Potentiometric detection of apomorphine in human plasma using a 3D printed sensor.

Apomorphine is a dopamine agonist that is used for the management of Parkinson's disease and has been proven to effectively decrease the off-time duration, where the symptoms recur, in Parkinson's disease patients. This paper describes the design and fabrication of the first potentiometric sensor for the determination of apomorphine in bulk and human plasma samples. The fabrication protocol involves stereolithographic 3D printing, which is a unique tool for the rapid fabrication of low-cost sensors. The solid-contact apomorphine ion-selective electrode combines a carbon-mesh/thermoplastic composite as the ion-to-electron transducer and a 3D printed ion-selective membrane, doped with the ionophore calix[6]arene. The sensor selectively measures apomorphine in the presence of other biologically present cations - sodium, potassium, magnesium, and calcium - as well as the commonly prescribed Parkinson's pharmaceutical, levodopa (L-Dopa). The sensor demonstrated a linear, Nernstian response, with a slope of 58.8 mV/decade over the range of 5.0 mM-9.8 µM, which covers the biologically (and pharmaceutically) relevant ranges, with a limit of detection of 2.51 µM. Moreover, the apomorphine sensor exhibited good stability (minimal drift of just 188 µV/hour over 10 h) and a shelf-life of almost 4 weeks. Experiments performed in the presence of albumin, the main plasma protein to which apomorphine binds, demonstrate that the sensor responds selectively to free-apomorphine (i.e., not bound or complexed forms). The utility of the sensor was confirmed through the successful determination of apomorphine in spiked human plasma samples.

Smartphone-based detection of levodopa in human sweat using 3D printed sensors.

Parkinson's disease (PD) is one of the leading neurological disorders negatively impacting health on a global scale. Patients diagnosed with PD require frequent monitoring, prescribed medications, and therapy for extended periods as symptom severity worsens. The primary pharmaceutical treatment for PD patients is levodopa (L-Dopa) which reduces many symptoms experienced by PD patients (e.g., tremors, cognitive ability, motor dysfunction, etc.) through the regulation of dopamine levels in the body. Herein, the first detection of L-Dopa in human sweat using a low-cost 3D printed sensor with a simple and rapid fabrication protocol combined with a portable potentiostat wirelessly connected to a smartphone via Bluetooth is reported. By combining saponification and electrochemical activation into a single protocol, the optimized 3D printed carbon electrodes were able to simultaneously detect uric acid and L-Dopa throughout their biologically relevant ranges. The optimized sensors provided a sensitivity of 83 ± 3 nA/µM from 24 µM to 300 nM L-Dopa. Common physiological interferents found in sweat (e.g., ascorbic acid, glucose, caffeine) showed no influence on the response for L-Dopa. Lastly, a percent recovery of L-Dopa in human sweat using a smartphone-assisted handheld potentiostat resulted in the recovery of 100 ± 8%, confirming the ability of this sensor to accurately detect L-Dopa in sweat.

Symptoms of Women With High-Risk Early-Stage Ovarian Cancer.

OBJECTIVE: To assess the presentation, characteristics, and prognostic significance of symptoms in patients with high-risk early-stage epithelial ovarian cancer. METHODS: A retrospective chart review was performed on all patients enrolled in a phase III clinical trial (GOG 157). All patients had surgically staged, high-risk early-stage epithelial ovarian cancer (stage IA-IB and grade 3, any clear cell, stage IC or II). Chi-square and Kaplan-Meier estimates and Cox proportional hazards models were used for statistical analyses. RESULTS: Of 419 patients evaluated for symptoms, 301 (72%) presented with one or more symptoms, and 118 (28%) were asymptomatic but had a mass found on examination. Forty percent had only one symptom, and 32% had more than one symptom. Among those with at least one symptom, the most common were abdominal and pelvic pain (31%), and increased girth or fullness (26%). Overall, 23% of patients with tumors 10 cm or smaller, 27% of patients with tumors larger than 10 cm to 15 cm, and 46% of patients with tumors larger than 15 cm had multiple symptoms (P<.001). There was no significant difference in presentation of symptoms based on age, stage, or histologic subtype. Symptoms at diagnosis were not associated with recurrence or survival. CONCLUSION: More than 70% of patients with high-risk early-stage, epithelial ovarian cancer present with one or more symptoms, with the most common being abdominal or pelvic pain. The proportion of women with symptoms and the number of symptoms increase with enlarging tumor size.

3D Printed Ion-Selective Membranes and Their Translation into Point-of-Care Sensors.

This technical note describes a method for fabricating ion-selective membranes (ISMs) for use in potentiometric sensing by using 3D printing technology. Here, we demonstrate the versatility of this approach by fabricating ISMs and investigating their performance in both liquid-contact and solid-contact ion-selective electrode (ISE) configurations. Using 3D printed ISMs resulted in highly stable (drift of ∼17 µV/h) and highly reproducible (<1 mV deviation) measurements. Furthermore, we show the seamless translation of these membranes into reliable, carbon fiber- and paper-based potentiometric sensors for applications at the point-of-care. To highlight the modifiability of this approach, we fabricated sensors for bilirubin, an important biomarker of liver health; benzalkonium, a common preservative used in the pharmaceutical industry; and potassium, an important blood electrolyte. The ability to mass produce sensors using 3D printing is an attractive advantage over conventional methods, while also decreasing the time and cost associated with sensor fabrication.

"Shape-Coding": Morphology-Based Information System for Polymers and Composites.

Fiber-reinforced composites have become the material of choice for aerospace structures because of their favorable strength-to-weight ratio. Given the increasing amounts of counterfeit composite parts showing up in the complex aerospace supply chain, it is absolutely vital to track a composite part throughout its lifecycle-from production to usage and to disposal. Existing barcoding methods are invasive, affect the structural properties of composites, and/or are vulnerable to tampering. We describe a universal method to store information in fiber-reinforced composites based on solid-state in situ reduction leading to embedded nanoparticles with controlled morphologies. This simple, cost-effective, mild, surfactant-free, and one-step protocol for the fabrication of embedded platinum nanostructures leads to morphology-based barcodes for polymeric composites. We also describe a coding methodology wherein a 1 × 1 cm code can represent 3.4 billion parts to 95 trillion parts, depending on the resolution required along with access to morphology-based chemical encryption systems.

The effect of art therapy on the quality of life in patients with a gynecologic cancer receiving chemotherapy.

OBJECTIVES: Most art therapy research has involved patients with malignancies other than gynecologic cancer. The current study aimed to assess the impact of an art therapy intervention on the quality of life (QOL) in patients with gynecologic cancer who were receiving chemotherapy. METHODS: This was a prospective, non-randomized, pilot study. Eligible patients had a primary or recurrent gynecologic malignancy scheduled to be treated with at least 6 cycles of chemotherapy over 18 weeks. The intervention consisted of five sessions of art therapy during the chemotherapy. Patients completed a Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire prior to starting chemotherapy, and again at completion of the fifth session. Differences between the FACT-G scores were examined by paired t-tests. An increase in the mean FACT-G score indicated an improvement in QOL. At each session, the patients completed a separate, supplemental questionnaire to subjectively rate the benefit of the session and to express their experience with the art intervention. RESULTS: Twenty-four patients enrolled. Eight did not complete the study, leaving 16 evaluable patients. The mean FACT-G score pre-chemotherapy was 82.3 (95% CI: 75.5, 89.2), and post-art therapy was 78.6 (95% CI: 71.7, 85.5). The mean change in QOL was -3.7 points (95% CI: -10.7, 3.2, p = 0.270). A supplemental questionnaire indicated that 15 of 16 patients felt that art therapy was beneficial at each session. CONCLUSIONS: FACT-G scores did not significantly change over the course of chemotherapy in patients with gynecologic cancers receiving art therapy. Several published studies have indicated that chemotherapy is associated with a decline in QOL. Our results suggest art therapy may help to prevent or mitigate this decline.

Paper-based potentiometric sensing of free bilirubin in blood serum.

Bilirubin is predominantly formed in the liver as a result of breakdown of hemoglobin. Knowing the concentration of bilirubin in serum is important in evaluating the health of the liver, and for the diagnosis of hyperbilirubinemia (a condition that afflicts approximately 60% of full-term and 80% of pre-term newborns). This paper describes the design and fabrication of a potentiometric sensor for the determination of free bilirubin in serum. The sensor has a polymeric ion-selective membrane, and selectively measures free ionic bilirubin ("unbound" bilirubin - i.e., bilirubin not complexed to albumin or other complexing agents), in the presence of other anions - chloride, phosphate, pyruvate, deoxycholate, and lactate - also present in serum. The linear response range of the sensor (1.0 mM to 0.10 µM bilirubin, measured in a sodium phosphate buffer with pH 8.6) covers the clinically-relevant concentration of bilirubin in serum (5-500 µM). Free bilirubin could be detected in human blood serum with this potentiometric sensor. The components of the potentiometric bilirubin sensor were embedded in a paper-based device to provide a sensor that is disposable and easy to use, and thus is suitable for applications at the point-of-care. The paper-based potentiometric bilirubin sensor exhibited a response range of 5.0-0.10 mM (sufficient to cover the clinically-relevant concentration of bilirubin in serum). Only 15 µL of sample is required for measurement of the concentration of free bilirubin, and the analysis can be performed in less than two minutes.

Open-Source Potentiostat for Wireless Electrochemical Detection with Smartphones.

This paper describes the design and characterization of an open-source "universal wireless electrochemical detector" (UWED). This detector interfaces with a smartphone (or a tablet) using "Bluetooth Low Energy" protocol; the smartphone provides (i) a user interface for receiving the experimental parameters from the user and visualizing the result in real time, and (ii) a proxy for storing, processing, and transmitting the data and experimental protocols. This approach simplifies the design, and decreases both the size and the cost of the hardware; it also makes the UWED adaptable to different types of analyses by simple modification of the software. The UWED can perform the most common electroanalytical techniques of potentiometry, chronoamperometry, cyclic voltammetry, and square wave voltammetry, with results closely comparable to benchtop commercial potentiostats. Although the operating ranges of electrical current and voltage of the UWED (±1.5 V, ±180 µA) are more limited than most benchtop commercial potentiostats, its functional range is sufficient for most electrochemical analyses in aqueous solutions. Because the UWED is simple, small in size, assembled from inexpensive components, and completely wireless, it offers new opportunities for the development of affordable diagnostics, sensors, and wearable devices.

Breast Cancer Risk Assessment at the Time of Screening Mammography: Perceptions and Clinical Management Outcomes for Women at High Risk.

The purpose of this study was to evaluate the utility of a breast cancer risk assessment (BCRA) at the time of screening mammogram. Women whose BCRA indicated a high risk for cancer received a letter with instructions for breast health care and genetic counseling if appropriate. After 6 months this group received surveys to evaluate their risk perception and their recall of, and compliance with, recommendations. We also explored the impact of other variables such as a recommendation for genetic counseling and physician communication with the women. After the BCRA, the majority of high risk women reported no change in their perceived risk of cancer. A woman's perceived risk of cancer after a BCRA was significantly associated with her recall of recommendations for breast health care, but not with compliance. A recommendation for genetic counseling was not significantly related to women's perceived risk of cancer after the BCRA. Ten percent of women who should have obtained genetic counseling actually completed an appointment. Women who discussed their BCRA results with their physicians were more compliant with a six month breast exam with a doctor (53% vs 17%, p = 0.018). Overall, women felt that the BCRA was helpful and did not cause undue stress or anxiety. Although the cohort's compliance with recommendations was suboptimal, physicians' interactions with their patients may have a positive influence on their compliance.

Complex spatiotemporal behavior in the photosensitive ferroin-bromate-4-nitrophenol reaction.

Investigation illustrates that the bromate-4-nitrophenol reaction in a stirred batch reactor undergoes spontaneous oscillations under very broad initial reactant concentrations. The addition of ferroin has subtle influences on the nonlinear behavior, in which the frequency and total number of oscillations were greatly reduced at a low or high ferroin concentration, as opposed to the significant increase at a moderate ferroin concentration. Temporal oscillations with a modulating frequency were also observed in the ferroin-bromate-4-nitrophenol system. In a capillary tube the ferroin-bromate-4-nitrophenol reaction generated propagating wave trains with various complex behaviors such as period-doubled intermittent propagation failure. Illumination was found to have a profound effect on the temporal oscillations in the bromate-4-nitrophenol reaction and on those long lasting wave activities. Spectroscopic studies were able to identify 1,4-benzoquinone, 2-bromo-1,4-benzoquinone, and 2-bromo-4-nitrophenol as major components during the reaction.

Complex reaction dynamics in the cerium-bromate-2-methyl-1,4-hydroquinone photoreaction.

Spontaneous oscillations with a long induction time were observed in the bromate-2-methyl-1,4-hydroquinone photoreaction in a batch reactor, where removal of illumination effectively quenched any reactivity. A substantial lengthening of the oscillatory window and a dramatic increase in the complexity of the reaction behavior arose upon the addition of cerium ions, in which separate bifurcation regions and mixed mode oscillations were present. The complexity has a strong dependence on the intensity of illumination supplied to the system and on the initial concentrations of the reactants. (1)H NMR spectroscopy measurements show that the photoreduction of 2-methyl-1,4-benzoquinone leads to the formation of 2-methyl-1,4-hydroquinone and the compound 2-hydroxy-3-methyl-1,4-benzoquinone. Spectroscopic investigation also indicates that the presence of methyl group hinders the bromination of the studied organic substrate 2-methyl-1,4-hydroquinone, resulting in the formation of 2-methyl-1,4-benzoquinone.

Outcomes of patients with low-risk endometrial cancer surgically staged without lymphadenectomy based on intra-operative evaluation.

OBJECTIVE: The objective of the study was to evaluate clinical outcomes in patients with stage I endometrial cancer undergoing surgical management without lymphadenectomy based on intra-operative assessment for low-risk disease. METHODS: Between 2000 and 2009, a total of 179 patients were surgically staged without lymphadenectomy for low-risk stage I endometrial cancer. Low-risk cancer was defined by intra-operative criteria based on both gross and frozen tissue microscopic evaluation: 1) G1 or G2 endometrioid histology; 2) myoinvasion <50%; 3) no cervical disease, and 4) no intra-abdominal metastasis. Records were reviewed for postoperative complications, pathological diagnoses, adjuvant radiation treatment, cancer recurrence, and mortality. RESULTS: Morbidity, cancer recurrence, and disease-specific mortality were low. Postoperative complications occurred in 5 patients (2.8%). Nine patients (5.0%) were offered adjuvant radiation for higher risk disease diagnosed on final pathology. Radiation morbidity was minimal: grade 1 vaginal toxicity in 2 patients. Three patients (1.7%) experienced recurrent cancer with mean time to recurrence of 43.7 months. Five year overall survival was 95.8%. The five year probability of disease-specific death was 1.1%. CONCLUSION: In an institution with reliable capability of pathological frozen tissue diagnosis, omission of lymph node dissection is a reasonable option in the surgical management of those patients with low-risk disease diagnosed by intra-operative factors.

Mixed mode and sequential oscillations in the cerium-bromate-4-aminophenol photoreaction.

Cerium was introduced to the bromate-aminophenol photochemical oscillator to implement coupled autocatalytic feedbacks. Mixed mode and sequential oscillations emerged in the studied system, making it one of the few chemical oscillators known to support consecutive bifurcations in a batch system. The complex reaction behavior showed a strong dependence on the intensity of illumination supplied to the system. Removal of illumination during an oscillatory window affected both the frequency and amplitude of the oscillation but did not fully extinguish them, indicating that the cerium-bromate-4-aminophenol oscillator was photosensitive rather than photo-controlled. A moderate light intensity allowed for a slow evolution of the system, which proved to be critical for the emergence of transient complex oscillations. Variation of individual reaction parameters was carried out, which indicated that the development of complex oscillations occur in a narrow region and a phase diagram in the 4-aminophenol and sulfuric acid plane demonstrated this. Simulations provide strong support that transient complex oscillations observed experimentally arise from the coupling of two autocatalytic cycles.

Nonlinear dynamical behavior in the photodecomposition of N-bromo-1,4-benzoquinone-4-imine.

Photodecomposition of N-bromo-1,4-benzoquinone-4-imine in water with and without the presence of oxidants was investigated, exhibiting nonlinear kinetic features such as autocatalytic excursion. An acidic environment was found to be essential for the observed photodecomposition. Mechanistic studies through NMR and mass spectrometry show the conversion of N-bromo-1,4-benzoquinone-4-imine into 1,4-benzoquinone. When bromate was introduced to the studied system, transient spontaneous oscillations were uncovered, forming a new photocontrolled chemical oscillator. The system's sensitivity to the intensity of the illumination is great as decreases halt the oscillations from occurring. Phase diagrams show that as the concentration of N-bromo-1,4-benzoquinone-4-imine is increased, broader concentration ranges of both bromate and sulfuric acid allow the system to exhibit spontaneous oscillations. Electrospray-TOF mass spectroscopy and (13)C NMR spectra suggest that 3,4,4-tribromo-2-hydroxycyclohexa-2,5-dienone is a major product in the bromate system.

A gynecologic oncology group phase II trial of two p53 peptide vaccine approaches: subcutaneous injection and intravenous pulsed dendritic cells in high recurrence risk ovarian cancer patients.

PURPOSE: Peptide antigens have been administered by different approaches as cancer vaccine therapy, including direct injection or pulsed onto dendritic cells; however, the optimal delivery method is still debatable. In this study, we describe the immune response elicited by two vaccine approaches using the wild-type (wt) p53 vaccine. EXPERIMENTAL DESIGN: Twenty-one HLA-A2.1 patients with stage III, IV, or recurrent ovarian cancer overexpressing the p53 protein with no evidence of disease were treated in two cohorts. Arm A received SC wt p53:264-272 peptide admixed with Montanide and GM-CSF. Arm B received wt p53:264-272 peptide-pulsed dendritic cells IV. Interleukin-2 (IL-2) was administered to both cohorts in alternative cycles. RESULTS: Nine of 13 patients (69%) in arm A and 5 of 6 patients (83%) in arm B developed an immunologic response as determined by ELISPOT and tetramer assays. The vaccine caused no serious systemic side effects. IL-2 administration resulted in grade 3 and 4 toxicities in both arms and directly induced the expansion of T regulatory cells. The median overall survival was 40.8 and 29.6 months for arm A and B, respectively; the median progression-free survival was 4.2 and. 8.7 months, respectively. CONCLUSION: We found that using either vaccination approach generates comparable specific immune responses against the p53 peptide with minimal toxicity. Accordingly, our findings suggest that the use of less demanding SC approach may be as effective. Furthermore, the use of low-dose SC IL-2 as an adjuvant might have interfered with the immune response. Therefore, it may not be needed in future trials.

Robotic radical prostatectomy at a teaching community hospital: outcomes and safety.

OBJECTIVES: This study describes the early experience of robotic prostatectomy exclusively at a teaching community hospital. METHODS: This is a retrospective report of 153 consecutive patients on whom 4 physicians were the operating surgeon. RESULTS: The average hospital stay was 1.5 days, the mean operative time was 175 minutes, and the estimated operative blood loss was <300mL. The perioperative complication rate was 7.8% (12/153). The prostate-specific antigen failure rate was 2% (2/114). Urinary continence was maintained in 98% of patients 9 months after surgery. Postoperative Gleason scores differed significantly from preoperative biopsy results (P<0.001). Pathological records reported positive margins in 35% (54/153) of specimens. T3 tumors had positive margins more than twice as often as T2 tumors (P<0.002). Surgeon experience correlated with shorter operative times (P=0.001), but not with positive margins. Increasing body mass index was associated with increased operating time (P<0.001). CONCLUSIONS: Robotic prostatectomy appears to be a safe and successful option for prostate cancer treatment in a teaching community hospital.

Associations between p53 overexpression and multiple measures of clinical outcome in high-risk, early stage or suboptimally-resected, advanced stage epithelial ovarian cancers A Gynecologic Oncology Group study.

OBJECTIVE: The Gynecologic Oncology Group (GOG) performed a detailed analysis of p53 overexpression in previously-untreated women with invasive early or advanced stage epithelial ovarian cancer (EOC). METHODS: Women were eligible for the study if they provided a tumor block for translational research and participated in either GOG-157, a randomized phase III trial of three versus (vs.) six cycles of paclitaxel+carboplatin in high-risk, early stage EOC, or GOG-111, a randomized phase III trial of cyclophosphamide+cisplatin vs. paclitaxel+cisplatin in suboptimally-resected, advanced stage EOC. The N-terminal DO-7 p53 antibody was used to examine the expression of the major normal and mutant p53-isoforms. p53 overexpression was defined as >or=10% tumor cells exhibiting nuclear staining. RESULTS: p53 was overexpressed in 51% (73/143) and 66% (90/136) of cases in the GOG-157 and GOG-111 cohorts, respectively. In the GOG-157 cohort, p53 overexpression was not associated with any clinical characteristics or overall survival (OS) but was associated with worse progression-free survival (PFS) (logrank test: p=0.013; unadjusted Cox modeling: p=0.015). In the GOG-111 cohort, p53 overexpression was associated with GOG performance status (p=0.018) and grade (p=0.003), but not with age, stage, cell type or with tumor response and disease status after primary chemotherapy, PFS or OS. Adjusted Cox regression modeling demonstrated that p53 overexpression was not an independent prognostic factor for PFS or OS in either cohort. CONCLUSIONS: p53 overexpression assessed by DO-7 immunostaining is common in early and advanced stage EOC, but has limited prognostic value in women treated with surgical staging and platinum-based combination chemotherapy.

Randomized trial comparing 3 methods of postoperative analgesia in gynecology patients: patient-controlled intravenous, scheduled intravenous, and scheduled subcutaneous.

OBJECTIVE: The objective of the study was to determine whether any of 3 routes of opioid administration (patient-controlled analgesia [PCA], scheduled intermittent intravenous [i.v.], or scheduled intermittent subcutaneous [s.q.]) provides superior pain relief and satisfaction among patients undergoing abdominal gynecologic surgery. STUDY DESIGN: Patients were randomized to intravenous hydromorphone by PCA, i.v. hydromorphone via scheduled nurse-administered doses, or s.q. hydromorphone via scheduled nurse-administered doses. Self-reported pain and satisfaction were recorded over 48 hours following arrival at the nursing unit. Linear mixed effects modeling was used to compare outcomes among the groups. RESULTS: Neither pain scores nor satisfaction differed by group. PCA patients had higher total opioid use (P < .0001) and a higher rate of pruritus (P = .04). CONCLUSION: Given these findings as well as those in previous literature, no specific method of postoperative analgesia appears to be superior.

Sequential prolonged oral topotecan and prolonged oral etoposide as second-line therapy in ovarian or peritoneal carcinoma: a phase I Gynecologic Oncology Group study.

OBJECTIVE: Preclinical models suggest synergy when topoisomerase I and II inhibitors are given sequentially, but not simultaneously. A phase I study was conducted in previously treated ovarian or peritoneal carcinoma to determine the tolerability (maximum number of days) of sequential oral topotecan and oral etoposide. METHODS: Topotecan (0.8 mg/m(2)) was administered daily (days 1-5) followed by etoposide (50 mg/m(2)) administered daily for up to 5 days (days 8-12). Patients on dose levels 3 and 4 repeated topotecan for up to 5 days starting on day 15 after the initial topotecan and etoposide sequence. Cycles were repeated every 28 days. Dose-limiting toxicities (DLT) were defined as: neutrophils <1000/microl or platelets <50,000/microl before completing administration of etoposide or topotecan; neutropenic fever; platelets <20,000/microl; or a delay greater than 2 weeks in starting cycle 2 due to hematologic toxicity (ANC <1500/microl or platelets <100,000/microl on scheduled day of treatment). RESULTS: Nineteen patients were entered into this trial, and a total of 54 cycles (range 1-10) of therapy were administered. Dose-limiting toxicities, principally neutropenia, occurred when therapy was administered for 3 of 4 weeks. CONCLUSION: Oral topotecan and oral etoposide administered at these doses daily for 5 days sequentially for a maximum of three (out of every four) weeks of therapy are tolerable. In some cases, it may be necessary to hold therapy the third week. Based on the activity seen in this patient population, it is planned to take this regimen into a phase II setting.