ADDITIONAL PNEUMATIC RETINOPEXY IN PATIENTS WITH PERSISTENT RETINAL DETACHMENT AFTER SCLERAL BUCKLING.

PURPOSE: To investigate the efficacy, safety, and indications for additional pneumatic retinopexy (PR) in patients with persistent retinal detachment after scleral buckling. METHODS: This retrospective study included patients who underwent additional PR after scleral buckling for primary rhegmatogenous retinal detachment (n = 78). We defined "inadequate buckle" as retinal detachment persistence because of low buckle height despite accurate buckle placement and "buckle misplacement" as an uncovered tear because of incorrect buckle placement. RESULTS: The anatomical success rate after additional PR was 52.6%. Development of proliferative vitreoretinopathy Grade B (hazard ratio, 5.73; P < 0.001) and inferior retinal tears (hazard ratio, 2.12; P = 0.040) were significant risk factors for anatomical failure. The most common cause of anatomical failure was proliferative vitreoretinopathy (19 of 37; 51.4%), and epiretinal membrane formation was a common complication after additional PR (22 of 78; 28.2%). The anatomical success rate with additional PR was significantly higher in the inadequate buckle group than in the misplacement group (8 of 9 [88.9%] vs. 1228 [42.9%]; P = 0.023). CONCLUSION: Development of proliferative vitreoretinopathy Grade B and inferior retinal tears were significantly associated with anatomical failure after additional PR. Additional PR may benefit patients with superior retinal tears or low buckle height and those without proliferative vitreoretinopathy.

Targeting E3 ubiquitin ligases and their adaptors as a therapeutic strategy for metabolic diseases.

Posttranslational modification of proteins via ubiquitination determines their activation, translocation, dysregulation, or degradation. This process targets a large number of cellular proteins, affecting all biological pathways involved in the cell cycle, development, growth, and differentiation. Thus, aberrant regulation of ubiquitination is likely associated with several diseases, including various types of metabolic diseases. Among the ubiquitin enzymes, E3 ubiquitin ligases are regarded as the most influential ubiquitin enzymes due to their ability to selectively bind and recruit target substrates for ubiquitination. Continued research on the regulatory mechanisms of E3 ligases and their adaptors in metabolic diseases will further stimulate the discovery of new targets and accelerate the development of therapeutic options for metabolic diseases. In this review, based on recent discoveries, we summarize new insights into the roles of E3 ubiquitin ligases and their adaptors in the pathogenesis of metabolic diseases by highlighting recent evidence obtained in both human and animal model studies.

Antioxidant Properties of Kombucha Made with Tartary Buckwheat Tea and Burdock Tea.

Kombucha is a beverage fermented by SCOBY, which is a symbiotic culture of bacteria and yeast. Recently, kombucha has received significant attention due to its health benefits, which include antioxidant and anti-obesity effects. In this study, we investigated the characteristics of kombucha made with Tartary buckwheat and burdock, both known for their high polyphenols content. First, the total polyphenol content and antioxidant activity were measured by 2,2-diphenyl-1-picrylhydrazyl and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radical scavenging assays, which revealed a polyphenol content of 180 ug/mL in Tartary buckwheat kombucha and a high radical scavenging ability of over 90% in both kombucha preparations. Analysis of the changes in the organic acid content during fermentation revealed increases in various organic acid contents, such as glucuronic acid, lactic acid, and acetic acid. Glucuronic acid, especially, which has many functional properties in health, was found to be produced at a concentration of 4.03 g/L in Tartary buckwheat kombucha. Pancreatic lipase inhibitory ability analysis revealed inhibitory effects of 40.47% and 57.68% for Tartary buckwheat and burdock kombucha, respectively. The results of this study confirmed the antioxidant and anti-obesity effects of kombucha made from Tartary buckwheat and burdock, indicating the potential value of these ingredients as functional kombucha ingredients.

Synthesis and biological evaluation of novel N-benzyltriazolyl-hydroxamate derivatives as selective histone deacetylase 6 inhibitors.

Histone deacetylases (HDAC) regulate post-translational acetylation and the inhibition of these enzymes has emerged as an intriguing disease therapeutic. Among them, class IIb HDAC6 has the unique characteristic of mainly deacetylating cytoplasmic proteins, suggesting clinical applications for neurodegenerative diseases, inflammation, and cancer. In this study, we designed a novel N-benzyltriazolyl-hydroxamate scaffold based on the known HDAC6 inhibitors nexturastat A and tubastatin A. Among the 27 derivatives, 3-fluoro-4-((3-(2-fluorophenyl)-1H-1,2,4-triazol-1-yl)methyl)-N-hydroxybenzamide 4u (HDAC6 IC50 = 7.08 nM) showed nanomolar HDAC6 inhibitory activity with 42-fold selectivity over HDAC1. Structure-activity relationship (SAR) and computational docking studies were conducted to optimize the triazole capping group. Docking analysis revealed that the capping group aligned with the conserved L1 pocket of HDAC6 and was associated with subtype selectivity. Overall, our study explored the triazole-based biaryl capping group and its substitution and orientation, suggesting a rationale for the design of HDAC6-selective inhibitors.

Hepatocyte Kctd17 Inhibition Ameliorates Glucose Intolerance and Hepatic Steatosis Caused by Obesity-induced Chrebp Stabilization.

BACKGROUND & AIMS: Obesity predisposes to type 2 diabetes (T2D) and nonalcoholic fatty liver disease (NAFLD), but underlying mechanisms are incompletely understood. Potassium channel tetramerization domain-containing protein 17 (Kctd17) levels are increased in livers from obese mice and humans. In this study, we investigated the mechanism of increased Kctd17 and whether it is causal to obesity-induced metabolic complications. METHODS: We transduced Rosa26-LSL-Cas9 knockin mice with AAV8-TBG-Cre (Control), AAV8-U6-Kctd17 sgRNA-TBG-Cre (L-Kctd17), AAV8-U6-Oga sgRNA-TBG-Cre (L-Oga), or AAV8-U6-Kctd17/Oga sgRNA-TBG-Cre (DKO). We fed mice a high-fat diet (HFD) and assessed for hepatic glucose and lipid homeostasis. We generated Kctd17, O-GlcNAcase (Oga), or Kctd17/Oga-knockout hepatoma cells by CRISPR-Cas9, and Kctd17-directed antisense oligonucleotide to test therapeutic potential in vivo. We analyzed transcriptomic data from patients with NAFLD. RESULTS: Hepatocyte Kctd17 expression was increased in HFD-fed mice due to increased Srebp1c activity. HFD-fed L-Kctd17 or Kctd17 antisense oligonucleotide-treated mice show improved glucose tolerance and hepatic steatosis, whereas forced Kctd17 expression caused glucose intolerance and hepatic steatosis even in lean mice. Kctd17 induced Oga degradation, resulting in increasing carbohydrate response element-binding protein (Chrebp) protein, so concomitant Oga knockout negated metabolic benefits of hepatocyte Kctd17 deletion. In patients with NAFLD, KCTD17 messenger RNA was positively correlated with expression of Chrebp target and other lipogenic genes. CONCLUSIONS: Srebp1c-induced hepatocyte Kctd17 expression in obesity disrupted glucose and lipid metabolism by stabilizing Chrebp, and may represent a novel therapeutic target for obesity-induced T2D and NAFLD.

Paradoxical carbon dioxide embolism during laparoscopic hepatectomy without intracardiac shunt: A case report.

BACKGROUND: Laparoscopic hepatectomy has recently become popular because it results in less bleeding than open hepatectomy. However, CO2 embolism occurs more frequently. Most CO2 embolisms during laparoscopic surgery are self-resolving and non-symptomatic; however, severe CO2 embolism may cause hypotension, cyanosis, arrhythmia, and cardiovascular collapse. In particular, paradoxical CO2 embolisms are highly likely to cause neurological deficits. We report a case of paradoxical CO2 embolism found on transesophageal echocardiography (TEE) during laparoscopic hepatectomy, although the patient had no intracardiac shunt. CASE SUMMARY: A 71-year-old man was admitted for laparoscopic left hemihepatectomy. During left hepatic vein ligation, the inferior vena cava was accidentally torn. We observed a sudden drop in oxygen saturation to 85%, decrease in systolic blood pressure (SBP) below 90 mmHg, and reduction in end-tidal CO2 to 24 mmHg. A "mill-wheel" murmur was auscultated over the precordium. The fraction of inspired oxygen was increased to 100% with 5 cmH2O of positive end-expiratory pressure (PEEP) and hyperventilation was maintained. Norepinephrine infusion was increased to maintain SBP above 90 mmHg. A TEE probe was inserted, revealing gas bubbles in the right side of the heart, left atrium, left ventricle, and ascending aorta. The surgeon reduced the pneumoperitoneum pressure from 17 to 14 mmHg and repaired the damaged vessel laparoscopically. Thereafter, the patient's hemodynamic status stabilized. The patient was transferred to the intensive care unit, recovering well without complications. CONCLUSION: TEE monitoring is important to quickly determine the presence and extent of embolism in patients undergoing laparoscopic hepatectomy.

Total Synthesis of Eliglustat via Diastereoselective Amination of Chiral para-Methoxycinnamyl Benzyl Ether.

Eliglustat (Cerdelga®, Genzyme Corp. Cambridge, MA, USA) is an approved drug for a non-neurological type of Gaucher disease. Herein, we describe the total synthesis of eliglustat 1 starting from readily available 1,4-benzodioxan-6-carbaldehyde via Sharpless asymmetric dihydroxylation and diastereoselective amination of chiral para-methoxycinnamyl benzyl ethers using chlorosulfonyl isocyanate as the key steps. Notably, the reaction between syn-1,2-dibenzyl ether 6 and chlorosulfonyl isocyanate in the mixture of toluene and hexane (10:1) afforded syn-1,2-amino alcohol 5 at a 62% yield with a diastereoselectivity > 20:1. This observation can be explained by competition between the SNi and the SN1 mechanisms, leading to the retention of stereochemistry.

TMI-1, TNF-α-Converting Enzyme Inhibitor, Protects Against Paclitaxel-Induced Neurotoxicity in the DRG Neuronal Cells In Vitro.

Background: Chemotherapy-induced peripheral neuropathy (CIPN) negatively impacts cancer survivors' quality of life and is challenging to treat with existing drugs for neuropathic pain. TNF-α is known to potentiate TRPV1 activity, which contributes to CIPN. Here, we assessed the role of TMI-1, a TNF-α-converting enzyme inhibitor, in paclitaxel (PAC)-induced neurotoxicity in dorsal root ganglion (DRG) cells. Materials and Methods: Immortalized DRG neuronal 50B11 cells were cultured and treated with PAC or PAC with TMI-1 following neuronal differentiation. Cell viability, analysis of neurite growth, immunofluorescence, calcium flow cytometry, western blotting, quantitative RT-PCR, and cytokine quantitation by ELISA were performed to determine the role of TMI-1 in neurotoxicity in neuronal cells. Results: PAC administration decreased the length of neurites and upregulated the expression of TRPV1 in 50B11 cells. TMI-1 administration showed a protective effect by suppressing inflammatory signaling, and secretion of TNF-α. Conclusion: TMI-1 partially protects against paclitaxel-induced neurotoxicity by reversing the upregulation of TRPV1 and decreasing levels of inflammatory cytokines, including TNF-α, IL-1ß, and IL-6 in neuronal cells.

Transient involuntary movement disorder after spinal anesthesia: A case report.

BACKGROUND: Spinal anesthesia is commonly used for various surgeries. While many complications occur after induction of spinal anesthesia, involuntary movement is an extremely rare complication. CASE SUMMARY: Herein, we report the case of a 54-year-old healthy male patient who experienced involuntary movements after intrathecal injection of local anesthetics. This patient had undergone metal implant removal surgery in both the lower extremities; 7 h after intrathecal hyperbaric bupivacaine administration, involuntary raising of the left leg began to occur every 2 min. When the movement disorder appeared, the patient was conscious and cooperative. No other specific symptoms were noted in the physical examination conducted immediately after the involuntary leg raising started; moreover, the patient's motor and sensory assessments were normal. The symptom gradually subsided. Twelve hours after the symptom first occurred, its frequency decreased to approximately once every three hours. Two days postoperatively, the symptoms had completely disappeared without intervention. CONCLUSION: Anesthesiologists should be aware that movement disorders can occur after spinal anesthesia and be able to identify the cause, such as electrolyte imbalance or epilepsy, since immediate action may be required for treatment. Furthermore, it is crucial to know that involuntary movement that develop following spinal anesthesia is mostly self-limiting and may not require additional costly examinations.

Synthesis and biological evaluation of novel purinyl quinazolinone derivatives as PI3Kδ-specific inhibitors for the treatment of hematologic malignancies.

Phosphatidylinositol 3-kinases (PI3Ks) mediate intracellular signal transduction. Aberrant PI3K signaling is associated with oncogenesis and disease progression in solid tumors and hematologic malignancies. Idelalisib (1), a first-in-class PI3Kδ inhibitor for the treatment of hematologic malignancies, was developed, but its sales were limited by black box warnings due to unexpected adverse effects. Therefore, to overcome these adverse events, various quinazolinone derivatives were synthesized and evaluated in vitro based on their inhibitory activity against the PI3K enzyme and the viability of cell lines such as MOLT and SUDHL. Among them, 6f (IC50 = 0.39 nM) and 6m (IC50 = 0.09 nM) showed excellent enzyme activity, and 6m displayed an approximately four-fold higher selectivity for PI3Kγ/δ compared with Idelalisib (1). Furthermore, in vivo PK experiments with 6f and 6m revealed that 6f (AUClast = 81.04 h*ng/mL, Cmax = 18.34 ng/mL, Tmax = 0.5 h, t1/2 = 10.2 h in 1 mpk dose) had improved PK compared with 1. Finally, further experiments will be conducted with 6f selected as a candidate, and the potential for it to be developed as a treatment with good efficacy for hematologic malignancies will be determined.

Concealed congenital long QT syndrome during velopharyngeal dysfunction correction: a case report.

The congenital long QT syndrome (LQTS) is an inherited cardiac disorder characterized by increased QT intervals and a tendency to experience ventricular tachycardia, which can cause fainting, heart failure, or sudden death. A 4-year-old female patient undergoing velopharyngeal correction surgery under general anesthesia suddenly developed Torsades de pointes. Although the patient spontaneously resolved to sinus rhythm without treatment, subsequent QT prolongation persisted. Here, we report a case of concealed LQTS with a literature review.

Synthesis and biological evaluation of quinoxaline derivatives as specific c-Met kinase inhibitors.

A series of novel quinoxaline derivatives were synthesized and evaluated for their inhibitory activity against c-Met kinase enzyme. Most of the tested compounds exhibited potent inhibitory activity. All the synthesized quinoxaline compounds were further examined against c-Met overexpressed human gastric cancer cell line (MKN-45), which showed good inhibitory activity. Among the synthesized compounds, compound 4 exhibited better tumor growth inhibition in the animal model study; we also confirmed its acceptable drug property and highly selective target activity.

Efficacy of vitrectomy combined with an intraoperative dexamethasone implant in refractory diabetic macular edema.

AIMS: To evaluate the safety and efficacy of vitrectomy combined with an intraoperative dexamethasone (Ozurdex®) implant in refractory diabetic macular edema (DME). METHODS: Patients who were diagnosed at our institution as having DME refractory to more than 6 months of non-surgical treatment and underwent intravitreal dexamethasone implantation combined with vitrectomy. All patients were followed up for more than 12 months. Best-corrected visual acuity (BCVA, logMAR), central macular thickness (CMT), and intraocular pressure at the initial visit and 1, 3, 4, 6, and 12 months after treatment were recorded. RESULTS: Twenty-two eyes (22 patients) were included in this study. The mean preoperative BCVA was 0.68 and the mean CMT was 470.80 µm. The total number of the previous injections was 5.1 ± 1.6. The mean BCVA was significantly improved at all visits, and the mean CMT was also significantly reduced (p < 0.05). Sixteen eyes (73%) did not need additional implantations during follow-up. CONCLUSIONS: Vitrectomy combined with an intraoperative dexamethasone (Ozurdex) implant was an effective and safe treatment option in patients with refractory DME.

Gene expression profiles of immune-regulatory genes in whole blood of cattle with a subclinical infection of Mycobacterium avium subsp. paratuberculosis.

Johne's disease is a chronic wasting disease of ruminants caused by Mycobacterium avium subsp. paratuberculosis (MAP), resulting in inflammation of intestines and persistent diarrhea. The initial host response against MAP infections is mainly regulated by the Th1 response, which is characterized by the production of IFN-γ. With the progression of disease, MAP can survive in the host through the evasion of the host's immune response by manipulating the host immune response. However, the host response during subclinical phases has not been fully understood. Immune regulatory genes, including Th17-derived cytokines, interferon regulatory factors, and calcium signaling-associated genes, are hypothesized to play an important role during subclinical phases of Johne's disease. Therefore, the present study was conducted to analyze the expression profiles of immune regulatory genes during MAP infection in whole blood. Different expression patterns of genes were identified depending on the infection stages. Downregulation of IL-17A, IL-17F, IL-22, IL-26, HMGB1, and IRF4 and upregulation of PIP5K1C indicate suppression of the Th1 response due to MAP infection and loss of granuloma integrity. In addition, increased expression of IRF5 and IRF7 suggest activation of IFN-α/ß signaling during subclinical stages, which induced indoleamine 2,3-dioxygenase mediated depletion of tryptophan metabolism. Increased expression of CORO1A indicate modulation of calcium signaling, which enhanced the survival of MAP. Taken together, distinct host gene expression induced by MAP infection indicates enhanced survival of MAP during subclinical stages.

Total Synthesis and Anti-inflammatory Evaluation of Penchinone A and Its Structural Analogues.

The first total synthesis and biological evaluation of penchinone A and its structural analogues are described. The key steps for the preparation of penchinone A derivatives involve the oxime-directed palladium(II)-catalyzed oxidative acylation, Claisen rearrangement, and base-mediated olefin migration. This transformation efficiently provides a range of allyl-substituted biaryl ketones with site-selectivity and functional group compatibility. In addition, all synthetic compounds were screened for anti-inflammatory activity against nitric oxide (NO), tumor necrosis factor alpha (TNF-α), and interleukin-6 (IL-6) with lipopolysaccharide (LPS)-induced RAW264.7 cells. Generally, a range of penchinone A derivatives potently inhibited NO, TNF-α, and IL-6 productions, compared to dexamethasone as a positive control. Notably, penchinone A (8g) and its derivatives (8e and 8f) were found to exhibit anti-inflammatory activity stronger than that of dexamethasone.

Radiologic and Clinical Courses of Degenerative Lumbar Scoliosis (10°-25°) after a Short-Segment Fusion.

STUDY DESIGN: Retrospective study. PURPOSE: We report the surgical outcomes of small degenerative lumbar scoliosis (DLS) patients treated by a short-segment fusion and followed for a minimum of 5 years. OVERVIEW OF LITERATURE: Several surgical options are available for the treatment of DLS, such as decompression only, decompression plus a short-segment fusion, or decompression with a long segment fusion. Few studies have evaluated the results of a short-segment fusion in patients with DLS over time. METHODS: Seventy small DLS patients (Cobb's angle, 10°-25°) with a minimum follow-up of 5 years were treated with a short-segment fusion between March 2004 and February 2010. The mean patient age was 71 (male:female=16:54), with a follow-up of 6.5 years (range, 5.0-11.6). The Cobb's angle, 1 and 2 segment coronal upper intervertebral angle, 1 and 2 segment sagittal upper intervertebral angle, the lumbar lordosis angle, and the C7 plumb lines (coronal and sagittal) were evaluated using simple radiographs, and visual analog scale (VAS), back pain was assessed preoperatively, immediately after surgery, and at 3, 6, and 12 months and 3 and 5 years after surgery. To identify factors influencing the radiologic progression, age, number of fusion segments, vertebral levels of fusion, body mass index, lowest instrumented vertebra (L5 or S1), bone mineral density (>-2.5, ≤-2.5), and the presence of an interbody fusion were analyzed. RESULTS: The Cobb's angle and 1 segment coronal upper intervertebral angle showed more progression during follow up, particularly at 6 and 12 months after surgery. Clinical outcomes and radiological results were found to be significantly associated (p=0.041). No statistically significant association was found between other factors affecting radiologic progression from postoperative 6 months to 1 year. CONCLUSIONS: Radiologic variables (the Cobb's angle and coronal upper intervertebral angle-1) should be carefully considered and clinical caution exercised from 6 to 12 months after short-segment fusion in small DLS (10°-25°).

Efficacy of pretreating oil palm fronds with an acid-base mixture catalyst.

Oil palm fronds are abundant but recalcitrant to chemical pretreatment. Herein, an acid-base mixture was applied as a catalyst to efficiently pretreat oil palm fronds. Optimized conditions for the pretreatment were a 0.1M acidic acid-base mixture and 3min ramping to 190°C and 12min holding. The oil palm fronds pretreated and washed with the acid-base mixture exhibited an enzymatic digestibility of 85% by 15 FPU Accellerase 1000/g glucan after 72h hydrolysis, which was significantly higher than the enzymatic digestibilities obtained by acid or alkali pretreatment alone. This could be attributed to the synergistic actions of the acid and base, producing an 87% glucose recovery with 100% and 40.3% removal of xylan and lignin, respectively, from the solids. Therefore, an acid-base mixture can be a feasible catalyst to deconstruct oil palm fronds for sugar production.

Synthesis and anti-inflammatory evaluation of N-sulfonyl anthranilic acids via Ir(III)-catalyzed C-H amidation of benzoic acids.

The iridium(III)-catalyzed ortho-C-H amidation of benzoic acids with sulfonyl azides is described. These transformations allow the facile generation of N-sulfonyl anthranilic acids, which are known as crucial scaffolds found in biologically active molecules. In addition, all synthetic products were evaluated for in vitro anti-inflammatory activity against interleukin-1ß (IL-1ß) and cyclooxygenase-2 (COX-2) with lipopolysaccharide (LPS)-induced RAW264.7 cells. Notably, compounds 4c and 4d, generated from p-OMe- and p-Br-sulfonyl azides, were found to display potent anti-inflammatory property stronger than that of well-known NSAIDs ibuprofen.

Rhodium-Catalyzed [3 + 2] Annulation of Cyclic N-Acyl Ketimines with Activated Olefins: Anticancer Activity of Spiroisoindolinones.

The rhodium(III)-catalyzed redox-neutral coupling reaction of N-acyl ketimines generated in situ from 3-hydroxyisoindolinones with various activated olefins is described. This approach leads to the synthesis of bioactive spiroisoindolinone derivatives in moderate to high yields. In the case of internal olefins such as maleimides, maleates, fumarates, and cinnamates, spiroindanes were obtained by the [3 + 2] annulations reaction. In sharp contrast, acrylates and quinones displayed the ß-H elimination followed by Prins-type cyclization furnishing spiroindenes. The synthetic compounds were evaluated for in vitro anticancer activity against androgen-sensitive human prostate adenocarcinoma cells (LNCaP), human prostate adenocarcinoma cells (DU145), human endometrial adenocarcinoma cells (Ishikawa), human breast cancer cell (MCF-7), and triple negative human breast cancer cells (MDA-MB-231). Notably, quinone-containing spiroindenes displayed potent anticancer activity about 2- to 3-fold stronger than that of anticancer agent doxorubicin.

Does the Effect of Inferior Turbinate Outfracture Persist?

BACKGROUND: To resolve nasal obstruction in rhinoplasty, inferior turbinate outfracture is performed widely alone or combined with other procedures. There are conflicting reports on the effect of inferior turbinate outfracture. This study evaluated the persistence of morphologic changes after inferior turbinate outfracture. METHODS: This retrospective study enrolled 55 patients who underwent inferior turbinate outfracture without septal surgery to approach the sphenoid sinus for brain tumor removal. Coronal paranasal sinus computed tomographic images obtained preoperatively and 6 months postoperatively were compared. The authors measured the shortest distance from the median line to the medial border of the conchal bone and the shortest distance from the medial border of the conchal bone to the lateral nasal line. The authors also gauged the projection angle of the conchal bone and constitutional thickness of the inferior turbinate. RESULTS: After inferior turbinate outfracture, the shortest distance from the median line to the medial border of the conchal bone increased, and shortest distance from the medial border of the conchal bone to the lateral nasal line decreased. The projection angle decreased significantly by 6 months postoperatively. After outfracture, the thickness of the medial mucosa had increased significantly, wheras the thickness of the conchal bone had decreased significantly (p < 0.05). CONCLUSIONS: The effect of inferior turbinate outfracture is preserved for at least 6 months. Moreover, compensatory hypertrophy of the medial mucosa develops in the inferior turbinate after outfracture. Therefore, outfracture with medial submucosal volume reduction would be recommended as the best procedure for treating inferior turbinate hypertrophy. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.