Sham Injection Research Articles

Phillyrin Prevents Ovariectomy-Induced Osteolysis by Inhibiting Osteoclast Differentiation.

Postmenopausal osteoporosis is a metabolic disease caused by an imbalance between osteoclasts and osteoblasts. At present, the drug strategy for treating postmenopausal osteoporosis has some limitations and is unable to satisfy the demands of patients. Phillyrin (Phil) is an herbal extract from Forsythiae Fructus, with an inhibitory effect on osteolysis. In this study, we described the role of Phil in ovariectomy-induced osteoporosis and its effect on osteoclast differentiation in vitro. Eighteen female C57BL/6 mice were randomly divided into three groups: sham group (sham surgery and injection with 0.9% normal saline), ovariectomized group (ovariectomy and injection with 0.9% normal saline), and Phil group (ovariectomy and injecting Phil with 100 mg/kg for 2 days). Mice were sacrificed after 6-week Phil administration and femurs were harvested for microcomputed tomography (micro-CT) and histomorphology analyses. In vitro, we used different concentrations of Phil to study its effect on osteoclastogenesis. The results showed that the BV/TV, Tb.Th, and Tb.N in trabecular bone were increased in the Phil group compared with the OVX group, and the trabecular bone mass was remarkably decreased in the OVX group compared with the sham group. The number of osteoclasts was increased in the OVX group compared to the sham group, and the number and area of osteoclasts were decreased in the Phil group compared to the control group. Compared with the OVX group, the number and area of osteoclasts were reduced in the Phil group. In conclusion, Phil could inhibit the formation of osteoclasts, promote the growth of bone trabecular, and relieve osteoporosis caused by ovariectomy, with a certain clinical adoption value.

Pulsed-Focused Ultrasound Provides Long-Term Suppression of Epileptiform Bursts in the Kainic Acid-Induced Epilepsy Rat Model

Focused ultrasound (FUS) has potential utility for modulating regional brain excitability and possibly aiding seizure control; however, the duration of any beneficial effect is unknown. This study explores the efficacy and time course of a short series of pulsed FUS in suppressing EEG epileptiform spikes/bursts in a kainic acid (KA) animal model of temporal lobe epilepsy. Forty-four male Sprague–Dawley rats were recorded for 14 weeks with EEG while software calculated EEG numbers of epileptiform spikes and bursts (≥ 3 spikes/s). Four regimens of FUS given in a single session at week 7 were evaluated, with mechanical index (MI) ranging from 0.25 to 0.75, intensity spatial peak temporal average (ISPTA) from 0.1 to 2.8 W per cm2, duty cycle from 1 to 30%, and three consecutive pulse trains for 5 or 10 min each. Controls included sham injections in four and KA without FUS in eleven animals. Histological analysis investigated tissue effects. All animals receiving KA evidenced EEG spikes, averaging 10,378 ± 1651 spikes per 8 h and 1255 ± 199 bursts per 8 h by weeks 6–7. The KA-only group showed a 30% of increase in spikes and bursts by week 14. Compared to the KA-only group, spike counts were reduced by about 25%, burst counts by about 33%, and burst durations by about 50% with FUS. Behavioral seizures were not analyzed, but electrographic seizures longer than 10 s declined up to 70% after some FUS regimens. Repeated-measure ANOVA showed a significant effect of higher intensity and longer sonication duration FUS treatment using 0.75-MI, ISPTA 2.8 W/cm2, 30% duty cycle for 10-min sonications (group effect, F (4, 15) = 6.321, p < 0.01; interaction effect, F (44, 165) = 1.726, p < 0.01), with the hippocampal protective effect lasting to week 14, accompanied by decreased inflammation and gliosis effect. In contrast, spike and burst suppression were achieved using an FUS regimen with 0.25-MI ISPTA 0.5 W/cm2, 30% duty cycle for 10-min sonications. This regimen reduced inflammation and gliosis at weeks 8–14 and protected hippocampal tissue. This study demonstrates that low-intensity pulsed ultrasound can modulate epileptiform activity for up to 7 weeks and, if replicated in the clinical setting, might be a practical treatment for epilepsy.

Impact of Baseline Quantitative OCT Features on Response to Risuteganib for the Treatment of Dry Age-Related Macular Degeneration: The Importance of Outer Retinal Integrity

The purpose of the study was to perform a post hoc analysis to explore the effect of baseline anatomic characteristics identified on OCT on best-corrected visual acuity (BCVA) responses to risuteganib from the completed phase II study in subjects with dry age-related macular degeneration (AMD). Post hoc analysis of a randomized, double-masked, placebo-controlled, phase II study. Eyes with intermediate dry AMD with BCVA between 20/40 and 20/200. Patients with concurrent vision-influencing or macula-obscuring ocular pathologies were excluded. Patients were randomized to receive a 1-mg intravitreal risuteganib injection or a sham injection at baseline. A second 1-mg intravitreal injection of risuteganib was given at week 16 to those in the treatment arm. Two independent, masked reading centers evaluated the baseline anatomic characteristics on OCT to explore features associated with positive responses to risuteganib. Treatment response was defined as a gain of ≥ 8 letters in BCVA from baseline to week 28 in the treatment arm, compared with baseline to week 12 in the sham group. Anatomic parameters, measured by retinal segmentation platforms, including measures of retinal thickness were compared between the responders and nonresponders to risuteganib. Thirty-nine patients completed the study and underwent analysis. In the treatment arm, 48% of eyes demonstrated treatment responses, compared with 7% in the sham group. In the quantitative anatomic assessment, enhanced ellipsoid integrity, greater outer retinal thickness, and decreased geographic atrophy were associated with increased BCVA gains to risuteganib. This post hoc analysis demonstrated that baseline OCT features may help determine the likelihood of a functional response to risuteganib. The characterization of higher-order OCT features may provide important information regarding biomarkers for treatment response and could facilitate optimized clinical trial enrollment and enrichment.

PD44-06 PUDENDAL BLOCK ANALGESIA WITH VAGINAL SURGERY: A RANDOMIZED, DOUBLE-BLIND, PLACEBO CONTROLLED TRIAL

You have accessJournal of UrologyCME1 May 2022PD44-06 PUDENDAL BLOCK ANALGESIA WITH VAGINAL SURGERY: A RANDOMIZED, DOUBLE-BLIND, PLACEBO CONTROLLED TRIAL Emily Slopnick, Graham Chapman, David D. Sheyn, Sarah Sears, Megan Abrams, Kasey M. Roberts, Robert Pollard, and Jeffrey Mangel Emily SlopnickEmily Slopnick More articles by this author , Graham ChapmanGraham Chapman More articles by this author , David D. SheynDavid D. Sheyn More articles by this author , Sarah SearsSarah Sears More articles by this author , Megan AbramsMegan Abrams More articles by this author , Kasey M. RobertsKasey M. Roberts More articles by this author , Robert PollardRobert Pollard More articles by this author , and Jeffrey MangelJeffrey Mangel More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002605.06AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Effective opioid-sparing postoperative analgesia often requires a multimodal approach, which may include regional nerve blocks. The objective of this randomized controlled trial is to determine whether a pudendal nerve block is associated with improved postoperative pain control and decreased opioid consumption compared to a sham injection at the time of vaginal pelvic reconstructive surgery (PRS). METHODS: In this randomized, double-blind, placebo controlled trial, we enrolled women undergoing benign vaginal PRS at a single academic institution. Exclusion criteria included patients with a diagnosis of chronic pelvic pain, inability to receive non-narcotic analgesia, or any concurrent abdominal procedure. Patients were randomized to receive a transvaginal pudendal nerve block (9mL 0.25% bupivacaine + 1mL 40mg/mL triamcinolone) or a sham injection (10mL normal saline) at the conclusion of surgery. The injection syringe was wrapped by pharmacy to blind the surgeon. Postoperatively, all patients received routine care. Primary endpoints were visual analog pain scores (VAS) and postoperative opioid requirement, measured in the post-anesthesia recovery unit (PACU) and on post-operative days (POD) 1 and 4. A power calculation determined 60 patients were required to show a mean difference of 20mm on a 100mm VAS. Opioid administration was standardized as morphine milligram equivalents (MME), and VAS scores were compared with Wilcoxon-Mann-Whitney analysis. RESULTS: We randomized 71 patients: 36 pudendal block and 35 sham injection. The study groups were well matched with no differences in baseline characteristics or type of surgery performed. Pelvic organ prolapse repairs were the most common procedures (n=63, 87.5%). There was no difference in anesthetic dose or operative time between groups. Pain scores were equivalent between groups in the PACU (mean VAS 53.1 block vs 56.4 sham, p=0.517) and on POD 4 (mean VAS 26.7 block vs 35.5 sham, p=0.131). On POD 1, the intervention group did report less pain than the sham group (mean VAS 29.2 vs 42.5, p=0.047). Patients who received a pudendal block took fewer opioid medications than those in the sham group at all time points, but this difference did not meet statistical significance (PACU 5 vs 7.8 MME, POD1 7.5 vs 11.25 MME, POD4 7.5 vs 21.25 MME, all p>0.05). CONCLUSIONS: Pudendal nerve block resulted in decreased pain reported in the immediate postoperative period and less opioid use, though not statistically significant. Pudendal block may be an additional tool for non-narcotic perioperative analgesia with vaginal PRS. Source of Funding: None © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e710 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Emily Slopnick More articles by this author Graham Chapman More articles by this author David D. Sheyn More articles by this author Sarah Sears More articles by this author Megan Abrams More articles by this author Kasey M. Roberts More articles by this author Robert Pollard More articles by this author Jeffrey Mangel More articles by this author Expand All Advertisement PDF DownloadLoading ...

Sympathetic blockade on diet induced thermogenesis in the congenic LA/Ntul//-cp rat

The effects of overfeeding highly palatable diets via the cafeteria feeding diet method (Café) has been shown to be a reliable experimental model to induce diet induced thermogenesis (DIT) in young adult normally lean rats of several strains. Groups of young adult lean LA/ Ntul//-cp rats were offered a Purina chow diet (CHOW) or the same diet plus a daily café supplement both ad libitum from 10 until 24 weeks of age. The drug α-methylparatyrosine (α-MPT) was administered to groups (250 mg α-MPT/kg BW, i.p.) to ablate sympathetic (SNS) activity or a sham injection of physiologic saline given, and measures of fasting resting thermogenesis obtained at thermal neutrality (30°C) before and after the α-MPT or sham administration. The Café diet resulted in a 67% increase in body weight (BW) and a ~25% increase in resting oxygen consumption (VO2) following café overfeeding in both groups, while only a 40% increase in BW and no additional increase in VO2 occurred in normally CHOW fed rats while the sham injection was without any variations from normal physiologic responses as predicted. Sympathetic blockade with α-MPT was associated with modest decreases in body temperature and an average ~12-15% decrease in VO2 in the café treated group, but when the VO2 data were arithmetically corrected to isothermal conditions only a net 3% decrease occurred in CHOW fed rats and was without effect on the SHAM group. Serum T3 concentrations increased by 92% and urinary catecholamine excretion of VMA &gt;250% following the café diet, but the urinary vanilmandelic acid (VMA) excretion was virtually nil following the sympathetic blockade. These observations indicate that the SNS-mediated contribution component to DIT following prolonged café overfeeding under conditions of thermal neutrality contribute approximately 50% of the thermic response. While under normal long term CHOW feeding the SNS component may be as little as 3% of the thermic response, and thus, the total thermic response of DIT likely represents a combination of short acting SNS and longer acting non-SNS mechanisms, including a likely significant thyroidal component in normally lean animals.

C16 Peptide and Ang-1 Improve Functional Disability and Pathological Changes in an Alzheimer's Disease Model Associated with Vascular Dysfunction.

Alzheimer’s disease (AD) is a neurological disorder characterized by neuronal cell death, tau pathology, and excessive inflammatory responses. Several vascular risk factors contribute to damage of the blood–brain barrier (BBB), secondary leak-out of blood vessels, and infiltration of inflammatory cells, which aggravate the functional disability and pathological changes in AD. Growth factor angiopoietin-1 (Ang-1) can stabilize the endothelium and reduce endothelial permeability by binding to receptor tyrosine kinase 2 (Tie2). C16 peptide (KAFDITYVRLKF) selectively binds to integrin ανβ3 and competitively inhibits leukocyte transmigration into the central nervous system by interfering with leukocyte ligands. In the present study, 45 male Sprague-Dawley (SD) rats were randomly divided into three groups: vehicle group, C16 peptide + Ang1 (C + A) group, and sham control group. The vehicle and C + A groups were subjected to two-vessel occlusion (2-VO) with artery ligation followed by Aβ1-42 injection into the hippocampus. The sham control group underwent sham surgery and injection with an equal amount of phosphate-buffered saline (PBS) instead of Aβ1-42. The C + A group was administered 1 mL of drug containing 2 mg of C16 and 400 µg of Ang-1 daily for 2 weeks. The sham control and vehicle groups were administered 1 mL of PBS for 2 weeks. Our results showed that treatment with Ang-1 plus C16 improved functional disability and reduced neuronal death by inhibiting inflammatory cell infiltration, protecting vascular endothelial cells, and maintaining BBB permeability. The results suggest that these compounds may be potential therapeutic agents for AD and warrant further investigation.

Scleral crosslinking using genipin can compromise retinal structure and function in tree shrews

Scleral crosslinking using genipin has been identified as a promising treatment approach for myopia control. The efficacy of genipin to alter biomechanical properties of the sclera has been shown in several animal models of myopia but its safety profile remains unclear. In this safety study, we aim to investigate the effect of scleral crosslinking using retrobulbar injections of genipin on retinal structure and function at genipin doses that were shown to be effective in slowing myopia progression in juvenile tree shrews. To this end, three or five retrobulbar injections of genipin at 0 mM (sham), 10 mM, or 20 mM were performed in one eye every other day. Form deprivation myopia was induced in the injected eye. We evaluated retinal function using full-field electroretinography and retinal structure using in vivo optical coherence tomography imaging and ex vivo histology. The optical coherence tomography results revealed significant thinning of the peripapillary retinal nerve fiber layer in all genipin treated groups including the lowest dose group, which showed no significant treatment effect in slowing myopia progression. In contrast, inducing form deprivation myopia alone and in combination with sham injections caused no obvious thinning of the retinal nerve fiber layer. Electroretinography results showed a significant desensitizing shift of the b-wave semi-saturation constant in the sham group and the second highest genipin dose group, and a significant reduction in b-wave maxima in the two highest genipin dose groups. The ex vivo histology revealed noticeable degeneration of photoreceptors and retinal pigment epithelium in one of two investigated eyes of the highest genipin dose group. While scleral crosslinking using genipin may still be a feasible treatment option for myopia control, our results suggest that repeated retrobulbar injections of genipin at 10 mM or higher are not safe in tree shrews. An adequate and sustained delivery strategy of genipin at lower concentrations will be needed to achieve a safe and effective scleral crosslinking treatment for myopia control in tree shrews. Caution should be taken if the proposed treatment approach is translated to humans.

Resolution of outer retinal abnormalities in eyes with vitreomacular traction without macular hole in the OASIS trial

Background/aimsTo describe the clinical impact of external limiting membrane (ELM) disruption, ellipsoid zone (EZ) disruption and subretinal fluid (SRF) seen on optical coherence tomography (OCT) in eyes with vitreomacular traction...

Dimethyl malonate slows succinate accumulation and preserves cardiac function in a swine model of hemorrhagic shock.

Succinate (SI) is a citric acid cycle metabolite that accumulates in tissues during hemorrhagic shock (HS) due to electron transport chain uncoupling. Dimethyl malonate (DMM) is a competitive inhibitor of SI dehydrogenase, which has been shown to reduce SI accumulation and protect against reperfusion injury. Whether DMM can be therapeutic after severe HS is unknown. We hypothesized that DMM would prevent SI buildup during resuscitation (RES) in a swine model of HS, leading to better physiological recovery after RES. The carotid arteries of Yorkshire pigs were cannulated with a 5-Fr catheter. After placement of a Swan-Ganz catheter and femoral arterial line, the carotid catheters were opened and the animals were exsanguinated to a mean arterial pressure (MAP) of 45 mm. After 30 minutes in the shock state, the animals were resuscitated to a MAP of 60 mm using lactated ringers. A MAP above 60 mm was maintained throughout RES. One group received 10 mg/kg of DMM (n = 6), while the control received sham injections (n = 6). The primary end-point was SI levels. Secondary end-points included cardiac function and lactate. Succinate levels increased from baseline to the 20-minute RES point in control, while the DMM cohort remained unchanged. The DMM group required less intravenous fluid to maintain a MAP above 60 (450.0 vs. 229.0 mL; p = 0.01). The DMM group had higher pulmonary capillary wedge pressure at the 20-minute and 40-minute RES points. The DMM group had better recovery of cardiac output and index during RES, while the control had no improvement. While lactate levels were similar, DMM may lead to increased ionized calcium levels. Dimethyl malonate slows SI accumulation during HS and helps preserve cardiac filling pressures and function during RES. In addition, DMM may protect against depletion of ionized calcium. Dimethyl malonate may have therapeutic potential during HS.

Infrapatellar Fat Pad Mesenchymal Stromal Cell–Derived Exosomes Accelerate Tendon-Bone Healing and Intra-articular Graft Remodeling After Anterior Cruciate Ligament Reconstruction

Background: Exosomes derived from mesenchymal stromal cells (MSCs) reportedly enhance the healing process. However, no studies have investigated the effect of exosomes from infrapatellar fat pad (IPFP) MSCs on tendon-bone healing and intra-articular graft remodeling after anterior cruciate ligament reconstruction (ACLR). Purpose: To evaluate the in vivo effect of exosomes from IPFP MSCs on tendon-bone healing and intra-articular graft remodeling in a rat model of ACLR. Study Design: Controlled laboratory study. Methods: A total of 90 skeletally mature male Sprague Dawley rats underwent unilateral ACLR using an autograft. All rats were randomly divided into 3 groups: sham injection (SI) group (n = 30), control injection (CI) group (n = 30), and IPFP MSC–derived exosome injection (IMEI) group (n = 30). At 2, 4, and 8 weeks postoperatively, tendon-bone healing and intra-articular graft remodeling were evaluated via biomechanical testing, micro–computed tomography, and histological analysis; macrophage polarization was evaluated using immunohistochemical staining. Results: Biomechanical testing demonstrated a significantly higher failure load and stiffness in the IMEI group than in the SI and CI groups at 4 and 8 weeks postoperatively. Moreover, a thinner graft-to-bone healing interface with more fibrocartilage was observed in the IMEI group at both time points. Micro–computed tomography revealed greater new bone ingrowth in the IMEI group than in the other groups, as demonstrated by smaller mean bone tunnel areas and a larger bone volume/total volume ratio. Additionally, more cellular infiltration was observed in the intra-articular graft in the IMEI group than in the other groups at 4 weeks, followed by more regularly organized fibers with mature collagen at 8 weeks. Notably, similar trends of macrophage polarization were found at both the graft-to-bone interface and the intra-articular graft in the IMEI group, with significantly fewer proinflammatory M1 macrophages and larger numbers of reparative M2 macrophages than in the SI and CI groups. Conclusion: IPFP MSC–derived exosomes accelerated tendon-bone healing and intra-articular graft remodeling after ACLR, which may have resulted from the immunomodulation of macrophage polarization. Clinical Relevance: The IPFP can be easily harvested by most orthopaedic surgeons. Exosomes from IPFP MSCs, constituting a newly emerging cell-free approach, may represent a treatment option for improving tendon-bone healing and intra-articular graft remodeling after ACLR.

Editor's Spotlight/Take 5: Persistent Tennis Elbow Symptoms Have Little Prognostic Value: A Systematic Review and Meta-analysis.

Editor's Spotlight/Take 5: Persistent Tennis Elbow Symptoms Have Little Prognostic Value: A Systematic Review and Meta-analysis.

Association of Pegcetacoplan With Progression of Incomplete Retinal Pigment Epithelium and Outer Retinal Atrophy in Age-Related Macular Degeneration

Change in areas of incomplete retinal pigment epithelium (RPE) and outer retinal atrophy (iRORA) within eyes with geographic atrophy (GA) might reflect similar changes among eyes with drusen but no GA. To evaluate the potential association of pegcetacoplan with progression of iRORA in eyes with GA secondary to AMD. This post hoc analysis of the phase 2 multicenter, randomized, single-masked, sham-controlled FILLY trial of intravitreal pegcetacoplan for 12 months took place from February 2 to July 7, 2020. Participants comprised 167 patients with GA secondary to AMD who received pegcetacoplan monthly (n = 41) or every other month (n = 56) or a sham injection (n = 70) in the FILLY trial, completed the month 12 study visit, and did not develop exudative AMD. Intravitreal pegcetacoplan, 15 mg, or sham injection, monthly or every other month for 12 months. Masked readers analyzed spectral-domain optical coherence tomography scans in regions beyond a perimeter of 500 μm from the GA border according to the Classification of Atrophy Meetings criteria. Primary outcome measures were progression from iRORA to complete RPE and outer retina atrophy (cRORA) from baseline to 6 and 12 months. Among the 167 patients in the study, at baseline, iRORA was present in 45.0% of study eyes (18 of 40) in the pegcetacoplan monthly group, 61.8% of study eyes (34 of 55) in the pegcetacoplan every other month group, and 50.7% of study eyes (34 of 67) in the sham group. At 12 months, progression from iRORA to cRORA occurred in 50.0% of study eyes (9 of 18) in the pegcetacoplan monthly group (P = .02 vs sham), 60.6% of study eyes (20 of 33) in the pegcetacoplan every other month group (P = .06 vs sham), and 81.8% of study eyes (27 of 33) in the sham group. Compared with sham treatment, the relative risk of progression at 12 months from iRORA to cRORA was 0.61 (95% CI, 0.37-1.00) for eyes in the pegcetacoplan monthly group and 0.74 (95% CI, 0.54-1.02) for eyes in the pegcetacoplan every other month group. Eyes receiving intravitreal pegcetacoplan had lower rates of progression from iRORA to cRORA compared with controls, suggesting a potential role for pegcetacoplan therapy earlier in the progression of AMD prior to the development of GA. ClinicalTrials.gov Identifier: NCT02503332.

Analgesic Effect of Intrathecal Morphine Combined with Low-Dose Bupivacaine on Postoperative Analgesia after Liver Resection: A Randomized Controlled Study.

Although intrathecal morphine and bupivacaine are increasingly implemented in effective postoperative pain control, there is a lack of consensus on the dosage as high doses of bupivacaine may inadvertently cause unwanted side effects. The purpose of this study was to compare the effects of intrathecal morphine injection and low-dose bupivacaine with morphine injection. In total, 90 patients were divided into 3 groups: (1) sham injection for the control group; (2) morphine 400 mcg for the morphine group (M); and (3) morphine 400 mcg and bupivacaine 5 mg for the morphine and bupivacaine group (M + B). Our primary outcome was time to first rescue analgesic. The VAS (visual analogue scale) pain score was compared until POD (postoperative day)1. Total fentanyl dose was compared until POD2. Side effects were monitored until POD3. Although time to first rescue was significantly shorter in the control group compared to group M and group M + B (p < 0.001), both groups (M and M + B) were comparable to each other. There was a significant decrease in the VAS score and total fentanyl administration in group M and group M + B compared to the control group. Pruritus and tingling were more prevalent in the M + B group (p = 0.023; p = 0.010). The addition of 5 mg bupivacaine may be insufficient in providing further analgesic benefits; however, higher doses may aggravate side effects.

Prophylactic Ranibizumab to Prevent Neovascular Age-Related Macular Degeneration in Vulnerable Fellow Eyes: A Randomized Clinical Trial

To determine whether prophylactic ranibizumab prevents the development of neovascular age-related macular degeneration (nAMD) in eyes with intermediate age-related macular degeneration (AMD) for patients with preexisting nAMD in their contralateral eye. Multicenter randomized clinical trial. Adults aged 50 years and older with intermediate AMD (multiple intermediate drusen [≥63 μm and <125 μm] or ≥1 large drusen [≥125 μm] and pigmentary changes) in the study eye and nAMD in the contralateral eye. Intravitreal ranibizumab injection (0.5 mg) or sham injection every 3 months for 24 months. Conversion to nAMD over 24 months (primary). Change in best-corrected visual acuity from baseline to 24 months (secondary). Among 108 enrolled participants (54 [50%] in each group), all except 2 were non-Hispanic Whites, 61 participants (56%) were female, and the mean age was 78 years. The mean baseline visual acuity was 77.7 letters (Snellen equivalent 20/32). Conversion to nAMD over 24 months occurred among 7 of 54 eyes (13%) in both groups (ranibizumab vs. sham hazard ratio= 0.91 [95% confidence interval (CI), 0.32-2.59]; P= 0.86). At 24 months, the cumulative incidence of nAMD adjusted for loss to follow-up was 14% (95% CI, 4%-23%) in the ranibizumab group and 15% (95% CI, 4%-25%) in the sham group. At 24 months, the mean change in visual acuity from baseline was-2.1 letters (standard deviation, 5.4 letters) with ranibizumab and-1.4 letters (standard deviation, 7.7 letters) with sham (adjusted difference=-0.8 letters [95% CI, -3.7 to 2.2 letters]; P= 0.62). The proportion of eyes that lost at least 10 letters of visual acuity from baseline at 24 months was 2 of 39 (5%) with ranibizumab and 4 of 40 (10%) with sham. There were no serious ocular adverse events in either group. Quarterly dosing of 0.5 mg ranibizumab in eyes with intermediate AMD did not reduce the incidence of nAMD compared with sham injections; however, the study was likely underpowered given the 95% CI, and a clinically meaningful effect cannot be excluded. There also was no effect on visual acuity at 24 months. Other strategies to reduce neovascular conversion in these vulnerable eyes are needed.

Deficits of Learning and Spatial Memory are Associated with Increased Pyknosis of Pyramidal Neurons of the Hippocampus of Adult Rats with Chronic Hydrocephalus

&#x0D; Background: The hippocampus is the brain's center for the consolidation of short-term and spatial memory that enables navigation. Hippocampal injury occurs in hydrocephalus and is associated with loss of memory.&#x0D; Objective: We assessed pyknotic changes in kaolin-induced chronic hydrocephalus in adult rats using qualitative and quantitative means, and related these to memory deficits in the rats.&#x0D; Methods: Adult rats were randomly divided into control and experimental groups. Hydrocephalus was induced by intracisternal injection of 0.1ml sterile kaolin suspension for 6weeks. Control rats received sham injections. Spatial memory was assessed with the Morris water maze test. Coronal sections of the brains were grouped into either mild or moderate hydrocephalus and then stained with H&amp;E and cresyl violet stains. Thus, there were three groups: control, mild hydrocephalus and moderate hydrocephalus (n=10), respectively.&#x0D; Results: Shrinking and thinning of the hippocampal tissue, distortion of the pyramidal layer and pyknotic cells were observed in the CA1 and CA3 regions of the hydrocephalic rats. The pyknotic indices in the mild hydrocephalic rat (Cornus Ammonis, CA) CA1, CA2, CA3 (54.30±1.38; 27.62±0.83; 57.61±0.74) and moderate hydrocephalic rat CA1, CA2, CA3 (48.18±0.67; 32.00±0.84; 42.41±1.19) regions were significantly increased compared to the controls' CA1, CA2, CA3 (12.14±0.56; 9.21±0.36; 13.04±0.59).&#x0D; Conclusion: Chronic hydrocephalus in adult rats was associated with cell death in all the regions of the hippocampus, irrespective of the degree of ventricular enlargement. The extent of cell death corresponded with the severity of learning and memory deficits.&#x0D; Background: The hippocampus is the center of the brain for the consolidation of short-term memory and spatial memory that enables navigation. Hippocampal damage occurs in hydrocephalus and is associated with memory loss.&#x0D; Objective: We assessed pyknotic changes in chronic kaolin-induced hydrocephalus in adult rats using qualitative and quantitative means, and related them to memory deficits in rats.&#x0D; Methods: Adult rats were randomly assigned to control and experimental groups. Hydrocephalus was induced by intracisternal injection of 0.1 ml of sterile kaolin suspension for 6 weeks. Control rats received sham injections. Spatial memory was assessed by the Morris water maze test. Coronal sections of brains were grouped into mild or moderate hydrocephalus and then stained with H&amp;E and cresyl violet. There were therefore three groups: control, mild hydrocephalus and moderate hydrocephalus (n=10), respectively.&#x0D; RESULTS: Shrinking and thinning of hippocampal tissue, distortion of the pyramidal layer, and pyknotic cells were observed in the CA1 and CA3 regions of hydrocephalic rats. The pyknotic indices in the CA1, CA2 and CA3 regions of mild hydrocephalic rats (Cornus Ammonis, CA) (54.30±1.38; 27.62±0.83; 57.61±0.74) and hydrocephalic rats moderate CA1, CA2 and CA3 (48.18±0.67; 32.00±0.84; 42.41±1.19) were significantly increased compared to the CA1, CA2, CA3 regions of controls (12.14±0.56; 9.21±0.36; 13.04±0.59).&#x0D; Conclusion: Chronic hydrocephalus in adult rats was associated with cell death in all regions of the hippocampus, regardless of the degree of ventricular enlargement. The extent of cell death corresponded to the severity of learning and memory deficits.&#x0D; Key words: Chronic hydrocephalus, hippocampus, adult rats, memory, pyknotic cells.&#x0D; &#x0D; Keywords: Adult rats; Chronic hydrocephalus; hippocampus; memory; pyknotic cells.

Intra-articular placebo effect in the treatment of knee osteoarthritis: a survey of the current clinical evidence.

Knee osteoarthritis (KOA) is a debilitating disease characterized by chronic pain, stiffness, and decreased mobility. Intra-articular injectable therapies show good clinical efficacy in improving symptoms; however, these therapies and their comparators (intra-articular saline) have been associated with a large underlying placebo effect. We aimed to describe the existing evidence on the challenges, hypotheses, and potential solutions to mitigate the intra-articular placebo effect in clinical trials in KOA. A targeted literature review was conducted by searching Embase, MEDLINE®, and CENTRAL using predefined study selection criteria. All eligible studies identified were extracted for relevant data, and results were narratively summarized. Forty-three studies were included following screening. Challenges associated with the intra-articular placebo effect included its ability to mask the comparative efficacy of active treatments in trials (n = 7 studies), long-lasting effects (up to 6 months; n = 3), and substantial variation of placebo effect sizes across populations (n = 3). Hypotheses for the mechanism of the placebo effect included aspiration of synovial fluid during administration (n = 6) and dilution of inflammatory mediators (n = 2). Factors affecting the placebo effect size were more invasive routes of administration (e.g., injection versus oral; n = 4) and patient expectations (n = 2). Proposed solutions included the suggestion for readers to weigh the relevance of clinical trial evidence against the presence of large underlying placebo effects (n = 9), discontinuation of intra-articular saline as an appropriate placebo (n = 5), and inclusion of ‘no treatment’ or sham injection as a control (n = 4). The intra-articular placebo effect is a well-documented occurrence in KOA clinical trials, and it is suggested that it be accounted for when designing randomized controlled trials. Awareness and understanding of the intra-articular placebo effect in KOA are required for fair interpretation of clinical trial evidence.

Abstract PO-023: Impaired adipose anabolism drives fat wasting in pancreatic cancer cachexia

Abstract Purpose/Objectives: The disease associated wasting condition, cachexia, is a common complication of pancreatic ductal adenocarcinoma (PDAC) that impacts quality of life and portends poor survival. Cachexia remains refractory to nutritional supplementation, but the mechanisms underlying this phenotype are unclear. By examining the adipose response to different nutritional contexts in cachectic mice, we sought to understand the relative contributions of enhanced catabolism and impaired anabolism on adipose tissue wasting. Materials/Methods: Adult C57BL/6J mice received orthotopic PDAC tumor injections (KrasG12D; p53R172H/+; Pdx1-cre) or sham injections. Mice were fasted 24 h or fasted and refed 24 h at mid-cachexia time point, and gross fat pads were weighed to assess anabolic potential. 3T3-L1 cells were treated with PDAC cell conditioned media during or after differentiation to model cachexia in vitro. Lipolytic rate was quantified as normalized quantity of glycerol released from inguinal (iWAT) and gonadal (gWAT) fat pads ex vivo or differentiated 3T3-L1 cells in vitro. Lipogenesis was measured in vitro using Oil-red-O staining. Adipose tissue mRNA levels were measured using bulk RNAseq and confirmed with qPCR. Malabsorption was assessed via fecal protease activity and total fecal protein and lipid content. Results: Adipose tissue in PDAC and control mice were equally sensitive to fasting/food restriction. Both iWAT and gWAT fat pads from PDAC mice showed decreased lipolysis ex vivo, associated with decreased lipase (Atgl &amp; Lipe) mRNA expression. In the fast/refeed paradigm, PDAC mice were unable to restore both iWAT and gWAT mass after refeed, in contrast to control mice. We found no evidence of malabsorption at this timepoint by any measure. RNAseq on gWAT revealed 614 differentially expressed genes between PDAC and control mice. Downregulated (n=111) genes were most closely associated with adipogenesis (adj p&amp;lt;.05), and expression of adipogenesis master regulators Pparg and Cebpa reduced in WAT from PDAC mice. Upregulated genes were associated with increased RELA and NFkB activity (adj p&amp;lt;5 × 10−22) and inflammatory response hallmarks. Treatment of 3T3-L1 cells with PDAC conditioned media phenocopied in vivo model, showing impaired lipolysis and lipogenesis, associated with decreased expression of lipolytic, adipogenic, and lipogenic genes. Conclusions: Adipose tissue wasting in PDAC cachexia can result from impaired anabolism in the absence of enhanced lipolysis or malabsorption. This deficit in adipogenesis is mediated by a cancer cell secreted product and is associated with increased inflammatory signaling in adipocytes, most likely via RELA and NFkB activity. Restoring adipose anabolic potential may provide a novel approach to cachexia treatment in PDAC. Citation Format: Katherine Pelz, Grace McCarthy, Heike Mendez, Samantha Z. Brown, Jonathan R. Brody, Aaron J. Grossberg. Impaired adipose anabolism drives fat wasting in pancreatic cancer cachexia [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-023.

Host Genotype and Tissue Type Determine DWV Infection Intensity.

Varroa mite-vectored viruses such as Deformed wing virus (DWV) are of great concern for honey bee health as they can cause disease in individuals and increase colony mortality. Two genotypes of DWV (A and B) are prevalent in the United States and may have differential virulence and pathogenicity. Honey bee genetic stocks bred to resist Varroa mites also exhibit differential infection responses to the Varroa mite-vectored viruses. The goal of this project was to determine if interactions between host genotype could influence the overall infection levels and dissemination of DWV within honey bees. To do this, we injected DWV isolated from symptomatic adult bees into mite-free, newly emerged adult bees from five genetic stocks with varying levels of resistance to Varroa mites. We measured DWV-A and DWV-B dissemination among tissues chosen based on relevance to general health outcomes for 10 days. Injury from sham injections did not increase DWV-A levels but did increase DWV-B infections. DWV injection increased both DWV-A and DWV-B levels over time with significant host stock interactions. While we did not observe any differences in viral dissemination among host stocks, we found differences in virus genotype dissemination to different body parts. DWV-A exhibited the highest initial levels in heads and legs while the highest initial levels of DWV-B were found in heads and abdomens. These interactions underscore the need to evaluate viral genotype and tissue specificity in conjunction with host genotype, particularly when the host has been selected for traits relative to virus-vector and virus resistance.

Efficacy of intravitreal povidone-iodine administration for the treatment of Candida albicans endophthalmitis in rabbits

This study aimed to investigate the efficacy of intravitreal povidone-iodine (PI) administration for the treatment of Candida albicans endophthalmitis. Forty New Zealand white rabbits were divided into four groups (n = 10 per group). After the induction of endophthalmitis using Candida albicans, groups A, B, and C received single intravitreal injections of 0.035 mg voriconazole, 0.3 mg PI, and their combination, respectively. Rabbits that were administered sham injections were in group D as controls. Fundus photography, vitreous culture, electroretinography (ERG), and histologic examinations of the retina were conducted on day 7. The anterior chamber flare (grade 0 to 4), severity of iritis (grade 0 to 4), and vitreous opacity (grade 0 to 3) were scored. Candida albicans was cultured in the vitreous sample. On day 7, the vitreous opacities were found in all groups. Compared to that in group D, groups A, B, and C showed a lower score for flare (p < 0.001) and iritis (p < 0.001) and less fungal growth in the vitreous culture (n = 2, 1, 1, and 10 in groups A, B, C, and D, respectively; p < 0.001). Furthermore, ERG and histologic findings demonstrated less affected a- and b-waves and damaged retinal tissues in groups A, B, and C. However, these findings were not different among groups A, B, and C. PI significantly improved Candida albicans endophthalmitis, and the effect was comparable that of the voriconazole, although some vitreous opacities remained. No synergistic effect of the combination of PI and voriconazole was observed. Intravitreal PI may be useful to treat Candida albicans endophthalmitis.

Disease-modifying effects of ranibizumab for central retinal vein occlusion

PurposeTo identify anatomic endpoints altered by intravitreal ranibizumab in central retinal vein occlusion (CRVO) to determine any potential underlying disease modification that occurs with anti-vascular endothelial growth factor (anti-VEGF) therapy beyond best-corrected visual acuity and central optical coherence tomography outcomes.MethodsA post hoc analysis of a double-masked, multicenter, randomized clinical trial was performed. A total of 392 patients with macular edema after CRVO were randomized 1:1:1 to receive monthly intraocular injections of 0.3 or 0.5 mg of ranibizumab or sham injections. Central reading center-read data were reviewed to explore potential anatomic endpoints altered by therapy.ResultsAt 6 months, there was a reduction in the ranibizumab groups compared with sham groups with respect to total area of retinal hemorrhage (median change from baseline in disc areas: − 1.17 [sham], − 2.37 [ranibizumab 0.3 mg], − 1.64 [ranibizumab 0.5 mg]), development of disc neovascularization (prevalence: 3% [sham], 0% [ranibizumab 0.3 mg], 0% [ranibizumab 0.5 mg]), and presence of papillary swelling (prevalence: 22.9% [sham], 8.0% [ranibizumab 0.3 mg], 8.3% [ranibizumab 0.5 mg], p < 0.01). There was no difference between groups in collateral vessel formation. Analysis of vitreous and preretinal hemorrhage could not be performed due to low frequency of events in both treated and sham groups.ConclusionsRanibizumab for CRVO resulted in beneficial disease-modifying effects through a reduction in retinal hemorrhage, neovascularization, and papillary swelling. These findings may form the basis for future work in the development of a treatment response or severity scale for eyes with CRVO.