A Rare Case of Small Bowel Obstruction in a 15-Year-Old Girl: Internal Hernia Associated with Meckel's Diverticulum.

BACKGROUND Meckel's diverticulum is a congenital remnant of the omphalomesenteric duct and is the most common congenital gastrointestinal malformation. Most patients are asymptomatic, but a rare presentation is with subacute small bowel obstruction (SBO) due to herniation of bowel loops through an internal hernia formed by the Meckel's diverticulum and adjacent mesentery that forms an internal hernia. This report is of a 15-year-old girl presenting as an emergency with vomiting and small bowel obstruction due to an internal hernia associated with Meckel's diverticulum. CASE REPORT We present a case of a 15-year-old girl who presented to the Children's Emergency (CE) department with persistent vomiting and abdominal distension and tenderness. X-rays demonstrated dilated small bowel loops, prompting admission under Pediatric Surgery (PAS). A subsequent computed tomography (CT) scan was performed, which demonstrated multiple dilated small bowel loops, confirming SBO, and a blind-ending "C-shaped" bowel loop at the region of the terminal ileum. A diagnostic laparotomy was performed, which confirmed the presence of a Meckel's diverticulum. The tip of the Meckel's diverticulum was adherent to part of the small bowel mesentery, forming an internal hernia defect through which a loop of proximal ileum had herniated, resulting in SBO. She then underwent a laparoscopy-assisted transumbilical Meckel's diverticulectomy (LATUM). The patient recovered uneventfully and was discharged on the 4th postoperative day. CONCLUSIONS In children presenting with SBO, the possibility of Meckel's diverticulum as an etiology should be considered as a differential diagnosis. Early diagnosis and prompt intervention will improve clinical outcomes and avoid complications.

Control of Drug-Excipient Particle Attributes with Droplet Microfluidic-based Extractive Solidification Enables Improved Powder Rheology.

PURPOSE: Industrial implementation of continuous oral solid dosage form manufacturing has been impeded by the poor powder flow properties of many active pharmaceutical ingredients (APIs). Microfluidic droplet-based particle synthesis is an emerging particle engineering technique that enables the production of neat or composite microparticles with precise control over key attributes that affect powder flowability, such as particle size distribution, particle morphology, composition, and the API's polymorphic form. However, the powder properties of these microparticles have not been well-studied due to the limited mass throughputs of available platforms. In this work, we produce spherical API and API-composite microparticles at high mass throughputs, enabling characterization and comparison of the bulk powder flow properties of these materials and greater understanding of how particle-scale attributes correlate with powder rheology. METHODS: A multi-channel emulsification device and an extractive droplet-based method are harnessed to synthesize spherical API and API-excipient particles of artemether. As-received API and API crystallized in the absence of droplet confinement are used as control cases. Particle attributes are characterized for each material and correlated with a comprehensive series of powder rheology tests. RESULTS: The droplet-based processed artemether particles are observed to be more flowable, less cohesive, and less compressible than conventionally synthesized artemether powder. Co-processing the API with polycaprolactone to produce composite microparticles reduces the friction of the powder on stainless steel, a common equipment material. CONCLUSIONS: Droplet-based extractive solidification is an attractive particle engineering technique for improving powder processing and may aid in the implementation of continuous solid dosage form manufacturing.

Development of a serum miRNA panel for detection of early stage non-small cell lung cancer.

Minimally invasive testing for early detection of lung cancer to improve patient survival is a major unmet clinical need. This study aimed to develop and validate a serum multi-microRNA (multimiR) panel as a minimally invasive test for early detection of nonsmall cell lung cancer (NSCLC) regardless of smoking status, gender, and ethnicity. Our study included 744 NSCLC cases and 944 matched controls, including smokers and nonsmokers, male and female, with Asian and Caucasian subjects. Using RT-qPCR and a tightly controlled workflow, we quantified the absolute expression of 520 circulating microRNAs (miRNAs) in a Chinese cohort of 180 early stage NSCLC cases and 216 healthy controls (male smokers). Candidate biomarkers were verified in two case-control cohorts of 432 Chinese and 218 Caucasians, respectively (including females and nonsmokers). A multimiR panel for NSCLC detection was developed using a twofold cross-validation and validated in three additional Asian cohorts comprising 642 subjects. We discovered 35 candidate miRNA biomarkers, verified 22 of them, and developed a five-miR panel that detected NSCLC with area under curve (AUC) of 0.936-0.984 in the discovery and verification cohorts. The panel was validated in three independent cohorts with AUCs of 0.973, 0.916, and 0.917. The sensitivity of five-miR test was 81.3% for all stages, 82.9% for stages I and II, and 83.0% for stage I NSCLC, when the specificity is at 90.7%. We developed a minimally invasive five-miR serum test for detecting early stage NSCLC and validated its performance in multiple patient cohorts independent of smoking status, gender, and ethnicity.

Drug Development in Soft Tissue Sarcomas: Novel Targets and Recent Early Phase Trial Results.

Soft tissue sarcomas are a heterogeneous group of rare malignancies with few effective standard therapies. Our understanding of the underlying biology driving tumorigenesis in these mesenchymal tumors have led to a growth in drug development for soft tissue sarcomas. This review focuses on novel targets in soft tissue sarcomas, describes early clinical trial results of drugs directed at these targets, and discusses the data surrounding the use of these compounds in clinical practice and rationale for possible future US Food and Drug Administration approvals.

Microfluidic droplet liquid reactors for active pharmaceutical ingredient crystallization by diffusion controlled solvent extraction.

A novel method for crystallization utilizing solvent/antisolvent extraction in microfluidic droplet liquid reactors has been developed for rapid and low-cost screening of crystal polymorphism (i.e. molecular crystallographic arrangement or internal structure) and habit (i.e. crystallographic shape or external structure). The method involves a ternary solvent system consisting of a dispersed phase of two miscible fluids, one in which the active pharmaceutical ingredient (API) is soluble (solvent) and one in which the API is insoluble (antisolvent). The solvent/antisolvent dispersed phase is immiscible with a third continuous phase. Crystallization of an API, GSK1, was controlled within droplets by altering the rate of solvent extraction from droplets into the continuous phase, thereby decreasing API solubility. Crystal size, habit, and population per droplet were directly impacted by the solvent's rate of extraction. Single crystals were grown in individual droplets by slow extraction of solvent into the surrounding continuous phase, which occurs when crystal growth gradually reduces API concentration such that it is maintained within the metastable zone throughout extraction. Rapid extraction of solvent from droplets results in API concentration significantly exceeding its metastable limit, producing a greater number of crystal nuclei compared to slow extraction conditions. When holding constant solubilized API mass per droplet, crystal sizes were larger for slow extraction rates (l = 96.3, w = 16.6 µm) compared to fast extraction rates (l = 48.8, w = 9.5 µm) as a result of crystal growth occurring on fewer crystal nuclei per droplet. Crystal habit can be controlled by adjusting the solvent extraction rate and consequently the saturation, where minimal saturation resulted in a rhombohedral habit and comparatively higher saturation resulted in an acicular habit with a higher aspect ratio. Antisolvents were tested using two hydrophobic APIs demonstrating the method's capability for rapidly identifying favorable crystal morphologies for downstream manufacturability using miniscule amounts of API.

Ionic Liquid Aqueous Two-Phase Systems From a Pharmaceutical Perspective.

Aqueous Two-Phase Systems (ATPSs) have been extensively studied for their ability to simultaneously separate and purify active pharmaceutical ingredients (APIs) and key intermediates with high yields and high purity. Depending on the ATPS composition, it can be adapted for the separation and purification of cells, nucleic acids, proteins, antibodies, and small molecules. This method has been shown to be scalable, allowing it to be used in the milliliter scale for early drug development to thousands of liters in manufacture for commercial supply. The benefits of ATPS in pharmaceutical separations is increasingly being recognized and investigated by larger pharmaceutical companies. ATPSs use identical instrumentation and similar methodology, therefore a change from traditional methods has a theoretical low barrier of adoption. The cost of typical components used to form an ATPS at large scale, particularly that of polymer-polymer systems, is the primary challenge to widespread use across industry. However, there are a few polymer-salt examples where the increase in yield at commercial scale justifies the cost of using ATPSs for macromolecule purification. More recently, Ionic Liquids (ILs) have been used for ATPS separations that is more sustainable as a solvent, and more economical than polymers often used in ATPSs for small molecule applications. Such IL-ATPSs still retain much of the attractive characteristics such as customizable chemical and physical properties, stability, safety, and most importantly, can provide higher yield separations of organic compounds, and efficient solvent recycling to lower financial and environmental costs of large scale manufacturing.

Humanitarian and primary healthcare needs of refugee women and children in Afghanistan.

This Commentary describes the situation and healthcare needs of Afghans returning to their country of origin. With more than 600,000 Afghans returned from Pakistan and approximately 450,000 Afghans returned from Iran in 2016, the movement of people, which has been continuing in 2017, presents additional burden on the weak health system and confounds new health vulnerabilities especially for women and children. Stewardship and response is required at all levels: the central Ministry of Public Health, Provincial Health Departments and community leaders all have important roles, while continued support from development partners and technical experts is needed to assist the health sector to address the emergency and primary healthcare needs of returnee and internally displaced women, children and families.

Dacron Skirt Reconstruction of the Left Ventricular Outflow Tract: Extending the Capabilities of a Valved Conduit.

Aortic root reconstruction in the setting of redo aortic valve procedures or infective endocarditis may be technically challenging, particularly because of variable destruction or distortion of the left ventricular outflow tract. Homograft aortic root replacement is an excellent option for aortic root abscesses but is limited by homograft availability. We describe a simple technique of a bioprosthetic valved conduit constructed on the table using a Dacron (DuPont, Wilmington, DE) skirt below the valve. The use of the Dacron skirt facilitates easy reconstruction of the left ventricular outflow tract.

Security and privacy preserving approaches in the eHealth clouds with disaster recovery plan.

Cloud computing was introduced as an alternative storage and computing model in the health sector as well as other sectors to handle large amounts of data. Many healthcare companies have moved their electronic data to the cloud in order to reduce in-house storage, IT development and maintenance costs. However, storing the healthcare records in a third-party server may cause serious storage, security and privacy issues. Therefore, many approaches have been proposed to preserve security as well as privacy in cloud computing projects. Cryptographic-based approaches were presented as one of the best ways to ensure the security and privacy of healthcare data in the cloud. Nevertheless, the cryptographic-based approaches which are used to transfer health records safely remain vulnerable regarding security, privacy, or the lack of any disaster recovery strategy. In this paper, we review the related work on security and privacy preserving as well as disaster recovery in the eHealth cloud domain. Then we propose two approaches, the Security-Preserving approach and the Privacy-Preserving approach, and a disaster recovery plan. The Security-Preserving approach is a robust means of ensuring the security and integrity of Electronic Health Records, and the Privacy-Preserving approach is an efficient authentication approach which protects the privacy of Personal Health Records. Finally, we discuss how the integrated approaches and the disaster recovery plan can ensure the reliability and security of cloud projects.

Reconstructive valve surgery within 10 days of stroke in endocarditis.

BACKGROUND: The optimal timing of surgical treatment for infective endocarditis complicated by cerebrovascular events is controversial, largely due to the perceived risk of perioperative intracranial bleeding. Current guidelines suggest waiting 2 weeks between the diagnosis of stroke and surgery. The aim of this study was to investigate the clinical and neurological outcomes of early surgery following a stroke. METHODS: This was a single-center retrospective analysis of 12 consecutive patients requiring surgery for infective endocarditis between 2011 and 2014 at Rush University Medical Center, with either ischemic (n = 6) and/or hemorrhagic (n = 6) cerebrovascular complications. All underwent computed tomographic angiography prior to early valve reconstructive surgery to identify potentially actionable neurological findings. Early valve surgery was performed for ongoing sepsis or persistent emboli. Neurologic risk and outcome were assessed pre- and postoperatively using the National Institutes of Health Stroke Scale and the Glasgow Outcome Scale, respectively. RESULTS: All 12 patients underwent surgical treatment within 10 days of the diagnosis of stroke. Mortality in the immediate postoperative period was 8%. Eleven of the 12 patients exhibited good neurological recovery in the immediate postoperative period, with a Glasgow Outcome Scale score ≥ 3. There was no correlation between duration of cardiopulmonary bypass and neurological outcomes. CONCLUSION: Early cardiac surgery in patients with infective endocarditis and stroke maybe lifesaving with a low neurological risk. Comprehensive neurovascular imaging may help in identifying patient-related risk factors.

Complex Tricuspid Valve Repair in Patients With Pacer Defibrillator-Related Tricuspid Regurgitation.

Tricuspid valve regurgitation in patients with heart failure or in those undergoing complex cardiac operations is associated with increased morbidity and mortality. We report our results with a technique of repairing the tricuspid valves while retaining the pacer defibrillator lead. Patients had tricuspid valve repairs that included repositioning of the pacer defibrillator lead, approximation of septal and inferior/posterior leaflets in a modified cleft repair, and implantation of a tricuspid annuloplasty ring. This procedure was performed in more than 42 patients with good success.

Data selection in EEG signals classification.

The alcoholism can be detected by analyzing electroencephalogram (EEG) signals. However, analyzing multi-channel EEG signals is a challenging task, which often requires complicated calculations and long execution time. This paper proposes three data selection methods to extract representative data from the EEG signals of alcoholics. The methods are the principal component analysis based on graph entropy (PCA-GE), the channel selection based on graph entropy (GE) difference, and the mathematic combinations channel selection, respectively. For comparison purposes, the selected data from the three methods are then classified by three classifiers: the J48 decision tree, the K-nearest neighbor and the Kstar, separately. The experimental results show that the proposed methods are successful in selecting data without compromising the classification accuracy in discriminating the EEG signals from alcoholics and non-alcoholics. Among them, the proposed PCA-GE method uses only 29.69% of the whole data and 29.5% of the computation time but achieves a 94.5% classification accuracy. The channel selection method based on the GE difference also gains a 91.67% classification accuracy by using only 29.69% of the full size of the original data. Using as little data as possible without sacrificing the final classification accuracy is useful for online EEG analysis and classification application design.

Approach to using mechanism-based structure activity relationship (SAR) analysis to assess human health hazard potential of nanomaterials.

With the increasing use and development of engineered nanoparticles in electronics, consumer products, pesticides, food and pharmaceutical industries, there is a growing concern about potential human health hazards of these materials. A number of studies have demonstrated that nanoparticle toxicity is extremely complex, and that the biological activity of nanoparticles will depend on a variety of physicochemical properties such as particle size, shape, agglomeration state, crystal structure, chemical composition, surface area and surface properties. Nanoparticle toxicity can be attributed to nonspecific interaction with biological structures due to their physical properties (e.g., size and shape) and biopersistence, or to specific interaction with biomolecules through their surface properties (e.g., surface chemistry and reactivity) or release of toxic ions. The toxic effects of most nanomaterials have not been adequately characterized and currently, there are many issues and challenges in toxicity testing and risk assessment of nanoparticles. Based on the possible mechanisms of action and available in vitro and in vivo toxicity database, this paper proposes an approach to using mechanism-based SAR analysis to assess the relative human health hazard/risk potential of various types of nanomaterials.

Geometric perturbations in multiheaded papillary tip positions associated with acute ovine ischemic mitral regurgitation.

BACKGROUND: Novel surgical approaches are focusing on the "ventricular disease" of ischemic mitral regurgitation (IMR), to correct altered papillary muscle (PM) tip positions (apical displacement) and ameliorate leaflet tethering. Due to the anatomic complexity of the subvalvular apparatus, however, the precise geometric perturbations of the multiheaded PM tips associated with IMR remain uncharacterized. METHODS: In 6 adult sheep, we implanted 3 markers on each PM. To specifically identify distinct PM tips, 1 marker was placed on the PM origin of the dominant chord to the anterior, posterior, and commissural leaflets. Nine markers were placed on the edge of the posterior mitral leaflet, and 5 on the edge of the anterior mitral leaflet. Eight markers were sewn around the mitral annulus. Animals were studied immediately postoperatively, with biplane videofluoroscopy and transesophageal echocardiography, before and during acute snare occlusion of the proximal left circumflex coronary artery, to induce IMR. Papillary muscle tip and leaflet edge geometry was expressed as the orthogonal distance of each respective marker to the least-squares mitral annulus plane at end-systole. In addition, the distance from each PM tip marker to the mitral annulus "saddle horn" was calculated. RESULTS: Acute left circumflex occlusion significantly increased mitral regurgitation from a baseline of 0.7 ± 0.3 to 2.5 ± 0.5 (P < .05). The IMR was associated with posterior leaflet restriction near the central leaflet edge, with simultaneous prolapse of both leaflets near the posterior commissure. No apical displacement of PM tips was observed during IMR, although the posterior PM moved farther away from the midseptal annulus. CONCLUSIONS: During acute ischemia, no apical displacement of any PM tip was observed. Posterior PM movement away from the annular saddle horn, and toward the annulus, was associated with IMR and leaflet prolapse near the posterior commissure, and with restriction near the valve center. These data may help guide development of surgical interventions aimed at PM repositioning.

Tetrabromobisphenol A (TBBPA): Possible modes of action of toxicity and carcinogenicity in rodents.

Due to potential consumer exposures, the toxicity of tetrabromobisphenol A (TBBPA) has been extensively studied. Reviews of TBBPA concluded no concerns regarding human health risks. The low toxicity of TBBPA is consistent with low bioavailability. However, some oral toxicity studies in rodents with TBBPA reported changes in thyroid hormone levels and a carcinogenicity study with TBBPA showed increased incidences of uterine tumors in rats. This review analyzes several modes of action (MoA) that may account for the observed thyroxine hormone changes and the uterine tumors. It concludes that the potential modes of action for thyroid changes induced by TBBPA are expected to exhibit a threshold for adverse effects due to the ability of the mammalian organism to compensate small changes in thyroid hormone levels. Regarding MoAs for the uterine tumors, TBBPA does not exert genotoxic or estrogenic effects. Available evidence suggests that TBBPA may increase levels of circulating estrogens by a competitive inhibition of estrogen conjugation and produce uterine tumors by promoting pre-existing Tp53-mutations due to increased estrogen levels resulting in increased cell proliferation.

Recent microfluidic devices for studying gamete and embryo biomechanics.

The technical challenges of biomechanic research such as single cell analysis at a high monetary cost, labor, and time for just a small number of measurements is a good match to the strengths of microfluidic devices. New scientific discoveries in the fertilization and embryo development process, of which biomechanics is a major subset of interest, is crucial to fuel the continual improvement of clinical practice in assisted reproduction. The following review will highlight some recent microfluidic devices tailored for gamete and embryo biomechanics where biomimicry arises as a major theme of microfluidic device design and function, and the application of fundamental biomechanic principles are used to improve outcomes of cryopreservation.

Elongation of fibers from highly viscous dextran solutions enables fabrication of rapidly dissolving drug carrying fabrics.

A simple method is presented for forming thread-like fibers from highly viscous dextran solutions. Based on the cohesive and adhesive forces between a dextran solution and the substrate to which it is applied, multiple fibers of approximately 10 µm in diameter can be elongated simultaneously. These fibers can be woven into multiple layers to produce fabrics of varying fiber orientations and mechanical properties. Various bioactive agents can be incorporated into the dextran solution prior to fiber formation, including hemostatic and antibiotic agents. Fabrics containing thrombin are capable of coagulating human platelet poor plasma in vitro. Fabrics containing antibiotics are capable of suppressing bacterial growth in a disk diffusion assay. These data suggest that this new material composed entirely of dextran has promise as a drug delivery component in wound dressings.

A transgenic mouse model demonstrating the oncogenic role of mutations in the polycomb-group gene EZH2 in lymphomagenesis.

The histone methyltransferase EZH2 is frequently mutated in germinal center-derived diffuse large B-cell lymphoma and follicular lymphoma. To further characterize these EZH2 mutations in lymphomagenesis, we generated a mouse line where EZH2(Y641F) is expressed from a lymphocyte-specific promoter. Spleen cells isolated from the transgenic mice displayed a global increase in trimethylated H3K27, but the mice did not show an increased tendency to develop lymphoma. As EZH2 mutations often coincide with other mutations in lymphoma, we combined the expression of EZH2(Y641F) by crossing these transgenic mice with Eµ-Myc transgenic mice. We observed a dramatic acceleration of lymphoma development in this combination model of Myc and EZH2(Y641F). The lymphomas show histologic features of high-grade disease with a shift toward a more mature B-cell phenotype, increased cycling and gene expression, and epigenetic changes involving important pathways in B-cell regulation and function. Furthermore, they initiate disease in secondary recipients. In summary, EZH2(Y641F) can collaborate with Myc to accelerate lymphomagenesis demonstrating a cooperative role of EZH2 mutations in oncogenesis. This murine lymphoma model provides a new tool to study global changes in the epigenome caused by this frequent mutation and a promising model system for testing novel treatments.

Extended wakefulness: compromised metabolics in and degeneration of locus ceruleus neurons.

Modern society enables a shortening of sleep times, yet long-term consequences of extended wakefulness on the brain are largely unknown. Essential for optimal alertness, locus ceruleus neurons (LCns) are metabolically active neurons that fire at increased rates across sustained wakefulness. We hypothesized that wakefulness is a metabolic stressor to LCns and that, with extended wakefulness, adaptive mitochondrial metabolic responses fail and injury ensues. The nicotinamide adenine dinucleotide-dependent deacetylase sirtuin type 3 (SirT3) coordinates mitochondrial energy production and redox homeostasis. We find that brief wakefulness upregulates SirT3 and antioxidants in LCns, protecting metabolic homeostasis. Strikingly, mice lacking SirT3 lose the adaptive antioxidant response and incur oxidative injury in LCns across brief wakefulness. When wakefulness is extended for longer durations in wild-type mice, SirT3 protein declines in LCns, while oxidative stress and acetylation of mitochondrial proteins, including electron transport chain complex I proteins, increase. In parallel with metabolic dyshomeostasis, apoptosis is activated and LCns are lost. This work identifies mitochondrial stress in LCns upon wakefulness, highlights an essential role for SirT3 activation in maintaining metabolic homeostasis in LCns across wakefulness, and demonstrates that extended wakefulness results in reduced SirT3 activity and, ultimately, degeneration of LCns.