Small RNA sequencing reveals snoRNAs and piRNA-019825 as novel players in diabetic kidney disease.

INTRODUCTION: Micro- and macrovascular complications are common among persons with type 2 diabetes. Recently there has been growing interest to investigate the potential of circulating small non-coding RNAs (sncRNAs) as contributors to the development of diabetic complications. In this study we investigate to what extent circulating sncRNAs levels associate with prevalent diabetic kidney disease (DKD) in persons with type 2 diabetes. METHODS: Plasma sncRNAs levels were determined using small RNA-seq, allowing detection of miRNAs, snoRNAs, piRNAs, tRNA fragments, and various other sncRNA classes. We tested for differentially expressed sncRNAs in persons with type 2 diabetes, with DKD (n = 69) or without DKD (n = 405). In secondary analyses, we also tested the association with eGFR, albuminuria (UACR), and the plasma proteome. RESULTS: In total seven sncRNAs were negatively associated with prevalent DKD (all PFDR ≤ 0.05). Including one microRNA (miR-143-5p), five snoRNAs (U8, SNORD118, SNORD24, SNORD107, SNORD87) and a piRNA (piR-019825 | DQ597218). Proteomic analyses showed that the seven sncRNAs, and especially the piRNA piR-019825, were associated with plasma levels of 24 proteins of which several have known associations with kidney function including TNF sR-I (TNFRFS1A), DAN (NBL1) and cystatin C (CST3). CONCLUSION: We have identified novel small non-coding RNAs, primarily from classes other than microRNAs, that are associated with diabetic kidney disease. Our results show that the involvement of small non-coding RNAs in DKD goes beyond the already known microRNAs and also involves other classes of sncRNA, in particular snoRNAs and the piRNA piR-019825, that have never been studied before in relation to kidney function.

Factors influencing CDC- recommended preventative behaviors through the COVID-19 pandemic in college students.

Objective: To understand how student perceptions of physical health and generalized concern about infection influenced engagement in COVID-19 preventive behaviors. Participants: 418 full-time undergraduate and graduate students attending a public university in South Carolina, USA. Methods: A self-administered survey was distributed during the 2020-2021 academic year. The health belief model, structural equation modeling, and regression methods were used to evaluate associations between students' perceived physical health and the use of CDC-recommended mitigation strategies. Results: Our findings suggest that an individual's perception of their own physical health impacted engagement in preventive behaviors by influencing concerns about disease severity (p = 0.01) and susceptibility (p = 0.03). However, perceived physical health was not associated with perceived benefits (p = 0.21), barriers (p = 0.57), or self-efficacy (p = 0.62) of mitigation strategies. Conclusions: Intrapersonal factors may play a strong role in the way a student undertakes disease control and prevention.

A qualitative study of fourteen African countries' nursing workforce and labour market.

AIM: The aim of this study was to describe factors affecting nursing education and labour markets in countries in East, Central, and Southern Africa, and critical areas for investment. BACKGROUND: An understanding about the relationship between the supply of nurses (determined by types of educational programmes, and the quantity and quality of nurse graduates), and workforce demand is critical to health policy development. METHODS: Six focus groups and 14 key informant interviews with nursing leaders and experts were conducted. Participants included government chief nursing officers, registrars of regulatory bodies, association leaders and heads of nursing education. The data were transcribed, coded and analysed using inductive techniques. FINDINGS: Participants discussed challenges and strengths of nursing education, school and regulatory infrastructure, financing mechanisms for the nursing workforce, the state of nursing jobs and scope of nursing practice. CONCLUSION: Strengthened regulations and leadership are needed to improve investment in nursing, the quality of nursing education, and working conditions and to promote the achievement of better health outcomes. IMPLICATIONS FOR NURSING POLICY: Clarifying scope of practice for nurses in the health sector and creating competency-based requirements is important. Governments should establish positions that align with updated competencies and provide fair and safe working conditions. The current and ongoing investment case for nursing requires improved data systems and a commitment to use labour market data for decision-making.

Evaluation of classic and novel ultrasound signs of placenta accreta spectrum.

OBJECTIVES: Improvement in the antenatal diagnosis of placenta accreta spectrum (PAS) would allow preparation for delivery in a referral center, leading to decreased maternal morbidity and mortality. Our objectives were to assess the performance of classic ultrasound signs and to determine the value of novel ultrasound signs in the detection of PAS. METHODS: This was a retrospective cohort study of women with second-trimester placenta previa who underwent third-trimester transvaginal ultrasound and all women with PAS in seven medical centers. A retrospective image review for signs of PAS was conducted by three maternal-fetal medicine physicians. Classic signs of PAS were defined as placental lacunae, bladder-wall interruption, myometrial thinning and subplacental hypervascularity. Novel signs were defined as small placental lacunae, irregular placenta-myometrium interface (PMI), vascular PMI, non-tapered placental edge and placental bulge towards the bladder. PAS was diagnosed based on difficulty in removing the placenta or pathological examination of the placenta. Multivariate regression analysis was performed and receiver-operating-characteristics (ROC) curves were generated to assess the performance of combined novel signs, combined classic signs and a model combining classic and novel signs. RESULTS: A total of 385 cases with placenta previa were included, of which 55 had PAS (28 had placenta accreta, 11 had placenta increta and 16 had placenta percreta). The areas under the ROC curves for classic markers, novel markers and a model combining classic and novel markers for the detection of PAS were 0.81 (95% CI, 0.75-0.88), 0.84 (95% CI, 0.77-0.90) and 0.88 (95% CI, 0.82-0.94), respectively. A model combining classic and novel signs performed better than did the classic or novel markers individually (P = 0.03). An increasing number of signs was associated with a greater likelihood of PAS. With the presence of 0, 1, 2 and ≥ 3 classic ultrasound signs, PAS was present in 5%, 24%, 57% and 94% of cases, respectively. CONCLUSIONS: We have confirmed the value of classic ultrasound signs of PAS. The use of novel ultrasound signs in combination with classic signs improved the detection of PAS. These findings have clinical implications for the detection of PAS and may help guide the obstetric management of patients diagnosed with these placental disorders. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Clinical decision support system RHINA in the diagnosis and treatment of acute or chronic rhinosinusitis.

BACKGROUND: Rhinosinusitis is an inflammation of the sinonasal cavity which affects roughly one in seven people per year. Acute rhinosinusitis (ARS) is mostly, apart from allergic etiology, caused by a viral infection and, in some cases (30-50%), by a bacterial superinfection. Antibiotics, indicated only in rare cases according to EPOS guidelines, are nevertheless prescribed in more than 80% of ARS cases, which increases the resistant bacterial strains in the population. METHODS: We have designed a clinical decision support system (CDSS), RHINA, based on a web application created in HTML 5, using JavaScript, jQuery, CCS3 and PHP scripting language. The presented CDSS RHINA helps general physicians to decide whether or not to prescribe antibiotics in patients with rhinosinusitis. RESULTS: In a retrospective study of a total of 1465 patients with rhinosinusitis, the CDSS RHINA presented a 90.2% consistency with the diagnosis and treatment made by the ENT specialist. CONCLUSION: Patients assessed with the assistance of our CDSS RHINA would decrease the over-prescription of antibiotics, which in turn would help to reduce the bacterial resistance to the most commonly prescribed antibiotics.

Demographic Assessment of Mono(2-ethylhexyl) Phthalate (MEHP) and Monoethyl Phthalate (MEP) Concentrations in Common Bottlenose Dolphins (Tursiops truncatus) From Sarasota Bay, FL, USA.

Common bottlenose dolphins (Tursiops truncatus) have previously demonstrated exposure to phthalate esters. Phthalates and phthalate esters are commonly added to consumer goods to enhance desirable properties. As the amount of plastic marine debris increases, these chemicals can easily leach from these products into the surrounding environment. To evaluate demographic variability in exposure, eight phthalate metabolites were quantified in urine samples collected from free-ranging bottlenose dolphins sampled in Sarasota Bay, FL, USA (2010-2019; n = 51). Approximately 75% of individual dolphins had detectable concentrations of at least one phthalate metabolite. The most frequently detected metabolites were mono(2-ethylhexyl) phthalate (MEHP; n = 28; GM = 4.57 ng/mL; 95% CI = 2.37-8.80; KM mean = 7.95; s.d. = 15.88) and monoethyl phthalate (MEP; GM = 4.51 ng/mL; 95% CI = 2.77-7.34; ROS mean = 2.24; s.d. = 5.58). Urinary concentrations of MEHP and MEP were not significantly different between sex (MEHP p = 0.09; MEP p = 0.22) or age class (i.e., calf/juvenile vs. adult; MEHP p = 0.67; MEP p = 0.13). Additionally, there were no significant group differences in the likelihood of MEHP or MEP detection for any demographic as determined by a Peto-Peto test. Frequency of detection was similar for both metabolites between males and females (MEHP p = 0.10; MEP p = 0.40) as well as between juveniles and adults (MEHP p = 0.50; MEP: p = 0.60). These findings suggest ubiquitous exposure risk for both sexes and age classes, warranting further investigation into potential sources and health implications.

Lessons learnt from the field: a qualitative evaluation of adolescent experiences of a universal mental health education program.

teen Mental Health First Aid (teenMHFA) is a school-based mental health program that trains adolescents to support peers who are experiencing mental health problems or crises. The program has been evaluated for adolescents aged 15-18 years as part of a randomized controlled trial, however qualitative feedback from students on their perceptions of the program is yet to be explored. The current study describes the perspectives of students who took part in the trial. Feedback on the perceived strengths and weaknesses of the program was provided by 979 Year 10 students (M = 15.82 years, female = 43.94%, English as a first language = 72.77%) at four government funded public schools in Melbourne, Australia via online surveys. A content and thematic analysis was performed on the data using a six-step process. Students generally found the program relevant and they connected with the visual material, personal stories and interactive activities. Suggestions for improvements included encouraging active student participation in classroom discussion and providing opportunities to practice skills. School-based mental health education can benefit from input from stakeholder perspectives, particularly when designing mental health content for delivery by external trainers.

Clinical profiles of post-load glucose subgroups and their association with glycaemic traits over time: An IMI-DIRECT study.

AIM: To examine the hypothesis that, based on their glucose curves during a seven-point oral glucose tolerance test, people at elevated type 2 diabetes risk can be divided into subgroups with different clinical profiles at baseline and different degrees of subsequent glycaemic deterioration. METHODS: We included 2126 participants at elevated type 2 diabetes risk from the Diabetes Research on Patient Stratification (IMI-DIRECT) study. Latent class trajectory analysis was used to identify subgroups from a seven-point oral glucose tolerance test at baseline and follow-up. Linear models quantified the associations between the subgroups with glycaemic traits at baseline and 18 months. RESULTS: At baseline, we identified four glucose curve subgroups, labelled in order of increasing peak levels as 1-4. Participants in Subgroups 2-4, were more likely to have higher insulin resistance (homeostatic model assessment) and a lower Matsuda index, than those in Subgroup 1. Overall, participants in Subgroups 3 and 4, had higher glycaemic trait values, with the exception of the Matsuda and insulinogenic indices. At 18 months, change in homeostatic model assessment of insulin resistance was higher in Subgroup 4 (ß = 0.36, 95% CI 0.13-0.58), Subgroup 3 (ß = 0.30; 95% CI 0.10-0.50) and Subgroup 2 (ß = 0.18; 95% CI 0.04-0.32), compared to Subgroup 1. The same was observed for C-peptide and insulin. Five subgroups were identified at follow-up, and the majority of participants remained in the same subgroup or progressed to higher peak subgroups after 18 months. CONCLUSIONS: Using data from a frequently sampled oral glucose tolerance test, glucose curve patterns associated with different clinical characteristics and different rates of subsequent glycaemic deterioration can be identified.

Myelopreservation with the CDK4/6 inhibitor trilaciclib in patients with small-cell lung cancer receiving first-line chemotherapy: a phase Ib/randomized phase II trial.

BACKGROUND: Chemotherapy-induced damage of hematopoietic stem and progenitor cells (HSPC) causes multi-lineage myelosuppression. Trilaciclib is an intravenous CDK4/6 inhibitor in development to proactively preserve HSPC and immune system function during chemotherapy (myelopreservation). Preclinically, trilaciclib transiently maintains HSPC in G1 arrest and protects them from chemotherapy damage, leading to faster hematopoietic recovery and enhanced antitumor immunity. PATIENTS AND METHODS: This was a phase Ib (open-label, dose-finding) and phase II (randomized, double-blind placebo-controlled) study of the safety, efficacy and PK of trilaciclib in combination with etoposide/carboplatin (E/P) therapy for treatment-naive extensive-stage small-cell lung cancer patients. Patients received trilaciclib or placebo before E/P on days 1-3 of each cycle. Select end points were prespecified to assess the effect of trilaciclib on myelosuppression and antitumor efficacy. RESULTS: A total of 122 patients were enrolled, with 19 patients in part 1 and 75 patients in part 2 receiving study drug. Improvements were seen with trilaciclib in neutrophil, RBC (red blood cell) and lymphocyte measures. Safety on trilaciclib+E/P was improved with fewer ≥G3 adverse events (AEs) in trilaciclib (50%) versus placebo (83.8%), primarily due to less hematological toxicity. No trilaciclib-related ≥G3 AEs occurred. Antitumor efficacy assessment for trilaciclib versus placebo, respectively, showed: ORR (66.7% versus 56.8%, P = 0.3831); median PFS [6.2 versus 5.0 m; hazard ratio (HR) 0.71; P = 0.1695]; and OS (10.9 versus 10.6 m; HR 0.87; P = 0.6107). CONCLUSION: Trilaciclib demonstrated an improvement in the patient's tolerability of chemotherapy as shown by myelopreservation across multiple hematopoietic lineages resulting in fewer supportive care interventions and dose reductions, improved safety profile, and no detriment to antitumor efficacy. These data demonstrate strong proof-of-concept for trilaciclib's myelopreservation benefits. CLINICAL TRAIL NUMBER: NCT02499770.

Effect of community members' willingness to disclose a mental disorder on their psychiatric symptom scores: analysis of data from two randomised controlled trials of mental health first aid training.

AIMS: The prevalence of common mental disorders has not declined in high-income countries despite substantial increases in service provision. A possible reason for this lack of improvement is that greater willingness to disclose mental disorders might have led to increased reporting of psychiatric symptoms, thus masking reductions in prevalence. This masking hypothesis was tested using data from two trials of interventions that increased willingness to disclose and that also measured symptoms. Both interventions involved Mental Health First Aid (MHFA) training, which is known to reduce stigma, including unwillingness to disclose a mental health problem. METHODS: A cross-lagged panel analysis was carried out on data from two large Australian randomised controlled trials of MHFA training. The first trial involved 1643 high school students in Year 10 (mean age 15.87 years), who were randomised to receive either teen MHFA training or physical first aid training as the control. The second trial involved 608 Australia public servants who were randomised to receive either eLearning MHFA, blended eLearning MHFA or eLearning physical first aid as the control. In both trials, willingness to disclose a mental disorder as described in vignettes and psychiatric symptoms (K6 scale) were measured pre-training, post-training and at 12-month follow-up. RESULTS: Both trials found that MHFA training increased willingness to disclose. However, a cross-lagged panel analysis showed no effect of this change on psychiatric symptom scores. CONCLUSIONS: Greater willingness to disclose did not affect psychiatric symptom scores. Because the trials increased willingness to disclose through a randomly assigned intervention, they provide a strong causal test of the masking hypothesis. It is therefore unlikely that changes in willingness to disclose are masking reductions in prevalence in the population.

The case for a national survey of eating disorders in Australia.

In this Commentary we outline the case for a national survey of eating disorders in Australia. Given the recent focus of the federal government to provide further funding for mental health research, we call for a national survey to be made a key priority. Such high-quality, nationally representative data are critically important to informing all other domains of eating disorders research in the Australian context, and to informing the research agenda internationally.

Partial maxillectomy for ameloblastoma of the maxilla with infratemporal fossa involvement: A combined endoscopic endonasal and transoral approach.

Ameloblastoma represents the most common epithelial odontogenic tumor. Because of the proximity of the maxillary tumors to the orbit and skull base, it should be managed as radically as possible. Maxillectomy, mainly via the transfacial or transoral approach, represents the most common type of surgical procedure. Drawback of these approaches is limited control of the superiomedial extent of the tumour in the paranasal area. We report the use of a combined endoscopic endonasal and transoral approach to manage maxillary plexiform ameloblastoma in a 48-year-old male patient. A combined endoscopic endonasal and transoral approach enabled the radical removal of tumour with a 1.5cm margin of radiographically intact bone with good control from both intrasinusal and intraoral aspects. Adequate visualization of the extent of the lesion (e.g. orbit, infratemporal fossa, anterior cranial base) had been achieved. Non-complicated healing was achieved. This technique of partial maxillectomy led to very good aesthetic and functional results. No recurrence had been noted during review appointments. The combination of endoscopic endonasal and transoral approach for a partial maxillectomy allows sufficient reduction of the defect, thus eliminating the necessity for reconstruction and reducing the morbidity associated with it.

Lacunar-canalicular network in femoral cortical bone is reduced in aged women and is predominantly due to a loss of canalicular porosity.

The lacunar-canalicular network (LCN) of bone contains osteocytes and their dendritic extensions, which allow for intercellular communication, and are believed to serve as the mechanosensors that coordinate the processes of bone modeling and remodeling. Imbalances in remodeling, for example, are linked to bone disease, including fragility associated with aging. We have reported that there is a reduction in scale for one component of the LCN, osteocyte lacunar volume, across the human lifespan in females. In the present study, we explore the hypothesis that canalicular porosity also declines with age. To visualize the LCN and to determine how its components are altered with aging, we examined samples from young (age: 20-23 y; n = 5) and aged (age: 70-86 y; n = 6) healthy women donors utilizing a fluorescent labelling technique in combination with confocal laser scanning microscopy. A large cross-sectional area of cortical bone spanning the endosteal to periosteal surfaces from the anterior proximal femoral shaft was examined in order to account for potential trans-cortical variation in the LCN. Overall, we found that LCN areal fraction was reduced by 40.6% in the samples from aged women. This reduction was due, in part, to a reduction in lacunar density (21.4% decline in lacunae number per given area of bone), but much more so due to a 44.6% decline in canalicular areal fraction. While the areal fraction of larger vascular canals was higher in endosteal vs. periosteal regions for both age groups, no regional differences were observed in the areal fractions of the LCN and its components for either age group. Our data indicate that the LCN is diminished in aged women, and is largely due to a decline in the canalicular areal fraction, and that, unlike vascular canal porosity, this diminished LCN is uniform across the cortex.

TAK-228 (formerly MLN0128), an investigational dual TORC1/2 inhibitor plus paclitaxel, with/without trastuzumab, in patients with advanced solid malignancies.

PURPOSE: This phase I trial evaluated the safety, pharmacokinetic profile, and antitumor activity of investigational oral TORC1/2 inhibitor TAK-228 plus paclitaxel, with/without trastuzumab, in patients with advanced solid malignancies. METHODS: Sixty-seven patients received TAK-228 6-40 mg via three dosing schedules; once daily for 3 days (QDx3d QW) or 5 days per week (QDx5d QW), and once weekly (QW) plus paclitaxel 80 mg/m2 (dose-escalation phase, n = 47) and with/without trastuzumab 2 mg/kg (expansion phase, n = 20). Doses were escalated using a modified 3 + 3 design, based upon dose-limiting toxicities in cycle 1. RESULTS: TAK-228 pharmacokinetics exhibited dose-dependent increase in exposure when dosed with paclitaxel and no apparent differences when administered with or 24 h after paclitaxel. Dose-limiting toxicities were dehydration, diarrhea, stomatitis, fatigue, rash, thrombocytopenia, neutropenia, leukopenia, and nausea. The maximum tolerated dose of TAK-228 was determined as 10-mg QDx3d QW; the expansion phase proceeded with 8-mg QDx3d QW. Overall, the most common grade ≥3 drug-related toxicities were neutropenia (21%), diarrhea (12%), and hyperglycemia (12%). Of 54 response-evaluable patients, eight achieved partial response and six had stable disease lasting ≥6 months. CONCLUSION: TAK-228 demonstrated a safety profile consistent with other TORC inhibitors and promising preliminary antitumor activity in a range of tumor types; no meaningful difference was noted in the pharmacokinetics of TAK-228 when administered with or 24 h after paclitaxel. These findings support further investigation of TAK-228 in combination with other agents including paclitaxel, with/without trastuzumab, in patients with advanced solid tumors. CLINICALTRIALS. GOV IDENTIFIER: NCT01351350.

Variants in Pharmacokinetic Transporters and Glycemic Response to Metformin: A Metgen Meta-Analysis.

Therapeutic response to metformin, a first-line drug for type 2 diabetes (T2D), is highly variable, in part likely due to genetic factors. To date, metformin pharmacogenetic studies have mainly focused on the impact of variants in metformin transporter genes, with inconsistent results. To clarify the significance of these variants in glycemic response to metformin in T2D, we performed a large-scale meta-analysis across the cohorts of the Metformin Genetics Consortium (MetGen). Nine candidate polymorphisms in five transporter genes (organic cation transporter [OCT]1, OCT2, multidrug and toxin extrusion transporter [MATE]1, MATE2-K, and OCTN1) were analyzed in up to 7,968 individuals. None of the variants showed a significant effect on metformin response in the primary analysis, or in the exploratory secondary analyses, when patients were stratified according to possible confounding genotypes or prescribed a daily dose of metformin. Our results suggest that candidate transporter gene variants have little contribution to variability in glycemic response to metformin in T2D.

The parasite Ichthyophonus sp. in Pacific herring from the coastal NE Pacific.

The protistan parasite Ichthyophonus occurred in populations of Pacific herring Clupea pallasii Valenciennes throughout coastal areas of the NE Pacific, ranging from Puget Sound, WA north to the Gulf of Alaska, AK. Infection prevalence in local Pacific herring stocks varied seasonally and annually, and a general pattern of increasing prevalence with host size and/or age persisted throughout the NE Pacific. An exception to this zoographic pattern occurred among a group of juvenile, age 1+ year Pacific herring from Cordova Harbor, AK in June 2010, which demonstrated an unusually high infection prevalence of 35%. Reasons for this anomaly were hypothesized to involve anthropogenic influences that resulted in locally elevated infection pressures. Interannual declines in infection prevalence from some populations (e.g. Lower Cook Inlet, AK; from 20-32% in 2007 to 0-3% during 2009-13) or from the largest size cohorts of other populations (e.g. Sitka Sound, AK; from 62.5% in 2007 to 19.6% in 2013) were likely a reflection of selective mortality among the infected cohorts. All available information for Ichthyophonus in the NE Pacific, including broad geographic range, low host specificity and presence in archived Pacific herring tissue samples dating to the 1980s, indicate a long-standing host-pathogen relationship.

Persistence of external signs in Pacific herring Clupea pallasii Valenciennes with ichthyophoniasis.

The progression of external signs of Ichthyophonus infection in Pacific herring Clupea pallasii Valenciennes was highly variable and asynchronous after intraperitoneal injection with pure parasite preparations; however, external signs generally persisted through the end of the study (429 days post-exposure). Observed signs included papules, erosions and ulcers. The prevalence of external signs plateaued 35 days post-exposure and persisted in 73-79% of exposed individuals through the end of the first experiment (147 days post-exposure). Among a second group of infected herring, external signs completely resolved in only 10% of the fish after 429 days. The onset of mortality preceded the appearance of external signs. Histological examination of infected skin and skeletal muscle tissues indicated an apparent affinity of the parasite for host red muscle. Host responses consisted primarily of granulomatous inflammation, fibrosis and necrosis in the skeletal muscle and other tissues. The persistence and asynchrony of external signs and host response indicated that they were neither a precursor to host mortality nor did they provide reliable metrics for hindcasting on the date of exposure. However, the long-term persistence of clinical signs in Pacific herring may be useful in ascertaining the population-level impacts of ichthyophoniasis in regularly observed populations.

P544The importance of contractile reserve when assessing asymptomatic patients with aortic stenosis.

Asymptomatic patients may exhibit symptoms during objective exercise testing, but whether symptoms are due to the obstructively of the valve (typified by the mean gradient) or underlying ventricular function remains unknown. While the mean gradient is an easy parameter to measure no consensus about the measurement of contractile reserve exists. Longitudinal abnormalities may occur in the presence of a normal ejection fraction and the augmentation of these parameters is poorly described. To obtain an objective regarding patients exercise ability is best determined using cardiopulmonary exercise testing. We therefore examined echocardiographic predictors of exercise ability during cardiopulmonary exercise testing.24 asymptomatic patients with moderate to severe or severe aortic stenosis and preserved ejection fraction underwent stress echocardiography with simultaneous cardiopulmonary exercise testing. The primary assessment of exercise ability was the VO2peak and OUES. Echocardiography was measured at rest and during maximal exercise (defined as RER > 1)OUES and VO2peak showed a poor relationship with conventional parameters of severity including peak and mean gradients, AVA and dimensionless index, resting systolic function (by EF and TDI). During exercise systolic augmentation had a good relationship with exercise ability but the exercise mean gradient and exercise LVEF did not.Longitudinal systolic function and particularly systolic augmentation is the strongest predictor of exercise ability when compared to conventional measures of severity.VO2peakOUESS' exerciseRho=0.69 (p=0.001)R= 0.71 (p=0.001)S' restRho=0.52 (p=0.01)R= 0.44 (p=ns)Rest AV max VRho= 0.09 (p=ns)R= -0.08 (p=ns)Rest AV mean PGRho= 0.34 (p=ns)R=-0.10 (p=ns)Exercise AV max VRho=0.43 (p=0.05)R=0.23 (p=ns)Exercise AVmean PGRho= 0.51 (p=0.001)R=0.26 (p=ns)Rest AVARho=0.40 (p=ns)Rho=0.46 (p=0.04)Dimensionless indexRho=0.15 (p=ns)R=0.13 (p=ns)LVEF restRho=-0.18 (p=ns)R=-0.32 (p=ns)LVEF exerciseRho=0.18 (p=ns)R=0.17 (p=ns)S' - systolic velocity; V - velocity; AV - aortic valve; AVA- aortic valve area; LVEF - left ventricular ejection fraction.

Infecting Pacific Herring with Ichthyophonus sp. in the Laboratory.

The protistan parasite Ichthyophonus sp. occurs in coastal populations of Pacific Herring Clupea pallasii throughout the northeast Pacific region, but the route(s) by which these planktivorous fish become infected is unknown. Several methods for establishing Ichthyophonus infections in laboratory challenges were examined. Infections were most effectively established after intraperitoneal (IP) injections with suspended parasite isolates from culture or after repeated feedings with infected fish tissues. Among groups that were offered the infected tissues, infection prevalence was greater after multiple feedings (65%) than after a single feeding (5%). Additionally, among groups that were exposed to parasite suspensions prepared from culture isolates, infection prevalence was greater after exposure by IP injection (74%) than after exposure via gastric intubation (12%); the flushing of parasite suspensions over the gills did not lead to infections in any of the experimental fish. Although the consumption of infected fish tissues is unlikely to be the primary route of Ichthyophonus sp. transmission in wild populations of Pacific Herring, this route may contribute to abnormally high infection prevalence in areas where juveniles have access to infected offal.

A randomized phase II study of the telomerase inhibitor imetelstat as maintenance therapy for advanced non-small-cell lung cancer.

BACKGROUND: Continuation or 'switch' maintenance therapy is commonly used in patients with advancd non-small-cell lung cancer (NSCLC). Here, we evaluated the efficacy of the telomerase inhibitor, imetelstat, as switch maintenance therapy in patients with advanced NSCLC. PATIENTS AND METHODS: The primary end point of this open-label, randomized phase II study was progression-free survival (PFS). Patients with non-progressive, advanced NSCLC after platinum-based doublet (first-line) chemotherapy (with or without bevacizumab), any histology, with Eastern Cooperative Oncology Group performance status 0-1 were eligible. Randomization was 2 : 1 in favor of imetelstat, administered at 9.4 mg/kg on days 1 and 8 of a 21-day cycle, or observation. Telomere length (TL) biomarker exploratory analysis was carried out in tumor tissue by quantitative PCR (qPCR) and telomerase fluorescence in situ hybridization. RESULTS: Of 116 patients enrolled, 114 were evaluable. Grade 3/4 neutropenia and thrombocytopenia were more frequent with imetelstat. Median PFS was 2.8 and 2.6 months for imetelstat-treated versus control [hazard ratio (HR) = 0.844; 95% CI 0.54-1.31; P = 0.446]. Median survival time favored imetelstat (14.3 versus 11.5 months), although not significantly (HR = 0.68; 95% CI 0.41-1.12; P = 0.129). Exploratory analysis demonstrated a trend toward longer median PFS (HR = 0.43; 95% CI 0.14-1.3; P = 0.124) and overall survival (OS; HR = 0.41; 95% CI 0.11-1.46; P = 0.155) in imetelstat-treated patients with short TL, but no improvement in median PFS and OS in patients with long TL (HR = 0.86; 95% CI 0.39-1.88; and HR = 0.51; 95% CI 0.2-1.28; P = 0.145). CONCLUSIONS: Maintenance imetelstat failed to improve PFS in advanced NSCLC patients responding to first-line therapy. There was a trend toward a improvement in median PFS and OS in patients with short TL. Short TL as a predictive biomarker will require further investigation for the clinical development of imetelstat.