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Ovarian hyperstimulation syndrome (OHSS) may be a severe complication of controlled ovarian hyperstimulation during assisted reproductive technology. During OHSS, fluid shifts from the intravascular space to the third-space compartments as the result of an increase in capillary permeability. This can cause fluid accumulation in peritoneal as well as thoracic cavities. The patient presented with symptoms of severe OHSS (bilateral hydrothorax and pulmonary effusion), requiring bilateral ultrasound-guided paracentesis and bilateral thoracentesis during her Emergency Room visits and hospitalization. Due to distant effects from the increased capillary permeability, the patient presented fluid in the middle ear, which led to the development of serous otitis media 12 days after egg retrieval. This was resolved 2-3 weeks later after being treated with antihistamines and antibiotics given by her Ear, Nose, and Throat doctor. OHSS risk may be reduced by continuous monitoring of patients undergoing ovulation induction, using an appropriate gonadotropin dosage, and using additional agents known to decrease its risk. If OHSS still occurs, symptomatic treatment and a multidisciplinary team of professionals may be needed to prevent fluid build-up complications. In contrast to many published articles about OHSS and its complications, this is the first case report of a patient presenting serous otitis media as a complication of severe OHSS., (© 2023 International Federation of Gynecology and Obstetrics.)

Purpose: We examined the utility of echocardiographic 2-dimensional speckle tracking strain imaging (SI) for the evaluation of segmental myocardial dysfunction before and after radiation therapy (RT) and the relationship to dose exposure., Methods and Materials: We prospectively recruited 40 women with left-sided breast cancer, undergoing only adjuvant RT to the left chest. Comparisons of traditional echocardiographic parameters and SI parameters at baseline and 6 weeks after RT were analyzed. Regional strain and strain rate (SR) parameters were obtained from all 18 left ventricular segments. The correlation of change in strain parameters with segmental radiation dose was examined., Results: We observed a significant reduction in global and segmental systolic strain parameters at 6 weeks after RT compared with baseline, with the largest decrement in the apical segments; this corresponded with the segments receiving the highest radiation dose exposure (apical peak systolic strain of -21.21% ± 3.49% before RT vs -18.69% ± 3.34% after RT, percentage change of 11.88%, P=.002; apical peak systolic SR of -1.17 ± 0.24 s -1 before RT vs -1.04 ± 0.19 s -1 after RT, percentage change of 11.11%, P=.008). There was a modest correlation between the apical segment systolic strain reduction and radiation dose exposure (apical segment Δ change and apical radiation dose, r=0.345, P=.031; apical segment percentage change and apical radiation dose, r=0.346, P=.031). A significant reduction in early diastolic SR was observed in the apical segments after treatment compared with baseline (apical early diastolic SR, 1.54 ± 0.45 s -1 before RT vs 1.35 ± 0.33 after RT s -1 ; percentage change, 12.34%; P=.034)., Conclusions: Two-dimensional SI detected dose-related regional myocardial dysfunction in the acute phase after RT in chemotherapy-naive left-sided breast cancer patients. Although the long-term effects remain unknown, this imaging modality may have a potential role in the evaluation of irradiation-related cardiotoxicity., (Copyright © 2017 Elsevier Inc. All rights reserved.)

LOXL2 catalyzes the oxidative deamination of ε-amines of lysine and hydroxylysine residues within collagen and elastin, generating reactive aldehydes (allysine). Condensation with other allysines or lysines drives the formation of inter- and intramolecular cross-linkages, a process critical for the remodeling of the ECM. Dysregulation of this process can lead to fibrosis, and LOXL2 is known to be upregulated in fibrotic tissue. Small-molecules that directly inhibit LOXL2 catalytic activity represent a useful option for the treatment of fibrosis. Herein, we describe optimization of an initial hit 2, resulting in identification of racemic-trans-(3-((4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)(3-fluoro-4-hydroxypyrrolidin-1-yl)methanone 28, a potent irreversible inhibitor of LOXL2 that is highly selective over LOX and other amine oxidases. Oral administration of 28 significantly reduced fibrosis in a 14-day mouse lung bleomycin model. The (R,R)-enantiomer 43 (PAT-1251) was selected as the clinical compound which has progressed into healthy volunteer Phase 1 trials, making it the "first-in-class" small-molecule LOXL2 inhibitor to enter clinical development.

Two series of novel LOXL2 enzyme inhibitors are described: benzylamines substituted with electron withdrawing groups at the para -position and 2-substituted pyridine-4-ylmethanamines. The most potent compound, (2-chloropyridin-4-yl)methanamine 20 (hLOXL2 IC 50 = 126 nM), was shown to be selective for LOXL2 over LOX and three other amine oxidases (MAO-A, MAO-B, and SSAO). Compound 20 is the first published small molecule inhibitor selective for LOXL2 over LOX.

Autotaxin (ATX) is a secreted glycoprotein that converts lysophosphatidylcholine (LPC) to the bioactive phospholipid lysophosphatidic acid (LPA) and is the major enzyme generating circulating LPA. Inhibition of LPA signaling has profound antifibrotic effects in multiple organ systems, including lung, kidney, skin, and peritoneum. However, other LPA-generating pathways exist, and the role of ATX in localized tissue LPA production and fibrosis remains unclear and controversial. In this study, we describe the preclinical pharmacologic, pharmacokinetic, and pharmacodynamic properties of a novel small-molecule ATX inhibitor, PAT-505 [3-((6-chloro-2-cyclopropyl-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl) thio)-2-fluorobenzoic acid sodium salt]. PAT-505 is a potent, selective, noncompetitive inhibitor that displays significant inhibition of ATX activity in plasma and liver tissue after oral administration. When dosed therapeutically in a Stelic Mouse Animal Model of nonalcoholic steatohepatitis (NASH), PAT-505 treatment resulted in a small but significant improvement in fibrosis with only minor improvements in hepatocellular ballooning and hepatic inflammation. In a choline-deficient, high-fat diet model of NASH, therapeutic treatment with PAT-505 robustly reduced liver fibrosis with no significant effect on steatosis, hepatocellular ballooning, or inflammation. These data demonstrate that inhibiting autotaxin is antifibrotic and may represent a novel therapeutic approach for the treatment of multiple fibrotic liver diseases, including NASH., (Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.)

Aim: Innovative e-health strategies are emerging, to tailor and provide convenient, systematic and high-quality survivorship care for an expanding cancer survivor population. This pilot study tests the application of an e-health platform, "Healthy.me," in a breast cancer survivor cohort at Liverpool and Macarthur Cancer Therapy Centres, New South Wales, Australia., Methods: Fifty breast cancer patients were recruited to use the Healthy.me website, designed by the Centre of Health Informatics at the University of New South Wales, over a 4-month period. Telephone and online questionnaires were used at 1 and 4 months and a face-to-face feedback at study completion, to gather qualitative and quantitative data regarding feasibility of Healthy.me., Results: Healthy.me was reported to be a useful online resource by most users. Usage declined from 76% at 1 month to 48% at 4 months. Breast cancer survivors enjoyed a variety of tailored information regarding health and life-style issues. Positive aspects of Healthy.me were the convenient access to trusted information, and interaction with their peers and healthcare professionals. Barriers to usage contributing to usage decline were lack of reported patient time to re-access information, limited content updates and technical factors., Conclusions: This pilot study suggested the potential of an e-health strategy such as Healthy.me in addressing the needs of a growing breast cancer survivor population. Ongoing development of a more robust e-health resource and integration with primary care models is warranted., (© 2016 John Wiley & Sons Australia, Ltd.)

Autotaxin (ATX) is a secreted enzyme that hydrolyzes lysophosphatidylcholine to lysophosphatidic acid (LPA). LPA is a bioactive phospholipid that regulates diverse biological processes, including cell proliferation, migration, and survival/apoptosis, through the activation of a family of G protein-coupled receptors. The ATX-LPA pathway has been implicated in many pathologic conditions, including cancer, fibrosis, inflammation, cholestatic pruritus, and pain. Therefore, ATX inhibitors represent an attractive strategy for the development of therapeutics to treat a variety of diseases. Mouse and rat ATX have been crystallized previously with LPA or small-molecule inhibitors bound. Here, we present the crystal structures of human ATX in complex with four previously unpublished, structurally distinct ATX inhibitors. We demonstrate that the mechanism of inhibition of each compound reflects its unique interactions with human ATX. Our studies may provide a basis for the rational design of novel ATX inhibitors., (Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.)

Purpose: To evaluate 2-dimensional strain imaging (SI) for the detection of subclinical myocardial dysfunction during and after radiation therapy (RT)., Methods and Materials: Forty women with left-sided breast cancer, undergoing only adjuvant RT to the left chest, were prospectively recruited. Standard echocardiography and SI were performed at baseline, during RT, and 6 weeks after RT. Strain (S) and strain rate (Sr) parameters were measured in the longitudinal, circumferential, and radial planes. Correlation of change in global longitudinal strain (GLS % and Δ change) and the volume of heart receiving 30 Gy (V30) and mean heart dose (MHD) were examined., Results: Left ventricular ejection fraction was unchanged; however, longitudinal systolic S and Sr and radial S were significantly reduced during RT and remained reduced at 6 weeks after treatment [longitudinal S (%) -20.44 ± 2.66 baseline vs -18.60 ± 2.70* during RT vs -18.34 ± 2.86* at 6 weeks after RT; longitudinal Sr (s(-1)) -1.19 ± 0.21 vs -1.06 ± 0.18* vs -1.06 ± 0.16*; radial S (%) 56.66 ± 18.57 vs 46.93 ± 14.56* vs 49.22 ± 15.81*; *P<.05 vs baseline]. Diastolic Sr were only reduced 6 weeks after RT [longitudinal E Sr (s(-1)) 1.47 ± 0.32 vs 1.29 ± 0.27*; longitudinal A Sr (s(-1)) 1.19 ± 0.31 vs 1.03 ± 0.24*; *P<.05 vs baseline], whereas circumferential strain was preserved throughout. A modest correlation between S and Sr and V30 and MHD was observed (GLS Δ change and V30 ρ = 0.314, P=.05; GLS % change and V30 ρ = 0.288, P=.076; GLS Δ change and MHD ρ = 0.348, P=.03; GLS % change and MHD ρ = 0.346, P=.031)., Conclusions: Subclinical myocardial dysfunction was detected by 2-dimensional SI during RT, with changes persisting 6 weeks after treatment, though long-term effects remain unknown. Additionally, a modest correlation between strain reduction and radiation dose was observed., (Copyright © 2015 Elsevier Inc. All rights reserved.)

G-protein coupled inwardly rectifying potassium (GIRK) channels are effectors determining degree of analgesia experienced upon opioid receptor activation by endogenous and exogenous opioids. The impact of GIRK-related genetic variation on human pain responses has received little research attention. We used a tag single nucleotide polymorphism (SNP) approach to comprehensively examine pain-related effects of KCNJ3 (GIRK1) and KCNJ6 (GIRK2) gene variation. Forty-one KCNJ3 and 69 KCNJ6 tag SNPs were selected, capturing the known variability in each gene. The primary sample included 311 white patients undergoing total knee arthroplasty in whom postsurgical oral opioid analgesic medication order data were available. Primary sample findings were then replicated in an independent white sample of 63 healthy pain-free individuals and 75 individuals with chronic low back pain (CLBP) who provided data regarding laboratory acute pain responsiveness (ischemic task) and chronic pain intensity and unpleasantness (CLBP only). Univariate quantitative trait analyses in the primary sample revealed that 8 KCNJ6 SNPs were significantly associated with the medication order phenotype (P < .05); overall effects of the KCNJ6 gene (gene set-based analysis) just failed to reach significance (P = .054). No significant KCNJ3 effects were observed. A continuous GIRK Related Risk Score (GRRS) was derived in the primary sample to summarize each individual's number of KCNJ6 "pain risk" alleles. This GRRS was applied to the replication sample, which revealed significant associations (P < .05) between higher GRRS values and lower acute pain tolerance and higher CLBP intensity and unpleasantness. Results suggest further exploration of the impact of KCNJ6 genetic variation on pain outcomes is warranted., (Copyright © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Aims: The delineation of target volumes has been radiation oncologist led. If radiation therapists were to undertake this task, work processes may be more efficient and the skills set of radiation therapy staff broadened. This study was undertaken to quantify interobserver variability of breast target volumes between radiation oncologists and radiation therapists., Materials and Methods: The planning computed tomography datasets of 30 patients undergoing tangential breast radiotherapy were utilised. Four radiation oncologists and four radiation therapists independently contoured the clinical target volume (CTV) of the breast on planning computed tomography using a written protocol. The mean CTV volumes and the mean distance between centres of volume (COV) were determined for both groups to determine intergroup variation. Each of the radiation oncologists' readings in turn has been used as the gold standard and compared with that of the radiation therapists. The concordance index for each patient's CTV was determined relative to the gold standard for each group. A paired t-test was used for statistical comparison between the groups. An intraclass correlation coefficient was calculated to measure the agreement between the radiation oncologist and radiation therapist groups., Results: The mean concordance index was 0.81 for radiation oncologists and 0.84 for radiation therapists. The intraclass correlation coefficient for the mean volume was 0.995 (95% confidence interval 0.981-0.998) between radiation oncologist- and radiation therapist-contoured volumes. The intraclass correlation for the mean difference between radiation oncologists' and radiation therapists' COV was 0.999 (95% confidence interval 0.999-1.000)., Conclusions: Interobserver variability between radiation oncologists and radiation therapists was found to be low. Radiation therapists could potentially assume the role of CTV voluming for breast radiotherapy provided a standardised contouring protocol is in place., (Copyright © 2010 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)