Continuous molecular monitoring of human dermal interstitial fluid with microneedle-enabled electrochemical aptamer sensors.

The ability to continually collect diagnostic information from the body during daily activity has revolutionized the monitoring of health and disease. Much of this monitoring, however, has been of physical "vital signs", with the monitoring of molecular markers having been limited to glucose, primarily due to the lack of other medically relevant molecules for which continuous measurements are possible in bodily fluids. Electrochemical aptamer sensors, however, have a recent history of successful in vivo demonstrations in rat animal models. Herein, we present the first report of real-time human molecular data collected using such sensors, successfully demonstrating their ability to measure the concentration of phenylalanine in dermal interstitial fluid after an oral bolus. To achieve this, we used a device that employs three hollow microneedles to couple the interstitial fluid to an ex vivo, phenylalanine-detecting sensor. The resulting architecture achieves good precision over the physiological concentration range and clinically relevant, 20 min lag times. By also demonstrating 90 days dry room-temperature shelf storage, the reported work also reaches another important milestone in moving such sensors to the clinic. While the devices demonstrated are not without remaining challenges, the results at minimum provide a simple method by which aptamer sensors can be quickly moved into human subjects for testing.

Opportunities and challenges in the diagnostic utility of dermal interstitial fluid.

The volume of interstitial fluid (ISF) in the human body is three times that of blood. Yet, collecting diagnostically useful ISF is more challenging than collecting blood because the extraction of dermal ISF disrupts the delicate balance of pressure between ISF, blood and lymph, and because the triggered local inflammation further skews the concentrations of many analytes in the extracted fluid. In this Perspective, we overview the most meaningful differences in the make-up of ISF and blood, and discuss why ISF cannot be viewed generally as a diagnostically useful proxy for blood. We also argue that continuous sensing of small-molecule analytes in dermal ISF via rapid assays compatible with nanolitre sample volumes or via miniaturized sensors inserted into the dermis can offer clinically advantageous utility, particularly for the monitoring of therapeutic drugs and of the status of the immune system.

Voltammetry Peak Tracking for Longer-Lasting and Reference-Electrode-Free Electrochemical Biosensors.

Electrochemical aptamer-based sensors offer reagent-free and continuous analyte measurement but often suffer from poor longevity and potential drift even with a robust 3-electrode system. Presented here is a simple, software-enabled approach that tracks the redox-reporter peak in an electrochemical aptamer-based sensor and uses the measurement of redox peak potential to reduce the scanning window to a partial measure of redox-peak-height vs. baseline (~10X reduction in voltage range). This same measurement further creates a virtual reference standard in buffered biofluids such as blood and interstitial fluid, thereby eliminating the effects of potential drift and the need for a reference electrode. The software intelligently tracks voltammogram peak potential via the inflection points of the rising and falling slopes of the measured redox peak. Peak-tracking-derived partial scanning was validated over several days and minimized electrochemically induced signal loss to <5%. Furthermore, the peak-tracking approach was shown to be robust against confounding effects such as fouling. From an applied perspective in creating wearable biosensors, the peak-tracking approach further enables use of a single implanted working electrode, while the counter/reference-electrode may utilize a simple gel-pad electrode on the surface of the skin, compared to implanting working, counter, and reference electrodes conventionally used for stability and reliability but is also costly and invasive. Cumulatively, peak-tracking provides multiple leaps forward required for practical molecular monitoring by extending sensor longevity, eliminating potential drift, simplifying biosensor device construction, and in vivo placement for any redox-mediated sensor that forms parabolic-like data.

Doctor Google: Correlating internet search trends for epistaxis with metropolitan climates.

OBJECTIVE: Variation in weather patterns is often cited as a risk factor for epistaxis although robust studies investigating specific climate factors are lacking. As society is increasingly utilizing the Internet to learn more about their medical conditions, we explore whether Internet search activity related to epistaxis is influenced by fluctuations in climate. METHODS: Internet search activity for epistaxis-related search terms during 2012-2017 were extracted from Google Trends and localized to six highly populated cities in the US: New York, New York; Los Angeles, California; Chicago, Illinois; Houston, Texas; Philadelphia, Pennsylvania; and Atlanta, Georgia. Data were compared to local average monthly climate data from the National Centers for Environmental Information for the same time period. RESULTS: Spearmen correlations (r) were statistically strongest for dew point temperature (rNewYork = -0.82; rPhiladelphia = -0.74; rChicago = -0.65; rAtlanta = -0.49, rLosAngeles = -0.3). This was followed closely by relative humidity (rNewYork = -0.63; rPhiladelphia = -0.57; rLosAngeles = -0.44; rAtlanta = -0.42; rHouston = -0.40) and average temperature (rNewYork = -0.8; rPhiladelphia = -0.72; rChicago = -0.62; rAtlanta = -0.45). Overall, correlations were most significant and predictable for cities with the greatest seasonal climate shifts (New York, Philadelphia, and Chicago). The weakest environmental factor was barometric pressure, which was found to be moderately positive in Atlanta (rbarometric = 0.31), Philadelphia (rbarometric = 0.30) and New York (rbarometric = 0.27). CONCLUSIONS: Google Trends data for epistaxis-related search activity responds closely to climate patterns in most cities studied, thus underscoring the potential utility of Internet search activity data as a resource for epidemiologic study and for the identification of at risk populations.

Surgical management of rhinosinusitis in endoscopic-endonasal skull-base surgery.

BACKGROUND: Endoscopic-endonasal skull base surgery (ESBS) provides an important approach to select pathologies. There remains a paucity of data, however, regarding morbidity in patients undergoing ESBS with comorbid acute rhinosinusitis (ARS), a fungal ball (FB), or chronic rhinosinusitis (CRS). METHODS: A retrospective database review between January 2008 and January 2013 identified 35 patients with concurrent skull-base pathology and refractory ARS, FB, CRS, and CRS with nasal polyposis (CRSP) who underwent endoscopic sinus surgery (ESS) and ESBS. RESULTS: Two of 35 (5.7%) had an FB, 3 of 35 (8.6%) had ARS, 19 of 35 (54.2%) had CRSP, and 11 of 35 (31.4%) had CRS. Five of 35 (14.3%) were staged procedures whereas 30 of 35 (85.7%) underwent concurrent ESS and ESBS. Four patients (80%) who were staged carried diagnoses of an FB and ARS. Two patients in the concurrent group required revision ESS for recurrent polyposis. There were no cases of intraorbital or intracranial infectious complications. CONCLUSION: Management of the paranasal sinuses is paramount to maintain healthy sinonasal function in patients undergoing ESBS. In our experience, most cases of CRS and CRSP can be surgically managed at the time of ESBS without increased risk of intracranial infection. Patients with ARS at the time of surgery or an FB should be staged to avoid postoperative ESBS morbidity.

Comprehensive management of the paranasal sinuses in patients undergoing endoscopic endonasal skull base surgery.

OBJECTIVE: The endonasal route often provides the most direct and safe approach to skull base pathology. In this article we review the literature with regard to management of the paranasal sinuses in the setting of skull base surgery. METHODS: We describe our institutional experience and review the literature of concurrent management of the sinusitis in patients undergoing endoscopic skull base surgery. RESULTS: Patients should be optimized preoperatively to ensure the endonasal route is a safe corridor to enter the intracranial cavity. Often the paranasal sinuses can be surgically addressed at the same time as endoscopic skull base surgery. We describe the technical details of management of the paranasal sinuses when addressing skull base pathology. CONCLUSIONS: Careful management of the paranasal sinuses throughout the peri-operative course is paramount to optimizing sinonasal function and safety.

Surgical pathway seeding of clivo-cervical chordomas.

UNLABELLED: Objective Clival chordomas are slow-growing aggressive tumors that originate from the extra-axial remnants of the notochord. Current management of these tumors use surgical resection combined with radiation therapy. Given the location and invasive nature of these tumors, complete resection is difficult. A variety of both open and endoscopic therapeutic approaches have evolved and combined with the improvements in proton therapy, long-term control of these tumors appears to be improving. However, in recent literature the relatively rare complication of surgical seeding or surgical pathway recurrence has been reported. We report a case of surgical seeding following primary resection and review the world literature regarding surgical pathway recurrence. Study Design Retrospective chart review and review of current literature. Methods We report a case of a patient with a large chordoma that required treatment with a staged endoscopic endonasal and external transcervical approach. The patient subsequently developed recurrent disease along the cervical skin incision due to surgical seeding. Literature review and case reports were identified by a comprehensive search of Medline for the years 1950 to 2012. Results The overall surgical pathway recurrence rate for clival chordoma resection based on analysis of the open nonendoscopic published case studies was 14 of 497 (2.8%). Conclusion Tumor seeding can occur anywhere along the operative route and is often outside the field of radiotherapy. Increased awareness of this rare occurrence is necessary. The use of novel techniques to minimize exposure to tumor including primary endoscopic resection and so-called clean oncologic technique may help limit tumor seeding. LEVEL OF EVIDENCE: 4.

Airway management and perioperative concerns in acromegaly patients undergoing endoscopic transsphenoidal surgery for pituitary tumors.

OBJECTIVES: Patients with acromegaly present unique challenges to cranial base surgery and anesthesia teams in the perioperative period, especially with regard to airway management. Abnormal airway anatomy may result from soft tissue hypertrophy and bony alterations. Additional perioperative challenges relate to the management of medical comorbidities. We aim to review perioperative airway concerns in acromegalic patients for the skull base surgeon in order to reduce preventable perioperative complications. STUDY DESIGN: Case series with chart review. SETTING: Tertiary care academic institution. SUBJECTS: Thirty-two acromegaly patients undergoing endoscopic transsphenoidal pituitary surgery. RESULTS: Videoscopic direct laryngoscopy intubation was required in 7 of 32 patients (21.9%) and fiberoptic intubation in 4 of 32 patients (12.5%). Overall failure rate for first intubation technique used was 12.5% (4/32). Cardiovascular comorbidities (hypertension and conduction abnormalities predominated) were present in 16 of 32 patients (50%), and obstructive sleep apnea, or other respiratory conditions, existed in 12 of 32 patients (37.5%). CONCLUSIONS: Acromegaly patients present a particular challenge to the endoscopic skull base surgeon. Despite preoperative anesthesia and otolaryngology evaluation, many of these patients will experience an unanticipated airway challenge during intubation. Preoperative preparation and perioperative awareness of anatomic and physiologic abnormalities of acromegalic patients is essential for successful endoscopic surgery in this unique population.

Nasoseptal flap repair after endoscopic transsellar versus expanded endonasal approaches: is there an increased risk of postoperative cerebrospinal fluid leak?

OBJECTIVES/HYPOTHESIS: The development of expanded endoscopic endonasal approaches (EEAs) has allowed resection of cranial-base lesions beyond the sella. One major criticism is an increased risk of postoperative cerebrospinal fluid (CSF) leakage because of the larger skull base defect. We evaluated our experience with vascularized pedicled nasoseptal flap (PNSF) reconstruction and compared the postoperative CSF leak rates between patients undergoing endoscopic transsphenoidal (transsellar) approaches versus expanded EEA (transplanum-transtuberculum, transcribriform, transclival). STUDY DESIGN: Retrospective analysis at a tertiary care medical center. METHODS: A retrospective review of a prospective database was performed on patients who underwent PNSF reconstruction for intraoperative high-flow CSF leaks after EEA between December 2008 and August 2011. Demographic data, repair materials, surgical approach, and incidence of postoperative CSF leaks were collected. RESULTS: Thirty-seven transsellar defects (group I) were repaired with a PNSF, and 32 expanded EEA defects (19 transplanum-transtuberculum, 10 transcribriform, three transclival) (group II) were repaired with a PNSF. No postoperative CSF leaks occurred in group I. One delayed postoperative CSF leak was encountered in group II leading to a 3.1% leak rate in that group. The incidence of postoperative CSF leakage was not significantly different between the two groups (P > .05). Our overall success rate in this series using a PNSF was 98.6%. CONCLUSIONS: Based on our data, there is no significant increased risk of postoperative CSF leak between transsellar and expanded EEA defects when a PNSF is used. The potential risk of postoperative CSF leaks associated with larger defects created through expanded EEA can be minimized by multilayered closure with a PNSF and meticulous surgical technique.

Graduated endoscopic multiangle approach for access to the infratemporal fossa: a cadaveric study with clinical correlates.

OBJECTIVE: The infratemporal fossa (ITF) has historically been one of the most difficult regions of the skull base to access surgically. Available open approaches are complex, are associated with high morbidity, and do not always afford optimal visualization. Endoscopic access to the ITF improves visualization for management of many sinonasal and lateral skull base lesions involving this region. The purpose of this study is to evaluate a graduated multiangle approach for endoscopic access to this area using a cadaveric model. STUDY DESIGN AND SETTING: Cadaveric study at an academic medical center. METHODS: Endoscopic dissection was performed on a total of 10 sides of 5 fresh cadaveric heads. Four different approaches to the ITF were studied: ipsilateral endonasal, endoscopically assisted Caldwell-Luc, contralateral endonasal via septotomy, and endoscopically assisted Gillies transtemporal. High-quality endoscopic pictures and high-definition videos of each technique were obtained in order to document the differences in access achieved with each approach. RESULTS: The combination of the 4 different endoscopic techniques allowed complete access to all areas of the ITF. The endoscopically assisted Caldwell-Luc improved anteroposterior access, the contralateral septotomy approach resulted in excellent far lateral access, and the endoscopically assisted Gillies approach allowed posterosuperior visualization and instrumentation. CONCLUSION: Endoscopic access to the ITF can be accomplished by each of the 4 methods described. A multiangle, graduated approach can provide surgeons the ability to customize surgical access depending on the location of a specific lesion within the ITF.

Modified mini-Lothrop/extended Draf IIB procedure for contralateral frontal sinus disease: a case series.

BACKGROUND: Management of frontal sinus disease represents one of the most challenging aspects of endoscopic sinus surgery. In select cases, anatomic variations (outflow tract osteoneogenesis, scarring, fat prolapsed from previous orbital decompression) may hinder ipsilateral access using traditional endoscopic approaches. We previously proposed a modification of the standard Draf IIB procedure which incorporates a frontal intersinus septectomy (modified mini-Lothrop procedure/extended Draf IIB) to access and manage recalcitrant unilateral frontal sinus obstruction inaccessible ipsilaterally in cadaver specimens. In this study, we describe this technique, and present a case series of 4 patients who benefited from this approach. METHODS: A retrospective analysis at a large tertiary referral center was performed on all patients undergoing frontal sinus surgery between July 2008 and June 2011. Four patients with frontal sinus recess obstruction inaccessible from the ipsilateral side and treated with the modified mini-Lothrop procedure/extended Draf IIB were identified. RESULTS: All 4 patients underwent successful frontal sinusotomies via a Modified mini-Lothrop procedure/extended Draf IIB without complications and had a patent drainage pathway assessed endoscopically after a mean follow-up of 21 (range, 9-28) months. CONCLUSION: The modified mini-Lothrop procedure/extended Draf IIB represents a feasible approach and adequate alternative to more traditional endoscopic and open frontal sinus procedures in select cases. This modification was successful in addressing difficult to access unilateral frontal sinus disease in this small cohort.

Community-acquired methicillin-resistant Staphylococcus aureus skull base osteomyelitis with occipital condylar cerebrospinal fluid leak in an immunocompetent patient.

Community acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) is emerging as an important pathogen in paranasal sinus disease. However, sinonasal CA-MRSA has not been reported as a source of central skull base osteomyelitis. We report an unusual case of a previously healthy and immunocompetent adult who developed meningitis, central skull base osteomyelitis, and occipital condylar cerebrospinal fluid rhinorrhea from CA-MRSA sphenoid sinusitis requiring endoscopic surgical repair. This case clearly demonstrates the expanding spectrum of severe infections caused by CA-MRSA, which requires prompt diagnosis, a high level of suspicion, and appropriate medical and/or surgical management.

Endoscopic nasoseptal flap repair of skull base defects: is addition of a dural sealant necessary?

OBJECTIVE: We compared the incidence of postoperative cerebrospinal fluid (CSF) leaks in patients undergoing endoscopic skull base repair with a pedicled nasoseptal flap (PNSF) with or without the addition of a dural sealant. STUDY DESIGN AND SETTING: Retrospective analysis at a tertiary care medical center. METHODS: A retrospective analysis was performed at our tertiary care medical center on patients who underwent endoscopic repair of high-flow CSF leaks using a PNSF between December 2008 and August 2011. Repair materials, incidence of postoperative CSF leaks, and demographic data were collected. RESULTS: Thirty-two high-flow CSF leaks were repaired with a PNSF alone without dural sealant (group A), and 42 were repaired with a PNSF with the addition of a dural sealant (group B). In group A, there were no postoperative CSF leaks (0%), whereas in group B, there was 1 delayed postoperative CSF leak, resulting in a 2.4% leak rate. The incidence of postoperative CSF leakage was not significantly different between the 2 groups (P = .38). The overall postoperative CSF leak rate was 1.4%. CONCLUSIONS: The use of dural sealants when performing endoscopic PNSF repair of high-flow CSF leaks is not supported by our data. In addition, this practice may significantly increase surgical cost. We encountered no postoperative CSF leaks in patients with high-flow CSF leaks treated with PNSF alone without dural sealants. Meticulous surgical technique and proper positioning of the PNSF seem to obviate the need for dural sealants during endoscopic skull base reconstruction of high-flow CSF leaks.

Modified hemi-Lothrop procedure for supraorbital ethmoid lesion access.

The supraorbital ethmoid (SOE) cell is an accessory ethmoid cell in the frontal area that extends into and pneumatizes superolaterally along the orbital plate of the frontal bone. The outflow pathway of the SOE cell can become obstructed, leading to an SOE mucocele. Given their lateral location, SOE lesions are traditionally treated through external approaches, although some authors have advocated treatment through standard endoscopic routes. We present a case of a large, supraorbital ethmoid mucocele treated with a novel modified hemi-Lothrop procedure (MHLP). This technique provides the benefit of an angulated approach to increase lateral visualization and bimanual, binostril instrumentation through a superior septectomy window.