Neurologic pathologies of the vertebral spine.

At some institutions, musculoskeletal and general radiologists rather than neuroradiologists are responsible for reading magnetic resonance imaging (MRI) of the spine. However, neurological findings, especially intrathecal ones, can be challenging. Intrathecal neurological findings in the spine can be classified by location (epidural, intradural extramedullary, and intramedullary) or etiology (tumor, infection, inflammatory, congenital). In this paper, we provide a succinct review of the intrathecal neurological findings that can be seen on MRI of the spine, primarily by location and secondarily by etiology, in order that this may serve as a helpful guide for musculoskeletal and general radiologists when encountering intrathecal neurological pathologies.

Imaging findings of the injured in the massive Beirut blast.

PURPOSE: (1) Describe imaging utilization and findings within two weeks of the 2020 Beirut blast according to the mechanism of injury, (2) determine the appropriate imaging modality per organ/system, and (3) describe changes in the workflow of a radiology department to deal with massive crises. MATERIALS AND METHODS: Two hundred sixty patients presented to the largest emergency department in Beirut and underwent imaging within 2 weeks of the blast. In this retrospective study, patients were divided into early (1) and late (2) imaging groups. Patients' demographic, outcome, type and time of imaging studies, body parts imaged, and mechanism and types of injuries were documented. RESULTS: Two hundred five patients in group 1 underwent 502 and 55 patients in group 2 underwent 145 imaging studies. Tertiary blast injuries from direct impact and falling objects were the most common type of injuries followed by secondary (shrapnel) injuries. Both types of injuries affected mostly the head and neck and upper extremities. Plain radiographs were adequate for the extremities and CT for the head and neck. A regularly updated and practiced emergency plan is essential to mobilize staff and equipment and efficiently deliver radiology services during crises. CONCLUSION: Because the powerful Beirut blast occurred at the port located in the periphery of the city, most injuries seen on imaging were of the upper extremities and head and neck caused by the severe blast wind or penetrating shrapnel and resulted from people using their arms to protect their heads and bodies from direct impact and falling objects.

COVID-19-induced myocarditis in patient with anomalous origin of the left circumflex artery from the right coronary artery: a case report.

The prevalence of coronary artery anomalies has been increasing due to the increasing usage of coronary angiography. There is a paucity of literature concerning management of viral-induced myocarditis in patients with anomalous coronary artery. We present a very unusual case of a 44-year-old man with anomalous origin of the left circumflex artery from the proximal ostium of the right coronary artery who was admitted for COVID-19-induced myocarditis. He presented with signs of heart failure and coronary angiography revealed the left circumflex artery with a separate ostium originating from the proximal right coronary artery. He was treated medically with Bisoprolol, Perindopril Arginine, Rivaroxaban, and Furosemide. His condition improved rapidly and he resumed regular life within 1 month. Coexistence of cardiac disease such as viral-induced myocarditis with an underlying anomalous origin of the coronary artery is challenging to spot and can lead to worse outcomes in case of misdiagnosis and inaccurate management.

A prevalência de anomalias da artéria coronária vem aumentando devido ao uso crescente da angiografia coronariana. Há uma escassez de literatura sobre o manejo da miocardite induzida por vírus no contexto de artéria coronária anômala. Apresentamos um caso incomum de um homem de 44 anos com origem anômala da artéria circunflexa esquerda do óstio proximal da artéria coronária direita admitido por miocardite induzida por COVID-19. O paciente apresentava sinais de insuficiência cardíaca, e a cineangiocoronariografia revelou artéria circunflexa esquerda de óstio separado originando-se da artéria coronária direita proximal. Ele foi tratado clinicamente com bisoprolol, perindopril arginina, rivaroxabana e furosemida. Sua condição melhorou rapidamente, e o paciente recuperou uma vida normal em 1 mês. A coexistência de doença cardíaca, como miocardite induzida por vírus com uma origem anômala subjacente da artéria coronária, é difícil de detectar e pode levar a resultados piores em caso de diagnóstico incorreto e manejo impreciso.

MRI Findings of Arachnoiditis, Revisited. Is Classification Possible?

BACKGROUND: Prior imaging studies characterizing lumbar arachnoiditis have been based on small sample numbers and have reported inconsistent results. PURPOSE: To review the different imaging patterns of lumbosacral arachnoiditis, their significance, and clinical implications. STUDY TYPE: Retrospective. POPULATION: A total of 96 patients (43 women; average age 61.3 years) with imaging findings of arachnoiditis (postsurgical: N = 49; degenerative: N = 29; vertebral fracture: N = 6; epidural and subdural hemorrhage: N = 3, infectious: N= 1; other: N = 8) from January 2009 to April 2018. FIELD STRENGTH/SEQUENCE: Sagittal and axial T2-weighted Turbo Spin Echo at 1.5 T and 3 T. ASSESSMENT: Chart review was performed to assess the cause of arachnoiditis, and imaging was reviewed by two musculoskeletal and three neurology radiologists, blinded to the clinical data and to each other's imaging interpretation. Previous classification included a three-group system based on the appearance of the nerve roots on T2-weighted images. A fourth group was added in our review as "nonspecified" and was proposed for indeterminate imaging findings that did not fall into the classical groups. The presence/absence of synechiae/fibrous bands that distort the nerve roots and of spinal canal stenosis was also assessed. STATISTICAL TESTS: The kappa score was used to assess agreement between readers for both classification type and presence/absence of synechiae. RESULTS: Postsurgical (51%) and degenerative changes (30%) were the most common etiologies. About 7%-55% of arachnoiditis were classified as group 4. There was very poor classification agreement between readers (kappa score 0.051). There was also poor interreader agreement for determining the presence of synechiae (kappa 0.18) with, however, strong interreader agreement for the presence of synechia obtained between the most experienced readers (kappa 0.89). DATA CONCLUSION: This study demonstrated the lack of consensus and clarity in the classification system of lumbar arachnoiditis. The presence of synechia has high interreader agreement only among most experienced readers and promises to be a useful tool in assessing arachnoiditis. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 2.

Emergence of gram-negative organisms as the cause of infections in patients with sickle cell disease.

BACKGROUND: Patients with sickle cell disease are at higher risk of infections with encapsulated bacteria due to immature immune responses and functional asplenia. We aimed to study our patient population for the emergence of gram-negative organisms other than Salmonella as the cause of osteomyelitis and document a vast decrease in Streptococcus pneumoniae bacteremia rates. METHODS: We conducted a retrospective chart review of 158 patients with sickle cell disease registered at our hospital. Over a period of 13 years, every patient presenting to the emergency department (ED) with fever had their medical record reviewed for blood cultures, wound cultures, and magnetic resonance imaging results for osteomyelitis. RESULTS: The number of patients presenting to the ED with fever was 105, with 581 febrile episodes and 893 blood cultures. Among those, no culture grew Streptococcus pneumoniae, 14 grew coagulase-negative staphylococci (1.5%), one grew Salmonella enterica Paratyphi B, and three grew Salmonella enterica group C (in the same patient). The total number of osteomyelitis episodes in patients with sickle cell disease presenting with fever and documented by imaging was nine (1.5%). In patients with osteomyelitis, organisms were isolated in four patients (44%), including Enterobacter cloacae, Bacteroides, Pseudomonas aeruginosa, and Salmonella enterica group C. CONCLUSIONS: Immunization against Streptococcus pneumoniae and the use of prophylactic penicillin has virtually eliminated pneumococcal bacteremia among our patients. We observed the emergence of gram-negative organisms other than Salmonella as the cause of osteomyelitis in patients with sickle cell disease.

Routine surveillance imaging after end of therapy for pediatric extracranial tumors: A retrospective analysis.

Frequent surveillance imaging is routine practice for pediatric patients after cancer therapy. This retrospective study evaluated the follow-up of 301 children with extracranial tumors diagnosed between 2002 and 2012, at a tertiary pediatric cancer center in Beirut, Lebanon. Recurrence occurred in 15% of patients, at a median of 12 months after end of primary therapy. Outcome was not different comparing patients with recurrence detected via imaging surveillance versus clinically. False positive findings in 55 patients led to further interventions. These results raise important questions regarding benefit of current surveillance practices as standard care, especially in countries with limited resources.

Cortical bone invasion in non-transfusion-dependent thalassemia: tumefactive extramedullary hematopoiesis reviewed.

OBJECTIVE OF THE STUDY: To assess the prevalence of cortical bone invasion (CBI) with secondary extramedullary hematopoiesis (EMH) in patients with non-transfusion-dependent thalassemia (NTDT), to determine its predilection sites on thoracic and abdominal imaging, to determine whether there is an association between various clinical and hematological parameters, and to evaluate its various findings mainly on magnetic resonance imaging (MRI), in addition to computed tomography (CT) scans. MATERIALS AND METHODS: This is a retrospective cohort study of 57 patients with NTDT imaged by CT or MRI. Both clinical and laboratory data were gathered. An imaging scoring system was used to describe the appearance of CBI by MRI. RESULTS: Twenty-seven patients (47.4 %) were found to have CBI and EMH with the most common location being the thoracic spine. Splenectomy and lower hemoglobin level were found to be independent risk factors for its development. Most lesions were homogenous (70 %), had predominant red marrow signal (67 %), and well-defined margins (89 %). CONCLUSION: CBI and secondary tumefactive EMH are common findings in patients with NTDT, with distinct imaging and clinical characteristics. An increased risk was seen in patients with splenectomy and lower hemoglobin. The imaging scoring system described is helpful in diagnosing and describing this entity, hence precluding unnecessary biopsies.

Estrogen regulation of the transient outward K(+) current involves estrogen receptor α in mouse heart.

BACKGROUND AND OBJECTIVE: We have previously shown that androgens upregulate cardiac K(+) channels and shorten repolarization. However, the effects that estrogens (E2) and estrogen receptors (ER) might have on the various repolarizing K(+) currents and underlying ion channels remain incompletely understood. Accordingly, our objective was to verify whether and how E2 and its ERs subtypes influence these K(+) currents. METHODS AND RESULTS: In order to examine the influence of E2 and ERs on K(+) currents we drastically lowered the E2 level through ovariectomy (OVX; 74% reduction vs CTL) and in parallel, we used female mice lacking either ERα (ERαKO) or ERß (ERßKO). In OVX mice, results showed a specific increase of 35% in the density of the Ca(2+)-independent transient outward K(+) current (Ito) compared to CTL. Western blots showed increase in Kv4.2 and Kv4.3 sarcolemmal protein expression while qPCR revealed higher mRNA expression of only Kv4.3 in OVX mice. This upregulation of Ito was correlated with a shorter ventricular action potential duration and QTc interval. In ERαKO but not ERßKO mice, the mRNA of Kv4.3 was selectively increased. Furthermore, when ventricular myocytes obtained from ERαKO and ERßKO were cultured in the presence of E2, results showed that E2 reduced Ito density only in ERßKO myocytes confirming the repressive role of E2-ERα in regulating Ito. CONCLUSION: Altogether, these results suggest that E2 negatively regulates the density of Ito through ERα, this highlights a potential role for this female hormone and its α-subtype receptor in modulating cardiac electrical activity.

Interleukin-1ß reduces L-type Ca2+ current through protein kinase Cϵ activation in mouse heart.

Inflammation is now widely recognized as a key component of heart disease. Patients suffering from arrhythmias and heart failure have increased levels of tumor necrosis factor-α (TNFα) and interleukin-1ß (IL-1ß). Evidence suggests that these cytokines are important mediators of cardiac remodeling; however, their effects on ion channels and arrhythmogenesis remain incompletely understood. The L-type Ca(2+) current (ICaL) is a major determinant of the plateau phase of cardiac action potential and has a critical excitation-contraction coupling role. Thus, altering its properties could have detrimental effects on cardiac electrical and contractile functions. Accordingly, the objective of this study was to elucidate the effect of TNFα and IL-1ß on ICaL, while exploring the underlying regulatory mechanisms. Neonatal mouse ventricular myocytes were treated with a pathophysiological concentration (30 pg/ml) of TNFα and IL-1ß for 24 h. Voltage-clamp recordings showed that TNFα had no effect on ICaL, whereas IL-1ß decreased the current density by 36%. Although both IL-1ß- and TNFα-treated myocytes showed significant increase in reactive oxidative species (ROS), Western blot experiments revealed that only IL-1ß increased PKCϵ membrane translocation. The antioxidant N-acetyl-L-cysteine normalized ROS levels and restored ICaL density. Furthermore, the PKCϵ translocation inhibitor ϵ-V1-2 blocked the effect of IL-1ß on ICaL. The reduction of ICaL by IL-1ß was also seen in cultured adult ventricular myocytes. Overall, chronic IL-1ß treatment decreased ICaL density in cardiomyocytes. These effects implicated ROS signaling and PKCϵ activation. These findings could contribute to explain the role of IL-1ß in the development of arrhythmia and heart failure.

Upregulation of the hyperpolarization-activated current increases pacemaker activity of the sinoatrial node and heart rate during pregnancy in mice.

BACKGROUND: Pregnancy is associated with a faster heart rate (HR), which is a risk factor for arrhythmias. However, the underlying mechanisms for this increased HR are poorly understood. Therefore, this study was performed to gain mechanistic insight into the pregnancy-induced increase in HR. METHODS AND RESULTS: Using surface ECG we observed that pregnant (P) mice have faster HR (531±14 beats per minute [bpm]) compared with nonpregnant (NP) mice (470±27 bpm; P<0.03). Results obtained with Langendorff-perfused hearts showed that this difference persisted in the absence of autonomic nervous innervation (NP, 327±16 bpm; P, 385±18 bpm; P<0.02). Spontaneous action potentials of sinoatrial node cells from pregnant mice exhibited higher automaticity (NP, 292±13 bpm; P, 330±12 bpm; P=0.047) and steeper diastolic depolarization (NP, 0.20±0.03 V/s; P, 0.40±0.06 V/s; P=0.004). Pregnancy increased the density of the hyperpolarization-activated current (If) (at -90mV: NP, -15.2±1.0 pA/pF; P, -28.6±2.9 pA/pF; P=0.0002) in sinoatrial node cells. Voltage dependence of the If activation curve and the intracellular cAMP levels were unchanged in sinoatrial node cells of pregnant mice. However, there was a significant increase in HCN2 channel protein expression with no change in HCN4 expression. Maximal depolarizing shift of the If activation curve induced by isoproterenol was attenuated in pregnancy. This reduced response to isoproterenol may be attributable to the lower cAMP sensitivity of HCN2 isoform compared with that of HCN4. CONCLUSIONS: This study shows that an increase in If current density contributes to the acceleration of sinoatrial node automaticity and explains, in part, the higher HR observed in pregnancy.

Outcome of Ewing sarcoma in a multidisciplinary setting in Lebanon.

Treatment of Ewing sarcoma (ES) necessitates coordinated multi-disciplinary care. We analyzed outcome for 39 patients treated at a single institution in Lebanon, a developing country with available multidisciplinary treatment modalities, where financial barriers to care are overcome by a fundraising system. Median follow-up was 58 months. Five-year overall and event-free survival were 76% and 58%, respectively, for localized disease, and 40% and 38%, respectively, for metastatic disease. We conclude that, in a country with emerging economy, by following international protocols and ensuring availability of needed resources, outcome of patients with ES is similar to that in developed countries.

Pulmonary Edema Following Nifedipine Use in Pregnancy: A Case Report.

Calcium channel blockers are generally considered safe for use during pregnancy. They have several indications, including second-line therapy for lowering blood pressure and tocolytic therapy. We present the case of a 24-year-old woman, G1P0, with a twin gestation at 22 weeks, who presented with acute respiratory distress. Her symptoms occurred shortly after starting nifedipine as tocolytic therapy. Investigations revealed signs of volume overload and pulmonary edema. Extensive cardiac and infectious workups were normal. Obstetrical ultrasound did not show any signs of ovarian hyperstimulation syndrome. Based on these findings, she was diagnosed with acute pulmonary edema following tocolytic therapy with oral nifedipine. Nifedipine was stopped, and intravenous furosemide was started, resulting in rapid clinical improvement. We are reporting this case to raise awareness of this rare but life-threatening adverse event associated with nifedipine use in pregnant patients.

Prevalence and risk factors for atypical femoral fracture among Lebanese patients with hip and shaft fractures.

This retrospective study investigates the prevalence of atypical femoral fractures (AFFs) among patients admitted with hip and shaft fractures at a tertiary referral center in Beirut, Lebanon. We analyzed electronic medical records and radiology studies of patients aged above 40 admitted with hip and shaft fractures between January 2006 and December 2019. Fractures were confirmed by ICD9 or ICD10 codes. All cases were reviewed by radiologists, and AFFs were identified according to the 2013 revised ASBMR criteria. We identified 1366 hip and shaft fracture patients, of which 14 female patients had 19 AFFs. This represents a prevalence of 1.0% among all hip and shaft fractures patients and 1.7% among all female hip and shaft fracture patients. Bilateral AFFs were found in 5 of the 14 patients. Patients with AFF tended to be younger, with a mean age of 74.3 (±8.6) yr compared to 78.0 (±10.6) for patients with non-AFF fractures. A total of 36% of AFF patients had a prior history of non-traumatic fracture at first admission. A high percentage of patients with AFFs reported intake of proton pump inhibitors (42.9%) and glucocorticoids (21.4%). Bisphosphonate exposure was noted in 64.3% of AFF patients. None of the AFF patients were active smokers or consumed alcohol regularly. BMD assessments were available for 7 AFF patients, indicating osteoporosis in 4 and osteopenia in 3 cases. Hip axis length measurements showed no significant difference between AFF patients (N = 7) and sex and age-matched controls (N = 21). The study underlines the prevalence and characteristics of AFFs in Lebanon, which is consistent with the numbers reported in the literature (0.32%-5%). A larger prospective study that includes hospitals across the nation is needed to gain a more comprehensive view of the prevalence of AFFs in the Lebanese population.

Para-articular and intra-articular soft tissue lesions: Radiologic-pathologic correlation.

Articular masses comprise various disease entities including benign or malignant proliferative processes and other non-neoplastic processes such as infection, deposition diseases, vascular malformations, and other lesions. Many diseases that lead to intra-articular or para-articular masses have distinct imaging features, particularly on MRI. Radiologists can localize masses to the joint space by knowing the articular anatomy and can reach a suggested diagnosis by looking at precise imaging findings. In this review article, we first define the concept of articular space (intraarticular, para-articular) and the normal joint anatomy and histology. We provide a general and comprehensive approach for evaluation of articular lesions on MRI. We then describe specific imaging and histologic features of typical benign and malignant soft tissue articular neoplasms and some non-neoplastic mimickers; and provide a radio-pathologic correlation of the different described entities.

Cyclophosphamide and topotecan as first-line salvage therapy in patients with relapsed ewing sarcoma at a single institution.

The combination of cyclophosphamide and topotecan (cyclo/topo) has shown objective responses in relapsed Ewing sarcoma, but the response duration is not well documented. We reviewed characteristics and outcome of 14 patients with Ewing sarcoma, treated uniformly at a single institution and offered cyclo/topo at first relapse. Six patients (43%) had relapse at distant sites. All patients received first-line salvage therapy with cyclophosphamide 250 mg/m and topotecan 0.75 mg/m, daily for 5 days repeated every 21 days. The median number of cycles was 4 (range 1 to 10). All toxicities were manageable, the most common being transient cytopenias. There were also 4 episodes of febrile neutropenia, and 3 episodes of gross hematuria. Response was assessable in 13 patients and showed progressive disease in 6 (46%), stable disease in 4 (31%), and partial response in 3 (23%). Nine patients had local control, consisting of radical surgery in 2, radiation in 3, and a combination in 4 patients. Response, when it occurred, was maintained for a median of 8 months (range, 4 to 28 mo). Four patients (29%) are alive at 3, 7, 9, and 110 months after relapse; 1 is receiving cyclo/topo, 1 is on third-line therapy, and 2 are in second and fourth remission. The low toxicity of this combination, and the lack of sustained responses, warrant its investigation in combination with targeted or novel therapeutic agents in relapsed disease.

Correlation of non-mass-like abnormal MR signal intensity with pathological findings surrounding pediatric osteosarcoma and Ewing's sarcoma.

OBJECTIVE: The aim of this work was to determine the role of MRI in interpreting abnormal signals within bones and soft tissues adjacent to tumor bulk of osteosarcoma and Ewing's sarcoma in a pediatric population by correlating MR findings with histopathology. MATERIALS AND METHODS: Thirty patients met the inclusion criteria, which included (1) osteosarcoma or Ewing's sarcoma, (2) MR studies no more than 2 months prior to surgery, (3) presence of abnormal MR signal surrounding the tumor bulk, (4) pathological material from resected tumor. The patients received standard neoadjuvant chemotherapy. Using grid maps on gross pathology specimens, the abnormal MR areas around the tumor were matched with the corresponding grid sections. Histopathology slides of these sections were then analyzed to determine the nature of the regions of interest. The MR/pathological correlation was evaluated using Mann-Whitney U test and Fisher's exact test. RESULTS: Twenty-seven patients had osteosarcoma and three patients had Ewing's sarcoma. Of the studied areas, 17.4% were positive for tumor (viable or necrotic). There was no statistically significant correlation between areas positive for tumor and age, gender, signal extent and intensity on MRI, or tissue type. There was, however, a statistically significant correlation between presence of tumor and the appearance of abnormal soft tissue signals. A feathery appearance correlated with tumor-negative areas whereas a bulky appearance correlated with tumor-positive regions. CONCLUSIONS: MR imaging is helpful in identifying the nature of abnormal signal areas surrounding bone sarcomas that are more likely to be tumor-free, particularly when the signal in the soft tissues surrounding the tumor is feathery and edema-like in appearance.

Rhabdomyosarcoma treatment and outcome at a multidisciplinary pediatric cancer center in Lebanon.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Outcome of patients treated on standard protocols, in a multidisciplinary cancer center setting outside of clinical trials, is not well reported. We reviewed characteristics and outcome of 23 pediatric patients treated at a single, multidisciplinary cancer center in Lebanon, between April 2002 and December 2010. Median follow-up was 41 months. The most commonly affected primary site was the head and neck (48%, n = 11). Nineteen tumors (82.6%) were of embryonal histology. Tumor size was ≥5 cm in eight (34.8%) patients. Sixteen patients (69.6%) had localized disease, and one (4.4%) had metastatic disease. Fifteen (65.2%) had Group III tumors. All patients received chemotherapy, for a duration ranging 21-51 weeks. Upfront surgical resection was performed in 10 patients (43.5%). Eighteen patients (78.3%) received radiation therapy. The 5-year overall and disease-free survival rates were 83% and 64%, respectively. Relapse correlated with absence of surgery. Treatment of childhood RMS in a multidisciplinary cancer center in Lebanon results in similar survival to that in developed countries when similar protocols are applied. There was a higher incidence of local relapse, but those were salvageable with further therapy and surgical local control.

Snapping of bilateral biceps femoris tendons: A case report and brief review.

Snapping of the biceps femoris tendon is a rare cause of lateral knee pain often due to multiple factors including fibular head deformity and thickening of the anterior band of the biceps femoris tendon inserting on the tibia. Understanding the complex and poorly understood anatomy of the biceps femoris tendon is crucial and essential for proper diagnosis of its snapping. In this report, we describe the rare entity of bilateral biceps femoris tendon snapping in a young man using a multimodality diagnostic approach.

Long-term follow-up of children treated with the Repiphysis expandable prosthesis for lower extremity bone sarcoma.

Expandable endoprostheses provide a limb salvage option for skeletally immature patients with bone sarcoma of the lower extremities. Initial reports of the Repiphysis prosthesis were encouraging; however, medium-term follow-up revealed high complication rates. We report on the long-term follow-up of a cohort of patients treated with the Repiphysis prosthesis. Eleven patients were included in the study. Data collected included sex, age at surgery, duration of follow-up, site of disease, histologic diagnosis, number of lengthening sessions, amount lengthened, postoperative complications, endoprosthetic failure, mode of endoprosthetic failure, duration from index surgery to failure and to revision, type of revision surgery and final limb-length discrepancy. The average duration of follow-up from the time of surgery was 180 months (range, 144-215 months). Fifteen Repiphysis implants were used in 11 patients. All implants failed with an average time from surgery to failure of 36 months (range, 3-72 months). Twenty-four complications were observed: one wound dehiscence, two deep infections, 18 mechanical failures, implant collapse with destruction of proximal tibia epiphysis in two and one periprosthetic proximal femur fracture with dislodgement of the stem. Despite being an option for limb salvage, the Repiphysis prosthesis has a high rate of mechanical failure and need for revision, similar to other expandable implants. The authors, therefore, recommend full disclosure of the potential short- and long-term complications and need for revision, as well as alternative treatment options if their use is considered. Level of evidence: IV (Therapeutic).