Silicon Micropore-Based Parallel Plate Membrane Oxygenator.

Extracorporeal membrane oxygenation (ECMO) is a life support system that circulates the blood through an oxygenating system to temporarily (days to months) support heart or lung function during cardiopulmonary failure until organ recovery or replacement. Currently, the need for high levels of systemic anticoagulation and the risk for bleeding are main drawbacks of ECMO that can be addressed with a redesigned ECMO system. Our lab has developed an approach using microelectromechanical systems (MEMS) fabrication techniques to create novel gas exchange membranes consisting of a rigid silicon micropore membrane (SµM) support structure bonded to a thin film of gas-permeable polydimethylsiloxane (PDMS). This study details the fabrication process to create silicon membranes with highly uniform micropores that have a high level of pattern fidelity. The oxygen transport across these membranes was tested in a simple water-based bench-top set-up as well in a porcine in vivo model. It was determined that the mass transfer coefficient for the system using SµM-PDMS membranes was 3.03 ± 0.42 mL O2 min-1 m-2 cm Hg-1 with pure water and 1.71 ± 1.03 mL O2 min-1 m-2 cm Hg-1 with blood. An analytic model to predict gas transport was developed using data from the bench-top experiments and validated with in vivo testing. This was a proof of concept study showing adequate oxygen transport across a parallel plate SµM-PDMS membrane when used as a membrane oxygenator. This work establishes the tools and the equipoise to develop future generations of silicon micropore membrane oxygenators.

Factors associated with trauma recidivism in young children.

BACKGROUND: Trauma recidivism is associated with future trauma-associated morbidity and mortality. Previous evidence suggests that socioeconomic factors predict trauma recidivism in older children (10-18 years); however, risk factors in US children 10 years and younger have not been studied. We sought to determine the factors associated with trauma recidivism in young children 10 years and younger. METHODS: We conducted a retrospective cohort study of pediatric trauma patients 10 years and younger who presented to a single American College of Surgeons-verified Level I pediatric trauma center from July 1, 2017, to June 30, 2021. All patients were evaluated for prior injury during trauma registry entry. Characteristics at the index injury were collected via chart review. Patients were geocoded to assess Social Vulnerability Index. Logistic regression examined factors associated with recidivism. Best subset selection was used to compare multivariable models and identify the most predictive and parsimonious model. Statistical significance was set at p < 0.05. RESULTS: Of the 3,518 patients who presented in the study period, 169 (4.8%) experienced a prior injury. Seventy-six percent (n = 128) had one prior injury presentation, 18% (n = 31) had two prior presentations, and 5.9% (n = 10) had three or more. Falls were the most common mechanism in recidivists (63% vs. 52%, p = 0.009). Child physical abuse occurred in 6.5% of patients, and 0.9% experienced penetrating injury. The majority (n = 137 [83%]) were discharged home from the emergency department. There was no significant difference in the frequency of penetrating injury and child physical abuse between recidivists and nonrecidivists. Following logistic regression, the most parsimonious model demonstrated that recidivism was associated with comorbidities, age, falls, injury location, nontransfer, and racialization. No significant associations were found with Social Vulnerability Index and insurance status. CONCLUSION: Medical comorbidities, young age, injury location, and falls were primarily associated with trauma recidivism. Support for parents of young children and those with special health care needs through injury prevention programs could reduce trauma recidivism in this population. LEVEL OF EVIDENCE: Prognostic and Epidemiological; Level III.

Management challenges of a large upper extremity vascular malformation in a patient with capillary malformation-arteriovenous malformation syndrome.

We describe a 17-year-old boy with capillary malformation-arteriovenous malformation syndrome and a massive vascular malformation of the right chest wall, shoulder, and upper arm. Persistent growth of the malformation caused cutaneous ulcerations and recurrent massive bleeding episodes. We proceeded with a modified shoulder disarticulation preceded by ligation of the subclavian artery and innominate vein by median sternotomy. After a staged debulking resection of the residual chest wall arteriovenous malformation with rotational transverse rectus abdominis myocutaneous flap coverage, the patient was discharged home safely. This report demonstrates that a multidisciplinary approach is critical for management of life-threatening complications in capillary malformation-arteriovenous malformation patients.

Multiple genetic alterations in papillary thyroid cancer are associated with younger age at presentation.

BACKGROUND: There is a significant gender and age disparity in thyroid cancer incidence and outcome. The molecular basis for these divergent clinical presentations and outcome are essentially unknown. METHODS: The primary tumor genotype in 217 patients with papillary thyroid cancer was determined for six common somatic genetic alterations (RET/PTC1, RET/PTC3, and NTRK1 rearrangements, and BRAF V600E, KRAS, and NRAS hotspot mutations) by PCR and direct sequencing, and nested PCR. Univariate and multivariate analyses were performed to determine the association of genetic changes and age, gender, and other clinicopathologic factors. RESULTS: One hundred twenty-one of the 190 conventional papillary thyroid carcinoma samples (63.7%) had at least one genetic alteration, and 27 of the samples (14.2%) had more than one alteration. In the follicular variant of papillary thyroid carcinomas, 13 of the 27 samples (48.1%) had at least one genetic alteration and three of the 27 samples (11.1%) had more than one. The presence of multiple genetic alterations was associated with younger age at diagnosis (P=0.034), mean difference of 8 y earlier. We found no significant association with the number or type of genetic alterations present by gender, tumor size, extent of tumor differentiation, multicentricity, lymph node metastasis, distant metastases, TNM stage, and the AMES risk group. The association of multiple genetic alterations and younger age were independent of tumor size, lymph node or distant metastasis, TNM stage, or AMES risk group. CONCLUSIONS: Multiple genetic alterations are more common in younger patients with papillary thyroid cancer, but there is no difference in the type or number of genetic alterations by gender. Our findings suggest that multiple genetic alterations in thyroid cancer may be associated with earlier disease initiation and or progression.

Molecular testing for somatic mutations improves the accuracy of thyroid fine-needle aspiration biopsy.

BACKGROUND: Thyroid fine-needle aspiration (FNA) biopsy is indeterminate or suspicious in up to 30% of cases and these patients are commonly subjected to at least a diagnostic hemithyroidectomy. If malignant on histology, a completion thyroidectomy is usually performed, which may be associated with higher morbidity. To determine the clinical utility of genetic testing in thyroid FNA biopsy, we conducted a prospective clinical trial. METHODS: Four hundred seventeen patients with 455 thyroid nodules were enrolled and had genetic testing for common somatic mutations (BRAF, NRAS, KRAS) and gene rearrangements (RET/PTC1, RET/PTC3, RAS, TRK1) by PCR and direct sequencing and by nested PCR, respectively. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of genetic testing in thyroid FNA biopsy were determined based on the histologic diagnosis. RESULTS: One hundred twenty-five of 455 thyroid nodule FNA biopsies were indeterminate or suspicious on cytologic examination. Overall, 50 mutations were identified (23 BRAF, 4 RET/PTC1, 2 RET/PTC3, 21 NRAS) in the thyroid FNA biopsies. There were significantly more mutations detected in malignant thyroid nodules than in benign (P = 0.0001). For thyroid FNA biopsies that were indeterminate or suspicious, genetic testing had a sensitivity of 12%, specificity of 98%, PPV of 38%, and NPV of 65%. CONCLUSIONS: Genetic testing for somatic mutations in thyroid FNA biopsy samples is feasible and identifies a subset of malignant thyroid neoplasms that are indeterminate or suspicious on FNA biopsy. Genetic testing for common somatic genetic alterations thus could allow for more definitive initial thyroidectomy in those with positive results.

Sterilization effects on ultrathin film polymer coatings for silicon-based implantable medical devices.

Novel biomaterials for medical device applications must be stable throughout all stages of preparation for surgery, including sterilization. There is a paucity of information on the effects of sterilization on sub-10 nm-thick polymeric surface coatings suitable for silicon-based bioartificial organs. This study explores the effect of five standard sterilization methods on three surface coatings applied to silicon: polyethylene glycol (PEG), poly(sulfobetaine methacrylate) (pSBMA), and poly (2-methacryloyloxyethyl phosphorylcholine) (pMPC). Autoclave, dry heat, hydrogen peroxide (H2 O2 ) plasma, ethylene oxide gas (EtO), and electron beam (E-beam) treated coatings were analyzed to determine possible polymer degradation with sterilization. Poststerilization, there were significant alterations in contact angle, maximum change resulting from H2 O2 (Δ - 14°), autoclave (Δ + 15°), and dry heat (Δ + 23°) treatments for PEG, pSBMA, and pMPC, respectively. Less than 5% coating thickness change was found with autoclave and EtO on PEG-silicon, E-beam on pSBMA-silicon and EtO treatment on pMPC-silicon. H2 O2 treatment resulted in at least 30% decrease in thickness for all coatings. Enzyme-linked immunosorbent assays showed significant protein adsorption increase for pMPC-silicon following all sterilization methods. E-beam on PEG-silicon and dry-heat treatment on pSBMA-silicon exhibited maximum protein adsorption in each coating subset. Overall, the data suggest autoclave and EtO treatments are well-suited for PEG-silicon, while E-beam is best suited for pSBMA-silicon. pMPC-silicon was least impacted by EtO treatment. H2 O2 treatment had a negative effect on all three coatings. These results can be used to determine which surface modifications and sterilization processes to utilize for devices in vivo. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 2327-2336, 2018.

Lower Gastrointestinal Bleeding & Intussusception.

Relatively uncommon compared with the adult population, lower gastrointestinal bleeding in children requires expeditious evaluation and management because of the variety of causes ranging from benign to life-threatening conditions. The causes of lower gastrointestinal bleeding (LGIB) vary with patient age. This review focuses on the differential diagnosis and management of LGIB in children. Because intussusception is one of the most common sources of LGIB, particular attention will be given to its diagnosis and management.

Radiologic assessment of fetal tracheal balloon occlusion.

Fetal endoscopic tracheal occlusion (FETO) is a novel technique to treat cases of isolated severe congenital diaphragmatic hernia (CDH). Although there are benefits of MRI over ultrasound in assessing lung volumes, it is unknown whether there are benefits of MRI for localizing the tracheal balloon. This is a retrospective study reviewing the imaging characteristics of FETO in patients who underwent both MRI and ultrasound exams done to localize tracheal balloons.

An intravascular bioartificial pancreas device (iBAP) with silicon nanopore membranes (SNM) for islet encapsulation under convective mass transport.

Diffusion-based bioartificial pancreas (BAP) devices are limited by poor islet viability and functionality due to inadequate mass transfer resulting in islet hypoxia and delayed glucose-insulin kinetics. While intravascular ultrafiltration-based BAP devices possess enhanced glucose-insulin kinetics, the polymer membranes used in these devices provide inadequate ultrafiltrate flow rates and result in excessive thrombosis. Here, we report the silicon nanopore membrane (SNM), which exhibits a greater hydraulic permeability and a superior pore size selectivity compared to polymer membranes for use in BAP applications. Specifically, we demonstrate that the SNM-based intravascular BAP with ∼10 and ∼40 nm pore sized membranes support high islet viability (>60%) and functionality (<15 minute insulin response to glucose stimulation) at clinically relevant islet densities (5700 and 11 400 IE per cm2) under convection in vitro. In vivo studies with ∼10 nm pore sized SNM in a porcine model showed high islet viability (>85%) at clinically relevant islet density (5700 IE per cm2), c-peptide concentration of 144 pM in the outflow ultrafiltrate, and hemocompatibility under convection. These promising findings offer insights on the development of next generation of full-scale intravascular devices to treat T1D patients in the future.

Correction: An intravascular bioartificial pancreas device (iBAP) with silicon nanopore membranes (SNM) for islet encapsulation under convective mass transport.

Correction for 'An intravascular bioartificial pancreas device (iBAP) with silicon nanopore membranes (SNM) for islet encapsulation under convective mass transport' by Shang Song et al., Lab Chip, 2017, 17, 1778-1792.

Diffusive Silicon Nanopore Membranes for Hemodialysis Applications.

Hemodialysis using hollow-fiber membranes provides life-sustaining treatment for nearly 2 million patients worldwide with end stage renal disease (ESRD). However, patients on hemodialysis have worse long-term outcomes compared to kidney transplant or other chronic illnesses. Additionally, the underlying membrane technology of polymer hollow-fiber membranes has not fundamentally changed in over four decades. Therefore, we have proposed a fundamentally different approach using microelectromechanical systems (MEMS) fabrication techniques to create thin-flat sheets of silicon-based membranes for implantable or portable hemodialysis applications. The silicon nanopore membranes (SNM) have biomimetic slit-pore geometry and uniform pores size distribution that allow for exceptional permeability and selectivity. A quantitative diffusion model identified structural limits to diffusive solute transport and motivated a new microfabrication technique to create SNM with enhanced diffusive transport. We performed in vitro testing and extracorporeal testing in pigs on prototype membranes with an effective surface area of 2.52 cm2 and 2.02 cm2, respectively. The diffusive clearance was a two-fold improvement in with the new microfabrication technique and was consistent with our mathematical model. These results establish the feasibility of using SNM for hemodialysis applications with additional scale-up.

Prevalence, clinicopathologic features, and somatic genetic mutation profile in familial versus sporadic nonmedullary thyroid cancer.

BACKGROUND: Although hereditary nonmedullary thyroid cancer is recognized as a distinct and isolated familial syndrome, the precise prevalence and genetic basis are poorly understood. Moreover, whether familial nonmedullary thyroid cancer (FNMTC) has a more aggressive clinical behavior is controversial. The objectives of this study were to determine the prevalence of FNMTC, and compare the extent of disease and tumor somatic genetic alteration in patients with familial and sporadic papillary thyroid cancer. METHODS: The main study entry criterion was patients who had a thyroid nodule that required a clinical evaluation with fine-needle aspiration biopsy and or thyroidectomy. A family history questionnaire was used to determine the presence of familial and sporadic thyroid cancer. Thyroid nodule fine-needle aspiration biopsy samples and tumor tissue at the time of thyroidectomy were used to test for somatic genetic mutations (BRAF V600E, NRAS, KRAS, NTRK1, RET/PTC1, and RET/PTC3). RESULTS: There were 402 patients with 509 thyroid nodules enrolled in the study. The prevalence of FNMTC was 8.8% in all patients with thyroid cancer and 9.4% in patients with only papillary thyroid cancer. None of the patients with FNMTC had another familial cancer syndrome. There was no significant difference in gender, tumor size, lymph node metastasis, and overall stage between sporadic and familial cases of thyroid cancer. Patients with FNMTC were younger at diagnosis than patients with sporadic papillary thyroid cancer (p < 0.002). Seventy-nine of the 504 thyroid nodules had somatic genetic mutations (29 BRAF V600E, 29 NRAS, 8 KRAS, 1 NTRK1, 4 RET/PTC1, and 8 RET/PTC3). There was no significant difference in the number or type of somatic mutations between sporadic and hereditary cases of papillary thyroid cancer. CONCLUSIONS: We found a higher prevalence of FNMTC in patients with papillary thyroid cancer than previously reported. Patients with FNMTC present at a younger age. Somatic mutations and extent of disease are similar in sporadic and FNMTC cases.

Clinical and molecular features of papillary thyroid cancer in adolescents and young adults.

BACKGROUND: Age disparities in thyroid cancer incidence and outcome among adolescents and young adults (AYAs) with thyroid cancer are under reported. In this study, the authors compared the molecular and clinical features of papillary thyroid cancer (PTC) in AYAs with the same features among patients in other age groups. METHODS: One thousand eleven patients underwent initial treatment for PTC at the University of California at San Francisco. Patients were subdivided into 2 age groups: ages 15 to 39 years (the AYA group) and aged ≥40 years. Demographic, clinical, and survival data in the cohort also were compared with data from the National Cancer Instsitute's Surveillance, Epidemiology, and End Results (SEER) Program. In a subset of the study cohort, the primary tumors were analyzed by genome-wide expression analyses, genotyping for common somatic mutations, and pathway-specific gene expression arrays between the age groups. RESULTS: The percentage of women and the lymph node metastasis rate were significantly higher in the AYA group. In the AYA group, the rate of distant metastasis was lower. Disease-free survival and median overall survival were significantly higher in the AYA group. The better survival in AYA patients also was apparent in the national SEER data. An unsupervised cluster analysis of gene expression data revealed no distinct clustering by age in 96 PTC samples. The frequency and type of somatic mutations in the primary tumors did not differ significantly between age groups (the AYA group vs the group aged ≥40 years). Six genes (extracellular matrix protein 1 [ECM1], v-erb-2 erythroblastic leukemia viral oncogene homolog 2 [ERBB2], urinary plasminogen activator [UPA], 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 2 [PFKFB2], meis homeobox 2 [MEIS2], and carbonic anhydrase II [CA2]) had significant differential expression between age groups. CONCLUSIONS: The extent of disease at presentation and the survival of patients with PTC differed between AYAs and older patients. The current results indicated that these differences may be caused by several candidate genes and that these genes are expressed differentially and may play an important role in tumor cell biology. However, no distinct gene expression profiles exist for patients with PTC that distinguish between AYAs and patients aged ≥40 years.

A prospective study evaluating the accuracy of using combined clinical factors and candidate diagnostic markers to refine the accuracy of thyroid fine needle aspiration biopsy.

BACKGROUND: Approximately 30% of fine needle aspiration biopsies of the thyroid have inconclusive results. We conducted a prospective trial to determine whether clinical and molecular markers could be used in combination to improve the accuracy of thyroid fine needle aspiration biopsy. METHODS: Clinical, tumor genotyping for common somatic mutations (BRAF V600E, NRAS, KRAS, RET/PTC1, RET/PTC3, and NTRK1), and the gene expression levels of 6 candidate diagnostic markers were analyzed by univariate and multivariate methods in 341 patients to determine whether they could distinguish reliably benign from malignant thyroid neoplasms, and a scoring model was derived. RESULTS: By a multivariate analysis, fine needle aspiration biopsy cytology classification, the presence of a NRAS mutation, and the tissue inhibitor of metalloproteinase 1 expression level were associated jointly with malignancy. The overall accuracy of the scoring model, including these 3 variables, to distinguish benign from malignant thyroid tumors was 91%, including 67% for the indeterminate and 77% for the suspicious FNA subgroups. CONCLUSION: Fine needle aspiration biopsy cytology classification, the presence of NRAS mutation, and tissue inhibitor of metalloproteinase 1 messenger RNA expression levels in combination provide a greater diagnostic accuracy than fine needle aspiration biopsy cytology alone to allow selection of more definitive initial operative treatment. The sensitivity of the scoring model, however, was too low to avoid the need for diagnostic thyroidectomies for indeterminate fine needle aspiration biopsy findings.

Clinical features and genetic predisposition to hereditary nonmedullary thyroid cancer.

BACKGROUND: Approximately 5% of the nonmedullary thyroid cancers are hereditary. Hereditary nonmedullary thyroid cancer may occur as a minor component of familial cancer syndromes (familial adenomatous polyposis, Gardner's syndrome, Cowden's disease, Carney's complex type 1, Werner's syndrome, and papillary renal neoplasia) or as a primary feature (familial nonmedullary thyroid cancer [FNMTC]). The goal of this article was to review our current knowledge on the hereditary nonmedullary thyroid cancer. SUMMARY: Epidemiologic and clinical kindred studies have demonstrated that FNMTC is a unique clinical entity. Most studies suggest that FNMTC is associated with more aggressive disease than sporadic cases, with higher rates of multicentric tumors, lymph node metastasis, extrathyroidal invasion, and shorter disease-free survival. A hereditary predisposition to nonmedullary thyroid cancer is well established, but the susceptibility genes for isolated FNMTC have not been identified. However, additional susceptibility loci for FNMTC have been recently identified in classic isolated cases of FNMTC (1q21, 6q22, 8p23.1-p22, and 8q24). CONCLUSIONS: More studies are needed to validate chromosomal susceptibility loci and identify the susceptibility genes for FNMTC. The discovery of the predisposing genes may allow for screening and early diagnosis, which could lead to improved outcomes for patients and their families.