Zodasiran, an RNAi Therapeutic Targeting ANGPTL3, for Mixed Hyperlipidemia.

BACKGROUND: Angiopoietin-like 3 (ANGPTL3) inhibits lipoprotein and endothelial lipases and hepatic uptake of triglyceride-rich lipoprotein remnants. ANGPTL3 loss-of-function carriers have lower levels of triglycerides, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and non-HDL cholesterol and a lower risk of atherosclerotic cardiovascular disease than noncarriers. Zodasiran is an RNA interference (RNAi) therapy targeting expression of ANGPTL3 in the liver. METHODS: We conducted a double-blind, placebo-controlled, dose-ranging phase 2b trial to evaluate the safety and efficacy of zodasiran in adults with mixed hyperlipidemia (fasting triglyceride level of 150 to 499 mg per deciliter and either an LDL cholesterol level of ≥70 mg per deciliter or a non-HDL cholesterol level of ≥100 mg per deciliter). Eligible patients were randomly assigned in a 3:1 ratio to receive subcutaneous injections of zodasiran (50, 100, or 200 mg) or placebo on day 1 and week 12 and were followed through week 36. The primary end point was the percent change in the triglyceride level from baseline to week 24. RESULTS: A total of 204 patients underwent randomization. At week 24, substantial mean dose-dependent decreases from baseline in ANGPTL3 levels were observed with zodasiran (difference in change vs. placebo, -54 percentage points with 50 mg, -70 percentage points with 100 mg, and -74 percentage points with 200 mg), and significant dose-dependent decreases in triglyceride levels were observed (difference in change vs. placebo, -51 percentage points, -57 percentage points, and -63 percentage points, respectively) (P<0.001 for all comparisons). Other differences in change from baseline as compared with placebo included the following: for non-HDL cholesterol level, -29 percentage points with 50 mg, -29 percentage points with 100 mg, and -36 percentage points with 200 mg; for apolipoprotein B level, -19 percentage points, -15 percentage points, and -22 percentage points, respectively; and for LDL cholesterol level, -16 percentage points, -14 percentage points, and -20 percentage points, respectively. We observed a transient elevation in glycated hemoglobin levels in patients with preexisting diabetes who received the highest dose of zodasiran. CONCLUSIONS: In patients with mixed hyperlipidemia, zodasiran was associated with significant decreases in triglyceride levels at 24 weeks. (Funded by Arrowhead Pharmaceuticals; ARCHES-2 ClinicalTrials.gov number, NCT04832971.).

Glucagon and GLP-1 receptor dual agonist survodutide for obesity: a randomised, double-blind, placebo-controlled, dose-finding phase 2 trial.

BACKGROUND: Obesity is a widespread and chronic condition that requires long-term management; research into additional targets to improve treatment outcomes remains a priority. This study aimed to investigate the safety, tolerability, and efficacy of glucagon receptor-GLP-1 receptor dual agonist survodutide (BI 456906) in obesity management. METHODS: In this randomised, double-blind, placebo-controlled, dose-finding phase 2 trial conducted in 43 centres in 12 countries, we enrolled participants (aged 18-75 years, BMI ≥27 kg/m2, without diabetes) and randomly assigned them by interactive response technology (1:1:1:1:1; stratified by sex) to subcutaneous survodutide (0·6, 2·4, 3·6, or 4·8 mg) or placebo once-weekly for 46 weeks (20 weeks dose escalation; 26 weeks dose maintenance). The primary endpoint was the percentage change in bodyweight from baseline to week 46. Primary analysis included the modified intention-to-treat population (defined as all randomly assigned patients who received at least one dose of trial medication and who had analysable data for at least one efficacy endpoint) and was based on the dose assigned at randomisation (planned treatment), including all data censored for COVID-19-related discontinuations; the sensitivity analysis was based on the actual dose received during maintenance phase (actual treatment) and included on-treatment data. Safety analysis included all participants who received at least one dose of study drug. The trial is registered with ClinicalTrials.gov (NCT04667377) and EudraCT (2020-002479-37). FINDINGS: Between March 30, 2021, and Nov 11, 2021, we enrolled 387 participants; 386 (100%) participants were treated (0·6 mg, n=77; 2·4 mg, n=78; 3·6 mg, n=77; 4·8 mg, n=77; placebo n=77) and 233 (60·4%) of 386 completed the 46-week treatment period (187 [61%] of 309 receiving survodutide; 46 [60%] of 77 receiving placebo). When analysed according to planned treatment, mean (95% CI) changes in bodyweight from baseline to week 46 were -6·2% (-8·3 to -4·1; 0·6 mg); -12·5% (-14·5 to -10·5; 2·4 mg); -13·2% (-15·3 to -11·2; 3·6 mg); -14·9% (-16·9 to -13·0; 4·8 mg); -2·8% (-4·9 to -0·7; placebo). Adverse events occurred in 281 (91%) of 309 survodutide recipients and 58 (75%) of 77 placebo recipients; these were primarily gastrointestinal in 232 (75%) of 309 survodutide recipients and 32 (42%) of 77 placebo recipients. INTERPRETATION: All tested survodutide doses were tolerated, and dose-dependently reduced bodyweight. FUNDING: Boehringer Ingelheim.

Efficacy of Levothyroxine Sodium Soft Gelatin Capsules in Thyroidectomized Patients Taking Proton Pump Inhibitors: An Open-Label Study.

Background: Treatment with proton pump inhibitors (PPIs) and antacids affects the gastrointestinal absorption of levothyroxine sodium (LT4) tablets. Patients with hypothyroidism taking LT4 and PPIs or antacids, thus, require appropriate monitoring. The objective of this study was to determine whether a soft gelatin capsule of LT4 (Tirosint®) would obviate the effect of PPIs on LT4 absorption. The objective was achieved by assessing the effects of a switch from a conventional LT4 tablet form to the same dose as soft capsules in thyroidectomized patients on treatment with LT4 and PPIs. Methods: Patients with history of hypothyroidism due to total thyroidectomy on stable treatment with LT4 tablets, and with gastrointestinal disease treated with PPIs, were switched to a 12-week treatment with Tirosint at the same dose of the LT4 tablets, while maintaining treatment with PPIs. Serum thyrotropin (TSH) levels were the primary endpoint of the study. Secondary efficacy endpoints were: serum levels of free thyroxine (fT4), total thyroxine (TT4), free triiodothyronine (fT3), total triiodothyronine (TT3), creatine-phosphokinase (CPK), sex-hormone binding globulin, ferritin, angiotensin converting enzyme, and a lipid panel. Results: Forty-seven patients (36 females and 11 males, mean age 55.4 years) were enrolled and 45 of them completed the study (2 patients withdrew consent). During treatment with Tirosint, mean TSH levels demonstrated a statistically significant decrease (mean changes from baseline: -0.32 mIU/L at week 6 and -0.68 mIU/L at week 12) and concomitant increases in thyroid hormone (TH) levels from baseline to week 12, which were statistically significant for fT3 and TT3 (mean changes from baseline: 0.26 pmol/L and 0.10 nmol/L, respectively). Significant decreases of serum low-density lipoprotein, total cholesterol, and CPK levels were observed at week 12. No signs/symptoms arose during the study that could be specifically correlated to either hypo- or hyperthyroidism. Conclusions: In thyroidectomized patients taking PPIs and replacement LT4, a switch from conventional LT4 tablets to LT4 soft capsules at the same dose was associated with a significant decrease in TSH and increase in TH, indicating that LT4 absorption may be less affected by PPIs when given in the form of soft capsules. Clinical Trial Registration: NCT03094416.

Safety and Feasibility of Cervical and Thoracic Transcutaneous Spinal Cord Stimulation to Improve Hand Motor Function in Children With Chronic Spinal Cord Injury.

OBJECTIVE: In adults with cervical spinal cord injury (SCI), transcutaneous spinal stimulation (scTS) has improved upper extremity strength and control. This novel noninvasive neurotherapeutic approach combined with training may modulate the inherent developmental plasticity of children with SCI, providing even greater improvements than training or stimulation alone. Because children with SCI represent a vulnerable population, we first must establish the safety and feasibility of any potential novel therapeutic approach. The objectives of this pilot study were to determine the safety, feasibility, and proof of principle of cervical and thoracic scTS for short-term effect on upper extremity strength in children with SCI. MATERIALS AND METHODS: In this nonrandomized, within-subject repeated measure design, seven participants with chronic cervical SCI performed upper extremity motor tasks without and with cervical (C3-C4 and C6-C7) and thoracic (T10-T11) site scTS. Safety and feasibility of using cervical and thoracic sites scTS were determined by the frequency count of anticipated and unanticipated risks (eg, pain, numbness). Proof-of-principle concept was tested via change in force production during hand motor tasks. RESULTS: All seven participants tolerated cervical and thoracic scTS across the three days, with a wide range of stimulation intensities (cervical sites = 20-70 mA and thoracic site = 25-190 mA). Skin redness at the stimulation sites was observed in four of 21 assessments (19%) and dissipated in a few hours. No episode of autonomic dysreflexia was observed or reported. Hemodynamic parameters (systolic blood pressure and heart rate) remained within stable limits (p > 0.05) throughout the assessment time points at baseline, with scTS, and after the experiment. Hand-grip and wrist-extension strength increased (p < 0.05) with scTS. CONCLUSIONS: We indicated that short-term application of scTS via two cervical and one thoracic site is safe and feasible in children with SCI and resulted in immediate improvements in hand-grip and wrist-extension strength in the presence of scTS. CLINICAL TRIAL REGISTRATION: The Clinicaltrials.gov registration number for the study is NCT04032990.

Tropifexor plus cenicriviroc combination versus monotherapy in nonalcoholic steatohepatitis: Results from the phase 2b TANDEM study.

BACKGROUND AND AIMS: With distinct mechanisms of action, the combination of tropifexor (TXR) and cenicriviroc (CVC) may provide an effective treatment for NASH. This randomized, multicenter, double-blind, phase 2b study assessed the safety and efficacy of TXR and CVC combination, compared with respective monotherapies. APPROACH AND RESULTS: Patients (N = 193) were randomized 1:1:1:1 to once-daily TXR 140 µg (TXR 140 ), CVC 150 mg (CVC), TXR 140 µg + CVC 150 mg (TXR 140 + CVC), or TXR 90 µg + CVC 150 mg (TXR 90 + CVC) for 48 weeks. The primary and secondary end points were safety and histological improvement, respectively. Rates of adverse events (AEs) were similar across treatment groups. Pruritus was the most frequently experienced AE, with highest incidence in the TXR 140 group (40.0%). In TXR and combination groups, alanine aminotransferase (ALT) decreased from baseline to 48 weeks (geometric mean change: -21%, TXR 140 ; -16%, TXR 140 + CVC; -13%, TXR 90 + CVC; and +17%, CVC). Reductions in body weight observed at week 24 (mean changes from baseline: TXR 140 , -2.5 kg; TXR 140 + CVC, -1.7 kg; TXR 90 + CVC, -1.0 kg; and CVC, -0.1 kg) were sustained to week 48. At least 1-point improvement in fibrosis stage/steatohepatitis resolution without worsening of fibrosis was observed in 32.3%/25.8%, 31.6%/15.8%, 29.7%/13.5%, and 32.5%/22.5% of patients in the TXR 140 , CVC, TXR 140 + CVC, and TXR 90 + CVC groups, respectively. CONCLUSIONS: The safety profile of TXR + CVC combination was similar to respective monotherapies, with no new signals. TXR monotherapy showed sustained ALT and body weight decreases. No substantial incremental efficacy was observed with TXR + CVC combination on ALT, body weight, or in histological end points compared with monotherapy.

Activity-Based Restorative Therapy Promotes Progression from Asymmetry to Symmetry in Posture and Gait in a Child with Chronic, Incomplete Spinal Cord Injury.

Incomplete spinal cord injuries (ISCI) in pediatrics and adults can lead to asymmetric motor impairments exhibiting as asymmetries of posture and gait. Recently, rehabilitation guidelines for adults with neurologic injuries have focused on gaining a functional gait pattern as measured by speed and distance, even if asymmetry deficits persist. Activity-based restorative therapies (ABRT) take advantage of activity-dependent neuroplasticity to change an individual's neuromuscular capacity. This is a report of an ambulatory child with chronic ISCI presenting with significant postural and gait asymmetries who enrolled in an ABRT program. Across 79 ABRT sessions, the child gained symmetry during sitting, standing, and walking. Even though this child was a functional ambulator at enrollment, targeting symmetry of movements via improved neuromuscular capacity further enhanced her achievement of kinematically appropriate function for participation in daily activities.

Tropifexor for nonalcoholic steatohepatitis: an adaptive, randomized, placebo-controlled phase 2a/b trial.

The multimodal activities of farnesoid X receptor (FXR) agonists make this class an attractive option to treat nonalcoholic steatohepatitis. The safety and efficacy of tropifexor, an FXR agonist, in a randomized, multicenter, double-blind, three-part adaptive design, phase 2 study, in patients with nonalcoholic steatohepatitis were therefore assessed. In Parts A + B, 198 patients were randomized to receive tropifexor (10-90 µg) or placebo for 12 weeks. In Part C, 152 patients were randomized to receive tropifexor 140 µg, tropifexor 200 µg or placebo (1:1:1) for 48 weeks. The primary endpoints were safety and tolerability to end-of-study, and dose response on alanine aminotransferase (ALT), aspartate aminotransferase (AST) and hepatic fat fraction (HFF) at week 12. Pruritus was the most common adverse event in all groups, with a higher frequency in the 140- and 200-µg tropifexor groups. Decreases from baseline in ALT and HFF were greater with tropifexor versus placebo at week 12, with a relative decrease in least squares mean from baseline observed with all tropifexor doses for ALT (tropifexor 10-90-µg dose groups ranged from -10.7 to -16.5 U l-1 versus placebo (-7.8 U l-1) and tropifexor 140- and 200-µg groups were -18.0 U l-1 and -23.0 U l-1, respectively, versus placebo (-8.3 U l-1)) and % HFF (tropifexor 10-90-µg dose groups ranged from -7.48% to -15.04% versus placebo (-6.19%) and tropifexor 140- and 200-µg groups were -19.07% and -39.41%, respectively, versus placebo (-10.77%)). Decreases in ALT and HFF were sustained up to week 48; however, similar trends in AST with tropifexor at week 12 were not observed. As with other FXR agonists, dose-related pruritus was frequently observed. Clinicaltrials.gov registration: NCT02855164.

Transcutaneous Spinal Stimulation From Adults to Children: A Review.

Neuromodulation via spinal stimulation is a promising therapy that can augment the neuromuscular capacity for voluntary movements, standing, stepping, and posture in individuals with spinal cord injury (SCI). The spinal locomotor-related neuronal network known as a central pattern generator (CPG) can generate a stepping-like motor output in the absence of movement-related afferent signals from the limbs. Using epidural stimulation (EP) in conjunction with activity-based locomotor training (ABLT), the neural circuits can be neuromodulated to facilitate the recovery of locomotor functions in persons with SCI. Recently, transcutaneous spinal stimulation (scTS) has been developed as a noninvasive alternative to EP. Early studies of scTS at thoracolumbar, coccygeal, and cervical regions have demonstrated its effectiveness in producing voluntary leg movements, posture control, and independent standing and improving upper extremity function in adults with chronic SCI. In pediatric studies, the technology of spinal neuromodulation is not yet widespread. There are a limited number of publications reporting on the use of scTS in children and adolescents with either cerebral palsy, spina bifida, or SCI.

Durability of Improved Trunk Control Following Activity-Based Locomotor Training in Children With Acquired Spinal Cord Injuries.

BACKGROUND: A recent study in pediatric spinal cord injury (SCI) demonstrated activity-based locomotor training (ABLT) improved trunk control, measured by the Segmental Assessment of Trunk Control (SATCo). It is not known whether improved trunk control is maintained and, if so, for how long. OBJECTIVES: The purpose was to determine the durability of improvements in trunk control after ABLT is stopped. We hypothesized that SATCo scores at follow-up would not significantly regress (a) beyond the score measured at discharge and (b) to the initial SATCo pre-ABLT level. METHODS: Patients were assessed pre ABLT, after completing an episode of care, and upon returning to the clinic 1 or more months without ABLT. Durability is a score change less than 3, which is the measurement error of the SATCo. RESULTS: Twenty-eight children (10 females; 4 ± 2.5 years old) completed at least 40 sessions of ABLT and returned for the follow-up 8 ± 7 months (range, 1-38) after the episode of care. Trunk control improved 6 ± 3/20 points with ABLT (p < .0001). At the follow-up, average SATCo score decreased 2 ± 2/20 points, and the follow-up SATCo score was 4 ± 3 points higher than pre ABLT (p < .0001). There was no correlation between the change in SATCo scores and changes in age, weight, height or elapsed time between discharge and follow-up. CONCLUSION: Improvements in trunk control due to ABLT were maintained, indicating ABLT is neurotherapeutic. Although not achieving complete recovery of trunk control, the immediate effects and sustained improvements provide support for a clinical shift to neurotherapeutic approaches and for continued research to achieve enhanced recovery.

A Multi-Systems Approach to Human Movement after ACL Reconstruction: The Integumentary System.

Postoperative management of anterior cruciate ligament (ACL) reconstruction has traditionally focused on the evaluation and intervention of musculoskeletal components such as range of motion and patients' reports of function. The integumentary system can provide early indications that rehabilitation may be prolonged due to protracted or poor healing of the incision sites. Full evaluation of the reconstruction over time, including direction of the incisions, appearance of surgical sites, level of residual innervation, and health of the individual should be considered when determining time-based goals and plans for returning an athlete to activity. Skin care techniques should be used to minimize strain and promote wound healing at the surgical sites, which in turn allows for implementation of other interventions that target other body systems such as locomotion, strength training, and cardiopulmonary conditioning. The integration of the integumentary system with cardiovascular, neurological, and muscular systems is required for a successful return to activity. A multi-physiologic systems approach may provide a unique viewpoint when aiming to attain a greater appreciation of the integumentary system and its integration with other body systems following ACL reconstruction. The purpose of this clinical commentary is to discuss integumentary considerations within a multi-physiologic systems approach to human movement after ACL reconstruction, including an anatomical review, key elements of assessment, and integrated intervention strategies. LEVEL OF EVIDENCE: 5.

Acceleration and Jerk After a Jump Stabilization Task in Individuals With and Without Chronic Ankle Instability.

Studies have demonstrated that individuals with chronic ankle instability (CAI) have diminished dynamic stability. Jerk-based measures have been utilized to examine dynamic balance because of their ability to quantify changes in acceleration and may provide an understanding of the postural corrections that occur during stabilizing following a jumping task. The purpose of this study was to compare acceleration and jerk following a jump stabilization task between individuals with CAI and the uninjured controls. Thirty-nine participants volunteered to participate in this case control study. Participants completed a jump stabilization task requiring them to jump off 2 feet, touch a marker set at 50% of their maximal vertical jump height, land on a single limb, and maintain balance for 3 seconds. Acceleration was calculated as the second derivative, and jerk was calculated as the third derivative of the displacement of the resultant vector position. Participants with CAI had greater acceleration (mean difference = 55.6 cm/s2; 95% confidence interval, 10.3 to 100.90; P = .017) and jerk compared with the uninjured controls (mean difference = 1804.5 cm/s3; 95% confidence interval, 98.7 to 3510.3; P = .039). These results suggest that individuals with CAI made faster and more frequent active postural control corrections to regain balance following a jump compared with the uninjured controls.

Correlations of Single-Leg Performance Tests to Patient-Reported Outcomes After Primary Anterior Cruciate Ligament Reconstruction.

OBJECTIVE: To determine the relationship between patient-reported outcomes (PROs) to the single-leg step-down test (SLSD) and the Y-balance anterior reach (YB-A) 6 months after primary anterior cruciate ligament reconstruction (ACLR). DESIGN: Cross-sectional. SETTING: Laboratory. PARTICIPANTS: Sixty-six patients 6 months after ACLR participated. INTERVENTIONS: Patients performed the SLSD, YB-A, and completed PROs after ACLR. MAIN OUTCOME MEASURES: Patients completed the International Knee Documentation Committee Score (IKDC), the Lysholm Activity Scale, the Tampa Scale of Kinesiophobia (TSK-11), and the Knee Injury and Osteoarthritis Outcome Score (KOOS)-Symptom, -Sport, and -Quality of Life (QOL) subscales. The SLSD requires subjects to complete as many single-leg step-downs as possible in 60 seconds, and the YB-A involves reaching anteriorly on a single limb. Pearson product moment correlations were used to assess relationships between the YB-A and SLSD performance to each PRO. RESULTS: Single-leg step-down test symmetry was significantly correlated with the TSK-11 (r = -0.70), KOOS-Sport (r = 0.40), -Symptom (r = 0.46), and -QOL (r = 0.42). The YB-A symmetry was significantly correlated with the KOOS-Symptom (r = 0.30) and KOOS-Sport (r = 0.30). CONCLUSIONS: Single-leg step-down test performance demonstrated stronger relationships to patient-reported knee function than the YB-A. Furthermore, the SLSD symmetry was strongly correlated with fear of movement. The SLSD provides a robust method for clinicians to assess dynamic knee function and may aid in identifying patients who could benefit from intervention to reduce fear of movement or reinjury.

Emricasan to prevent new decompensation in patients with NASH-related decompensated cirrhosis.

BACKGROUND & AIMS: Non-alcoholic steatohepatitis is a leading cause of end-stage liver disease. Hepatic steatosis and lipotoxicity cause chronic necroinflammation and direct hepatocellular injury resulting in cirrhosis, end-stage liver disease and hepatocellular carcinoma. Emricasan is a pan-caspase inhibitor that inhibits excessive apoptosis and inflammation; it has also been shown to decrease portal pressure and improve synthetic function in mice with carbon tetrachloride-induced cirrhosis. METHODS: This double-blind, placebo-controlled study randomized 217 individuals with decompensated NASH cirrhosis 1:1:1 to emricasan (5 mg or 25 mg) or placebo. Patients were stratified by decompensation status and baseline model for end-stage liver disease-sodium (MELD-Na) score. The primary endpoint comprised all-cause mortality, a new decompensation event (new or recurrent variceal hemorrhage, new ascites requiring diuretics, new unprecipitated hepatic encephalopathy ≥grade 2, hepatorenal syndrome, spontaneous bacterial peritonitis), or an increase in MELD-Na score ≥4 points. RESULTS: There was no difference in event rates between either of the emricasan treatment groups and placebo, with hazard ratios of 1.02 (95% CI 0.59-1.77; p = 0.94) and 1.28 (95% CI 0.75-2.21; p = 0.37) for 5 mg and 25 mg of emricasan, respectively. MELD-Na score progression was the most common outcome. There was no significant effect of emricasan treatment on MELD-Na score, international normalized ratio, total serum bilirubin, albumin level or Child-Pugh score. Emricasan was generally safe and well-tolerated. CONCLUSIONS: Emricasan was safe but ineffective for the treatment of decompensated NASH cirrhosis. However, this study may guide the design and conduct of future clinical trials in decompensated NASH cirrhosis. LAY SUMMARY: Patients with decompensated cirrhosis related to non-alcoholic steatohepatitis are at high risk of additional decompensation events and death. Post hoc analyses in previous pilot studies suggested that emricasan might improve portal hypertension and liver function. In this larger randomized study, emricasan did not decrease the number of decompensation events or improve liver function in patients with a history of decompensated cirrhosis related to non-alcoholic steatohepatitis. CLINICALTRIALS. GOV IDENTIFIER: NCT03205345.

20-HETE Enzymes and Receptors in the Neurovascular Unit: Implications in Cerebrovascular Disease.

20-HETE is a potent vasoconstrictor that is implicated in the regulation of blood pressure, cerebral blood flow and neuronal death following ischemia. Numerous human genetic studies have shown that inactivating variants in the cytochrome P450 enzymes that produce 20-HETE are associated with hypertension, stroke and cerebrovascular disease. However, little is known about the expression and cellular distribution of the cytochrome P450A enzymes (CYP4A) that produce 20-HETE or the newly discovered 20-HETE receptor (GPR75) in the brain. The present study examined the cell types and regions in the rat forebrain that express CYP4A and GPR75. Brain tissue slices from Sprague Dawley (SD), Dahl Salt-Sensitive (SS) and CYP4A1 transgenic rat strains, as well as cultured human cerebral pericytes and cerebral vascular smooth muscle cells, were analyzed by fluorescent immunostaining. Tissue homogenates from these strains and cultured cells were examined by Western blot. In the cerebral vasculature, CYP4A and GPR75 were expressed in endothelial cells, vascular smooth muscle cells and the glial limiting membrane of pial arteries and penetrating arterioles but not in the endothelium of capillaries. CYP4A, but not GPR75, was expressed in astrocytes. CYP4A and GPR75 were both expressed in a subpopulation of pericytes on capillaries. The diameters of capillaries were significantly decreased at the sites of first and second-order pericytes that expressed CYP4A. Capillary diameters were unaffected at the sites of other pericytes that did not express CYP4A. These findings implicate 20-HETE as a paracrine mediator in various components of the neurovascular unit and are consistent with 20-HETE's emerging role in the regulation of cerebral blood flow, blood-brain barrier integrity, the pathogenesis of stroke and the vascular contributions to cognitive impairment and dementia. Moreover, this study highlights GPR75 as a potential therapeutic target for the treatment of these devastating conditions.

Enhancement of Drug Seeking Following Drug Taking in a Sexual Context Requires Anterior Cingulate Cortex Activity in Male Rats.

Individual variance in vulnerability to develop addictions is influenced by social factors. Specifically, drug-taking in a sexual context appears to enhance further drug-seeking behavior in human users, as these users identify the effects of drugs to enhance sexual pleasure as a primary reason for continued drug use. Methamphetamine (Meth) is commonly used in this context. Similarly, male rats that self-administered Meth immediately followed by sexual behavior display enhanced drug-seeking behavior, including attenuation of extinction and increased reinstatement to seeking of Meth-associated cues. Hence, drug-taking in a sexual context enhances vulnerability for addiction. However, the neural mechanisms by which this occurs are unknown. Here the hypothesis was tested that medial prefrontal cortex is essential for this effect of Meth and sex when experienced concurrently. First it was shown that CaMKII neurons in the anterior cingulate area (ACA) were co-activated by both Meth and sex. Next, chemogenetic inactivation of ACA CaMKII cells using AAV5-CaMKIIa-hM4Di-mCherry was shown not to affect Meth-induced locomotor activity or sexual behavior. Subsequently, chemogenetic inactivation of ACA CaMKII neurons during Meth self-administration followed by sexual behavior was shown to prevent the effects of Meth and sex on enhanced reinstatement of Meth-seeking but did not affect enhanced drug-seeking during extinction tests. These results indicate that ACA CaMKII cell activation during exposure to Meth in a sexual context plays an essential role in the subsequent enhancement of drug-seeking during reinstatement tests.

Gait deviations and muscle strength deficits in subjects with patellar instability.

BACKGROUND: Abnormal tracking of the patella is a hallmark sign of patellar instability (PI). Gait deviations and strength deficits may exacerbate abnormal tracking. The identification of modifiable gait deviations and strength deficits can aid in developing more effective management strategies for individuals with PI. The purpose of this study was to identify modifiable gait and strength deficits in subjects with PI. METHODS: 32 subjects (16 PI, 16 controls, 3 males/13 females in each group, 21.1 years old, 23.5 BMI), performed an instrumented gait analysis while walking at 1.5 m per second. Subjects' peak hip adduction angles, external rotation angles, hip abduction moments, knee flexion angles, knee adduction angles, and knee extensor moments were measured during walking. Hip abduction, hip external rotation, and knee extension strength were assessed with a handheld dynamometer. RESULTS: Individuals with PI displayed significantly lower peak knee adduction angles (1.8 ± 2.8° PI, 5.5 ± 4.5° control, p < .01) and peak hip abduction moments (0.2 ± 0.1 Nm/kg*m PI, 0.4 ± 0.1 Nm/kg*m control, p < .01). Subjects with PI were weaker in knee extension strength (14.5 ± 4.1 kg/m PI, 23.8 ± 7.2 kg/m control, p < .01), hip abduction strength (12.1 ± 2.0 kg/m PI, 17.8 ± 4.0 kg/m control, p < .01), and hip external rotation strength (5.5 ± 1.9 kg/m PI, 7.1 ± 1.3 kg/m control, p = .01). CONCLUSION: Subjects with patellar instability have smaller joint moments and a more valgus knee position while walking. Coupled with deficits in muscle strength, this likely contributes to subjective reports of chronic patellar instability. LEVEL OF EVIDENCE: III.

A Phase II Open-Label Study of Bermekimab in Patients with Hidradenitis Suppurativa Shows Resolution of Inflammatory Lesions and Pain.

The objective of this study was to evaluate the safety and efficacy of bermekimab, an IL-1α inhibitor, in the treatment of hidradenitis suppurativa (HS). This study was a phase II, multicenter, open-label study of two dose cohorts of bermekimab in patients with moderate-to-severe HS who are naïve to or have failed prior anti-TNF therapy. Patients with HS (n = 42) were divided into groups A and B based on whether or not they had previously failed an anti-TNF therapy. In group A (n = 24), bermekimab was administered subcutaneously at a dose of 400 mg weekly (13 doses) in patients who had previously failed anti-TNF therapy; in group B (n = 18), bermekimab was administered subcutaneously at a dose of 400 mg weekly (13 doses) in patients who were anti-TNF naïve. Bermekimab, previously found to be effective in treating HS, was evaluated using a subcutaneous formulation in patients with HS naïve to or having failed anti-TNF therapy. There were no bermekimab-related adverse events with the exception of injection site reactions. Bermekimab was effective despite treatment history, with 61% and 63% of patients naïve to and having failed anti-TNF therapy, respectively, achieving HS clinical response after 12 weeks of treatment. A significant reduction in abscesses and inflammatory nodules of 60% (P < 0.004) and 46% (P < 0.001) was seen in anti-TNF naïve and anti-TNF failure groups, respectively. Clinically and statistically significant reduction was seen in patients experiencing pain, with the Visual Analogue Scale pain score reducing by 64% (P < 0.001) and 54% (P < 0.001) in the anti-TNF naïve and anti-TNF failure groups, respectively. IL-1α is emerging as an important clinical target for skin disease, and bermekimab may represent a new therapeutic option for treating moderate-to-severe HS.

Effect of Blood Flow Restriction Training on Quadriceps Muscle Strength, Morphology, Physiology, and Knee Biomechanics Before and After Anterior Cruciate Ligament Reconstruction: Protocol for a Randomized Clinical Trial.

BACKGROUND: Despite best practice, quadriceps strength deficits often persist for years after anterior cruciate ligament reconstruction. Blood flow restriction training (BFRT) is a possible new intervention that applies a pressurized cuff to the proximal thigh that partially occludes blood flow as the patient exercises, which enables patients to train at reduced loads. This training is believed to result in the same benefits as if the patients were training under high loads. OBJECTIVE: The objective is to evaluate the effect of BFRT on quadriceps strength and knee biomechanics and to identify the potential mechanism(s) of action of BFRT at the cellular and morphological levels of the quadriceps. DESIGN: This will be a randomized, double-blind, placebo-controlled clinical trial. SETTING: The study will take place at the University of Kentucky and University of Texas Medical Branch. PARTICIPANTS: Sixty participants between the ages of 15 to 40 years with an ACL tear will be included. INTERVENTION: Participants will be randomly assigned to (1) physical therapy plus active BFRT (BFRT group) or (2) physical therapy plus placebo BFRT (standard of care group). Presurgical BFRT will involve sessions 3 times per week for 4 weeks, and postsurgical BFRT will involve sessions 3 times per week for 4 to 5 months. MEASUREMENTS: The primary outcome measure was quadriceps strength (peak quadriceps torque, rate of torque development). Secondary outcome measures included knee biomechanics (knee extensor moment, knee flexion excursion, knee flexion angle), quadriceps muscle morphology (physiological cross-sectional area, fibrosis), and quadriceps muscle physiology (muscle fiber type, muscle fiber size, muscle pennation angle, satellite cell proliferation, fibrogenic/adipogenic progenitor cells, extracellular matrix composition). LIMITATIONS: Therapists will not be blinded. CONCLUSIONS: The results of this study may contribute to an improved targeted treatment for the protracted quadriceps strength loss associated with anterior cruciate ligament injury and reconstruction.

Three-dimensional imaging of KNDy neurons in the mammalian brain using optical tissue clearing and multiple-label immunocytochemistry.

Kisspeptin/Neurokinin B/Dynorphin (KNDy) neurons of the arcuate nucleus (ARC) play a key role in the regulation of fertility. The ability to detect features of KNDy neurons that are essential for fertility may require three-dimensional (3D) imaging of the complete population. Recently developed protocols for optical tissue clearing permits 3D imaging of neuronal populations in un-sectioned brains. However, these techniques have largely been described in the mouse brain. We report 3D imaging of the KNDy cell population in the whole rat brain and sheep hypothalamus using immunolabelling and modification of a solvent-based clearing protocol, iDISCO. This study expands the use of optical tissue clearing for multiple mammalian models and provides versatile analysis of KNDy neurons across species. Additionally, we detected a small population of previously unreported kisspeptin neurons in the lateral region of the ovine mediobasal hypothalamus, demonstrating the ability of this technique to detect novel features of the kisspeptin system.

Hemoglobin Level at Stage 1 Discharge has No Impact on Inter-stage Growth and Stability in Single Ventricle Infants.

Hemoglobin levels (Hgb) of infants with a single ventricle (SV) are traditionally maintained high to maximize oxygen-carrying capacity during stage 1 palliation (S1P), stage 2 palliation (S2P), and between stages (IS). A single-center observational cohort study was performed to determine if red blood cell transfusion during the convalescent phase of the S1P (late S1P transfusion) to achieve higher Hgb is associated with benefits during the IS including improved growth and decreased acute medical events. 137 infants <1 year with SV with SIP undergoing care from January 2008 to June 2015 were retrospectively evaluated. 78 (57%) infants received a late S1P transfusion. Median Hgb at S1P discharge was 15.9 g/dL (IQR 14.7-17.1) and median Hgb S2P at admission was 15.3 g/dL (IQR 14-16.3). Median daily weight gain was 22 g/day during IS (IQR 17-26) and median daily length gain was 0.09 cm (IQR 0.06-0.11). Hgb at SIP discharge was not associated with IS growth or fewer IS acute events. However, late S1P transfusions were associated with illness severity at S1P and more complicated S1P care. Our data suggest that SV infants after S1P, who are steadily recovering, do not benefit from late transfusion to raise their hemoglobin level at discharge.