Germline C1GALT1C1 mutation causes a multisystem chaperonopathy.

Mutations in genes encoding molecular chaperones can lead to chaperonopathies, but none have so far been identified causing congenital disorders of glycosylation. Here we identified two maternal half-brothers with a novel chaperonopathy, causing impaired protein O-glycosylation. The patients have a decreased activity of T-synthase (C1GALT1), an enzyme that exclusively synthesizes the T-antigen, a ubiquitous O-glycan core structure and precursor for all extended O-glycans. The T-synthase function is dependent on its specific molecular chaperone Cosmc, which is encoded by X-chromosomal C1GALT1C1. Both patients carry the hemizygous variant c.59C>A (p.Ala20Asp; A20D-Cosmc) in C1GALT1C1. They exhibit developmental delay, immunodeficiency, short stature, thrombocytopenia, and acute kidney injury (AKI) resembling atypical hemolytic uremic syndrome. Their heterozygous mother and maternal grandmother show an attenuated phenotype with skewed X-inactivation in blood. AKI in the male patients proved fully responsive to treatment with the complement inhibitor Eculizumab. This germline variant occurs within the transmembrane domain of Cosmc, resulting in dramatically reduced expression of the Cosmc protein. Although A20D-Cosmc is functional, its decreased expression, though in a cell or tissue-specific manner, causes a large reduction of T-synthase protein and activity, which accordingly leads to expression of varied amounts of pathological Tn-antigen (GalNAcα1-O-Ser/Thr/Tyr) on multiple glycoproteins. Transient transfection of patient lymphoblastoid cells with wild-type C1GALT1C1 partially rescued the T-synthase and glycosylation defect. Interestingly, all four affected individuals have high levels of galactose-deficient IgA1 in sera. These results demonstrate that the A20D-Cosmc mutation defines a novel O-glycan chaperonopathy and causes the altered O-glycosylation status in these patients.

ADGRL1 haploinsufficiency causes a variable spectrum of neurodevelopmental disorders in humans and alters synaptic activity and behavior in a mouse model.

ADGRL1 (latrophilin 1), a well-characterized adhesion G protein-coupled receptor, has been implicated in synaptic development, maturation, and activity. However, the role of ADGRL1 in human disease has been elusive. Here, we describe ten individuals with variable neurodevelopmental features including developmental delay, intellectual disability, attention deficit hyperactivity and autism spectrum disorders, and epilepsy, all heterozygous for variants in ADGRL1. In vitro, human ADGRL1 variants expressed in neuroblastoma cells showed faulty ligand-induced regulation of intracellular Ca2+ influx, consistent with haploinsufficiency. In vivo, Adgrl1 was knocked out in mice and studied on two genetic backgrounds. On a non-permissive background, mice carrying a heterozygous Adgrl1 null allele exhibited neurological and developmental abnormalities, while homozygous mice were non-viable. On a permissive background, knockout animals were also born at sub-Mendelian ratios, but many Adgrl1 null mice survived gestation and reached adulthood. Adgrl1-/- mice demonstrated stereotypic behaviors, sexual dysfunction, bimodal extremes of locomotion, augmented startle reflex, and attenuated pre-pulse inhibition, which responded to risperidone. Ex vivo synaptic preparations displayed increased spontaneous exocytosis of dopamine, acetylcholine, and glutamate, but Adgrl1-/- neurons formed synapses in vitro poorly. Overall, our findings demonstrate that ADGRL1 haploinsufficiency leads to consistent developmental, neurological, and behavioral abnormalities in mice and humans.

Telomere biology disorders may manifest as common variable immunodeficiency (CVID).

Telomere biology disorders (TBD) are caused by germline pathogenic variants in genes related to telomere maintenance and are characterized by critically short telomeres. In contrast to classical dyskeratosis congenita (DC), which is typically diagnosed in infancy, adult or late onset TBD frequently lack the typical DC triad and rather show variable organ manifestations and a cryptic disease course, thus complicating its diagnosis. Common variable immunodeficiency (CVID), on the other hand, is a primary antibody deficiency (PAD) syndrome. PADs are a heterogenous group of diseases characterized by hypogammaglobulinemia which occurs due to dysfunctional B lymphocytes and additional autoimmune and autoinflammatory complications. Genetic screening reveals a monogenic cause in a subset of CVID patients (15-35%). In our study, we screened the exomes of 491 CVID patients for the occurrence of TBD-related variants in 13 genes encoding for telomere/telomerase-associated proteins, which had previously been linked to the disease. We found 110/491 patients (22%) carrying 91 rare candidate variants in these 13 genes. Following the American College of Medical Genetics and Genomics (ACMG) guidelines, we classified two variants as benign, two as likely benign, 64 as variants of uncertain significance (VUS), four as likely pathogenic, and one heterozygous variant in an autosomal recessive disease gene as pathogenic. We performed telomere length measurement in 42 of the 110 patients with candidate variants and CVID. Two of these 42 patients showed significantly shorter telomeres compared to controls in both lymphocytes and granulocytes. Following the evaluation of the published literature and the patient's manifestations, we re-classified two VUS as likely pathogenic variants. Thus, 0.5-1% of all CVID patients in our study carry possibly pathogenic variants in telomere/telomerase-associated genes. Our data adds CVID to the broad clinical spectrum of cryptic adult-onset TBD. As the molecular diagnosis greatly impacts patient management and treatment strategies, we advise inclusion of all TBD-associated genes-despite their low prevalence-into the molecular screening of patients with antibody deficiencies.

Correction: Lombardi et al. AcidoCEST-UTE MRI Reveals an Acidic Microenvironment in Knee Osteoarthritis. Int. J. Mol. Sci. 2022, 23, 4466.

In the original publication, there was a mistake in Figure 1 as published [...].

Hemodynamic Effects of Ketamine Compared With Propofol or Dexmedetomidine as Continuous ICU Sedation.

BACKGROUND: Ketamine has seen increased use for sedation in the intensive care unit. In contrast to propofol or dexmedetomidine, ketamine may provide a positive effect on hemodynamics. OBJECTIVE: The objective of this study was to compare the development of clinically significant hypotension or bradycardia (ie, negative hemodynamic event) between critically ill adults receiving sedation with ketamine and either propofol or dexmedetomidine. METHODS: This was a retrospective cohort study of adults admitted to an intensive care unit at an academic medical center between January 2016 and January 2021. RESULTS: Patients in the ketamine group (n = 78) had significantly less clinically significant hypotension or bradycardia compared with those receiving propofol or dexmedetomidine (n = 156) (34.6% vs 63.5%; P < 0.001). Patients receiving ketamine also experienced smaller degree of hypotension observed by percent decrease in mean arterial pressure (25.3% [17.4] vs 33.8% [14.5]; P < 0.001) and absolute reduction in systolic blood pressure (26.5 [23.8] vs 42.0 [37.8] mm Hg; P < 0.001) and bradycardia (15.5 [24.3] vs 32.0 [23.0] reduction in beats per minute; P < 0.001). In multivariate logistic regression modeling, receipt of propofol or dexmedetomidine was the only independent predictor of a negative hemodynamic event (odds ratio [OR]: 3.3, 95% confidence interval [CI], 1.7 to 6.1; P < 0.001). CONCLUSION AND RELEVANCE: Ketamine was associated with less clinically relevant hypotension or bradycardia when compared with propofol or dexmedetomidine, in addition to a smaller absolute decrease in hemodynamic parameters. The clinical significance of these findings requires further investigation.

AcidoCEST-UTE MRI Reveals an Acidic Microenvironment in Knee Osteoarthritis.

A relationship between an acidic pH in the joints, osteoarthritis (OA), and pain has been previously demonstrated. Acidosis Chemical Exchange Saturation Transfer (acidoCEST) indirectly measures the extracellular pH through the assessment of the exchange of protons between amide groups on iodinated contrast agents and bulk water. It is possible to estimate the extracellular pH in the osteoarthritic joint using acidoCEST MRI. However, conventional MR sequences cannot image deep layers of cartilage, meniscus, ligaments, and other musculoskeletal tissues that present with short echo time and fast signal decay. Ultrashort echo time (UTE) MRI, on the other hand, has been used successfully to image those joint tissues. Here, our goal is to compare the pH measured in the knee joints of volunteers without OA and patients with severe OA using acidoCEST-UTE MRI. Patients without knee OA and patients with severe OA were examined using acidoCEST-UTE MRI and the mean pH of cartilage, meniscus, and fluid was calculated. Additionally, the relationship between the pH measurements and the Knee Injury and Osteoarthritis Outcome Score (KOOS) was investigated. AcidoCEST-UTE MRI can detect significant differences in the pH of knee cartilage, meniscus, and fluid between joints without and with OA, with OA showing lower pH values. In addition, symptoms and knee-joint function become worse at lower pH measurements.

Flexibility in Drug Product Development: A Perspective.

The process of bringing a drug to market involves innumerable decisions to refine a concept into a final product. The final product goes through extensive research and development to meet the target product profile and to obtain a product that is manufacturable at scale. Historically, this process often feels inflexible and linear, as ideas and development paths are eliminated early on to allow focus on the workstream with the highest probability of success. Carrying multiple options early in development is both time-consuming and resource-intensive. Similarly, changing development pathways after significant investment carries a high "penalty of change" (PoC), which makes pivoting to a new concept late in development inhibitory. Can drug product (DP) development be made more flexible? The authors believe that combining a nonlinear DP development approach, leveraging state-of-the art data sciences, and using emerging process and measurement technologies will offer enhanced flexibility and should become the new normal. Through the use of iterative DP evaluation, "smart" clinical studies, artificial intelligence, novel characterization techniques, automation, and data collection/modeling/interpretation, it should be possible to significantly reduce the PoC during development. In this Perspective, a review of ideas/techniques along with supporting technologies that can be applied at each stage of DP development is shared. It is further discussed how these contribute to an improved and flexible DP development through the acceleration of the iterative build-measure-learn cycle in laboratories and clinical trials.

Supramolecular Reorientation During Deposition Onto Metal Surfaces of Quasi-Two-Dimensional Langmuir Monolayers Composed of Bifunctional Amphiphilic, Twisted Perylenes.

Supramolecular dye structures, which are often ruled by π-π interactions between planar chromophores, crucially determine the optoelectronic properties of layers and interfaces. Here, we present the interfacial assembly of perylene monoanhydride and monoimide that do not feature a planar chromophore but contain chlorine substituents in the bay positions to yield twisted chromophores and hence modified π-stacking. The assembly of the twisted perylene monoanhydride and monoimide is driven by their amphiphilicity that ensures proper Langmuir layer formation. The shielding of the hydrophilic segment upon attaching an alkyl chain to the imide moiety yielded a more rigid Langmuir layer, even though the degrees of freedom were increased due to this modification. For the characterization of the Langmuir layer's supramolecular structure, the layers were deposited onto glass, silver, and gold substrates via Langmuir-Blodgett (LB) and Langmuir-Schaefer (LS) techniques and were investigated with atomic force microscopy and surface-enhanced resonance Raman spectroscopy (SERRS). From the similarity between all SERR spectra of the LS and LB layers, we concluded that the perylenes have changed their orientation upon LB deposition to bind to the silver surface of the SERRS substrate via sulfur atoms. In the Langmuir layer, the perylenes, which are π-stacked with half of the twisted chromophores, must already be inclined and cannot achieve full parallel alignment because of the twisting-induced steric hindrance. However, upon rotation, the energetically most favorable antiparallel aligned structures can be formed and bind to the SERRS substrate. Thus, we present, to the best of our knowledge, the first fabrication of quasi-two-dimensional films from twisted amphiphilic perylene monoimides and their reassembly during LB deposition. The relation between the molecular structure, supramolecular interfacial assembly, and its adoption during adsorption revealed here is crucial for the fabrication of defined functionalizations of metal surfaces, which is key to the development of organic (opto)electronic devices.

Loss of supervillin causes myopathy with myofibrillar disorganization and autophagic vacuoles.

The muscle specific isoform of the supervillin protein (SV2), encoded by the SVIL gene, is a large sarcolemmal myosin II- and F-actin-binding protein. Supervillin (SV2) binds and co-localizes with costameric dystrophin and binds nebulin, potentially attaching the sarcolemma to myofibrillar Z-lines. Despite its important role in muscle cell physiology suggested by various in vitro studies, there are so far no reports of any human disease caused by SVIL mutations. We here report four patients from two unrelated, consanguineous families with a childhood/adolescence onset of a myopathy associated with homozygous loss-of-function mutations in SVIL. Wide neck, anteverted shoulders and prominent trapezius muscles together with variable contractures were characteristic features. All patients showed increased levels of serum creatine kinase but no or minor muscle weakness. Mild cardiac manifestations were observed. Muscle biopsies showed complete loss of large supervillin isoforms in muscle fibres by western blot and immunohistochemical analyses. Light and electron microscopic investigations revealed a structural myopathy with numerous lobulated muscle fibres and considerable myofibrillar alterations with a coarse and irregular intermyofibrillar network. Autophagic vacuoles, as well as frequent and extensive deposits of lipoproteins, including immature lipofuscin, were observed. Several sarcolemma-associated proteins, including dystrophin and sarcoglycans, were partially mis-localized. The results demonstrate the importance of the supervillin (SV2) protein for the structural integrity of muscle fibres in humans and show that recessive loss-of-function mutations in SVIL cause a distinctive and novel myopathy.

Pharmacokinetics and pharmacodynamics of intravenous continuous rate infusion and repeated intramuscular administration of dexmedetomidine in standing horses.

An ideal dexmedetomidine protocol has yet to be determined for standing sedation in horses. It was hypothesized that an IV bolus followed by CRI dexmedetomidine would have a quicker increase in plasma concentrations compared with repeated IM injections. In a crossover design, eight adult, female horses were randomly placed into two groups: the CRI group (IV bolus dexmedetomidine at 0.005 mg/kg followed by a CRI at 0.01 mg/kg/h for 15 min then 0.005 mg/kg/h for 60 min) and the IM group (dexmedetomidine at 0.01 mg/kg, followed by 0.005 mg/kg in 30-min intervals for 60 min). Clearance and elimination half-life were 134 ± 67.4 ml/kg/min and 44.3 ± 26.3 min, respectively, in the CRI group, and apparent clearance and half-life were 412 ± 306 ml/kg/min (Cl/F) and 38.9 ± 18.6 min, respectively, in the IM group. Analgesia was evaluated using mechanical pressure threshold. Intravenous dexmedetomidine produced faster onset of sedation and increased pressure threshold compared with IM administration. Individual horses had a large variability in dexmedetomidine plasma concentrations between CRI and IM administration. The odds of a decreased GI motility following IV administration was 12.34 times greater compared with IM administration.

Optimization of Critical Quality Attributes in Tablet Film Coating and Design Space Determination Using Pilot-Scale Experimental Data.

In this study, the novel high-speed tablet film coating process in the continuous manufacturing was investigated. The influence of key process variables (inlet air flow rate, inlet air temperature, and suspension spray rate) were investigated using a Box-Behnken experimental design method. Statistical regression models were developed to predict the outlet air temperature and relative humidity, the coating efficiency, the tablet moisture content, and coating uniformity. The effects of the three key process variables were comprehensively investigated based on mathematical analysis, contour plots, and interaction plots. The results indicate that all the process responses are affected by changing the inlet air flow rate, temperature, and suspension spray rate. A design space (DS) in terms of failure probability was determined based on specifications for tablet moisture content (< 3.5%) and coating uniformity (tablet weight standard deviation < 4 mg for tablet weight of 200 mg) using Monte Carlo simulations. Independent experiments were carried out and successfully validated the robustness and accuracy of the determined DS for the investigated tablet film coating process. All the data were generated using an industrial pilot-scale novel high-speed tablet coating unit from a continuous manufacturing line. The work facilitates the quality by design implementation of continuous pharmaceutical manufacturing.

Cancer diagnostic profile in children with structural birth defects: An assessment in 15,000 childhood cancer cases.

BACKGROUND: Birth defects are established risk factors for childhood cancer. Nonetheless, cancer epidemiology in children with birth defects is not well characterized. METHODS: Using data from population-based registries in 4 US states, this study compared children with cancer but no birth defects (n = 13,111) with children with cancer and 1 or more nonsyndromic birth defects (n = 1616). The objective was to evaluate cancer diagnostic characteristics, including tumor type, age at diagnosis, and stage at diagnosis. RESULTS: Compared with the general population of children with cancer, children with birth defects were diagnosed with more embryonal tumors (26.6% vs 18.7%; q < 0.001), including neuroblastoma (12.5% vs 8.2%; q < 0.001) and hepatoblastoma (5.0% vs 1.3%; q < 0.001), but fewer hematologic malignancies, including acute lymphoblastic leukemia (12.4% vs 24.4%; q < 0.001). In age-stratified analyses, differences in tumor type were evident among children younger than 1 year and children 1 to 4 years old, but they were attenuated among children 5 years of age or older. The age at diagnosis was younger in children with birth defects for most cancers, including leukemia, lymphoma, astrocytoma, medulloblastoma, ependymoma, embryonal tumors, and germ cell tumors (all q < 0.05). CONCLUSIONS: The results indicate possible etiologic heterogeneity in children with birth defects, have implications for future surveillance efforts, and raise the possibility of differential cancer ascertainment in children with birth defects. LAY SUMMARY: Scientific studies suggest that children with birth defects are at increased risk for cancer. However, these studies have not been able to determine whether important tumor characteristics, such as the type of tumor diagnosed, the age at which the tumor is diagnosed, and the degree to which the tumor has spread at the time of diagnosis, are different for children with birth defects and children without birth defects. This study attempts to answer these important questions. By doing so, it may help scientists and physicians to understand the causes of cancer in children with birth defects and diagnose cancer at earlier stages when it is more treatable.

Inherited cases of CNOT3-associated intellectual developmental disorder with speech delay, autism, and dysmorphic facies.

De novo pathogenic variants in CNOT3 have recently been reported in a developmental delay disorder (intellectual developmental disorder with speech delay, autism, and dysmorphic facies [IDDSADF, OMIM: #618672]). The patients present with a variable degree of developmental delay and behavioral problems. To date, all reported disease-causing variants occurred de novo and no parent-child transmission was observed. We report for the first time autosomal dominant transmissions of the CNOT3-associated developmental disorder in two unrelated families. The clinical characteristics in our patients match the IDDSADF features reported so far and suggest substantial variability of the phenotype within the same family.

Patient with an autosomal-recessive MBTPS1-linked phenotype and clinical features of Silver-Russell syndrome.

Pathogenic variants in the MBTPS1 gene encoding the Site 1 protease have been described so far only in one growth retarded patients with skeletal deformities, large ears, a triangular face reminiscent to Silver-Russell syndrome (SRS), and elevated blood lysosomal enzymes. We now report on the identification of a second adult patient homozygous for one of the two published pathogenic MBTPS1 variants (p.Asp365Gly) by Whole Exome Sequencing (WES), and a comparable phenotype. With this case, the association of pathogenic variants in MBTPS1 with a recognizable disorder could be confirmed, and the autosomal recessive inheritance is further established. As the variant was identified after a long diagnostic odyssey of the family, this example illustrates the need to apply WES in the diagnostic workup in case of growth retardation as early as possible. By compiling the clinical data of this new patient with those of the already reported patient, a better prognosis for future patients with MBTPS1 variants can be issued, and clinical management can be adjusted.

Achiral symmetry breaking and positive Gaussian modulus lead to scalloped colloidal membranes.

In the presence of a nonadsorbing polymer, monodisperse rod-like particles assemble into colloidal membranes, which are one-rod-length-thick liquid-like monolayers of aligned rods. Unlike 3D edgeless bilayer vesicles, colloidal monolayer membranes form open structures with an exposed edge, thus presenting an opportunity to study elasticity of fluid sheets. Membranes assembled from single-component chiral rods form flat disks with uniform edge twist. In comparison, membranes composed of a mixture of rods with opposite chiralities can have the edge twist of either handedness. In this limit, disk-shaped membranes become unstable, instead forming structures with scalloped edges, where two adjacent lobes with opposite handedness are separated by a cusp-shaped point defect. Such membranes adopt a 3D configuration, with cusp defects alternatively located above and below the membrane plane. In the achiral regime, the cusp defects have repulsive interactions, but away from this limit we measure effective long-ranged attractive binding. A phenomenological model shows that the increase in the edge energy of scalloped membranes is compensated by concomitant decrease in the deformation energy due to Gaussian curvature associated with scalloped edges, demonstrating that colloidal membranes have positive Gaussian modulus. A simple excluded volume argument predicts the sign and magnitude of the Gaussian curvature modulus that is in agreement with experimental measurements. Our results provide insight into how the interplay between membrane elasticity, geometrical frustration, and achiral symmetry breaking can be used to fold colloidal membranes into 3D shapes.

Risk factors for primary congenital glaucoma in the National Birth Defects Prevention Study.

Primary congenital glaucoma (PCG) is a rare but serious birth defect. Genetic mutations have been implicated in the development of PCG, but little is known about nongenetic risk factors. This study investigates potential risk factors for PCG in the National Birth Defects Prevention Study (NBDPS), a large population-based case-control study of major birth defects in the United States. The analysis includes case infants with PCG (N = 107) and control infants without birth defects (N = 10,084) enrolled in NBDPS from birth years 2000-2011. Pregnancy/infant clinical characteristics, demographics, and parental health history were collected through maternal interview. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were computed to examine associations with all PCG cases and isolated PCG cases without other major malformations. Associations with all the cases included term low birth weight (<2,500 g; aOR = 2.80, CI 1.59-4.94), non-Hispanic black maternal race/ethnicity (aOR = 2.42, CI 1.42-4.13), maternal history of seizure (aOR = 2.73, CI 1.25-5.97), maternal antihypertensive use (aOR = 3.60, CI 1.52-8.53), and maternal sexually transmitted infection (aOR = 2.75, CI 1.17-6.44). These factors were also associated with isolated PCG, as was maternal use of nonsteroidal anti-inflammatory drugs (aOR = 2.70, CI 1.15-6.34). This study is among the first to examine a wide array of potential risk factors for PCG in a population-based sample.

Next generation sequencing and imprinting disorders: Current applications and future perspectives: Lessons from Silver-Russell syndrome.

Imprinting Disorders are a group of rare diseases with overlapping phenotypes which are associated with similar molecular changes and affect imprinted chromosomal regions. Clinical features mainly occur prenatally or in childhood, but have a severe lifelong impact on health. Due to their clinical and molecular heterogeneity, the diagnosis of imprinting disorders is often challenging and requires testing of a broad spectrum of genomic variants and aberrant methylation of imprinted loci (epimutations). A significant number of patients suspicious for imprinting disorders remain without a molecular confirmation, and in these cases differential diagnoses have to be considered. In fact, in patients with clinical features suggestive for imprinting disorders, the precise identification of the molecular cause is relevant for both clinical management as well as for genetic counselling. Thus, a comprehensive testing approach has to be applied. Next generation sequencing (NGS) based studies show that this technique is a valuable tool to improve the diagnostic efficiency particularly in entities with broad differential diagnoses. Furthermore, the development of diverse NGS approaches allows new insights in the function of imprinted regions, their structures, interactions and regulation. Based on a large cohort of patients referred for routine Silver Russel syndrome testing, the appropriateness and limitations of first trial tests in imprinting disorders are demonstrated in this report, but the chances of genomic NGS approaches for diagnostics and research are elucidated as well. Finally, the significance of the precise molecular diagnosis for the personalized management of the patient, and genetic counselling of the family will be discussed.

Sharp transection of the suspensory ligament as an alternative to digital strumming during canine ovariohysterectomy.

OBJECTIVE: To compare time efficiency and nociceptive input between digital strumming (DS) and sharp transection (ST) of the suspensory ligament during ovariohysterectomy (OVH). STUDY DESIGN: Randomized controlled trial. ANIMALS: 30 adult female dogs. METHODS: Dogs were randomly assigned to ST or DS procedures. Measures of nociception were assessed through measurements of preoperative and intraoperative heart rate during manipulation of the suspensory ligament. Measures of pain were assessed through preoperative and postoperative pain scores by using the short form Glasgow Composite Pain Scale. Time efficiency was measured through total surgical time and the time to release each suspensory ligament. RESULTS: After body weight was accounted for, the total surgical time was 1.1 minutes (P = .06) faster for ST than for DS, and each additional kilogram of body weight increased total surgical time by 0.1 minutes (P = .02). Digital strumming had 30.6-fold greater odds of taking greater than 1 minute compared with ST (P = .001). The heart rate from baseline to peak was 7.4 beats per minute lower in the ST group than in the DS group (P = .06). No complications were observed, and there was no difference in postoperative pain scores between treatments. CONCLUSION: Sharp transection was faster and generated less intraoperative acceleration in heart rate but did not differ in postoperative outcomes compared with DS. CLINICAL SIGNIFICANCE: Sharp transection is a viable alternative to DS for breakdown of the suspensory ligament during canine OVH. Sharp transection may improve surgical efficiency, especially when performing large volumes in the spay/neuter setting and could influence veterinary student training.

Assessment of spatial heterogeneity in continuous twin screw wet granulation process using three-compartmental population balance model.

In this study, a novel three-compartmental population balance model (PBM) for a continuous twin screw wet granulation process is developed, combining the techniques of PBM and regression process modeling. The developed model links screw configuration, screw speed, and blend throughput with granule properties to predict the granule size distribution (GSD) and volume-average granule diameter. The granulator screw barrel was divided into three compartments along barrel length: wetting compartment, mixing compartment, and steady growth compartment. Different granulation mechanisms are assumed in each compartment. The proposed model therefore considers spatial heterogeneity, improving model prediction accuracy. An industrial data set containing 14 experiments is applied for model development. Three validation experiments show that the three-compartmental PBM can accurately predict granule diameter and size distribution at randomly selected operating conditions. Sixteen combinations of aggregation and breakage kernels are investigated in predicting the experimental GSD to best judge the granulation mechanism. The three-compartmental model is compared with a one-compartmental model in predicting granule diameter at different experimental conditions to demonstrate its advantage. The influence of the screw configuration, screw speed and blend throughput on the volume-average granule diameter is analyzed based on the developed model.

Reconfigurable self-assembly through chiral control of interfacial tension.

From determining the optical properties of simple molecular crystals to establishing the preferred handedness in highly complex vertebrates, molecular chirality profoundly influences the structural, mechanical and optical properties of both synthetic and biological matter on macroscopic length scales. In soft materials such as amphiphilic lipids and liquid crystals, the competition between local chiral interactions and global constraints imposed by the geometry of the self-assembled structures leads to frustration and the assembly of unique materials. An example of particular interest is smectic liquid crystals, where the two-dimensional layered geometry cannot support twist and chirality is consequently expelled to the edges in a manner analogous to the expulsion of a magnetic field from superconductors. Here we demonstrate a consequence of this geometric frustration that leads to a new design principle for the assembly of chiral molecules. Using a model system of colloidal membranes, we show that molecular chirality can control the interfacial tension, an important property of multi-component mixtures. This suggests an analogy between chiral twist, which is expelled to the edges of two-dimensional membranes, and amphiphilic surfactants, which are expelled to oil-water interfaces. As with surfactants, chiral control of interfacial tension drives the formation of many polymorphic assemblages such as twisted ribbons with linear and circular topologies, starfish membranes, and double and triple helices. Tuning molecular chirality in situ allows dynamical control of line tension, which powers polymorphic transitions between various chiral structures. These findings outline a general strategy for the assembly of reconfigurable chiral materials that can easily be moved, stretched, attached to one another and transformed between multiple conformational states, thus allowing precise assembly and nanosculpting of highly dynamical and designable materials with complex topologies.