Novel CHRNA3 variants identified in a patient with bladder dysfunction, dysautonomia, and gastrointestinal dysmotility.

Congenital anomalies of the kidney and urinary tract (CAKUT) are estimated to be responsible for 20%-50% of congenital anomalies and are also a leading etiology of early-onset renal disease. Primary CAKUT are caused by genetic factors that impair proper in-utero genitourinary tract development and secondary CAKUT result from the influence of environmental factors. The CHRNA3 gene, which encodes the Alpha-3 subunit of the nicotinic acetylcholine receptor, is hypothesized to be associated with Megacystis-microcolon-intestinal hyperperistalsis syndrome. More recently, pathogenic variants in CHRNA3 have been identified in individuals with CAKUT as well as individuals with panautonomic failure. Here we present a patient with neurogenic bladder, vesicoureteral reflux, mydriasis, and gastrointestinal dysmotility found to have novel compound heterozygous variants in CHRNA3. These findings support the consideration of CHRNA3 disruption in the differential for CAKUT with dysautonomia and gastrointestinal dysmotility.

Developing a Batch Isolation Procedure and Running It in an Automated Semicontinuous Unit: AWL CFD25 Case Study.

A key challenge during the transition from laboratory/small batch to continuous manufacturing is the development of a process strategy that can easily be adopted for a larger batch/continuous process. Industrial practice is to develop the isolation strategy for a new drug/process in batch using the design of experiment (DoE) approach to determine the best isolation conditions and then transfer the isolation parameters selected to a large batch equipment/continuous isolation process. This stage requires a series of extra investigations to evaluate the effect of different equipment geometry or even the adaptation of the parameters selected to a different isolation mechanism (e.g., from dead end to cross flow filtration) with a consequent increase of R&D cost and time along with an increase in material consumption. The CFD25 is an isolation device used in the first instance to develop an isolation strategy in batch (optimization mode) using a screening DoE approach and to then verify the transferability of the strategy to a semicontinuous process (production mode). A d-optimal screening DoE was used to determine the effect of varying the input slurry. Properties such as solid loading, particle size distribution, and crystallization solvent were investigated to determine their impact on the filtration and washing performance and the characteristics of the dry isolated product. A series of crystallization (ethanol, isopropanol, and 3-methylbutan-1-ol) and wash solvents (n-heptane, isopropyl acetate and n-dodcane) were used for the process. To mimic a real isolation process, paracetamol-related impurities, acetanilide and metacetamol, were dissolved in the mother liquor. The selected batch isolation strategy was used for the semicontinuous isolation run. Throughput and filtration parameters, such as cake resistance and flow rate, cake residual liquid content and composition, cake purity, particle-particle aggregation, and extent and strength of agglomerates, were measured to evaluate the consistency of the isolated product produced during a continuous experiment and compared with the isolated product properties obtained during the batch process development. Overall, the CFD25 is a versatile tool which allows both new chemical entity process development in batch and the production of the active pharmaceutical ingredient in semicontinuous mode using the same process parameters without changing equipment. The isolated product properties gained during the semicontinuous run are overall comparable between samples. The residual solvent content and composition differs between some samples due to filter plate blockage. In general, the mean properties obtained during semicontinuous running are comparable with the product properties simulated using the DoE.

What Urinary Colony Count Indicates a Urinary Tract Infection in Children?

Post-hoc analysis of the Randomized Intervention for Children with Vesicoureteral Reflux study suggests that, in concordance with European guidelines, using bacteriologic criterion of ≥10 000 colony forming units/mL of a single organism does not decrease diagnostic specificity of an urinary tract infection in children aged 2 months to 6 years in a properly collected urine if symptoms/fever and pyuria are present. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00405704.

A novel method of teaching surgical techniques to residents--computerized enhanced visual learning (CEVL) with simulation to certify mastery of training: a model using newborn clamp circumcision.

OBJECTIVE: To assess the learning process of combining a web-based video of a simulated surgical procedure with a step-by-step checklist of the same procedure in achieving competency of the simulated technique, in this case a newborn clamp circumcision. Fundamental to this particular learning process is immediate mentor step-by-step feedback which specifically follows the procedure's step-by-step checklist. MATERIALS AND METHODS: Pediatric residents naïve to newborn circumcision were enrolled (n = 7). A circumcision simulator, instruments, and web access to the learning module were provided. Residents trained independently and then performed two simulations with the mentor. The first simulation was completed with formative scored feedback. The learner then performed a second scored simulation. RESULTS: All learners showed improvement between the first and second simulation (mean 85.3-97.4). All residents achieved competency (96/100 or greater) by the second simulation. On post-procedure surveys, learners demonstrated increased comfort and reduced apprehension in performing the procedure. CONCLUSION: Combining a web-accessible video of a procedure, a checklist, and a simulator followed by a single mentor session with immediate formative feedback which follows the steps of the checklist is a useful method to teach the simulation technique of circumcision. We plan to study if this paradigm is transferable to clinical circumcision.

Rationale and design issues of the Randomized Intervention for Children With Vesicoureteral Reflux (RIVUR) study.

OBJECTIVE: Our goal is to determine if antimicrobial prophylaxis with trimethoprim/sulfamethoxazole prevents recurrent urinary tract infections and renal scarring in children who are found to have vesicoureteral reflux after a first or second urinary tract infection. DESIGN, PARTICIPANTS, AND METHODS: The Randomized Intervention for Children With Vesicoureteral Reflux (RIVUR) study is a double-blind, randomized, placebo-controlled trial. Six hundred children aged 2 to 72 months will be recruited from both primary and subspecialty care settings at clinical trial centers throughout North America. Children who are found to have grades I to IV vesicoureteral reflux after the index febrile or symptomatic urinary tract infection will be randomly assigned to receive daily doses of either trimethoprim/sulfamethoxazole or placebo for 2 years. Scheduled follow-up contacts include in-person study visits every 6 months and telephone interviews every 2 months. Biospecimens (urine and blood) and genetic specimens (blood) will be collected for future studies of the genetic and biochemical determinants of vesicoureteral reflux, recurrent urinary tract infection, renal insufficiency, and renal scarring. RESULTS: The primary outcome is recurrence of urinary tract infection. Secondary outcomes include time to recurrent urinary tract infection, renal scarring (assessed by dimercaptosuccinic acid scan), treatment failure, renal function, resource utilization, and development of antimicrobial resistance in stool flora. CONCLUSIONS: The RIVUR study will provide useful information to clinicians about the risks and benefits of prophylactic antibiotics for children who are diagnosed with vesicoureteral reflux after a first or second urinary tract infection. The data and specimens collected over the course of the study will allow researchers to better understand the pathophysiology of recurrent urinary tract infection and its sequelae.

Cephalopod coloration model. II. Multiple layer skin effects.

A mathematical model of multiple layer skin coloration in cephalopods, a class of aquatic animals, is presented. The model incorporates diffuse and specular reflection from both pigment and structural photonic components found in the skin of these animals. Specific physical processes of this coloration are identified and modeled utilizing available biological materials data. Several examples of combination spectra are calculated to illustrate multiple layer and incident light effects as well as the potentially rich repertoire of color schemes available to these animals. A detailed understanding of the physical principles underlying cephalopod coloration is expected to yield insights into their possible functions.

Cephalopod coloration model. I. Squid chromatophores and iridophores.

We have developed a mathematical model of skin coloration in cephalopods, a class of aquatic animals. Cephalopods utilize neurological and physiological control of various skin components to achieve active camouflage and communication. Specific physical processes of this coloration are identified and modeled, utilizing available biological materials data, to simulate active spectral changes in pigment-bearing organs and structural iridescent cells. Excellent agreement with in vitro measurements of squid skin is obtained. A detailed understanding of the physical principles underlying cephalopod coloration is expected to yield insights into the behavioral ecology of these animals.

Layer-in-layer hierarchical nanostructures fabricated by combining holographic polymerization and block copolymer self-assembly.

We report the combination of top-down and bottom-up nanomanufacturing techniques to fabricate active, hierarchically structured volume reflection gratings. Holographic polymerization (H-P) formed lamellar structures of approximately 200 nm in thickness, confining a block copolymer (BCP) to approximately 100 nm domains. Subsequently, the BCP self-assembles into nanolayers with a period of approximately 21 nm. We envisage that this approach opens a gateway to fabricating hierarchical nanostructures at different length scales.

Insight into the nonlinear absorbance of two related series of two-photon absorbing chromophores.

A comprehensive photophysical study of the linear and nonlinear absorption properties has been carried out on two series of two-photon absorbing dyes to gain insight into how structure-property relationships influence observed nonlinear absorption. The materials studied consist of an electron accepting benzothiazole group connected to an electron donating diphenylamine via a fluorene bridging group. Two series differ from each other by the addition of one phenyl group and for each series one-arm (dipolar, AF240 and AF270), two-arm (quadrupolar, AF287 and AF295), and three-arm (octupolar, AF350 and AF380) versions were studied. Overall the AF240 series exhibits higher intrinsic two-photon absorption (TPA) cross-sections than the AF270 series as well as enhanced nanosecond nonlinear absorption, with an increase with number of branches. The enhanced nanosecond nonlinearity is understood by taking into account the contribution from the singlet and triplet excited states and was verified by a two-photon assisted excited-state absorption model that satisfactorily predicts the nonlinear absorption of the chromophores.

Determination of large nematic pre-tilt in liquid crystal cells with mechanically rubbed photorefractive Ce:SBN windows.

We report on the determination of liquid crystal pre-tilt inside cells fabricated using single crystal birefringent and dichroic windows of cerium doped strontium barium niobate. We show that the average pre-tilt is significantly affected by the crystalline windows, leading to much larger values than those obtained with glass windows using identical fabrication methods. The same technique can be used to determine pre-tilts as large as 40 degrees, which is significantly larger than normally measurable using the cell rotation method.

Energy transfer between incident laser and elastically backscattered waves in nonlinear absorption media.

A model of energy transfer by nearly degenerate two-beam coupling in media exhibiting two-photon and excited state absorption is presented and discussed. The two beams include an incident laser, which has a nonlinear time dependent phase, and an elastically backscattered wave derived from the incident laser. Superposition of these two waves creates an index modulation, arising from a spatially modulated, two-photon-created excited-state population, which couples the forward and backward propagating waves. Reflectance of the stimulated wave and transmittance of the incident laser are computed, including the effects of two-photon absorption andexcited state absorption as well as energy transfer between the two beams, and the relevance of the results to experimental measurements is discussed. The backscattered wave has a frequency that is unshifted with respect to that of the incident laser, and the small signal gain is proportional to the square of the incident laser intensity. The different effects due tomultimode and chirped waves are also discussed.

Polymer crystallization/melting induced thermal switching in a series of holographically patterned Bragg reflectors.

Holographic photopolymerization (H-P) is a simple, fast and attractive means to fabricate one-, two- and three-dimensional complex structures. Liquid crystals, nanoparticles and silicate nano-plates have been patterned into submicron periodical structures. In this article, we report fabrication of a one-dimensional reflection grating structure by patterning a semicrystalline polymer, polyethylene glycol (PEG), in Norland resin (thiol-ene based UV curable resin) matrix using the H-P technique. Sharp notches observed in the reflection grating of this Norland/PEG system indicate a finite Δ present in the system due to spatial segregation of the PEG and Norland resin. The notch position red shifts upon heating and the diffraction efficiency (ratio between diffraction and incident light intensity, DE) increases from ∼20% to 60% for the Norland 65/PEG 4600 grating. This dynamic behavior of the reflection grating is also fully reversible. The unique thermal switching behavior is attributed to the melting/formation of PEG crystals during heating/cooling. By employing different molecular weight PEGs which have different melting temperatures, a series of switching temperatures have been achieved. Since PEG can be easily coupled with a variety of functional groups, this research might shed light on fabricating multifunctional Bragg gratings using the H-P technique.

Optically switchable liquid crystal photonic structures.

Photo-optic materials offer the possibility of light controlled photonic devices, intelligent and environmentally adaptive optical materials. One strategy for creating these materials is the combination of structure formation through holographic photopolymerization and the variable optical properties of liquid crystals. Holographically patterned, polymer stabilized liquid crystals (HPSLCs) have proven to be useful optical materials. By incorporating photo-optic, azobenzene-derived liquid crystal blends into such material systems, we have generated practical photoresponsive optical materials.

Switchable orthorhombic F photonic crystals formed by holographic polymerization-induced phase separation of liquid crystal.

Electrically switchable photonic crystals are simply and rapidly formed by holographic polymerization-induced phase separation of liquid crystal from a monomer-liquid crystal mixture. We report the fabrication and electro-optical properties of liquid-crystal-filled polymer photonic crystals of orthorhombic F symmetry. Inverse opal and fcc structures can also be obtained. The crystals exhibit electrically switchable Bragg diffraction at ~8-10 V/microm with crystal structure in good agreement with theoretical expectations. These photonic crystals compare favorably with liquid-crystal-imbibed colloidal crystal arrays.