Reconstruction in open anterior skull base surgery: A review and algorithmic approach.

PURPOSE: Defects resulting from open resection of anterior skull base neoplasms are difficult to reconstruct. Our objective was to review the literature and describe an evidence-based algorithm that can guide surgeons reconstructing anterior skull base defects. METHODS: A research librarian designed database search strategies. Two investigators independently reviewed the resulting abstracts and full text articles. Studies on reconstruction after open anterior skull base resection were included. Studies of lateral and posterior skull base reconstruction, endoscopic endonasal surgery, traumatic and congenital reconstruction were excluded. Based on the review, a reconstructive algorithm was proposed. RESULTS: The search strategy identified 603 unique abstracts. 53 articles were included. Adjacent subsites resected, defect size, radiotherapy history, and contraindications to free tissue transfer were identified as key factors influencing decision making and were used to develop the algorithm. Discussion of the reconstructive ladder as it applies to skull base reconstruction and consideration of patient specific factors are reviewed. Patients with a prior history of radiotherapy or with simultaneous resection of multiple anatomic subsites adjacent to the anterior skull base will likely benefit from free tissue transfer. CONCLUSIONS: Reconstruction of anterior skull base defects requires knowledge of the available reconstructive techniques and consideration of defect-specific and patient-specific factors.

p16 immunohistochemistry for primary tumor detection in HPV-positive squamous cell carcinoma of unknown primary.

PURPOSE: To examine the potential benefit of reevaluation of original slides and p16 immunohistochemistry (IHC) of tonsillectomy specimens for primary tumor identification in cases of human papillomavirus (HPV) positive squamous cell carcinoma (SCC) of the head and neck of unknown primary. MATERIALS AND METHODS: Through a retrospective review, we identified all patients 18 or older who presented at our institution from 2003 to 2015 with histologically confirmed HPV-positive SCC in a cervical lymph node with unidentified primary tumor after initial workup. For patients for whom specimens were available, an expert head and neck pathologist re-reviewed original hematoxylin and eosin (H&E) slides to confirm absence of tumor and performed p16 IHC and deep sectioning of tissue blocks to identify potential tumor foci. RESULTS: Among 735 patient records assessed, 80 were HPV-positive SCC with unknown primary, 28 of which did not have a primary tumor identified, and 20 with original specimens available. Upon re-review of 103 original H&E slides, invasive SCC was identified for 2 patients. Deep sectioning and p16 IHC did not identify additional primary tumors. CONCLUSION: Re-review of original slides by an expert head and neck pathologist, but not p16 staining or deeper H&E sections, was able to identify additional tumors.

Successful immunotherapy induces previously unidentified allergen-specific CD4+ T-cell subsets.

Allergen immunotherapy can desensitize even subjects with potentially lethal allergies, but the changes induced in T cells that underpin successful immunotherapy remain poorly understood. In a cohort of peanut-allergic participants, we used allergen-specific T-cell sorting and single-cell gene expression to trace the transcriptional "roadmap" of individual CD4+ T cells throughout immunotherapy. We found that successful immunotherapy induces allergen-specific CD4+ T cells to expand and shift toward an "anergic" Th2 T-cell phenotype largely absent in both pretreatment participants and healthy controls. These findings show that sustained success, even after immunotherapy is withdrawn, is associated with the induction, expansion, and maintenance of immunotherapy-specific memory and naive T-cell phenotypes as early as 3 mo into immunotherapy. These results suggest an approach for immune monitoring participants undergoing immunotherapy to predict the success of future treatment and could have implications for immunotherapy targets in other diseases like cancer, autoimmune disease, and transplantation.

Stereotactic Body Radiation Therapy for Isolated Local Recurrence After Surgical Resection of Pancreatic Ductal Adenocarcinoma Appears to be Safe and Effective.

BACKGROUND: A standardized treatment regimen for unresectable isolated local recurrence (ILR) of pancreatic ductal adenocarcinoma has not been established. This study evaluated the outcomes for patients with ILR who underwent stereotactic body radiation therapy (SBRT). METHODS: The records of patients with ILR who underwent SBRT between 2010 and 2016 were retrospectively reviewed. Symptom palliation and treatment-related toxicity were recorded. Associations between patient or treatment characteristics and overall survival (OS), progression-free survival (PFS), and local progression-free survival (LPFS) were assessed. RESULTS: The study identified 51 patients who received SBRT for ILR. Of the 51 patients, 26 (51%) had not received radiation therapy before SBRT. The median OS was 36 months after diagnosis. From the first day of SBRT, the median OS, PFS, and LPFS were respectively 16, 7, and 10 months. Patients with a recurrence-free interval of 9 months or longer after surgery had superior OS (P = 0.019). Maintenance chemotherapy after SBRT was associated with superior OS (P < 0.001) and LPFS (P = 0.027). In the multivariable analysis, poorly differentiated tumor grade [hazard ratio (HR) 11.274], positive surgical margins (HR 0.126), and reception of maintenance chemotherapy (HR 0.141) were independently associated with OS. Positive surgical margins (HR 0.255) and maintenance chemotherapy (HR 0.299) were associated with improved LPFS. Of 16 patients, 10 (63%) experienced abdominal pain relief after SBRT. Four patients (8%) experienced grade 3 gastrointestinal toxicity, and one patient experienced grade 4 gastrointestinal toxicity. CONCLUSIONS: Use of SBRT for ILR improved pain for a majority of the patients with acceptable acute and late toxicity. The findings show that SBRT is a feasible treatment for select patients with ILR. For those who receive SBRT, maintenance chemotherapy should be considered.

Reconstitution of homomeric GluA2(flop) receptors in supported lipid membranes: functional and structural properties.

AMPA receptors (AMPARs) are glutamate-gated ion channels ubiquitous in the vertebrate central nervous system, where they mediate fast excitatory neurotransmission and act as molecular determinants of memory formation and learning. Together with detailed analyses of individual AMPAR domains, structural studies of full-length AMPARs by electron microscopy and x-ray crystallography have provided important insights into channel assembly and function. However, the correlation between the structure and functional states of the channel remains ambiguous particularly because these functional states can be assessed only with the receptor bound within an intact lipid bilayer. To provide a basis for investigating AMPAR structure in a membrane environment, we developed an optimized reconstitution protocol using a receptor whose structure has previously been characterized by electron microscopy. Single-channel recordings of reconstituted homomeric GluA2(flop) receptors recapitulate key electrophysiological parameters of the channels expressed in native cellular membranes. Atomic force microscopy studies of the reconstituted samples provide high-resolution images of membrane-embedded full-length AMPARs at densities comparable to those in postsynaptic membranes. The data demonstrate the effect of protein density on conformational flexibility and dimensions of the receptors and provide the first structural characterization of functional membrane-embedded AMPARs, thus laying the foundation for correlated structure-function analyses of the predominant mediators of excitatory synaptic signals in the brain.

Building Affordable, Durable, Medium-fidelity Ballistic Gel Phantoms for Ultrasound-guided Nerve Block Training.

Ultrasound phantoms - alternatives to live human tissue - give learners the opportunity to practice ultrasound-guided regional anesthesia without introducing undue risk to patients. Gelatin-based phantoms provide educators with durable and reusable task trainers; however, commercially available gel-based phantoms are expensive. Here, we investigate the production of durable, low-cost, ballistic gel-based ultrasound phantoms for median, femoral, suprainguinal fascia iliaca plane, and serratus anterior plane nerve blocks, as well as a methodology for producing a phantom for any ultrasound-guided nerve block procedure. Computer-aided design (CAD) software was utilized to design four phantoms replicating the anatomy of median, femoral, suprainguinal fascia iliaca plane, and serratus anterior plane nerve blocks, including relevant landmarks and tissue planes. Plastic models of the desired tissue planes were 3D printed and used to create silicone molds. Ballistic gel was melted and mixed with flour and dye to create a liquid, echogenic ballistic gel, which was poured into the silicone molds. Vessels were simulated by creating negative space in the ballistic gel using metal rods. Nerves were simulated using yarn submerged in ultrasound gel. Simulated bones were designed using CAD and 3D printed. Ballistic gel is a versatile, durable medium that can be used to simulate a variety of tissues and can be melted and molded into any shape. Under ultrasound, these phantoms provide realistic tissue planes that represent the borders between different layers of skin, muscle, and fascia. The echogenicity of the muscle tissue layers, nerves, vessels, and bones is realistic, and bones have significant posterior shadowing as would be observed in a human subject. These phantoms cost $200 each for the first phantom and $60 for each subsequent phantom. These phantoms require some technical skill to design, but they can be built for just 4% of the cost of their commercial counterparts.

Erector spinae plane blocks for analgesia after percutaneous nephrolithotomy A pathway to reduce opioids.

INTRODUCTION: Despite its minimally invasive nature, percutaneous nephrolithotomy (PCNL ) may be associated with significant pain. Challenges in pain control may prevent timely discharge (and expose patients to adverse effects of opioid use). We sought to evaluate whether our patients who underwent erector spinae plane (ESP) regional blocks experienced improved postoperative pain control and decreased opioid use after PCNL (compared with those who did not receive blocks). METHODS: We retrospectively reviewed consecutive PCNL cases on patients admitted for greater than 24 hours without pre-existing opioid regimens for chronic pain. Cases were completed by a single high-volume surgeon. Patients who accepted an ESP block were compared to those who did not receive a block. Patients received either a single injection or a disposable pump delivering intermittent boluses of ropivacaine 0.2%. Demographic and perioperative data were analyzed. The primary outcomes were opioid use measured in morphine milligram equivalent (MME ) and patient-reported pain scores during the first 24 hours of hospitalization. RESULTS: From March 2019 to August 2021, 44 patients were identified who met criteria - 28 of whom received an ESP block (including 14 continuous blocks). The patients who received blocks had significantly decreased opioid use (18.3 vs. 81.3 MME, p=0.004) and a longer mean time to first non-zero pain score (p=0.004). Continuous blocks had similar opioid use to single shot blocks (21.0 vs. 15.6 MME, p=0.952). CONCLUSIONS: ESP regional blocks appear to offer an effective adjunct method for pain control after PCNL and may reduce post-PCNL opioid use while maintaining adequate patient analgesia.

Visual Attention to Facial Defects Predicts Willingness to Pay for Reconstructive Surgery.

Background: The relationship between the value of reconstructive surgery and the visual attention drawn by facial deformity has not been studied. Objectives: We hypothesized that willingness to pay (WTP) for reconstructive surgery would increase as visual attention to deformity increased in a Mohs defect eye-tracking model. Methods: We conducted a randomized observational study. Eighty casual observers participated in timed eye-tracking trials utilizing preoperative and postoperative photographs from 32 patients with facial Mohs defects. Fixation on each defect was quantified in milliseconds. For each photograph, casual observers reported how much they would be willing to pay for a perfect reconstruction and rated defect severity and patient attractiveness. The associations between defect fixation time and WTP, attractiveness, and severity were modeled using a multivariate mixed-effects model. Results: Increased defect fixation time was associated with increased WTP (regression coefficient = 0.332651, p < 0.001), decreased attractiveness (regression coefficient = -0.221779, p < 0.001), and increased severity (regression coefficient = 0.363111, p < 0.001). As defect fixation time increased, WTP increased exponentially. Conclusions: Observer WTP for facial reconstruction increases exponentially as defects become more distracting. These findings justify the dedication of health care resources to reconstructive procedures that decrease attentional distraction to the greatest extent possible.

Do Attending and Trainee Surgeons Agree on What Happens in the Operating Room During Septoplasty?

Background: Surgeons must select cases whose complexity aligns with their skill set. Objectives: To determine how accurately trainees report involvement in procedures, judge case complexity, and assess their own skills. Methods: We recruited attendings and trainees from two otolaryngology departments. After performing septoplasty, they completed identical surveys regarding case complexity, achievement of goals, who performed which steps, and trainee skill using the septoplasty global assessment tool (SGAT) and visual analog scale (VAS). Agreement regarding which steps were performed by the trainee was assessed with Cohen's kappa coefficients (κ). Correlations between trainee and attending responses were measured with Spearman's correlation coefficients (rho). Results: Seven attendings and 42 trainees completed 181 paired surveys. Trainees and attendings sometimes disagreed about which steps were performed by trainees (range of κ = 0.743-0.846). Correlation between attending and trainee responses was low for VAS skill ratings (range of rho = 0.12-0.34), SGAT questions (range of rho = 0.03-0.53), and evaluation of case complexity (range of rho = 0.24-0.48). Conclusion: Trainees sometimes disagree with attendings about which septoplasty steps they perform and are limited in their ability to judge complexity, goals, and their skill.

AFM observation of single, functioning ionotropic glutamate receptors reconstituted in lipid bilayers.

BACKGROUND: Ionotropic glutamate receptors (iGluRs) are responsible for extracellular signaling in the central nervous system. However, the relationship between the overall structure of the protein and its function has yet to be resolved. Atomic force microscopy (AFM) is an important technique that allows nano-scale imaging in liquid. In the present work we have succeeded in imaging by AFM of the external features of the most common iGluR, AMPA-R (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor), in a physiological environment. METHODS: Homomeric GluR3 receptors were over-expressed in insect cells, purified and reconstituted into lipid membranes. AFM images were obtained in a buffer from membranes immobilized on a mica substrate. RESULTS: Using Au nanoparticle-conjugated antibodies, we show that proteins reconstitute predominantly with the N-terminal domain uppermost on the membrane. A tetrameric receptor structure is clearly observed, but it displays considerable heterogeneity, and the dimensions differ considerably from cryo-electron microscopy measurements. CONCLUSIONS: Our results indicate that the extracellular domains of AMPA-R are highly flexible in a physiological environment. GENERAL SIGNIFICANCE: AFM allows us to observe the protein surface structure, suggesting the possibility of visualizing real time conformational changes of a functioning protein. This knowledge may be useful for neuroscience as well as in pharmaceutical applications.

Diagnostic Tool Using the Diagnostic Criteria for Temporomandibular Disorders: A Randomized Crossover-Controlled, Double-Blinded, Two-Center Study.

AIMS: To assess the speed and accuracy of a checklist user interface for the Diagnostic Criteria for Temporomandibular Disorders (DC/TMD). METHODS: A diagnostic tool formatted as a checklist was developed and compared to an existing diagnostic tool, the DC/TMD diagnsostic decision trees. Both types of tools use the DC/TMD and were tested by dental students, interns, and residents in the USA and Japan for diagnosis of hypothetical patients. The comparisons were done in a randomized, crossover, controlled, double-blinded trial. RESULTS: Overall, subjects using the experimental tool answered 25% more correct diagnoses (P < .001) and missed 27% fewer diagnoses (P < .01). They were also able to finalize their diagnoses faster than those using the control tool, in 16% less time (P < .05). The difference in accuracy was more pronounced in complex cases, while the difference in speed was more pronounced in simple cases. CONCLUSION: This checklist is an alternative user interface for the DC/TMD.

Melanoma metastatic to the hyoid bone.

Metastatic melanoma may be included in the differential diagnosis of hyoid masses in patients with a history of melanoma. Hyoid resection is well tolerated and of diagnostic and therapeutic benefit in patients with tumors metastatic to the hyoid bone.

Dynamics of bacteriorhodopsin 2D crystal observed by high-speed atomic force microscopy.

We have used high-speed atomic force microscopy to study the dynamics of bacteriorhodopsin (bR) molecules at the free interface of the crystalline phase that occurs naturally in purple membrane. Our results reveal temporal fluctuations at the crystal edges arising from the association and dissociation of bR molecules, most predominantly pre-formed trimers. Analysis of the dissociation kinetics yields an estimate of the inter-trimer single-bond energy of -0.9kcal/mol. Rotational motion of individual bound trimers indicates that the inter-trimer bond involves W10-W12 tryptophan residues.

The Impact of a Stepwise Approach to Primary Tumor Detection in Squamous Cell Carcinoma of the Neck With Unknown Primary.

OBJECTIVES/HYPOTHESIS: To examine the cumulative effect of diagnostic steps for primary tumor identification in patients with head and neck squamous cell carcinoma of unknown primary (HNSCCUP), including lingual tonsillectomy, and the impact of primary tumor identification on subsequent treatment. STUDY DESIGN: Retrospective analysis. METHODS: We reviewed the records of 110 patients diagnosed with HNSCCUP between 2003 and 2015. Results of diagnostic imaging (fluorodeoxyglucose-positron emission tomography/computed tomography [FDG-PET/CT]), tumor detection with direct laryngoscopy with biopsies, palatine tonsillectomy, and transoral robotic surgery (TORS) lingual tonsillectomy were recorded. Associations between demographic and treatment variables with overall survival (OS) and progression-free survival (PFS) were modeled with Cox proportional hazards models. RESULTS: FDG-PET/CT was suspicious for a primary site in 23/77 (30%) patients. Direct laryngoscopy identified a primary tumor in 34/110 patients (31%). Forty-seven patients underwent palatine tonsillectomy, which identified 17 primaries (36%), yielding a cumulative primary tumor identification of 51/110 (46%). Fourteen patients underwent TORS lingual tonsillectomy, which identified eight primaries (57%), resulting in a cumulative identification of 59/110 (53%). The detection rate increased from 28/63 (44%) to 31/47 (66%) after the addition of TORS lingual tonsillectomy to our institutional approach. Detection rates varied by HPV status. Primary tumor identification altered subsequent radiation planning, as patients with an identified primary tumor received radiation to a smaller volume of tissue than did those without an identified primary tumor. However, there was no significant association between primary tumor identification and OS or PFS. CONCLUSIONS: A stepwise approach to primary tumor identification identifies a primary tumor in a majority of patients. LEVEL OF EVIDENCE: 4 Laryngoscope, 129:1610-1616, 2019.

beta-Sheet structured beta-amyloid(1-40) perturbs phosphatidylcholine model membranes.

The disruption of intracellular calcium homeostasis plays a central role in the pathology of Alzheimer's disease, which is also characterized by accumulation of the amyloid-beta peptides Abeta40 and Abeta42. These amphipathic peptides may become associated with neuronal membranes and affect their barrier function, resulting in the loss of calcium homeostasis. This suggestion has been extensively investigated by exposing protein-free model membranes, either vesicles or planar bilayers, to soluble Abeta. Primarily unstructured Abeta has been shown to undergo a membrane-induced conformational change to either primarily beta-structure or helical structure, depending, among other factors, on the model membrane composition. Association of Abeta renders lipid bilayers permeable to ions but there is dispute whether this is due to the formation of discrete transmembrane ion channels of Abeta peptides, or to a non-specific perturbation of bilayer integrity by lipid head group-associated Abeta. Here, we have attempted incorporation of Abeta in the hydrophobic core of zwitterionic bilayers, the most simple model membrane system, by preparing proteoliposomes by hydration of a mixed film of Abeta peptides and phosphatidylcholine (PC) lipids. Despite the use of a solvent mixture in which Abeta40 and Abeta42 are almost entirely helical, the Abeta analogs were beta-structured in the resulting vesicle dispersions. When Abeta40-containing vesicles were fused into a zwitterionic planar bilayer, the typical irregular "single channel-like" conductance of Abeta was observed. The maximum conductance increased with additional vesicle fusion, while still exhibiting single channel-like behavior. Supported bilayers formed from Abeta40/PC vesicles did not exhibit any channel-like topological features, but the bilayer destabilized in time. Abeta40 was present primarily as beta-sheets in supported multilayers formed from the same vesicles. The combined observations argue for a non-specific perturbation of zwitterionic bilayers by surface association of small amphipathic Abeta40 assemblies.

Stereotactic body radiation therapy for palliative management of pancreatic adenocarcinoma in elderly and medically inoperable patients.

Stereotactic body radiation therapy (SBRT) represents a promising treatment option for patients with localized pancreatic ductal adenocarcinoma (PDAC) who cannot tolerate surgical therapy. We retrospectively reviewed the records of patients with localized PDAC treated with SBRT at our institution between 2010 and 2016 to identify patients deemed medically inoperable due to poor performance status, advanced age, and/or comorbid conditions. Overall survival (OS), progression-free survival (PFS), and local progression-free survival (LPFS) were estimated using Kaplan-Meier curves. Twenty-nine patients were included. Median age was 74 (IQR 68-79). Thirteen patients (45%) had an Eastern Cooperative Oncology Group performance status of 2. Six patients (19%) had chronic obstructive pulmonary disease, 9 (31%) had cardiovascular disease, and 17 (58%) had diabetes mellitus. SBRT was delivered over 5 fractions to a median dose of 28 Gy (IQR, 25-33). Twenty-two patients (76%) received induction chemotherapy prior to SBRT, and 9 (31%) received maintenance chemotherapy after SBRT. Median OS was 13 months from diagnosis. Median OS and PFS were 8 and 6 months from SBRT, respectively. Six and 12-month LPFS rates were 91% and 78%, respectively. Patients receiving induction chemotherapy had superior survival from diagnosis than those who did not (14 vs. 7 months, p = 0.01). Three patients (10%) experienced acute grade ≥3 toxicity, and 1 patient (4%) experienced grade ≥3 late toxicity. Symptom relief was achieved at three-month follow-up in 8 of 11 patients (73%) experiencing abdominal pain. These results suggest SBRT may be safe and effective for patients who cannot tolerate surgery.

Directional motion contrast sensitivity in developmental dyslexia.

The present study compared the perception of visual motion in two dyslexia classification schemes; the [Boder, E. (1973). Developmental dyslexia: a diagnostic approach based on three atypical reading-spelling patterns. Developmental Medicine and Child Neurology, 15, 663-687.] dyseidetic, dysphonetic and mixed subgroups and [Williams, M. J., Stuart, G. W., Castles, A., & McAnally, K. I. (2003). Contrast sensitivity in subgroups of developmental dyslexia. Vision Research, 43, 467-477.] surface, phonological and mixed subgroups by measuring the contrast sensitivity for drifting gratings at three spatial frequencies (1.0, 4.0, and 8.0 c/deg) and five drift velocities (0.75, 3.0, 6.0, 12.0, and 18.0 cyc/s) in a sample of 32 children with dyslexia and 32 matched normal readers. The findings show that there were no differences in motion direction perception between normal readers and the group with dyslexia when dyslexia was taken as a homogeneous group. Motion direction perception was found to be intact in the dyseidetic and surface dyslexia subgroups and significantly lowered in both mixed dyslexia subgroups. The one inconsistency in the findings was that motion direction perception was significantly lowered in the [Boder, E. (1973). Developmental dyslexia: a diagnostic approach based on three atypical reading-spelling patterns. Developmental Medicine and Child Neurology, 15, 663-687.] dysphonetic subgroup and intact in the [Williams, M. J., Stuart, G. W., Castles, A., & McAnally, K. I. (2003). Contrast sensitivity in subgroups of developmental dyslexia. Vision Research, 43, 467-477.] phonological subgroup. The findings also provide evidence for the presence of a disorder in sequential and temporal order processing that appears to reflect a difficulty in retaining sequences of non-meaningful auditory and visual stimuli in short-term working memory in children with dyslexia.

Electrically conducting, ultra-sharp, high aspect-ratio probes for AFM fabricated by electron-beam-induced deposition of platinum.

We report on the fabrication of electrically conducting, ultra-sharp, high-aspect ratio probes for atomic force microscopy by electron-beam-induced deposition of platinum. Probes of 4.0 ±1.0 nm radius-of-curvature are routinely produced with high repeatability and near-100% yield. Contact-mode topographical imaging of the granular nature of a sputtered gold surface is used to assess the imaging performance of the probes, and the derived power spectral density plots are used to quantify the enhanced sensitivity as a function of spatial frequency. The ability of the probes to reproduce high aspect-ratio features is illustrated by imaging a close-packed array of nanospheres. The electrical resistance of the probes is measured to be of order 100 kΩ.

Wells syndrome (eosinophilic cellulitis): Proposed diagnostic criteria and a literature review of the drug-induced variant.

BACKGROUND: Wells syndrome is an uncommon inflammatory dermatosis first described in 1971 by Wells. The clinical eruption is characterized by varying morphology and severity and usually follows a relapsing remitting course. The majority of the reported cases are of unknown etiology, drug induced Wells syndrome has rarely been reported. A literature search using MEDLINE was performed. We recorded the features of our case and of the additional cases of drug induced Wells syndrome in the literature. MAIN OBSERVATIONS: Including our case there are 25 cases of drug-induced Wells syndrome reported. Causative drugs include antibiotics, anticholinergic agents, anaesthetics, non-steroidal anti-inflammatory agents, thyroid medications, chemotherapeutic agents, thiomersal containing vaccinations, anti-tumor necrosis factor agents and thiazide diuretics. CONCLUSIONS: To the authors knowledge this is the first reported case of drug-induced Wells syndrome from thiazide diuretics. The diagnosis of Wells syndrome is often controversial and we propose a set of diagnostic criteria.