Biodosimetric analysis of head and neck cancer patients undergoing radiotherapy by dicentric chromosome aberration assay.

BACKGROUND: Biodosimetry is the quantification of absorbed radiation dose using biological material obtained from an exposed individual. Radiation can cause different types of chromosomal aberrations, including stable aberrations like translocations and unstable ones like micronuclei, dicentric chromosomes (DC), acentric, and ring forms. Dicentric chromosome assay has become the "gold standard" for cytogenetic biodosimetry due to its reproducibility, specificity (low baseline rates), and sensitivity to low doses. Using existing calibration curves and models obtained from in vitro irradiation of blood, the yield of DCs can be used to estimate the average whole-body absorbed dose. PURPOSE: To evaluate and compare the in vivo dose-response relation of DC aberration formation in peripheral blood lymphocytes of head and neck cancer (HNC) patients undergoing radiotherapy (RT) alone, cisplatin-based chemoradiation (CCRT), accelerated fractionation RT (AFRT), and CCRT with gefitinib (GCRT). METHODOLOGY: This prospective observational and analytical study was conducted from 2018 to 2021 in the Department of Radiation Oncology and Genetic Lab of tertiary care, teaching hospital after approval from the Institutional Ethics Committee. Biodosimetric analysis was done weekly in patients undergoing RT (n = 20) versus CCRT (n = 20), CCRT (n = 12) versus AFRT (n = 12), and CCRT (n = 6) versus GCRT (n = 6). The yield of DCs was measured in blood samples taken before starting treatment, that is, day 0 and during RT on days 6, 11, and 16 in RT alone versus CCRT; on days 7 and 13 in CCRT versus AFRT; and days 6 and 11 in CCRT versus GCRT from a blood sample drawn 1-2 h after RT. Phytohemagglutinin-stimulated lymphocytes were cultured using heparinized blood in RPMI-1640 medium supplemented with fetal bovine serum. Cells were arrested at metaphase using demecolcine, harvested by centrifugation, mounted, and stained with Giemsa. Cytogenetic analysis was performed by analyzing at least 100 metaphases with well-spread chromosomes. DC aberrations and acentric fragments were identified and recorded. To standardize the findings as per the customized field for every patient, the mean DC yield per cm2 of the irradiated area was calculated and compared. RESULTS: The mean yield of DC/cm2 in the CCRT group was greater than the RT alone group by 16.33%, 28.57%, and 18.68% on days 6, 11, and 16 of treatment, respectively. This difference between the two groups at day 6 (P = 0.001), day 11 (P < 0.001), and day 16 (P < 0.001) was found to be statistically significant. The mean yield of DC/cm2 in the CCRT group was greater than the AFRT group by 7.9% and 18.3% on days 7 and 13 of treatment, respectively. This difference at day 7 (P < 0.001) and day 13 (P < 0.001) was found to be statistically significant. The mean yield of DC/cm2 in the CCRT group was greater than the GCRT group by 22.7% and 21.8% on days 6 and 11 of treatment, respectively. The difference at day 6 (P = 0.01) was statistically significant but, on day 11 (P = 0.065) this difference was found insignificant. CONCLUSION: There is a dose-dependent increase in the yield of DCs in lymphocytes of HNC patients undergoing RT with subsequent fractions. Cisplatin-based chemoradiation is the superior method of treatment intensification radio-biologically proven by higher DC yield.

Block Copolymer Micellization of DNA Origami Promotes Solubility in Organic Solvents.

The DNA origami technique allows the precise synthesis of complex, biocompatible nanomaterials containing small molecules, biomolecules, and inorganic nanoparticles. The negatively charged phosphates in the backbone make DNA highly water-soluble and require salts to shield its electrostatic repulsion. DNA origamis are therefore not soluble in most organic solvents. While this is not problematic for applications in biochemistry, biophysics, or nanomedicine, other potential applications, processes, and substrates are incompatible with saline solutions, which include the synthesis of many nanomaterials, and reactions in templated synthesis, the operation of nanoelectronic devices, or semiconductor fabrication. To overcome this limitation, we coated DNA origami with amphiphilic poly(ethylene glycol) polylysine block copolymers and transferred them into various organic solvents including chloroform, dichloromethane, acetone, or 1-propanol. Our approach maintains the shape of the nanostructures and protects functional elements bound to the structure, such as fluorophores, gold nanoparticles, or proteins. The DNA origami polyplex micellization (DOPM) strategy hence enables solubilization or a phase transfer of complex structures into various organic solvents, which significantly expands the use of DNA origami for a range of potential applications and technical processes.

A novel technique for invasive aortic valve pressure gradient measurement using a 6 Fr Swan-Ganz catheter: a case series.

BACKGROUND: Simultaneous left ventricular (LV) and aortic (Ao) pressure gradient assessment has been rendered challenging since the recall of the Langston catheter. Here we describe a simple method for simultaneous LV and Ao pressure gradient assessment using a Swan-Ganz catheter. CASE SUMMARY: We describe two cases where assessment of simultaneous left ventricle and Ao valve gradients was done using a Swan-Ganz catheter to assess the degree of Ao stenosis and dynamic LV outflow obstruction. DISCUSSION: Using Swan-Ganz catheter assessment of simultaneous left ventricle and Ao valve gradients can simplify the procedure with reduced cost and increased patient safety.

Novel targeted therapies for metastatic breast cancer.

Metastatic breast cancer (mBC) continues to be a leading cause of cancer-related death in women. Even though mortality rates have improved over recent years, the 5-year survival rate of advanced BC is still at only 27%. As researchers and clinicians attempt to tackle this challenge, there has been extensive research and many trials studying treatment options for BC patients with metastatic disease, with numerous new therapies being discovered as a result. We review the most pertinent novel agents to enter the scope of BC treatment, including CDK4/6 inhibitors, PI3K inhibitors, mTOR inhibitors, immunotherapy, PARP inhibitors, and more.

Peripheral Arterial Disease in Women: The Gender Effect.

Peripheral arterial disease (PAD) is a common atherosclerotic disease approximately affecting 8.5 million Americans above age 40 and is associated with significant functional impairment, morbidity and mortality from both cardiovascular and non-cardiovascular causes. PAD has increasing prevalence in females contrary to previous findings. Compared to men, women with PAD are more asymptomatic or have atypical symptoms. Women with PAD have increased quality of life impairment, increased risk of depression and increased cardiovascular mortality. The intent of this review is to provide an update on gender differences in PAD that can help in timely diagnosis and appropriate management through intensive cardiovascular risk factor modification, exercise program and guideline directed therapy to improve cardiovascular outcomes.

Dual versus triple antithrombotic therapy in patients undergoing percutaneous coronary intervention-meta-analysis and meta-regression.

BACKGROUND: Anti-thrombotic regimen in patients on long term anticoagulation requiring coronary intervention remains a clinical challenge. METHODS: We performed a meta-analysis of observational studies and randomized controlled trials comparing outcomes of triple therapy (dual antiplatelet therapy and anticoagulant) with dual therapy (P2Y12 inhibitor and anticoagulant) in patients on long-term anticoagulants after percutaneous coronary intervention (PCI). Major bleeding was the primary outcome. RESULTS: Three observational studies and 3 randomized controlled trials with a total of 6654 patients met our selection criteria. At a mean follow up of 12.5 months major bleeding was lower in dual therapy cohort compared to triple therapy (2.2% vs 5.2%, RR 0.60, 95% CI 0.44-0.81, P = 0.001). No difference was observed between the two groups for major adverse cardiac events (11.8% vs 13.0%, RR 1.03, CI 0.79-1.34, P = 0.85), all-cause mortality (3.9% vs 5.6%, RR 0.94, CI 0.65-1.36, P = 0.76), myocardial infarction (3.7% vs 3.9%, RR 1.12, CI 0.83-1.50, P = 0.47), target vessel revascularization (6.8% vs 7.1%, RR 1.12, CI 0.72-1.74, P = 0.60), thromboembolic events (1.3% vs 1.6%, RR 0.95, CI 0.55-1.64, P = 0.85) and stent thrombosis (1.3% vs 1.4%, RR1.36, CI 0.84-2.21, P = 0.21). CONCLUSION: For patients undergoing PCI and requiring long term anticoagulation, a strategy of P2Y12 inhibitor plus anticoagulant confers a benefit of less major bleeding with no difference in major adverse cardiac events, mortality, myocardial infarction, target vessel revascularization, stent thrombosis or thromboembolism compared with triple therapy.

Triangulated Wireframe Structures Assembled Using Single-Stranded DNA Tiles.

The field of structural DNA nanotechnology offers a wide range of design strategies with which to build structures with a desired aspect ratio, size, and shape. Compared with traditional close-packed DNA structures, triangulated wireframe structures require less material per surface or volume unit and improve the stability in biologically relevant conditions due to the reduced electrostatic repulsion. Herein, we expand the design space of the DNA single-stranded tile method to cover a range of anisotropic, finite, triangulated wireframe structures as well as a number of one-dimensional crystalline assemblies. These structures are composed of six-arm junctions with a single double helix as connecting edges that assemble in physiologically relevant salinities. For a reliable folding of the structures, single-stranded spacers 2-4 nucleotides long have to be introduced in the junction connecting neighboring arms. Coarse-grained molecular dynamics simulations using the oxDNA model suggests that the spacers prevent the stacking of DNA helices, thereby facilitating the assembly of planar geometries.

DNA-encircled lipid bilayers.

Lipid bilayers and lipid-associated proteins play crucial roles in biology. As in vivo studies and manipulation are inherently difficult, membrane-mimetic systems are useful for the investigation of lipidic phases, lipid-protein interactions, membrane protein function and membrane structure in vitro. In this work, we describe a route to leverage the programmability of DNA nanotechnology and create DNA-encircled bilayers (DEBs). DEBs are made of multiple copies of an alkylated oligonucleotide hybridized to a single-stranded minicircle, in which up to two alkyl chains per helical turn point to the inside of the toroidal DNA ring. When phospholipids are added, a bilayer is observed to self-assemble within the ring such that the alkyl chains of the oligonucleotides stabilize the hydrophobic rim of the bilayer to prevent formation of vesicles and support thermotropic lipid phase transitions. The DEBs are completely free of protein and can be synthesized from commercially available components using routine equipment. The diameter of DEBs can be varied in a predictable manner. The well-established toolbox from structural DNA nanotechnology, will ultimately enable the rational design of DEBs so that their size, shape or functionalization can be adapted to the specific needs of biophysical investigations of lipidic phases and the properties of membrane proteins embedded into DEB nanoparticle bilayers.

Optimum Antithrombotic Therapy in Patients Requiring Long-Term Anticoagulation and Undergoing Percutaneous Coronary Intervention.

Management of patients on long-term anticoagulation requiring percutaneous coronary intervention is challenging. Triple therapy with oral anticoagulant and dual antiplatelet therapy is the standard of care. However, there is no strong evidence to support this strategy. There is emerging data regarding the safety and efficacy of dual therapy with oral anticoagulant and single antiplatelet therapy in these patients. In this comprehensive review we highlight available evidence regarding various antithrombotic regimens' efficacy and safety in patient with coronary artery disease undergoing percutaneous coronary intervention with long-term anticoagulation therapy requirements.

Cryptogenic Stroke and Patent Foramen Ovale.

Nearly one-half of patients with cryptogenic stroke have a patent foramen ovale (PFO). The dilemma of whether to close these PFOs percutaneously, in an effort to reduce the risk of recurrent paradoxical embolism, has been a matter of ongoing debate for more than a decade. Early randomized clinical trials failed to demonstrate a significant benefit of percutaneous PFO closure for secondary prevention of cryptogenic stroke in an intention-to-treat analysis. The long-term follow-up data from the RESPECT trial and 2 new randomized trials (CLOSE and REDUCE) have clarified these findings. They showed that with good patient selection, transcatheter PFO closure significantly reduces the risk of recurrent stroke compared with medical therapy in patients with cryptogenic stroke, with no increased risk of serious adverse events or influence on major bleeding.

Mentoring in Surgery-Mentor, Parshuram, Dronacharya, Krishan.

Success in any profession has no well-defined predictors. Knowledge, skills, training, and talent come in plenty but fail at times to achieve the universal goal of success. Some attribute it to luck. Apart from the tangible ingredients of a successful career, the intangibles like luck or something ill-defined is a real challenge. The intangibles seem like a chasm, an abyss, or a phantom obstacle. Presence of a guiding spirit who can handhold you to overcome these is essential for success. The aim of a professional is to learn, earn, and yearn for creativity. Practice of surgery is an ideal career to pursue the learning, earning, and yearning. More than any other profession, the guiding handholding spirit is required in surgical profession, the concept of mentoring. Originating from the Greco-Roman times when kind Odysseus left his son Telemachus under the care of his friend, mentor, it has become a universal defining necessity for a successful career in surgery. Indian history replete with such examples of mentorship, good as in the case of Dronacharya to Kaurvas but bad as denied by an able, competent, aspiring student like Eklavya. In the medical profession, there are very few Indian role models of mentorship. One name that comes to our mind is Dr. Krishan Mahajan. The more said is less revealed about him. "Knife before wife" was his commonly spoken advice to all who sought his mentorship. "Hard work is not easy but it is fair" so said a famous boxer, Larry Holmes. It is more than true for our profession as it is better to prepare and prevent, rather than repair and repent.

Structural Transformation of Wireframe DNA Origami via DNA Polymerase Assisted Gap-Filling.

The programmability of DNA enables constructing nanostructures with almost any arbitrary shape, which can be decorated with many functional materials. Moreover, dynamic structures can be realized such as molecular motors and walkers. In this work, we have explored the possibility to synthesize the complementary sequences to single-stranded gap regions in the DNA origami scaffold cost effectively by a DNA polymerase rather than by a DNA synthesizer. For this purpose, four different wireframe DNA origami structures were designed to have single-stranded gap regions. This reduced the number of staple strands needed to determine the shape and size of the final structure after gap filling. For this, several DNA polymerases and single-stranded binding (SSB) proteins were tested, with T4 DNA polymerase being the best fit. The structures could be folded in as little as 6 min, and the subsequent optimized gap-filling reaction was completed in less than 3 min. The introduction of flexible gap regions results in fully collapsed or partially bent structures due to entropic spring effects. Finally, we demonstrated structural transformations of such deformed wireframe DNA origami structures with DNA polymerases including the expansion of collapsed structures and the straightening of curved tubes. We anticipate that this approach will become a powerful tool to build DNA wireframe structures more material-efficiently, and to quickly prototype and test new wireframe designs that can be expanded, rigidified, or mechanically switched. Mechanical force generation and structural transitions will enable applications in structural DNA nanotechnology, plasmonics, or single-molecule biophysics.

Influence of Atrial Fibrillation on Outcomes in Patients Who Underwent Primary Percutaneous Coronary Intervention for ST-Segment Elevation Myocardial Infarction.

Atrial fibrillation (AF) is a common co-morbidity among patients presenting with acute ST-segment elevation myocardial infarction (STEMI). Previously, small studies have reported an association between AF and poorer outcomes among patients with STEMI. We performed this study to investigate the impact of AF on in-hospital outcomes in patients with STEMI treated with primary percutaneous coronary intervention (PPCI) using a large national database. The study population constituted of patients 18 years and older with a primary discharge diagnosis of STEMI and who underwent PPCI. Using a 2:1 matching protocol, matched groups of patients with AF (N = 24,680) and without (N = 49,198) were developed. Among 1,493,859 patients with STEMI who underwent PPCI, 129,354 patients (8.7%) had AF. In the propensity-matched cohort, adjusted in-hospital mortality was significantly higher for patients with AF compared with patients with no AF (10.3% vs 9.4%) (adjusted odds ratio [OR] 1.10; confidence interval [CI] 1.06 to 1.16; p <0.0001). Patients with AF were also at higher risk of heart failure, cardiogenic shock, acute stroke, acute kidney injury, vascular complications, need for blood transfusion, and a composite outcome of gastrointestinal and retroperitoneal bleeding. Patients with AF were less likely to be treated with drug-eluting stent compared with patients without AF (51.4% vs 56.6%) (adjusted OR 0.81; CI 0.79 to 0.84; p <0.001). Among patients presenting with STEMI and who underwent PPCI, AF is present in about 8% of patients. In a propensity-matched analysis using a large national database, AF was found to be independently associated with a higher risk of in-hospital mortality and of other complications in these patients.

Contemporary Sex-Based Differences by Age in Presenting Characteristics, Use of an Early Invasive Strategy, and Inhospital Mortality in Patients With Non-ST-Segment-Elevation Myocardial Infarction in the United States.

BACKGROUND: Prior studies have reported higher inhospital mortality in women versus men with non-ST-segment-elevation myocardial infarction. Whether this is because of worse baseline risk profile compared with men or sex-based disparities in treatment is not completely understood. METHODS AND RESULTS: We queried the 2003 to 2014 National Inpatient Sample databases to identify all hospitalizations in patients aged ≥18 years with the principal diagnosis of non-ST-segment-elevation myocardial infarction. Complex samples multivariable logistic regression models were used to examine sex differences in use of an early invasive strategy and inhospital mortality. Of 4 765 739 patients with non-ST-segment-elevation myocardial infarction, 2 026 285 (42.5%) were women. Women were on average 6 years older than men and had a higher comorbidity burden. Women were less likely to be treated with an early invasive strategy (29.4% versus 39.2%; adjusted odds ratio, 0.92; 95% confidence interval, 0.91-0.94). Women had higher crude inhospital mortality than men (4.7% versus 3.9%; unadjusted odds ratio, 1.22; 95% confidence interval, 1.20-1.25). After adjustment for age (adjusted odds ratio, 0.96; 95% confidence interval, 0.94-0.98) and additionally for comorbidities, other demographics, and hospital characteristics, women had 10% lower odds of inhospital mortality (adjusted odds ratio, 0.90; 95% confidence interval, 0.89-0.92). Further adjustment for differences in the use of an early invasive strategy did not change the association between female sex and lower risk-adjusted inhospital mortality. CONCLUSIONS: Although women were less likely to be treated with an early invasive strategy compared with men, the lower use of an early invasive strategy was not responsible for the higher crude inhospital mortality in women, which could be entirely explained by older age and higher comorbidity burden.

Safety and efficacy of second-generation drug-eluting stents compared with bare-metal stents: An updated meta-analysis and regression of 9 randomized clinical trials.

The efficacy of second-generation drug-eluting stents (DES; eg, everolimus and zotarolimus) compared with bare-metal stents (BMS) in patients undergoing percutaneous coronary intervention was challenged recently by new evidence from large clinical trials. Thus, we aimed to conduct an updated systematic review and meta-analysis of randomized clinical trials (RCTs) evaluating the efficacy and safety of second-generation DES compared with BMS. Electronic databases were systematically searched for all RCTs comparing second-generation DES with BMS and reporting clinical outcomes. The primary efficacy outcome was major adverse cardiac events (MACE); the primary safety outcome was definite stent thrombosis. The DerSimonian and Laird method was used for estimation of summary risk ratios (RR). A total of 9 trials involving 17 682 patients were included in the final analysis. Compared with BMS, second-generation DES were associated with decreased incidence of MACE (RR: 0.78, 95% confidence interval [CI]: 0.69-0.88), driven by the decreased incidence of myocardial infarction (MI) (RR: 0.67, 95% CI: 0.48-0.95), target-lesion revascularization (RR: 0.47, 95% CI: 0.42-0.53), definite stent thrombosis (RR: 0.57, 95% CI: 0.41-0.78), and definite/probable stent thrombosis (RR: 0.54, 95% CI: 0.38-0.80). The incidence of all-cause mortality was similar between groups (RR: 0.94, 95% CI: 0.79-1.10). Meta-regression showed lower incidences of MI with DES implantation in elderly and diabetic patients (P = 0.026 and P < 0.0001, respectively). Compared with BMS, second-generation DES appear to be associated with a lower incidence of MACE, mainly driven by lower rates of target-lesion revascularization, MI, and stent thrombosis. However, all-cause mortality appears similar between groups.

Meta-Analysis of Aspirin Versus Dual Antiplatelet Therapy Following Coronary Artery Bypass Grafting.

Although aspirin monotherapy is considered the standard of care after coronary artery bypass grafting (CABG), more recent evidence has suggested a benefit with dual antiplatelet therapy (DAPT) after CABG. We performed a meta-analysis of observational studies and randomized controlled trials comparing outcomes of aspirin monotherapy with DAPT in patients after CABG. Subgroup analyses were conducted according to surgical technique (i.e., on vs off pump) and clinical presentation (acute coronary syndrome vs no acute coronary syndrome). Random effects overall risk ratios (RR) were calculated using the DerSimonian and Laird model. Eight randomized control trials and 9 observational studies with a total of 11,135 patients were included. At a mean follow-up of 23 months, major adverse cardiac events (10.3% vs 12.1%, RR 0.84, confidence interval [CI] 0.71 to 0.99), all-cause mortality (5.7% vs 7.0%, RR 0.67, CI 0.48 to 0.94), and graft occlusion (11.3% vs 14.2%, RR 0.79, CI 0.63 to 0.98) were less with DAPT than with aspirin monotherapy. There was no difference in myocardial infarction, stroke, or major bleeding between the 2 groups. In conclusion, DAPT appears to be associated with a reduction in graft occlusion, major adverse cardiac events, and all-cause mortality, without significantly increasing major bleeding compared with aspirin monotherapy in patients undergoing CABG.

Trends of Incidence, Clinical Presentation, and In-Hospital Mortality Among Women With Acute Myocardial Infarction With or Without Spontaneous Coronary Artery Dissection: A Population-Based Analysis.

OBJECTIVES: The authors sought to determine the clinical characteristics and in-hospital survival of women presenting with acute myocardial infarction (AMI) and spontaneous coronary artery dissection (SCAD). BACKGROUND: The clinical presentation and in-hospital survival of women with AMI and SCAD remains unclear. METHODS: The National Inpatient Sample (2009 to 2014) was queried for all women with a primary diagnosis of AMI and concomitant SCAD. Iatrogenic coronary dissection was excluded. The main outcome was in-hospital mortality. Propensity score matching and multivariable logistic regression analyses were performed. RESULTS: Among 752,352 eligible women with AMI, 7,347 had a SCAD diagnosis. Women with SCAD were younger (61.7 vs. 67.1 years of age) with less comorbidity. SCAD was associated with higher incidence of in-hospital mortality (6.8% vs. 3.4%). In SCAD patients, a decrease in in-hospital mortality was evident with time (11.4% in 2009 vs. 5.0% in 2014) and concurred with less percutaneous coronary intervention (PCI) (82.5% vs. 69.1%). Propensity score yielded 7,332 SCAD and 14,352 patients without SCAD. The odds ratio (OR) of in-hospital mortality remained higher with SCAD after propensity matching (OR: 1.87, 95% confidence interval [CI]: 1.65 to 2.11) and on multivariable regression analyses (OR: 2.41, 95% CI: 2.07 to 2.80). PCI was associated with higher mortality in SCAD patients presenting with non-ST-segment elevation myocardial infarction (OR: 2.01; 95% CI: 1.00 to 4.47), but not with STEMI (OR: 0.62; 95% CI: 0.41 to 0.96). CONCLUSIONS: Women presenting with AMI and SCAD appear to be at higher risk of in-hospital mortality. Lower rates of PCI were associated with improved survival, with evidence of worse outcomes when PCI was performed for SCAD in the setting of non with ST-segment elevation myocardial infarction.

Identification and Quantification of Patent Foramen Ovale-Mediated Shunts: Echocardiography and Transcranial Doppler.

Once deemed benign, patent foramen ovale (PFO)-mediated right-to-left shunting has now been linked to stroke, migraine, and hypoxemia. Contrast transesophageal echocardiography is considered the standard technique for identifying a PFO, allowing visualization of the atrial septal anatomy and differentiation from non-PFO right-to-left shunts. Transthoracic echocardiography is the most common method for PFO imaging, being cost-effective, but has the lowest sensitivity. Transcranial Doppler is highly sensitive but is unable to differentiate cardiac from pulmonary shunts; it is the best method to quantitate shunt severity, being more sensitive than transthoracic or transesophageal echocardiography so is our preferred screening method for PFO.