planning, and enhance the client's sense of agency. A clinical case example is included to provide an emphasis on clinical application. We conclude by noting potential mechanisms for facilitating change through the use of self-monitoring. Continued examination of applied clinical practice, including strategies such as self-monitoring, is needed to further our understanding of the mechanisms of therapeutic change.

Objective Following a successful 2005–2012 phase with three regional practice-based research networks (PBRNs), a single, unified national network called “The National Dental PBRN” was created in 2012 in the United States to improve oral health by conducting practice-based research and serving dental professionals through education and collegiality. Methods Central administration is based in Alabama. Regional centres are based in Alabama, Florida, Minnesota, Oregon, New York and Texas, with a Coordinating Centre in Maryland. Ideas for studies are prioritized by the Executive Committee, comprised mostly of full-time clinicians. Results To date, 2763 persons have enrolled, from all six network regions; enrollment continues to expand. They represent a broad range of practitioners, practice types, and patient populations. Practitioners are actively improving every step of the research process, from idea generation, to study development, field testing, data collection, and presentation and publication. Conclusions Practitioners from diverse settings are partnering with fellow practitioners and academics to improve clinical practice and meet the needs of clinicians and their patients. Clinical significance This “nation's network” aims to serve as a precious national resource to improve the scientific basis for clinical decision-making and foster movement of the latest evidence into routine practice.

SummaryThe mammalian intestine is colonized with a diverse community of bacteria that perform many beneficial functions but can threaten host health upon tissue invasion. Epithelial cell-intrinsic innate immune responses are essential to limit the invasion of both commensal and pathogenic bacteria and maintain beneficial host-bacterial relationships; however, little is known about the role of various cellular processes, notably autophagy, in controlling bacterial interactions with the intestinal epithelium in vivo. We demonstrate that intestinal epithelial cell autophagy protects against tissue invasion by both opportunistically invasive commensals and the invasive intestinal pathogen Salmonella Typhimurium. Autophagy is activated following bacterial invasion of epithelial cells through a process requiring epithelial cell-intrinsic signaling via the innate immune adaptor protein MyD88. Additionally, mice deficient in intestinal epithelial cell autophagy exhibit increased dissemination of invasive bacteria to extraintestinal sites. Thus, autophagy is an important epithelial cell-autonomous mechanism of antibacterial defense that protects against dissemination of intestinal bacteria.

We developed and evaluated a brief (8-session) version of cognitive-behavioral therapy (BCBT) for anxiety disorders in youth ages 6 to 13. This report describes the design and development of the BCBT program and intervention materials (therapist treatment manual and child treatment workbook) and an initial evaluation of child treatment outcomes. Twenty-six children who met diagnostic criteria for a principal anxiety diagnosis of separation anxiety disorder, generalized anxiety disorder, and/or social phobia were enrolled. Results suggest that BCBT is a feasible, acceptable, and beneficial treatment for anxious youth. Future research is needed to examine the relative efficacy of BCBT and CBT for child anxiety in a randomized controlled trial.

Background The Dental Practice-Based Research Network (DPBRN) provided a means to investigate whether certain procedures were performed routinely. The authors conducted a study to quantify rubber dam use during root canal treatment (RCT) among general dentists and to test the hypothesis that certain dentist or practice characteristics were associated with rubber dam use. Methods DPBRN practitioner-investigators (P-Is) answered a questionnaire that included items about rubber dam use and other forms of isolation during RCT. DPBRN enrollment questionnaire data provided information regarding practitioner and practice characteristics. Results A total of 729 (74 percent) of 991 P-Is responded; 524 were general dentists who reported providing at least some RCTs and reported the percentage of RCTs for which they used a rubber dam. Of these 524 P-Is, 44 percent used a rubber dam for all RCTs, 24 percent used it for 51 to 99 percent of RCTs, 17 percent used it for 1 to 50 percent of RCTs, and 15 percent never used it during RCT. Usage varied significantly by geographic region and practice type. The use of cotton rolls and other forms of isolation also was reported. Conclusions Similar to other reports in the literature, not all DPBRN general dentists used a rubber dam during RCT. Clinical Implications Because the clinical reference standard is to use a rubber dam during RCT, increasing its use may be important.

SummaryA major unanswered question in neuroscience is whether there exists genomic variability between individual neurons of the brain, contributing to functional diversity or to an unexplained burden of neurological disease. To address this question, we developed a method to amplify genomes of single neurons from human brains. Because recent reports suggest frequent LINE-1 (L1) retrotransposition in human brains, we performed genome-wide L1 insertion profiling of 300 single neurons from cerebral cortex and caudate nucleus of three normal individuals, recovering >80% of germline insertions from single neurons. While we find somatic L1 insertions, we estimate

SummaryHemimegalencephaly (HMG) is a developmental brain disorder characterized by an enlarged, malformed cerebral hemisphere, typically causing epilepsy that requires surgical resection. We studied resected HMG tissue to test whether the condition might reflect somatic mutations affecting genes critical to brain development. We found that two out of eight HMG samples showed trisomy of chromosome 1q, which encompasses many genes, including AKT3, a gene known to regulate brain size. A third case showed a known activating mutation in AKT3 (c.49G→A, creating p.E17K) that was not present in the patient's blood cells. Remarkably, the E17K mutation in AKT3 is exactly paralogous to E17K mutations in AKT1 and AKT2 recently discovered in somatic overgrowth syndromes. We show that AKT3 is the most abundant AKT paralog in the brain during neurogenesis and that phosphorylated AKT is abundant in cortical progenitor cells. Our data suggest that somatic mutations limited to the brain could represent an important cause of complex neurogenetic disease.

A previous report suggested that successful cognitive behavioral therapy (CBT) for child anxiety reduced substance use problems at 7.4-year follow-up, but that report did not include predictors of: (a) substance use disorder (SUD; e.g., attention deficit-hyperactivity disorder symptoms, negative life events, family substance abuse, additional treatment), or (b) treatment outcome (e.g., severity of internalizing pathology, age). Analyses incorporating these factors tested previously reported findings in 72 participants (ages 15–22 at follow-up; 84% of the 7.4-year follow-up sample), using parent and youth diagnostic interviews and report measures. The majority of previously reported associations between less successful treatment and later substance use problems remained significant after controlling for known predictors of SUD and treatment outcome. Our findings bolster previous conclusions that effective CBT for child anxiety may have ameliorative effects on the target disorder and later substance use problems.

The current article offers suggestions for ways to adapt empirically supported treatments (ESTs). A specific manualized EST (Coping Cat; Kendall & Hedtke, 2006a) is used to illustrate the concept of “flexibility within fidelity” (Kendall & Beidas, 2007; Kendall, Gosch, Furr, & Sood, 2008). Flexibility within fidelity stresses the importance of using ESTs while considering and taking into account individual client presentations. In this discussion, recommendations are offered for the use of the Coping Cat with younger youth, adolescents, and youth with secondary comorbidities (i.e., social skills deficits, inattentive symptoms, and depressive symptoms).

CMV is the most clinically significant viral infection in HCT recipients. Control CMV reactivation after HCT is highly dependent on CMV-specific T cells. Despite dramatic technical advances, the clinical utility of functional assays of virus-specific T cells to predict CMV reactivation following HCT remains to be established. Using 13-color flow cytometry, we studied CD8+T cell responses to pp65 and IE-1 CMV peptide stimulation in cryopreserved PBMC from three clinically distinct subgroups (n=10 each) of HCT patients: 1) Elite Controllers (EC) : CMV seropositive (R+) recipients who never reactivated CMV based on weekly surveillance testing; 2) Spontaneous Controllers (SC): CMV R+ recipients who spontaneously resolved low-grade viremia (1,000 IU/mL) requiring antiviral therapy. NC had lower numbers of CD8+ T cells that simultaneously produced 3-4 cytokines in response to CMV peptides compared to EC and SC (18, 26 and 34%, respectively) suggesting that progressive CMV viremia is associated with loss of CD8+ T cell polyfunctionality. Among 15 possible cytokine signatures, we identified two CMV-specific CD8+ T cell cytokine signatures, measured at day +30, that were strongly associated with the risk of CMV reactivation (Fig. 1): i) the non-protective signature (NPS) consisting of IL-2negIFNγposTNFαnegMIP-1βpos CD8+ T cells was positively associated with CMV reactivation (4.9% of CMV-specific CD8+ T cells vs. 19.4 P=0.002 for EC vs. SC/NC; 4.9 vs. 10.8 P=0.02 for EC vs. SC; 4.9 vs. 22.8 P=0.005 for EC vs. NC for pp65 stimulated cells; similar trends were observed in IE-1 stimulated cells); ii) the protective signature (PS) consisted of quadruple producers (IL-2posIFNγposTNFαposMIP-1βpos), and was significantly reduced among NC vs. SC following pp65 and IE-1 stimulation (0.05% of CMV-specific CD8+ T cells vs. 2.85 for pp65, P= 0.02; 0 vs. 1.25 for IE-1, P= 0.02); this association was also found in superantigen-stimulated cells. Production of IFNγ alone or in combination did not predict reactivation (P=0.49). Since NC trended toward more frequent recurrence of CMV viremia compared to SC (60 vs. 10%, respectively; P=0.06), we explored the association between PS and NPS and number of episodes of CMV reactivation (Fig. 1). We observed a significant stepwise increase in the levels of the NPS in pp65-stimulated cells in patients who experienced 0 vs. 1 and ≥2 episodes of CMV reactivation (4.9, 18.3 P=0.002, and 22.4 P=0.06). In addition, patients with ≥2 episodes of CMV had the lowest levels of the PS across groups (0 vs. 2.2% for ≥2 vs. 1 episode P=0.02). Similar trends were observed in IE-1 stimulated cells. Whereas T-cell depletion, aGVHD, lymphoid malignancy and CMV donor serostatus were not associated with risk of CMV in this small cohort, a NPS >10% was associated with increased risk of CMV reactivation (OR: 21, CI95 2-215; P=0.01) and need for treatment (OR: 14, CI95 1.5-137; P=0.02); and a PS >2% was associated with trend toward reduced risk of need for treatment (OR: 0.1, CI95 0.01-1.05; P=0.06). Multivariable modeling was not performed due to sample size. Time to event curves showed that high levels of NPS (>10%) predicted risk of CMV reactivation (log-rank P=0.0002). This remained true in analyses restricted to patients with CMV reactivation after day 30 (log-rank P=0.01). High levels of NPS or low levels of PS ( 18 graft products were available. As expected CMV-specific responses were not detected in grafts from CMV seronegative donors. Among the 9 CMV seropositive grafts, NPS expression was null across groups suggesting that the NPS is an immune phenotype that is absent in healthy donors; there was a stepwise decrease in the number of quadruple producer CD8+ T cells in CMV seropositive grafts for EC, SC and NC: 3.4 (n=3), 2 (n=4) and 0 (n=2), respectively, suggesting that donor PS might influence recipient reactivation. In conclusion, we have identified two novel CMV-specific CD8+ T cell cytokine signatures with robust predictive value for risk of CMV reactivation and need for treatment. These biomarkers might be useful in guiding clinical decision making in HCT recipients. Disclosures No relevant conflicts of interest to declare.

Mutations in the ERK pathway occur in approximately one-third of all human cancers and most often involve production of mutant RAS or BRAF. Several studies, including our own, have shown that mutations in the BRAF and RAS genes are generally mutually exclusive. This study was performed to determine the relative oncogenic potential of the BRAF and RAS oncogenes. BRAF(V600E)-, H-RAS(G12V)-, and N-RAS(Q61R)-transfected mouse embryonic fibroblasts (MEFs) that lack p53 (p53(-/-)) or contain mutations at codon 172 (p53(R172H) and p53(R172P)) were able to induce morphologically transformed foci in p53(-/-) and p53(R172H) MEFs but not in p53(R172P) MEFs. Interestingly, BRAF(V600E) was less potent than mutant H-RAS(G12V) or N-RAS(Q61R) was in cooperating with mutant p53 as the numbers and sizes of foci induced by BRAF(V600E) were significantly lower and smaller. In vitro growth characteristics and anchorage-independent growth of transfected MEFs corroborated the transformed phenotype, and in vivo tumorigenesis confirmed the results. These results indicate that mutant BRAF(V600E) is weakly oncogenic compared with mutant RAS and that they both cooperate with p53(-/-) and p53(R172H) but not with p53(R172P) in oncogenic transformation.

Background Practice-based research networks (PBRNs) are consortia of practices committed to improving clinical practice. They have become more common and include dental PBRNs. Few reports in the literature, however, have addressed the structure and function of dental PBRNs. Methods After initial development in Alabama, the Dental Practice-Based Research Network (DPBRN) now includes practitioner-investigators in seven U.S. states and three Scandinavian countries. Although most of the function and structure was developed at the inception of DPBRN, valuable input from practitioner-investigators has led to significant ongoing refinements. Results DPBRN practitioner-investigators have contributed to research at each stage of its development, leading to substantial improvements in study designs and customization of study protocols to their daily clinical practices. Practitioner-investigators also have helped refine the structure and function of DPBRN to foster the potential impact of research. Conclusions Practitioners from diverse settings are partnering with fellow practitioners and academics to improve daily clinical practice and meet the needs of clinicians and their patients in DPBRN. Practice Implications Dental PBRNs can improve clinical practice by engaging dentists in the development and implementation of studies that are of direct interest to them and their patients, and by incorporating findings from these studies into their daily clinical practice.

Prison-based research has been limited due to concern that prisoners may represent a vulnerable population secondary to possible coercion and limited capacity for voluntary informed consent. This study was designed to assess decisional capacity and susceptibility to coercion in prison research subjects. Subjects were 30 mentally ill prisoners and 30 healthy controls. The groups were compared on ability to provide informed consent to a hypothetical drug trial, susceptibility to possible coercion, neuropsychological functioning, and psychiatric symptoms. Results indicated that all controls and all but one of the prisoners demonstrated adequate capacity to consent to the hypothetical drug trial. However, when decisional capacity was measured quantitatively, prisoners performed significantly worse regarding two aspects of this ability. Regarding possible coercion, prisoners’ main reasons for participating in research included avoiding boredom, meeting someone new, appearing cooperative in hopes of being treated better, and helping society. Neuropsychological functioning was strongly positively correlated with decisional capacity and negatively correlated with susceptibility to possible coercion, whereas psychiatric symptoms were only weakly correlated with these variables. In conclusion, a very high percentage of particularly vulnerable, mentally ill prisoners demonstrated adequate capacity to consent to research. Lower scores on a quantitative measure of decisional capacity suggest that extra care should be taken during the consent process when working with these subjects. The reasons prisoners gave for participating in our research indicated that the prison setting may have influenced their decision to participate, but that they were not actually coerced into doing so. Despite serious past incidents, ethicists will need to consider the possibility that prisoners have become an overprotected population.

Background Cracked teeth are ubiquitous in the adult dentition. The objective of this study was to determine which patient traits and behaviors and external tooth and crack characteristics correlate with cracked teeth being symptomatic. Methods Dentists in The National Dental Practice-Based Research Network enrolled a convenience sample of patients each with a single, vital posterior tooth with at least 1 observable external crack in this observational study; they enrolled 2,975 cracked teeth from 209 practitioners. The authors collected data at the patient level, tooth level, and crack level. They used generalized estimating equations to obtain significant ( P Results Characteristics positively associated with cracked tooth symptoms, after adjusting for demographics, included patients who clenched, ground, or pressed their teeth together (OR, 1.30; 95% confidence interval [CI], 1.12-1.50), molars (OR, 1.58; 95% CI, 1.30-1.92), teeth with a wear facet through enamel (OR, 1.22; 95% CI, 1.01-1.40), carious lesions (OR, 1.31; 95% CI, 1.07-1.60), cracks that were on the distal surface of the tooth (OR, 1.31; 95% CI, 1.13-1.52), and cracks that blocked transilluminated light (OR, 1.31, 95% CI, 1.09-1.57). Teeth with stained cracks were negatively associated with having cracked tooth symptoms (OR, 0.68; 95% CI, 0.55-0.84). Conclusions The greatest likelihood of a cracked tooth being symptomatic was found when patients reported clenching or grinding their teeth and had a molar with a distal crack that blocked transilluminated light. Practical Implications This information can help inform dentists in the decision-making process regarding the prognosis for a cracked tooth.

Small DNA tumor viruses such as simian virus 40 (SV40) and polyomavirus (Py) take advantage of host cell proteins to transcribe and replicate their DNA. Interactions between the viral T antigens and host proteins result in cell transformation and tumor induction. Large T antigen of SV40 interacts with p53, pRb/p107/p130 family members, and the cyclic AMP-responsive element-binding protein (CREB)-binding protein (CBP)/p300. Py large T antigen is known to interact only with pRb and p300 among these proteins. Here we report that Py large T binds to CBP in vivo and in vitro. In co-transfection assays, Py large T inhibits the co-activation functions of CBP/p300 in CREB-mediated transactivation but not in NF-kappa B-mediated transactivation. p53 appears not to be involved in the functions of CREB-mediated transactivation and is not essential for large T:CBP interaction. Mutations introduced into a region of Py large T with homology to adenovirus E1A and SV40 large T prevent binding to the co-activators. These mutant large T antigens fail to inhibit CREB-mediated transactivation. The CBP/p300-binding Py mutants are able to transform established rat embryo fibroblasts but are restricted in their ability to induce tumors in the newborn mouse, indicating that interaction of large T with the co-activators may be essential for virus replication and spread in the intact host.

This article focuses on dental practice-based research networks (PBRNs) as one of the solutions to the oftentimes slow and inefficient process of translating research evidence into clinical practice. This article identifies two major issues that are faced when setting up a dental practice-based research network. Using a dental practice-based research network that the author is involved with as an example, this article then discusses what is involved in undertaking a research project in your office. Also discussed are the types of projects being done in this new setting and how this author believes these studies will be one of the bridges toward developing evidenced based dentistry in private practice.

Bilateral lesions centered in the posterodorsal amygdala of female rats resulted in hyperphagia and excessive weight gain (mean = 65.3 g in 20 days compared to 6.8 g for control animals). The brain damage always extended posteriorly into the ventral hippocampal formation. However, lesions that were confined to the ventral hippocampus or amygdalohippocampal area had no effect on daily food intake or body weight, nor did lesions at any other hippocampal site. In a previous study, lesions of the basolateral, corticomedial, and anterior groups of amygdaloid nuclei failed to affect food intake or body weight. It is concluded that the posterodorsal aspect of the amygdala is the critical site for this experimentally induced obesity syndrome. New coordinates for the effective site are presented.

Objectifs L’evaluation de l’efficience permet de comparer les couts et les consequences de strategies alternatives. Cet outil d’aide a la decision repose sur des modeles mathematiques qui requierent des donnees d’efficacite, de tolerance, de qualite de vie et de couts des technologies de sante evaluees. Cependant, la disponibilite et la qualite des donnees demeurent problematiques et contribuent a l’incertitude sur le resultat de l’efficience. L’utilisation des donnees individuelles des essais cliniques (evaluation ex. ante) ou d’etudes observationnelles et des donnees de cout collectees en vie reelle (evaluation ex. post) demeure le gold standard au regard des recommandations de la HAS en matiere d’evaluation medico-economique, mais l’acces a ces donnees reste difficile, d’ou le recours alternatif aux donnees agregees, moins precises mais souvent publiees et, aux dires d’experts, considerees comme etant moins robustes. Il semble donc opportun de s’interroger sur l’impact de l’utilisation des donnees d’efficacite et de tolerance (individuelles versus agregees) et de couts (estimees en vie reelle versus estimees lors des essais cliniques et/ou a dires d’experts) issues de differentes sources sur les resultats d’efficience. Cette etude vise a analyser cet impact avec une application dans le cancer du rein metastatique et le melanome metastatique. Methodes Une comparaison des resultats issus d’analyses cout-utilite reposant sur l’utilisation de jeux de donnees differents sera realisee : donnees individuelles d’efficacite issues des essais (scenario 1) versus donnees agregees d’efficacite disponibles dans la litterature (scenario 2) ; donnees de cout estimees en vie reelle (scenario 3) versus donnees de cout estimees lors des essais cliniques et completees par une analyse du PMSI et/ou de dires d’experts (scenario 4). Pour les deux pathologies d’interet, les donnees agregees d’efficacite seront collectees a travers une revue systematique de la litterature et les donnees individuelles seront collectees a partir des bases de donnees des essais cliniques mises en ligne sur un portail dedie. Les donnees de cout en vie reelle seront estimees a travers une analyse de la base Donnees de consommation inter-regimes (DCIR) d’Ile-de-France, les autres donnees de couts seront estimees a partir des donnees de consommation des ressources recueilles dans les essais cliniques et completees par une analyse PMSI et/ou de dires d’experts. Resultats L’acces aux donnees agregees d’efficacite ne presente pas de difficultes particulieres en dehors des biais de publication et des delais entre la disponibilite des donnees et leurs publications. En revanche et malgre la volonte des industriels et des pouvoirs publics de faciliter l’acces aux donnees individuelles des essais cliniques ou aux donnees de l’Assurance maladie pour les chercheurs, l’acces a ces donnees reste complexe et necessite une evaluation prealable du protocole de recherche ainsi que des delais importants d’instruction des dossiers. Par ailleurs, bien que le PMSI soit plus accessible, il ne comporte pas de donnees sur la consommation de ressources en ville. Conclusion L’acces aux donnees de sante dans un temps opportun demeure important pour l’evaluation medico-economique, notamment dans un domaine comme l’oncologie ou les avancees therapeutiques progressent vite, rendant l’evaluation medico-economique rapidement obsolete.

Results in a previous report established the presence of dominant genetic factor(s) in C3H/BiDa mice which contributed to the unusually high susceptibility of this strain to polyoma virus-induced tumors (Freund et al. (1992) Virology 191, 724-731). Here we show that C57BR/cdJ mice, while identical to C3H/BiDa at the H-2 locus, are almost completely lacking in susceptibility. Analysis of crosses between these two H-2 k strains has shown that susceptibility is due to a single dominant autosomal gene, designated Pyv S . On an H-2 k background, Pyv S acts in a highly penetrant manner to confer susceptibility to induction of a broad range of tumors by the virus. Analysis of F1 mice between C3H/BiDa and the highly resistant C57BL/6 (H-2 b ) strain shows that Pyv S can partially overcome the immunologically mediated resistance associated with an H-2 b haplotype. Pyv S does not encode cell receptors for the virus, nor does it affect levels of virus replication or anti-viral humoral responses in the host. Studies with early passage embryo fibroblasts in culture show that Pyv S does not affect intracellular events essential for either productive infection or cell transformation by the virus. Pyv S thus determines a generalized susceptibility of the host to polyoma-induced tumors but apparently does not act at the level of target cells for tumor induction.

A mutant strain of polyoma virus encoding a truncated middle T protein has been studied for its ability to replicate and induce tumors following inoculation into newborn mice. Virus replication in the acute period prior to expected onset of tumors as well as persistence of virus in older animals were followed. The mutant virus proved to be defective in replication and persistence and failed to induce tumors. These results demonstrate that middle T plays an essential role in productive viral infection in the animal. Since the mutant virus encodes normal large and small T proteins, the results also indicate that functions associated with these T antigens, including large T binding of the retinoblastoma tumor suppressor gene product and the ability to immortalize, are insufficient to cause development of tumors in this system.

• A retrospective analysis was performed using the French national hospital database (PMSI), an exhaustive hospital discharge database that covers all hospital stays in public and private hospitals in France. For each hospital stay, the PMSI provides a compilation of administrative data (i.e. age, gender, residence code) and medical data (i.e. diagnosis, medical procedures performed during hospital stays). Each hospital stay is then classified in a diagnosis related group (DRG) and can be linked to a patient using the unique patient identification number. • We extracted all hospital stays from 2007 to 2013 with the ICD-10 codes for both renal cell carcinoma (C64*) and metastasis (C77*, C78*,C79*). Among hospital stays for mRCC, we extracted incident cases identified by the absence of hospitalization for mRCC and the absence of metastasis in the previous year. Hospital stays for which the patient identification number was not adequately recorded as well as hospital stays that could not be classified into a DRG were excluded. Hospital stays for non incident cases and patients aged under 18 were also excluded. • Included patients were followed until death and data were censored on December 2013 for living patients. • Descriptive analysis were performed in terms of hospital stays and patients. • The cost of hospitalizations for mRCC was calculated from the perspective of the French national health insurance. For this purpose, the DRG tariffs for both public and private settings were used. Context & Objective • Kidney cancer accounts for approximately 3% of all cancers in France(1). In 2012, there were 11,573 new cases of kidney cancer and 3,957 deaths in France(2). • Renal cell carcinoma (RCC) accounts for 85% to 92% of kidney cancer cases (1,3–4). Approximately 25% to 30% of patients with RCC have metastasis at diagnosis and up to 50% of patients who undergo curative renal resection are likely to develop metastatic renal cell carcinoma (mRCC)(4).

Specific glycosylation inhibitors were used to show that N-glycans, and not O-glycans or glycolipids, constitute the major class of receptors on 3T3 cells for polyoma virus. Sialic acid (SA)-specific lectins were used in attempts to confirm the expected SA linkage on N-linked glycans. A lectin specific for α2,6 linked SA, a non-receptor type, was slightly more effective in blocking infection than a lectin specific for α2,3 linked SA which corresponds to the known receptor specificity. Possible explanations are suggested for this unexpected result.