Longitudinal impact of screening colonoscopy on greenhouse gas emissions.

BACKGROUND AND AIM: Colonoscopy is the gold-standard screening test for colorectal cancer. However, it has come under scrutiny for its carbon footprint and contribution to greenhouse gas (GHG) emissions compared to other medical procedures. Notwithstanding, screening colonoscopies may have a positive effect on GHG emissions that is unknown. This study estimated the carbon emissions prevented by screening colonoscopies in the U.S. METHODS: Using the reported number of screening colonoscopies performed annually in the U.S. and the absolute risk reduction (ARR) reported in the NorDICC trial, we calculated the expected minimum number of cancer treatment and surveillance visits prevented through screening based on the cancer stage. The average carbon emission averted per mile traveled was computed using the Environmental Protection Agency's (EPA) GHG equivalencies calculator. The final estimate of carbon emissions averted over a decade by screening colonoscopies performed in one year was determined. RESULT: 6.3 million screening colonoscopies performed in one year prevent 1,134,000 colorectal cancers over a ten-year period. Of these, 38∙3% (434,254) are localized, 38∙8% (440,281) are regional, and 22∙9% (259,465) are metastatic disease. The minimum number of post-diagnosis visits prevented is 11 for stage I, ≥ 21 for stage II, ≥25 for stage III, and ≥ 20 for stage IV disease, comprised of diagnostic, surgical evaluation, chemotherapy, and surveillance visits. The total number of visits prevented by screening is 2,388,397 for stage I, 5,254,421 for stage II, 13,120,369 for stage III, and 9,210,972 for stage IV disease. Approximately 395 million miles of travel and 158,263 metric tons of CO2, equivalent to 177 million pounds of coal burned, 19 billion smartphones charged, or 18 million gallons of gasoline consumed, were saved over ten years through screening. CONCLUSION: Colorectal cancer screening decreases cancer-related GHG emissions and minimizes the environmental impact of cancer treatment.

Dysregulation of cardiac mitochondrial aldehyde dehydrogenase 2: Studies in dogs with chronic heart failure.

Mitochondrial (MITO) dysfunction occurs in the failing heart and contributes to worsening of heart failure (HF). Reduced aldehyde dehydrogenase 2 (ALDH2) in left ventricular (LV) myocardium of diabetic hearts has been implicated in MITO dysfunction through accumulation of toxic aldehydes including and elevated levels of 4-hydroxy-2-nonenal (4HNE). This study examined whether dysregulation of MITO ALDH2 (mALDH2) occurs in mitochondria of the failing LV and is associated with increased levels of 4HNE. LV tissue from 7 HF and 7 normal (NL) dogs was obtained. Protein quantification of total mitochondrial ALDH2 (t-mALDH2), phosphorylated mALDH2 (p-mALDH2), total MITO protein kinase c epsilon (t-mPKCε), phosphorylated mPKCε (p-mPKCε) was performed by Western blotting, and total mALDH2 enzymatic activity was measured. Protein adducts of 4HNE-MITO and 4HNE-mALDH2 were also measured in MITO fraction by Western Blotting. Protein level of t-mALDH2 was decreased in HF compared with NL dogs (0.63 ± 0.07 vs 1.17 ± 0.08, p < 0.05) as did mALDH2 enzymatic activity (51.39 ± 3 vs. 107.66 ± 4 nmol NADH/min/mg, p < 0.05). Phosphorylated-mALDH2 and p-mPKCε were unchanged. 4HNE-MITO proteins adduct levels increased in HF compared with NL (2.45 ± 0.08 vs 1.30 ± 0.03 du, p < 0.05) as did adduct levels of 4HNE-mALDH2 (1.60 ± 0.20 vs 0.39 ± 0.08, p < 0.05). In isolated failing cardiomyocytes (CM) exposure to 4HNE decreased mALDH2 activity, increased ROS and 4HNE-ALDH2 adducts, and worsened MITO function. Stimulation of mALDH2 activity with ALDA-1 in isolated HF CMs compared to NL CMs improved ADP-stimulated respiration and maximal ATP synthesis to a greater extant (+47 % and +89 %, respectively). Down-regulation of mALDH2 protein levels and activity occurs in HF and contributes to MITO dysfunction and is likely caused by accumulation of 4HNE-mALDH2 adduct. Increasing mALDH2 activity (via ALDA-1) improved MITO function in failing CMs.

A Phase I Study of Acapatamab, a Half-life Extended, PSMA-Targeting Bispecific T-cell Engager for Metastatic Castration-Resistant Prostate Cancer.

PURPOSE: Safety and efficacy of acapatamab, a prostate-specific membrane antigen (PSMA) x CD3 bispecific T-cell engager were evaluated in a first-in-human study in metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: Patients with mCRPC refractory to androgen receptor pathway inhibitor therapy and taxane-based chemotherapy received target acapatamab doses ranging from 0.003 to 0.9 mg in dose exploration (seven dose levels) and 0.3 mg (recommended phase II dose) in dose expansion intravenously every 2 weeks. Safety (primary objective), pharmacokinetics, and antitumor activity (secondary objectives) were assessed. RESULTS: In all, 133 patients (dose exploration, n = 77; dose expansion, n = 56) received acapatamab. Cytokine release syndrome (CRS) was the most common treatment-emergent adverse event seen in 97.4% and 98.2% of patients in dose exploration and dose expansion, respectively; grade ≥ 3 was seen in 23.4% and 16.1%, respectively. Most CRS events were seen in treatment cycle 1; incidence and severity decreased at/beyond cycle 2. In dose expansion, confirmed prostate-specific antigen (PSA) responses (PSA50) were seen in 30.4% of patients and radiographic partial responses in 7.4% (Response Evaluation Criteria in Solid Tumors 1.1). Median PSA progression-free survival (PFS) was 3.3 months [95% confidence interval (CI): 3.0-4.9], radiographic PFS per Prostate Cancer Clinical Trials Working Group 3 was 3.7 months (95% CI: 2.0-5.4). Acapatamab induced T-cell activation and increased cytokine production several-fold within 24 hours of initiation. Treatment-emergent antidrug antibodies were detected in 55% and impacted serum exposures in 36% of patients in dose expansion. CONCLUSIONS: Acapatamab was safe and tolerated and had a manageable CRS profile. Preliminary signs of efficacy with limited durable antitumor activity were observed. Acapatamab demonstrated pharmacokinetic and pharmacodynamic activity.

Optimization of biometry for best refractive outcome in cataract surgery.

High-precision biometry and accurate intraocular lens (IOL) power calculation have become essential components of cataract surgery. In clinical practice, IOL power calculation involves measuring parameters such as corneal power and axial length and then applying a power calculation formula. The importance of posterior corneal curvature in determining the true power of the cornea is increasingly being recognized, and newer investigative modalities that can estimate both the anterior and posterior corneal power are becoming the standard of care. Optical biometry, especially using swept-source biometers, with an accuracy of 0.01-0.02 mm, has become the state-of-the-art method in biometry. With the evolution of IOL formulas, the ultimate goal of achieving a given target refraction has also moved closer to accuracy. However, despite these technological efforts to standardize and calibrate methods of IOL power calculation, achieving a mean absolute error of zero for every patient undergoing cataract surgery may not be possible. This is due to inherent consistent bias and systematic errors in the measurement devices, IOL formulas, and the individual bias of the surgeon. Optimization and personalization of lens constants allow for the incorporation of these systematic errors as well as individual bias, thereby further improving IOL power prediction accuracy. Our review provides a comprehensive overview of parameters for accurate biometry, along with considerations to enhance IOL power prediction accuracy through optimization and personalization. We conducted a detailed search in PubMed and Google Scholar by using a combination of MeSH terms and specific keywords such as "ocular biometry," "IOL power calculations," "prediction accuracy of refractive outcome in cataract surgery," "effective lens position," "intraocular lens calculation formulas," and "optimization of A-constants" to find relevant literature. We identified and analyzed 121 relevant articles, and their findings were included.

A randomized controlled trial to assess safety and efficacy between terminal chop, stop and chop, and direct chop.

PURPOSE: The goal in developing new techniques of cataract surgery is to provide a safer, more efficient surgical experience with the lowest complication rate and endothelial cell loss. We compared the efficiency and safety of stop-and-chop, direct chop, and the novel terminal chop techniques of nuclear fragmentation for cataracts grade II-V. METHODS: We conducted a prospective randomized clinical trial comparing three different techniques of phacoemulsification, namely, stop-and-chop, direct chop, and terminal chop to assess any differences between them and to establish whether any one method was superior to the others. The pre- and postoperative parameters studied, included central corneal thickness (CCT), ultrasonic time (UST), endothelial cell density (CD), cell loss and effective phacoemulsification time (EPT), average cumulative dissipative energy (CDE), and best-corrected visual acuity, among others. RESULTS: 307 eyes were recruited to the study, 102 were recruited to the stop-and-chop group, 103 to the direct chop group, and 102 to the terminal chop group. Statistical differences were found between the techniques with regard to postoperative CCT among NS II (P. 0001) and NS IV cataracts (P = .005) with the lowest values in the terminal chop group among NS II, NS III, and NS IV cataracts. Endothelial cell loss was minimum with a terminal chop in NS II (P = .018) and NS IV cataracts (P = .245). CDE was minimum in terminal chop across different cataract densities. CONCLUSION: Terminal chop showed improvement over the other two techniques in terms of CDE and was comparable to them with regard to other parameters.

Varicella Zoster Reactivation Manifesting as Serpiginous Peripheral Keratitis and Disciform Keratitis Occurring After Necrotizing Fasciitis in an Immunocompromised Male: A Case Report.

Reactivation of herpes zoster ophthalmicus (HZO) can present as corneal involvement without any precedent neuralgia or characteristic herpetic rash. This form of HZO can be the first manifestation of reactivation of varicella zoster virus and can masquerade as peripheral ulcerative keratitis. A 45-year-old male treated for necrotizing fasciitis (NF) one month back presented with painful diminution of vision in the right eye (RE) for two weeks without any associated vesicular rash or neuralgia. On examination, best-corrected visual acuity in RE was 2/60 with non-marginal upper lid defect, and multiple linear contracture scars involving the upper lid, right temple, and preauricular region. There were associated peripheral corneal ring infiltrates, disc-shaped central stromal edema, and reduced corneal sensation. The patient had a history of chicken pox in childhood and was recently diagnosed with seropositive rheumatoid arthritis (RA). Though corneal scrapings were negative on Tzanck smear, a presumptive clinical diagnosis of herpetic disciform keratitis was made, and the patient was started on oral and topical acyclovir with steroids. This was confirmed with improving clinical course and detection of herpes zoster DNA on polymerase chain reaction from corneal scrapings. Lid reconstruction for associated lid defect was performed using paramedian forehead flap, which was remodeled at 16 weeks. Our case, a seropositive RA patient, had reactivation of varicella zoster manifesting as peripheral serpiginous and disciform keratitis activated after NF. There are a few case reports of periorbital NF following HZO in immunocompromised patients. However, till date, no case of HZO occurring after periorbital NF has been reported. Also, in our case, reactivation of HZO presented as disciform and serpiginous keratitis without any precedent herpetic rash or neuralgia.

Acute-Onset Postoperative Herpetic Endophthalmitis: A Case Report.

Herpes simplex virus uveitis without corneal reactivation is more frequent than previously thought. Although herpes simplex virus has been implicated as a cause of postoperative uveitis and endophthalmitis, it has not been reported as a cause of acute postoperative endophthalmitis within the early postoperative period, specifically within one week following cataract extraction. A 55-year-old man with vascularized irregular central disc-shaped stromal corneal opacity with complicated cataracts underwent cataract surgery. Intraoperatively, there was posterior capsular rent, requiring anterior vitrectomy. On postoperative day three, the patient had an increase in inflammation in the anterior chamber (grade 4+) with marked vitreous haze (grade 4). Vitreous taps were negative for bacteria and fungi, and despite intravitreal injections of vancomycin and ceftazidime, the patient had worsening of inflammation with increasing exudates and the appearance of the fibrinous membrane in the anterior chamber. Polymerase chain reaction (PCR) of aqueous and vitreous samples at this point of time yielded positive serology for herpes viral DNA, and the patient was started on oral valacyclovir. The ocular inflammation resolved soon after switching to oral valacyclovir. Typical acute postoperative endophthalmitis starts two to seven days after surgery, and the most common isolate in vitreous biopsies is coagulase-negative staphylococci. We report a rare case of acute-onset herpetic endophthalmitis presenting within 72 hours following cataract surgery for a complicated cataract in a patient with a history of pre-existing healed viral keratitis. Our case highlights that a suspicion of viral endophthalmitis should be kept in mind as a cause of acute-onset post-cataract surgery endophthalmitis, especially in cases of surgery that fail to yield a positive result on Gram's stain, culture or PCR for bacteria and fungi.

Lens Coloboma: A Rare Association of Congenital Rubella Syndrome.

Congenital rubella syndrome (CRS) may affect all ocular structures in general, either in isolation or in combination. Typical ocular complications in CRS include cataracts, microcornea, microphthalmia, glaucoma, nystagmus, and retinopathy. We report a case of a four-year-old girl who presented with bilateral total cataracts with sensory nystagmus, a poorly dilating pupil, iris hypoplasia, high axial myopia in the right eye (RE), and a retinal detachment in the left eye (LE). The systemic evaluation revealed microcephaly with an associated patent ductus arteriosus (PDA) and mild pulmonary arterial hypertension (PAH). Based on these findings, the child was diagnosed with clinically confirmed CRS. The child was taken up for right-eye cataract surgery. Intra-operatively, a lens coloboma involving the temporal equator of the lens along with a highly tessellated fundus was noted. Two weeks post-cataract surgery, the child had a best corrected visual acuity (BCVA) of 6/24. However, four weeks after the surgery, the child developed total rhegmatogenous retinal detachment in the right eye, for which pars plana vitrectomy with endolaser and silicon oil tamponade was done. Four weeks later, the child's BCVA in the right eye was 6/36, which was maintained until the last follow-up of four months. Lens coloboma may be isolated or may occur in association with chorioretinal coloboma. Ours is the first case of unilateral atypical lens coloboma associated with high myopia and bilateral cataracts in a patient with congenital rubella syndrome. Lens colobomas with high myopia have not been reported previously as ocular associations of CRS. Our case highlights that in children with CRS presenting with unilateral or bilateral congenital cataracts, the possibility of lenticular coloboma as a coexistent association should be kept in mind while taking these cases for cataract surgery.

Field emission scanning electron microscopic, X-ray diffraction and ultraviolet spectroscopic analysis of Terminalia bellerica based silver nanoparticles and evaluation of their antioxidant, catalytic and antibacterial activity.

In recent years, scientists have come up with ways to make nanoparticles that are inexpensive and good for the environment. Terminalia bellerica-based silver nanoparticles (TBAgNPs) were made in this study using methanol extract from T. bellerica fruits. This method was quick, economical, and good for the environment. The biosynthesized TBAgNPs were used as antioxidants, antibacterial agents, and anti-catalytic agents. Analytical techniques like XRD, FESEM, and UV-Vis were used to find out more about the spherical TBAgNPs that were made. Also, Cefotaxime-resistant bacteria found in hospitals were used to test how well the TBAgNPs killed bacteria. With the Bauer-agar Kirby's gel diffusion and Mueller-Hinton broth methods, the ability of the synthesized TBAgNPs to stop bacterial growth was tested. After the TBAgNPs were studied, it was found that the average size of their crystals was between 10 and 25 nm. 2,2-Diphenyl-1-picrylhydrazyl (DPPH) reducing tests showed that these AgNPs could act as antioxidants, and TBAgNPs (%inhibition = 20.90% to 94.94%) were better antioxidant than ascorbic acid (%inhibition = 13.80% to 86.10%) and extract (%inhibition = 16.90% to 80.50%). The reduction of methylene blue (MB) to leucomethylene blue (LMB) with sodium borohydride (NaBH4) was used as a model to test the catalytic potential of TBAgNPs. On UV spectroscopic analysis at room temperature, TBAgNPs at different concentrations were able to reduce methylene blue effectively. For Escherichia coli and Klebsiella pneumoniae, the minimum inhibitory concentration (MIC) for TBAgNPs was 0.625 µg/mL and 1.25 µg/mL, respectively. Based on these results, silver nanoparticles made with Terminalia bellerica extract may have much biological importance and could be used in making useful therapeutic applications.

Modified Two-Stage Approach for Management of Combined Rhegmatogenous Retinal Detachment and Choroidal Detachment With Extreme Hypotony.

Combined rhegmatogenous retinal detachment (RRD) and serous choroidal detachment (CD) present a significant challenge. No global standard of care exists for treating these complex RRDs. There is a lower failure rate when such detachments are treated with pars plana vitrectomy than with scleral buckle alone. The use of pre-operative steroids may not work in cases with moderate-to-severe CDs with severe hypotony where suprachoroidal fluid drainage is required to reduce inflammatory mediators, thus preventing proliferative vitreoretinopathy (PVR). We report a case of a 62-year-old male who had a combined RRD and severe CD with vitreous hemorrhage in the left eye (LE). There was extreme hypotony leading to a severely deformed and distorted globe with poor visualization of the fundus. The patient was started on 60 mg of oral prednisolone, and a posterior subtenon injection of 20 mg of triamcinolone acetonide was given to reduce inflammation and CD. However, despite one week of pre-operative steroids, there was severe hypotony. The patient was taken for pars plana vitrectomy with drainage of suprachoroidal fluid. Intra-operatively even after drainage of suprachoroidal fluid via inferotemporal posterior sclerotomy, hypotony persisted, and media was very hazy, precluding us from proceeding with vitrectomy in the first sitting. Oral steroids were continued, and vitrectomy was done in the second sitting, 72 hours later, with long-term silicone oil tamponade. Post-operatively patient had a well-formed globe with an attached retina and a good visual acuity. Our case thereby highlights that combined retinal and CD is a complicated diagnosis that presents with many pre-operative, intra-operative, and post-operative challenges. We could achieve good anatomical and functional success using a modified two-stage approach in our unusual case of combined RRD wth CD with extreme hypotony.

Intrastromal keratopigmentation: a boon for unsightly corneal scars.

PURPOSE: The aim of this study was to improve cosmesis in patients with corneal opacity (CO) using newer organic micronized pigments. METHODS: Settings: Tertiary Care eye center, Design: Retrospective study. INCLUSION CRITERIA: Patients with unsightly corneal scars not suitable for keratoplasty, eccentric corneal opacity not requiring keratoplasty, or lenticular opacity/anterior or posterior capsular opacities in non-seeing eyes. Micronized organic pigment was used for keratopigmentation by the intrastromal pocket technique (ISPT) in deep corneal opacities and lenticular opacities, whereas the intrastromal needle puncture technique (ISNT) was used in superficial opacities or corneoiridic scars. The records of 463 patients were reviewed and analyzed for the duration of the past 7 years. RESULTS: Two hundred and ninety-three (63.2%) patients underwent ISNT, eight underwent combined technique, and the rest underwent ISPT. The postoperative follow-up period showed more watering and redness in the needle puncture technique (p > 0.001), which resolved in 70.4% of patients by the end of 4 weeks. Repeat procedures were required in 5.3% of the patients with ISNT. The patient's satisfaction grading showed excellent levels in 375 (80.9%) patients, 45 (9.7%) had good satisfaction levels, and the rest had average satisfaction levels. CONCLUSION: Intrastromal keratopigmentation is a boon for unsightly corneal scars and gives respite to the patients from the social stigma.

CD8+ T cell-intrinsic IL-6 signaling promotes resistance to anti-PD-L1 immunotherapy.

Although immune checkpoint inhibitors (ICIs) are established as effective cancer therapies, overcoming therapeutic resistance remains a critical challenge. Here we identify interleukin 6 (IL-6) as a correlate of poor response to atezolizumab (anti-PD-L1) in large clinical trials of advanced kidney, breast, and bladder cancers. In pre-clinical models, combined blockade of PD-L1 and the IL-6 receptor (IL6R) causes synergistic regression of large established tumors and substantially improves anti-tumor CD8+ cytotoxic T lymphocyte (CTL) responses compared with anti-PD-L1 alone. Circulating CTLs from cancer patients with high plasma IL-6 display a repressed functional profile based on single-cell RNA sequencing, and IL-6-STAT3 signaling inhibits classical cytotoxic differentiation of CTLs in vitro. In tumor-bearing mice, CTL-specific IL6R deficiency is sufficient to improve anti-PD-L1 activity. Thus, based on both clinical and experimental evidence, agents targeting IL-6 signaling are plausible partners for combination with ICIs in cancer patients.

Regression of choroidal metastasis from breast carcinoma with palbociclib.

BACKGROUND: Uveal metastasis is reported to be the most common intraocular malignancy. The most common site of origin of ocular metastases in females is the breast. In some cases, uveal metastatic lesions respond to systemic chemotherapy. We report a case of a patient who developed choroidal metastasis, while on endocrine therapy with selective estrogen receptor modulator (SERM), tamoxifen, for estrogen receptor (ER) positive, progesterone receptor (PR) positive and (human epidermal growth factor receptor 2) HER2 negative primary breast carcinoma, which then regressed following systemic chemotherapy with palbociclib. CASE DESCRIPTION: An 83-year-old female, with a history of modified radical mastectomy, chemotherapy and radiation therapy for infiltrating duct carcinoma of the breast, presented with a choroidal metastatic lesion in the left eye along with liver and lung metastases, 3 years after the primary carcinoma was treated. At the time of presentation, she was on tamoxifen. The choroidal tumor showed regression after the introduction of palbociclib, a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor. CONCLUSION: This report highlights the use of palbociclib, in the palliative treatment of choroidal metastasis from primary breast cancer. The use of chemotherapy for choroidal metastasis can help avoid external beam radiation therapy and its concurrent side effects. Although there are a few reports involving the use of palbociclib for metastatic breast carcinoma, all of those have been in conjunction with and/or following non-response to other treatment modalities. Ours is the first report wherein palbociclib has been used as the first-line palliative chemotherapy and helped in regression of choroidal metastasis.

RAPD as a clinical alert for early evidence of dysthyroid optic neuropathy.

Dysthyroid optic neuropathy (DON) is a serious manifestation of thyroid eye disease (TED) resulting in permanent visual loss. There is controversy regarding the diagnostic features of DON. Relative afferent pupil defect (RAPD) in TED is highly specific for DON. Our first patient, a 42-year-old male presented with proptosis and intermittent blurring of vision with best corrected visual acuity of 6/6 in both eyes and right RAPD as an early sign of DON. Our second patient, a 54-year-old female presented with proptosis and clinical activity score <3 at the time of presentation. She developed intermittent blurring of vision with left RAPD on her second presentation as clue of bilateral asymmetric DON in her eyes, though BCVA was 6/6 both eyes. Both cases of bilateral asymmetric DON had RAPD as early specific sign of DON, which prompted us to do detailed radio-imaging to confirm DON, hence highlighting the importance of RAPD.

Infectious crystalline keratopathy: A case series.

This is the case series of three patients of infectious crystalline keratopathy (ICK) presented to us after undergoing penetrating keratoplasty between 2010 to 2020. The lesions showed classical crystalline patterns and clinical diagnosis was made. The patients were treated by broad spectrum antibiotics till the complete resolution of the lesions. The cases highlight the clinical features, diagnosis and management of this rare and resistant disease.

Relapsing neuromyelitis optica in an adolescent girl.

Early differentiation of neuromyelitis optica spectrum disorder (NMO-SD) from multiple sclerosis (MS) is of paramount importance as NMO-SD (especially relapsing variant) has more severe morbidity than MS. We describe a case of an adolescent girl who presented with repeated episodes of optic neuritis over a period of 4 years with normal brain MRI scans. She was treated initially as relapsing remitting MS, before showing clinical evidence of transverse myelitis (TM), and eventually being diagnosed as NMO-SD. Pulse intravenous methyl prednisolone along with immunosuppressive therapy led to remission of her disease. However, delay in diagnosis as NMO-SD led to visual disability in the left eye. Therefore, in young patients with recurrent optic neuritis and normal brain MRI, it may be prudent to get spinal MRI done to look for TM, even when asymptomatic. In addition, we should keep a low threshold for requesting aquaporin-4 antibody testing in these patients.

Intravenous Infusion of the ß3-Adrenergic Receptor Antagonist APD418 Improves Left Ventricular Systolic Function in Dogs With Systolic Heart Failure.

BACKGROUND: Unlike ß1- and ß2-adrenergic receptors (ARs), ß3-AR stimulation inhibits cardiac contractility and relaxation. In the failing left ventricular (LV) myocardium, ß3-ARs are upregulated, and can be maladaptive in the setting of decompensation by contributing to LV dysfunction. This study examined the effects of intravenous infusions of the ß3-AR antagonist APD418 on cardiovascular function and safety in dogs with systolic heart failure (HF). METHODS AND RESULTS: Three separate studies were performed in 21 dogs with coronary microembolization-induced HF (LV ejection fraction [LVEF] of approximately 35%). Studies 1 and 2 (n = 7 dogs each) were APD418 dose escalation studies (dosing range, 0.35-15.00 mg/kg/h) designed to identify an effective dose of APD418 to be used in study 3. Study 3, the sustained efficacy study, (n = 7 dogs) was a 6-hour constant intravenous infusion of APD418 at a dose of 4.224 mg/kg (0.70 mg/kg/h) measuring key hemodynamic endpoints (e.g., EF, cardiac output, the time velocity integral of the mitral inflow velocity waveform representing early filling to time-velocity integral representing left atrial contraction [Ei/Ai]). Studies 1 and 2 showed a dose-dependent increase of LVEF and Ei/Ai, the latter being an index of LV diastolic function. In study 3, infusion of APD418 over 6 hours increased LVEF from 31 ± 1% to 38 ± 1% (P < .05) and increased Ei/Ai from 3.4 ± 0.4 to 4.9 ± 0.5 (P < .05). Vehicle had no effect on the LVEF or Ei/Ai. In study 3, APD418 had no significant effects on the HR or the systemic blood pressure. CONCLUSIONS: Intravenous infusions of APD418 in dogs with systolic HF elicit significant positive inotropic and lusitropic effects. These findings support the development of APD418 for the in-hospital treatment of patients with an acute exacerbation of chronic HF.