Is a severe preoperative condition a contraindication for aortic valve-sparing reimplantation in type A aortic dissection?

BACKGROUND: Type A aortic dissection (TAAD) surgical management is still under debate. The purpose of this study was to demonstrate the feasibility and safety of the aortic valve-sparing root reconstruction (AVSR) procedure in 92 consecutive patients operated for TAAD, even when preoperative condition was severe (malperfusion, shock or both). METHODS: Our hospital database was reviewed to identify all patients who underwent an AVSR procedure for TAAD over 14 years. From May 2000 to June 2014, 92 consecutive patients were studied regarding to their preoperative condition. RESULTS: Age (61±13 years) and logistic Euroscore (23.4±15.3%) as well as cross-clamping (113±39 min), cardiopulmonary bypass (142±49 min) and circulatory arrest (22±13 min) times were collected. Hospital mortality was 16.3%. Mean follow-up was complete for a mean period of 27.6 months. One patient had early reoperation for aortic insufficiency. Actuarial survival at 1 year was 82.5%. The analysis of each group showed comparable mortality and morbidity in between patients. CONCLUSIONS: Based upon our experience in the management of TAAD, a reimplantation procedure could be performed regardless preoperative malperfusion or shock, with an acceptable postoperative over mortality or morbidity. A word of caution should be brought to patients over 70 years old.

Gastrointestinal stromal tumor in North Africa and the middle east: updates in presentation and management from an 11-year retrospective cohort.

OBJECTIVES: This study described the epidemiological, clinical, and survival profiles of patients with gastrointestinal stromal tumor (GIST) in North Africa and the Middle East (AfME). METHODS: This regional, multicenter, observational, retrospective study collected 11-year data on demographics, medical history, disease characteristics, current treatment approaches of GIST, the safety of the most common tyrosine kinase inhibitors (TKIs), second cancers, and survival status. RESULTS: Data of 201 eligible patients were analyzed: mean age was 56.9 ± 12.6 years; 111 (55.2%) patients were men, 21 (10.4%) patients had previous personal malignancy. The most common clinical presentation of GIST was dysphagia [92 (45.8%) patients]. The stomach was the most common primary site in 120 (60.7%) patients, 171 (85.1%) patients had localized disease at diagnosis. 198 (98.5%) GIST cases were CD117/CD34-positive. Imatinib was used in the neoadjuvant (18/21 patients), adjuvant (85/89 patients), and first-line metastatic treatment (28/33 patients) settings. The most common non-hematological toxicity associated with TKIs was vomiting in 32/85 (37.6%) patients. Overall, 100 (49.8%) patients (95%CI: 42.8-56.7%) were alive and disease-free while 30 (14.9%) patients were alive with active disease. CONCLUSION: Presentation of GIST in our AfME population is consistent with global reports, being more frequent in patients >50 years old and having the stomach as the most common primary site. Unlike what is usually reported, though, we did have more patients with lymphatic spread of the disease. Despite the global trend and advances in the treatment of GIST according to molecular profile, this is still far to happen in our population given the lack of access to molecular profiles and the high associated cost.

Implantation of ascyrus medical dissection stent, our first-hand experience.

BACKGROUND: Acute type A aortic dissection is associated with high perioperative morbidity and mortality. Ascyrus Medical Dissection Stent (Cryolife, Kennesaw, USA) is a novel uncovered hybrid stent graft developed to be used as an adjunct to standard surgical approach to promote true lumen expansion and enhance aortic remodeling. METHODS: From March 2021 to March 2022, four consecutive patients presented with acute Debakey type I aortic dissection and underwent emergent surgical repair with Tirone David procedure and implantation of Ascyrus Medical Dissection Stent. We reviewed patient's files retrospectively and described the perioperative outcomes. RESULTS: All four device implantations were successful. Overall 30-day mortality was 0%. Malperfusion that was present in two patients pre-operatively improved after Ascyrus Medical Dissection Stent implantation. No aortic reinterventions were needed. No aortic injury related to the device was noted. Favourable changes in aortic true lumen and false lumen dimensions were found in most of our patients but the stent was compressed at the isthmus in one patient. CONCLUSION: Ascyrus Medical Dissection Stent is a reliable and secure device. However, its benefits remain unclear when it comes to a positive remodeling and seems less likelihood comparable to a frozen elephant trunk. The main reason seems to be an insufficient radial force of the stent.

Aortic isthmus massive calcifications: an unusual case of secondary hypertension.

We present the case of a 63-year-old woman who was hospitalized five times in 4 months for episodes of heart failure, associated with a sustained hypertension despite a fivefold therapy. The pathophysiological mechanism of the hypertension was a secondary hyperaldosteronism linked to a renal hypoperfusion due to the narrowing of the thoracic aorta by a huge calcified plaque, mimicking an aortic coarctation.

SERCA2 phosphorylation at serine 663 is a key regulator of Ca2+ homeostasis in heart diseases.

Despite advances in cardioprotection, new therapeutic strategies capable of preventing ischemia-reperfusion injury of patients are still needed. Here, we discover that sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA2) phosphorylation at serine 663 is a clinical and pathophysiological event of cardiac function. Indeed, the phosphorylation level of SERCA2 at serine 663 is increased in ischemic hearts of patients and mouse. Analyses on different human cell lines indicate that preventing serine 663 phosphorylation significantly increases SERCA2 activity and protects against cell death, by counteracting cytosolic and mitochondrial Ca2+ overload. By identifying the phosphorylation level of SERCA2 at serine 663 as an essential regulator of SERCA2 activity, Ca2+ homeostasis and infarct size, these data contribute to a more comprehensive understanding of the excitation/contraction coupling of cardiomyocytes and establish the pathophysiological role and the therapeutic potential of SERCA2 modulation in acute myocardial infarction, based on the hotspot phosphorylation level of SERCA2 at serine 663 residue.

Frequency and mutational spectrum of PIK3CA gene mutations in breast cancer patients: Largest and first report from Lebanon.

The PIK3CA pathway is one of the most frequently altered pathways in human cancers, especially in breast cancer with approximately 40% of HR+/HER2- advanced breast cancer cases exhibiting mutations in the PIK3CA gene. While the mutations can occur across the entire gene, the most common are observed in exon 9 corresponding to the helical domain, and in exon 20 encompassing the kinase domain. This study constitutes the first attempt at determining the frequency and mutational spectrum in Lebanese breast cancer patients. For this purpose, DNA samples from 280 breast cancer patients from across Lebanon were screened for PIK3CA mutations using the Therascreen® PIK3CA RGQ Real-time PCR assay. In line with previous reports, 38.57% of cases were positive for at least one PIK3CA mutation, among which approximately 59% were in exon 9 and 37% in exon 20. However, PIK3CA mutations are breast cancer are heterogeneous whereby 20% of known PIK3CA mutants might not be detected by compact PCR based assays. Thus, the adoption of comprehensive Next Generation Sequencing based panels to decipher the complete clinical, molecular and immunohistochemical profile of breast cancer tumor requires further investigation.

Does extracorporeal life support influence outcome after surgical management of post infarct ventricular septal rupture? A monocenter retrospective study.

BACKGROUND: Ventricular septal rupture (VSR) is an uncommon but life-threatening complication of acute myocardial infarction. Extra corporeal life support (ECLS) use in the preoperative setting allows hemodynamic stabilization for a delayed surgery. We aimed to assess the role of ECLS in the preoperative period of post infarction VSR surgery. METHODS: We retrospectively analyzed all consecutive patients operated for VSR between January 2007 and August 2019. We assessed baseline characteristics, pre and post-operative clinical status and the use of ECLS in the peri-operative period. RESULTS: A total of 39 patients were included. Mean age was 69.8 years. In-hospital mortality was 48.7%. Survivors and non-survivor patients had similar characteristics except for lower postoperative ejection fraction (32% vs. 42%, P=0.02) and more acute renal failure (71.4% vs. 10%, P=0.0005) in the non-survivor group. Patients who received ECLS preoperatively were younger (72 vs. 65, P=0.02) and had more preoperative invasive ventilation (16% vs. 50%, P=0.04). Cardiopulmonary bypass (CPB, 140 min vs. 75 min, P=0.0008) and cross clamping times (94 min vs. 52 min, P=0.0026) were significantly higher in the ECLS group. There were more bleeding complications in the ECMO group (45.4% vs. 0%, P=0.0019) and more need for reintervention (63.3% vs. 13%, P=0.015). There was no difference in mortality between the two groups. There was no difference in postoperative characteristics between urgent and delayed surgery. CONCLUSIONS: In our study, post-operative ECLS use was associated with more bleeding complications and need for reintervention. Although mortality was similar, bleeding complications remain a major limitation for the systematic use of ECLS in the post-operative period.

Diagnosis and management of patients with stage III non­small cell lung cancer: A joint statement by the Lebanese Society of Medical Oncology and the Lebanese Pulmonary Society (Review).

Proper management of stage III non-small cell lung cancer (NSCLC) might result in a cure or patient long-term survival. Management should therefore be preceded by adequate and accurate diagnosis and staging, which will inform therapeutic decisions. A panel of oncologists, surgeons and pulmonologists in Lebanon convened to establish a set of recommendations to guide and unify clinical practice, in alignment with international standards of care. Whilst chest computerized tomography (CT) scanning remains a cornerstone in the discovery of a lung lesion, a positron-emission tomography (PET)/CT scan and a tumor biopsy allows for staging of the cancer and defining the resectability of the tumor(s). A multidisciplinary discussion meeting is currently widely advised for evaluating patients on a case-by-case basis, and should include at least the treating oncologist, a thoracic surgeon, a radiation oncologist and a pulmonologist, in addition to physicians from other specialties as needed. The standard of care for unresectable stage III NSCLC is concurrent chemotherapy and radiation therapy, followed by consolidation therapy with durvalumab, which should be initiated within 42 days of the last radiation dose; for resectable tumors, neoadjuvant therapy followed by surgical resection is recommended. This joint statement is based on the expertise of the physician panel, available literature and evidence governing the treatment, management and follow-up of patients with stage III NSCLC.

Bicolor K-edge spectral photon-counting CT imaging for the diagnosis of thoracic endoleaks: A dynamic phantom study.

PURPOSE: The purpose of this study was to investigate the feasibility of identifying and characterizing the three most common types of endoleaks within a thoracic aorta aneurysm model using bicolor K-edge imaging with a spectral photon-counting computing tomography (SPCCT) system in combination with a biphasic contrast agent injection. MATERIALS AND METHODS: Three types of thoracic endoleaks (type 1, 2 and 3) were created in a dynamic anthropomorphic thoracic aorta phantom. Protocol consisted in an injection of an iodinated contrast material followed 80 seconds after an injection of a gadolinium-based contrast agent (GBCA). The phantom was scanned using a clinical prototype SPCCT during bicolor phase imaging consisting in an early distribution of GBCA and a late distribution of iodine. Conventional and spectral images were reconstructed for differentiating between the contrast agents and measuring their respective attenuation values and concentrations inside and outside the stent graft. RESULTS: Conventional images failed to provide specific dynamic imaging contrast agents in the aneurysmal sac and outside the stent graft while spectral images differentiated their specific distribution. In type 1 and 3 thoracic endoleaks, GBCA concentration was measured outside the stent graft at 6.1 ± 3.7 (standard deviation [SD]) mg/mL and 6.0 ± 4.0 (SD) mg/mL, respectively, in favor of an early blood flow. In type 2 thoracic endoleak, iodine was measured outside the stent graft at 24.3 ± 5.5 (SD) mg/mL in favor of a late blood flow in the aneurysmal sac. CONCLUSION: Bicolor K-edge imaging enabled SPCCT allows a bicolor characterization of thoracic aorta endoleaks in a single acquisition in combination with a biphasic contrast agent injection.

Prevalence of Her2-neu status and its clinicopathological association in newly diagnosed gastric cancer patients.

BACKGROUND: This study aimed to report the prevalence of HER2-neu in newly diagnosed early or metastatic gastric cancer (GC) patients, to determine the percentage of patients achieving various IHC scores correlating with the ISH results and to establish a database for GC patients in Lebanon. METHODS: This was a national, multicenter, descriptive and cross-sectional study in patients with histologically confirmed early or metastatic GC newly diagnosed. All eligible patients underwent the IHC and ISH tests in a central laboratory. Demographics, medical history and histopathology data were collected. RESULTS: One hundred fifty-seven patients were included (mean age at diagnosis: 63 ± 14.1 years) during a 3.5 year period. The prevalence of HER2-neu over expression was 21% (95% CI: 15.3-27.4) using ICH and ISH. Agreement between IHC and ISH results was significantly substantial (kappa = 0.681; p-value < 0.001). Over expressed HER2-neu status was significantly associated with high ECOG performance status only. CONCLUSIONS: The prevalence of HER2-neu over expression in newly diagnosed early or metastatic GC patients seemed to be high in Lebanon. The database generated allows to monitor trends in the epidemiology and management of GC.

Hemodynamic Changes Before and After Endovascular Treatment of Type B Aortic Dissection by 4D Flow MRI.

Objective: The standard treatment for complicated Stanford type B aortic dissection (TBAD) is thoracic endovascular aortic repair (TEVAR). Functional parameters, specifically blood flow, are not measured in the clinical assessment of TEVAR, yet they are of outmost importance in patient outcome. Consequently, we investigated the impact of TEVAR on the flows in the aorta and its branches in TBAD using 4D Phase-Contrast Magnetic Resonance Imaging (4D Flow MRI). Methods: Seven patients with TBAD scheduled for TEVAR underwent pre and post-operative 4D Flow MRI. An experienced reader assessed the presence of helical flow in the false lumen (FL) using streamlines and measured net flow at specific locations. In addition, forward and reverse flows, stasis, helicity, and absolute helicity were computed automatically along the aorta centerline. Average values were then computed in the segmented vessels. Impact of TEVAR on these parameters was assessed with a Wilcoxon signed rank test. Impact of the metallic stent on the velocity quantification was assessed using intra-class correlation coefficient (ICC) between velocities measured intra-stent and in adjacent stent-free regions. Results: FL helical flow was observed proximally in 6 cases and distally in 2 cases pre-operatively. Helical flow disappeared post-TEVAR proximally, but developed distally for 2 patients. Intra-stent measures were similar to stent-free with a median difference of 0.1 L/min and an ICC equal to 0.967 (p < 0.01). Forward flow increased from 59.9 to 81.6% in the TL and significantly decreased in the FL from 15.9 to 3.3%. Similarly, reverse flow increased in the TL from 4.36 to 10.8% and decreased in the FL from 10.3 to 4.6%. No significant changes were observed in net flow for aortic branches (p > 0.05). A significant increase in FL stasis was observed (p = 0.04). Discussion: TEVAR significantly increased forward flow in the TL and significantly decreased both forward and reverse flows in the FL. Interestingly, reverse flow in the TL increased post-TEVAR, which could be due to increased rigidity of the wall, due to the metallic stent. User independent helicity quantification enabled detection of elevated helicity at the level of secondary entry tears which had been missed by streamline visualization.

Neo-adjuvant FOLFIRINOX in borderline resectable and locally advanced pancreatic adenocarcinoma.

BACKGROUND: Surgery and systemic therapy provide the best option for long-term cancer control in localized resectable pancreas cancer. The present study assessed the efficacy and safety of neoadjuvant treatment with FOLFIRINOX in patients with borderline resectable (BR) and locally advanced (LA) pancreas cancer (PDAC). METHODS: This was a prospective noninterventional observational trial of neoadjuvant FOLFIRINOX in BR and LA PDAC. The primary objective was the R0/R1 surgical resection rate. Secondary objectives included progression free survival (PFS) and overall survival (OS), tolerability, and toxicity. RESULTS: Forty-nine patients were enrolled between 2013 and 2019; the majority had LA disease (59.2%). Median age was 61 years, and median Ca 19-9 level pretreatment was 523.4 µmol/L. Following neoadjuvant FOLFIRINOX, 11 patients (22.5%) underwent surgical resection, the majority of which were BR at diagnosis (72.7%). Median OS and PFS for the entire group were 25 (95% CI: 17.2-32.8) and 12 months (95% CI: 9.7-13.3), respectively. Median PFS in BR patients was 14 (95% CI: 10.5-17.5) compared to 12 months (95% CI: 5.2-18.8) in patients with LA patients. Median OS and PFS were not reached in patients who underwent surgical resection as compared to 22 (95% CI: 18.6-25.4) and 9 months (95% CI: 4.2-13.9) in those who did not, respectively. Grade 3/4 neutropenia, leukopenia, neuropathy, nausea/vomiting, and diarrhea occurred in 6.3%, 2.1%, 10.4%, 4.2%, and 8.3%, respectively. CONCLUSION: Neoadjuvant FOLFIRINOX is an active regimen for patients with LA/BR PDAC with a resection rate of 22.5%. These results are in line with prior data.

Palbociclib and letrozole in hormone-receptor positive advanced breast cancer: Predictive response and prognostic factors.

CDK 4/6 inhibitors have been yielding propitious results when with hormone therapy in the management of Her2-negative and hormone-receptor (HR)-positive metastatic breast cancer, palbociclib being one of the first molecules investigated in this setting. However, the response to CDK4/6 inhibitors is variable. To identify predictive and prognostic factors of response to this therapeutic regimen. Eligible patients were females with HR+ and Her2- advanced breast cancer, receiving Palbociclib in combination with Letrozole. PFS was the primary endpoint in the evaluation of response to treatment. This survival was then further segregated according to various characteristics: histological (type, grade, hormone receptors), metastatic site, line of treatment, response type at initial assessment, and best response achieved. The data was then processed by two statistical analysis models: Kaplan-Meier and univariate preceding multivariate Cox proportional risks. Sixty patients were included and followed for a median follow-up duration of 15.98 months. PFS recorded a median of 19.07 months (95% CI=15.43-22.71). PFS had a median of 12.99 months in the absence of progesterone receptors (vs 20.05 months in the case of positive estrogen and progesterone receptors; P = 0.046), a median of 13.02 months in the presence of liver metastases (vs 22.98 months in the absence of liver metastases; P = 0.007), and 15.94 months in the case of second-line and beyond (vs 22.98 months in the case of first-line; P = 0.033). Regarding the Hazard Ratio of progression, we note age (HR 0.941; P = 0.019), liver metastases (HR 2.751; P = 0.051), response at initial evaluation (HR<1; P < 0.001) and best response (HR<1; P = 0.003). PFS reached similar figures to those of international studies. The absence of progesterone receptors, presence of liver metastases, and use as second-line or beyond are associated with a reduced median PFS. One year age increase (protective factor), liver metastases (risk factor), response at initial evaluation, and best response achieved are identified as the most predictive factors of the response to this treatment regimen and of the progression risk.

Ventricular septal rupture: insights into an old disease.

Ventricular septal rupture (VSR) is a serious complication of ST-elevation myocardial infarction (STEMI) and surgery is the reference treatment. We aimed at describing trends in management and mortality during the last four decades and reporting mortality predictors in these patients. We conducted a single-center retrospective study of patients sustaining a VSR from 1981 to 2020. We screened 274 patients and included 265 for analysis. The number of patients decreased over the years: 80, 88, 56, and 50 in each 10-year time span. In-hospital mortality decreased significantly since 1990 (logrank 0.007). The median age was 72.0 years IQR [66-78] and 188 patients (70.9%) were operated on. IABP was used more routinely (p < 0.0001). In-hospital mortality was assessed at 66.8% (177 patients) and main predictors of death were a time from MI to surgery < 8 days HR 2.7 IC95% [1.9-3.8] p < 0.0001, a Killip class > 2 HR 2.5 IC [1.9-3.4] p < 0.0001 and Euroscore 2 > 20 HR 2.4 IC [1.8-3.2] p < 0.0001. A "time from MI to surgery" of 8 days offers the best ability to discriminate between patients with or without mortality. The ability of "Euroscore 2 and Killip" to detect the patients most likely to wait 8 days for surgery was at 0.81 [0.73-0.89] p < 0.0001. Mortality remains high over the years. Euroscore 2, Killip class, and time from MI to surgery are the main mortality predictors. Patients with a Killip < 3 and a Euroscore < 20 should be monitored at least 8 days since MI before being referred to surgery.

A Non-Interventional Multicenter Study of First-Line Bevacizumab in Combination with Chemotherapy in Patients with Metastatic Colorectal Cancer in Lebanon.

PURPOSE: When combined with chemotherapy, bevacizumab improves progression-free survival (PFS) in metastatic colorectal cancer (mCRC). This observational trial was designed to assess the safety and efficacy of bevacizumab plus first-line chemotherapy in a real-world setting in Lebanon. PATIENTS AND METHODS: A non-interventionaL multicenter study of first-LIne AVastin® (bevacizumab) in combination with chEmotherapy in patients with metastatic colorectal cancer (LLIVE) is a multicenter, prospective, Lebanon-based, observational study that enrolled mCRC patients who received first-line bevacizumab plus chemotherapy combination. The primary end point of the study was PFS. Secondary endpoints comprised the overall response rate (ORR) and the safety and tolerability of bevacizumab. RESULTS: A total of 196 patients were enrolled between July 2010 and August 2013. The median duration of follow-up was 11 months. Median duration of bevacizumab treatment was 4 months with FOLFOX being the chiefly chemotherapy regimen used in the first-line setting (26%). Median PFS was 8.22 months (95% confidence interval (CI): 7.005-9.443). The ORR was 50.3% (complete response 7.5%, partial response 42.8%). The most common adverse event encountered was hypertension (28%) followed by epistaxis (4.8%), diarrhea (4%), anemia (4%) and headache (4%). Grade 3/4 adverse events occurred in 15.2% of patients. CONCLUSION: The trial further substantiated the efficacy and safety of bevacizumab and chemotherapy in the first-line treatment of mCRC patients in Lebanon.

Does the Addition of a Gastroepiploic Artery to Bilateral Internal Thoracic Artery Improve Survival?

It is unclear whether the additional conduit to supplement bilateral internal thoracic arteries (BITA) influences the patient outcome in coronary surgery. This retrospective study compared long-term survival of patients undergoing left-sided BITA grafting in which the third conduit to the right coronary system (RCA) was either vein graft (SVG) or gastroepiploic artery (GEA). From 1989 to 2014, 1432 consecutive patients underwent left-sided revascularization with BITA associated with SVG (n = 599) or GEA (n = 833) to RCA. Propensity score was calculated by logistic regression model and patients were matched 1 to 1 leading to 2 groups of 320 matched patients. The primary end point was the overall mortality from any cause. GEA was used in significantly lower risk patients. The 30-day mortality was 1.6% without influence of the graft configuration. Postoperative follow-up was 13.6 ± 6.6 years and was 94% complete. The significant difference in patients' survival observed at 20 years in favor of GEA in unmatched groups (48 ± 4% vs 33 ± 6%, P < 0.001) was not confirmed in matched groups (41 ± 7% vs 36 ± 7%, P = 0.112). In multivariable Cox model analysis, the conduit used to RCA did not influence the long-term survival in matched groups, like no other graft configuration or operative parameter. Only complete revascularization remained predictor of survival (P = 0.016), with age (P < 0.0001), diabetes status (P = 0.007), and left ventricle ejection fraction (P < 0.0001). Long-term survival in patients undergoing BITA grafting is not affected by using GEA as third arterial conduit in alternative to SVG. Further studies are necessary to assess its impact on long-term cardiac events.

Management of breast cancer patients with BRCA gene mutations in Lebanon of the Middle East: perspectives and challenges.

BACKGROUND: This commentary explores and discusses the challenges oncologists face in diagnosing and managing breast cancer patients with BRCA gene mutations in Lebanon and the Middle East. METHODS: Key opinion leaders shared their recommendations to achieve better patient outcomes and satisfaction based on evidence-based medicine and their clinical experience in BRCA management. RESULTS: Challenges associated with BRCA management can be divided into four main levels: physicians, patients, test, and treatment factors. More genetic counselors are to be identified given their important role in the management of individuals with BRCA gene mutations. CONCLUSION: Genetic counseling, continuing education, infrastructure, testing, expertise, and financial support are needed to fulfill the unmet needs in the management of BRCA mutation carriers.

Chest wall infarction following bilateral internal thoracic harvesting for coronary revascularization in a patient with previous aortic abdominal aneurysm surgery: A rare complication.

A 75 years old man with previous aortic abdominal aneurysm surgery through a transverse laparotomy underwent bilateral internal thoracic artery to coronary artery bypass grafting. He immediately thereafter developed a severe chest and upper abdominal walls ischemia with metabolic acidosis, and finally deep sternum wound infection and upper abdominal wall necrosis. He benefitted from sternal reconstruction and vaccum assisted treatment, with delayed pectus major flap reconstruction. Chest and abdominal wall infarction following bilateral internal thoracic artery (BITA) harvesting is a very rare but life-threatening complication. Caution use of BIMA should be in order in patients with inferior epigastric artery flow impairment.