Silmitasertib plus gemcitabine and cisplatin first-line therapy in locally advanced/metastatic cholangiocarcinoma: A Phase 1b/2 study.

BACKGROUND AND AIMS: This study aimed to investigate safety and efficacy of silmitasertib, an oral small molecule casein kinase 2 inhibitor, plus gemcitabine and cisplatin (G+C) versus G+C in locally advanced/metastatic cholangiocarcinoma. APPROACH AND RESULTS: This work is a Phase 1b/2 study (S4-13-001). In Phase 2, patients received silmitasertib 1000 mg twice daily for 10 days with G+C on Days 1 and 8 of a 21-day cycle. Primary efficacy endpoint was progression-free survival (PFS) in the modified intent-to-treat population (defined as patients who completed at least one cycle of silmitasertib without dose interruption/reduction) from both phases (silmitasertib/G+C n = 55, G+C n = 29). The response was assessed by Response Evaluation Criteria in Solid Tumors v1.1. The median PFS was 11.2 months (95% confidence interval [CI], 7.6, 14.7) versus 5.8 months (95% CI, 3.1, not evaluable [NE]) ( p  = 0.0496); 10-month PFS was 56.1% (95% CI, 38.8%, 70.2%) versus 22.2% (95% CI, 1.8%, 56.7%); and median overall survival was 17.4 months (95% CI, 13.4, 25.7) versus 14.9 months (95% CI, 9.9, NE) with silmitasertib/G+C versus G+C. Overall response rate was 34.0% versus 30.8%; the disease control rate was 86.0% versus 88.5% with silmitasertib/G+C versus G+C. Almost all silmitasertib/G+C (99%) and G+C (93%) patients reported at least one treatment emergent adverse event (TEAE). The most common TEAEs (all grades) with silmitasertib/G+C versus G+C were diarrhea (70% versus 13%), nausea (59% vs. 30%), fatigue (47% vs. 47%), vomiting (39% vs. 7%), and anemia (39% vs. 30%). Twelve patients (10%) discontinued treatment because of TEAEs during the study. CONCLUSIONS: Silmitasertib/G+C demonstrated promising preliminary evidence of efficacy for the first-line treatment of patients with locally advanced/metastatic cholangiocarcinoma.

13C15N: glucagon-based novel isotope dilution mass spectrometry method for measurement of glucagon metabolism in humans.

BACKGROUND: Glucagon serves as an important regulatory hormone for regulating blood glucose concentration with tight feedback control exerted by insulin and glucose. There are critical gaps in our understanding of glucagon kinetics, pancreatic α cell function and intra-islet feedback network that are disrupted in type 1 diabetes. This is important for translational research applications of evolving dual-hormone (insulin + glucagon) closed-loop artificial pancreas algorithms and their usage in type 1 diabetes. Thus, it is important to accurately measure glucagon kinetics in vivo and to develop robust models of glucose-insulin-glucagon interplay that could inform next generation of artificial pancreas algorithms. METHODS: Here, we describe the administration of novel 13C15N heavy isotope-containing glucagon tracers-FF glucagon [(Phe 6 13C9,15N; Phe 22 13C9,15N)] and FFLA glucagon [(Phe 6 13C9,15N; Phe 22 13C9,15N; Leu 14 13C6,15N; Ala 19 13C3)] followed by anti-glucagon antibody-based enrichment and LC-MS/MS based-targeted assays using high-resolution mass spectrometry to determine levels of infused glucagon in plasma samples. The optimized assay results were applied for measurement of glucagon turnover in subjects with and without type 1 diabetes infused with isotopically labeled glucagon tracers. RESULTS: The limit of quantitation was found to be 1.56 pg/ml using stable isotope-labeled glucagon as an internal standard. Intra and inter-assay variability was < 6% and < 16%, respectively, for FF glucagon while it was < 5% and < 23%, respectively, for FFLA glucagon. Further, we carried out a novel isotope dilution technique using glucagon tracers for studying glucagon kinetics in type 1 diabetes. CONCLUSIONS: The methods described in this study for simultaneous detection and quantitation of glucagon tracers have clinical utility for investigating glucagon kinetics in vivo in humans.

The Safety of Micro-Implants for the Brain.

Technological advancements in electronics and micromachining now allow the development of discrete wireless brain implantable micro-devices. Applications of such devices include stimulation or sensing and could enable direct placement near regions of interest within the brain without the need for electrode leads or separate battery compartments that are at increased risk of breakage and infection. Clinical use of leadless brain implants is accompanied by novel risks, such as migration of the implant. Additionally, the encapsulation material of the implants plays an important role in mitigating unwanted tissue reactions. These risks have the potential to cause harm or reduce the service of life of the implant. In the present study, we have assessed post-implantation tissue reaction and migration of borosilicate glass-encapsulated micro-implants within the cortex of the brain. Twenty borosilicate glass-encapsulated devices (2 × 3.5 × 20 mm) were implanted into the parenchyma of 10 sheep for 6 months. Radiographs were taken directly post-surgery and at 3 and 6 months. Subsequently, sheep were euthanized, and GFAP and IBA-1 histological analysis was performed. The migration of the implants was tracked by reference to two stainless steel screws placed in the skull. We found no significant difference in fluoroscopy intensity of GFAP and a small difference in IBA-1 between implanted tissue and control. There was no glial scar formation found at the site of the implant's track wall. Furthermore, we observed movement of up to 4.6 mm in a subset of implants in the first 3 months of implantation and no movement in any implant during the 3-6-month period of implantation. Subsequent histological analysis revealed no evidence of a migration track or tissue damage. We conclude that the implantation of this discrete micro-implant within the brain does not present additional risk due to migration.

Multipeptide stimulated PBMCs generate TEM/TCM for adoptive cell therapy in multiple myeloma.

Multiple Myeloma (MM) patients suffer disease relapse due to the development of therapeutic resistance. Increasing evidence suggests that immunotherapeutic strategies can provide durable responses. Here we evaluate the possibility of adoptive cell transfer (ACT) by generating ex vivo T cells from peripheral blood mononuclear cells (PBMCs) isolated from MM patients by employing our previously devised protocols. We designed peptides from antigens (Ags) including cancer testis antigens (CTAs) that are over expressed in MM. We exposed PBMCs from different healthy donors (HDs) to single peptides. We observed reproducible Ag-specific cluster of differentiation 4+ (CD4+) and CD8+ T cell responses on exposure of PBMCs to different single peptide sequences. These peptide sequences were used to compile four different peptide cocktails. Naïve T cells from PBMCs from MM patients or HDs recognized the cognate Ag in all four peptide cocktails, leading to generation of multiclonal Ag-specific CD4+ and CD8+ effector and central memory T (TEM and TCM, respectively) cells which produced interferon-gamma (IFN-γ), granzyme B and perforin on secondary restimulation. Furthermore, this study demonstrated that immune cells from MM patients are capable of switching metabolic programs to induce effector and memory responses. Multiple peptides and cocktails were identified that induce IFN-γ+, T1-type, metabolically active T cells, thereby paving the way for feasibility testing of ACT in phase I clinical trials.

Deep Learning Algorithm Predicts Angiographic Coronary Artery Disease in Stable Patients Using Only a Standard 12-Lead Electrocardiogram.

BACKGROUND: Current electrocardiogram analysis algorithms cannot predict the presence of coronary artery disease (CAD), especially in stable patients. This study assessed the ability of an artificial intelligence algorithm (ECGio; HEARTio Inc, Pittsburgh, PA) to predict the presence, location, and severity of coronary artery lesions in an unselected stable patient population. METHODS: A cohort of 1659 stable outpatients was randomly divided into training (86%) and validation (14%) subsets, maintaining population characteristics. ECGio was trained and validated using electrocardiograms paired with retrospectively collected angiograms. Coronary artery lesions were classified in 2 analyses. The primary classification was no to mild (< 30% diameter stenosis [DS]) vs moderate (30%-70% DS) vs severe (≥ 70% DS) CAD. The secondary classification was yes/no based on ≥ 50% DS in any vessel. RESULTS: In the primary analysis, 22 patients had no angiographic CAD and were grouped mild CAD (56 patients, DS < 30%), 31 had moderate CAD (DS 30%-70%), and 113 had severe CAD (DS ≥ 70%). Weighted average sensitivity was 93.2%, and weighted average specificity was 96.4%. In the secondary analysis, 93 had significant CAD, and 128 did not. There was sensitivity of 93.1% and specificity of 85.6% in determining the presence of clinically significant disease (≥ 50% DS) in any vessel. ECGio was able to predict stenosis with average vessel error in the left anterior descending coronary artery of 18%, the left circumflex coronary artery of 19%, the right coronary artery of 18%, and the left main coronary artery of 8%. CONCLUSIONS: This study strongly suggests that it is possible to use an artificial intelligence algorithm to determine the presence and severity of CAD in stable patients, using data from a 12-lead electrocardiogram.

Factors associated with electrical stimulation-induced performance fatigability are dependent upon stimulation location.

NEW FINDINGS: What is the central question of this study? How does peripheral nerve stimulation (PNS) compare with neuromuscular electrical stimulation (NMES) used clinically to reduce muscle atrophy? What is the main finding and its importance? NMES resulted in progressive increases in M-wave duration and delay of muscle relaxation throughout a single stimulation protocol, findings not observed with PNS. This suggests PNS recruits from a wider pool of muscle fibres/motor units, providing a more favourable alternative to NMES for rehabilitation intervention. ABSTRACT: Neuromuscular electrical stimulation (NMES) is increasingly viewed as a central tenet to minimise muscle loss during periods of disuse/illness - typically applied directly over a muscle belly. Peripheral nerve stimulation (PNS) is afforded less attention, despite providing a more global contractile stimulus to muscles. We investigated NMES versus PNS in relation to performance fatigability and peripheral contributions to voluntary force capacity. Two fatigue protocols were assessed separately: (1) over-quadriceps NMES and (2) peripheral (femoral) nerve stimulation (PNS). Before and after each session, a maximal voluntary contraction (MVC) was performed to assess force loss. Knee-extensor force was measured throughout to assess contractile function in response to submaximal electrical stimulation, and M-wave features quantified myoelectrical activity. NMES and PNS induced similar voluntary (MVC, NMES: -12 ± 9%, PNS: -10 ± 8%, both P < 0.001) and stimulated (NMES: -45 ± 12%, PNS -27 ± 27%, both P < 0.001) force reductions. Although distinct between protocols, myoelectrical indicators of muscle recruitment (M-wave area and amplitude) and nerve conduction time did not change throughout either protocol. Myoelectrical propagation speed, represented as M-wave duration, and the delay before muscle relaxation began both progressively increased during NMES only (P < 0.05 and P < 0.001, respectively). NMES myoelectrical changes suggested performance fatigability, indicating activation of superficial fibres only, which was not observed with PNS. This suggests PNS recruits a wider pool of muscle fibres and motor units and is a favourable alternative for rehabilitation. Future work should focus on implementing PNS interventions in clinically relevant scenarios such as immobilisation, care homes and critical illness.

Selective optogenetic stimulation of efferent fibers in the vagus nerve of a large mammal.

BACKGROUND: Electrical stimulation applied to individual organs, peripheral nerves, or specific brain regions has been used to treat a range of medical conditions. In cardiovascular disease, autonomic dysfunction contributes to the disease progression and electrical stimulation of the vagus nerve has been pursued as a treatment for the purpose of restoring the autonomic balance. However, this approach lacks selectivity in activating function- and organ-specific vagal fibers and, despite promising results of many preclinical studies, has so far failed to translate into a clinical treatment of cardiovascular disease. OBJECTIVE: Here we report a successful application of optogenetics for selective stimulation of vagal efferent activity in a large animal model (sheep). METHODS AND RESULTS: Twelve weeks after viral transduction of a subset of vagal motoneurons, strong axonal membrane expression of the excitatory light-sensitive ion channel ChIEF was achieved in the efferent projections innervating thoracic organs and reaching beyond the level of the diaphragm. Blue laser or LED light (>10 mW mm-2; 1 ms pulses) applied to the cervical vagus triggered precisely timed, strong bursts of efferent activity with evoked action potentials propagating at speeds of ∼6 m s-1. CONCLUSIONS: These findings demonstrate that in species with a large, multi-fascicled vagus nerve, it is possible to stimulate a specific sub-population of efferent fibers using light at a site remote from the vector delivery, marking an important step towards eventual clinical use of optogenetic technology for autonomic neuromodulation.

Preeclamptic Women Have Decreased Circulating IL-10 (Interleukin-10) Values at the Time of Preeclampsia Diagnosis: Systematic Review and Meta-Analysis.

A key immunomodulatory cytokine, IL-10 (interleukin-10), has been shown to be dysregulated in preeclampsia, a pregnancy-specific hypertensive disorder, further characterized by multi-system involvement. However, studies have reported inconsistent findings about circulating IL-10 levels in preeclamptic versus normotensive pregnancies. The aim of the present systematic review and meta-analysis was to assess circulating IL-10 levels in preeclamptic and normotensive pregnancies at 2 time points: before, and at the time of preeclampsia diagnosis. PubMED, EMBASE, and Web of Science databases were searched to include all published studies examining circulating IL-10 levels in preeclamptic and normotensive pregnancies. Differences in IL-10 levels were evaluated by standardized mean differences. Of 876 abstracts screened, 56 studies were included in the meta-analysis. Circulating IL-10 levels were not different before the time of active disease (standardized mean differences, -0.01 [95% CI, -0.11 to 0.08]; P=0.76). At the time of active disease, women with preeclampsia (n=1599) had significantly lower IL-10 levels compared with normotensive controls (n=1998; standardized mean differences, -0.79 [95% CI, -1.22 to -0.35]; P=0.0004). IL-10 levels were lower in both early/severe and late/mild forms of preeclampsia. Subgroup analysis revealed that IL-10 measurement methodology (ELISA or multiplex bead array) and the sample type (plasma or serum) significantly influenced the observed differences, with the use of sera paired with ELISA technology providing the best distinction in IL-10 levels between preeclamptic and normotensive pregnancies. These findings support the role of decreased IL-10 levels in the pathophysiology of preeclampsia. Future studies should address the therapeutic potential of IL-10 in preeclampsia.

A Capacitive Pressure Sensor Interface IC with Wireless Power and Data Transfer.

This paper presents a capacitive pressure sensor interface circuit design in 180 nm XH018 CMOS technology for an implantable capacitive pressure sensor, which has a wireless power supply and wireless data transfer function. It integrates full-bridge rectifiers, shorting control switches, low-dropout regulators, bandgap references, analog front end, single slope analog to digital converter (ADC), I2C, and an RC oscillator. The low-dropout regulators regulate the wireless power supply coming from the rectifier and provide a stable and accurate 1.8 V DC voltage to other blocks. The capacitance of the pressure sensor is sampled to a discrete voltage by the analog front end. The single slope ADC converts the discrete voltage into 11 bits of digital data, which is then converted into 1 kbps serial data out by the I2C block. The "1" of serial data is modulated to a 500 kHz digital signal that is used to control the shorting switch for wireless data transfer via inductive back scatter. This capacitive pressure sensor interface IC has a resolution of 0.98 mmHg (1.4 fF), average total power consumption of 7.8 mW, and ±3.2% accuracy at the worst case under a -20 to 80 °C temperature range, which improves to ±0.86% when operated between 20 and 60 °C.

Ubiquitin-binding associated protein 2 regulates KRAS activation and macropinocytosis in pancreatic cancer.

Macropinocytosis supports the metabolic requirement of RAS-transformed pancreatic ductal adenocarcinoma cells (PDACs). However, regulators of RAS-transformation (activation) that lead to macropinocytosis have not been identified. Herein, we report that UBAP2 (ubiquitin-binding associated protein 2), regulates the activation of KRAS and macropinocytosis in pancreatic cancer. We demonstrate that UBAP2 is highly expressed in both pancreatic cancer cell lines and tumor tissues of PDAC patients. The expression of UBAP2 is associated with poor overall survival in several cancers, including PDAC. Silencing UBAP2 decreases the levels of activated KRAS, and inhibits macropinocytosis, and tumor growth in vivo. Using a UBAP2-deletion construct, we demonstrate that the UBA-domain of UBAP2 is critical for the regulation of macropinocytosis and maintaining the levels of activated KRAS. In addition, UBAP2 regulates RAS downstream signaling and helps maintain RAS in the GTP-bound form. However, the exact mechanism by which UBAP2 regulates KRAS activation is unknown and needs further investigation. Thus, UBAP2 may be exploited as a potential therapeutic target to inhibit macropinocytosis and tumor growth in activated KRAS-driven cancers.

Targeted genotype analyses of GWAS-derived lean body mass and handgrip strength-associated single-nucleotide polymorphisms in elite master athletes.

Recent large genome-wide association studies (GWAS) have independently identified a set of genetic loci associated with lean body mass (LBM) and handgrip strength (HGS). Evaluation of these candidate single-nucleotide polymorphisms (SNPs) may be useful to investigate genetic traits of populations at higher or lower risk of muscle dysfunction. As such, we investigated associations between six SNPs linked to LBM or HGS in a population of elite master athletes (MA) and age-matched controls as a representative population of older individuals with variable maintenance of muscle mass and function. Genomic DNA was isolated from buffy coat samples of 96 individuals [consisting of 48 MA (71 ± 6 yr, age-graded performance 83 ± 9%) and 48 older controls (75 ± 6 yr)]. SNP validation and sample genotyping were conducted using the tetra-primer amplification refractory mutation system (ARMS). For the three SNPs analyzed that were previously associated with LBM (FTO, IRS1, and ADAMTSL3), multinomial logistic regression revealed a significant association of the ADAMTSL3 genotype with %LBM (P < 0.01). For the three HGS-linked SNPs, neither GBF1 nor GLIS1 showed any association with HGS, but for TGFA, multinomial logistic regression revealed a significant association of genotype with HGS (P < 0.05). For ADAMTSL3, there was an enrichment of the effect allele in the MA (P < 0.05, Fisher's exact test). Collectively, of the six SNPs analyzed, ADAMTSL3 and TGFA showed significant associations with LBM and HGS, respectively. The functional relevance of the ADAMTSL3 SNP in body composition and of TGFA in strength may highlight a genetic component of the elite MA phenotype.

Thermal evaluation of a hermetic transcutaneous energy transfer system to power mechanical circulatory support devices in destination therapy.

Current generation left ventricular assist devices (LVADs) are powered by a percutaneous driveline. The high prevalence of driveline infections has motivated the development of transcutaneous energy transfer (TET) systems which eliminate driveline associated complications by wirelessly delivering power across the skin. Destination therapy (DT) requires long-term reliable operation of the TET electronics suggesting the use of hermetic packaging techniques as used in all other chronically implanted devices. TET coils dissipate heat during operation and in order for the technology to be suitable for patient use, sufficient power must be delivered while maintaining temperatures at levels deemed safe. The heating of a TET system designed for DT which uses hermetic packaging technology was evaluated in silico and in vivo. A numerical model was used to evaluate the temperature of the TET coils. The TET system was fabricated and assessed in vivo using an ovine model. The receiving coil was implanted subcutaneously in a sheep and the transmission coil placed in contact with the skin and concentric to the implanted coil. Temperatures of the system were measured using sensors fixed to the surface of the coils. Numerical modeling indicated that the maximum temperatures of the primary and secondary coil surfaces were 38.13°C and 38.41°C, respectively, when delivering 10 W continuously. Stable temperatures were observed in vivo after 70 minutes and the maximum skin and implant surface temperatures were 37.73°C and 38.31°C, respectively. This study showed that a hermetic, chronically implantable TET system is thermally safe when continuously delivering 10 W of power, sufficient to power modern LVADs.

Analysis of the polycystin complex (PCC) in human urinary exosome-like vesicles (ELVs).

The polycystin-1 (PC1), polycystin-2 (PC2) and fibrocystin proteins, the respective products of the PKD1, PKD2 and PKHD1 genes, are abundant in urinary exosome-like vesicles (ELVs) where they form the polycystin complex (PCC). ELVs are 100 nm diameter membrane vesicles shed into the urine by the cells lining the nephron. Using MS/MS analysis of ELVs from individuals with PKD1 mutations and controls, we show that in addition to the well-described GPS/GAIN cleavage event in PC1 at 3048 aa and the proprotein convertase cleavage (PPC) event in fibrocystin at 3616 aa, there are multiple other cleavage events in these proteins. The C-terminal 11 transmembrane portion of PC1 undergoes three cleavage events in vivo. The absence of peptides from the C-terminal cytoplasmic tail of fibrocystin implies a cleavage event close to its single TM domain prior to loading onto the ELVs. There is also evidence that the C-terminal tail of PC2 is also cleaved in ELVs. Native gel analysis of the PCC shows that the entire complex is  > 2 MDa in size and that N-terminal GPS/GAIN cleaved PC1 and PPC cleaved fibrocystin ectodomains can be released under non-reducing conditions and resolve at 300 kDa. This paper shows that the three major human cystogene proteins are detectable in human urinary ELVs and that all three undergo post-translational proteolytic processing. Human urinary ELVs may be a useful source of material in the search for proteins that interact with the PCC.

Injection Molded Liquid Crystal Polymer Package for Chronic Active Implantable Devices With Application to an Optogenetic Stimulator.

Implanted electronics require protection from the body's fluids to avoid moisture induced failure. This study presents an injection molded liquid crystal polymer (LCP) package to protect active implantable devices for chronic applications, such as in optogenetic research. The technology is applied and assessed through a custom package for a fully implantable optogenetic stimulation system, built on a versatile telemetry system that can incorporate additional stimulating and recording channels. An adapted quasi-steady state model predicts the lifetime of an enclosure, where the definition of the lifetime is the time before the internal relative humidity (RH) reaches a time constant, or 63%RH, a conservative limit to minimize the risk of corrosion. The lifetime of the LCP optogenetic device is 94 days, and can be extended to 326 days with the inclusion of 5% w/v silica gel desiccant. Samples of the LCP optogenetic device containing humidity sensors testing in saline at 38 °C support the RH change predictions. Desiccants inside the implant enclosure can store permeating moisture and prolong the life expectancy of LCP-based implants to years or decades. The results of this study demonstrates the feasibility of providing reliable protection for chronic optogenetic implants, and the technology can be transferred to other applications as an easily-manufactured, cost-effective, radiofrequency compatible alternative to hermetic packaging for chronic studies.

Design, Synthesis, and Actions of an Innovative Bispecific Designer Peptide.

Despite optimal current therapies, cardiovascular disease remains the leading cause for death worldwide. Importantly, advances in peptide engineering have accelerated the development of innovative therapeutics for diverse human disease states. Additionally, the advancement of bispecific therapeutics targeting >1 signaling pathway represents a highly innovative strategy for the treatment of cardiovascular disease. We, therefore, engineered a novel, designer peptide, which simultaneously targets the pGC-A (particulate guanylyl cyclase A) receptor and the MasR (Mas receptor), potentially representing an attractive cardiorenoprotective therapeutic for cardiovascular disease. We engineered a novel, bispecific receptor activator, NPA7, that represents the fusion of a 22-amino acid sequence of BNP (B-type natriuretic peptide; an endogenous ligand of pGC-A) with Ang 1-7 (angiotensin 1-7)-the 7-amino acid endogenous activator of MasR. We assessed NPA7's dual receptor activating actions in vitro (second messenger production and receptor interaction). Further, we performed an intravenous peptide infusion comparison study in normal canines to study its biological actions in vivo, including in the presence of an MasR antagonist. Our in vivo and in vitro studies demonstrate the successful synthesis of NPA7 as a bispecific receptor activator targeting pGC-A and MasR. In normal canines, NPA7 possesses enhanced natriuretic, diuretic, systemic, and renal vasorelaxing and cardiac unloading properties. Importantly, NPA7's actions are superior to that of the individual native pGC-A or MasR ligands. These studies advance NPA7 as a novel, bispecific designer peptide with potential cardiorenal therapeutic benefit for the treatment of cardiovascular disease, such as hypertension and heart failure.

Noninvasive in vivo optical coherence tomography tracking of chronic otitis media in pediatric subjects after surgical intervention.

In an institutional review board-approved study, 25 pediatric subjects diagnosed with chronic or recurrent otitis media were observed over a period of six months with optical coherence tomography (OCT). Subjects were followed throughout their treatment at the initial patient evaluation and preoperative consultation, surgery (intraoperative imaging), and postoperative follow-up, followed by an additional six months of records-based observation. At each time point, the tympanic membrane (at the light reflex region) and directly adjacent middle-ear cavity were observed in vivo with a handheld OCT probe and portable system. Imaging results were compared with clinical outcomes to correlate the clearance of symptoms in relation to changes in the image-based features of infection. OCT images of most all participants showed the presence of additional infection-related biofilm structures during their initial consultation visit and similarly for subjects imaged intraoperatively before myringotomy. Subjects with successful treatment (no recurrence of infectious symptoms) had no additional structures visible in OCT images during the postoperative visit. OCT image findings suggest surgical intervention consisting of myringotomy and tympanostomy tube placement provides a means to clear the middle ear of infection-related components, including middle-ear fluid and biofilms. Furthermore, OCT was demonstrated as a rapid diagnostic tool to prospectively monitor patients in both outpatient and surgical settings.

Comparison of Trends and In-Hospital Outcomes of Concurrent Carotid Artery Revascularization and Coronary Artery Bypass Graft Surgery: The United States Experience 2004 to 2012.

OBJECTIVES: The aim of this study was to compare trends and outcomes of 3 approaches to carotid revascularization in the coronary artery bypass graft (CABG) population when performed during the same hospitalization. BACKGROUND: The optimal approach to managing coexisting severe carotid and coronary disease remains controversial. Carotid endarterectomy (CEA) or carotid artery stenting (CAS) are used to decrease the risk of stroke in patients with carotid disease undergoing CABG surgery. METHODS: The authors conducted a serial, cross-sectional study with time trends of 3 revascularization groups during the same hospital admission: 1) combined CEA+CABG; 2) staged CEA+CABG; and 3) staged CAS+CABG from the Nationwide Inpatient Sample database 2004 to 2012. The primary composite endpoints were in-hospital all-cause death, stroke, and death/stroke. RESULTS: During the 9-year period, 22,501 concurrent carotid revascularizations and CABG surgeries during the same hospitalization were performed. Of these, 15,402 (68.4%) underwent combined CEA+CABG, 6,297 (28.0%) underwent staged CEA+CABG, and 802 (3.6%) underwent staged CAS+CABG. The overall rate of CEA+CABG decreased by 16.1% (ptrend = 0.03) from 2004 to 2012, whereas the rate of CAS+CABG did not significantly change during these years (ptrend = 0.10). The adjusted risk of death was greater, whereas risk of stroke was lower with both combined CEA+CABG (death odds ratio [OR]: 2.08, 95% confidence interval [CI]: 1.08 to 3.97; p = 0.03; stroke OR: 0.65, 95% CI: 0.42 to 1.01; p = 0.06) and staged CEA+CABG (death OR: 2.40, 95% CI: 1.43 to 4.05; p = 0.001; stroke OR: 0.50, 95% CI: 0.31 to 0.80; p = 0.004) approaches compared with CAS+CABG. The adjusted risk of death or stroke was similar in the 3 groups. CONCLUSIONS: In patients with concomitant carotid and coronary disease undergoing combined revascularization, combined CEA+CABG is utilized most frequently, followed by staged CEA+CABG and staged CAS+CABG strategies. The staged CAS+CABG strategy was associated with lower risk of mortality, but higher risk of stroke. Future studies are needed to examine the risks/benefits of different carotid revascularization strategies for high-risk patients requiring concurrent CABG.

Subclavian Artery Disease: Diagnosis and Therapy.

The diagnosis of brachiocephalic disease is often overlooked. Symptoms include arm claudication and vertebrobasilar insufficiency. In patients who have had the use of the internal mammary artery for coronary bypass surgery, the development of symptoms of myocardial ischemia should alert the clinician to the possibility of subclavian artery stenosis. Also, in patients who have had axillofemoral bypass, lower-extremity claudication may occur. Recognition involves physical examination and accurate noninvasive testing. Endovascular therapy has proven to be effective in alleviating symptoms in properly selected patients.