How Aqueous Solvation Impacts the Frequencies and Intensities of Infrared Absorption Bands in Flavin: The Quest for a Suitable Solvent Model.

FTIR spectroscopy accompanied by quantum chemical simulations can reveal important information about molecular structure and intermolecular interactions in the condensed phase. Simulations typically account for the solvent either through cluster quantum mechanical (QM) models, polarizable continuum models (PCM), or hybrid quantum mechanical/molecular mechanical (QM/MM) models. Recently, we studied the effect of aqueous solvent interactions on the vibrational frequencies of lumiflavin, a minimal flavin model, using cluster QM and PCM models. Those models successfully reproduced the relative frequencies of four prominent stretching modes of flavin's isoalloxazine ring in the diagnostic 1450-1750 cm-1 range but poorly reproduced the relative band intensities. Here, we extend our studies on this system and account for solvation through a series of increasingly sophisticated models. Only by combining elements of QM clusters, QM/MM, and PCM approaches do we obtain an improved agreement with the experiment. The study sheds light more generally on factors that can impact the computed frequencies and intensities of IR bands in solution.

Natural disasters: a comprehensive study using EMDAT database 1995-2022.

INTRODUCTION: The frequency, intensity, and geographical reach of natural disasters, fueled in part by factors such as climate change, population growth, and urbanization, have undeniably been escalating concerns around the world. DESIGN AND METHODS: This is a retrospective analysis of natural disasters recorded in the Emergency Events Database from 1995 to 2022. RESULTS: Between 1995 and 2022, 11,360 natural disasters occurred, with a mean of 398 per year. Asia experienced the most disasters (4390) and the highest number of casualties (918,198). Hydrological disasters were the most common subgroup (4969), while geophysical disasters led in terms of deaths (770,644). Biological disasters caused the most injuries (2544), particularly in Africa. CONCLUSION: Recognizing the historical impacts of the various subtypes of natural disasters may help different regions better risk analyze and mitigate the unique risks associated with such events.

Effect of influenza vaccine subsidies for older adults on vaccination coverage and mortality before and during the COVID-19 pandemic: an ecological study in Japan.

OBJECTIVE: We aimed to determine how municipal subsidies for seasonal influenza vaccines for the elderly affected vaccination coverage and health outcomes and how responses to vaccine prices changed during the COVID-19 pandemic. STUDY DESIGN AND METHODS: This ecological study includes 1245 municipalities in Japan between 2019 and 2020. Fixed-effects regression analysis was performed to evaluate the effect of influenza vaccine cost subsidy for people aged 65 years or older on vaccination coverage, all-cause mortality, and influenza-related mortality. RESULTS: The vaccination rate increased when patients' copayments decreased, and reducing the copayment by 1000 Japanese Yen (JPY) was estimated to increase the vaccination rate by 6.3% (95% confidence interval [CI] 4.5-8.2%) in the adjusted model. When examining the additional effect of a zero price compared to a nearly zero price, we found that a zero price increased the immunization rate by 6.4% (95% CI 1.4-11.5%). The effect of copayment on the increase in vaccination coverage was significantly lower during the pandemic than in the pre-pandemic period. The municipal and prefectural analyses found no association between influenza vaccine copayments and all-cause, influenza, or pneumonia mortality. CONCLUSION: Cost subsidies and the zero-price effect were shown to increase vaccination coverage but were not associated with relevant mortality measures. Although the impact was attenuated under pandemic conditions, cost subsidy effectively increases the vaccination rate.

Impact of Lactobacillus crispatus-containing oral and vaginal probiotics on vaginal health: a randomised double-blind placebo controlled clinical trial.

Health of reproductive tract is tightly associated with balance of microbial communities in this area. Bacterial vaginosis (BV) and vulvovaginal candidiasis (VVC) represent common disturbances of vaginal communities. Vaginal discharge due to BV or VVC is a very frequent reason for visiting gynaecologist. We aimed to evaluate the impact of the novel evidence-based probiotics on BV and VVC patients. The study group included 89 BV and 93 VVC patients (aged 18-50 years) who were recruited into randomised double-blind placebo-controlled two-arm parallel trial. The patients of each diagnosis group received oral or vaginal probiotic capsules, or placebo capsules during 3 months. A probiotic capsule contained two (DSM32717 and DSM32720, in case of BV) or three (DSM32720, DSM32718 and DSM32716, in case of VVC) Lactobacillus crispatus strains. Vaginal, intestinal and general health was monitored weekly by questionnaire. Blood analyses were done in the beginning and at the end of trial. Vaginal samples were collected monthly, microscopic and molecular analyses were performed. The study revealed that both oral and vaginal capsules reduced the signs and symptoms in BV patients. Remarkable improvement was noted in Nugent score, amount and smell of discharge, but also in itching/irritation. Consumption of vaginal probiotics significantly increased the lactobacilli counts in their vagina while mean proportion of some BV-related bacteria decreased. In VVC patients, both oral and vaginal capsules lowered the combined score of two most important symptoms, amount of discharge and itching/irritation. In conclusion, the novel formulations of evidence-based well-focused probiotic L. crispatus strains are effective against BV and VVC being suitable for both vaginal and oral administration. Clinical trial registration: ISRCTN34840624, BioMed Central.

The upper extremity regional anaesthesia trifecta: three upper extremity nerve blocks for awake upper-limb surgery in a patient with a history of contralateral pneumonectomy.

While regional anaesthesia plays a pivotal role in the perioperative management of patients undergoing upper extremity surgery, its utility can be limited by the risk of hemi-diaphragmatic paresis. Furthermore, each approach to blocking the brachial plexus has associated limitations that may result in incomplete upper extremity anaesthesia. We describe the combination of three upper extremity nerve blocks to achieve surgical anaesthesia of the whole arm for a patient who had previously undergone a contralateral pneumonectomy. On this occasion, she required upper arm lipectomy and arteriovenous fistula formation. Adequate blockade was achieved with no significant perioperative complications. This case demonstrates the potential of this approach for patients with respiratory compromise undergoing upper limb procedures.

Prognostic factors for surgical outcomes among patients with multilevel cervical spondylotic myelopathy.

OBJECTIVE: Many clinical and imaging characteristics can influence the prognosis of multilevel cervical spondylotic myelopathy (M-CSM). This study investigated the factors that influence surgical outcomes among patients with M-CSM. PATIENTS AND METHODS: This prospective study included 30 patients who underwent surgical treatment for M-CSM from June 2019 to June 2021. RESULTS: The average age was 62.29 years, and the average follow-up time was 13.13 months. Preoperative, postoperative, and follow-up Modified Japanese Orthopaedic Association (mJOA) scores were 10.17, 13.53, and 16.17, respectively. The average postoperative and follow-up recovery rates were 45.46% and 76.69%, respectively. Patients older than 60 years (p = 0.04), male patients (p = 0.023), and smokers (p = 0.027) had lower preoperative mJOA scores than other groups. Patients with symptoms duration longer than 6 months had lower recovery rates (p = 0.021) than those with shorter symptom duration. Patients with intramedullary hyperintensity in ≤ 2 vertebra (p = 0.041) or anterior surgery (p = 0.022) had better postoperative recovery rates than their counterparts. A shorter period of hyperintensity in the intramedullary region on sagittal T2-weighted magnetic resonance imaging (T2W MRI) was significantly associated with faster discharge (p = 0.044). Patients with type 3 (discrete focal) hyperintensity in the intramedullary region on axial T2W MRI had a 6.75-fold increase in experiencing less than 50% postoperative recovery compared with other groups (odds ratio: 6.75, 95% confidence interval: 2.73-16.67). CONCLUSIONS: Good prognostic factors for a shorter recovery included hyperintensity in the intramedullary region for ≤ 2 levels, shorter period of hyperintensity in the intramedullary region on sagittal T2W MRI, and an anterior surgical approach. A duration of symptoms longer than 6 months and discrete hyperintensity in the intramedullary region on axial T2W MRI were poor prognostic indicators associated with a longer recovery period.

Persistent Coronary Vasomotor Tone During Myocardial Ischemia Occurs at the Capillary Level and May Involve Pericytes.

Background: There is persistent coronary vasomotor tone during myocardial ischemia, despite ongoing coronary arteriolar dilatation. The mechanism underlying this vasodilatory tone, which can be unmasked by coronary vasodilators, is unclear. We hypothesized that persistent microvascular resistance during myocardial ischemia occurs at the level of capillaries and may be caused by pericytes. Methods: We studied nine instrumented dogs where coronary blood flow and coronary driving pressure were reduced to half by placement of stenoses. Myocardial blood flow and myocardial blood volume were measured with myocardial contrast echocardiography before and during adenosine administration. In three animals, the heart was perfusion-fixed under these conditions for electron microscopic assessment of capillary and pericyte size. Results: During ischemia, myocardial blood volume decreased and myocardial vascular resistance remained unchanged. Adenosine administration reversed the decline in myocardial blood volume and decreased myocardial vascular resistance. Electron microscopy showed larger capillaries in ischemic beds receiving adenosine than ischemic beds not receiving adenosine. Pericytes in beds receiving adenosine also tended to be larger. Conclusion: Capillaries are the site of persistent vasomotor tone during myocardial ischemia; any other site of vascular regulation (arterioles or venules) cannot explain these myocardial contrast echocardiography findings, which are confirmed on post-mortem electron microscopic examination. The decrease in capillary size is likely caused by pericyte contraction in an attempt to maintain a constant capillary hydrostatic pressure. Adenosine relaxes pericytes, restores myocardial blood volume, reduces myocardial vascular resistance, and improves regional function during ischemia. These findings could have important therapeutic implications.

Design, synthesis, and evaluation of novel (E)-N'-(3-allyl-2-hydroxy)benzylidene-2-(4-oxoquinazolin-3(4H)-yl)acetohydrazides as antitumor agents.

In our continuing search for novel small-molecule anticancer agents, we designed and synthesized a series of novel (E)-N'-(3-allyl-2-hydroxy)benzylidene-2-(4-oxoquinazolin-3(4H)-yl)acetohydrazides (5), focusing on the modification of substitution in the quinazolin-4(3H)-one moiety. The biological evaluation showed that all 13 designed and synthesized compounds displayed significant cytotoxicity against three human cancer cell lines (SW620, colon cancer; PC-3, prostate cancer; NCI-H23, lung cancer). The most potent compound 5l displayed cytotoxicity up to 213-fold more potent than 5-fluorouracil and 87-fold more potent than PAC-1, the first procaspase-activating compound. Structure-activity relationship analysis revealed that substitution of either electron-withdrawing or electron-releasing groups at positions 6 or 7 on the quinazolin-4(3H)-4-one moiety increased the cytotoxicity of the compounds, but substitution at position 6 seemed to be more favorable. In the caspase activation assay, compound 5l was found to activate the caspase activity by 291% in comparison to PAC-1, which was used as a control. Further docking simulation also revealed that this compound may be a potent allosteric inhibitor of procaspase-3 through chelation of the inhibitory zinc ion. Physicochemical and ADMET calculations for 5l provided useful information of its suitable absorption profile and some toxicological effects that need further optimization to be developed as a promising anticancer agent.

Plasma Oxylipins: A Potential Risk Assessment Tool in Atherosclerotic Coronary Artery Disease.

Background: While oxylipins have been linked to coronary artery disease (CAD), little is known about their diagnostic and prognostic potential. Objective: We tested whether plasma concentration of specific oxylipins may discriminate among number of diseased coronary arteries and predict median 5-year outcomes in symptomatic adults. Methods: Using a combination of high-performance liquid chromatography (HPLC) and quantitative tandem mass spectrometry, we conducted a targeted analysis of 39 oxylipins in plasma samples of 23 asymptomatic adults with low CAD risk and 74 symptomatic adults (≥70% stenosis), aged 38-87 from the Greater Portland, Oregon area. Concentrations of 22 oxylipins were above the lower limit of quantification in >98% of adults and were compared, individually and in groups based on precursors and biosynthetic pathways, in symptomatic adults to number of diseased coronary arteries [(1) n = 31; (2) n = 23; (3) n = 20], and outcomes during a median 5-year follow-up (no surgery: n = 7; coronary stent placement: n = 24; coronary artery bypass graft surgery: n = 26; death: n = 7). Results: Plasma levels of six quantified oxylipins decreased with the number of diseased arteries; a panel of five oxylipins diagnosed three diseased arteries with 100% sensitivity and 70% specificity. Concentrations of five oxylipins were lower and one oxylipin was higher with survival; a panel of two oxylipins predicted survival during follow-up with 86% sensitivity and 91% specificity. Conclusions: Quantification of plasma oxylipins may assist in CAD diagnosis and prognosis in combination with standard risk assessment tools.

Novel 4-Oxoquinazoline-Based N-Hydroxypropenamides as Histone Deacetylase Inhibitors: Design, Synthesis, and Biological Evaluation.

Two series of novel 4-oxoquinazoline-based N-hydroxypropenamides (9a-m and 10a-m) were designed, synthesized, and evaluated for their inhibitory and cytotoxicity activities against histone deacetylase (HDAC). The compounds showed good to potent HDAC inhibitory activity and cytotoxicity against three human cancer cell lines (SW620, colon; PC-3, prostate; NCI-H23, lung cancer). In this series, compounds with the N-hydroxypropenamide functionality impeded at position 7 on the 4-oxoquinazoline skeleton (10a-m) were generally more potent than compounds with the N-hydroxypropenamide moiety at position 6 (9a-m). Also, the N 3-benzyl-substituted derivatives (9h-m, 10h-m) exhibited stronger bioactivity than the N 3-alkyl-substituted ones (9a-e, 10a-e). Two compounds 10l and 10m were the most potent ones. Their HDAC inhibitory activity (IC50 values, 0.041-0.044 µM) and cytotoxicity (IC50 values, 0.671-1.211 µM) were approximately 2- to 3-fold more potent than suberoylanilide hydroxamic acid (SAHA). Some compounds showed up to 10-fold more potent HDAC6 inhibition compared to their inhibitory activity in total HDAC extract assay. Analysis of selected compounds 10l and 10m revealed that these compounds strongly induced both early and late apoptosis and arrested SW620 cells at the G2/M phase. Docking studies were carried out on the HDAC6 isoform for series 10a-m and revealed some important features contributing to the inhibitory activity of synthesized compounds.

Does the time from diagnostic biopsy to neoadjuvant chemotherapy affect the rate of pathologic complete response in stages I-III breast cancer?

Background: Studies in the adjuvant setting suggest that the timing of breast cancer diagnosis, surgery, and chemotherapy might affect outcomes. In the neoadjuvant setting, data exploring whether expeditious neoadjuvant chemotherapy (nac) after diagnosis improves the rate of pathologic complete response (pcr) in breast cancer are limited. Methods: Patients who received nac and completed treatment between May 2012 and December 2018 were identified from a prospectively collected database at BC Cancer. Time from diagnosis to start of nac was calculated. Patients were grouped into those who did and did not experience a pcr, and those who started nac within 28 days or after 28 days [time to nac (ttn)]. The association between pcr and ttn was tested using logistic regression. Results: In the time period studied, 482 patients who received nac were identified. After exclusions, 421 patients met the eligibility criteria. Median time from biopsy to chemotherapy was 33 days (range: 7-140 days). In 149 patients (35.4%), nac was received within 28 days of diagnosis (range: 7-28 days); in 272 patients (64.6%), it was received after more than 28 days (range: 29-140 days). The overall pcr rate was 31.8%. A trend toward a higher pcr rate, although not statistically significant, was observed in the group that initiated chemotherapy within 28 days (34.2% vs. 30.5%, p = 0.43). In the logistic regression model, rates of pcr were associated with receptor status, but not age, stage, or ttn. Conclusions: In the neoadjuvant setting, we observed no difference in the rate of pcr in patients who started nac within 28 days or after 28 days.

Therapeutic Ultrasound Improves Myocardial Blood Flow and Reduces Infarct Size in a Canine Model of Coronary Microthromboembolism.

BACKGROUND: Therapeutic ultrasound (TUS) has been used to lyse infarct-related coronary artery thrombus. There has been no study examining the effect of TUS specifically on myocardial microthromboemboli seen in acute myocardial infarction and acute coronary syndromes. The aim of this study was to test the hypothesis that TUS improves myocardial blood flow (MBF) and reduces infarct size (IS) in this situation by dissolving myocardial microthrombi. METHODS: An open-chest canine model of myocardial microthromboembolism was created by disrupting a thrombus in the left anterior descending coronary artery, and 1.05- and 0.25-MHz TUS (n = 7 each) delivered epicardially for 30 min was compared with control (n = 6). MBF and IS (as a percentage of left anterior descending coronary artery perfusion bed size) were measured 60 min after treatment. In addition, immunohistochemistry was performed to assess microthrombi, and histopathology was performed to define inflammation. RESULTS: Transmural, epicardial, and endocardial myocardial blood volume and MBF (measured using myocardial contrast echocardiography) and percentage wall thickening were significantly higher 60 min after receiving TUS compared with control. The ratio of IS to left anterior descending coronary artery perfusion bed size was significantly smaller (P = .03) in the 1.05-MHz TUS group (0.14 ± 0.04) compared with the control (0.31 ± 0.06, P = .04) and 0.25-MHz (0.36 ± 0.08) groups. MBF versus percentage wall thickening exhibited a linear relation (r = 0.65) in the control and 1.05-MHz TUS groups but not in the 0.25-MHz TUS group (r = 0.29). The presence of myocardial microemboli in vessels >10 µm in diameter was significantly reduced in the 1.05-MHz TUS group compared with the other two groups. The distribution and intensity of inflammation was higher in the 0.25-MHz TUS group compared with the other groups. CONCLUSIONS: TUS at 1.05 MHz is effective in restoring myocardial blood volume and MBF, thus reducing IS by clearing the microcirculation of microthrombi. IS reduction is not seen at 0.25 MHz, despite improvement in MBF, which may be related to the increased inflammation noted at this frequency. Because both acute myocardial infarction and acute coronary syndromes are associated with microthromboembolism, these results suggest that TUS could have a potential adjunctive role in the treatment of both conditions.

Ranolazine may exert its beneficial effects by increasing myocardial adenosine levels.

We hypothesized that ranolazine-induced adenosine release is responsible for its beneficial effects in ischemic heart disease. Sixteen open-chest anesthetized dogs with noncritical coronary stenosis were studied at rest, during dobutamine stress, and during dobutamine stress with ranolazine. Six additional dogs without stenosis were studied only at rest. Regional myocardial function and perfusion were assessed. Coronary venous blood was drawn. Murine endothelial cells and cardiomyocytes were incubated with ranolazine and adenosine metabolic enzyme inhibitors, and adenosine levels were measured. Cardiomyocytes were also exposed to dobutamine and dobutamine with ranolazine. Modeling was employed to determine whether ranolazine can bind to an enzyme that alters adenosine stores. Ranolazine was associated with increased adenosine levels in the absence (21.7 ± 3.0 vs. 9.4 ± 2.1 ng/mL, P < 0.05) and presence of ischemia (43.1 ± 13.2 vs. 23.4 ± 5.3 ng/mL, P < 0.05). Left ventricular end-systolic wall stress decreased (49.85 ± 4.68 vs. 57.42 ± 3.73 dyn/cm2, P < 0.05) and endocardial-to-epicardial myocardial blood flow ratio tended to normalize (0.89 ± 0.08 vs. 0.76 ± 0.10, P = nonsignificant). Adenosine levels increased in cardiac endothelial cells and cardiomyocytes when incubated with ranolazine that was reversed when cytosolic-5'-nucleotidase (cN-II) was inhibited. Point mutation of cN-II aborted an increase in its specific activity by ranolazine. Similarly, adenosine levels did not increase when cardiomyocytes were incubated with dobutamine. Modeling demonstrated plausible binding of ranolazine to cN-II with a docking energy of -11.7 kcal/mol. We conclude that the anti-adrenergic and cardioprotective effects of ranolazine-induced increase in tissue adenosine levels, likely mediated by increasing cN-II activity, may contribute to its beneficial effects in ischemic heart disease.NEW & NOTEWORTHY Ranolazine is a drug used for treatment of angina pectoris in patients with ischemic heart disease. We discovered a novel mechanism by which this drug may exhibit its beneficial effects. It increases coronary venous levels of adenosine both at rest and during dobutamine-induced myocardial ischemia. Ranolazine also increases adenosine levels in endothelial cells and cardiomyocytes in vitro, by principally increasing activity of the enzyme cytosolic-5'-nucleotidase. Adenosine has well-known myocardial protective and anti-adrenergic properties that may explain, in part, ranolazine's beneficial effect in ischemic heart disease.

Poly-ε-caprolactone scaffold for the reinforcement of stapled small intestinal anastomoses: a randomized experimental study.

BACKGROUND: Anastomotic leakage is a severe complication in gastrointestinal surgery. Different methods have been evaluated for anastomotic reinforcement to prevent anastomotic leakage. The aim of this study was to investigate the effect of a poly-ε-caprolactone (PCL) scaffold incorporated in the staple-line, on the anastomotic strength and histological wound healing, of small intestinal anastomoses in piglets. METHOD: This randomized experimental trial included 17 piglets. In each piglet, three end-to-end anastomoses were performed in the small intestine with a circular stapler, i.e. one control and two interventional anastomoses. On postoperative day 5, the anastomoses were resected and subjected to tension stretch test and histological examination. RESULTS: No anastomotic leakage occurred. In the interventional anastomoses, the mean value for maximal tensile strength was 15.7 N, which was significantly higher than control anastomoses 12.7 N (p = 0.01). No statistically significant differences were found between the two groups in the histopathological parameters. CONCLUSION: To conclude, this study has shown that the incorporation of a PCL scaffold in the staple-line was feasible and significantly increased the maximal tensile strength of small intestine anastomoses in piglets on postoperative day 5. The difference in histological parameters was not significantly distinct.

Examining the link between thoracic rotation and scapular dyskinesis and shoulder pain amongst college swimmers.

OBJECTIVES: In National Collegiate Athletic Association Division I swimmers, we examined the differences in thoracic spine rotation in swimmers with and without scapular dyskinesis and the relationship between thoracic spine rotation and shoulder pain/dysfunction according to the Kerlan-Jobe Orthopaedic Clinic (KJOC) score. DESIGN: Cross-sectional. SETTING: Laboratory-based. PARTICIPANTS: 34 NCAA Division I swimmers (13 males, 21 females). MAIN OUTCOME MEASURES: Self-reported upper extremity function and pain assessed with the KJOC questionnaire, thoracic spine range of motion, presence of scapular dyskinesis. RESULTS: Dyskinesis was present in 15 of 34 (44%) subjects. Thoracic rotation averaged 136.7° and KJOC averaged 87.7 with no differences between swimmers with or without dyskinesis. We observed no correlation between KJOC-identified shoulder pain/dysfunction and thoracic rotation. CONCLUSIONS: In our cohort of NCAA Division 1 swimmers, no differences were found between swimmers with or without scapular dyskinesis and extent of thoracic rotation. We found no correlation between thoracic rotation and the amount of self-reported pain and dysfunction experienced in the upper extremity. The presence of scapular dyskinesis in nearly half of our subjects indicates that swimmers need to be assessed for this abnormality. If observed, rehabilitation should address the dyskinesis and improve thoracic rotation in an attempt to alleviate further upper extremity pain and dysfunction.

Therapeutic Ultrasound Increases Myocardial Blood Flow in Ischemic Myocardium and Cardiac Endothelial Cells: Results of In Vivo and In Vitro Experiments.

BACKGROUND: Therapeutic ultrasound can reduce infarct size in a model of coronary thrombosis even when sonothrombolysis is ineffective. The aim of this study was to test the hypothesis that ultrasound-induced cardioprotection is mediated by molecules released from the vascular endothelium that increase myocardial blood flow (MBF) and also have direct tissue-salvaging effects. METHODS: In vivo and in vitro experiments were performed using a 1.05-MHz transducer. For the in vivo experiments 10 control and 10 ultrasound-treated dogs undergoing occlusion of the left anterior descending coronary artery were studied. MBF was measured using myocardial contrast echocardiography. For the in vitro experiments, primary mouse cardiac endothelial cells were exposed to ultrasound at baseline or following oxygen-glucose deprivation and endothelial nitric oxide synthase phosphorylation as well as adenosine and the eicosanoids epoxyeicosatrienoic acids, dihydroxyeicosatrienoic acids, and hydroxyl-eicosatetraenoic acids were measured. RESULTS: In vivo, ultrasound treatment caused higher MBF (20 ± 10 vs 10 ± 8, P = .03) and higher wall thickening (3 ± 3% vs 1 ± 0.4%, P = .01) in the collateral-derived border zone compared with control. Epicardial MBF in the left anterior descending coronary artery bed also tended to be higher (17 ± 17 vs 5 ± 4, P = .05) in ultrasound-treated versus control animals; however, endocardial MBF in this region was similar to that in controls (13 ± 14 vs 14 ± 7). In vitro, phosphorylated endothelial nitric oxide synthase and adenosine increased (by 129 ± 11% and 286 ± 63%, respectively, P < .01) with ultrasound compared with unstimulated cells. Similar results were obtained with epoxyeicosatrienoic acids. After oxygen-glucose deprivation, phosphorylated endothelial nitric oxide synthase decreased and was restored with application of ultrasound. Similar changes were noted with epoxyeicosatrienoic acids. Cell viability decreased with oxygen-glucose deprivation and returned to near baseline with ultrasound. CONCLUSIONS: Ultrasound increases MBF in ischemic tissue in vivo. This effect is likely mediated by the release of a plethora of coronary vasodilators during ultrasound treatment that also have direct tissue-salvaging effects. Therapeutic ultrasound, therefore, has potential for treatment of acute and chronic myocardial ischemia independent of its effect on thrombolysis.

Investigating intervention dose frequency for children with speech sound disorders and motor speech involvement.

BACKGROUND: Treatment outcome data for children with severe speech sound disorders with motor speech involvement (SSD-MSI) are derived from Phase I clinical research studies. These studies have demonstrated positive improvements in speech production. Currently there is no research examining the optimal treatment dose frequency for this population. The results of this study, which is the first of its kind, will inform the delivery of effective services for this population. AIMS: To investigate optimal treatment dose frequency for the Motor Speech Treatment Protocol (MSTP) for children with SSD-MSI. METHODS & PROCEDURES: A total of 48 children (aged 43-47 months) with SSD-MSI participated in the study. Participants received 45-min MSTP intervention sessions either once per week (lower dose frequency) or twice per week (higher dose frequency) for a 10-week period. Blinded outcome assessments were carried out at pre- and post-intervention. OUTCOMES & RESULTS: Treatment-related change was assessed at body structures, functions and activities participation level as per the World Health Organization's International Classification of Functioning framework: Children and Youth Version (ICF-CY) framework WHO (2007). These measures are related to articulation, functional communication and speech intelligibility. One-way analysis of variance (ANOVA) revealed that for all variables the baseline scores were not statistically different (p > 0.05) between the two dose-frequency groups. Overall, there was a significant main effect of Time (pre-post) across all variables (p < 0.01). However, repeated-measures ANOVA did not result in any statistical interactions (Time × Dose frequency) for any of the variables tested (p > 0.05). Only marginal clinical advantages (< 4% change in intelligibility) were noted with the 10 extra sessions. CONCLUSIONS & IMPLICATIONS: Overall, the MSTP intervention approach in conjunction with home practice led to significant positive changes for all measures in children with SSD-MSI. No statistical differences between high- and low-dose-frequency groups were observed for any of the variables. Clinical effects were examined using effect sizes, as well as changes in articulation, speech intelligibility and functional communication; these differed marginally between the two dose frequencies. This suggests limited benefits of 10 additional sessions per block. Thus, it is recommended that caregivers, speech-language therapists and policy-makers perform a cost-benefit analysis before determining the dose frequency, when considering additional sessions per block.

Report from the 20th annual Western Canadian Gastrointestinal Cancer Consensus Conference; Saskatoon, Saskatchewan; 28-29 September 2018.

The 20th annual Western Canadian Gastrointestinal Cancer Consensus Conference was held in Saskatoon, Saskatchewan, 28-29 September 2018. This interactive multidisciplinary conference is attended by health care professionals from across Western Canada (British Columbia, Alberta, Saskatchewan, and Manitoba) who are involved in the care of patients with gastrointestinal cancers. In addition, invited speakers from other provinces participate. Surgical, medical, and radiation oncologists, and allied health care professionals participated in presentations and discussion sessions for the purpose of developing the recommendations presented here. This consensus statement addresses current issues in the management of colorectal cancers.

Histopathological and immunophenotypic features of ipilimumab-associated colitis compared to ulcerative colitis.

BACKGROUND: Use of the immune checkpoint inhibitor ipilimumab is sometimes complicated by ipilimumab-associated colitis (Ipi-AC), an immune-mediated colitis that mimics inflammatory bowel disease. OBJECTIVE: We sought to characterize the histopathologic and immunophenotypic features of Ipi-AC and to directly compare these features to ulcerative colitis (UC). METHODS: This is a retrospective cohort study of 22 patients with Ipi-AC, 12 patients with treatment-naïve UC and five controls with diarrhoea but normal endoscopic findings. Immunohistopathologic features were described, and quantitative immunohistochemistry (IHC) was performed for CD4, CD8, CD20, CD138 and FOXP3. RESULTS: Endoscopic findings in both the Ipi-AC and UC groups included ulcerated, oedematous and erythematous mucosa. Involvement of the GI tract was more diffuse in Ipi-AC. As compared to UC, a smaller proportion of Ipi-AC biopsies had basal plasmacytosis (14% for Ipi-AC vs. 92% for UC, P < 0.0001) and crypt distortion (23% for Ipi-AC vs. 75% for UC, P = 0.003), whereas Ipi-AC biopsies had more apoptotic bodies in the left colon (17.6 ± 15.3 for Ipi-AC vs. 8.2 ± 4.2 for UC, P = 0.011). Cryptitis, ulcerations and crypt abscesses were common in both groups. Biopsy specimens from Ipi-AC had a lower density of CD20-positive lymphocytes than UC (275.8 ± 253.3 cells mm-2 for Ipi-AC vs. 1173.3 ± 1158.2 cells mm-2 for UC, P = 0.022) but had a similar density of CD4, CD8, CD138 and FOXP3-positive cells. CONCLUSIONS: Ipi-AC is a distinct pathologic entity with notable clinical and histopathological differences compared to UC. These findings provide insights into the pathophysiology of immune-related adverse events (iAEs) from ipilimumab therapy.