Cobalt-electrocatalytic HAT for functionalization of unsaturated C-C bonds.

The study and application of transition metal hydrides (TMHs) has been an active area of chemical research since the early 1960s1, for energy storage, through the reduction of protons to generate hydrogen2,3, and for organic synthesis, for the functionalization of unsaturated C-C, C-O and C-N bonds4,5. In the former instance, electrochemical means for driving such reactivity has been common place since the 1950s6 but the use of stoichiometric exogenous organic- and metal-based reductants to harness the power of TMHs in synthetic chemistry remains the norm. In particular, cobalt-based TMHs have found widespread use for the derivatization of olefins and alkynes in complex molecule construction, often by a net hydrogen atom transfer (HAT)7. Here we show how an electrocatalytic approach inspired by decades of energy storage research can be made use of in the context of modern organic synthesis. This strategy not only offers benefits in terms of sustainability and efficiency but also enables enhanced chemoselectivity and distinct, tunable reactivity. Ten different reaction manifolds across dozens of substrates are exemplified, along with detailed mechanistic insights into this scalable electrochemical entry into Co-H generation that takes place through a low-valent intermediate.

VOILA on the LUVMI-X Rover: Laser-Induced Breakdown Spectroscopy for the Detection of Volatiles at the Lunar South Pole.

The project Lunar Volatiles Mobile Instrumentation-Extended (LUVMI-X) developed an initial system design as well as payload and mobility breadboards for a small, lightweight rover dedicated for in situ exploration of the lunar south pole. One of the proposed payloads is the Volatiles Identification by Laser Analysis instrument (VOILA), which uses laser-induced breakdown spectroscopy (LIBS) to analyze the elemental composition of the lunar surface with an emphasis on sampling regolith and the detection of hydrogen for the inference of the presence of water. It is designed to analyze targets in front of the rover at variable focus between 300 mm and 500 mm. The spectrometer covers the wavelength range from 350 nm to 790 nm, which includes the hydrogen line at 656.3 nm as well as spectral lines of most major rock-forming elements. We report here the scientific input that fed into the concept and design of the VOILA instrument configuration for the LUVMI-X rover. Moreover, we present the measurements performed with the breadboard laboratory setup for VOILA at DLR Berlin that focused on verifying the performance of the designed LIBS instrument in particular for the detection and quantification of hydrogen and other major rock forming elements in the context of in situ lunar surface analysis.

Development of High Energy Density Diaminocyclopropenium-Phenothiazine Hybrid Catholytes for Non-Aqueous Redox Flow Batteries.

This report describes the design of diaminocyclopropenium-phenothiazine hybrid catholytes for non-aqueous redox flow batteries. The molecules are synthesized in a rapid and modular fashion by appending a diaminocyclopropenium (DAC) substituent to the nitrogen of the phenothiazine. Combining a versatile C-N coupling protocol (which provides access to diverse derivatives) with computation and structure-property analysis enabled the identification of a catholyte that displays stable two-electron cycling at potentials of 0.64 and 1.00 V vs. Fc/Fc+ as well as high solubility in all oxidation states (≥0.45 M in TBAPF6 /MeCN). This catholyte was deployed in a high energy density two-electron RFB, exhibiting >90 % capacity retention over 266 hours of flow cell cycling at >0.5 M electron concentration.

Hydroarylation of Arenes via Reductive Radical-Polar Crossover.

A photocatalytic system for the dearomative hydroarylation of benzene derivatives has been developed. Using a combination of an organic photoredox catalyst and an amine reductant, this process operates through a reductive radical-polar crossover mechanism where aryl halide reduction triggers a regioselective radical cyclization event, followed by anion formation and quenching to produce a range of complex spirocyclic cyclohexadienes. This light-driven protocol functions at room temperature in a green solvent system (aq. MeCN) without the need for precious metal-based catalysts or reagents or the generation of stoichiometric metal byproducts.

Selective C-F Functionalization of Unactivated Trifluoromethylarenes.

Fluorinated organic molecules are pervasive within the pharmaceutical and agrochemical industries due to the range of structural and physicochemical properties that fluorine imparts. Currently, the most abundant methods for the synthesis of the aryl-CF2 functionality have relied on the deoxyfluorination of ketones and aldehydes using expensive and poorly atom economical reagents. Here, we report a general method for the synthesis of aryl-CF2R and aryl-CF2H compounds through activation of the corresponding trifluoromethyl arene precursors. This strategy is enabled by an endergonic electron transfer event that provides access to arene radical anions that lie outside of the catalyst reduction potential. Fragmentation of these reactive intermediates delivers difluorobenzylic radicals that can be intercepted by abundant alkene feedstocks or a hydrogen atom to provide a diverse array of difluoalkylaromatics.

Radical Hydroarylation of Functionalized Olefins and Mechanistic Investigation of Photocatalytic Pyridyl Radical Reactions.

We report the photoredox alkylation of halopyridines using functionalized alkene and alkyne building blocks. Selective single-electron reduction of the halogenated pyridines provides the corresponding heteroaryl radicals, which undergo anti-Markovnikov addition to the alkene substrates. The system is shown to be mild and tolerant of a variety of alkene and alkyne subtypes. A combination of computational and experimental studies support a mechanism involving proton-coupled electron transfer followed by medium-dependent alkene addition and rapid hydrogen atom transfer mediated by a polarity-reversal catalyst.

Prediction of intraoperative transfusion requirements during orthotopic liver transplantation and the influence on postoperative patient survival.

BACKGROUND: Predicting blood product transfusion requirements during orthotopic liver transplantation (OLT) remains difficult. Our primary aim in this study was to determine which patient variables best predict recipient risk for large blood transfusion requirements during OLT. The secondary aim was to determine whether the amount of blood products transfused during OLT impacted patient survival. METHODS: Eight hundred four primary adult OLTs performed during a 9-year period were retrospectively analyzed, and predictive models were developed for blood product usage, usage >20 and usage >30 units of red blood cells (RBCs) plus cell salvage (CS). For survival analysis, potential predictors included all blood products administered during OLT. RESULTS: For analyses of RBC + CS usage, we used several statistical techniques: regression analysis, logistic regression, and classification and regression tree analysis. Several preoperative factors were highly statistically significant predictors of intraoperative blood product usage in each of the analyses, namely lower platelet count and higher Model for End-Stage Liver Disease Score or one or more of its components (creatinine, total bilirubin, international normalized ratio). Despite these highly significant associations, the models were unable to predict reliably that patients might require the largest amount of blood products during OLT. For example, the classification and regression tree analyses were able to predict only 32% and 11% of patients requiring >20 and >30 units of RBC + CS, respectively. Survival analysis demonstrated poorer survival among patients receiving larger amounts of RBC + CS during OLT. CONCLUSION: Prediction of intraoperative blood product requirements based on preoperatively available variables is unreliable; however, there is a strong measurable association between transfusion and postoperative mortality.

Predicting success in Cu-catalyzed C-N coupling reactions using data science.

Data science is assuming a pivotal role in guiding reaction optimization and streamlining experimental workloads in the evolving landscape of synthetic chemistry. A discipline-wide goal is the development of workflows that integrate computational chemistry and data science tools with high-throughput experimentation as it provides experimentalists the ability to maximize success in expensive synthetic campaigns. Here, we report an end-to-end data-driven process to effectively predict how structural features of coupling partners and ligands affect Cu-catalyzed C-N coupling reactions. The established workflow underscores the limitations posed by substrates and ligands while also providing a systematic ligand prediction tool that uses probability to assess when a ligand will be successful. This platform is strategically designed to confront the intrinsic unpredictability frequently encountered in synthetic reaction deployment.

Duct-to-duct biliary reconstruction in patients with primary sclerosing cholangitis undergoing liver transplantation.

BACKGROUND: Reconstruction of biliary drainage after liver transplantation (LTx) in patients with primary sclerosing cholangitis (PSC) has been a matter of controversy. Over recent years, the traditional method of Roux-en-Y hepaticojejunostomy (RY) has been challenged by duct-to-duct (DD) biliary reconstruction. METHODS: This study represents a retrospective review of biliary complications, patient and graft survival after LTx in PSC patients based on type of biliary reconstruction. Outcomes of DD reconstruction in this group of patients and non-PSC patients are compared. RESULTS: A total of 53 primary LTx procedures were performed for PSC between August 2005 and July 2010. Seven patients were excluded because unexpected cholangiocarcinoma was found in the explants (n=3) or because they received partial livers (n=4). Biliary reconstruction was performed as DD in 18 patients and RY in 28 patients. There were no bile leaks. Anastomotic stricture occurred in two (11%) patients in the DD group and one (4%) in the RY group. Two (7%) patients in the RY group developed non-PSC intrahepatic strictures and one had recurrence of PSC. Rates of 1- and 3-year patient and graft survival in the RY and DD groups were 96.7% and 96.7%, and 100% and 94.5%, respectively. In a group of 34 randomly selected patients transplanted for a non-PSC diagnosis with DD reconstruction during the same period, the anastomotic stricture rate was 9% and 1- and 3-year patient and graft survival rates were 97.0% and 88.5%; differences were not significant. CONCLUSIONS: Duct-to-duct biliary reconstruction at the time of LTx in selected PSC patients is both effective and safe, and shows outcomes comparable with those of RY reconstruction in these patients and those of DD reconstruction in non-PSC patients.

Side-to-side cavocavostomy with an endovascular stapler: Rescue technique for severe hepatic vein and/or inferior vena cava outflow obstruction after liver transplantation using the piggyback technique.

Venous outflow obstruction is a rare but potentially lethal complication after orthotopic liver transplantation (OLT) with the "piggyback" technique. Therapeutic options include angioplasty with or without stent placement, surgical reconstruction of the venous anastomosis, and retransplantation. Surgical options are technically very challenging and the outcomes discouraging. We describe here two cases of venous outflow obstruction in recipients of piggyback liver grafts, one involving both the vena cava and hepatic veins and the other affecting only hepatic vein outflow. Both patients were treated successfully with side-to-side cavo-cavostomy using an endovascular (endo-GIA) stapler. This novel technique is fast and effective in resolving the outflow obstruction.

Comparison of laparoscopic versus open liver tumor resection: a case-controlled study.

BACKGROUND: Although there are data in the literature about the safety and efficacy of laparoscopic liver resections, there are not many studies comparing laparoscopic versus open approaches in a case-matched design. The purpose of this study is to compare the perioperative outcome of laparoscopic versus open liver resections from a single institution. METHODS: Thirty-one patients underwent laparoscopic liver resection between April 1997 and August 2007, with a prospective laparoscopic program started in April 2006 (n=25). This group of patients was compared with 43 consecutive patients undergoing open resection who were matched by size of the lesion (5 cm or less for malignant and 8 cm or less for benign), anatomical location (segments 2, 3, 4b, 5, 6), and type of resection (wedge resection, segmentectomy, partial liver resection). Data were obtained from medical records as well as from a prospective database. Statistical analysis was performed using t-test and chi-square. All data are expressed as mean +/- standard error on the mean (SEM). RESULTS: Mean age in the laparoscopic group was 57.6+/-2.7 years versus 61.9+/-2.3 years in the open group (p=0.2). There were more women in the laparoscopic group [74% females (n=23) and 26% males (n=8)] versus in the open group [40% females (n=17) and 60% males (n=26)] (p=0.003). There were more patients with malignant lesions in the open group (73%) versus in the laparoscopic group (45%) (p=0.01). Eight patients underwent partial and 23 patients segmental/wedge liver resection in the laparoscopic group versus 15 patients who underwent partial and 28 patients segmental/wedge liver resection in the open group (p=0.7). Mean tumor size was 3.9+/-0.4 cm in the laparoscopic group versus 4.2+/-0.3 cm in the open group (p=0.5). Ten (32%) out of 31 cases in the laparoscopic group were hand-assisted. Inflow occlusion was used in 1 case (3%) in the laparoscopic group versus 16 (37.2%) in the open group. Mean operating time was 201+/-15 min for the laparoscopic group and 172+/-12 min for the open group (p=0.1). Mean estimated blood loss during the procedure was 122.5+/-45.4 cc for the laparoscopic group and 299.6+/-33.6 cc for the open group (p=0.002). Surgical margin was similar for malignant cases in both groups. Mean hospital stay was 3.2+/-1.0 days for the laparoscopic group and 6.8+/-0.7 days for the open group (p=0.004). The incidence of postoperative complications was 13% (n=4) in the laparoscopic and 16% (n=7) in the open group (p=0.7). CONCLUSION: This study shows that, with a longer operative time, the laparoscopic approach, despite the learning curve, offers advantages regarding operative blood loss, postoperative analgesic requirement, time to regular diet, hospital stay, and overall cost compared with the open approach for minor liver resections.

Cruveilhier-Baumgarten disease in a patient with Turner syndrome: case report of a rare indication for liver transplantation.

Some chromosomal alterations can be associated with vascular abnormalities. For instance, Turner syndrome can be complicated by agenesis or hypoplasia of the portal venous system causing presinusoidal portal hypertension. Liver transplantation to treat this condition overcomes portal hypertension and reconstitutes the diminished hepatic function due to severe atrophy of the portal venous inflow.

"Splenic artery steal syndrome" is a misnomer: the cause is portal hyperperfusion, not arterial siphon.

Splenic artery embolization (SAE) improves hepatic artery (HA) flow in liver transplant (OLT) recipients with so-called splenic artery steal syndrome. We propose that SAE actually improves HA flow by reducing the HA buffer response (HABR). Patient 1: On postoperative day (POD) 1, Doppler ultrasonography (US) showed patent vasculature with HA resistive index (RI) of 0.8. On POD 4, aminotransferases rose dramatically; his RI was 1.0 with no diastolic flow. Octreotide was begun, but on POD 5 US showed reverse diastolic HA flow with no signal in distal HA branches. After SAE, US showed markedly improved flow, RI was 0.6, diastolic flow in the main artery, and complete visualization of all distal branches. By POD 6, liver function had normalized. RI in the main HA is 0.76 at 2 months postsurgery. Patient 2: On POD 1, RI was 1.0. US showed worsening intrahepatic signal, with no signal in the intrahepatic branches and reversed diastolic flow despite good graft function. On POD 7, SAE improved the intrahepatic waveform and RI (from 1.0 to 0.72). Patient 3: Intraoperative reverse diastolic arterial flow persisted on PODs 1, 2, and 3, with progressive loss of US signal in peripheral HA branches. SAE on POD 4 improved the RI (0.86) and peripheral arterial branch signals. Patient 4: US on POD 1 showed good HA flow with a normal RI (0.7). A sudden waveform change on POD 2 with increasing RI (0.83) prompted SAE, after which the wave form normalized, with reconstitution of a normal diastolic flow (RI 0.68). In conclusion, these reports confirm the usefulness of SAE for poor HA flow but suggest that inflow steal was not the problem. Rather than producing an increase in arterial inflow, SAE worked by reducing portal flow and HABR, thereby reducing end-organ outflow resistance. Evidence of this effect is the marked reduction of the RI after the SAE to 0.6, 0.72, 0.86, and 0.68, in patients 1-4, respectively. SAE reduces excessive portal vein flow and thereby ameliorates an overactive HABR that can cause graft dysfunction and ultimately HA thrombosis.

Long-term outcome of biliary reconstruction for bile duct injuries from laparoscopic cholecystectomies.

BACKGROUND: Major bile duct injuries remain a potentially devastating complication after laparoscopic cholecystectomy. A retrospective review was conducted of patients who underwent a biliary-enteric reconstruction of a biliary injury to assess their long-term outcome. METHODS: Retrospective review of bile duct injury database from January 1990 to December 2005. RESULTS: A total of 144 patients were treated for bile duct injury, and 84 (58%) required a biliary-enteric reconstruction. Stratification by Bismuth-Strasberg injury level revealed E1 or E2 in 23, E3 in 33, E4 in 17, E5 in 1, and B+C in 10. Forty-four (52%) were operated within 7 days of laparoscopic cholecystectomy, the remainder operated at a median of 79 days after referral. Early or late mortality occurred in 3 (4%). At a mean follow-up of 67 months, 9 patients (11%) developed a biliary stricture presented at a median of 13 months after bile duct repair. Level of injury was very important in predicting a postoperative biliary stricture: E4 (35%) versus E3 (9%; P = .023), and E4 versus E1, E2 B+C (0%; P = .001). More strictures occurred in patients operated within 7 days of laparoscopic cholecystectomy (19%) versus delayed repair (8%; P = .053). Overall, 90% of patients are alive and nonstented; 5 patients have chronic liver disease (1 on the waiting list for liver transplant). Nonbiliary complications occurred in 15 patients; the total morbidity was 40%. CONCLUSIONS: Bile duct injuries that require a biliary-enteric repair are commonly associated with long-term complications. Level of injury and likely timing of repair predict risk of postoperative stricture.

Perioperative and oncologic outcomes of minimally invasive liver resection for colorectal metastases: A case-control study of 130 patients.

BACKGROUND: Our aim was to compare the perioperative and oncologic outcomes of open liver resection and minimally invasive liver resection in the management of colorectal liver metastases. METHODS: Patients who underwent minimally invasive liver resection for colorectal liver metastases between January 2006 and June 2015 at a single center were identified and matched by extent of resection to consecutive open liver resection patients from the same period. Clinicopathologic characteristics, perioperative data, recurrence, and survival outcomes were collected and analyzed based on intention-to-treat. RESULTS: Sixty-five patients underwent minimally invasive liver resection during this period and were matched to 65 consecutive open liver resection patients, with similar baseline demographic, tumor, and chemotherapy parameters. Conversion to open occurred in 5 (7.7%) minimally invasive liver resection patients. R0 resection rates and operative times were comparable, but the estimated blood loss was less in the minimally invasive liver resection group (median 200 mL vs 400 mL, P < .001), as were perioperative transfusion rates (4.6% vs 15.4%, P = .04). The duration of stay was shorter after minimally invasive liver resection (median 4 days vs 6 days, P < .001), while major and minor complication rates were similar and no perioperative mortality was recorded. At a median follow-up of 28 months, there was no difference regarding disease-free (P = .90) or overall survival (P = .37). CONCLUSION: In selected patients with colorectal liver metastases, minimally invasive liver resection resulted in similar oncologic outcomes, with decreased blood loss and shorter duration of stay compared to patients who underwent open liver resection.

Natural history of indeterminate pancreatic cysts.

BACKGROUND: The optimal treatment for incidental asymptomatic pancreatic cysts is not known. The purpose of this study was to determine whether nonmucinous cysts by cyst-aspiration analysis can be observed safely. METHODS: A prospective protocol was initiated in September of 1999 for all suspected cystic neoplasms. Asymptomatic patients with negative cyst aspirates (no extracellular mucin, and concentration of carcinoembryonic antigen in the cyst fluid <200 ng/mL) were followed-up clinically and radiographically. RESULTS: Through December 2004, 221 patients have been evaluated, and 80 (36%) initially were operated. There were 141 (64%) patients with indeterminate cysts, 98 have been followed-up for more than 12 months. Compared with resected patients, observed patients were older (62 vs 56 y, P < .006), and had smaller cysts (2.4 vs 4.0, P = .001). At a mean follow-up period of 24 months, 4 patients (4%) were resected. The indication, time to resection, and pathology were as follows: 2 patients for symptoms (abdominal pain and obstructive jaundice) at 24 and 72 months, respectively: mucinous and serous cystadenomas; 1 patient for an increase in size (6.6 to 7.8 cm) at 18 months: lymphoepithelial cyst; and 1 patient for abdominal pain and increase in size (2.0 to 3.7 cm) at 41 months: pseudocyst. The only patient resected for a mucinous neoplasm had a cyst fluid carcinoembryonic antigen level of 896 ng/mL. In the remaining observed patients, 20 (23%) showed a decrease in cyst size, and 16 (19%) showed an increase in size (mean diameter change, 21%). CONCLUSIONS: Initial follow-up evaluation indicates that asymptomatic patients without evidence of a mucinous neoplasm by cyst aspiration can be followed clinically and with interval imaging.

Cystadenoma and cystadenocarcinoma of the liver: a single center experience.

BACKGROUND: Biliary cystadenomas and cystadenocarcinomas comprise 5% of cystic lesions in the liver. Cystadenomas are often incorrectly diagnosed as simple cysts, which results in inadequate therapy. Recurrence and possible malignant transformation are consequences of incomplete excision. Cystadenocarcinomas are very rare tumors that are felt to be biologically indolent. STUDY DESIGN: A retrospective review of 18 cystadenomas and 4 cystadenocarcinomas treated at the Cleveland Clinic from July 1985 to November 2002. RESULTS: All 18 patients with cystadenomas were women; mean age was 48 years. The majority (16 of 18) were symptomatic. Preoperative CT scans demonstrated cyst(s) with septations in all patients. Fifty-five percent had undergone prior intervention(s) to treat the cyst. Thirteen patients had complete excision of the cystadenoma, either by enucleation or liver resection. None of the patients developed recurrent cystadenomas (mean followup 37 months). Of 4 patients with cystadenocarcinoma, 3 were women; mean age was 60 years. All were symptomatic. Preoperative CT scans demonstrated masses with both cystic and solid components. No patient had undergone prior intervention. All had a liver resection. Two patients died of metastatic disease at 6 and 12 months, respectively. One patient is alive and disease-free at 16 years; 1 is alive with metastatic disease 10 years after the liver resection. CONCLUSIONS: Cystadenomas are uncommon tumors that are often incorrectly diagnosed as simple cysts. Preoperative imaging that demonstrates the presence of internal septations highly suggests the diagnosis of cystadenoma. Intraoperative biopsy and frozen section(s) are essential, although they are not 100% accurate. Cystadenomas require complete excision to prevent recurrence and the possibility of malignant transformation. Cystadenocarcinomas are very rare. Despite complete resection, cystadenocarcinomas can recur in a short period of time. The biologic behavior of these tumors can vary widely.

Surgical Management of Caroli's Disease: Single Center Experience and Review of the Literature.

BACKGROUND: Caroli's disease is a rare congenital condition characterized by non-obstructive dilatation of intrahepatic ducts. In Caroli's syndrome, there is additionally an associated congenital hepatic fibrosis. METHODS: With institutional review board approval, we identified all patients with Caroli's disease and syndrome. RESULTS: Nine patients were identified, seven males and two females, with a median age of 40 years. Final pathological diagnoses included Caroli's disease (n = 6) and Caroli's syndrome (n = 3). Patients presented with deranged liver function, cholangitis, cholangiocarcinoma, abdominal pain, cirrhosis, or were diagnosed incidentally. Four patients underwent resection and two underwent liver transplantation. Of the resection group, two patients subsequently underwent transplantation for recurrent cholangitis due to anastomotic stricture in one patient and for end-stage liver disease in the other. All patients with Caroli's syndrome underwent liver transplantation. Three patients died during follow-up at 26.2, 7.8, and 3 months post-diagnosis with recurrence of cholangiocarcinoma, liver failure, and metastatic cholangiocarcinoma, respectively. Six patients are alive with a median follow-up of 60 months since presentation (range = 10-134 months). CONCLUSIONS: Caroli's disease and syndrome have a varied presentation. Most individuals with Caroli's disease may be adequately treated by resection, but transplantation is required for Caroli's syndrome patients due to the associated hepatic fibrosis.

Hepatic abscess after liver transplantation: 1990-2000.

BACKGROUND: Infections following solid-organ transplants are a major cause of morbidity and mortality. Few studies have reported the complications of hepatic abscesses. METHODS: This investigation consisted of a retrospective chart review of all solid-organ transplant recipients from 1990 to 2000. Criteria for diagnosis included parenchymal hepatic lesions, positive cultures from liver aspirates or blood cultures, or both, and a compatible clinical presentation. RESULTS: Of 2,175 recipients of all organ transplants (heart, lung, kidney, liver, pancreas), we identified 12 patients who had experienced 14 episodes of hepatic abscess, all in liver transplant recipients. Median time from transplant to hepatic abscess was 386 days (range 25-4,198). The most common predisposing factor was hepatic artery thrombosis (HAT), which occurred in eight patients, and was diagnosed at an average of 249 days (range 33-3,215) after transplantation. Clinical presentation of hepatic abscess was similar to that described in non-immunosuppressed patients. All but one patient showed hypoalbuminemia (<3.5 g/dL); those with HAT also had significantly elevated lactate dehydrogenase. Liver aspirates grew gram-positive aerobic bacteria (50% of isolates), gram-negative aerobic bacteria (30%), and anaerobes and yeasts (10% each). Patients received an average of 6 weeks of intravenous antibiotic therapy. Catheter drainage was successful in 70% of cases; and five patients required retransplantation. Altogether, five of the patients died, yielding a mortality rate of 42%. CONCLUSIONS: Hepatic abscess, a rare complication after liver transplantation, was frequently associated with hepatic artery thrombosis. Mortality was higher than in patients who had not undergone transplantation. Prolonged antibiotic therapy, drainage, and even retransplantation may be required to improve the outcome in these patients.