Impact of oral abrocitinib on signs, symptoms and quality of life among adolescents with moderate-to-severe atopic dermatitis: an analysis of patient-reported outcomes.

BACKGROUND: A significant improvement in clinical signs was demonstrated with abrocitinib relative to placebo in adolescents with moderate-to-severe atopic dermatitis (AD) in three phase 3, randomized, double-blinded, placebo-controlled studies (JADE TEEN [ClinicalTrials.gov, NCT03796676], JADE MONO-1 [NCT03349060] and JADE MONO-2 [NCT03575871]). OBJECTIVES: To evaluate the impact of abrocitinib on patient-reported signs/symptoms, including sleep loss and quality of life among adolescents with moderate-to-severe AD. METHODS: JADE TEEN, JADE MONO-1 and JADE MONO-2 were conducted in the Asia-Pacific region, Europe and North America and included patients aged 12-17 years with moderate-to-severe AD and inadequate response to ≥ 4 consecutive weeks of topical medication or treatment with systemic therapy for AD. Patients were randomly assigned (1 : 1 : 1, JADE TEEN; 2 : 2 : 1, JADE MONO-1/-2) to receive once-daily oral abrocitinib (200 or 100 mg) or placebo for 12 weeks in combination with topical therapy (JADE TEEN) or as monotherapy (JADE MONO-1/-2). Data from adolescent patients in JADE MONO-1/-2 were pooled for these analyses. RESULTS: At week 12, more adolescents treated with abrocitinib (200 or 100 mg) vs. placebo achieved a ≥ 4-point improvement from baseline in the Patient-Oriented Eczema Measure in JADE TEEN (83.9% and 77.0% vs. 60.2%) and JADE MONO-1/-2 (83.0% and 69.4% vs. 43.5%) and a ≥ 6-point improvement from baseline in the Children's Dermatology Life Quality Index in JADE TEEN (73.8% and 67.5% vs. 56.5%) and JADE MONO-1/-2 (70.0% and 57.1% vs. 19.0%). Significant improvements in SCORing Atopic Dermatitis Visual Analog Scale for sleep loss scores were demonstrated with abrocitinib vs. placebo at weeks 2-12 in JADE TEEN and JADE MONO-1/-2. CONCLUSIONS: Patient-reported signs/symptoms, including reduction of sleep loss and quality of life, were substantially improved with abrocitinib monotherapy or combination therapy relative to placebo in adolescents with moderate-to-severe AD.

Patient-reported outcomes from the JADE COMPARE randomized phase 3 study of abrocitinib in adults with moderate-to-severe atopic dermatitis.

BACKGROUND: In JADE COMPARE, abrocitinib improved severity of atopic dermatitis (AD) and demonstrated rapid itch relief. OBJECTIVES: We examined clinically meaningful improvements in selected patient-reported outcomes (PROs). METHODS: JADE COMPARE was a multicentre, phase 3 randomized, double-blind, placebo-controlled trial. Adults with moderate-to-severe AD were randomized 2:2:2:1 to receive 16 weeks of oral abrocitinib 200 or 100 mg once daily, dupilumab 300 mg subcutaneous injection every 2 weeks, or placebo, with background topical therapy. PROs included Dermatology Life Quality Index (DLQI), Patient-Oriented Eczema Measure (POEM), Night Time Itch Scale (NTIS), Pruritus and Symptoms Assessment for Atopic Dermatitis, Patient Global Assessment, SCORing Atopic Dermatitis, and Hospital Anxiety and Depression Scale. RESULTS: At week 16, the proportion of patients achieving POEM scores <3 was 21.3% and 11.7% for 200 and 100 mg abrocitinib, 12.4% for dupilumab, and 4.8% for placebo (vs. abrocitinib, P < 0.0001 and P = 0.04). Proportion achieving ≥4-point improvement from baseline in NTIS severity was 64.3% and 52.4% for 200 and 100 mg abrocitinib, 54.0% for dupilumab, and 34.4% for placebo (vs. abrocitinib, P < 0.0001 and P = 0.007). Proportion achieving ≥4-point improvement from baseline in DLQI was 85.0% and 74.4% for 200 and 100 mg abrocitinib, 83.4% for dupilumab, and 59.7% for placebo (vs. abrocitinib, P < 0.0001 and P = 0.005). CONCLUSION: Significant improvements in PROs were demonstrated with both abrocitinib doses vs. placebo, and abrocitinib 200 mg provided numerically greater effects compared with dupilumab in patients with moderate-to-severe AD.

Long-term cost and complications of surgery in patients with ulcerative colitis: a claims data analysis.

OBJECTIVES: Use claims data to assess healthcare resource utilization (HCRU) and cost for patients with ulcerative colitis (UC) who had surgery and patients who did not. METHODS: UC patients from a German health insurance were included between 01/01/2010-31/12/2017. Patients with proctocolectomy or colectomy between 01/07/2010 and 31/12/2014 were identified, and surgery date was set as index. For patients with IPAA, the last surgery in the 6 months was taken as index. Non-surgery patients received random index. After propensity score matching, UC-related HCRU and cost were observed for three years post-index. RESULTS: Of 21,392 UC patients, 85 underwent surgery and 2655 did not. After matching, 76 were included in the surgery group and 114 in the non-surgery group. Matched cohorts did not differ in baseline characteristics and mortality rates where high in both groups (21.1% and 29.0%, respectively). The percentage of patients with at least one hospitalization in the follow-up period was higher in the surgery (53.9%) compared to the non-surgery group (25.4%, p<0.001). In contrast, the number of outpatient prescriptions of UC-related drugs in the non-surgery group (11.2) was almost twice as large as in the surgery group (5.8, p<0.001). Hospitalization cost was 4.6 times higher in the surgery (1955.5€) than in the non-surgery group (419.6€, p<0.001). Medication cost was three times higher in the non-surgery group (6519€) compared to the surgery group (2151.7€, p<0.001). CONCLUSIONS: Based on hospitalizations, outpatient visits, and medical treatment, results show a considerable patient burden in UC from surgery complications or disease exacerbation in case of colectomy.

Comparative efficacy and safety of systemic therapies used in moderate-to-severe atopic dermatitis: a systematic literature review and network meta-analysis.

Given the lack of head-to-head studies of systemic therapies in moderate-to-severe atopic dermatitis (AD), network meta-analyses (NMAs) can provide comparative efficacy and safety data to inform clinical decision-making. In this NMA, eligible randomized controlled trials (RCTs) published before 24 October 2019 were identified by a systematic literature review. Short-term (12-16 weeks) efficacy (Investigator's Global Assessment [IGA] and Eczema Area and Severity Index [EASI] responses), patient-reported outcomes (PROs) and safety data from each trial were abstracted and analysed separately for monotherapy and combination therapy (systemic plus topical anti-inflammatory therapy). RCTs were analysed in fixed-effects and random-effects Bayesian NMA models. Overall, 19 phase 2 and phase 3 RCTs of abrocitinib, baricitinib, dupilumab, lebrikizumab, nemolizumab, tralokinumab and upadacitinib were included. In monotherapy RCTs, upadacitinib 30 mg once daily (QD) had the numerically highest efficacy (83.6% achieved ≥50% improvement in EASI [EASI-50 response]), followed by abrocitinib 200 mg QD (74.6%), upadacitinib 15 mg QD (70.5%), dupilumab 300 mg every 2 weeks (Q2W) (63.4%) and abrocitinib 100 mg QD (56.7%). Similar trends in EASI-75 and EASI-90 response were observed. In combination therapy RCTs, abrocitinib 200 mg QD had the highest EASI-50 (86.6%), followed by dupilumab 300 mg Q2W (82.4%) and abrocitinib 100 mg QD (79.7%). Similar findings were observed for IGA response and PROs. In monotherapy and combination therapy RCTs, the probability of treatment-emergent adverse events (TEAEs) was higher among all active treatments than with placebo (except for dupilumab 300 mg Q2W [odds ratio (OR), 0.96; 95% credible interval (CrI), 0.45-2.18] and abrocitinib 100 mg QD [OR, 0.95; 95% CrI, 0.35-2.66] in combination therapy RCTs), although active treatments did not significantly differ from one another. Abrocitinib, dupilumab and upadacitinib were consistently the most effective systemic therapies in adult and adolescent patients with AD, with no significant TEAE differences in short-term RCTs.

Characteristics Associated with Treatment Response and Satisfaction in Women Undergoing OnabotulinumtoxinA and Sacral Neuromodulation for Refractory Urgency Urinary Incontinence.

PURPOSE: We sought to identify clinical and demographic characteristics associated with treatment response and satisfaction in women undergoing onabotulinumtoxinA and sacral neuromodulation therapies. MATERIALS AND METHODS: We analyzed data from the ROSETTA (Refractory Overactive Bladder: Sacral NEuromodulation versus BoTulinum Toxin Assessment) trial. Baseline participant characteristics and clinical variables were associated with 2 definitions of treatment response, including 1) a reduction in mean daily urgency incontinence episodes during 6 months and 2) a 50% or greater decrease in urgency incontinence episodes across 6 months. The OAB-S (Overactive Bladder-Satisfaction) questionnaire was used to assess satisfaction. RESULTS: A greater reduction in mean daily urgency incontinence episodes was associated with higher HUI-3 (Health Utility Index-3) scores in the onabotulinumtoxinA group and higher baseline incontinence episodes (each p <0.001) in the 2 groups. Increased age was associated with a lesser decrease in incontinence episodes in the 2 groups (p <0.001). Increasing body mass index (adjusted OR 0.82/5 points, 95% CI 0.70-0.96) was associated with reduced achievement of a 50% or greater decrease in incontinence episodes after each treatment. Greater age (adjusted OR 0.44/10 years, 95% CI 0.30-0.65) and a higher functional comorbidity index (adjusted OR 0.84/1 point, 95% CI 0.71-0.99) were associated with reduced achievement of a 50% or greater decrease in urgency incontinence episodes in the onabotulinumtoxinA group only (p <0.001 and 0.041, respectively). In the onabotulinumtoxinA group increased satisfaction was noted with higher HUI-3 score (p = 0.002) but there was less satisfaction with higher age (p = 0.001). CONCLUSIONS: Older women with multiple comorbidities, and decreased functional and health related quality of life had decreased treatment response and satisfaction with onabotulinumtoxinA compared to sacral neuromodulation for refractory urgency incontinence.

Computational and Experimental Study of Thermodynamics of the Reaction of Titania and Water at High Temperatures.

Gaseous titanium hydroxide and oxyhydroxide species were studied with quantum chemical methods. The results are used in conjunction with an experimental transpiration study of titanium dioxide (TiO2) in water vapor-containing environments at elevated temperatures to provide a thermodynamic description of the Ti(OH)4(g) and TiO(OH)2(g) species. The geometry and harmonic vibrational frequencies of these species were computed using the coupled-cluster singles and doubles method with a perturbative correction for connected triple substitutions [CCSD(T)]. For the OH bending and rotation, the B3LYP density functional theory was used to compute corrections to the harmonic approximations. These results were combined to determine the enthalpy of formation. Experimentally, the transpiration method was used with water contents from 0 to 76 mol % in oxygen or argon carrier gases for 20-250 h exposure times at 1473-1673 K. Results indicate that oxygen is not a key contributor to volatilization, and the primary reaction for volatilization in this temperature range is TiO2(s) + H2O(g) = TiO(OH)2(g). Data were analyzed with both the second and third law methods using the thermal functions derived from the theoretical calculations. The third law enthalpy of formation at 298.15 K for TiO(OH)2(g) at 298 K was -838.9 ± 6.5 kJ/mol, which compares favorably to the theoretical calculation of -838.7 ± 25 kJ/mol. We recommend the experimentally derived third law enthalpy of formation at 298.15 K for TiO(OH)2, the computed entropy of 320.67 J/mol·K, and the computed heat capacity [149.192 + (-0.02539)T + (8.28697 × 10-6)T2 + (-15614.05)/T + (-5.2182 × 10-11)/T2] J/mol-K, where T is the temperature in K.

STI/HIV Sexual Risk Behavior and Prevalent STI Among Incarcerated African American Men in Committed Partnerships: The Significance of Poverty, Mood Disorders, and Substance Use.

African Americans face disproportionate sexually transmitted infection including HIV (STI/HIV), with those passing through a correctional facility at heightened risk. There is a need to identify modifiable STI/HIV risk factors among incarcerated African Americans. Project DISRUPT is a cohort study of incarcerated African American men recruited from September 2011 through January 2014 from prisons in North Carolina who were in committed partnerships with women at prison entry (N = 207). During the baseline (in-prison) study visit, participants responded to a risk behavior survey and provided a urine specimen, which was tested for STIs. Substantial proportions reported multiple partnerships (42 %), concurrent partnerships (33 %), and buying sex (11 %) in the 6 months before incarceration, and 9 % tested positive for an STI at baseline (chlamydia: 5.3 %, gonorrhea: 0.5 %, trichomoniasis: 4.9 %). Poverty and depression appeared to be strongly associated with sexual risk behaviors. Substance use was linked to prevalent STI, with binge drinking the strongest independent risk factor (adjusted odds ratio: 3.79, 95 % CI 1.19-12.04). There is a continued need for improved prison-based STI testing, treatment, and prevention education as well as mental health and substance use diagnosis.

Long-term agroecosystem research in the central Mississippi river basin: introduction, establishment, and overview.

Many challenges currently facing agriculture require long-term data on landscape-scale hydrologic responses to weather, such as from the Goodwater Creek Experimental Watershed (GCEW), located in northeastern Missouri, USA. This watershed is prone to surface runoff despite shallow slopes, as a result of a significant smectitic clay layer 30 to 50 cm deep that restricts downward flow of water and gives rise to a periodic perched water table. This paper is the first in a series that documents the database developed from GCEW. The objectives of this paper are to (i) establish the context of long-term data and the federal infrastructure that provides it, (ii) describe the GCEW/ Central Mississippi River Basin (CMRB) establishment and the geophysical and anthropogenic context, (iii) summarize in brief the collected research results published using data from within GCEW, (iv) describe the series of papers this work introduces, and (v) identify knowledge gaps and research needs. The rationale for the collection derives from converging trends in data from long-term research, integration of multiple disciplines, and increasing public awareness of increasingly larger problems. The outcome of those trends includes being selected as the CMRB site in the USDA-ARS Long-Term Agro-Ecosystem Research (LTAR) network. Research needs include quantifying watershed scale fluxes of N, P, K, sediment, and energy, accounting for fluxes involving forest, livestock, and anthropogenic sources, scaling from near-term point-scale results to increasingly long and broad scales, and considering whole-system interactions. This special section informs the scientific community about this database and provides support for its future use in research to solve natural resource problems important to US agricultural, environmental, and science policy.

Universal pre-mixing dry-film stickers capable of retrofitting existing microfluidics.

Integrating microfluidic mixers into lab-on-a-chip devices remains challenging yet important for numerous applications including dilutions, extractions, addition of reagents or drugs, and particle synthesis. High-efficiency mixers utilize large or intricate geometries that are difficult to manufacture and co-implement with lab-on-a-chip processes, leading to cumbersome two-chip solutions. We present a universal dry-film microfluidic mixing sticker that can retrofit pre-existing microfluidics and maintain high mixing performance over a range of Reynolds numbers and input mixing ratios. To attach our pre-mixing sticker module, remove the backing material and press the sticker onto an existing microfluidic/substrate. Our innovation centers around the multilayer use of laser-cut commercially available silicone-adhesive-coated polymer sheets as microfluidic layers to create geometrically complex, easy to assemble designs that can be adhered to a variety of surfaces, namely, existing microfluidic devices. Our approach enabled us to assemble the traditional yet difficult to manufacture "F-mixer" in minutes and conceptually extend this design to create a novel space-saving spiral F-mixer. Computational fluid dynamic simulations and experimental results confirmed that both designs maintained high performance for 0.1 < Re < 10 and disparate input mixing ratios of 1:10. We tested the integration of our system by using the pre-mixer to fluorescently tag proteins encapsulated in an existing microfluidic. When integrated with another microfluidic, our pre-mixing sticker successfully combined primary and secondary antibodies to fluorescently tag micropatterned proteins with high spatial uniformity, unlike a traditional pre-mixing "T-mixer" sticker. Given the ease of this technology, we anticipate numerous applications for point-of-care devices, microphysiological-systems-on-a-chip, and microfluidic-based biomedical research.

Evaluation of direct workers' compensation costs for musculoskeletal injuries surrounding interventions to reduce patient lifting.

OBJECTIVES: We evaluated costs for workers' compensation (WC) injuries of a musculoskeletal (MS) nature in a large tertiary care hospital and an affiliated community hospital in the 13 years surrounding an institution-wide shift to a 'minimal manual patient-lifting environment' supported with inpatient mechanical lift equipment. METHODS: Negative binomial regression was used to model adjusted and discounted payment rates based on full-time equivalents (FTEs), and payment ratios. The risk of higher cost was assessed based on type of injury (patient-handling vs non-patient-handling), hospital, job, age, gender, institutional tenure and time since the implementation of lift equipment. Lagging was used to evaluate the latency of the intervention effect. RESULTS: Patient-handling injuries (n=1543) were responsible for 72% of MS injuries and 53% of compensation costs among patient care staff. Mean costs per claim were 5 times higher for those over age 45 than those <25 years of age. Physical and occupational therapy aides had the highest cost rates ($578/FTE) followed by nursing aides ($347/FTE) and patient transporters ($185/FTE). There was an immediate, marked decline in mean costs per claim and costs per FTE following the policy change and delivery of lift equipment. CONCLUSIONS: The observed patterns of changes in cost likely reflect the effects of activities other than use of lift equipment, including targeted efforts to close WC claims and an almost simultaneous policy that shifted cost responsibility to the budgets of managers on individual units. Inference was facilitated through the use of longitudinal data on the workgroups and an internal injury comparison.

Artelon as a Bio-Scaffold to Augment Collateral Ligament Repair after Knee Dislocation.

Introduction: Knee dislocations (KD) have high rates of multi-ligamentous injury (MLI). Collateral ligaments rupture in 50-60% of KDs. Traditionally, collateral ligaments have undergone primary repair, though microscopic healing is not optimal. Artelon is a degradable, polyurethane urea bio-scaffold thought to decrease mechanical forces and promote healing, motion, and strength. Currently, little evidence exists regarding its indications or outcomes. Material and methods: Thirty-two patients with KD and MLI undergoing collateral ligament repair at a level-I trauma centre between 2015-2020 were included. Patients age <18, with ipsilateral fractures or inadequate follow-up were excluded. The Artelon (AG) and primary ligamentous repair group (PR) each included 16 patients. Injury and perioperative variables were evaluated using SPSS® . Results: Thirty-two KDs were included in 32 patients, with 60% anterior. There were no significant differences between the two cohorts demographically or with regards to the type or severity of injury sustained. Meniscal pathology was addressed in 14 patients in both groups. Thirty-eight percent of all patients lacked >15° of knee flexion. Only one gross failure occurred, in the AG. No differences were noted in infection or re-operation. Lysholm Knee Scale and Tegner Activity Scale were not significantly different, although Tegner scores in both cohorts decreased from pre-injury scores. Conclusions: In summary, Artelon appears to be safe without increasing risk for hypersensitivity or infection when used for collateral ligament augmentation. Additionally, Artelon appeared to be non-inferior and statistically equivalent to primary repair in this setting and may have promise with use in certain types of knee dislocations.

Proprotein Convertase Subtilisin Kexin 9 (PCSK9) and nonHDL particles rise during normal pregnancy and differ by BMI.

BACKGROUND: Serum lipids, including total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-c), increase during pregnancy. Serum Proprotein Convertase Subtilisin Kexin 9 (PCSK9) is a vital regulator in lipoprotein metabolism. Circulating PCSK9 downregulates the LDL receptor on the surface of liver cells inhibiting clearance of LDL-c. OBJECTIVE: To determine the influence of weeks of pregnancy and obesity on circulating levels of essential lipid lipoproteins and PCSK9 in women with normal, uncomplicated pregnancies and deliveries. METHODS: We performed a comprehensive lipid and lipoprotein profile during each trimester of pregnancy in 70 mostly Caucasian women with uncomplicated normal pregnancies and deliveries. Based on their first trimester BMI, we placed them into one of three categories: (<25 kg/m2 n=23, 25-30 kg/m2 n=25, or >30 n=22) kg/m2. Cholesterol, triglycerides, LDL cholesterol (LDL-c), non-HDL particles, and lipoprotein(a) were measured by spectrophotometry, ion mobility, and immunoturbidimetric assays. Elisa assay determined PCSK9 (active and total). Homeostatic Model Assessment (HOMA-IR) assessed insulin resistance in the second and third trimesters of pregnancy. RESULTS: Total and active PCSK9, LDL-c, and nonHDL particle concentrations were higher than reported for non-pregnant normal values, increased after the first trimester of pregnancy, and were highest from mid-gestation to the last trimester of pregnancy in the overweight and the obese. CONCLUSION: PCSK9 levels rise as normal pregnancy progresses. Levels are higher in persons who are obese, even after adjustment for insulin resistance. Defining normal PCSK9 levels during pregnancy must adjust for gestational age and BMI.

Changes in hippocampal GABAA/cBZR density during limbic epileptogenesis: relationship to cell loss and mossy fibre sprouting.

Reduced GABA(A)/central benzodiazepine receptor (GABA(A)/cBZR) density, mossy fibre sprouting (MFS) and hippocampal cell loss are well described pathological features of human temporal lobe epilepsy (TLE), and animal models thereof. However, the temporal relationship of their development, and their roles in the emergence of the epilepsy, are uncertain. This was investigated in the kainic acid (KA)-induced post-status epilepticus (SE) model of TLE. Male Wistar rats (7 weeks, n=53) were randomised into control and KA groups. At 24h, 2, 4 or 6 weeks sham and KA post-SE animals were euthanised, brains extracted and GABA(A)/cBZR density, neuronal loss and MFS measured in hippocampal sub-regions. GABA(A)/cBZR density (B(max)) was measured by saturation-binding analysis using [(3)H]-flumazenil. At 24h post-SE GABA(A)/cBZR density was increased in almost all hippocampal subregions, but was decreased at the later time points with the exception of the dentate gyrus. There was significant neuronal loss in the CA3 SPc region (-24 ± 9.3%, p<0.05) at 24h, which remained stable at the later time points associated with an elevated GABA(A)/cBZR density per surviving neuron at 24h post-SE (+56.4%; p<0.05) which returned to control levels by 6 weeks post-SE. MFS in the dentate gyrus progressively increased over the 6 weeks following SE (+70.6% at 6 weeks), at which time there was a significant inverse relationship with GABA(A)/cBZR binding (r(2)=0.87; p=0.02). The temporal evolution of GABA(A)/cBZR density changes post-KA-induced SE, and the relationship with decreases in hippocampal pyramidal cell numbers and MFS, may point to a key role for these changes in the pathogenesis of acquired limbic epileptogenesis.

Cost-effectiveness of single-use negative-pressure therapy compared with standard care for prevention of reconstruction failure in prepectoral breast reconstruction.

BACKGROUND: Single-use negative-pressure wound therapy (sNPWT) has been reported to reduce the incidence of reconstruction failure in prepectoral breast reconstruction compared with standard surgical dressings. The aim of this economic evaluation was to investigate the cost-effectiveness of sNPWT compared with standard care for the prevention of reconstruction failure in prepectoral breast reconstruction in the UK. METHOD: A decision tree model was used to estimate the expected cost and effectiveness per patient. Effectiveness was measured both by the number of reconstruction failures avoided and the gain in quality-adjusted life-years (QALYs). The baseline incidence of reconstruction failure (8.6 per cent) was taken from a recently published study of 2655 mastectomies in the UK. The effectiveness of sNPWT used results from a clinical study comparing sNPWT with standard dressings. Previously published utility weights were applied. The cost of reconstruction failure was estimated from detailed resource data from patients with reconstruction failure, applying National Health Service reference costs. One-way, probabilistic, scenario and threshold analyses were conducted. RESULTS: The undiscounted cost per patient associated with reconstruction failure was estimated to be £23 628 (£22 431 discounted). The use of sNPWT was associated with an expected cost saving of £1706 per patient, an expected increase in QALYs of 0.0187 and an expected 0.0834 reconstruction failures avoided. Cost-effectiveness acceptability analysis demonstrated that, at a threshold of £20 000 per QALY, 99.94 per cent of the simulations showed sNPWT to be more cost-effective than standard care. CONCLUSION: Among patients undergoing immediate prepectoral breast reconstruction, the use of sNPWT is more cost-effective than standard dressings.

Implementing the National Academy's Vision and Strategy for Toxicity Testing: opportunities and challenges under the U.S. Toxic Substances Control Act.

In 2007, the U.S. National Academy of Sciences, National Research Council (NRC), issued the report Toxicity Testing in the 21st Century: A Vision and a Strategy. This report, which was commissioned by the U.S. Environmental Protection Agency (EPA), called for the U.S. EPA to develop a new approach for how this agency evaluates the toxicity of compounds. The report recommended that the agency move from its current testing system, which is based largely on traditional toxicology, to a testing system that is based primarily on human cell lines and in vitro systems. Successful implementation of the report's vision and strategy will require that scientists, lawyers, and policymakers work together to bridge the gap among disciplines. An important step in building this bridge requires an analysis of the U.S. legal system that frames toxicity testing. If the U.S. laws, regulations, and policies erect barriers that would prevent or impede the U.S. EPA adoption of the NRC vision and strategy, it is important to identify these challenges. At the same time, if existing laws, regulations, and policies are fertile ground for these recommendations, opportunities should be documented. This article discusses and evaluates the challenges and opportunities that arise under key provisions of one major U.S. toxics law, the Toxics Substances Control Act (TSCA).

Treatment of tarsal joint deformities with hinged transarticular external fixators in three young birds.

Pelvic limb deformities are common in many avian species. Three young birds, including a six-week-old Cockatoo and two three-month-old goslings, were presented with tarsal joint deformities. They were treated with an experimental prototype of a hinged linear external fixator, placed in a transarticular fashion, in order to maintain joint function during treatment. All birds had close to normal leg function at six to ten weeks postoperatively. These results suggest that the hinged external fixator may be a viable treatment option for tarsal joint deformities in young birds.

The zebrafish glypican knypek controls cell polarity during gastrulation movements of convergent extension.

Mutations in the zebrafish knypek locus impair gastrulation movements of convergent extension that narrow embryonic body and elongate it from head to tail. We demonstrate that knypek regulates cellular movements but not cell fate specification. Convergent extension movement defects in knypek are associated with abnormal cell polarity, as mutant cells fail to elongate and align medio-laterally. Positional cloning reveals that knypek encodes a member of the glypican family of heparan sulfate proteoglycans. Double mutant and overexpression analyses show that Knypek potentiates Wnt11 signaling, mediating convergent extension. These studies provide experimental and genetic evidence that glypican Knypek acts during vertebrate gastrulation as a positive modulator of noncanonical Wnt signaling to establish polarized cell behaviors underlying convergent extension movements.

Double labeling with [3H]thymidine and [125I]iododeoxyuridine as a method for determining the fate of injected DNA and cells in vivo.

Mice were injected intravenously and intraperitoneally with preparations of intestinal nucleoprotein, spleen nuclei, mouse thymus cells, or human kidney T cells whose DNA had been labeled with both [3H]thymidine (TdR) and [125I]-iododeoxyuridine (IUdR). Since free TdR is reutilized more efficiently than free IUdR produced by enzymic hydrolysis of the exogenous DNA, the ratio of [3H]TdR/[125I]IUdR in the DNA fraction of the tissues of the recipient mice provides a measure of the amount of intact exogenous DNA in the tissue. In most instances, the doubly labeled exogenous DNA was almost completely hydrolyzed within 1 day injection, but survival of the DNA from whole cells could be demonstrated in some cases.

Discussion effects on racial attitudes.

We predicted that discussion would enhance dominant group values, leading to increased polarization between homogeneously composed groups of high-, medium-, and low-prejudice high school subjects. In an experimental condition, group members made individual attitude judgments, discussed them, and remade judgments. Control groups discussed irrelevant materials before responding again to the attitude items. As predicted, discussion of the racial attitude items with others having similar attitudes significantly increased the gap between high- and low-prejudice groups.

Molecular code for cooperativity in hemoglobin.

Although tetrameric hemoglobin has been studied extensively as a prototype for understanding mechanisms of allosteric regulation, the functional and structural properties of its eight intermediate ligation forms have remained elusive. Recent experiments on the energetics of cooperativity of these intermediates, along with assignments of their quaternary structures, have revealed that the allosteric mechanism is controlled by a previously unrecognized symmetry feature: quaternary switching from form T to form R occurs whenever heme-site binding creates a tetramer with at least one ligated subunit on each dimeric half-molecule. This "symmetry rule" translates the configurational isomers of heme-site ligation into six observed switchpoints of quaternary transition. Cooperativity arises from both "concerted" quaternary switching and "sequential" modulation of binding within each quaternary form, T and R. Binding affinity is regulated through a hierarchical code of tertiary-quaternary coupling that includes the classical allosteric models as limiting cases.