Transcatheter Aortic Valve Implantation in Mixed Aortic Valve Disease: A Multicenter Study.

Mixed aortic valve disease (MAVD), defined by the concurrent presence of aortic stenosis (AS) and insufficiency is frequently seen in patients who have undergone transcatheter aortic valve implantation (TAVI). However, studies comparing the outcomes of TAVI in MAVD versus isolated AS have demonstrated conflicting results. Therefore, we aim to assess the outcomes of TAVI in patients with MAVD in comparison with those with isolated severe AS. Patients who underwent native valve TAVI for severe AS at 3 tertiary care academic centers between January 2012 and December 2020 were included and categorized into 3 groups based on concomitant aortic insufficiency (AI) as follows: group 1, no AI; group 2, mild AI; and group 3, moderate to severe AI. Outcomes of interest included all-cause mortality and all-cause readmission rates at 30 days and 1 year. Other outcomes include bleeding, stroke, vascular complications, and the incidence of paravalvular leak at 30 days after the procedure. Of the 1,588 patients who underwent TAVI during the study period, 775 patients (49%) had isolated AS, 606 (38%) had mild AI, and 207 (13%) had moderate to severe AI. Society of Thoracic Surgeons risk scores were significantly different among the 3 groups (5% in group 1, 5.5% in group 2, and 6% in group 3, p = 0.003). Balloon-expandable valves were used in about 2/3 of the population. No statistically significant differences in 30-day or 1-year all-cause mortality and all-cause readmission rates were noted among the 3 groups. Post-TAVI paravalvular leak at follow-up was significantly lower in group 1 (2.3%) and group 2 (2%) compared with group 3 (5.6%) (p = 0.01). In summary, TAVI in MAVD is associated with comparable outcomes at 1 year compared with patients with isolated severe AS.

Mechanical Circulatory Support in COVID-19.

Despite aggressive care, patients with cardiopulmonary failure and COVID-19 experience unacceptably high mortality rates. The use of mechanical circulatory support devices in this population offers potential benefits but confers significant morbidity and novel challenges for the clinician. Thoughtful application of this complex technology is of the utmost importance and should be done in a multidisciplinary fashion by teams familiar with mechanical support devices and aware of the particular challenges provided by this complex patient population.

Impact of COVID-19 on Acute Myocardial Infarction Care.

The global health crisis caused by the COVID-19 pandemic has evolved rapidly to overburden health care organizations around the world and has resulted in significant morbidity and mortality. Many countries have reported a substantial and rapid reduction in hospital admissions for acute coronary syndromes and percutaneous coronary intervention. The reasons for such abrupt changes in health care delivery are multifactorial and include lockdowns, reduction in outpatient services, reluctance to seek medical attention for fear of contracting the virus, and restrictive visitation policies adopted during the pandemic. This review discusses the impact of COVID-19 on important aspects of acute MI care.

Mechanical Circulatory Support in Patients With COVID-19 Presenting With Myocardial Infarction.

ST-segment elevation myocardial infarction (STEMI) complicating COVID-19 is associated with an increased risk of cardiogenic shock and mortality. However, little is known about the frequency of use and clinical impact of mechanical circulatory support (MCS) in these patients. We sought to define patterns of MCS utilization, patient characteristics, and outcomes in patients with COVID-19 with STEMI. The NACMI (North American COVID-19 Myocardial Infarction) is an ongoing prospective, observational registry of patients with COVID-19 positive (COVID-19+) with STEMI with a contemporary control group of persons under investigation who subsequently tested negative for COVID-19 (COVID-19-). We compared the baseline characteristics and in-hospital outcomes of COVID-19+ and patients with COVID-19- according to the use of MCS. The primary outcome was a composite of in-hospital mortality, stroke, recurrent MI, and repeat unplanned revascularization. A total of 1,379 patients (586 COVID-19+ and 793 COVID-19-) enrolled in the NACMI registry between January 2020 and November 2021 were included in this analysis; overall, MCS use was 12.3% (12.1% [n = 71] COVID-19+/MCS positive [MCS+] vs 12.4% [n = 98] COVID-19-/MCS+). Baseline characteristics were similar between the 2 groups. The use of percutaneous coronary intervention was similar between the groups (84% vs 78%; p = 0.404). Intra-aortic balloon pump was the most frequently used MCS device in both groups (53% in COVID-19+/MCS+ and 75% in COVID-19-/MCS+). The primary outcome was significantly higher in COVID-19+/MCS+ patients (60% vs 30%; p = 0.001) because of very high in-hospital mortality (59% vs 28%; p = 0.001). In conclusion, patients with COVID-19+ with STEMI requiring MCS have very high in-hospital mortality, likely related to the significantly higher pulmonary involvement compared with patients with COVID-19- with STEMI requiring MCS.

Mechanical Circulatory Support in COVID-19.

Despite aggressive care, patients with cardiopulmonary failure and COVID-19 experience unacceptably high mortality rates. The use of mechanical circulatory support devices in this population offers potential benefits but confers significant morbidity and novel challenges for the clinician. Thoughtful application of this complex technology is of the utmost importance and should be done in a multidisciplinary fashion by teams familiar with mechanical support devices and aware of the particular challenges provided by this complex patient population.

Impact of COVID-19 on Acute Myocardial Infarction Care.

The global health crisis caused by the COVID-19 pandemic has evolved rapidly to overburden health care organizations around the world and has resulted in significant morbidity and mortality. Many countries have reported a substantial and rapid reduction in hospital admissions for acute coronary syndromes and percutaneous coronary intervention. The reasons for such abrupt changes in health care delivery are multifactorial and include lockdowns, reduction in outpatient services, reluctance to seek medical attention for fear of contracting the virus, and restrictive visitation policies adopted during the pandemic. This review discusses the impact of COVID-19 on important aspects of acute MI care.

Sex differences in mortality and 90-day readmission rates after transcatheter aortic valve replacement: a nationwide analysis from the USA.

AIMS: To assess gender differences in in-hospital mortality and 90-day readmission rates among patients undergoing transcatheter aortic valve replacement (TAVR) in the USA. METHODS AND RESULTS: Hospitalizations for TAVR were retrospectively identified in the National readmissions database (NRD) from 2012 to 2017. Gender based differences in in-hospital mortality and 90-day readmissions were explored using multivariable logistic regression models. During the study period, an estimated 171 361 hospitalizations for TAVR were identified, including 79 722 (46.5%) procedures in women and 91 639 (53.5%) in men. Unadjusted in-hospital mortality and 90-day all-cause readmissions were significantly higher for women compared with men (2.7% vs. 2.3%, P = 0.002; 25.1% vs. 24.1%, P = 0.012, respectively). After adjusting for baseline characteristics, women had 13% greater adjusted odds of in-hospital mortality [adjusted odds ratio (aOR): 1.13, 95% confidence interval (CI): 1.02-1.26, P = 0.017], and 9% greater adjusted odds of 90-day readmission compared with men (aOR: 1.09, 95% CI: 1.05-1.14, P < 0.001). During the study period, there was a steady decrease in-hospital mortality (5.3% in 2012 to 1.6% in 2017; Ptrend < 0.001) and 90-day (29.9% in 2012 to 21.7% in 2017; Ptrend < 0.001) readmission rate in both genders. CONCLUSION: In-hospital mortality and readmission rates for TAVR hospitalizations have decreased over time across both genders. Despite these improvements, women undergoing TAVR continue to have a modestly higher in-hospital mortality, and 90-day readmission rates compared with men. Given the expanding indications and use of TAVR, further research is necessary to identify the reasons for this persistent gap and design appropriate interventions.

Transcatheter aortic valve replacement in mixed aortic valve disease: a systematic review and meta-analysis.

BACKGROUND: Utilization of transcatheter aortic valve replacement (TAVR) has expanded from high-risk patients to intermediate- and select low-risk candidates with severe aortic stenosis (AS). TAVR is currently not indicated for patients with aortic insufficiency, and its outcomes in mixed aortic valve disease (MAVD) are unclear. METHODS: A systematic search of PubMed, Medline, CINHAL, and Cochrane databases was performed to identify studies comparing TAVR outcomes in patients with AS vs. MAVD. Primary outcomes included 30-day and late all-cause mortality, and paravalvular regurgitation (PVR). Secondary outcomes were major bleeding, vascular complications, device implantation success, permanent pacemaker, and stroke. Pooled odds ratios (OR) and 95% confidence intervals (CIs) were calculated using Der Simonian-Laird random-effects model. RESULTS: Six observational studies with 58 879 patients were included in the analysis. There was no significant difference in 30-day all-cause mortality [OR 1.03 (95% CI 0.92-1.15); P = 0.63], however, MAVD group had higher odds of moderate-to-severe PVR [1.81 (1.41-2.31); P < 0.01]. MAVD patients had lower odds of device implantation success [0.60 (0.40-0.91); P = 0.02] while other secondary outcomes were similar in the two groups. CONCLUSIONS: TAVR in MAVD is associated with increased odds of paravalvular regurgitation and lower odds of device implantation success when compared to severe aortic stenosis.

Frequency, Etiology, and Impact of Unplanned Repeat Coronary Angiography After ST-Elevation Myocardial Infarction.

Unplanned repeat coronary angiography (CAG) after balloon angioplasty for ST-elevation myocardial infarction (STEMI) was common before the advent of coronary stenting. Limited data are available regarding the role of unplanned repeat CAG in contemporary percutaneous coronary intervention (PCI) for STEMI. Therefore, we analyzed a large, 2-center prospective STEMI registry (January 2011 to June 2020) stratified by the presence or absence of unplanned repeat CAG during index hospitalization. Patients with planned CAG for staged PCI or experimental drug administration were excluded. Among 3,637 patients with STEMI, 130 underwent unplanned repeat CAG (3.6%) during index hospitalization. These patients were more likely to have cardiogenic shock (16% vs 9.8%, p = 0.021), left anterior descending culprit (44% vs 31%, p <0.001), lower left ventricular ejection fraction (45% vs 52%, p <0.001), and higher peak troponin levels (22 vs 8 ng/ml, p <0.001) than those without repeat CAG. At repeat CAG, 80 patients had a patent stent (62%) including 65 requiring no further intervention (50%) and 15 who underwent intervention on a nonculprit lesion (12%). Only 32 patients had stent thrombosis (25%). Repeat CAG was associated with a higher incidence of recurrent MI (19% vs 0%, p <0.001) and major bleeding (12% vs 4.5%, p <0.001), yet similar in-hospital mortality (7% vs 6.4%, p = 0.93) than those without repeat CAG. In conclusion, in the era of contemporary PCI for STEMI, unplanned repeat CAG during index hospitalization was infrequent and more commonly observed in patients with left anterior descending culprit in the presence of significant left ventricular dysfunction or shock and was associated with higher in-hospital recurrent myocardial infarction and major bleeding complications.

Distal Coronary Perforation Sealing With Combined Coil and Fat Embolization.

Distal coronary perforation is a rare complication of percutaneous coronary intervention. While temporary balloon occlusion of the proximal coronary artery is the first step in perforation management, more definitive treatment options include covered stent implantation for large vessel perforations or fat/coil embolization for distal vessel perforations. We report a case of an 81-year old man who presented with inferior/posterior ST-segment elevation acute myocardial infarction. Coronary angiography showed a 90% distal left circumflex artery (LCx) stenosis. Percutaneous coronary intervention of the culprit vessel was challenging due to balloon uncrossable lesions in LCx and was complicated by distal coronary perforation due to excessive wire movement. Two Axium coils were delivered using a Finecross microcatheter but failed to seal the perforation. We performed fat embolization (proximal to the coils) that successfully sealed the perforation. In selected cases where coil embolization alone fails to seal a distal coronary perforation, combined coil and fat embolization might help achieve hemostasis.

Paradoxical and Retrograde Air Embolism from Pressurized Peripheral Bolus.

INTRODUCTION: Cerebral air embolism is a rare, yet serious neurological occurrence with unclear incidence and prevalence. Here, we present a case of fatal cerebral arterial and venous cerebral gas embolism in a patient with infective endocarditis and known large right-to-left shunt and severe tricuspid regurgitation following pressurized fluid bolus administration. Case Presentation. A 32-year-old female was admitted to the medical intensive care unit from a long-term acute care facility with acute on chronic respiratory failure. Her medical history was significant for intravenous heroin and cocaine abuse, methicillin-sensitive Staphylococcus aureus tricuspid valve infective endocarditis on vancomycin, patent foramen ovale, septic pulmonary embolism with cavitation, tracheostomy with chronic ventilator dependence, multifocal cerebral infarction, hepatitis C, nephrolithiasis, anxiety, and depression. After intravenous fluid administration, she became unresponsive with roving gaze, sluggish pupils, and hypotensive requiring vasopressors. CT of the brain showed diffuse arterial and venous cerebral air embolism secondary to accidental air administration from fluid bolus. Magnetic resonance imaging of the brain showed diffuse global anoxic injury and flattening of the globe at the optic nerve insertion. Given poor prognosis, her family chose comfort measures and she died. CONCLUSIONS: Fatal cerebral air embolism can occur through peripheral intravenous routes when the lines are inadequately primed and fluids administered with pressure. Caution must be exercised in patients with right-to-left shunting as air may gain access to systemic circulation.

Impact of gender on in-hospital mortality and 90-day readmissions in patients undergoing transcatheter edge-to-edge mitral valve repair: Analysis from the National Readmission Database.

BACKGROUND: Patients undergoing transcatheter edge-to-edge mitral valve repair (TEER) carry a high risk of rehospitalization due to disease, procedure, patient, hospital, and system related factors. AIMS: We aimed to explore the impact of gender on in-hospital mortality and 90-day readmissions in patients undergoing TEER. METHODS: We utilized the National Readmission Database from 2012 to 2018 to identify individuals who underwent TEER for mitral regurgitation. Gender-based differences in in-hospital mortality and 90-day readmissions were explored using multivariable logistic regression models. RESULTS: Between 2012 and 2018, an estimated 21,415 TEER procedural hospitalizations were identified, of which 9893 (46.2%) were in women and 11,522 (53.8%) were in men. Compared with men, women were older, from a lower socioeconomic status but had a lower co-morbidity burden. In-hospital mortality rate during the index hospitalization was similar in women and men (2.1% vs. 2.1%, p = 0.908). Ninety-day all-cause and heart failure readmission rates were significantly higher in women compared to men (30.2% vs. 25.4%; p < 0.001 and 28.1% vs. 23.9%; p = 0.020 respectively). In a multivariable analysis, women had 36% greater odds of 90-day readmission compared to men (adjusted odds ratio [aOR] 1.36, 95% CI: 1.22-1.52; p < 0.001). Trend analysis revealed no significant improvement in rates of 90-day readmission during the observation period for men or women (p = 0.245, p = 0.429, respectively). CONCLUSIONS: Following TEER, there has been no significant improvement in 90-day readmission rates between 2012 and 2018. Female gender is associated with higher 90-day all-cause and heart failure readmission rates.

ST-elevation myocardial infarction in nonagenarians: A nationwide analysis of trends and outcomes in the United States.

OBJECTIVE: To assess ST elevation myocardial infarction (STEMI) trends and outcomes in nonagenarians undergoing primary percutaneous coronary intervention (pPCI) compared to medical management. BACKGROUND: Although nonagenarians (age greater than 90 years) represent the fast-growing age decade of the US population, limited evidence is available regarding trends and outcomes of treatment strategies for STEMI in this population cohort. METHODS: We performed a retrospective analysis using the National Inpatient Sample (NIS) database to identify nonagenarians presenting with STEMI and treated with either pPCI or medical management. In-hospital mortality, in-hospital complications, length of stay and in-hospital costs were analyzed. RESULTS: Between 2010-2017, 41,042 STEMI hospitalizations were identified in nonagenarians, of which 11, 155 (27.2%) included pPCI whereas 29, 887 (72.8%) included medical management. STEMI hospitalizations among nonagenarians decreased over the study period. Overall unadjusted in-hospital mortality was 21.6%, and the hospitalizations that included pPCI had significantly lower mortality compared to the medical management (13.6% vs. 24.5%, p < .001). After adjusting for baseline characteristics, hospitalizations that included pPCI had 42.1% lower odds of in-hospital mortality (adjusted OR: 0.58, 95% CI: 0.50 to 0.67, p < .001). Altogether, in-hospital cardiac, bleeding and vascular complications, length of stay and in-hospital costs were higher in pPCI hospitalizations. CONCLUSION: In nonagenarians, STEMI mortality is high, but pPCI is associated with superior outcomes compared to medical management alone. Therefore, pPCI can be considered an acceptable treatment strategy in this population.

Early vs late cardiac surgery in patients with native valve endocarditis-United States Nationwide Inpatient database.

OBJECTIVE: Although the standard treatment of infective endocarditis (IE) is antimicrobial therapy, surgical intervention is required in some cases. However, the optimal timing of surgery remains unclear. Hence, we conducted a population-based analysis using the National Inpatient Sample (NIS) database to assess the outcomes of early versus late surgery in patients with native valve IE. METHODS: We queried the NIS database for all hospitalized patients between 2006 and 2016 with a primary diagnosis of IE who had cardiac surgery. We stratified surgery as early ≤7 or late >7 days of admission. Multivariable logistic regression models were used to assess in-hospital mortality and postoperative complications. Length of stay (LOS) and total hospital cost (HC) were evaluated using multivariable log-normal regression models. RESULTS: A total of 13 056 patients (57.6% in the early group and 42.4% in the late group) were included. The in-hospital mortality rate in the early group was 5.0% compared to 5.4% in the late intervention group (adjusted odds ratio, 1.20, 95% confidence interval [CI] 0.79-1.81). Overall median LOS was reduced in the early group by 48.2% (95% CI, 46.5%-49.9%, 12.4 days in the early group and 25.9 days in late group), as well as HC which was reduced in the early group by 28.3% (95% CI, 26.0%-30.6%). CONCLUSION: Among patients with native valve IE who needed cardiac surgery, the time of surgical intervention did not affect the in-hospital mortality. However, early surgery was associated with significantly shorter LOS and lower HC.

Lipoprotein(a) and calcific aortic valve stenosis: A systematic review.

Calcific aortic valve stenosis (AS) is the most common form of acquired valvular heart disease needing intervention and our understanding of this disease has evolved from one of degenerative calcification to that of an active process driven by the interplay of genetic factors and chronic inflammation modulated by risk factors such as smoking, hypertension and elevated cholesterol. Lipoprotein(a) [Lp (a)] is a cholesterol rich particle secreted by the liver which functions as the major lipoprotein carrier of phosphocholine-containing oxidized phospholipids. Lp(a) levels are largely genetically determined by polymorphisms in the LPA gene. While there is an extensive body of evidence linking Lp(a) to atherosclerotic cardiovascular disease, emerging evidence now suggests a similar association of Lp(a) to calcific AS. In this article, we performed a systematic review of all published literature to assess the association between Lp(a) and calcific aortic valve (AV) disease. In addition, we review the potential mechanisms by which Lp(a) influences the progression of valve disease. Our review identified a total of 21 studies, varying from case-control studies, prospective or retrospective observational cohort studies to Mendelian randomized studies that assessed the association between Lp(a) and calcific AS. All but one of the above studies demonstrated significant association between elevated Lp(a) and calcific AS. We conclude that there is convincing evidence supporting a causal association between elevated Lp(a) and calcific AS. In addition, elevated Lp(a) predicts a faster hemodynamic progression of AS, and increased risk of AV replacement, especially in younger patients. Further research into the clinical utility of Lp(a) as a marker for predicting the incidence, progression, and outcomes of sclerodegenerative AV disease is needed.

Treatment of Left Ventricular Thrombus With Direct Oral Anticoagulants: A Retrospective Observational Study.

BACKGROUND: There is limited data on the efficacy of direct oral anticoagulants (DOACs) for the treatment of left ventricular thrombus. Currently, vitamin K antagonists (VKAs) remain the preferred oral anticoagulant for left ventricular thrombus. In this retrospective study, we assessed the safety and efficacy of DOACs in comparison to VKAs in patients with a new diagnosis of left ventricular thrombus. METHODS: We retrospectively identified all patients admitted to the 5 Catholic Health Initiative Omaha hospitals with a diagnosis of left ventricular thrombus between January 2012 and March 2019 and were discharged on oral anticoagulants. Patients were stratified into 2 groups: VKAs or DOACs and followed for up to 1 year. We compared the outcomes of ischemic stroke, bleeding, and echocardiographic resolution of left ventricular thrombus between the 2 groups. RESULTS: A total of 99 patients were included in this study (mean age: 61 years, 29% females). Of these, 80 (81%) were discharged on VKAs and 19 (19%) on DOACs. Stroke within 1 year of diagnosis occurred in 2 patients in the VKA group and none in the DOAC group (P = 0.49). Bleeding events were observed in 5 patients (4 in the VKA group and 1 in the DOAC group; P = 0.96). Ninety patients had follow-up echocardiogram; resolution of left ventricular thrombus was similar between the 2 groups (VKAs vs DOACs: 81% vs 80%; P = 0.9). CONCLUSION: In patients with left ventricular thrombus, DOACs and VKAs had similar rates of stroke and bleeding. These findings need confirmation in randomized clinical trials.

RETRACTED ARTICLE: Patelloplasty in total knee arthroplasty with circumpatellar denervation versus without denervation - a randomized prospective study.

INTRODUCTION: Anterior knee pain is one of the major problems in total knee arthroplasty (TKA) and is often etiologically associated with a patellofemoral parts etiology. There is no consensus as to etiology or treatment. Denervation of the patella by electrocautery and patelloplasty along with removal of osteophytes have been used for treatment of anterior knee pain in TKA. The purpose of our study was to compare, in terms of the anterior knee pain and clinical outcomes of patelloplasty in total knee arthroplasty (TKA), patellar denervation by electrocautery and non-patellar-denervation treatment in a 2 year follow-up. MATERIALS AND METHODS: This study was conducted in a total of 108 patients, who underwent TKA at our institution between June 2015 and December 2016. Patients age 55 to 80 years, who are suffering from osteoarthritis, rheumatoid arthritis of knee were included in this study. Patients were randomly allocated into patelloplasty with denervation group and non-denervation group. The denervation of the patella was done in electrocautery group using a monopolar coagulation diathermy set to 50 W. (Valleylab Inc., Boulder, CO). Postoperatively, patients were assessed at regular intervals of 3, 6, 9, 12, 24 months. To assess patient outcomes, we used questionnaires to determine the Knee Society score (KSS - knee and function scores), a specific patellofemoral pain questionnaire (Kujala score) range of motion (ROM) and a visual analogue scale (VAS) to assess anterior knee pain. RESULTS: The data obtained were analyzed using SPSS version 17.0. Continuous variables were expressed as mean ± SD. Of the 108 patients, 9 patients were lost to follow-up. Among the remaining 99 patients, 50 were included in denervation group and 49 in non-denervation group. In our study, there was no statistically significant difference in Mean KUJALA score preoperatively (p > 0.05). Postoperatively, the mean KUJALA score was significantly higher in denervation group at 3, 6, 9, 12, 24 months of follow-up when compared to TKR with no denervation (p < 0.05). There was no statistically significant difference in Mean VAS score preoperatively (p > 0.05). However, 6, 12 and 24 months after the operation, the mean VAS score was significantly lower in denervation group. There was no statistically significant difference in Mean KSS score preoperatively and postoperatively (p > 0.05). The mean ROM was significantly higher in denervation group than in the group of TKR with no denervation (p < 0.05). CONCLUSION: In our study, less postoperative anterior knee pain, increased range of motion, significantly lower VAS scores were seen in the denervation group compared with non-denervation group. Circumferential denervation of patella during primary TKA along with patellar resurfacing is a safe procedure that improves patient satisfaction, decreases anterior knee pain and improves range of flexion in the postoperative period and at postoperative follow-ups.

Role of Yoga in Cardiac Disease and Rehabilitation.

PURPOSE: Cardiovascular disease continues to be the leading cause of morbidity and mortality around the world. Yoga, a combination of physical postures (asana), breathing exercises (pranayama), and meditation (dhyana), has gained increasing recognition as a form of mind-body exercise. In this narrative review, we intended to review the emerging evidence assessing the physiologic and clinical effects of yoga on the cardiovascular system and the potential role of yoga as a component of comprehensive cardiac rehabilitation. METHODS: We searched PubMed, Google Scholar, Embase, and Cochrane databases for literature related to cardiovascular effects of yoga from inception up until 2017. RESULTS: Yoga has been shown to have favorable effects on systemic inflammation, stress, the cardiac autonomic nervous system, and traditional and emerging cardiovascular risk factors. CONCLUSIONS: Yoga has shown promise as a useful lifestyle intervention that can be incorporated into cardiovascular disease management algorithms. Although many investigators have reported the clinical benefits of yoga in reducing cardiovascular events, morbidity, and mortality, evidence supporting these conclusions is somewhat limited, thereby emphasizing the need for large, well-designed randomized trials that minimize bias and methodological drawbacks.