Effect of Lower Extremity Nerve Decompression in Patients With Painful Diabetic Peripheral Neuropathy: The Diabetic Neuropathy Nerve Decompression Randomized, Observation Group and Placebo Surgery-Controlled Clinical Trial.

OBJECTIVE: To evaluate the effect of nerve decompression on pain in patients with lower extremity painful diabetic peripheral neuropathy (DPN). BACKGROUND: Currently, no treatment provides lasting relief for patients with DPN. The benefits of nerve decompression remain inconclusive. METHODS: This double-blinded, observation and same-patient sham surgery-controlled randomized trial enrolled patients aged 18 to 80 years with lower extremity painful DPN who failed 1 year of medical treatment. Patients were randomized to nerve decompression or observation group (2:1). Decompression-group patients were further randomized and blinded to nerve decompression in either the right or left leg and sham surgery in the opposite leg. Pain (11-point Likert score) was compared between decompression and observation groups and between decompressed versus sham legs at 12 and 56 months. RESULTS: Of 2987 screened patients, 78 were randomized. At 12 months, compared with controls (n=37), both the right-decompression group (n=22) and left-decompression group (n=18) reported lower pain (mean difference for both: -4.46; 95% CI: -6.34 to -2.58 and -6.48 to -2.45, respectively; P < 0.0001). Decompressed and sham legs equally improved. At 56 months, compared with controls (n=m 14), pain was lower in both the right-decompression group (n=20; mean difference: -7.65; 95% CI: -9.87 to -5.44; P < 0.0001) and left-decompression group (n=16; mean difference: -7.26; 95% CI: -9.60 to -4.91; P < 0.0001). The mean pain score was lower in decompressed versus sham legs (mean difference: 1.57 95% CI: 0.46 to 2.67; P =0.0002). CONCLUSIONS: Although nerve decompression was associated with reduced pain, the benefit of surgical decompression needs further investigation as a placebo effect may be responsible for part or all of these effects.

Abandoning the SIEA Flap for the Dual-Plane DIEP Reduces Fat Necrosis and Flap Failure.

BACKGROUND: Despite its limitations in abdominally based breast reconstruction, using the superficial inferior epigastric artery (SIEA) flap or system can be advantageous in specific clinical scenarios. To optimize outcomes in these cases, the authors performed a retrospective review of their flap series to advocate a new algorithm to use the superficial system. METHODS: A retrospective analysis was performed on 1700 consecutive free abdominal flaps for the presence of a dominant superficial system or poor deep inferior epigastric artery perforators (DIEP) on clinical examination or angiography. In this setting, the authors analyzed the primary outcome measures of fat necrosis and flap failure with use of the superficial system alone versus a "dual-plane DIEP," where there was an intraflap anastomosis performed between the DIEP pedicle and SIEA pedicle. A multivariable analysis was performed with 21 other potentially confounding variables and compared with outcomes with traditionally perfused DIEP flaps. RESULTS: Fat necrosis was present in 13% of 506 DIEP flaps, 34.1% of 41 SIEA system flaps, and 2.7% of 37 dual-plane DIEP flaps. Superficial system-only flaps were independent predictors of fat necrosis (OR, 6.55; P < 0.001) and flap failure (OR, 9.82; P = 0.002) compared with dual-plane DIEP flaps when used for the same indications. CONCLUSION: In settings of superficial dominance or need to augment perfusion to lateral zones in abdominal free flaps, performing a dual-plane DIEP flap instead of using the superficial system vasculature alone with an SIEA flap can decrease the odds of fat necrosis and flap failure to equal that of a standard DIEP flap. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Pedicled Pronator Quadratus Transposition for Functional Opponensplasty: A Cadaveric Anatomical Study for Feasibility.

BACKGROUND: Techniques on opponensplasty for chronic carpal tunnel syndrome have been described previously. A novel pronator quadratus (PQ) transposition for chronic carpal tunnel syndrome is described. In addition, the relationship of the distal perforating branch of the radial artery to the surrounding tissue is detailed to optimize further use of the PQ flap for clinical applications. METHODS: Ten cadaver hands underwent PQ dissection, and the perforating branch of the radial artery was identified. Measurements were taken from the radiocarpal joint and the radial styloid to the distal perforating branch. Finally, a proposed surgical technique of PQ transposition with proximal radius periosteum to the first metacarpophalangeal joint and anterior interosseous nerve transfer was performed. RESULTS: The average distance of the perforating branch from the radiocarpal joint was 10 ± 1.05 mm, and the average distance from the radial styloid was 17.1 ± 1.6 mm. Pronator quadratus transposed with a layer of radius periosteum demonstrated anatomical feasibility. CONCLUSIONS: The distal perforating branch of the radial artery predictably perfuses the PQ muscle, which may be used in the future as a means of opponensplasty for chronic carpal tunnel syndrome.

Do Preoperative Depressor Anguli Oris Muscle Blocks Predict Myectomy Outcomes? A Single-Cohort Comparison in Postparetic Facial Synkinesis.

SUMMARY: The complexity of facial synkinesis will likely benefit from an individualized approach to intervene on discrete synkinetic facial subunits. This overarching treatment algorithm requires understanding each synkinetic mimetic subunit. The depressor anguli oris muscle, because of its antagonistic relationship to the zygomaticus major, is of particular interest. This study aims to provide outcomes of depressor anguli oris muscle myectomies and the predictive value of preoperative lidocaine blocks. Preoperative depressor anguli oris muscle lidocaine blocks were administered to patients with postparetic facial synkinesis, and subsequent isolated depressor anguli oris muscle myectomies were performed on those who showed improvement and elected to proceed. Twenty synkinetic patients underwent isolated depressor anguli oris myectomies after lidocaine blockade, with an average follow-up of 9 months. Facial mimetic parameters and measurements were recorded and analyzed by Massachusetts Eye and Ear Infirmary Emotrics and National Institutes of Health ImageJ software to compare results from both blocks and myectomies. Both lidocaine block and depressor anguli oris myectomy improved dental show by 14.42 mm 2 and 23.012 mm 2 , respectively, and open mouth smile angles above a horizontal plane by 4.66 and 3.32 degrees, respectively. There was no statistical difference between the groups in terms of improvements noted in closed and open mouth smile angles above a horizontal plane, or in dental show ( p = 0.695, p = 0.351, and p = 0.242, respectively). Preoperative lidocaine blockade accurately predicts the improvement in dental show and modiolus smile angle that is provided by isolated depressor anguli oris muscle myectomy. This furthers our understanding of depressor anguli oris muscle abnormality in the overall spectrum of facial synkinesis. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Flap Monitoring Using Transcutaneous Oxygen or Carbon Dioxide Measurements.

Free tissue transfer is a cornerstone of complex reconstruction. In many cases, it represents the last option available for a patient and their reconstruction. At high-volume centers, the risk of free flap failure is low but its occurrence can be devastating. Currently, the mainstay for flap monitoring is the clinical examination. Though reliable when performed by experienced clinicians, the flap exam is largely subjective, is performed discontinuously, and often results in significant time delay between detection of flap compromise and intervention. Among emerging flap monitoring technologies, the most promising appear to be those that rely on noninvasive transcutaneous oxygen and carbon dioxide measurements, which provide information regarding flap perfusion. In this article, we review and summarize the literature on various techniques but primarily emphasizing those technologies that rely on transcutaneous gas measurements. We also define characteristics for the ideal flap monitoring tool and discuss critical barriers, predominantly cost, preventing more widespread utilization of adjunct monitoring technologies, and their implications.

Depressor Anguli Oris Myectomy versus Transfer to Depressor Labii Inferioris for Facial Symmetry in Synkinetic Facial Paralysis.

BACKGROUND: Postparalytic synkinesis presents with a combination of hypo- and hypertonic muscles, leading to facial asynchrony with animation and at rest. One ubiquitous finding is a hypertonic depressor anguli oris (DAO) muscle and a weak depressor labii inferioris (DLI) muscle. The goal of this study was to evaluate the utility of DAO myectomy with or without its transfer to the weakened DLI in improving critical components of the dynamic smile. METHODS: From 2018 to 2020, this single-center, prospective study included of postparetic facial synkinetic patients with evidence of DAO hypertonicity who underwent DAO myectomy with or without transfer to DLI. Objective facial measurements were used to compare the effectiveness of DAO to DLI transfer to pure DAO myectomy in improving asymmetry of the synkinetic hemiface. RESULTS: Twenty-one patients with unilateral postparetic facial synkinesis with DAO hypertonicity were included; 11 underwent DAO myectomy, while 10 underwent DAO to DLI transfer. Baseline demographics and facial measurements were similar between the groups. DAO myectomy resulted in increased modiolus resting position, closed-mouth smile modiolus angle and excursion, open-mouth smile modiolus angle, excursion, dental show, and decreased lower lip height deviation. DAO to DLI transfer demonstrated similar findings but lacked significant increase in excursion and resulted in worsened lower lip height deviation. CONCLUSION: These findings illustrate the utility of DAO myectomy in improving imbalance in the synkinetic patient and necessitate further technical refinements for DAO transfers or a different approach for improving lower lip depression in this subgroup of patients.

Upper-Extremity Phlegmasia Cerulea Dolens With Compartment Syndrome in Coronavirus Disease 2019 Sepsis.

A 54-year-old woman with leukemia presented with coronavirus disease 2019 and a right upper-extremity indwelling peripherally inserted central catheter line for chemotherapy administration. On hospital admission day 9, she developed acute right upper-extremity edema and pain. Ultrasound demonstrated complete superficial and deep venous thrombosis up to the proximal subclavian vein. Her examination result was consistent with acute phlegmasia cerulea dolens and compartment syndrome, but respiratory instability prevented transfer and vascular surgery intervention. Instead, we performed bedside fasciotomies and administered therapeutic heparin, and the limb was salvaged. This case underscores the potential for successful limb salvage in patients with phlegmasia in the setting of coronavirus disease 2019 via compartment release and therapeutic anticoagulation.

Topographic and Neural Anatomy of the Depressor Anguli Oris Muscle and Implications for Treatment of Synkinetic Facial Paralysis.

BACKGROUND: Synkinetic patients often fail to produce a satisfactory smile because of antagonistic action of a hypertonic depressor anguli oris muscle and concomitantly weak depressor labii inferioris muscle. This study investigated their neurovascular anatomy to partially explain this paradoxical depressor anguli oris hypertonicity and depressor labii inferioris hypotonicity and delineated consistent anatomical landmarks to assist in depressor anguli oris muscle injection and myectomy. METHODS: Ten hemifaces from five fresh human cadavers were dissected to delineate the neurovascular supply of the depressor anguli oris and depressor labii inferioris muscles in addition to the depressor anguli oris muscle relation to consistent anatomical landmarks. RESULTS: The depressor anguli oris muscle received innervation from both lower buccal and marginal mandibular facial nerve branches, whereas the depressor labii inferioris muscle was solely innervated by marginal mandibular branches. The mandibular depressor anguli oris origin was on average 39 mm wide, and its medial and lateral borders were located 17 mm from the symphysis and 41 mm from the mandibular angle, respectively. The depressor anguli oris fibers consistently passed anterior to the first mandibular molar toward their insertion into the modiolus, which was located 10 mm lateral and 10 mm caudal to the oral commissure. CONCLUSIONS: Depressor anguli oris muscle dual innervation versus depressor labii inferioris single innervation may explain why depressor anguli oris hypertonicity and depressor labii inferioris weakness are commonly observed concomitantly in synkinetic patients. Based on treatment goals, diagnostic percutaneous injection with lidocaine can be performed on the depressor anguli oris muscle along a cutaneous line from the modiolus to the mandibular first molar border, and an intraoral depressor anguli oris myectomy can be performed along that same transmucosal line.

The Effect of Depressor Anguli Oris Muscle Block on Facial Symmetry in Synkinetic Facial Paralysis Patients and Its Role in Preoperative Assessment.

BACKGROUND: Depressor anguli oris muscle hypertonicity in synkinetic facial paralysis patients may have an overpowering antagonistic effect on facial symmetry. Depressor anguli oris muscle block is a crucial diagnostic test before any treatment planning. Presented is the largest patient cohort analysis to date on static and dynamic facial symmetry changes after depressor anguli oris muscle block. METHODS: Unilateral synkinetic patients with depressor anguli oris muscle hypertonicity were included. Resting symmetry and smile modiolus angle, excursion, and exposure of teeth were measured on both synkinetic and healthy hemifaces before and after depressor anguli oris muscle block using Emotrics and FaceGram photographic analyses. RESULTS: Thirty-six patients were included. Before depressor anguli oris block, resting modiolus height was elevated on the synkinetic side (p = 0.047). During open-mouth smile, reduced modiolus angle (p < 0.0001), modiolus excursion (p < 0.0001), and exposure of teeth (p < 0.0001) were observed on the synkinetic hemiface. After depressor anguli oris block, resting modiolus height became symmetric (p = 0.64). During open-mouth smile, modiolus angle and exposure of teeth significantly increased (both p < 0.0001); excursion did not improve on the synkinetic side (p = 0.13) but unexpectedly improved in open-mouth smile on the healthy side (p = 0.0068). CONCLUSIONS: Depressor anguli oris muscle block improved resting symmetry and modiolus angle and exposure of teeth during smile, demonstrating the inhibitory mimetic role of a hypertonic depressor anguli oris muscle in synkinesis. It is a critical diagnostic and communication tool in the assessment and treatment planning of depressor anguli oris muscle hypertonicity, suggesting the potential effects of future depressor anguli oris myectomy. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Surgical Treatment of Upper Extremity Gunshot Injures: An Updated Review.

INTRODUCTION: Firearm morbidity and mortality have been increasing in recent years, and with this, the demand for medical personnel firearm injury treatment knowledge. Extremities contribute to a majority of firearm injuries, with these injuries being particularly complex because of neurovascular proximity within a confined space. Knowledge of firearm mechanism of injury and treatment management options is important for any trauma hand surgeon. Many factors play vital roles in the treatment of complex upper extremity (UE) gunshot wounds (GSWs). The aim of our review and case illustrations is to provide hand surgeons with an up-to-date guide for initial emergent management, soft tissue, bony, and nerve repair and reconstruction. PATIENT AND METHODS: A literature review was conducted in the current management of UE GSW injuries, and 2 specific patient case examples were included. High-energy versus low-energy GSWs were documented and compared, as well as containment injures. Management including soft tissue, bony, and nerve injuries was explored along with patient outcome. Based on these findings, guidelines for GSW management were purposed. CONCLUSION: Gunshot wounds of the UE encompass a group of highly heterogeneous injuries. High-energy wounds are more extensive, and concomitant injuries to bone, vessel, nerve, muscle, and soft tissue are common. Early treatment with adequate debridement, skeletal fixation, and soft tissue coverage is indicated for complex injuries, and antibiotic treatment in the pre-, peri-, and postoperative period is indicated for operative injuries. Soft tissue coverage options include the entire reconstructive ladder, with pattern of injury and considerations of wound characteristics dictating reconstructive choice. There are arguments to using either external or internal bony fixation techniques for bone fracture management, with choice tailored to the patient. For management of nerve injuries, we advocate earlier nerve repair and a shorter duration of observation before secondary reconstruction in selective cases. If transected nerve endings cannot be brought together, nerve autografts of shorter length are recommended to bridge nerve ending gaps. A significant number of patients with GSW fail to make necessary follow-up appointments, which adds to challenges in treatment.

Intraoperative Assessment of DIEP Flap Breast Reconstruction Using Indocyanine Green Angiography: Reduction of Fat Necrosis, Resection Volumes, and Postoperative Surveillance.

BACKGROUND: This study aims to characterize the effect of laser-assisted indocyanine green fluorescence angiography on fat necrosis and flap failure in deep inferior epigastric artery perforator (DIEP) flap breast reconstruction. METHODS: A retrospective review was performed on 1000 free flaps for breast reconstruction at a single center from 2010 to 2017. Indocyanine green angiography was used after completion of recipient-site anastomoses to subjectively assess for areas of hypoperfusion. A multivariable logistical analysis was conducted with 24 demographic and surgical factors and their effects on fat necrosis and flap failure. RESULTS: Five hundred six DIEP flaps were included in the statistical analyses. Thirteen percent of flaps had fat necrosis. Indocyanine green angiography was used for 200 flaps and was independently associated with a decrease in the odds of fat necrosis (OR, 0.38; p = 0.004). There was no reduction in flap failure rates when using indocyanine green angiography (OR, 1.15; p = 0.85). However, there was a decrease in flap loss with increasing venous coupler diameter (OR, 0.031 per 1-mm increase; p = 0.012). The 84.9-g higher weight of resected tissue before inset without indocyanine green angiography versus the weight of the tissue resected with indocyanine green angiography was statistically significant (p = 0.01). Per single incident of fat necrosis, our cohort underwent an additional 0.69 revision procedures, 1.22 imaging studies, 0.77 biopsies, and 1.7 additional oncologic office visits. CONCLUSION: Intraoperative indocyanine green fluorescence angiography decreases the odds of fat necrosis, saves volume when flap trimming at inset, and can significantly reduce the postoperative surveillance burden in DIEP-based breast reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Orbicularis Oculi Muscle Reinnervation Confers Corneal Protective Advantages over Static Interventions Alone in the Subacute Facial Palsy Patient.

BACKGROUND: Corneal protection is a priority in flaccid facial palsy patients. Denervation of the orbicularis oculi muscle results in weak palpebral closure and predisposes patients to severe corneal sequelae. While periorbital static procedures enhance corneal coverage in repose, voluntary closure is only regained through dynamic reinnervation of the muscle. This study aims to elucidate the added effect of dynamic reinnervation of the orbicularis oculi muscle on long-term corneal integrity as well as on dynamic closure of the palpebral aperture. METHODS: Retrospective review was performed on two groups of complete palsy patients: those who received solely periorbital static procedures and those who underwent concomitant orbicularis oculi muscle reinnervation and static lid procedures. Only patients with complete ophthalmic examinations were included. Corneal punctate epithelial erosions in addition to static and dynamic palpebral measurements were serially assessed preoperatively and postoperatively. RESULTS: Of 272 facial palsy patients, 26 fit the inclusion criteria. Eleven patients underwent combined muscle reinnervation involving facial-to-masseteric nerve coaptation in addition to static eye procedures, and 15 patients underwent solely static interventions. Analysis revealed a 65.3 percent lower mean punctate epithelial erosion score in reinnervation patients as compared with static patients when evaluated at more than 9 months postoperatively (p < 0.01). Reinnervation patients were also found to have 25.3 percent greater palpebral aperture closure (p < 0.05) and 32.8 percent higher closure velocity (p < 0.01) compared with static patients. CONCLUSION: In patients with subacute facial palsy, dynamic reanimation of the orbicularis oculi muscle with concomitant static interventions provides lasting corneal protection not seen in patients who receive solely static interventions. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Composite Tissue Preservation.

Composite tissue (CT) preservation is important to outcomes after replant or transplant. Since the first limb replant, the mainstay of preservation has been static cold storage with the amputated part being placed in moistened gauze over ice. Historically, the gold-standard in solid organ preservation has been static cold storage with specialized solution, but this has recently evolved in the last few decades to develop technologies such as machine perfusion and even persufflation. This review explores the impact of cooling and oxygenation on CT, summarizes the work done in the area of CT preservation, discusses lessons learned from our experience in solid organ preservation, and proposes future directions.

Reuse of the Masseteric Nerve for Dynamic Reanimation in Facial Palsy Patients with Previously Failed One-Stage Dynamic Smile Reanimation.

Failed primary dynamic smile reanimation procedures present significant challenges for the patient and surgeon alike. This is particularly true in older patients with a history of previous neck dissection and radiation therapy who underwent previous reconstruction with a free functional muscle transfer innervated with an ipsilateral masseter nerve. The objective of this study was to demonstrate feasibility, describe surgical technique, and assess results of reusing the masseter nerve to reinnervate a new free functional muscle transfer. Patients presenting between 2007 and 2017 to a single center after previously failed dynamic smile reanimation using the masseteric nerve who underwent a salvage dynamic procedure involving reuse of the masseteric nerve were analyzed for demographics, history of radiation therapy or chemotherapy, surgical techniques, and objective measurements using the MEEI Facegram software. The average age was 50 years, the average duration of palsy was 6.2 years, and the average preoperative House-Brackmann score was 6. Causes of palsy included Bell palsy in one, parotid malignancies in two, and a seventh cranial nerve schwannoma in one patient, with two patients requiring radiation therapy preoperatively. Three patients failed to achieve any motion after the first reanimation, and the fourth patient initially achieved excursion; however, because of cancer recurrence and resection of free functional muscle transfer, motion was subsequently lost. Average smile excursion after salvage was 11.32 mm and philtral deviation correction was 1.3 mm. Reusing the masseter nerve for dynamic smile restoration with free functional muscle transfer in previously failed reanimation patients is feasible and may provide successful reanimation. Careful patient evaluation and clear understanding of previous procedures are essential for success. CLINICAL QUESTION/LEVEL OF EVIDENCE:: Therapeutic, IV.

Optimizing Perforator Selection: A Multivariable Analysis of Predictors for Fat Necrosis and Abdominal Morbidity in DIEP Flap Breast Reconstruction.

BACKGROUND: This study aims to elucidate the important predicting factors for fat necrosis and abdominal morbidity in the patient undergoing deep inferior epigastric artery perforator flap reconstruction. METHODS: The authors conducted a retrospective review of 866 free-flap breast reconstructions performed at one institution from 2010 to 2016. Twenty-eight potential predictors were included in multivariable analyses to control for possible confounding interactions. RESULTS: Four hundred nine total deep inferior epigastric artery perforator flaps were included in the statistical analysis. Of these, 14.4 percent had flap fat necrosis, 21.3 percent had an abdominal wound or complication, and 6 percent had an abdominal bulge or hernia. Analysis showed an increase in the odds of fat necrosis with increasing flap weight (OR, 1.002 per 1-g increase; p = 0.0002). A decrease in the odds of fat necrosis was seen with lateral row (OR, 0.29; p = 0.001) and both medial and lateral row perforator flaps (OR, 0.21; p = 0.001), if indocyanine green angiography was used (OR, 0.46; p = 0.04), and with increasing total flow rate of the flap (OR, 0.62 per 1-mm/second increase; p = 0.05). Increased odds of abdominal bulge or hernia were seen with lateral row or both medial and lateral row perforators (OR, 3.21; p = 0.05) versus medial row perforator-based flaps, and with patients who had an abdominal wound postoperatively (OR, 2.59; p = 0.05). CONCLUSIONS: The authors' results suggest that using larger caliber perforators and perforators from the lateral row alone, or in addition to medial row perforators, can decrease fat necrosis more than simply harvesting more perforators alone. However, lateral and both medial and lateral row perforator flaps come at the cost of increasing abdominal bulge rates. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

Facial Reanimation in the Seventh and Eighth Decades of Life.

BACKGROUND: Treatment of facial paralysis in the older population is often relegated to static rather than dynamic reanimation for fear of poor outcomes. This pervasive approach lacks physiologic foundation and is not evidence based. Thus, the authors present an extensive literature review demonstrating weak evidence supporting this misguided concept, followed by detailed outcomes from three centers of the largest reported series to date of patients older than 60 years after reanimation performed using three techniques-lengthening temporalis myoplasty, free functional muscle, and nerve transfers. METHODS: A PubMed search spanning over 40 years identified all reports on reanimation in patients older than 60 years. In addition, detailed demographics, surgical techniques, and outcomes of 30 patients older than 60 years were analyzed. RESULTS: Of 629 articles, only 45 patients were identified, described in case reports or small series, lacking details or consistent long-term follow-up. In the clinical series, average age, preoperative House-Brackmann score, and comorbidities were similar among the groups. Highest excursion was observed in the free functional muscle group, followed by nerve transfer and temporalis myoplasty, averaging 10.4, 6.8, and 3.1 mm, respectively. The most notable philtral deviation correction was in the lengthening temporalis myoplasty group, followed by the free muscle and nerve transfer groups, averaging 5.6, 2.2, and 1.13 mm, respectively. Complication rates were highest in the free functional muscle group. CONCLUSIONS: Facial palsy patients should not be denied dynamic restoration based on age alone. Although surgical technique may vary based on duration of palsy, surgeon experience, and preference, with each presenting advantages and disadvantages, dynamic restoration is feasible regardless of age. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.