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Microglia are important players in surveillance and repair of the brain. Implanting an electrode into the cortex activates microglia, produces an inflammatory cascade, triggers the foreign body response, and opens the blood-brain barrier. These changes can impede intracortical brain-computer interfaces performance. Using two-photon imaging of implanted microelectrodes, we test the hypothesis that low-intensity pulsed ultrasound stimulation can reduce microglia-mediated neuroinflammation following the implantation of microelectrodes. In the first week of treatment, we found that low-intensity pulsed ultrasound stimulation increased microglia migration speed by 128%, enhanced microglia expansion area by 109%, and a reduction in microglial activation by 17%, indicating improved tissue healing and surveillance. Microglial coverage of the microelectrode was reduced by 50% and astrocytic scarring by 36% resulting in an increase in recording performance at chronic time. The data indicate that low-intensity pulsed ultrasound stimulation helps reduce the foreign body response around chronic intracortical microelectrodes., (© 2024. The Author(s).)

A series of activators of GCN2 (general control nonderepressible 2) kinase have been developed, leading to HC-7366, which has entered the clinic as an antitumor therapy. Optimization resulted in improved permeability compared to that of the original indazole hinge binding scaffold, while maintaining potency at GCN2 and selectivity over PERK (protein kinase RNA-like endoplasmic reticulum kinase). The improved ADME properties of this series led to robust in vivo compound exposure in both rats and mice, allowing HC-7366 to be dosed in xenograft models, demonstrating that activation of the GCN2 pathway by this compound leads to tumor growth inhibition.

Evasion of apoptosis is critical for the development and growth of tumors. The pro-survival protein myeloid cell leukemia 1 (Mcl-1) is an antiapoptotic member of the Bcl-2 family, associated with tumor aggressiveness, poor survival, and drug resistance. Development of Mcl-1 inhibitors implies blocking of protein-protein interactions, generally requiring a lengthy optimization process of large, complex molecules. Herein, we describe the use of DNA-encoded chemical library synthesis and screening to directly generate complex, yet conformationally privileged macrocyclic hits that serve as Mcl-1 inhibitors. By applying a conceptual combination of conformational analysis and structure-based design in combination with a robust synthetic platform allowing rapid analoging, we optimized in vitro potency of a lead series into the low nanomolar regime. Additionally, we demonstrate fine-tuning of the physicochemical properties of the macrocyclic compounds, resulting in the identification of lead candidates 57 / 59 with a balanced profile, which are suitable for future development toward therapeutic use.

Purpose: The integrated stress response (ISR) kinase PERK serves as a survival factor for both proliferative and dormant cancer cells. We aim to validate PERK inhibition as a new strategy to specifically eliminate solitary disseminated cancer cells (DCC) in secondary sites that eventually reawake and originate metastasis., Experimental Design: A novel clinical-grade PERK inhibitor (HC4) was tested in mouse syngeneic and PDX models that present quiescent/dormant DCCs or growth-arrested cancer cells in micro-metastatic lesions that upregulate ISR., Results: HC4 significantly blocks metastasis, by killing quiescent/slow-cycling ISRhigh, but not proliferative ISRlow DCCs. HC4 blocked expansion of established micro-metastasis that contained ISRhigh slow-cycling cells. Single-cell gene expression profiling and imaging revealed that a significant proportion of solitary DCCs in lungs were indeed dormant and displayed an unresolved ER stress as revealed by high expression of a PERK-regulated signature. In human breast cancer metastasis biopsies, GADD34 expression (PERK-regulated gene) and quiescence were positively correlated. HC4 effectively eradicated dormant bone marrow DCCs, which usually persist after rounds of therapies. Importantly, treatment with CDK4/6 inhibitors (to force a quiescent state) followed by HC4 further reduced metastatic burden. In HNSCC and HER2+ cancers HC4 caused cell death in dormant DCCs. In HER2+ tumors, PERK inhibition caused killing by reducing HER2 activity because of sub-optimal HER2 trafficking and phosphorylation in response to EGF., Conclusions: Our data identify PERK as a unique vulnerability in quiescent or slow-cycling ISRhigh DCCs. The use of PERK inhibitors may allow targeting of pre-existing or therapy-induced growth arrested "persister" cells that escape anti-proliferative therapies., (©2023 American Association for Cancer Research.)

Microglia are important players in surveillance and repair of the brain. Their activation mediates neuroinflammation caused by intracortical microelectrode implantation, which impedes the application of intracortical brain-computer interfaces (BCIs). While low-intensity pulsed ultrasound stimulation (LIPUS) can attenuate microglial activation, its potential to modulate the microglia-mediated neuroinflammation and enhance the bio-integration of microelectrodes remains insufficiently explored. We found that LIPUS increased microglia migration speed from 0.59±0.04 to 1.35±0.07 µm/hr on day 1 and enhanced microglia expansion area from 44.50±6.86 to 93.15±8.77 µm 2 /min on day 7, indicating improved tissue healing and surveillance. Furthermore, LIPUS reduced microglial activation by 17% on day 6, vessel-associated microglia ratio from 70.67±6.15 to 40.43±3.87% on day 7, and vessel diameter by 20% on day 28. Additionally, microglial coverage of the microelectrode was reduced by 50% in week 1, indicating better tissue-microelectrode integration. These data reveal that LIPUS helps resolve neuroinflammation around chronic intracortical microelectrodes.

Porcine islet xenotransplantation is a viable strategy to treat diabetes. Its translation has been limited by the pre-clinical development of a clinically available immunosuppressive regimen. We tested two clinically relevant induction agents in a non-human primate (NHP) islet xenotransplantation model to compare depletional versus nondepletional induction immunosuppression. Neonatal porcine islets were isolated from GKO or hCD46/GKO transgenic piglets and transplanted via portal vein infusion in diabetic rhesus macaques. Induction therapy consisted of either basiliximab (n = 6) or rhesus-specific anti-thymocyte globulin (rhATG, n = 6), combined with a maintenance regimen using B7 costimulation blockade, tacrolimus with a delayed transition to sirolimus, and mycophenolate mofetil. Xenografts were monitored by blood glucose levels and porcine C-peptide measurements. Of the six receiving basiliximab induction, engraftment was achieved in 4 with median graft survival of 14 days. All six receiving rhATG induction engrafted with significantly longer xenograft survival at 40.5 days (P = 0.03). These data suggest that depletional induction provides superior xenograft survival to nondepletional induction, in the setting of a costimulation blockade-based maintenance regimen., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

There is debate surrounding the appropriate threshold for lymph node harvest during esophagectomy in patients with esophageal cancer, specifically for those receiving preoperative radiation. The purpose of this study was to determine the impact of lymph node yield on survival in patients receiving preoperative chemoradiation for esophageal cancer. The National Cancer Database (NCDB) was utilized to identify patients with esophageal cancer that received preoperative radiation. The cohort was divided into patients undergoing minimal (<9) or extensive (≥9) lymph node yield. Demographic, operative, and postoperative outcomes were compared between the groups. Kaplan-Meier analysis with the log rank test was used to compare survival between the yield groups. Cox proportional hazards model was used to determine the association between lymph node yield and survival. In total, 886 cases were included: 349 (39%) belonging to the minimal node group and 537 (61%) to the extensive group. Unadjusted 5-year survival was similar between the minimal and extensive groups, respectively (37.3% vs. 38.8%; P > 0.05). After adjustment using Cox regression, extensive lymph node yield was associated with survival (hazard ratio 0.80, confidence interval 0.66-0.98, P = 0.03). This study suggests that extensive lymph node yield is advantageous for patients with esophageal cancer undergoing esophagectomy following induction therapy. This most likely reflects improved diagnosis and staging with extensive yield., (© The Author(s) 2020. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The activity of the secreted phosphodiesterase autotaxin produces the inflammatory signaling molecule LPA and has been associated with a number of human diseases including idiopathic pulmonary fibrosis (IPF). We screened a single DNA-encoded chemical library (DECL) of 225 million compounds and identified a series of potent inhibitors. Optimization of this series led to the discovery of compound 1 (X-165), a highly potent, selective, and bioavailable small molecule. Cocrystallization of compound 1 with human autotaxin demonstrated that it has a novel binding mode occupying both the hydrophobic pocket and a channel near the autotaxin active site. Compound 1 inhibited the production of LPA in human and mouse plasma at nanomolar levels and showed efficacy in a mouse model of human lung fibrosis. After successfully completing IND-enabling studies, compound 1 was approved by the FDA for a Phase I clinical trial. These results demonstrate that DECL hits can be readily optimized into clinical candidates.

Background: Existing research demonstrates superior short-term outcomes (length of stay, 1-year survival) after lung transplantation in patients with preoperative functional independence. The aim of this study was to determine whether advantages remain significant in the long-term., Methods: The United Network for Organ Sharing database was queried for adult, first-time, isolated lung transplantation records from January 2005 to December 2015. Stratification was performed based on Karnofsky Performance Status Score (3 groups) and on employment at the time of transplantation (2 groups). Kaplan-Meier and Cox analyses were performed to determine the association between these factors and survival in the long-term., Results: Of 16,497 patients meeting criteria, 1,581 (9.6%) were almost completely independent at the time of transplant vs 5,662 (34.3%) who were disabled (completely reliant on others for activities of daily living). Cox models adjusting for recipient, donor, and transplant factors demonstrated a statistically significant association between disability at the time of transplant and long-term death (hazard ratio, 1.26; 95% confidence interval, 1.14 to 1.40; p < 0.001). There were 15,931 patients with available data on paid employment at the time of transplantation. Multivariable analysis demonstrated a statistically significant association between employment at the time of transplantation and death (hazard ratio, 0.86; 95% confidence interval, 0.75 to 0.91; p < 0.001)., Conclusions: Preoperative functional independence and maintenance of employment are associated with superior long-term outcomes in lung recipients. The results highlight potential benefits of pretransplant functional rehabilitation for patients on the waiting list for lungs., (Copyright © 2018 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Septoplasty/septorhinoplasty is a common ear, nose and throat procedure offered for those patients with deviated septum who are suffering from nasal obstruction and functional or cosmetic problems. Although it is a basic and simple procedure, it could lead to catastrophic complications including major skull base injuries which result in cerebrospinal fluid (CSF) leaks. We describe two different cases of traumatic CSF leaks following septoplasty/septorhinoplasty at two different sites. The first patient suffered a CSF leak following septoplasty and presented to Alexandria University Hospital. The leak was still active at presentation and identified as coming from a defect in the roof of the sphenoid sinus and was repaired surgically. The second patient presented 4 days after her cosmetic septorhinoplasty with a CSF leak and significant pneumocephalus. She was managed conservatively. Understanding the anatomical variations of the paranasal sinuses and implementing proper surgical techniques are crucial in preventing intracranial complications when performing either septoplasty or septorhinoplasty. A good quality computed tomography of the nose and paranasal sinuses is a valuable investigation to avoid major complications especially CSF leaks following either procedure.

Recrudescence of latent and dormant viruses may lead to overwhelming viremia in immunosuppressed hosts. In immunocompromised hosts, Simian virus 40 (SV40) reactivation is known to cause nephritis and demyelinating central nervous system disease. Here, we report SV40 viremia leading to fatal interstitial pneumonia in an immunosuppressed host following renal allotransplantation., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Early activation of coagulation is an important factor in the initiation of innate immunity, as characterized by thrombotic microangiopathy (TMA). In transplantation, systemic anticoagulation is difficult due to bleeding. A novel "cytotopic" agent, thrombalexin (TLN), combines a cell-membrane-bound (myristoyl tail) anti-thrombin (hirudin-like peptide [HLL]), which can be perfused directly to the donor organ or cells. Thromboelastography was used to measure time to clot formation (r-time) in both rhesus and human blood, comparing TLN versus HLL (without cytotopic tail) versus negative control. Both TLN- and HLL-treated rhesus or human whole blood result in significantly prolonged r-time compared to kaolin controls. Only TLN-treated human endothelial cells and neonatal porcine islets prolonged time to clot formation. Detection of membrane-bound TLN was confirmed by immunohistochemistry and fluorescence activated cell sorter. In vivo, perfusion of a nonhuman primate kidney TLN-supplemented preservation solution in a sensitized model of transplantation demonstrated no evidence of TLN systemically. Histologically, TLN was shown to be present up to 4 days after transplantation. There was no platelet deposition, and TMA severity, as well as microvascular injury scores (glomerulitis + peritubular capillaritis), were less in the TLN-treated animals. Despite promising evidence of localized efficacy, no survival benefit was demonstrated., (© 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Man-made barriers are well known for their effects on ecosystems. Habitat fragmentation, for instance, is a recognised consequence of modern-day infrastructure. The aim of the present study was to investigate the diversity and abundance of tick species, as well as the risks of acquiring tick-borne infections in habitats adjacent to a freeway. Therefore, ixodid ticks were collected from the vegetation at two-week intervals (in the main tick season, from March to June) in eight habitats of different types (forest, grove, grassland) along both sides of a freeway. Ixodes ricinus females were molecularly screened for three species of tick-borne bacteria. In the study period, 887 ixodid ticks were collected. These included 704 I. ricinus (79.4%), 51 Dermacentor reticulatus (5.7%), 78 D. marginatus (8.8%), 35 Haemaphysalis inermis (3.9%) and 19 H. concinna (2.1%). There was no significant difference in the abundance of tick species between similar habitats separated by the freeway, except for the absence of Dermacentor spp. on one side. In I. ricinus females, the overall prevalence of Anaplasma phagocytophilum was low, and (in part due to this low rate) did not show significant difference between the two sides of the freeway. Rickettsia helvetica had significantly different overall prevalence between two distant habitats along the same side of the freeway (12.3% vs. 31.4%), but not between habitats on the opposite sides. Borrelia burgdorferi s.l. showed significantly different overall prevalence between habitats both on the same and on the opposite sides of the freeway (8.6-35.9%), and the difference was higher if relevant habitats were also separated by the freeway. Importantly, the prevalence rate of the Lyme disease agent was highest in a forested resting area of the freeway, and was significantly inversely proportional to the prevalence of A. phagocytophilum (taking into account all evaluated habitats), apparently related to deer population density. Prevalence rates of these bacteria also differed significantly on single sampling occasions between: (1) closely situated habitats of different types; (2) distant and either similar or different habitat types; and (3) habitats on the opposite sides of the freeway. In conclusion, the findings of the present study show that a fenced freeway may contribute to differences in tick species diversity and tick-borne pathogen prevalence along its two sides, and this effect is most likely a consequence of its barrier role preventing deer movements.

Costimulation blockade (CoB) via belatacept is a lower-morbidity alternative to calcineurin inhibitor (CNI)-based immunosuppression. However, it has higher rates of early acute rejection. These early rejections are mediated in part by memory T cells, which have reduced dependence on the pathway targeted by belatacept and increased adhesion molecule expression. One such molecule is leukocyte function antigen (LFA)-1. LFA-1 exists in two forms: a commonly expressed, low-affinity form and a transient, high-affinity form, expressed only during activation. We have shown that antibodies reactive with LFA-1 regardless of its configuration are effective in eliminating memory T cells but at the cost of impaired protective immunity. Here we test two novel agents, leukotoxin A and AL-579, each of which targets the high-affinity form of LFA-1, to determine whether this more precise targeting prevents belatacept-resistant rejection. Despite evidence of ex vivo and in vivo ligand-specific activity, neither agent when combined with belatacept proved superior to belatacept monotherapy. Leukotoxin A approached a ceiling of toxicity before efficacy, while AL-579 failed to significantly alter the peripheral immune response. These data, and prior studies, suggest that LFA-1 blockade may not be a suitable adjuvant agent for CoB-resistant rejection., (© 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.)

This research developed a single-score system to simplify and clarify decision-making in chemical alternatives assessment, accounting for uncertainty. Today, assessing alternatives to hazardous constituent chemicals is a difficult task-rather than comparing alternatives by a single definitive score, many independent toxicological variables must be considered at once, and data gaps are rampant. Thus, most hazard assessments are only comprehensible to toxicologists, but business leaders and politicians need simple scores to make decisions. In addition, they must balance hazard against other considerations, such as product functionality, and they must be aware of the high degrees of uncertainty in chemical hazard data. This research proposes a transparent, reproducible method to translate eighteen hazard endpoints into a simple numeric score with quantified uncertainty, alongside a similar product functionality score, to aid decisions between alternative products. The scoring method uses Clean Production Action's GreenScreen as a guide, but with a different method of score aggregation. It provides finer differentiation between scores than GreenScreen's four-point scale, and it displays uncertainty quantitatively in the final score. Displaying uncertainty also illustrates which alternatives are early in product development versus well-defined commercial products. This paper tested the proposed assessment method through a case study in the building industry, assessing alternatives to spray polyurethane foam insulation containing methylene diphenyl diisocyanate (MDI). The new hazard scoring method successfully identified trade-offs between different alternatives, showing finer resolution than GreenScreen Benchmarking. Sensitivity analysis showed that different weighting schemes in hazard scores had almost no effect on alternatives ranking, compared to uncertainty from data gaps., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

We determined the associations of HIV infection/CD4 count with markers of hepatocellular damage [elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT)] and liver synthetic function (decreased albumin) in HIV-infected (HIV(+)) antiretroviral therapy (ART)-naive and uninfected (HIV(-)) Rwandan women. In 2005, 710 HIV(+) ART-naive and 226 HIV(-) women enrolled in the Rwanda Women's Interassociation Study and Assessment. Liver enzymes were measured with abnormality defined as either AST or ALT ≥1.25 times the upper limit of normal. Low serum albumin level was defined as <3.5 g/dl. Multivariable logistic regression analysis identified independent predictors of elevated AST/ALT and low serum albumin. HIV(-) women had the lowest prevalence (6.6%) of abnormal AST/ALT, with the highest prevalence (16.4%) in HIV(+) women with CD4 <200 cells/μl (p=0.01). The odds of having serum albumin <3.5 g/dl was 5.7-fold higher in HIV(+) than HIV(-) women (OR=5.68, 95% CI: 3.32-9.71). The risk of low albumin decreased from low to high CD4 count, with OR=2.62, 95% CI: 1.66, 4.14 and OR=1.57, 95% CI: 1.01, 2.43 in HIV(+) women with a CD4 count <200 and 200-350 cells/μl, respectively vs. HIV(+) with CD4 >350 (p<0.001 and p<0.05 for all comparisons). Our findings suggest that HIV-associated liver damage may occur in ART-naive patients. Although liver abnormality prevalences in this cohort of HIV-infected Rwandan women are less than reported in developed countries, caution is needed for risk assessment measures to monitor and screen HIV-infected patients pre- and post-ART initiation in African clinical settings to curtail potential risks associated with HIV infection.

The school has been identified as a key setting to promote physical activity. The purpose of this study was to evaluate the effect of a classroom-based activity break on in-school step counts of primary school children. Data for 90 children (49 boys, 41 girls, 9.3 ± 1.4 years) from three Irish primary schools is presented. In each school one class was randomly assigned as the intervention group and another as controls. Children's step counts were measured for five consecutive days during school hours at baseline and follow-up. Teachers of the intervention classes led a 10 min activity break in the classroom each day (Bizzy Break!). Mean daily in-school steps for the intervention at baseline and follow-up were 5351 and 5054. Corresponding values for the control group were 5469 and 4246. There was a significant difference in the change in daily steps from baseline to follow-up between groups (p < .05). There was no evidence that girls and boys responded differently to the intervention (p > .05). Children participating in a daily 10 min classroom-based activity break undertake more physical activity during school hours than controls.

In a screen for thoracic malignancy-associated markers, thyroid stimulating hormone receptor (TSHR) was identified as a candidate as it binds to the previously-characterized lung cancer marker NKX2-1. We screened for mutations in all coding regions of the TSHR gene in 96 lung adenocarcinoma samples and their matched adjacent normal lung samples. We found one patient with a somatic mutation at codon 458 (exon 10), which is located at the transmembrane domain where most TSHR mutations have been found in thyroid-related diseases. This patient had lung adenocarcinoma with BAC (bronchioloalveolar carcinoma) features in the setting of a prior medical history significant for carotid stenosis and severe chronic obstructive pulmonary disease (COPD). In order to characterize the genetic features of TSHR in lung cancer, we checked for TSHR expression and copy number in the 96 lung cancer tissues. TSHR protein expression was generally overexpressed in multiple thoracic malignancies (adenocarcinoma, squamous cell carcinoma and malignant pleural mesothelioma) by immunohistochemistry. Our data suggest that aberrant TSHR function may contribute to lung cancer development or a subgroup of lung cancer with specific clinical phenotypes.

A case report describing an unusual complication following a 17-week elective termination of pregnancy in a pediatric patient that was managed laparoscopically., (Published by Elsevier Inc.)

Introduction: The IGF-1 receptor (IGF-1R) is a receptor tyrosine kinase and is well established as a key regulator of tumor cell growth and survival. There is also a growing body of data to support a role for the structurally and functionally related insulin receptor (IR) in human cancer. Bidirectional crosstalk between IGF-1R and IR is observed, where specific inhibition of either receptor confers a compensatory increase in the activity for the reciprocal receptor, therefore dual inhibition of both IGF-1R and IR may be important for optimal efficacy. The importance of IGF-1R and IR as targets in cancer is further underscored by their contribution to resistance against both cytotoxic and molecularly targeted anti-cancer therapeutics. Currently, both IGF-1R-neutralizing antibodies and small-molecule tyrosine kinase inhibitors of IGF-1R/IR are in clinical development., Areas Covered: The importance of IGF-1R and IR as cancer targets and how IGF-1R/IR inhibitors may sensitize tumor cells to the anti-proliferative and pro-apoptotic effects of other anti-tumor agents. The potential advantages of small molecule IGF-1R/IR inhibitors compared with IGF-1R-specific neutralizing antibodies, and the characteristics of small-molecule IGF-1R inhibitors that have entered clinical development., Expert Opinion: Because of compensatory crosstalk between IGF-1R and IR, dual IGF-1R and IR tyrosine kinase inhibitors may have superior anti-tumor activity compared to anti-IGF-1R specific antibodies. The clinical success for IGF-1R/IR inhibitors may ultimately be dependent upon our ability to correctly administer these agents to the right niche patient subpopulation using single agent therapy, when appropriate, or using the right combination therapy.

Comprehensive understanding of the transport and deposition of engineered nanoparticles (NPs) in subsurface is required to assess their potential negative impact on the environment. We studied the deposition behavior of functionalized quantum dot (QD) NPs (CdTe) in different types of sands (Accusand, ultrapure quartz, and iron-coated sand) at various solution ionic strengths (IS). The observed transport behavior in ultrapure quartz and iron-coated sand was consistent with conventional colloid deposition theories. However, our results from the Accusand column showed that deposition was minimal at the lowest IS (1mM) and increased significantly as the IS increased. The effluent breakthrough occurred with a delay, followed by a rapid rise to the maximum normalized concentration of unity. Negligible deposition in the column packed with ultrapure quartz sand (100mM) and Accusand (1mM) rules out the effect of straining and suggests the importance of surface charge heterogeneity in QD deposition in Accusand at higher IS. Data analyses further show that only a small fraction of sand surface area contributed in QD deposition even at the highest IS (100mM) tested. The observed delay in breakthrough curves of QDs was attributed to the fast diffusive mass transfer rate of QDs from bulk solution to the sand surface and QD mass transfer on the solid phase. Scanning electron microscopy (SEM) and energy-dispersive X-ray (EDX) analysis were used to examine the morphology and elemental composition of sand grains. It was observed that there were regions on the sand covered with layers of clay particles. EDX spectra collected from these regions revealed that Si and Al were the major elements suggesting that the clay particles were kaolinite. Additional batch experiments using gold NPs and SEM analysis were performed and it was observed that the gold NPs were only deposited on clay particles originally on the Accusand surface. After removing the clays from the sand surface, we observed negligible QD deposition even at 100mM IS. We proposed that nanoscale charge heterogeneities on clay particles on Accusand surface played a key role in QD deposition. It was shown that the value of solution IS determined the extent to which the local heterogeneities participated in particle deposition., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Over the past 2 decades, our increased understanding of tumor biology has resulted in the delivery of a new generation of molecularly targeted cancer drugs with greater efficacy and less toxicity. This understanding has also provided pharmaceutical and academic institutions with a greater appreciation for the complexities and challenges associated with discovering and developing molecularly targeted drugs. To deal with the complexities of tumor biology and the associated technologies needed to develop molecularly targeted drugs, there has been increased cooperation and collaboration between academic and pharmaceutical-industry researchers in a broader number of aspects of the drug discovery and development continuum, including structural biology and translational research. This collaborative effort has played a role in molecularly targeted drugs such as cetuximab, trastuzumab, imatinib, and new promising drug candidates such as OSI-906. Cooperative efforts by industry and academia have also provided important insights to optimize the use of such agents in the clinic. This review aims to emphasize the need for academic/industrial collaborations for success and efficiency through the drug discovery and development continuum, and will highlight several examples of collaborations between academic and industrial scientists that facilitated the development of molecularly targeted antitumor agents into the clinic., (2010 Mount Sinai School of Medicine.)

Purpose: To define the characteristics of effective mentor-protégé relationships in a Clinical Research Training Program (CRTP) and to assess the agreement among mentors and protégés regarding those attributes., Method: The authors administered an anonymous survey to protégés who completed the Albert Einstein College of Medicine's CRTP during its first seven years (2000-2006) and their mentors. Statements included aspects of mentoring thought to be important within the program, such as availability (Statement 1) and oversight of the thesis process (Statements 2-4). Additional statements were related both to career development (e.g., looking out for the best interests of the scholar and assisting in negotiations for a faculty position after program completion [Statements 5 and 6]) and to the expectation that the mentor would continue to be a resource for the protégé in years to come (Statement 7). The authors assessed overall agreement among mentors and protégés, using matched pair analysis., Results: Overall response was 70.7% (133/188), with fewer matched pairs (n = 50, 50%). Seventy-five percent of respondents agreed strongly or somewhat with all statements. Analysis indicated significant agreement with Statements 2, 4, 6, and 7. Median scores from protégés did not differ whether their mentor responded (paired) or not (unpaired); however, mentor-protégé pairs had significantly greater agreement with Statements 3-7 than unpaired mentors and protégés (P < .01)., Conclusions: Mentors and protégés seemed to agree that mentors within a CRTP demonstrated effective mentor attributes, including fostering a long-term relationship with the protégé.

Epidermal growth factor receptor (EGFR) and insulin-like growth factor-I receptor (IGF-IR) can cooperate to regulate tumor growth and survival, and synergistic growth inhibition has been reported for combined blockade of EGFR and IGF-IR. However, in preclinical models, only a subset of tumors exhibit high sensitivity to this combination, highlighting the potential need for patient selection to optimize clinical efficacy. Herein, we have characterized the molecular basis for cooperative growth inhibition upon dual EGFR and IGF-IR blockade and provide biomarkers that seem to differentiate response. We find for epithelial, but not for mesenchymal-like, tumor cells that Akt is controlled cooperatively by EGFR and IGF-IR. This correlates with synergistic apoptosis and growth inhibition in vitro and growth regression in vivo upon combined blockade of both receptors. We identified two molecular aspects contributing to synergy: (a) inhibition of EGFR or IGF-IR individually promotes activation of the reciprocal receptor; (b) inhibition of EGFR-directed mitogen-activated protein kinase (MAPK) shifts regulation of Akt from EGFR toward IGF-IR. Targeting the MAPK pathway through downstream MAPK/extracellular signal-regulated kinase kinase (MEK) antagonism similarly promoted IGF-driven pAkt and synergism with IGF-IR inhibition. Mechanistically, we find that inhibition of the MAPK pathway circumvents a negative feedback loop imposed on the IGF-IR- insulin receptor substrate 1 (IRS-1) signaling complex, a molecular scenario that parallels the negative feedback loop between mTOR-p70S6K and IRS-1 that mediates rapamycin-directed IGF-IR signaling. Collectively, these data show that resistance to inhibition of MEK, mTOR, and EGFR is associated with enhanced IGF-IR-directed Akt signaling, where all affect feedback loops converging at the level of IRS-1.

Introduction: A gap exists between asthma guidelines and actual care delivered. We developed an educational intervention using simulated physician-patient encounters as part of a project to improve asthma management by community-based primary care providers. We hypothesized that this type of skills-based interactive training would improve learners' care choices for simulated patients after training compared with their choices before training., Methods: After a pilot project was done on a small group of providers, a larger group of primary care providers (PCPs) was recruited to be trained with our interactive materials. The pilot session, with 39 providers, showed that the cases were felt to be appropriate, that the time allocated for discussion was adequate, that the models were useful, that the experience was educational, and that the experience captured their interest. Two subsequent training sessions were held with 240 PCPs. Participants completed a questionnaire to elicit perceived barriers and self-efficacy and then viewed a short simulated physician-patient dialogue. They then completed a set of scaled questions about treatment choices. This served as a pretest assessment. A similar simulation was then shown, and the group discussed their thoughts on diagnosis and treatment. Finally, they viewed another physician-patient interaction and responded to the same questions as posed for the pretest assessment; the responses before and after assessment were compared., Results: Following completion of the intervention, providers were significantly (p < 0.05) more likely to make use of controller medications, asthma equipment, and patient training. Significant (p < 0.05) increases were also seen in action plan development and the availability of office visits. Providers were significantly (p < 0.05) less likely to refer asthma patients to an emergency department or for hospitalization. Significant (p < 0.05) improvements were also seen in perceptions of self-efficacy and barriers to treatment. There were significant (p < 0.05) increases in learners' confidence about their own and patients' abilities to improve asthma care, and fewer barriers to asthma management were reported after the training., Discussion: This method of training resulted in learners showing a measurable improvement in their intent to follow guidelines as applied to simulated patients. An evaluation addressing actual patient outcomes will need to be done.

Monitoring of environmental contaminants in Canadian Arctic polar bears (Ursus maritimus) typically has used superficial adipose tissue samples collected as part of controlled native subsistence hunts. However, little attention has been paid to the compositional difference in contaminants that may exist among the major adipose depots that are routinely collected. To address this knowledge gap, we investigated the profiles and concentrations of chlorinated hydrocarbon contaminants (CHCs), including major polychlorinated biphenyl (PCB) congeners and organochlorine (OC) pesticides and metabolites, in six major adipose depots (i.e. superficial, inter-muscular and intra-abdominal regions) obtained from adult male polar bears in the vicinity of Resolute Bay, Canadian high Arctic. Concentrations and congener patterns of PCBs (20 congeners) and OCs (14 compounds; chlordanes and dichlorodiphenyltrichloroethanes and metabolites, chlorinated benzenes, hexachlorocyclohexane isomers, octachlorostyrene and dieldrin) were found to be relatively uniform throughout the adipose tissue of male polar bears. The only exception was the inter-muscular adipose depot from the cervical region, which was characterized, compared to other major depots routinely sampled, by lower proportions of higher-chlorinated and recalcitrant congeners such as CB170/190, 180, 194 and 206, and higher contribution of the lower-chlorinated PCBs, CB47, 74 and 99. No difference in the OC makeup and concentrations was found among the adipose depots investigated. In view of this, we conclude that the determination of CHCs in adipose tissue of polar bears from any major depots, with the potential exception of the fat under the neck muscles, would give a representative picture of the overall CHC composition and concentrations in polar bear fat for purpose of trend monitoring.

Study Objective: Exercise has the potential to improve the ability of a patient with cystic fibrosis (CF) to cope with the physical demands of everyday life, and may improve prognosis. The purpose of this study was to compare the effects of a home-based, semi-supervised, upper-body strength-training regimen with a similarly structured aerobic training regimen., Design: Data were collected during a 1-year randomized clinical trial., Setting: Counselors conducted in-home visits with the participants once per week for the first 8 weeks followed by monthly visits for the remainder of the study., Patients: Sixty-seven patients with CF, aged 8 to 18 years, participated in the trial., Intervention: Participants in both exercise conditions were encouraged to exercise at least three times per week for 1 year. Each child in the aerobic group was given a stair-stepping machine, and each child in the upper-body strength training group was given an upper-body-only weight-resistance machine., Measures and Results: Aerobic fitness, pulmonary function, quality of life, and strength were measured at baseline, at 6 months, and at 12 months. Strength training increased the maximum weight lifted for biceps curls significantly more than aerobic training (p < 0.02). However, this differential did not remain significant after control for increase in height. Both training procedures were associated with increased strength (p < 0.002) and physical work capacity (PWC) [p < 0.033]., Conclusions: We concluded that strength and aerobic training may increase upper-body strength, and that both types of training may increase PWC for children with CF. Future trials should be conducted with no-training control subjects and larger samples to increase statistical power.

Decisions about care at the end of life are not only influenced by doctor-patient-family relationships and physician practice, but also by institutional "culture." An institutional assessment of the quality of care provided to dying hospitalized patients was undertaken to characterize and identify factors influencing it and to find opportunities for improvement. An analysis of hospital data, three physician and nursing focus group discussions, structured review of records of targeted patients (61) who had an "expected death," and interviews with 31 surviving family members of the targeted patients served as the basis for an institutional needs assessment intended to precede the development of a quality improvement program to improve hospital care of patients at the end of life. Data were primarily gathered regarding older adults, including a significant number of nursing home residents. The assessment led to a methodology for developing a quality improvement program based upon feedback to physicians and nurses regarding the quality of end-of-life care.

Objectives: This report identifies trends in the number and rate of deaths due to law enforcement actions (International Classification of Diseases, Ninth Revision, category "legal intervention") in the United States., Methods: The Centers for Disease Control and Prevention's Compressed Mortality File was used to determine age-, race-, and sex-specific death rates due to legal intervention for the years 1979 through 1997., Results: Males account for nearly all deaths, with the death rate for Black males several times that of White males. For both Whites and Blacks, the highest rates of death were observed for ages 20 to 34. Death rates declined significantly from 1979 to 1988 and remained stable thereafter., Conclusions: While legal intervention is an uncommon cause of death, some subpopulations experience rates of death many times that of the US population as a whole.

We sought to describe the knowledge of, understanding of, and follow-up after atypical cervical cytology among low-income, urban women. Of 554 women who had an ASCUS or atypical Pap result in 1996,215 (39%) completed a telephone survey. Many (19%) had poor follow-up. Thirty percent of women denied ever being told of abnormal cytology; Spanish-speakers were more likely to be unaware (43.2% vs. 22.7%, p < .01) of abnormal cytology. Cancer fear was quite high, as were misconceptions regarding cause. Many women were unsatisfied with the information they received regarding their cytology.

Objectives: The main purpose of this study was to determine whether any clinical or demographic characteristics could identify adult female patients presenting to the emergency department (ED) with a history of domestic abuse. A second objective was to describe the frequency, types, and severity of this abuse., Methods: This study was a crosssectional survey of 611 women conducted in an academically-affiliated, urban ED. Domestic abuse was described as "recent" (within the preceding 12 months) or "lifetime" (recent or past). This included emotional, physical, and sexual abuse., Results: Recent (7.9%, n = 48) and lifetime (38%, n = 232) domestic abuse was reported. For recently abused women, violence had been severe (87.5%, n = 42) and was associated with 1) trauma (OR 5.4, 95% CI = 2.6 to 11.6), 2) obstetrical and gynecological syndromes (OR 5.6, 95% CI = 2.4 to 13.2), and 3) psychiatric symptoms and substance use (OR 7.3, 95% CI = 2.4 to 22.0). The sensitivities and positive predictive values of these risk factors individually (<27.1% and <25.0%, respectively) and in aggregate (56.3% and 20.9%, respectively) were low. These indicators predicted only 27 (56.3%) of recently abused women. Lifetime domestic violence was more likely in homeless women (OR 5.8, 95% CI = 2.2 to 15.0), although less likely in immigrants (OR 0.4, 95% CI = 0.3 to 0.7)., Conclusions: Clinical presentations and demographic characteristics of women presenting to the ED may not be sensitive or predictive indicators of domestic abuse. In the absence of typical clinical or demographic findings, asking all women in the ED about domestic abuse remains a necessary priority.

Objective: Our goals were to assess adherence to the National Cancer Institute clinical practice guideline for the management of atypical squamous cells of uncertain significance (ASCUS) Papanicolaou (Pap) test results in a community at high risk of cervical cancer. We also hoped to identify predictors of adherence to the guideline., Study Design: We used an historical cohort and collected data by chart abstraction., Population: Our study included women receiving care in 7 urban community health centers who had an initial ASCUS or atypical Pap test result in 1996. We excluded women with a history of cervical dysplasia or human immunodeficiency virus infection, yielding a final sample of 387 women., Outcomes: measured The outcome measured was the level of adherence to the guideline, defined as falling within 1 of 3 mutually exclusive categories (complete, moderate, or low)., Results: Care providers recommended colposcopy after an initial atypical Pap test result in 12% of cases and repeat cytology in 67%. Failure to document a plan for management was found in 19% of cases. Complete adherence was achieved for 27% of subjects, moderate adherence for 28%, and low adherence for 45%. The factors associated with complete versus moderate or low adherence included site of care, description of the abnormality (ASCUS vs atypia), availability of on-site colposcopy, and discussing the plan at a visit., Conclusions: Adherence with the National Cancer Institute clinical practice guideline in this setting was disappointing and varied substantially by site. Factors amenable to change that may improve follow-up include good communication of results with patients and providing colposcopy at the site of primary care.

Objective: To examine functioning during a dinner meal in families of a child with a chronic illness that requires dietary treatment recommendations, as compared to families of a child without a chronic illness., Methods: Ratings of seven dimensions of family functioning on the McMaster Mealtime Family Interaction Coding System (MICS) were obtained on 29 families of children with CF and 29 families of children with no chronic illness, ages 2 to 6 years, during a videotaped dinner meal at home., Results: Ratings of families with a child with CF were significantly lower than those for families of children without a chronic illness on Overall Family Functioning and five of the six MICS dimensions: Communication, Interpersonal Involvement, Affect Management, Behavior Control, and Role Allocation and approached significance on the Task Accomplishment dimension. The ratings of families of a child with CF were in the "clinically significant" range on all subcales, including Task ACCOMPLISHMENT., Conclusions: This study suggests that family functioning at mealtimes may be different in families of children with CF in which explicit dietary guidelines exist than in families of children with no illness or dietary guidelines. These results are discussed in terms of global family functioning and treatment approaches to dietary treatment recommendations.

Objectives: To assess prevalence of gun possession, attitudes regarding gun possession and gun violence, knowledge and influences of gun violence, and the potential role of physicians in gun violence prevention education among adolescents., Methods: An anonymous questionnaire was distributed to 9th through 12th grade high school students at 3 public high schools in New York City., Results: Three hundred forty-two surveys were distributed and returned. The prevalence of guns in the homes was 19.6%. Of respondents, 43.2% thought it was okay for anyone to have guns, and 57.3% had been injured or have had a relative injured by a gun. Although 11.6% of adolescents had felt the need to talk to an adult about guns, only 3.0% listed their physicians as one of these adults. However, if asked by their physician, 63.8% would discuss the issue with them. Only 5.7% of adolescents have had a physician speak to them about guns., Conclusions: The adolescent population surveyed is frequently exposed to gun violence. Although physicians rarely counsel adolescents regarding gun violence and firearm safety, many adolescents would be receptive to this mode of intervention.adolescence, attitude, firearm ownership, firearm violence, physician role.

Objective: To describe the differences in prevalence of tube feeding among states and to examine possible factors that could explain practice patterns., Design: Analysis of random samples from an interstate data bank comprised of the Minimum Data Set (MDS), a standardized, federally mandated assessment instrument for nursing home residents., Setting: Nursing homes in four states participating in a federal demonstration project of case mix payment plus five others with existing MDS data systems., Participants: Individuals 65 years of age and older (N = 57,029), who had very severe cognitive impairment, including total dependence in eating, and who resided in nursing homes during 1994, the most recent year for which uniform data were available., Measurements: State-by-state differences in prevalence of tube feeding, controlling for demographic and clinical variables., Results: The prevalence of tube feeding ranged from 7.5% in Maine to 40.1% in Mississippi. Each state had a significantly elevated prevalence of tube feeding compared with Maine, with odds ratios (ORs) ranging from 1.50 to 5.83, P < .001. Specific directives not to provide tube feeding (OR 0.41, P < .001), and white race (OR 0.45, P < .001) were strongly and negatively associated with tube feeding., Conclusions: Wide regional variations exist in the use of tube feeding of nursing home residents with equivalent impairments. Sociodemographic factors could be important, but more study is needed to determine whether physician characteristics, such as race, attitudes, or knowledge, have an impact and to clarify medical standards for the use of tube feeding in this population.

Context: Universal tuberculin skin testing of children has been shown to be costly and inefficient. In response, several authorities have recommended targeted screening based on epidemiological risk. In 1996, the New York City Department of Health (NYCDOH) developed questions to identify children who require a tuberculin skin test., Objective: To determine the sensitivity, specificity, and predictive validity of the NYCDOH tuberculosis risk assessment questionnaire., Design: Prospective criterion standard study in which tuberculin skin tests and the NYCDOH questionnaire were administered simultaneously between August 1996 and January 1998. Specific questions asked about contact with a tuberculosis case, birth in or travel to endemic areas, regular contact with high-risk adults, and human immunodeficiency virus infection in the child., Setting: Ambulatory clinic in South Bronx, New York, NY., Participants: Consecutive sample of 2920 children aged 1 to 18 years., Main Outcome Measures: Sensitivity, specificity, positive and negative predictive values of the questionnaire, and odds ratio (OR) of reactive skin test results., Results: The NYCDOH questionnaire identified 413 children (14%) as having at least 1 risk factor. Of these, 23 (5.6%) had a positive skin test result; 4 (0.16%) of the 2507 without risk factors had a positive result. Results for the full NYCDOH questionnaire were sensitivity, 85.2%; specificity, 86.0%; negative predictive value, 99.8%; positive predictive value, 5.4%; and OR, 35.2 (95% confidence interval, 12.1-102.4)., Conclusion: The NYCDOH questionnaire is a valid instrument for identifying children for tuberculin skin testing.

Objectives: We investigated the hypothesis that children with cystic fibrosis (CF) and their parents would show more maladaptive behaviors during dinner than children without CF and their parents., Study Design: Children with CF (n = 32) and their parents were compared with 29 children without CF and their parents on the rate and frequency of parent-child behaviors during a typical dinner in the families' homes by using multivariate analyses of variance., Results: When the rate of behavior, controlling for meal length, was examined, no differences were found between groups. However, parents of children with CF were found to differ from parents of control subjects in the frequency of direct and indirect commands (P <.05), coaxes (P <.01), physical prompts (P <.01), and feeding their child (P <.05). Children with CF were found to engage in more talk, spend more time away from the table, refuse food, and exhibit more noncompliance toward commands to eat than control children (P <.05 for all child variables). When behaviors were examined as a function of meal phase, parents of children with and without CF both showed an increase in commands (P <.01), coaxes (P <.05), feeds (P <.01), and physical prompts (P <.01) in the second half of the meal as compared with the first. Children with CF and the control children showed an increase in behaviors incompatible with eating during the second half of the meal compared with the first (P <.01). When faster eaters were compared with slower eaters, faster eaters consumed a higher percentage of the recommended daily allowance of energy (P <.01) than slower eaters and showed a trend to be at higher weight percentiles for age and sex (P =.08) regardless of group (CF or control)., Conclusions: Children with CF and their parents do not differ from children without CF and their parents in the rate of behaviors exhibited or types of strategies used to encourage eating. However, children with CF and their parents engage in these behaviors more frequently. Our data do not support typical parenting behaviors as effective in meeting the CF dietary requirements. Additional support in the form of child behavior management training may be needed to assist parents in meeting their child's caloric requirements.

Study Objectives: To assess the validity of purified protein derivative (PPD) readings by patients and trained health-care professionals as compared with a calibrated model., Design and Participants: Survey of a group of patients, nurses, medical assistants, and physicians at five neighborhood health centers in the Bronx, NY., Interventions: Participants were asked to read a calibrated model with four PPD indurations measuring 0 mm, 3 mm, 7 mm, and 13 mm. Indurations > or = 5 mm were to be considered "positive" reactions., Measurements and Results: Data were obtained from 233 patients and 80 trained professionals. All patients correctly measured the 0-mm induration site and were able to detect the presence of an induration in 99.3% of possible observations. Compared with professionals, patients had more variability in measurements and interpretations of the 3-, 7-, and 13-mm sites. Professionals detected 100% of all indurations. Patients' specificity for the 0- and 3-mm sites was 97.4% and 62.7%, respectively; whereas sensitivity for the 7- and 13-mm sites was 68.2% and 89.3%, respectively. Professionals' specificity for the 0- and 3-mm sites was 98.7% and 65.3%, respectively; their sensitivity for the 7- and 13-mm sites was 86.7% and 97.3%, respectively. Seventy percent of professionals agreed that the model was a realistic representation of PPD indurations., Conclusions: Patients can reliably distinguish between the presence and absence of an induration at a PPD injection site. They are not as reliable in the measurement and interpretation of test reactions. Professionals had considerable variability in their assessments of PPDs but were more precise overall in their assessments than patients.

The objective of this study was to determine whether rates of eye disease among the elderly are higher for residents of nursing homes than for persons who reside elsewhere. Articles reporting the prevalence of eye disease in geriatric populations (classified as nursing home or non-nursing home) were identified through a Medline search and a search of articles' bibliographies. Identified articles were reviewed, and the relevant data compared with prevalence rates obtained from 738 residents of two nursing homes in New York City. Each of the nursing home residents received an ocular examination upon admission that determined the presence or absence of four varieties of eye disease-i.e. cataracts, age-related macular degeneration, glaucoma, and diabetic retinopathy. Demographic data were obtained through chart review. Results indicate that prevalence rates of eye disease found in geriatric nursing home populations are generally higher than those found in other geriatric populations. With the exception of the rates for diabetic retinopathy, the rates found in the combined nursing home population sampled in this study were much higher than those reported in any previous study. It is concluded that eye disease is a more serious problem for elderly residents of nursing homes than for the elderly who reside in the community. Possible reasons for this are discussed.

Objective: To determine factors predictive of failure to return for colposcopy among women with significant abnormalities on Papanicolaou smears in a high-risk clinical population., Design: Telephone survey., Setting: An urban community health center., Participants: Two hundred seventy-nine women randomly selected from all women seen at the health center with abnormal Papanicolaou smears requiring colposcopy during 1993 to 1994. Six (2%) refused participation, and 19% could not be reached for inclusion. Subjects were mostly minority women receiving Medicaid., Main Outcome Measure: Completion of colposcopy., Results: Of the 279 selected women, 79% were interviewed. The rate of adherence with colposcopy was 75% for the respondents. Women who did not know the results of their smear or who incorrectly understood their results were significantly less likely to return for colposcopy (P = .001). Younger women, especially teenagers, were less likely to return (P = .02). Socioeconomic status, education, primary language, health beliefs, fear of cancer, and clinician's gender or discipline were not associated with rate of follow-up. Barriers involving transportation, child care, and insurance also did not predict follow-up., Conclusions: Effective communication of results is the most important factor related to follow-up after abnormal Papanicolaou smear in this setting. In other settings, other factors may be of greater importance.

Background: Advance directives have not been uniformly used by different segments of the US population and studies have consistently shown a lower prevalence of advance directives among African Americans and Hispanics compared with non-Hispanic whites., Objective: To examine barriers to completion of health care proxies for different ethnic groups., Methods: One hundred ninety-seven subjects aged 65 years or older self-identified as African American (n = 65), Hispanic (n = 65), or non-Hispanic white (n = 67) attending a geriatrics and internal medicine outpatient clinic of a large New York City teaching hospital were administered a questionnaire. Questionnaires were developed to examine potential barriers to completion of health care proxies. Barriers were drawn from the literature and from focus groups., Results: Significant predictors of proxy completion using logistic regression analysis included knowledge of health care proxies, availability of a health care agent, exposure to mechanical ventilation, age, and self-reported health status as fair to poor. Subjects who believed that a health care agent was irrelevant in the setting of involved family were significantly less likely to have completed a health care proxy. Although there were significant differences in the baseline completion rates of health care proxies for the 3 ethnic groups, ethnicity did not predict prior appointment of a health care agent in multivariate analysis., Conclusions: Differences in health care proxy completion rates across white, African American, and Hispanic elderly individuals in this New York City population seem to be related to potentially reversible barriers such as lack of knowledge and the perceived irrelevance of advance directives in the setting of involved family. Enhanced educational efforts of both health care personnel and patients could increase the rate of formal health care proxy appointment.

Background and Objectives: Clinicians in community health centers find it difficult to balance the demands of increased productivity and effective teaching. We hypothesized that precepting third-year students would decrease clinical productivity and that many elements related to the quality of the learning experience (e.g., amount of patient contact, student autonomy) would be adversely affected by pressure to see increasing numbers of patients., Methods: Students and preceptors in a 6-week family medicine clerkship completed daily surveys that measured the presence of quantifiable elements of the ambulatory teaching experience. They also rated the overall quality of learning during each session., Results: For 62 sessions for which both students and preceptors completed evaluations, students rated the overall quality of learning more highly than preceptors. For students, the elements most positively associated with quality of learning were total teaching time and the frequency with which family issues were raised. For preceptors, the elements that predicted quality of learning were the number of patients that students saw independently and total teaching time. The clinical productivity of preceptors did not differ for sessions with and without a student., Conclusions: Preceptors can be effective teachers who encourage student autonomy and who model behaviors central to family practice, without decreasing productivity.

Many people on the waiting list for organ donation die each year without receiving organs. The shortage of organs is even more pronounced in minority communities. Despite the fact that minorities are at higher risk, they may be less likely to support or consent to organ donation. This investigation was undertaken to study racial factors in organ donation, by focusing on differences in awareness, attitudes, and behavior. Three family practice centers in the Bronx with racially diverse but socioeconomically homogenous communities were studied. The study population consisted of a convenience sample of 163 patients who were approached for participation while they waited to see a doctor. Respondents filled out a 25-item survey that measured demographic information; their exposure to, awareness of, and attitudes toward organ donation; and whether they had signed an organ donor card. The results demonstrated overwhelming support for organ donation across all racial groups. Racial differences were found on awareness of and attitudes toward organ donation, and in the signing of organ donation cards. In contrast to other studies, racial minorities were not less likely than whites to support organ donation. These results suggest that making it easier for racial minorities to obtain organ donor cards could increase their rates of consenting to donate organs.

Study Objective: To investigate calorie intake, behavioral eating styles, and parent perception of eating behavior of school-age children with cystic fibrosis (CF) compared with healthy peers., Design: A two-group comparison study., Setting: A clinical sample of 28 school-age children with CF and a community sample of 28 healthy peers matched for age (6 to 12 years) and socioeconomic status., Measurements and Main Results: The children with CF consumed more calories per day (2175 cal/d) than the control children (1875 cal/d) and achieved a significantly higher recommended daily allowance (RDA) of energy (128% of the RDA) than the control children (91.61% of the RDA). Fifty-four percent of the CF sample were achieving the CF dietary recommendations of 120% of the RDA. Despite this energy intake, the CF sample was significantly below the control sample on weight (24.56 vs 31.23 kg), height (125.48 vs 133.06 cm), and z score for weight (-0.811 vs 0.528) and height (-0.797 vs 0.371). On measures of behavioral eating style, the CF sample had significantly longer meals (23.90 min) than the control sample (17.34 min) and had a significantly slower pace of eating (43.27% 10-second intervals with bites) than the control sample (51.29% 10-second intervals with bites) but did not differ significantly on the number of calories consumed during dinner. On a measure of parent report of mealtime behaviors, parents of the children with CF rated mealtime behavior problems of "dawdles" and "refuses food" as more intense (mean, 3. 46) than did the parents of control children (mean, 2.67). For the CF sample, a significant correlation was found between the parent intensity ratings of problem behavior in general and meal duration (r = .48), and a significant negative correlation was found between the parent intensity ratings of problem mealtime behaviors and the percentage of intervals with bites (pace of meal) (r = -.533)., Conclusions: Although the school-age children with CF were consuming more calories per day than their healthy peers, and more than 50% of the children in the CF sample were at or above the CF dietary recommendations, the children in the CF sample were significantly below the control children on measures of weight and height. The behavioral data suggest that increased caloric intake is not without cost, because the CF sample spent an additional 7 minutes per day at dinner and ate their meals at a slower pace than their healthy peers. These data were associated with higher intensity ratings of mealtime behaviors by parents of children with CF. These findings point to the need for individualized assessment of energy needs for school-age children with CF and comprehensive programs that teach parents behavioral strategies to motivate their children to meet these higher energy requirements in an adaptive manner.

The diastereoselectivities of several chiral acylnitroso dienophiles (9a-h, 12 and 15) derived from optically pure, N-protected alpha-amino hydroxamic acids (2a-h, 4 and 7) were determined in an intermolecular hetero Diels-Alder reaction with cyclopentadiene. The diastereomeric excesses ranged from 0 to 72%. Hydroxamic acids with polar functionality were examined extensively to determine the effect of hydrogen bonding on the cycloaddition. The largest increase in diastereoselectivity was observed with increasing the steric bulk at the alpha-position of the hydroxamic acids and not with potential hydrogen bonding interactions. The cycloadditions afforded synthetically useful quantities of functionally rich, enantiomerically pure heterocycles (10a-h, 11a-h, 13, 14, 16 and 17), which have been elaborated into a variety of biologically interesting products.