Aligned or misaligned: Are public funding models for speech-language pathology reflecting recommended evidence? An exploratory survey of Australian speech-language pathologists.

Government subsidised funding arrangements serve as an essential medium for families to access private speech-language pathology (SLP) services in Australia. This study aimed to investigate whether, from a provider perspective, contemporary public funding models (PFMs) align with best-available scientific evidence for management of children and young persons with swallowing and communication disorders within Australian private-practice settings. This exploratory study was distributed to paediatric speech-language pathologists throughout Australia via an online survey. A total of 121 valid surveys were completed by Australian speech-language pathologists with divergent career experiences. In comparing three familiar PFMs using mixed effects logistic regression models to estimate odds ratios, results indicated that perceived congruence with recommended scientific evidence for SLP management varied across PFMs: the odds of failing to align with scientific evidence was 4.92 times higher for Medicare's Chronic Disease Management Plan (MBS_CDMP) than for the National Disability Insurance Scheme; and 7.40 times higher in comparison to Medicare's Helping Children with Autism initiative. This study is the first to report on (in)congruence between PFMs that provide access to independent Australian SLP services for children and young persons and best available scientific evidence to inform clinical practice. Participants identified that: (a) four out of seven contemporary PFMs were unfamiliar to speech-language pathologists; and (b) MBS_CDMP initiative failed to align with the evidence-base for best scientific SLP management.

Cochlear implantation in advanced otosclerosis: utility of pre-operative radiological assessment in predicting intra-operative difficulty and final electrode position.

OBJECTIVE: This study aimed to determine if pre-operative radiological scoring can reliably predict intra-operative difficulty and final cochlear electrode position in patients with advanced otosclerosis. METHOD: A retrospective cohort study of advanced otosclerosis patients who underwent cochlear implantation (n = 48, 52 ears) was compared with a larger cohort of post-lingually deaf adult patients (n = 1414) with bilateral hearing loss and normal cochlear anatomy. Pre-operative imaging for advanced otosclerosis patients and final electrode position were scored and correlated with intra-operative difficulty and speech outcomes. RESULTS: Advanced otosclerosis patients benefit significantly from cochlear implantation. Mean duration of deafness was longer in the advanced otosclerosis group (19.5 vs 14.3 years; p < 0.05). CONCLUSION: Anatomical changes in advanced otosclerosis can result in increased difficulty of surgery. Evidence of pre-operative cochlear luminal changes was associated with intra-operative difficult insertion and final non-scala tympani position. Nearly all electrodes implanted in the advanced otosclerosis cohort were peri-modiolar. No reports of facial nerve stimulation were observed.

Disparities in access to ear and hearing care in Cambodia: a mixed methods study on patient experiences.

OBJECTIVE: Chronic suppurative otitis media is a major global disease disproportionately affecting low- and middle-income countries, but few studies have explored access to care for those with ear and hearing disorders. METHOD: In a tertiary hospital in Cambodia providing specialist ear services, a mixed method study was undertaken. This study had three arms: (1) quantitative analysis of patients undergoing ear surgery, (2) a questionnaire survey and (3) semi-structured in-depth interviews. RESULTS: Patients presented with advanced middle-ear disease and associated hearing loss at rates that are amongst the highest per capita levels globally. Patients reported several structural, financial and socio-cultural barriers to treatment. This study showed a significant burden of ear disease in Cambodia, which reflects a delay in receiving timely and effective treatment. CONCLUSION: This study highlights the opportunity to integrate effective ear and hearing care into primary care service provision, strengthening the package of activities delivered at government facilities.

Access to ear and hearing care services in Cambodia: a qualitative enquiry into experiences of key informants.

OBJECTIVE: In Cambodia, little is known about the state of ear and hearing care, or the roles providers or key stakeholders play in delivering services. METHOD: This was an exploratory study using semi-structured qualitative interviews and a questionnaire addressed to key stakeholders to explore their perceptions and experiences in providing services to people suffering from ear disease or hearing loss in Cambodia. RESULTS: Several challenges were described including a lack of hearing services to meet the demand, especially outside Phnom Penh in primary care and aural rehabilitation. Supply-side challenges include a shortage of trained professionals, facilities and resources, poor co-ordination between providers, unclear referral pathways, and long wait times. CONCLUSION: Now is an opportune time to build on the positive trend in providing integrated care for non-communicable diseases in Cambodia, through the integration of effective ear and hearing care into primary care and strengthening the package of activities delivered at government facilities.

Methylprednisolone applied directly to the round window reduces dizziness after cochlear implantation: a randomized clinical trial.

This prospective, double-blind controlled, randomized clinical trial of 43 adults showed that topical methylprednisolone applied to the round window during cochlear implantation was effective in protecting inner ear function. Postoperative vestibular disturbance was significantly lower in the steroid group (5%) than the control group (29%). Electrode impedances from the middle portion of the electrode array (electrodes 10-13) were significantly reduced in steroid-treated recipients compared to controls. Hearing and vestibular function analyses were under-powered to detect any drug changes due to limited participant data.

Worldwide host plants of the highly polyphagous, invasive Epiphyas postvittana (Lepidoptera: Tortricidae).

The light brown apple moth, Epiphyas postvittana (Walker) (Lepidoptera: Tortricidae), is a highly successful biological invader. It was accidentally introduced to several countries including New Zealand, Hawaii, England, and California. Light brown apple moth attacks a wide range of crop plants and other woody and herbaceous plants, but a more comprehensive analysis of its host range is needed for risk assessments, to evaluate the likely economic and environmental impacts, and to enable targeting of particular plant species for detection surveys and treatments. We reviewed and synthesized the host range and host selection behavior of light brown apple moth by using information from Australia and invaded countries. The host range of light brown apple moth is determined by the behavior of both adult females and larvae. Females use visual, chemical and physical cues to choose host plants. Larvae are capable of limited active dispersal by walking and longer range dispersal by ballooning on silken strands; therefore, larvae also may need to select host plants. We review larval performance indicators across a range of plants. Based on our review, there are at least 545 plant species in 363 genera from 121 families that have been reported as hosts of light brown apple moth. Some plants were reported only once and need verification. Nevertheless, many host plant species and their wide phylogenetic range (from ferns to higher dicotyledons) indicates that light brown apple moth is one of the most polyphagous insects known. This information and our categorization of frequency of host use are valuable for incursion response and pest management activities.

Two-component hearing sensations produced by two-electrode stimulation in the cochlea of a deaf patient.

Dissimilarities in perception elicited by stimulation with two electrodes were estimated. A two-dimensional spatial configuration was found to be suitable to represent the dissimilarity data, and the two dimensions could be interpreted as corresponding to the position of the apical and basal electrode of the two-electrode combination. A speech-processing strategy that converts acoustic, first and second formants to two-electrode stimulation is proposed.

ZD2767, an improved system for antibody-directed enzyme prodrug therapy that results in tumor regressions in colorectal tumor xenografts.

ZD2767 represents an improved version of antibody-directed enzyme prodrug therapy. It consists of a conjugate of the F(ab')2 A5B7 antibody fragment and carboxypeptidase G2 (CPG2) and a prodrug, 4-[N,N-bis(2-iodoethyl)amino]phenoxycarbonyl L-glutamic acid. The IC50 of the prodrug against LoVo colorectal tumor cells was 47 microM, and cleavage by CPG2 released the potent bis-iodo phenol mustard drug (IC50 = 0.34 microM). The drug killed both proliferating and quiescent LoVo cells. Administration of the ZD2767 conjugate to nude mice bearing LoVo colorectal xenografts resulted in approximately 1% of injected ZD2767 conjugate localizing/g of tumor after 72 h, and blood and normal tissue levels of the conjugate were 10-50-fold lower. A single round of therapy involving the administration of the prodrug 72 h after the conjugate to athymic mice bearing established LoVo xenografts resulted in approximately 50% of the tumors undergoing complete regressions, tumor growth delays greater than 30 days, and little toxicity (as judged by body-weight loss). Similar studies using a control antibody-CPG2 conjugate that does not bind to LoVo tumor cells resulted in a growth delay of less than 5 days, confirming the tumor specificity of this approach. These studies demonstrate the potential of ZD2767 for the treatment of colorectal cancer.

Absence of synergistic effects of CNS treatments on neuropsychologic test performance among children.

Three hypotheses are proposed to account for neurobehavioral impairments following treatment with cranial radiation therapy (CRT) and intrathecal (IT) chemotherapy: CNS treatments exert a synergistic effect (A x B), an additive effect (A + B), or a single-agent effect (A or B). Eighty-five long-term survivors of non-CNS cancers aged 6 to 16 years were classified into groups on the basis of CNS treatments: CRT-IT (n = 25), CRT-No IT (n = 11), No CRT-IT (n = 24), and No CRT-No IT (n = 25). Study I findings did not provide support for synergistic mechanisms; nonorthogonal analysis of variance showed interaction effects (CRT x IT) restricted to tactile-perceptual speed. However, main effects were significant for a single agent (CRT) across a wide range of measures. General intelligence, academic achievement, verbal knowledge and reasoning, and perceptual-motor abilities were found to be significantly lower among CRT-treated groups. Study II findings provided additional support for the role of CRT; Pearson correlations within the CRT-No IT group indicated significant negative associations between CRT dose estimates for cortical regions and perceptual-motor abilities.

The distributed annotation system.

BACKGROUND: Currently, most genome annotation is curated by centralized groups with limited resources. Efforts to share annotations transparently among multiple groups have not yet been satisfactory. RESULTS: Here we introduce a concept called the Distributed Annotation System (DAS). DAS allows sequence annotations to be decentralized among multiple third-party annotators and integrated on an as-needed basis by client-side software. The communication between client and servers in DAS is defined by the DAS XML specification. Annotations are displayed in layers, one per server. Any client or server adhering to the DAS XML specification can participate in the system; we describe a simple prototype client and server example. CONCLUSIONS: The DAS specification is being used experimentally by Ensembl, WormBase, and the Berkeley Drosophila Genome Project. Continued success will depend on the readiness of the research community to adopt DAS and provide annotations. All components are freely available from the project website http://www.biodas.org/.

The liver converts the antihypertensive hormone of the kidney. The renohepatic axis.

The antihypertensive neutral renomedullary lipid, derived from the renal papilla, causes a vasodepressor effect when injected into a peripheral vein, such as the inferior vena cava, after a lag period of 1 to 2 minutes. The blood pressure tracing is skewed (cuplike effect). The lag period is significantly reduced after injection of the antihypertensive lipid into the portal vein. The vasodepressor configuration (cuplike) is the same whether the lipid is injected into the vena cava or portal vein. Removal of the liver from the circulation prevents the depressor effect. Thus, passage through the liver is essential for antihypertensive lipid activity. Renoportal shunting of blood potentiates the antihypertensive function of the kidney after unclipping in the one-kidney, one clip hypertensive rat. Lack of a hepatic circulation prevents the antihypertensive function of the kidney after unclipping. Antihypertensive neutral renomedullary lipid and the renal venous effluent after unclipping have the same biological behavior. We conclude that antihypertensive neutral renomedullary lipid is a promolecule, the putative prohormone of the renal papilla and its renomedullary interstitial cells. The liver converts the antihypertensive prohormone of the kidney to an active antihypertensive substance. A renohepatic axis of blood pressure control appears to exist.

Detection of 4'-phosphopantetheine at the thioester binding site for L-valine of gramicidinS synthetase 2.

Biosynthesis of gramicidinS in Bacillus brevis is catalysed by a multienzyme system consisting of two multifunctional proteins, gramicidinS synthetase 1 and 2 codified by the grsA and grsB genes, respectively. GramicidinS synthetase 2 shows a modular architecture of four amino acid-activating domains each containing a thioester binding motif LGG H/D S L/I highly conserved in its C-terminal region, as demonstrated by sequence analysis of the grsB gene [W. Schlumbohm et al. (1991) J. Biol. Chem. 266, 23135-23141]. This multienzyme was specifically labeled at the thioester binding site of L-valine with [3H]N-ethylmaleimide using a substrate protection technique. After enzymatic digestion a labeled active site peptide was isolated in pure form by multistep methodology. This fragment was identified by gas-phase sequencing as the active site peptide of the thiotemplate site for L-Val by comparison with the grsB gene sequence. By mass spectrometry in combination with amino acid analysis it was demonstrated that a 4'-phosphopantetheine carrier was attached to the active serine in this motif. Our results give evidence that multiple peripheral 4'-phosphopantetheine carriers are involved in the formation of gramicidinS in contrast to a central carrier arm as assumed in the original version of the thiotemplate mechanism. A 'Multiple Carrier Model' of nonribosomal peptide biosynthesis is proposed.

Metabolic and contractile function enhancement during rat heart postnatal development.

Enhanced cardiac contractile function during the early post-birth period is a mammalian characteristic; however, concurrent metabolic measurements have not been systematically carried out. To define heart postnatal development, left ventricular pressure and rate of left ventricular pressure development (dP/dt) were measured in rats at 3, 5, 7, and 9 weeks post birth. When functional measurements were completed, the heart was excised, weighed, and tissue samples were used for chemical and/or enzymatic analyses. Left ventricular weight increased approximately 5-fold over the period studied, but was outstripped by 8-fold increases in body weight. Left ventricular DNA content increased dramatically between 3 weeks and 7 weeks post birth, then stabilized between 7 and 9 weeks post birth. Minor fluctuations in phosphofructokinase and lactate dehydrogenase enzyme activities suggest that glycolytic and anaerobic metabolisms undergo relatively small alterations as normal growth and development transpire. In contrast, enzymatic indices of aerobic metabolism (citrate synthase and malate dehydrogenase) were augmented approximately 6-fold without significant change in specific enzyme activity in purified mitochondria. Thus, mitochondria accumulated more rapidly than left ventricular tissue during heart growth. Magnesium-stimulated, myofibrillar ATPase enzyme activity approximately doubled over the intervening time between 3 weeks and 9 weeks post birth. Heart contractile function is augmented during normal growth roughly in parallel with increases in cell numbers, mitochondrial mass, and myofibrillar ATPase activity.

Novel inhibitors of prolyl 4-hydroxylase.

A series of 5-acyl sulfonamides derived from pyridine-2,5-dicarboxylic acid (15) has been prepared and several members of this series have been shown to be more potent, in vitro, as inhibitors of prolyl 4-hydroxylase than 15. Several chain-extended pyridinedicarboxylic acids have also been prepared and shown to be potent inhibitors of prolyl 4-hydroxylase. The structure-activity in both these series is discussed. The results indicate that the 5-carboxylic acid binding site, in the enzyme, can accept a carboxylic acid or an acyl sulfonamide equally well. This indicates a much greater degree of freedom in this distal carboxylic acid binding site than is predicted by the current theoretical model of the active site.

Optimization of alkylating agent prodrugs derived from phenol and aniline mustards: a new clinical candidate prodrug (ZD2767) for antibody-directed enzyme prodrug therapy (ADEPT).

Sixteen novel potential prodrugs derived from phenol or aniline mustards and their 16 corresponding drugs with ring substitution and/or different alkylating functionalities were designed. The [[[4-]bis(2-bromoethyl)-(1a), [[[4-[bis(2-iodoethyl)-(1b), and [[[4-[(2-chloroethyl)-[2-(mesyloxy)ethyl]amino]phenyl]oxy] carbonyl]-L-glutamic acids (1c), their [[[2- and 3-substituted-4-[bis(2-chloroethyl)amino]phenyl]oxy]carbonyl]-L- glutamic acids (1e-1), and the [[3-substituted-4-[bis(2-chloroethyl)amino]phenyl]carbamoyl]-L- glutamic acids (1o-r) were synthesized. They are bifunctional alkylating agents in which the activating effect of the phenolic hydroxyl or amino function is masked through an oxycarbonyl or a carbamoyl bond to a glutamic acid. These prodrugs were designed to be activated to their corresponding phenol and aniline nitrogen mustard drugs at a tumor site by prior administration of a monoclonal antibody conjugated to the bacterial enzyme carboxypeptidase G2 (CPG2) in antibody-directed enzyme prodrug therapy (ADEPT). The synthesis of the analogous novel parent drugs (2a-r) is also described. The viability of a colorectal cell line (LoVo) was monitored with the potential prodrugs and the parent drugs. The differential in the cytotoxicity between the potential prodrugs and their corresponding active drugs ranged between 12 and > 195 fold. Compounds 1b-d,f,o exhibited substantial prodrug activity, since a cytotoxicity differential of > 100 was achieved compared to 2b-d,f,o respectively. The ability of the potential prodrugs to act as substrates for CPG2 was determined (kinetic parameters KM and kcat), and the chemical stability was measured for all the compounds. The unsubstituted phenols with different alkylating functionalities (1a-c) proved to have the highest ratio of the substrates kcat:KM. From these studies [[[4-[bis(2-iodoethyl)amino]phenyl]oxy]carbonyl]-L-glutamic acid (1b) emerges as a new ADEPT clinical trial candidate due to its physicochemical and biological characteristics.

Methoxytetrahydropyrans. A new series of selective and orally potent 5-lipoxygenase inhibitors.

Investigation of the SAR of the lead (methoxyalkyl)thiazole 1-[3-(naphth-2-ylmethoxy)phenyl]-1-thiazol-2-ylprop yl methyl ether (1, ICI 211965) led to the methoxytetrahydropyrans, a new series of 5-lipoxygenase (5-LPO) inhibitors exemplified by the parent compound 4-[3-(naphth-2-ylmethoxy)phenyl]-4- methoxy-3,4,5,6-tetrahydro-2H-pyran (4f). In vitro 4f inhibited leukotriene C4 (LTC4) synthesis in zymosan-stimulated plasma-free mouse macrophages and LTB4 synthesis in A-23187-stimulated human whole blood (IC50s 0.5 nM and 0.07 microM, respectively). In the rat 4f inhibited LTB4 synthesis in blood ex vivo and in zymosan-inflamed air pouch exudate with an ED50 3 h after oral dosing of 10 mg/kg in each system. In seeking more potent orally active compounds, strategies were explored in congeners of 4f for reducing lipophilicity without sacrificing potency. For example, replacement of 2-naphthyl of 4f by various aza- and oxoheterocycles afforded compounds in which log P is reduced by 1.7-2.3 units while potency in human whole blood in vitro was maintained or enhanced relative to 4f. In addition, the oxoheterocyclic replacements provided compounds with improved oral potency and the preferred compound from this group is 6-[[3-fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4- yl)phenoxy]methyl]-1-methylquinol-2-one (4y). In the in vitro systems, 4y inhibited LT formation with IC50s in mouse macrophages and human whole blood of 3 nM and 0.02 microM, respectively. 4y did not inhibit the synthesis of cyclooxygenase (CO) products at concentrations up to 500 microM in human blood, a selectivity for 5-LPO over CO of greater than 20,000-fold. In the rat 4y inhibited the formation of LTB4 in blood ex vivo and in inflammatory exudate with ED50s 3 h after oral dosing of 0.9 and 0.3 mg/kg, respectively. 4y was more potent in vitro in human whole blood and in rat blood ex vivo at 3 h than either the 5-LPO inhibitor A-64077 or the FLAP antagonist MK-886. Based on these data 4y (ICI D2138) has been entered into development as an orally active, selective 5-LPO inhibitor for clinical evaluation in inflammatory conditions in which LTs are believed to play a role.

New mustard prodrugs for antibody-directed enzyme prodrug therapy: alternatives to the amide link.

Antibody-directed enzyme prodrug therapy (ADEPT) is a two-step approach for the treatment of cancer which seeks to generate a potent cytotoxic agent selectively at a tumor site. In this work described the cytotoxic agent is generated by the action of an enzyme CPG2 on a relatively nontoxic prodrug. The prodrug 1 currently on clinical trial is a benzamide and is cleaved by CPG2 to a benzoic acid mustard drug 1a. We have synthesized a series of new prodrugs 3-8 where the benzamide link has been replaced by, for example, carbamate or ureido. Some of these alternative links have been shown to be good substrates for CPG2 and therefore new candidates for ADEPT. The active drugs 3a and 4a derived from the best of these prodrugs are potent cytotoxic agents (1-2 microM) some 100 times more than 1a. The prodrugs 3 and 4 are some 100-200-fold less cytotoxic, in a proliferating cell assay, than their corresponding active drugs 3a and 4a.

Uteroplacental blood flow at rest and during exercise in late-gestation conscious rats.

The present studies were conducted to achieve three specific aims. First, techniques and procedures were developed to allow tissue and organ blood flow measurements by radioactive microsphere methodology in the conscious female rat. Second, technical aspects of the methodology were evaluated with emphasis on potential uteroplacental shunting of microspheres in the late-gestational period. Third, the above techniques and procedures were utilized to assess uteroplacental blood flow at rest and during exercise in conscious pregnant rats during the late stages of gestation, i.e., days 15, 19, and 22 of pregnancy. Results established the validity of tracer blood flow technical assumptions, and no significant increase in arteriovenous shunting of 15-microns microspheres either as pregnancy progressed or during superimposed exercise in near-term pregnant animals was detected. During the stages of pregnancy studied, cardiac output was enhanced approximately 20% near term. Marked and progressive increases in uterine blood flow were noted both in milliliters per minute and as percentage of cardiac output. Preferential placental perfusion during late-stage gestation was indicated by increased tissue flow (7 +/- 1, 84 +/- 12, 232 +/- 32 ml.min-1 x 100 g-1), increased percent cardiac output (1.7 +/- 0.1, 5.1 +/- 0.7, 11.0 +/- 1.7% cardiac output), and increased percent uterine blood flow (10 +/- 1, 59 +/- 3, 87 +/- 2% uterine flow) at days 15, 19, and 22 of gestation, respectively. Progressive maternal body weight increase during gestation enhanced exercise work intensity, as shown by heart rate and cardiac output at the end of 30 min of treadmill running at 8.5 m/min, 0% incline.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiac myofibrillar creatine kinase Km is not influenced by contractile protein binding.

Subcellular microcompartmentation underlies the proposed phosphorylcreatine shuttle mechanism in mammalian cardiac tissue. In mitochondria, CK coupling to oxidative phosphorylation via adenine nucleotide translocase decreases the Km for ATP and suggests both a functional and physical integration. In the present studies, substrate Km of myofibrillar CK was unaltered when determined in the intact, native state or after removal from the myofibril. In contrast to mitochondria, close spatial proximity between cardiac myofibrillar CK and ATPase is sufficient to establish phosphorylcreatine shuttle microcompartmentation.

Speech recognition for 40 patients receiving multichannel cochlear implants.

We collected data on 40 patients who received the Nucleus multichannel cochlear implant. Results were reviewed to determine if the coding strategy is effective in transmitting the intended speech features and to assess patient benefit in terms of communication skills. All patients demonstrated significant improvement over preoperative results with a hearing aid for both lipreading enhancement and speech recognition without lipreading. Of the patients, 50% demonstrated ability to understand connected discourse with auditory input only. For the 23 patients who were tested 12 months postoperatively, there was substantial improvement in open-set speech recognition.