Squaramide Organocatalyzed Addition of a Masked Acyl Cyanide to ß-Nitrostyrenes.

A method for the squaramide-organocatalyzed enantioselective addition of a silyl-protected masked acyl cyanide (MAC) reagent to various ß-nitrostyrenes is described. Reactions are carried out in a freezer and provide products cleanly and in high enantioselectivities at very low catalyst loadings. Adducts are then unmasked, providing various oxidation state 3 functional groups, thereby highlighting the utility of these MAC reagents and a new strategy for the preparation of ß-amino acids.

Real-world implications of aphantasia: episodic recall of eyewitnesses with aphantasia is less complete but no less accurate than typical imagers.

Individuals with aphantasia report an inability to voluntarily visually image and reduced episodic memory, yet episodic accounts provided by witnesses and victims are fundamental for criminal justice. Using the mock-witness paradigm, we investigated eyewitness memory of individuals with aphantasia versus typical imagers. Participants viewed a mock crime and 48 hours later were interviewed about the event, randomly allocated to one of three conditions. Two interview conditions included techniques designed to support episodic retrieval mode, namely (i) Mental Reinstatement of Context (MRC) and (ii) Sketch Reinstatement of Context (Sketch-RC). A third Control condition did not include retrieval support. Aphantasic mock-eyewitnesses recalled 30% less correct information and accounts were less complete, but they made no more errors and were as accurate as typical imagers. Interaction effects revealed reduced correct recall and less complete accounts for aphantasic participants in MRC interviews versus Sketch-RC and Control. Aphantaisic participants in the Control outperformed those in both the Sketch-RC and MRC, although Sketch-RC improved completeness by 15% versus MRC. Our pattern of results indicates reduced mental imagery ability might be compensated for by alternative self-initiated cognitive strategies. Findings offer novel insights into episodic recall performance in information gathering interviews when ability to voluntarily visualize is impoverished.

Recurrent ileocolic intussusception with appendiceal lead point in a 2-year-old child: an etiology to be aware of on ultrasound.

Ileocolic intussusception is a differential consideration in young pediatric patients presenting with acute abdominal pain. Appendiceal intussusception is an uncommon variant of ileocolic intussusception where the appendix is contained within the intussusception, which can be challenging to diagnose preoperatively. In this case report, we present a 25-month-old female presenting with intermittent, diffuse abdominal pain. Initial ultrasound evaluation demonstrated ileocolic intussusception, which was successfully reduced by air enema. The patient experienced recurrent symptoms and had several recurrent episodes of ileocolic intussusception with the appendix contained within the intussusceptum. After the fifth recurrence, the patient underwent surgical intervention. The inflamed appendix was discovered to be inverted within the cecum, resulting in a lead point for intussusception of the terminal ileum. The patient underwent laparoscopic reduction of the ileocolic intussusception and appendectomy. Few cases of appendiceal and concurrent ileocolic intussusception are described in the literature. It is important that radiologists and surgeons be aware of this entity when evaluating pediatric ileocolic intussusception, particularly at the time of ultrasound and air enema, in order to ensure appropriate management and prevent complications.

An Open-Label, Multicenter, Single-Dose Pharmacokinetic Study of a Novel Amphetamine Extended-Release Orally Disintegrating Tablet in Preschool-Aged Children.

Objective: In the U.S. ∼33% of children with attention-deficit/hyperactivity disorder (ADHD) are diagnosed during their preschool years (<6 years of age). The majority of these children are treated with a psychopharmacological treatment, despite limited data on pharmacokinetics (PKs), efficacy, or safety of these medications in this population. A phase 4, single-dose open-label study was conducted to assess the PK profile of amphetamine extended-release orally disintegrating tablets (AMP XR-ODT) under fasted conditions in preschool-aged children with ADHD. Methods: Preschool-aged children (aged 4 to <6 years) with a confirmed ADHD diagnosis were enrolled and administered AMP XR-ODT 3.1 mg under fasted conditions. Plasma samples were analyzed for d- and l-amphetamine (AMP) via liquid chromatography-tandem mass spectrometry. Area under the concentration-time curve from time 0 extrapolated to infinity (AUC0-inf), area under the concentration-time curve from time 0 to the last measurable plasma concentration (AUC0-T), maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), terminal half-life (t1/2), apparent volume of distribution (Vz/F), and apparent clearance (CL/F) for d- and l-AMP and safety were assessed. Results: The PK and safety analyses included 15 preschool-aged children (4 years old, n = 6; 5 years old, n = 9); 14 completed the study. Quantifiable plasma concentrations for d- and l-AMP were observed 1.5 hours postdose and throughout the 24-hour sampling period. For d- and l-AMP, mean AUC0-inf was 315.2 and 104.4 h·ng/mL, AUC0-T was 296.0 and 96.8 h·ng/mL, t1/2 was 8.0 and 9.2 hours, Cmax was 23.0 and 7.0 ng/mL, Tmax was 3.9 and 4.0 hours, CL/F was 6996.3 and 6837.1 mL/h, and Vz/F was 75,874.5 and 84,140.0 mL, respectively. Adverse events included tachycardia (n = 2), neutropenia (n = 1), increased alanine aminotransferase (n = 1), and aspartate aminotransferase (n = 1). Conclusions: AMP XR-ODT 3.1 mg was well tolerated in preschool-aged children, with detectable plasma AMP concentrations over 24 hours, and a PK profile consistent with once-daily dosing.

Synthesis and Evaluation of Aryl Quinolines as HIV-1 Integrase Multimerization Inhibitors.

HIV-1 integrase multimerization inhibitors have recently been established as an effective class of antiretroviral agents due to their potent ability to inhibit viral replication. Specifically, quinoline-based inhibitors have been shown to effectively impair HIV-1 replication, highlighting the importance of these heterocyclic scaffolds. Pursuant of our endeavors to further develop a library of quinoline-based candidates, we have implemented a structure-activity relationship study of trisubstituted 4-arylquinoline scaffolds that examined the integrase multimerization properties of substitution patterns at the 4-position of the quinoline. Compounds consisting of substituted phenyl rings, heteroaromatics, or polycyclic moieties were examined utilizing an integrase aberrant multimerization in vitro assay. para-Chloro-4-phenylquinoline 11b and 2,3-benzo[b][1,4]dioxine 15f showed noteworthy EC50 values of 0.10 and 0.08 µM, respectively.

Combined effects of virus, pesticide, and predator cue on the larval tiger salamander (Ambystoma tigrinum).

Emerging diseases and environmental contamination are two of the leading hypotheses for global amphibian declines. Yet few studies have examined the influence of contaminants on disease susceptibility, and even fewer have incorporated the role of natural stressors such as predation. We performed a factorial study investigating the interaction of the insecticide carbaryl, dragonfly predator cue, and the emerging pathogen Ambystoma tigrinum virus (ATV) on fitness correlates and disease susceptibility in tiger salamander larvae. Four week old larvae were exposed for 22 days in a 2 (0, 500 µg/l carbaryl) × 2 (control, predator cue water) × 2 (0, 1 × 10(4) pfu ATV) factorial designed laboratory study. Results show significant impacts to survival of larvae for both virus and predator cue treatments, as well as an interactive effect between the two, in which predator cue strongly exacerbated disease-driven mortality. There was a clear pattern of reduced survival with the addition of stressors, with those where all three stressors were present exhibiting the worst effects (a decrease in survival from 93 to 60%). On those that survived, we also detected several sub-lethal impacts in mass, SVL, and development. Predator cue and pesticide treatments significantly reduced both SVL and mass. Virus and predator treatments significantly slowed development. Stressors also exhibited opposing effects on activity. Predator cue caused a significant reduction in activity, whereas virus caused a significant increase in activity over time. These results highlight the importance of examining combined natural and introduced stressors to understand potential impacts on amphibian species. Such stressors may contribute to the emergence of ATV in particular regions, raising concerns about the influence of pesticides on disease emergence in general.

Mechanical dissociation of swine liver to produce organoid units for tissue engineering and in vitro disease modeling.

The complex intricate architecture of the liver is crucial to hepatic function. Standard protocols used for enzymatic digestion to isolate hepatocytes destroy tissue structure and result in significant loss of synthetic, metabolic, and detoxification processes. We describe a process using mechanical dissociation to generate hepatic organoids with preserved intrinsic tissue architecture from swine liver. Oxygen-supplemented perfusion culture better preserved organoid viability, morphology, serum protein synthesis, and urea production, compared with standard and oxygen-supplemented static culture. Hepatic organoids offer an alternative source for hepatic assist devices, engineered liver, disease modeling, and xenobiotic testing.

Impact of Enhanced Primary Care on equitable access to and economic efficiency of allied health services: a qualitative investigation.

OBJECTIVE: To evaluate new pathways to access allied health services introduced by the Enhanced Primary Care/Chronic Disease Management (EPC/CDM) initiative that may both increase or decrease equity to and efficiency in access. DESIGN: A qualitative study consisting of semi-structured in-depth interviews with a purposively selected group of allied health practitioners. PARTICIPANTS AND SETTING. Allied health practitioners in private practice in Queensland, Australia, from physiotherapy, occupational therapy, speech pathology, and exercise physiology backgrounds (n = 15). MAIN OUTCOME MEASURES. Interviews focused upon several issues including how referrals are made under the EPC/CDM initiative and what happens for patients once their five allotted sessions are expended. RESULTS. The EPC/CDM initiative appeared to address two key barriers of access to allied health services - costs to patient of access and patient awareness of benefits. However, gap payments may still be deterring economically disadvantaged patients from attending. DISCUSSION: The EPC/CDM initiative is increasing access to allied health services for people with chronic diseases. However, it is evident that this initiative may still not be meeting the needs of those most disadvantaged economically, and may lead to duplication of efforts by allied health practitioners when patients move between private and public health care sectors.

Engineered vascularized bone grafts.

Clinical protocols utilize bone marrow to seed synthetic and decellularized allogeneic bone grafts for enhancement of scaffold remodeling and fusion. Marrow-derived cytokines induce host neovascularization at the graft surface, but hypoxic conditions cause cell death at the core. Addition of cellular components that generate an extensive primitive plexus-like vascular network that would perfuse the entire scaffold upon anastomosis could potentially yield significantly higher-quality grafts. We used a mouse model to develop a two-stage protocol for generating vascularized bone grafts using mesenchymal stem cells (hMSCs) from human bone marrow and umbilical cord-derived endothelial cells. The endothelial cells formed tube-like structures and subsequently networks throughout the bone scaffold 4-7 days after implantation. hMSCs were essential for stable vasculature both in vitro and in vivo; however, contrary to expectations, vasculature derived from hMSCs briefly cultured in medium designed to maintain a proliferative, nondifferentiated state was more extensive and stable than that with hMSCs with a TGF-beta-induced smooth muscle cell phenotype. Anastomosis occurred by day 11, with most hMSCs associating closely with the network. Although initially immature and highly permeable, at 4 weeks the network was mature. Initiation of scaffold mineralization had also occurred by this period. Some human-derived vessels were still present at 5 months, but the majority of the graft vasculature had been functionally remodeled with host cells. In conclusion, clinically relevant progenitor sources for pericytes and endothelial cells can serve to generate highly functional microvascular networks for tissue engineered bone grafts.

Poly(glycerol sebacate) films prevent postoperative adhesions and allow laparoscopic placement.

BACKGROUND: The objectives of this study were to evaluate the efficacy of poly(glycerol) sebacate (PGS) films for the prevention of visceroparietal peritoneal (VP) adhesions and demonstrate the ease of laparoscopic PGS film placement. Peritoneal adhesions occur in nearly 95% of all abdominal operations. VP adhesions can cause serious postoperative complications. The interposition of a barrier between damaged peritoneal areas during re-epithelialization has been shown to prevent adhesion formation. Current barrier products have serious drawbacks, including poor degradability, variable efficacy, and difficult handling characteristics. METHODS: The efficacy of PGS films to prevent VP adhesions was evaluated in a rat peritoneal adhesion model. The animals were evaluated for the presence of VP adhesions at 3, 5, and 8 weeks. The laparoscopic applicability of PGS films was demonstrated by placement into a juvenile porcine abdomen using standard laparoscopic equipment and techniques. RESULTS: A statistically significant 94% reduction in VP adhesion formation rate was observed between control animals (75%) and animals with a PGS film barrier (4.8%). PGS films were easily placed in the juvenile porcine abdomen and could be readily repositioned without material loss or tissue damage. CONCLUSION: PGS films possess a unique combination of properties, including biocompatibility, resorbability, and ease of handling. PGS barrier films were shown to be efficacious in reducing VP adhesions in the rat model. They also can be placed using standard laparoscopic techniques. These promising results suggest that PGS films will be effective barriers to adhesion formation for patients undergoing open and laparoscopic abdominal operations.

Degradation behavior of poly(glycerol sebacate).

Poly(glycerol sebacate) (PGS), a promising scaffold material for soft tissue engineering applications, is a soft, tough elastomer with excellent biocompatibility. However, the rapid in vivo degradation rate of PGS limits its use as a scaffold material. To determine the impact of crosslink density on degradation rate, a family of PGS materials was synthesized by incrementally increasing the curing time from 42 to 144 h, at 120 degrees C and 10 mTorr vacuum. As expected, PGS became a stiffer, tougher, and stronger elastomer with increasing curing time. PGS disks were subcutaneously implanted into rats and periodically harvested; only mild tissue responses were observed and the biocompatibility remained excellent. Regardless of crosslink density, surface erosion degradation was observed. The sample dimensions linearly decreased with implantation time, and the mass loss rates were constant after 1-week implantation. As surface erosion degradation frequently correlates with enzymatic digestion, parallel in vitro digestion studies were conducted in lipase solutions which hydrolyze ester bonds. Enzymatic digestion played a significant role in degrading PGS, and the mass loss rates were not a function of curing time. Alternative chemistry approaches will be required to decrease the enzymatic hydrolysis rate of the ester bonds in PGS polymers.

Primary angioplasty in acute myocardial infarction: does age or race matter?

PURPOSE: Recent data suggest substantial variations in the treatment of acute myocardial infarction based on age, race, gender and socioeconomic status. We evaluated the use of primary angioplasty (PA) in acute myocardial infarction (AMI) in elderly and minority patients treated at an urban, teaching hospital. SUBJECTS AND METHODS: We reviewed the records of 322 patients with AMI admitted to an urban, teaching hospital from 1997-2000. Our main outcome was PA in AMI. Secondary outcomes included use of post-infarction therapies. Univariate analysis was performed on the variables of interest, age and race, as well as all candidate variables. RESULTS: Unadjusted analysis revealed that elderly and African-American patients were significantly less likely to receive PA for AMI, and post-infarction beta-blockers, (all p <.05). Other factors that had a significant negative impact on use of PA included do-not-resuscitate status, increasing acuity of presenting signs and symptoms, severity of illness, dementia and subendocardial infarcts (all p <.05). After adjustment for these potential confounders, increasing age remained inversely associated with both PA (p <.001), and use of standard post-myocardial infarction beta-blockers, (p <.05). Additionally, African-American patients in our study were less likely to undergo PA as initial AMI (p <.01). CONCLUSIONS: Our results indicate differences in the use of PA in the elderly and African-Americans. These differences are not explained by severity of illness and suggest that interventions and standard therapies may be withheld from those who may benefit most.

Willingness to pay for new Papanicolaou test technologies.

The amount of money a woman is willing to pay for liquid-based cytology technology has not been measured. In the present study, 175 women answered a questionnaire asking how much they would pay to decrease their risk of dying of cervical cancer if a new (liquid-based) Papanicolaou (Pap) test was used in place of the conventional smear. When women assumed that the new Pap test reduced the risk of dying of cervical cancer from 1 in 37,000 to 1 in 50,000, the mean amount they were willing to pay was $237. If women had more than 2 children, they were willing to pay more for the new Pap test than women with 2 or fewer children. These data indicate that liquid-based and conventional Pap tests are undervalued and that cost-effectiveness studies generally have not taken into account the preference of women for new Pap test technologies.