Family Socioeconomic Status and Children's Screen Time.

Objective: This mixed-methods study examined whether higher-SES children's digital technology use adhered to contemporaneous pediatric guidelines, how it compared to lower-SES children, and why, as analyses showed, higher-SES children's technology use far exceeded pediatric recommendations. Background: 2013 American Academy of Pediatrics (AAP) guidelines recommended limited "screen time" for children. Higher socioeconomic status (SES) families tend to follow guidelines, but digital technology use-simultaneously a health behavior and a pathway for building human capital-has complex implications. Method: Quantitative analyses provide new nationally representative estimates of the relationship between social class and 9- to 13-year-old children's technology time (including television), device access, and parenting rules (2014 PSID Child Development Supplement, N=427). Qualitative analyses of 77 longitudinal higher-SES parent interviews articulated explanatory processes. Results: Higher-SES children used technology as frequently as others and in excess of recommendations. Their device access, activities, and agency in adhering to rules, however, differed from others. Qualitative analysis uncovered processes that helped explain these findings: parents' ambivalence about technology and perception that expert guidance is absent or unrealistic, and children's exercise of agency to use technology facilitated by "concerted cultivation" parenting styles, led to higher-SES individualistic parenting practices that supported children's increased non-television technology use. Conclusion: Cultures and structures related to children's technology use are in flux, and classed norms and understandings are emerging to construct relevant class-based distinctions around parenting.

Stapled ß-Hairpins Featuring 4-Mercaptoproline.

Peptides constrained by intramolecular cross-links, especially stapled α-helices, have emerged as versatile scaffolds for drug development. However, there are fewer examples of similarly constrained scaffolds for other secondary structures. Here, we used a novel computational strategy to identify an optimal staple for antiparallel ß-strands, and then we incorporated that staple within a ß-hairpin peptide. The hairpin uses 4-mercaptoproline as a novel staple component, which contributes to a unique, kinked structure. The stapled hairpins show a high degree of structure in aqueous solution, excellent resistance to degradation in cell lysates, and cytosolic penetration at micromolar concentrations. They also overlay with a unique subset of kinked hairpin motifs at protein-protein interaction interfaces. Thus, these scaffolds represent promising starting points for developing inhibitors of cellular protein-protein interactions.

"Healthier Than Just Healthy": Families Transmitting Health as Cultural Capital.

As the relationship between social class and health strengthens and socioeconomic and health inequalities widen, understanding how parents' socioeconomic advantage translates into health and class advantages in the next generation is increasingly important. Our analyses illustrate how a classed performance of "health" is a fundamental component of transmitting cultural capital in families and communities. Socially advantaged parents' health and class goals for children are often met simultaneously by building children's cultural capital in community-specific ways. This study uses observational, interview, and focus group data from families in two middle-class communities to illustrate how health-focused cultural capital acquisition plays out in everyday life. As parents manage children's lives to ensure future advantages, they often focus on health-related behaviors and performances as symbols of class-based distinction for their children. The synergy between family and community cultural capital is strengthening class and health advantages for some children, even as health-focused cultural capital often has drawbacks for stress and well-being. The intensification of and value placed on "health" in cultural capital may have long-term implications for health, socioeconomic attainment, and inequalities. If health-focused cultural capital continues to become increasingly salient for status attainment, its importance could grow, widening these gaps and reducing intergenerational mobility.

Stapled Peptide Inhibitors of Autophagy Adapter LC3B.

A growing body of evidence suggests that autophagy inhibition enhances the effectiveness of chemotherapy, especially in difficult-to-treat cancers. Existing autophagy inhibitors are primarily lysosomotropic agents. More specific autophagy inhibitors are highly sought-after. The microtubule-associated protein 1A/1B light chain 3B protein, LC3B, is an adapter protein that mediates key protein-protein interactions at several points in autophagy pathways. In this work, we used a known peptide ligand as a starting point to develop improved LC3B inhibitors. We obtained structure-activity relationships that quantify the binding contributions of peptide termini, individual charged residues, and hydrophobic interactions. Based on these data, we used artificial amino acids and diversity-oriented stapling to improve affinity and resistance to biological degradation, while maintaining or improving LC3B affinity and selectivity. These peptides represent the highest-affinity LC3B-selective ligands reported to date, and they will be useful tools for further elucidation of LC3B's role in autophagy and in cancer.

Overcoming Wnt-ß-catenin dependent anticancer therapy resistance in leukaemia stem cells.

Leukaemia stem cells (LSCs) underlie cancer therapy resistance but targeting these cells remains difficult. The Wnt-ß-catenin and PI3K-Akt pathways cooperate to promote tumorigenesis and resistance to therapy. In a mouse model in which both pathways are activated in stem and progenitor cells, LSCs expanded under chemotherapy-induced stress. Since Akt can activate ß-catenin, inhibiting this interaction might target therapy-resistant LSCs. High-throughput screening identified doxorubicin (DXR) as an inhibitor of the Akt-ß-catenin interaction at low doses. Here we repurposed DXR as a targeted inhibitor rather than a broadly cytotoxic chemotherapy. Targeted DXR reduced Akt-activated ß-catenin levels in chemoresistant LSCs and reduced LSC tumorigenic activity. Mechanistically, ß-catenin binds multiple immune-checkpoint gene loci, and targeted DXR treatment inhibited expression of multiple immune checkpoints specifically in LSCs, including PD-L1, TIM3 and CD24. Overall, LSCs exhibit distinct properties of immune resistance that are reduced by inhibiting Akt-activated ß-catenin. These findings suggest a strategy for overcoming cancer therapy resistance and immune escape.

Formulation and evaluation of itraconazole liposomes for Hedgehog pathway inhibition.

Itraconazole (ITZ) is an FDA-approved antifungal agent that has recently been explored for novel biological properties. In particular, ITZ was identified as a potent inhibitor of the hedgehog (Hh) pathway, a cell signalling pathway that has been linked to a variety of cancers and accounts for ∼25% of paediatric medulloblastoma (MB) cases. To date, there is not a targeted therapeutic option for paediatric MB, resulting in long-term side effects such as hormone deficiency, organ damage and secondary cancers. A primary obstacle for developing targeted therapy for brain ailments is the presence of the blood-brain barrier (BBB), which protects the brain from potentially harmful substances. Due to its size and hydrophobicity, ITZ does not penetrate the BBB. Alternatively, liposomes are being increasingly used within the clinic to increase drug bioavailability, target specificity and BBB permeability. With this in mind, we have successfully developed ITZ-containing liposomes with an optimal size for BBB penetration (<100 nm) and encapsulation efficiency (∼95%) by utilizing a continuous manufacturing approach-turbulent coaxial jet in co-flow. Our preliminary in vitro data demonstrate that these liposomes inhibit the Hh pathway, albeit at a reduced level in comparison to free ITZ. (196/250 words).

Structure-Activity Relationships for Itraconazole-Based Triazolone Analogues as Hedgehog Pathway Inhibitors.

The Food and Drug Administration-approved antifungal agent, itraconazole (ITZ), has been increasingly studied for its novel biological properties. In particular, ITZ inhibits the hedgehog (Hh) signaling pathway and has the potential to serve as an anticancer chemotherapeutic against several Hh-dependent malignancies. We have extended our studies on ITZ analogues as Hh pathway inhibitors through the design, synthesis, and evaluation of novel des-triazole ITZ analogues that incorporate modifications to the triazolone/side chain region of the scaffold. Our overall results suggest that the triazolone/side chain region can be replaced with various functionalities (hydrazine carboxamides and meta-substituted amides) resulting in improved potency when compared to ITZ. Our studies also indicate that the stereochemical orientation of the dioxolane ring is important for both potent Hh pathway inhibition and compound stability. Finally, our studies suggest that the ITZ scaffold can be successfully modified in terms of functionality and stereochemistry to further improve its anti-Hh potency and physicochemical properties.

Repurposing the Clinically Efficacious Antifungal Agent Itraconazole as an Anticancer Chemotherapeutic.

Itraconazole (ITZ) is an FDA-approved member of the triazole class of antifungal agents. Two recent drug repurposing screens identified ITZ as a promising anticancer chemotherapeutic that inhibits both the angiogenesis and hedgehog (Hh) signaling pathways. We have synthesized and evaluated first- and second-generation ITZ analogues for their anti-Hh and antiangiogenic activities to probe more fully the structural requirements for these anticancer properties. Our overall results suggest that the triazole functionality is required for ITZ-mediated inhibition of angiogenesis but that it is not essential for inhibition of Hh signaling. The synthesis and evaluation of stereochemically defined des-triazole ITZ analogues also provides key information as to the optimal configuration around the dioxolane ring of the ITZ scaffold. Finally, the results from our studies suggest that two distinct cellular mechanisms of action govern the anticancer properties of the ITZ scaffold.

Mutations in Hedgehog acyltransferase (Hhat) perturb Hedgehog signaling, resulting in severe acrania-holoprosencephaly-agnathia craniofacial defects.

Holoprosencephaly (HPE) is a failure of the forebrain to bifurcate and is the most common structural malformation of the embryonic brain. Mutations in SHH underlie most familial (17%) cases of HPE; and, consistent with this, Shh is expressed in midline embryonic cells and tissues and their derivatives that are affected in HPE. It has long been recognized that a graded series of facial anomalies occurs within the clinical spectrum of HPE, as HPE is often found in patients together with other malformations such as acrania, anencephaly, and agnathia. However, it is not known if these phenotypes arise through a common etiology and pathogenesis. Here we demonstrate for the first time using mouse models that Hedgehog acyltransferase (Hhat) loss-of-function leads to holoprosencephaly together with acrania and agnathia, which mimics the severe condition observed in humans. Hhat is required for post-translational palmitoylation of Hedgehog (Hh) proteins; and, in the absence of Hhat, Hh secretion from producing cells is diminished. We show through downregulation of the Hh receptor Ptch1 that loss of Hhat perturbs long-range Hh signaling, which in turn disrupts Fgf, Bmp and Erk signaling. Collectively, this leads to abnormal patterning and extensive apoptosis within the craniofacial primordial, together with defects in cartilage and bone differentiation. Therefore our work shows that Hhat loss-of-function underscrores HPE; but more importantly it provides a mechanism for the co-occurrence of acrania, holoprosencephaly, and agnathia. Future genetic studies should include HHAT as a potential candidate in the etiology and pathogenesis of HPE and its associated disorders.

Urethrectomy following cystectomy for bladder cancer in men: practice patterns and impact on survival.

PURPOSE: The benefit of urethrectomy in patients with bladder cancer who are undergoing cystectomy is controversial. We describe the frequency of urethrectomy by bladder cancer stage and identify clinical characteristics that predict urethrectomy. We also investigated whether urethrectomy offers any additional independent survival benefit. MATERIALS AND METHODS: A total of 2,401 men who underwent radical cystoprostatectomy between 1991 and 2002 were identified in the Surveillance, Epidemiology and End Results-Medicare database. A multivariate logistic regression model was used to analyze factors driving urethrectomy. We then analyzed the records of 195 men who underwent urethrectomy to find predictors of that procedure as salvage for urethral recurrence vs concurrently with cystoprostatectomy or as a staged procedure. Using multivariate Cox regression analysis we analyzed whether urethrectomy had an independent effect on disease specific survival. RESULTS: The only significant predictor of urethrectomy was stage. Patients at a teaching hospital were more likely to undergo salvage urethrectomy for recurrence vs immediate urethrectomy compared to those at urban nonteaching hospitals. Patient age, race, number of comorbidities and tumor stage were significant independent predictors of survival. Survival in men who underwent urethrectomy concurrently with cystoprostatectomy was higher than in those who did not undergo urethrectomy but not statistically significant (HR = 0.775, 95% CI 0.592-1.014, p = 0.0632). CONCLUSIONS: Disease stage is related to urethrectomy performance. Age, race, stage and comorbidities were independent predictors of overall survival in patients with bladder cancer undergoing cystectomy. Urethrectomy did not confer a significant independent survival benefit.

Economic evaluation of treatment strategies for benign prostatic hyperplasia--is medical therapy more costly in the long run?

PURPOSE: Although medical therapy for newly diagnosed benign prostatic hyperplasia is initially less expensive than surgery, to our knowledge the long-term costs of these treatments are unknown. We defined longer term costs of these treatment strategies. MATERIALS AND METHODS: We examined spending on benign prostatic hyperplasia related services by examining health care claims for a 5-year period subsequent to a new benign prostatic hyperplasia diagnosis. Expenditures for subjects treated initially with surgery were compared to expenditures for those with initial medical treatment. Expenditures were projected during longer periods and the net current value of these expenditures was calculated. RESULTS: Of the 970 subjects identified who received benign prostatic hyperplasia treatment 913 (94.1%) relied on medical therapy as initial treatment. Of those subjects 832 (91.1%) were on alpha-blockers. The secondary treatment rates for surgery far exceeded those for medical therapy (37% vs 8%). Average total expenditures were higher for subjects who initially received surgery ($12,699, 95% CI 9,865-15,533) than for those initially treated with medication ($2,193, 95% CI 1,959-2,428). If future streams of spending were discounted at standard rates (3%), the costs of initial medical therapy as a treatment strategy would always be lower than those of initial surgical therapy even at 40 years. CONCLUSIONS: In a cohort of privately insured men with newly diagnosed benign prostatic hyperplasia monotherapy with alpha-blockers was the most common initial treatment. Surgical therapy was associated with higher treatment failure rates and higher costs during 5 years. Increased expenditures related to initial surgical therapy were consistent when projected over long time frames.

True prevalence of urinary incontinence among female nursing home residents.

OBJECTIVES: Urinary incontinence is a significant problem in nursing home residents in the United States. Estimates of its prevalence have often been based on data from medical records obtained at nursing home admission. To measure the sensitivity of this method of defining the prevalence of urinary incontinence among female nursing home residents, we examined data from a clinical survey. METHODS: We analyzed data from the National Nursing Home Survey, which collected information from nursing homes for each resident concerning admission diagnoses, presence of an indwelling Foley catheter or ostomy, need for assistance from equipment or personnel in using the toilet, and difficulty controlling urination. RESULTS: Residents' medical records revealed a very low rate of admission diagnoses of incontinence. However, clinical queries revealed a high prevalence of bladder dysfunction. More than one half of all female nursing home residents were reported to have "difficulty controlling urination," and more than one half needed assistance in using the toilet. CONCLUSIONS: Although only 1% to 2% of nursing home residents have a diagnosis of urinary incontinence, the true prevalence of bladder dysfunction in this group is much greater. The sharp divergence of National Nursing Home Survey data from published studies on the prevalence of incontinence in nursing homes highlights the limitations of using administrative data to study the epidemiology of bladder dysfunction.

Predictors and prevalence of erectile dysfunction in a racially diverse population.

BACKGROUND: To our knowledge, the burden of disease attributed to erectile dysfunction (ED) has not been adequately quantified across a complete spectrum of age and race using a global disease definition, as recommended by the National Institutes of Health consensus statement. To obtain a better understanding of the national estimates of prevalence and risk factors for ED, we analyzed data from the 2001-2002 National Health and Nutrition Examination Survey. METHODS: The National Health and Nutrition Examination Survey collects data by household interview. The sample design is a stratified, multistage, probability sample of clusters of persons representing the civilian noninstitutionalized population. Data include medical histories in which specific queries are made regarding urological symptoms (including ED). These items were selected for analysis in 3566 men, 20 years and older. RESULTS: In men 20 years and older, ED affected almost 1 in 5 respondents. Hispanic men were more likely to report ED (odds ratio [OR], 1.89), after controlling for other factors. The prevalence of ED increased dramatically with advanced age; 77.5% of men 75 years and older were affected. In addition, there were several modifiable risk factors that were independently associated with ED, including diabetes mellitus (OR, 2.69), obesity (OR, 1.60), current smoking (OR, 1.74), and hypertension (OR, 1.56). CONCLUSIONS: The burden of ED on the US population is significant. Hispanic men had an elevated risk for ED, a finding that requires confirmation in prospective studies. Obesity, hypertension, smoking, and diabetes mellitus are significantly associated with ED risk. Mitigation of these risk factors may ameliorate the burden of ED.

Urologic diseases in America Project: analytical methods and principal findings.

PURPOSE: The burden of urological diseases on the American public is immense in human and financial terms but it has been under studied. We undertook a project, Urologic Diseases in America, to quantify the burden of urological diseases on the American public. MATERIALS AND METHODS: We identified public and private data sources that contain population based data on resource utilization by patients with benign and malignant urological conditions. Sources included the Centers for Medicare and Medicaid Services, National Center for Health Statistics, Medical Expenditure Panel Survey, National Health and Nutrition Examination Survey, Department of Veterans Affairs, National Association of Children's Hospitals and Related Institutions, and private data sets maintained by MarketScan Health and Productivity Management (MarketScan, Chichester, United Kingdom), Ingenix (Ingenix, Salt Lake City, Utah) and Center for Health Care Policy and Evaluation. Using diagnosis and procedure codes we described trends in the utilization of urological services. RESULTS: In 2000 urinary tract infections accounted for more than 6.8 million office visits and 1.3 million emergency room visits, and 245,000 hospitalizations in women with an annual cost of more than 2.4 billion dollars. Urinary tract infections accounted for more than 1.4 million office visits, 424,000 emergency room visits and 121,000 hospitalizations in men with an annual cost of more than 1 billion dollars. Benign prostatic hyperplasia was the primary diagnosis in more than 4.4 million office visits, 117,000 emergency room visits and 105,000 hospitalizations, accounting for 1.1 billion dollars in expenditures that year. Urolithiasis was the primary diagnosis for almost 2 million office visits, more than 600,000 emergency room visits, and more than 177,000 hospitalizations, totaling more than 2 billion dollars in annual expenditures. Urinary incontinence in women was the primary cause for more than 1.1 million office visits in 2000 and 452 million dollars in aggregate primary cause for more than 1.1 million office visits in 2000 and 452 million dollars in aggregate annual expenditures. Other manuscripts in this series present further detail for specific urologic conditions. CONCLUSIONS: Recent trends in epidemiology, practice patterns, resource utilization and costs for urological diseases have broad implications for quality of health care, access to care and the equitable allocation of scarce resources for clinical care and research.

Pharmacy benefits and the use of drugs by the chronically ill.

CONTEXT: Many health plans have instituted more cost sharing to discourage use of more expensive pharmaceuticals and to reduce drug spending. OBJECTIVE: To determine how changes in cost sharing affect use of the most commonly used drug classes among the privately insured and the chronically ill. DESIGN, SETTING, AND PARTICIPANTS: Retrospective US study conducted from 1997 to 2000, examining linked pharmacy claims data with health plan benefit designs from 30 employers and 52 health plans. Participants were 528,969 privately insured beneficiaries aged 18 to 64 years and enrolled from 1 to 4 years (960,791 person-years). MAIN OUTCOME MEASURE: Relative change in drug days supplied (per member, per year) when co-payments doubled in a prototypical drug benefit plan. RESULTS: Doubling co-payments was associated with reductions in use of 8 therapeutic classes. The largest decreases occurred for nonsteroidal anti-inflammatory drugs (NSAIDs) (45%) and antihistamines (44%). Reductions in overall days supplied of antihyperlipidemics (34%), antiulcerants (33%), antiasthmatics (32%), antihypertensives (26%), antidepressants (26%), and antidiabetics (25%) were also observed. Among patients diagnosed as having a chronic illness and receiving ongoing care, use was less responsive to co-payment changes. Use of antidepressants by depressed patients declined by 8%; use of antihypertensives by hypertensive patients decreased by 10%. Larger reductions were observed for arthritis patients taking NSAIDs (27%) and allergy patients taking antihistamines (31%). Patients with diabetes reduced their use of antidiabetes drugs by 23%. CONCLUSIONS: The use of medications such as antihistamines and NSAIDs, which are taken intermittently to treat symptoms, was sensitive to co-payment changes. Other medications--antihypertensive, antiasthmatic, antidepressant, antihyperlipidemic, antiulcerant, and antidiabetic agents--also demonstrated significant price responsiveness. The reduction in use of medications for individuals in ongoing care was more modest. Still, significant increases in co-payments raise concern about adverse health consequences because of the large price effects, especially among diabetic patients.

The effects of doxapram hydrochloride (dopram-V) on laryngeal function in healthy dogs.

Laryngeal dysfunction is assessed most accurately by direct visualization of the larynx under a light plane of anesthesia. If the plane of anesthesia used is too deep, laryngeal structures may appear paralyzed and remain in a paramedian position. Doxapram hydrochloride is a known respiratory stimulant. We hypothesized that doxapram would significantly increase intrinsic laryngeal motion in healthy anesthetized dogs. The goal of this study was to evaluate the effect of doxapram on the area of rima glottidis (RG) in healthy dogs. Thirty healthy dogs were studied. Dogs were premedicated with butorphanol tartrate (0.22 mg/kg IV), acepromazine maleate (0.05 mg/kg SC), and glycopyrrolate (0.005 mg/kg SC), followed by induction with propofol (4 mg/kg IV). Intrinsic laryngeal motion observed in each dog was recorded on videotape after induction. Doxapram then was administered (2.2 mg/kg IV) and respirations again were recorded. Representative breaths for each dog were photographed during 4 phases of respiration (inspiration at rest, inspiration with doxapram, expiration at rest, and expiration with doxapram). The area of the RG then was calculated by using a computer-assisted analysis program. Results of each category were compared by using a 1-way analysis of variance; P < or = .05 was considered significant. Doxapram visibly increased respiratory effort, and was associated with increased intrinsic laryngeal motion. Compared to the resting state, the area of the RG was significantly increased after doxapram administration during both inspiration and expiration. We propose the routine use of doxapram during laryngoscopy to increase intrinsic laryngeal motion and aid in the diagnosis of laryngeal dysfunction.