Effects of the selective AMPA modulator NBI-1065845 on the pharmacokinetics of midazolam or ethinyl estradiol-levonorgestrel in healthy adults.

This parallel-arm, phase I study investigated the potential cytochrome P450 (CYP)3A induction effect of NBI-1065845 (TAK-653), an investigational α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor potentiator in phase II development for major depressive disorder. The midazolam treatment arm received the sensitive CYP3A substrate midazolam on Day 1, followed by NBI-1065845 alone on Days 5-13; on Day 14, NBI-1065845 was administered with midazolam, then NBI-1065845 alone on Day 15. The oral contraceptive treatment arm received ethinyl estradiol-levonorgestrel on Day 1, then NBI-1065845 alone on Days 5-13; on Day 14, NBI-1065845 was administered with ethinyl estradiol-levonorgestrel, then NBI-1065845 alone on Days 15-17. Blood samples were collected for pharmacokinetic analyses. The midazolam treatment arm comprised 14 men and 4 women, of whom 16 completed the study. Sixteen of the 17 healthy women completed the oral contraceptive treatment arm. After multiple daily doses of NBI-1065845, the geometric mean ratios (GMRs) (90% confidence interval) for maximum observed concentration were: midazolam, 0.94 (0.79-1.13); ethinyl estradiol, 1.00 (0.87-1.15); and levonorgestrel, 0.99 (0.87-1.13). For area under the plasma concentration-time curve (AUC) from time 0 to infinity, the GMRs were as follows: midazolam, 0.88 (0.78-0.98); and ethinyl estradiol, 1.01 (0.88-1.15). For levonorgestrel, the GMR for AUC from time 0 to the last quantifiable concentration was 0.87 (0.78-0.96). These findings indicate that NBI-1065845 is not a CYP3A inducer and support its administration with CYP3A substrates. NBI-1065845 was generally well tolerated, with no new safety signals observed after coadministration of midazolam, ethinyl estradiol, or levonorgestrel.

Predictors of 1- and 12-month mortality in bifurcation coronary intervention: a contemporary perspective.

Aim: Bifurcation-PCI is performed frequently, although without extensive evidence to back up a definitive solution for its complexity. We set out to identify factors associated with 1- and 12-month mortality after bifurcation-PCI between 2017 and 2021 in our tertiary center in Wales, UK. Results: Of 732 bifurcation PCI cases (mean age 69; 25% female), 67% were in ACS, 42% were left main PCI and 25.3% involved two-stent strategy. 30-day and 12-month mortality were 1.9 and 8.2%, respectively. Age, diabetes, smoking and renal failure are associated with mortality after bifurcation-PCI, while the choice between provisional and 2-stent strategies did not impact mortality/TLR. Conclusion: Awareness of 'real-world' outcomes of bifurcation-PCI should be used for appropriate patient selection, technique planning and procedural consent.

Aortic regurgitation management: a systematic review of clinical practice guidelines and recommendations.

Guidelines for the diagnosis and management of aortic regurgitation (AR) contain recommendations that do not always match. We systematically reviewed clinical practice guidelines and summarized similarities and differences in the recommendations as well as gaps in evidence on the management of AR. We searched MEDLINE and Embase (1 January 2011 to 1 September 2021), Google Scholar, and websites of relevant organizations for contemporary guidelines that were rigorously developed as assessed by the Appraisal of Guidelines for Research and Evaluation II tool. Three guidelines met our inclusion criteria. There was consensus on the definition of severe AR and use of echocardiography and of multimodality imaging for diagnosis, with emphasis on comprehensive assessment by the heart valve team to assess suitability and choice of intervention. Surgery is indicated in all symptomatic patients and aortic valve replacement is the cornerstone of treatment. There is consistency in the frequency of follow-up of patients, and safety of non-cardiac surgery in patients without indications for surgery. Discrepancies exist in recommendations for 3D imaging and the use of global longitudinal strain and biomarkers. Cut-offs for left ventricular ejection fraction and size for recommending surgery in severe asymptomatic AR also vary. There are no specific AR cut-offs for high-risk surgery and the role of percutaneous intervention is yet undefined. Recommendations on the treatment of mixed valvular disease are sparse and lack robust prospective data.

Tricuspid regurgitation management: a systematic review of clinical practice guidelines and recommendations.

Tricuspid regurgitation (TR) is a highly prevalent condition and an independent risk factor for adverse outcomes. Multiple clinical guidelines exist for the diagnosis and management of TR, but the recommendations may sometimes vary. We systematically reviewed high-quality guidelines with a specific focus on areas of agreement, disagreement, and gaps in evidence. We searched MEDLINE and EMBASE (1 January 2011 to 30 August 2021), the Guidelines International Network International, Guideline Library, National Guideline Clearinghouse, National Library for Health Guidelines Finder, Canadian Medical Association Clinical Practice Guidelines Infobase, Google Scholar, and websites of relevant organizations for contemporary guidelines that were rigorously developed (as assessed by the Appraisal of Guidelines for Research and Evaluation II tool). Three guidelines were finally retained. There was consensus on a TR grading system, recognition of isolated functional TR associated with atrial fibrillation, and indications for valve surgery in symptomatic vs. asymptomatic patients, primary vs. secondary TR, and isolated TR forms. Discrepancies exist in the role of biomarkers, complementary multimodality imaging, exercise echocardiography, and cardiopulmonary exercise testing for risk stratification and clinical decision-making of progressive TR and asymptomatic severe TR, management of atrial functional TR, and choice of transcatheter tricuspid valve intervention (TTVI). Risk-based thresholds for quantitative TR grading, robust risk score models for TR surgery, surveillance intervals, population-based screening programmes, TTVI indications, and consensus on endpoint definitions are lacking.

Repeated echocardiographic imaging of aortic stenosis: Real-life lessons.

BACKGROUND: Timing of aortic valve intervention is dependent on the accuracy and reproducibility of echocardiographic (ECHO) parameters. We aimed to assess haemodynamic subsets of aortic stenosis (AS), their change over time, and variability of ECHO parameters. METHOD: This retrospective, longitudinal study compared sequential ECHO over 15 months to identify concordant or discordant aortic valve area (AVA) and mean pressure gradient (MPG) in order to determine the real world variability of echocardiographic indices. RESULTS: We included 143 patients with a mean age of 76.0 years. The median length of time between studies was 112 days (IQR 38-208). Initially, participants were classified as 9 (6.4%) mild, 47 (33.6%) moderate, and 84 (60.0%%) severe AS. In 80 (55.9%) AVA and MPG were concordant; stroke volume index (SVi) was < 35 mL/m2 in 53 (74.6%). AS severity was downgraded in 29 (20.7%) patients. MPG was most consistent and AVA was the least consistent between successive investigations (intraclass correlation coefficients R = .86 and R = .76, respectively). Even small variations in left ventricular outflow tract (LVOT) measurement of 1 standard deviation reclassified up to 67% of participants from severe to non-severe. CONCLUSION: Almost half of patients with AS have valve area/gradient discordance. Variations in LVOT diameter measurement commensurate with clinical practice reclassified AS severity in up to two-third of cases. Change in AS severity should only be accepted following careful scrutiny of all available ECHO data.

Outcome of isolated aortic valve replacement in patients with classic and paradoxical low-flow, low-gradient aortic stenosis.

OBJECTIVE: To analyze operative outcomes and mid-term results after isolated aortic valve replacement (AVR) in low-flow, low-gradient aortic stenosis (LFLG AS) by comparing the 2 subcategories (classic low-flow, low-gradient aortic stenosis [CLFLG] and paradoxical low-flow, low-gradient aortic stenosis [PLFLG]). METHODS: This was a retrospective analysis of prospectively collected data for all isolated AVR in LFLG AS performed in our center during the last 13 years (n = 198; CLFLG AS, n = 66, 33% and PLFLG AS, n = 132, 67%). Median follow-up was 3.7 ± 3.3 years. RESULTS: Preoperative mean gradient was 30.2 ± 8.8 mm Hg in the CLFLG AS group and 31.4. ± 7.0 mmHg in the PLFLG AS group (P = .001). Female sex, hypertension, and neurologic and renal disease were more frequent in the PLFLG AS group (P < .01) whereas advanced New York Heart Association class, atrial fibrillation, and pulmonary hypertension were more frequent in the CLFLG AS group (P < .01). In-hospital mortality was 3% in the CLFLG AS group and 2.3% in the PLFLG AS group, P = .08. One- and five-year mortality rates were significantly greater in the CLFLG AS group (27% and 42% vs 6% and 20% in the PLFLG AS group, respectively, P = .001). On follow-up, 90% of the total survivors were in New York Heart Association class I-II, and 51% of the patients in the CLFLG AS group had an improvement in their ventricular function. CONCLUSIONS: AVR can be performed in LFLG AS with low in-hospital mortality. CLFLG AS carries similar in-hospital mortality to PLFLG AS but greater mid-term mortality. Surgery provided excellent functional status among survivors.

Low-flow low-gradient aortic stenosis: surgical outcomes and mid-term results after isolated aortic valve replacement.

OBJECTIVES: To analyse operative outcomes and mid-term results following isolated aortic valve replacement (AVR) in patients with low-flow low-gradient severe aortic stenosis (LFLG AS) compared with normal flow high-gradient aortic stenosis (NFHG AS). METHODS: A retrospective analysis of data for all isolated AVRs performed for AS at our centre in the last 17 years (n = 846). Two groups were identified: LFLG AS (n = 198, 23%) [subdivided into: True LFLG AS (n = 66, 33%) and paradoxical LFLG AS (n = 132, 67%)] and NFHG AS (n = 648, 77%). Follow-up was done by clinical visits and telephone interviews. The mean follow-up was 5.8 ± 4.2 years. RESULTS: The mean age was 71.5 ± 9.7 years in the LFLG AS group and 68.7 ± 10.8 years in the NFHG group (P = 0.01). The LFLG AS group had a mean gradient 31.2 ± 7.4 mmHg compared with 59.1 ± 16.6 mmHg in the NFHG group (P = 0.001). Diabetes, chronic obstructive pulmonary disease, previous coronary disease, peripheral vascular disease, atrial fibrillation and pulmonary hypertension were significantly more frequent in the LFLG AS patients (P < 0.01). The in-hospital mortality rate was 2% in the LFLG and 1% in the NFHG group, P = 0.13. One- and 5-year mortality rates were significantly higher in the LFLG group (13 and 28 vs 4 and 16% in the NFHG, respectively, P = 0.001). Patients with true LFLG AS also had a significantly higher long-term mortality than those with paradoxical LFLG AS (27 vs 6% at 1 year and 42 vs 20% at 5 years, P < 0.05). CONCLUSIONS: AVR in patients with LFLG AS is associated with similar surgical mortality but increased mid-term mortality compared with NFHG AS. Patients with true LFLG AS have the worst outcomes. Surgery should still be offered for LFLG AS on prognostic grounds and for symptomatic benefit among survivors.

The Use of Multidimensional Modeling of the Aorta in Planning the Resection of an Aortic Angiosarcoma.

PURPOSE: We report a technique of finite-element multidimensional modeling that was used to help with the planning of and the resection of an angiosarcoma in a single patient. DESCRIPTION: A patient was referred to our department with suspected aortic angiosarcoma. We visualized and reconstructed the computed tomography and magnetic resonance imaging scans of this patient to create finite-element multidimensional models of his diseased aorta. EVALUATION: This technique and the multidimensional models were very helpful in assessing the tumor size and its extension. It also facilitated preoperative planning of the aortic resection and repair. CONCLUSION: Finite-element multidimensional modeling is a useful technique for preoperative planning of aortic operations in patients with angiosarcoma.

Accessory mitral valve--an unexpected intra-operative TEE finding causing left ventricular outflow tract obstruction in an adult.

There is a long-standing debate between proponents of routine intra-operative echo and those who want it restricted to selected groups of patients (such as those undergoing valve repair or correction of congenital abnormalities). We present a case where routine transesophageal echocardiography (TEE) identified completely unexpected pathology, with implications for the postoperative follow-up and for patient outcomes. A 64-year-old male, with a history of surgical repair of coarctation of the aorta in childhood, was admitted for elective valve replacement for severe aortic stenosis (AS). Previous transthoracic echocardiography had not identified any other pathology apart from AS, but routine intra-operative TEE picked up severe turbulence in the left ventricular outflow tract (LVOT). On further analysis this was due to 2 mechanisms: a localized subaortic membrane and a "cystic" mass attached to the anterior mitral leaflet, protruding into the LVOT in systole. Multiplane imaging of the mass disclosed an accessory mitral valve (MV), a rare congenital abnormality. The patient had excision of the stenosed aortic valve and of the subaortic membrane, while the accessory MV was spared, as the surgeon judged its removal might distort the mitral apparatus. Postoperative recovery was unremarkable and the patient went home with symptomatic improvement. This case illustrates the fact that even "standard" cardiac procedures can benefit from intra-operative TEE which, in our view, should be available for all patients who undergo heart surgery.

AedesCAPA-PVK-1 displays diuretic and dose dependent antidiuretic potential in the larval mosquito Aedes aegypti (Liverpool).

This study reveals that AedesCAPA-PVK-1 (GPTVGLFAFPRV-NH(2)) inhibits basal and serotonin stimulated fluid secretion in the Malpighian tubules of larval Aedes aegypti at femtomolar concentrations. Conversely 10(-4)moll(-1) of the peptide stimulated fluid secretion rates. The diuretic effects of 10(-4)moll(-1)AedesCAPA-PVK-1 and antidiuretic effects of 10(-15)moll(-1)AedesCAPA-PVK-1 were abolished by protein kinase A (PKA) and protein kinase G (PKG) inhibition, respectively. Similar to the peptide, 10(-3)moll(-1) cGMP stimulated fluid secretion but doses in the micromolar to nanomolar range inhibited fluid secretion of the Malpighian tubules. Stimulatory effects of cGMP were abolished by PKA inhibition and inhibitory effects of cGMP were abolished by PKG inhibition. Furthermore, the nitric oxide synthase inhibitor l-NAME attenuated the inhibitory effects of AedesCAPA-PVK-1 but did not affect inhibition by cGMP. Based on the results we propose that AedesCAPA-PVK-1 inhibits fluid secretion rates of larval Malpighian tubules via the NOS/cGMP/PKG pathway and that high doses of the peptide lead to diuresis through the cGMP mediated activation of PKA.

A single active nanoelectromechanical tuning fork front-end radio-frequency receiver.

Nanoelectromechanical systems (NEMS) offer the potential to revolutionize fundamental methods employed for signal processing in today's telecommunication systems, owing to their spectral purity and the prospect of integration with existing technology. In this work we present a novel, front-end receiver topology based on a single device silicon nanoelectromechanical mixer-filter. The operation is demonstrated by using the signal amplification in a field effect transistor (FET) merged into a tuning fork resonator. The combination of both a transistor and a mechanical element into a hybrid unit enables on-chip functionality and performance previously unachievable in silicon. Signal mixing, filtering and demodulation are experimentally demonstrated at very high frequencies ( > 100 MHz), maintaining a high quality factor of Q = 800 and stable operation at near ambient pressure (0.1 atm) and room temperature (T = 300 K). The results show that, ultimately miniaturized, silicon NEMS can be utilized to realize multi-band, single-chip receiver systems based on NEMS mixer-filter arrays with reduced system complexity and power consumption.

Novel use of transesophageal echocardiographic probe for intraoperative epicardial imaging.

We studied 3 patients in whom standard transesophageal echocardiography was either not feasible nor offered suboptimal images. A standard multi-plane transesophageal echocardiography probe was covered in a sterile sheath containing ultrasonic gel, and the tip of the probe was placed on the beating heart by the surgeon. Echocardiographic imaging planes were selected by combining multi-plane imaging with "flexion" and "extension" of the probe by the echocardiographer, with minimal surgical manipulation. Good-quality "epicardial-transesophageal echocardiography" images were obtained in all cases, allowing effective decision-making by the surgeon. The small size of the probe and availability of multi-plane imaging allowed comprehensive and detailed imaging of the heart with minimal manipulation of the probe. There were no side effects attributable to the epicardial-transesophageal echocardiography. The new technique of epicardial echocardiography with a multi-plane transesophageal echocardiography probe overcomes the limitations of conventional transesophageal echocardiography and of epicardial echocardiography in selected patients and allows excellent visualization of cardiac structure and function with minimal interference with the surgical field, and with no extra expenditure.

Gas gangrene of the thigh in a morbidly obese patient with occult colon cancer.

SUMMARY: We report a case of atraumatic gas gangrene and myonecrosis of the leg secondary to infection with Clostridium septicum in a severely obese patient with an occult cancer. She was treated successfully for both conditions. A review of the current literature describes this constellation of findings and the appropriate treatment.:

Directed submucosal tunneling permits in-line endoscope positioning for transgastric natural orifice translumenal endoscopic surgery (NOTES).

BACKGROUND: Submucosal dissection is demonstrated to be a technically feasible, safe means of obtaining peroral transgastric peritoneal access for natural orifice translumenal endoscopic surgery (NOTES). The authors hypothesized that their previously described self-approximating translumenal access technique (STAT) could be used to create directed gastric submucosal tunnels permitting in-line endoscope positioning with predetermined abdominal locations that might otherwise be difficult to access. METHODS: In this study, 14 domestic farm swine underwent peroral transgastric peritoneoscopy. Under direct endoscopic visualization, a submucosal tunnel was created by dissecting between the mucosal and muscular layers of the stomach. Each tunnel was created with one of four intraabdominal locations (right upper quadrant, left upper quadrant, lesser sac, and pelvis) as the final target for in-line endoscope positioning. Once peritoneal access had been achieved, in-line positioning was assessed and peritoneoscopy was performed. The submucosal tunnels were closed with endoscopically placed clips. The animals were killed 2 weeks after the procedure, and necropsy was performed. RESULTS: Submucosal tunnels were successfully directed at predetermined intraabdominal targets in 12 of the 14 animals. The mean dissection time required to create the tunnel was 51 +/- 32 min. All the transgastric tunnels were successfully closed with endoscopically placed clips (mean, 3.2 +/- 1.1), and at necropsy showed no evidence of gastrotomy leak in any of the animals. One animal experienced a duodenal perforation unrelated to the transgastric tunneling and was killed on postoperative day 2. The remaining animals recovered and gained weight (mean, 5.5 +/- 1.2 kg) in the 2-week survival period. CONCLUSIONS: Directed submucosal dissection is technically feasible in a porcine model and permits in-line endoscope positioning with predetermined abdominal target locations. The STAT approach provides safe peritoneal access, allows for a simple reliable endoclip closure, and has an excellent short-term survival rate. This method of achieving transgastric access may be an enabling technique for future NOTES procedures.

Technique for transesophageal endoscopic cardiomyotomy (Heller myotomy): video presentation at the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) 2008, Philadelphia, PA.

BACKGROUND: Previous investigators have shown the feasibility of performing an esophageal myotomy using natural orifice translumenal endoscopic surgery (NOTES), but have been unsuccessful at extending the myotomy onto the body of the stomach. METHODS: In a nonsurvival porcine model, the authors used the self-approximating translumenal access technique (STAT) to create a submucosal tunnel in the upper esophagus and to extend it onto the body of the stomach allowing a complete cardiomyotomy. RESULTS: The STAT approach was successfully used to create a submucosal tunnel and perform a complete myotomy of the gastroesophageal junction without complication. CONCLUSIONS: A complete Heller-type cardiomyotomy can be successfully performed using transesophegeal NOTES.

An unusual suspect: coconut bezoar after laparoscopic Roux-en-Y gastric bypass.

Nausea and vomiting after gastric bypass are common, but some of the underlying causes may be life threatening or, in some cases, unusual. This case report describes a patient who underwent laparoscopic Roux-en-Y gastric bypass and whose postoperative course was complicated by a bezoar in the gastric pouch. To our knowledge, this is the first published report addressing a coconut bezoar in the gastric pouch after gastric bypass surgery. Coconut (cocos nucifera) is known to form emulsions and suspensions, properties likely to have contributed to this patient's condition. Nutritional counseling should be an ongoing process in the postoperative care of gastric bypass patients in an effort to prevent serious complications that may arise from dietary indiscretions.