Regulation of Blood Pressure by Targeting CaV1.2-Galectin-1 Protein Interaction.

BACKGROUND: L-type CaV1.2 channels play crucial roles in the regulation of blood pressure. Galectin-1 (Gal-1) has been reported to bind to the I-II loop of CaV1.2 channels to reduce their current density. However, the mechanistic understanding for the downregulation of CaV1.2 channels by Gal-1 and whether Gal-1 plays a direct role in blood pressure regulation remain unclear. METHODS: In vitro experiments involving coimmunoprecipitation, Western blot, patch-clamp recordings, immunohistochemistry, and pressure myography were used to evaluate the molecular mechanisms by which Gal-1 downregulates CaV1.2 channel in transfected, human embryonic kidney 293 cells, smooth muscle cells, arteries from Lgasl1-/- mice, rat, and human patients. In vivo experiments involving the delivery of Tat-e9c peptide and AAV5-Gal-1 into rats were performed to investigate the effect of targeting CaV1.2-Gal-1 interaction on blood pressure monitored by tail-cuff or telemetry methods. RESULTS: Our study reveals that Gal-1 is a key regulator for proteasomal degradation of CaV1.2 channels. Gal-1 competed allosterically with the CaVß subunit for binding to the I-II loop of the CaV1.2 channel. This competitive disruption of CaVß binding led to CaV1.2 degradation by exposing the channels to polyubiquitination. It is notable that we demonstrated that the inverse relationship of reduced Gal-1 and increased CaV1.2 protein levels in arteries was associated with hypertension in hypertensive rats and patients, and Gal-1 deficiency induces higher blood pressure in mice because of the upregulated CaV1.2 protein level in arteries. To directly regulate blood pressure by targeting the CaV1.2-Gal-1 interaction, we administered Tat-e9c, a peptide that competed for binding of Gal-1 by a miniosmotic pump, and this specific disruption of CaV1.2-Gal-1 coupling increased smooth muscle CaV1.2 currents, induced larger arterial contraction, and caused hypertension in rats. In contrasting experiments, overexpression of Gal-1 in smooth muscle by a single bolus of AAV5-Gal-1 significantly reduced blood pressure in spontaneously hypertensive rats. CONCLUSIONS: We have defined molecularly that Gal-1 promotes CaV1.2 degradation by replacing CaVß and thereby exposing specific lysines for polyubiquitination and by masking I-II loop endoplasmic reticulum export signals. This mechanistic understanding provided the basis for targeting CaV1.2-Gal-1 interaction to demonstrate clearly the modulatory role that Gal-1 plays in regulating blood pressure, and offering a potential approach for therapeutic management of hypertension.

Percutaneous Decommissioning of Left Ventricular Assist Device.

BACKGROUND: The left ventricular assist device (LVAD) has revolutionised our treatment of advanced stage heart failure, giving debilitated patients a new lease on life. A small proportion of these LVAD patients can be bridged-to-recovery. The identification of these patients and decision to wean, however, can be challenging. METHODS: The need to fully explant the device upon recovery has evolved to a minimalist approach aiming to avoid injury to the 'recovered' heart. A review of the evolution of explant strategies was performed to guide our decision to wean the LVAD in our early experience. RESULTS: Between 2009 and 2014, two patients in our series of 69 LVAD implants (2.9%) were successfully weaned off their LVADs. The second patient had a minimal access implantation of his HeartWare Ventricular Assist Device (HVAD, Medtronic Inc, Framingham, MA, USA). His clinical variables and minimalist weaning strategy are described. CONCLUSIONS: A case of LVAD decommissioning by thrombosis of the outflow graft, using percutaneous Amplatzer Vascular Plug II (St. Jude Medical, St. Paul, MN, USA) without surgery is reported.

Therapeutic Hypothermia May Improve Neurological Outcomes in Extracorporeal Life Support for Adult Cardiac Arrest.

BACKGROUND: Limited data exists on patients receiving therapeutic hypothermia during extracorporeal life support (ECLS). We investigated outcomes and prognostic factors in these patients. METHODS: A retrospective review was conducted for 225 consecutive adult patients treated with ECLS between July 2003 and January 2016. Extracorporeal life support was initiated for refractory cardiac arrest (>10 mins) in 79 patients (35.1%). Patient demographics, ECLS-related complications, in-hospital mortality and neurological outcomes were analysed. RESULTS: The mean age was 49.9±12.4 years. Sixty-two patients (78.5%) were male. The mean duration of CPR and ECLS were respectively, 32.0±23.3 mins and 5.4±4.0 days. Therapeutic hypothermia (34oC) was maintained for 24hours in 14 patients (17.7%). Thirty-five patients (44.3%) were weaned off ECLS. Twenty-one patients (26.6%) survived to hospital discharge with 16 (20.3%) recovering good neurological function. Compared to ECLS at normothermia, neurologically favourable survival was higher in the hypothermia group (42.9% vs 15.4%, p=0.020). Multivariable analysis identified a non-shockable rhythm [odds ratio (OR) 5.1, confidence interval (CI) 1.5-16.8], ischaemic hepatitis (OR 6.2, CI 1.1-33.6) and hypoxic ischaemic encephalopathy (OR 5.1, CI 1.5-17.1) as predictors of in-hospital mortality. Therapeutic hypothermia (OR 4.9, CI 1.2-20.4) and acute renal failure (OR 0.19, CI 0.05-0.70) were predictors of neurologically favourable survival. CONCLUSIONS: In this report of patients treated with ECLS, in-hospital survival and survival with good neurological performance were 26.6% and 20.3% respectively. A non-shockable rhythm, ischaemic hepatitis and hypoxic ischaemic encephalopathy were predictors of in-hospital mortality. Therapeutic hypothermia during ECLS was associated with improved neurological outcomes.

Alternative splicing generates a novel truncated Cav1.2 channel in neonatal rat heart.

L-type Cav1.2 Ca(2+) channel undergoes extensive alternative splicing, generating functionally different channels. Alternatively spliced Cav1.2 Ca(2+) channels have been found to be expressed in a tissue-specific manner or under pathological conditions. To provide a more comprehensive understanding of alternative splicing in Cav1.2 channel, we systematically investigated the splicing patterns in the neonatal and adult rat hearts. The neonatal heart expresses a novel 104-bp exon 33L at the IVS3-4 linker that is generated by the use of an alternative acceptor site. Inclusion of exon 33L causes frameshift and C-terminal truncation. Whole-cell electrophysiological recordings of Cav1.233L channels expressed in HEK 293 cells did not detect any current. However, when co-expressed with wild type Cav1.2 channels, Cav1.233L channels reduced the current density and altered the electrophysiological properties of the wild type Cav1.2 channels. Interestingly, the truncated 3.5-domain Cav1.233L channels also yielded a dominant negative effect on Cav1.3 channels, but not on Cav3.2 channels, suggesting that Cavß subunits is required for Cav1.233L regulation. A biochemical study provided evidence that Cav1.233L channels enhanced protein degradation of wild type channels via the ubiquitin-proteasome system. Although the physiological significance of the Cav1.233L channels in neonatal heart is still unknown, our report demonstrates the ability of this novel truncated channel to modulate the activity of the functional Cav1.2 channels. Moreover, the human Cav1.2 channel also contains exon 33L that is developmentally regulated in heart. Unexpectedly, human exon 33L has a one-nucleotide insertion that allowed in-frame translation of a full Cav1.2 channel. An electrophysiological study showed that human Cav1.233L channel is a functional channel but conducts Ca(2+) ions at a much lower level.

Transatrial transcatheter tricuspid valve-in-valve technique.

A novel approach to reoperative tricuspid valve replacement using the transcatheter valve-in-valve concept is studied. Three consecutive transapica transcatheter tricuspid Sapien balloon-expandable valve-in-valve cases, including the first-in-man case, are described. The technical lessons learnt and the clinical outcomes are elaborated.

Transcatheter aortic valve replacement: where will we be in 5 years?

PURPOSE OF REVIEW: Transcatheter aortic valve implantation (TAVI) has developed in less than 2 decades to be a viable procedure, carving out a niche position in our armamentarium to treat high-risk patients with aortic valve disease. Rapid advances are occurring in prosthesis design, catheter delivery system, imaging, and the hybrid operating room. RECENT FINDINGS: The PARTNER (Placement of AoRTic traNscathetER valve) randomized trial, cohort B confirms the superiority of the transfemoral TAVI compared with standard medical therapy with regard to overall survival and cardiac functional status. Major stroke and vascular complications, however, remain higher in the transfemoral TAVI group. Large European registries of both the transapical and transfemoral TAVI are reporting improved procedural success and early survival. The CoreValve and SAPIEN valves remain the forerunners, with accumulating evidence for use, and published 3-year prosthesis durability data for the latter. SUMMARY: Evidence is accumulating in support of TAVI for high-risk nonoperative aortic stenosis. Even before the PARTNER cohort A results, comparing TAVI and conventional aortic valve replacement, become available, the next generation devices and technological improvements are well underway to make the procedure even more reproducible.

Staphylococcal driveline infections are the predominant type of left ventricular assist device associated infections in Singapore.

BACKGROUND: Left ventricular assist device (LVAD) associated infections (LVADIs) have substantial morbidity and mortality. We aim to describe the incidence and epidemiology of LVADIs in an Asian cohort. This is currently not well studied. METHODS: We conducted a retrospective review of 52 patients who underwent LVAD implantation from 1 May 2009-31 December 2014 in National Heart Centre Singapore. LVADIs were defined based on definitions proposed by the International Society for Heart and Lung Transplantation. RESULTS: There were 39 males and 13 females. Seventy-three percent had Heartmate II LVAD implant while 27% received Heartware HVAD. Eighty-one percent were implanted as bridge to heart transplantation, 19% as destination therapy. Forty-five episodes of LVADIs occurred in 25 patients. Overall LVADI incidence was 47.5 cases per 100 patient-years. Driveline infections (58%) were the commonest type of LVADI. The commonest causative organisms were coagulase-negative staphylococci (33%), Staphylococcus aureus (31%) and Corynebacterium species (19%). Twelve percent of patients with LVADI required surgical debridement and one patient required pump exchange due to pump pocket infection. All-cause mortality was 13%. CONCLUSIONS: The findings of our study add to the understanding and epidemiology of LVADIs, particularly in the Asian setting. This can contribute to the development of evidence based strategies to prevent and manage LVADIs.

Thoracic complications of radiofrequency ablation of recurrent hepatoma.

INTRODUCTION: Radiofrequency ablation (RFA) for unresectable primary or secondary hepatic malignancies have gained widespread availability and acceptance over the past 5 years. Complication rates have been reported to range from 0% to 27%. CLINICAL PICTURE: We report a patient with symptomatic right pleural effusion due to a diaphragmatic fistula and another with biliptysis post-RFA, for recurrent hepatoma. TREATMENT: Percutaneous drainage of both the pleural effusion and biloma was performed. However, surgical repair of the diaphragmatic fistula was only required for the former for persistent drainage. OUTCOME: Both patients were successfully treated with minimal morbidity. CONCLUSION: High index of suspicion is required for the early diagnosis and treatment of diaphragmatic fistulas. Simple catheter drainage can potentially obviate the need for surgery.

Paradoxical orthodeoxia in a patient with a large thoracic aortic aneurysm.

INTRODUCTION: Orthodeoxia is a rare clinical syndrome characterised by dyspnoea and arterial deoxygenation that accompanies a change from a supine to erect position. CLINICAL PICTURE: We describe an unusual case of "paradoxical orthodeoxia" in a 70-year-old man with a thoracic aortic aneurysm: arterial desaturation when supine that improved when erect. TREATMENT AND OUTCOME: Non-invasive imaging revealed compression of the left pulmonary artery by the aneurysm (thoracic computed tomography) and patent foramen ovale (transesophageal echocardiography). Nuclear studies show decreased relative left lung perfusion attributable to the former, and right-to-left atrial shunt attributable to the latter. The degree of right-to-left shunt increases in the supine position: nuclear pulmonary shunt study shows shunt extent of 21% when supine versus 10% erect. CONCLUSION: A physioanatomical explanation is proposed.

The safe volume threshold for chest drain removal following pulmonary resection.

A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was 'In patients undergoing pulmonary resection, is there a safe drainage volume threshold for chest drain removal?' Altogether 1054 papers were found, of which 5 papers represented the best evidence. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. Chest drainage threshold, where used, ranged from 250 to 500 ml/day. Both randomized controlled trials showed no significant difference in reintervention rates with a higher chest drainage volume threshold. Four studies that performed analysis on other complications showed no statistical significant difference with a higher chest drainage volume threshold. Four studies evaluating length of hospital stay showed reduced or no difference in the length of stay with a higher chest drainage volume threshold. Two cohort studies reported the mortality rate of 0-0.01% with a higher chest drainage volume threshold. We conclude that early chest drain removal after pulmonary resection, accepting a higher chest drainage volume threshold of 250-500 ml/day is safe, and may result in shorter hospital stay without increasing reintervention, morbidity or mortality.

Aberrant Splicing Promotes Proteasomal Degradation of L-type CaV1.2 Calcium Channels by Competitive Binding for CaVß Subunits in Cardiac Hypertrophy.

Decreased expression and activity of CaV1.2 calcium channels has been reported in pressure overload-induced cardiac hypertrophy and heart failure. However, the underlying mechanisms remain unknown. Here we identified in rodents a splice variant of CaV1.2 channel, named CaV1.2e21+22, that contained the pair of mutually exclusive exons 21 and 22. This variant was highly expressed in neonatal hearts. The abundance of this variant was gradually increased by 12.5-folds within 14 days of transverse aortic banding that induced cardiac hypertrophy in adult mouse hearts and was also elevated in left ventricles from patients with dilated cardiomyopathy. Although this variant did not conduct Ca2+ ions, it reduced the cell-surface expression of wild-type CaV1.2 channels and consequently decreased the whole-cell Ca2+ influx via the CaV1.2 channels. In addition, the CaV1.2e21+22 variant interacted with CaVß subunits significantly more than wild-type CaV1.2 channels, and competition of CaVß subunits by CaV1.2e21+22 consequently enhanced ubiquitination and subsequent proteasomal degradation of the wild-type CaV1.2 channels. Our findings show that the resurgence of a specific neonatal splice variant of CaV1.2 channels in adult heart under stress may contribute to heart failure.

Percutaneous transcatheter aortic valve implantation for degenerated surgical bioprostheses: the first case series in Asia with one-year follow-up.

INTRODUCTION: Percutaneous transcatheter aortic valve implantation (TAVI) has become an established therapy for inoperable and high-surgical-risk patients with severe aortic stenosis. Although TAVI in patients with degenerated surgical aortic bioprostheses (i.e. valve-in-valve TAVI) is increasingly reported in Western studies, such data is lacking in Asian patients. We describe the initial experience of valve-in-valve TAVI in Asia. METHODS: Eight patients who underwent valve-in-valve TAVI due to degenerated aortic bioprostheses were enrolled. The mechanism of bioprosthetic valve failure was stenotic, regurgitation or mixed. All procedures were performed via transfemoral arterial access, using the self-expanding CoreValve prosthesis or balloon-expandable SAPIEN XT prosthesis. RESULTS: The mean age of the patients was 71.6 ± 13.2 years and five were male. Mean duration to surgical bioprosthesis degeneration was 10.2 ± 4.1 years. Valve-in-valve TAVI was successfully performed in all patients. CoreValve and SAPIEN XT prostheses were used in six and two patients, respectively. There were no deaths, strokes or permanent pacemaker requirement at 30 days, with one noncardiac mortality at one year. All patients experienced New York Heart Association functional class improvement. Post-procedure mean pressure gradients were 20 ± 11 mmHg and 22 ± 8 mmHg at 30 days and one year, respectively. Residual aortic regurgitation (AR) of more than mild severity occurred in one patient at 30 days. At one year, only one patient had mild residual AR. CONCLUSION: In our experience of valve-in-valve TAVI, procedural success was achieved in all patients without adverse events at 30 days. Good clinical and haemodynamic outcomes were sustained at one year.

Unresectable desmoid tumours causing obstructive uropathy in familial adenomatous polyposis.

Desmoid tumour-related ureteral obstruction in familial adenomatous polyposis presents difficult management problems. Its role in altering prognosis for the worse in young patients has been neglected. Two patients are reported and 14 cases in the literature reviewed. Both our patients developed intra-abdominal desmoid tumours following proctocolectomies with pouch reconstruction (performed 0.7 and 2.5 years earlier). Despite therapy with sulindac and tamoxifen, both suffered progressive ureteral obstruction that required initial percutaneous drainage. Ureteral stenting was effective and safe in both patients (10 and 18 months' follow-up, respectively), but the long-term outcome awaits assessment. The optimal regimen of adjuvant medical therapy is uncertain. Successful renal autotransplantation and combination chemotherapy have been tried after failure of conventional therapy.

Minimal-access left ventricular assist device implantation.

OBJECTIVE: The left ventricular assist device (LVAD) is typically implanted through a full sternotomy on cardiopulmonary bypass (CPB). Minimally invasive surgery (MIS) modifications include multiple smaller incisions, using "virgin" territory, and minimized CPB time. METHODS: Forty-two LVAD implantations were retrospectively reviewed. Twenty-five minimally invasive implantations (MIS, 20 HeartMate II and 5 HeartWare) were compared with 17 sternotomy implantations (12 HeartMate II and 5 HeartWare). The choice of MIS incisions was device dependent: (1) three separate incisions for the HeartMate II or (2) two incisions for the HeartWare device. Four HeartWare LVADs were implanted off-pump (three using the MIS approach). RESULTS: The median patient age was 52 years (range, 18-69 years). Overall survival was 81% at a mean (SD) follow-up of 495 (375) days. Thirty-day mortality was 9.5% (one MIS and three sternotomy patients). Five patients (11.9%) died while on LVAD, 18 (42.9%) underwent transplantation, 6 (14.3%) underwent weaning and explantation, and 13 (31.0%) remained on support. Preoperative ventilatory and circulatory supports were more common in the sternotomy group. The MIS patients had shorter CPB time [51.4 (34.9) vs 83.6 (40.4) minutes, P = 0.014] and showed a trend toward lower red blood cell and platelet transfusion requirement. The durations of hospitalization, inotropic support, intensive care unit stay, and LVAD support were not significantly different. CONCLUSIONS: Minimally invasive surgery LVAD implantation is feasible. The shorter CPB duration and off-pump approach may be advantageous. Avoiding sternotomy may also reduce adhesions encountered during subsequent cardiac transplantation.

Surgical risk algorithm as a measure of successful adoption of transapical transcatheter aortic valve implantation.

OBJECTIVE: This study was performed to assess the Society of Thoracic Surgeons (STS) score as a measure of successful adoption of transapical transcatheter aortic valve implantation (TAVI). METHODS: The STS score for estimated surgical mortality was calculated and used to select the first 140 consecutive patients undergoing transapical TAVI. The STS score also was used to estimate postoperative morbidity. The comparisons were made between the observed and estimated mortality and morbidity in the entire group, as well as in the first 35, second 35, and last 70 consecutive patients. RESULTS: The differences in outcomes between the first 35, second 35, and last 70 patients were statistically significant for surgical mortality (20.0% vs 14.3% vs 2.9%; P = .045), composite morbidity/mortality (34.3% vs 40.1% vs 15.7%; P = .020), and long length of stay (34.3% vs 45.7% vs 18.6%; P = .027). There were trends of marked decreases in prolonged ventilation (11.4% vs 20.0% vs 4.3%; P = .061), and acute renal failure (14.3% vs 20.0% vs 4.3%; P = .059). In the first 70 patients there were no significant differences between observed and STS estimated incidences in mortality and composite mortality/major morbidity. In the latter 70 patients the observed incidences were lower than STS predicted values in mortality (2.9% vs 9.6%; P = .056), composite major morbidity/mortality (15.7% vs 33.8%; P = .001), and prolonged ventilation (4.3% vs 25.1%; P < .0001). CONCLUSIONS: Only after a protracted learning curve did the anticipated benefits of transapical TAVI materialize for patients at high risk for surgery as predicted by the STS risk algorithms.

Transapical transcatheter aortic valve-in-valve implantation: clinical and hemodynamic outcomes beyond 2 years.

OBJECTIVE: The feasibility of transapical valve-in-valve aortic valve implantation into a failed aortic surgical bioprosthesis has been confirmed. The purpose of the present study was to investigate the clinical and hemodynamic outcomes more than 2 years after transapical valve-in-valve aortic valve implantation. METHODS: From April 2007 to May 2010, 8 consecutive patients underwent transapical valve-in-valve aortic valve implantation of either 23- or 26-mm Edwards-SAPIEN balloon-expandable bioprostheses into failed surgical tissue valves (21- to 25-mm valves). Clinical and echocardiographic follow-up was performed in all patients. The mean follow-up duration was 27.8 ± 15.7 months (range, 18-55 months). RESULTS: Transapical valve-in-valve aortic valve implantation was successful in all patients (mean age, 84.1 ± 1.6 years). The predicted operative mortality was 42.1% ± 15.7% by logistic European System for Cardiac Operative Risk Evaluation and 14.4% ± 9.6% using the Society of Thoracic Surgeons risk calculator. The observed 30-day mortality was 12.5%. No strokes or valve embolization/migrations occurred. The mean hospital stay was 9.0 ± 9.1 days. The New York Heart Association class decreased from preoperative class III-IV to postoperative class I in 6 of 7 survivors. The 2-year survival was 87.5%. No late mortality occurred during the follow-up period. The echocardiographic results at 1 to 4 years of follow-up demonstrated stable valve position and function in all patients. The transaortic valve pressure gradients after valve-in-valve aortic valve implantation were greater than 20 mm Hg and less than 15 mm Hg in patients with 21- or 23-mm and 25-mm surgical valves, respectively. CONCLUSIONS: Transapical valve-in-valve aortic valve implantation provides good clinical outcomes and stable valve function beyond 2 years of follow-up. The best hemodynamic and clinical outcomes can be achieved in the patients with a surgical valve size of 25 mm or greater. Valve-in-valve aortic valve implantation could become a viable approach for selected high-risk patients with failed surgical bioprostheses.

Minimal-access left ventricular assist device explantation.

Patients on left ventricular assist device (LVAD) support can be successfully bridged to recovery. A novel explantation technique is reviewed. Six HeartMate II patients were successfully explanted off-pump through a combination of a left anterior minithoracotomy and a subxiphoid incision. A retrospective review of the institutional LVAD database was performed. The median LVAD support duration was 191 days (range, 69-307 days). There was no procedural or 30-day mortality associated with the LVAD explantation, and all patients are in New York Heart Association I to II at a median follow-up of 688 days (range, 127-1033 days). This procedure was associated with minimal blood transfusion and short intensive care unit stay (median, 1 day; range, 1-5 days) and hospitalization (median, 4.5 days; range, 3-19 days). One postexplant embolic cerebral infarct occurred. The HeartMate II LVAD can be safely explanted through a less conventional minimal-access approach.

Mild to moderate aortic stenosis and coronary bypass surgery.

BACKGROUND: Aortic stenosis (AS) is the most common valvular disease in adult cardiac surgery and its incidence continues to rise. Increasingly older patients are being referred for coronary artery bypass grafting (CABG) with mild to moderate AS. Concomitant aortic valve replacement (AVR) for patients with moderate or severe AS undergoing CABG is warranted regardless of symptoms. Concomitant AVR remains contentious in patients with less than moderate severity AS undergoing CABG. MATERIALS AND METHODS: We review the contemporary literature aiming to resolve this dilemma in clinical practice. The assessment of these patients is reviewed. Considerations include identifying the rapid progressors, and balancing the risks of concomitant valve surgery against the potential prognostic gains. RESULTS: Pathophysiological links between degenerative calcific AS and coronary artery disease suggest that the disease is an active, progressive process with mutually shared risk factors. Statins, however, offer limited protection against AS, despite its established role in coronary artery disease. Age, atherosclerosis risk, valve morphology, motion, and hemodynamics identify the rapid progressors, whilst the patients' general comorbidities and life expectancy influence the risk-benefit profile of concomitant operations. CONCLUSION: A precise echocardiographic quantification of the stenotic grade is mandatory before adopting any therapeutic strategy. Concomitant AVR for moderate AS is recommended if surgical risk is not prohibitive. Concomitant AVR for mild AS in 'rapid progressors' (i.e. moderate-severe valve calcification) may be considered, but patients should have reasonable life expectancy exceeding 5 years. Moderately restricted leaflet motions, gradient increase of > 10 mm Hg per year, and aortic jet velocity increase > 0.4 m/s per year further supports intervention. Comorbidities increasing atherosclerotic burden and renal dialysis accelerate AS progression and increase surgical risk. Procedural advances in interventional cardiology and minimally invasive cardiac surgery may further expand the options available for these patients.