Applying the ICF-CY to Specialist Speech-Language Pathologists' Practice With Toddlers With Cleft Palate Speech.

OBJECTIVE: To evaluate how the practice of specialist speech-language pathologists (SLPs) working with young children with cleft palate ± cleft lip (CP±L) maps onto the International Classification of Functioning, Disability, and Health - Children and Youth version (ICF-CY) and consider the functionality of the categories of the ICF-CY for this specialist area of practice. DESIGN: Cross-sectional, qualitative study. SETTING: Semistructured face-to-face interviews were conducted with SLPs working in tertiary-level hospitals, universities, and public clinics. PARTICIPANTS: Six specialist SLPs with 17 to 39 years of experience working with young children with CP±L as researchers and clinicians in Australia, Brazil, Denmark, Ireland, New Zealand, and the United States. MAIN OUTCOME MEASURE(S): Specialists' practices were captured using in-depth, semistructured interviews. Data collected were analyzed by directed content analysis applying the ICF-CY as a coding schema. RESULTS: In total, 4077 data points were coded. Most mapped onto Body Structures (684, 16.8%), Body Functions (906, 22.2%), and Environmental Factors (1626, 39.9%) with less emphasis on Activities and Participation (560, 13.7%). A "best fit" approach was taken to topics that did not map exactly onto categories of the ICF-CY (eg, velopharyngeal insufficiency [VPI]); however, there was not always an ideally suitable category available. CONCLUSIONS: The current study revealed strengths and challenges in categorizing practice within the ICF-CY for children with CP±L, including collaboration with parents and significant others, specificity around speech, language, and articulation, and the different types of VPI. Therefore, future discussion around how best to use the framework with children with CP±L is needed.

Outcome following surgical stabilization of distal diaphyseal and supracondylar femoral fractures in dogs.

Signalment, clinical features, fixation techniques, complications, and outcome for dogs presenting with distal diaphyseal and supracondylar femoral fractures were retrospectively reviewed. A total of 45 dogs with unilateral femoral fractures were included. Supracondylar femoral plates were the most popular method of fixation. However, various fixation techniques resulted in favorable outcomes in most dogs with 19/45 cases achieving full function and 22/45 achieving acceptable function. Degree of fracture comminution did not appear to affect complication rate or be a surrogate for worse clinical outcome.

Résultats de stabilisation chirurgicale de fractures fémorales diaphysaires distales et supracondylaires chez le chien. Une étude rétrospective portant sur le signalement, la présentation clinique, les techniques de réduction de fracture, les complications et les résultats de chiens atteints de fractures fémorales supracondyliennes et diaphysaires distales a été réalisée. Quarante-cinq chiens présentant une fracture fémorale unilatérale ont été inclus au total. Les plaques fémorales supracondyliennes représentaient la méthode d'ostéosynthèse la plus courante. Diverses techniques de fixation ont abouti à des résultats favorables dans la majorité des cas, avec 19/45 cas récupérant une fonction complète et 22/45 une fonction considérée acceptable. Le degré de comminution de la fracture n'apparaissait pas comme étant un facteur de risque de complication ou étant associé à des résultats défavorables.(Traduit par Emilie Fauchon et Emilie Hanot).

Transcription of Vietnamese Adults' and Children's Consonants by English-Speaking Speech-Language Pathologists.

OBJECTIVE: To examine English-speaking speech-language pathologists' (SLPs) transcription of consonants in Vietnamese words and identification of correct/incorrect productions of Vietnamese children's speech. PARTICIPANTS AND METHODS: Twenty English-speaking SLPs completed three tasks. Task 1: transcription of 22 English words using the International Phonetic Alphabet. Task 2: transcription of 47 words spoken by Vietnamese adults. Task 3: transcription of 94 Vietnamese words spoken by Vietnamese children and identification of correct/incorrect productions. Participants completed questionnaires exploring language proficiency, transcription skill, musicality and confidence with multilingual clients. RESULTS: Task 1: participants demonstrated good accuracy transcribing English words (M = 97.2%). Task 2: an average of 52.9% consonants were transcribed correctly (89.4% when Vietnamese-English common transcription errors were considered). Common transcription errors included voicing of plosives, place and syllable-final omission. Accuracy was higher on shared English and Vietnamese consonantal articulations (e.g., /b/ and /m/). Task 3: on average, SLPs correctly identified accuracy of 73.8% of Vietnamese children's productions and transcribed 69.2% consonants correctly (83.8% when Vietnamese-English common transcription errors were considered). Musicality was correlated with SLPs' accuracy of transcription. CONCLUSION: English-speaking SLPs have some skills transcribing Vietnamese adults and transcribing and identifying correct/incorrect productions of children's speech. SLPs may use knowledge of common transcription errors to support understanding of their transcription of speech.

Evaluation of a pre-tied ligature loop for canine total lung lobectomy.

OBJECTIVE: To determine the ability of a pre-tied ligature loop (PLL) to create a seal against physiological airway pressures after total lung lobectomy and report outcomes in dogs requiring lung lobectomy. STUDY DESIGN: Ex vivo experimental randomized study and clinical case study. SAMPLE POPULATION: Thirty cadaveric canine lung lobes and 5 client-owned dogs. METHODS: Thirty canine lung lobes from dogs weighing 22.5-35 kg were randomized to lobectomy with stapler, PLL, or suture ligation. After lobectomy, each bronchial stump was submerged in water, and the mainstem airway pressure was increased to 80 mm Hg. Leakage was compared between techniques. The PLL was subsequently used in 5 dogs (17-25 kg) with neoplastic disease requiring total lung lobectomy. RESULTS: Two stapled and 4 sutured bronchial stumps leaked at supraphysiological pressures >15 mm Hg. One stapled bronchial stump failed at a physiological airway pressure (5 mm Hg). None of the PLL lobectomies leaked. The incidence of bronchial stump failures did not differ among techniques (P = .15). Lung lobectomy was performed successfully with the PLL in 5 clinical cases with no intraoperative or postoperative complications; median follow-up time was 6 months. CONCLUSION: Bronchial ligation with the PLL reliably resisted physiological airway pressures and performed comparably to current standard techniques in cadavers. The PLL provided an adequate air and vascular seal in 5 clinical cases undergoing total lung lobectomy. CLINICAL RELEVANCE: Pre-tied ligature loops provide an alternative method for total lung lobectomy in dogs.

Discovery and In Vivo Efficacy of AZ-PRMT5i-1, a Novel PRMT5 Inhibitor with High MTA Cooperativity.

PRMT5, a type 2 arginine methyltransferase, has a critical role in regulating cell growth and survival in cancer. With the aim of developing MTA-cooperative PRMT5 inhibitors suitable for MTAP-deficient cancers, herein we report our efforts to develop novel "MTA-cooperative" compounds identified through a high-throughput biochemical screening approach. Optimization of hits was achieved through structure-based design with a focus on improvement of oral drug-like properties. Bioisosteric replacement of the original thiazole guanidine headgroup, spirocyclization of the isoindolinone amide scaffold to both configurationally and conformationally lock the bioactive form, and fine-tuning of the potency, MTA cooperativity, and DMPK properties through specific substitutions of the azaindole headgroup were conducted. We have identified an orally available in vivo lead compound, 28 ("AZ-PRMT5i-1"), which shows sub-10 nM PRMT5 cell potency, >50-fold MTA cooperativity, suitable DMPK properties for oral dosing, and significant PRMT5-driven in vivo efficacy in several MTAP-deficient preclinical cancer models.

Ultrasonographic and colour Doppler features of intrapancreatic splenic tissue in a cat.

Case summary: A 2-year-old female neutered domestic longhair cat was referred for a 3-day history of lethargy and anorexia. Physical examination documented abdominal distension and pain, which, alongside marked electrolyte imbalances on blood biochemistry, was highly suspicious for a gastrointestinal obstruction. This was confirmed on diagnostic imaging, with abdominal ultrasonography also identifying an incidental, well-defined small lobular hypoechoic nodule adjacent to the tail of the spleen, with high vascularity on Doppler interrogation. This was identified as a focal nodule at the tip of the left limb of the pancreas at surgery, and resected via partial pancreatectomy. Histopathological examination confirmed intrapancreatic splenic tissue. Relevance and novel information: This case report presents the first available ultrasonographic description and images of intrapancreatic splenic tissue in a cat. It is thought to be a benign lesion of low clinical significance and therefore defining its imaging characteristics may allow for improvement in diagnostic suspicion without resorting to excisional surgery.

Optimization of hERG and Pharmacokinetic Properties for Basic Dihydro-8H-purin-8-one Inhibitors of DNA-PK.

The DNA-PK complex is activated by double-strand DNA breaks and regulates the non-homologous end-joining repair pathway; thus, targeting DNA-PK by inhibiting the DNA-PK catalytic subunit (DNA-PKcs) is potentially a useful therapeutic approach for oncology. A previously reported series of neutral DNA-PKcs inhibitors were modified to incorporate a basic group, with the rationale that increasing the volume of distribution while maintaining good metabolic stability should increase the half-life. However, adding a basic group introduced hERG activity, and basic compounds with modest hERG activity (IC50 = 10-15 µM) prolonged QTc (time from the start of the Q wave to the end of the T wave, corrected by heart rate) in an anaesthetized guinea pig cardiovascular model. Further optimization was necessary, including modulation of pK a, to identify compound 18, which combines low hERG activity (IC50 = 75 µM) with excellent kinome selectivity and favorable pharmacokinetic properties.

Preclinical Characterization of AZD5305, A Next-Generation, Highly Selective PARP1 Inhibitor and Trapper.

PURPOSE: We hypothesized that inhibition and trapping of PARP1 alone would be sufficient to achieve antitumor activity. In particular, we aimed to achieve selectivity over PARP2, which has been shown to play a role in the survival of hematopoietic/stem progenitor cells in animal models. We developed AZD5305 with the aim of achieving improved clinical efficacy and wider therapeutic window. This next-generation PARP inhibitor (PARPi) could provide a paradigm shift in clinical outcomes achieved by first-generation PARPi, particularly in combination. EXPERIMENTAL DESIGN: AZD5305 was tested in vitro for PARylation inhibition, PARP-DNA trapping, and antiproliferative abilities. In vivo efficacy was determined in mouse xenograft and PDX models. The potential for hematologic toxicity was evaluated in rat models, as monotherapy and combination. RESULTS: AZD5305 is a highly potent and selective inhibitor of PARP1 with 500-fold selectivity for PARP1 over PARP2. AZD5305 inhibits growth in cells with deficiencies in DNA repair, with minimal/no effects in other cells. Unlike first-generation PARPi, AZD5305 has minimal effects on hematologic parameters in a rat pre-clinical model at predicted clinically efficacious exposures. Animal models treated with AZD5305 at doses ≥0.1 mg/kg once daily achieved greater depth of tumor regression compared to olaparib 100 mg/kg once daily, and longer duration of response. CONCLUSIONS: AZD5305 potently and selectively inhibits PARP1 resulting in excellent antiproliferative activity and unprecedented selectivity for DNA repair deficient versus proficient cells. These data confirm the hypothesis that targeting only PARP1 can retain the therapeutic benefit of nonselective PARPi, while reducing potential for hematotoxicity. AZD5305 is currently in phase I trials (NCT04644068).

Persistence, strength, isolation, and trauma: An ethnographic exploration of raising children with cleft palate.

BACKGROUND: The lives of families of young children with cleft palate (±lip) are complex. Multiple interventions are required as part of the long-term multidisciplinary treatment for children with CP±L, with an impairment-focused approach prevailing. Research with young children with CP±L has focused on treatment and intervention, and previous qualitative research has been collected predominantly via interviews, so little is understood about the day-to-day lives of families of young children with CP±L. AIMS: (1) To increase understanding of the lives of children with CP±L and their families by applying an ethnographic lens to improve clinical practice (2) to identify key interactions and encounters that shape the experiences of children with CP±L and their families (3) to examine how family-centered practice can enhance practitioner-family relationships in providing effective and evidence-based care for children with CP±L. METHOD: Ethnographic observations of seven families of children with CP±L and their families and educators including parents, siblings, aunts, grandparents, and teachers involved multiple site visits. Rich data were collected to gather information about different aspects of their lives (such as their strengths, routines, preferences, challenges and experiences). There were 84 artefacts collected: 18 interviews, 29 videos, one extended audio recording of a mealtime, seven photos contributed by families, seven case history questionnaires, and 22 field notes. These data were analyzed inductively using thematic analysis. RESULTS: Three overarching themes and 11 subthemes were identified: (1) the whole child (persistence, communication, activities, mealtimes), (2) family strength and support (strong families, external support, attitudes, advocacy, positive medical experiences) and (3) family isolation and trauma (negative medical experiences, traumatic and challenging experiences). CONCLUSION: This is the first study to use ethnographic methodology to facilitate the collection of unique insights into the lives of young children with CP±L and their families to improve clinical practice for SLPs. The unique application of family-centered practice with these families promoted trust and highlighted their challenges and strengths which could be considered by SLPs to provide holistic intervention.

Developing a Sustainable Model for Medicaid Enrollment at the HOPES Free Clinic.

When Virginia expanded Medicaid, many citizens still faced barriers to enrolling in Medicaid. In response, a student-led Medicaid Enrollment Team was created at the HOPES free clinic to provide comprehensive enrollment assistance. In reviewing this program, this paper outlines steps taken that may be used by future enrollment efforts.

Holistic Communication Assessment for Young Children With Cleft Palate Using the International Classification of Functioning, Disability and Health:Children and Youth.

Purpose Children with a cleft palate (± cleft lip; CP±L) can have difficulties communicating and participating in daily life, yet speech-language pathologists typically focus on speech production during routine assessments. The International Classification of Functioning, Disability and Health: Children and Youth Version (ICF-CY; World Health Organization, 2007) provides a framework for holistic assessment. This tutorial describes holistic assessment of children with CP±L illustrated by data collected from a nonclinical sample of seven 2- to 3-year-old children, 13 parents, and 12 significant others (e.g., educators and grandparents). Method Data were collected during visits to participants' homes and early childhood education and care centers. Assessment tools applicable to domains of the ICF-CY were used to collect and analyze data. Child participants' Body Functions including speech, language, and cognitive development were assessed using screening and standardized assessments. Participants' Body Structures were assessed via oral motor examination, case history questionnaires, and observation. Participants' Activities and Participation as well as Environmental and Personal Factors were examined through case history questionnaires, interviews with significant others, parent report measures, and observations. Results Valuable insights can be gained from undertaking holistic speech-language pathology assessments with children with CP±L. Using multiple tools allowed for triangulation of data and privileging different viewpoints, to better understand the children and their contexts. Several children demonstrated speech error patterns outside of what are considered cleft speech characteristics, which underscores the importance of a broader assessment. Conclusion Speech-language pathologists can consider incorporating evaluation of all components and contextual factors of the ICF-CY when assessing and working with young children with CP±L to inform intervention and management practices.

Systems Pharmacology Model of Gastrointestinal Damage Predicts Species Differences and Optimizes Clinical Dosing Schedules.

Gastrointestinal (GI) adverse events (AEs) are frequently dose limiting for oncology agents, requiring extensive clinical testing of alternative schedules to identify optimal dosing regimens. Here, we develop a translational mathematical model to predict these clinical AEs starting from preclinical GI toxicity data. The model structure incorporates known biology and includes stem cells, daughter cells, and enterocytes. Published data, including cellular numbers and division times, informed the system parameters for humans and rats. The drug-specific parameters were informed with preclinical histopathology data from rats treated with irinotecan. The model fit the rodent irinotecan-induced pathology changes well. The predicted time course of enterocyte loss in patients treated with weekly doses matched observed AE profiles. The model also correctly predicts a lower level of AEs for every 3 weeks (Q3W), as compared to the weekly schedule.

The brain-penetrant clinical ATM inhibitor AZD1390 radiosensitizes and improves survival of preclinical brain tumor models.

Poor survival rates of patients with tumors arising from or disseminating into the brain are attributed to an inability to excise all tumor tissue (if operable), a lack of blood-brain barrier (BBB) penetration of chemotherapies/targeted agents, and an intrinsic tumor radio-/chemo-resistance. Ataxia-telangiectasia mutated (ATM) protein orchestrates the cellular DNA damage response (DDR) to cytotoxic DNA double-strand breaks induced by ionizing radiation (IR). ATM genetic ablation or pharmacological inhibition results in tumor cell hypersensitivity to IR. We report the primary pharmacology of the clinical-grade, exquisitely potent (cell IC50, 0.78 nM), highly selective [>10,000-fold over kinases within the same phosphatidylinositol 3-kinase-related kinase (PIKK) family], orally bioavailable ATM inhibitor AZD1390 specifically optimized for BBB penetration confirmed in cynomolgus monkey brain positron emission tomography (PET) imaging of microdosed 11C-labeled AZD1390 (Kp,uu, 0.33). AZD1390 blocks ATM-dependent DDR pathway activity and combines with radiation to induce G2 cell cycle phase accumulation, micronuclei, and apoptosis. AZD1390 radiosensitizes glioma and lung cancer cell lines, with p53 mutant glioma cells generally being more radiosensitized than wild type. In in vivo syngeneic and patient-derived glioma as well as orthotopic lung-brain metastatic models, AZD1390 dosed in combination with daily fractions of IR (whole-brain or stereotactic radiotherapy) significantly induced tumor regressions and increased animal survival compared to IR treatment alone. We established a pharmacokinetic-pharmacodynamic-efficacy relationship by correlating free brain concentrations, tumor phospho-ATM/phospho-Rad50 inhibition, apoptotic biomarker (cleaved caspase-3) induction, tumor regression, and survival. On the basis of the data presented here, AZD1390 is now in early clinical development for use as a radiosensitizer in central nervous system malignancies.

A Placebo-Controlled Study on the Effects of the Glucagon-Like Peptide-1 Mimetic, Exenatide, on Insulin Secretion, Body Composition and Adipokines in Obese, Client-Owned Cats.

Glucagon-like Peptide-1 mimetics increase insulin secretion and reduces body weight in humans. In lean, healthy cats, short-term treatment has produced similar results, whereas the effect in obese cats or with extended duration of treatment is unknown. Here, prolonged (12 weeks) treatment with the Glucagon-like Peptide-1 mimetic, exenatide, was evaluated in 12 obese, but otherwise healthy, client-owned cats. Cats were randomized to exenatide (1.0 µg/kg) or placebo treatment twice daily for 12 weeks. The primary endpoint was changes in insulin concentration; the secondary endpoints were glucose homeostasis, body weight, body composition as measured by dual-energy x-ray absorptiometry and overall safety. An intravenous glucose tolerance test (1 g/kg body weight) was conducted at week 0 and week 12. Exenatide did not change the insulin concentration, plasma glucose concentration or glucose tolerance (P>0.05 for all). Exenatide tended to reduce body weight on continued normal feeding. Median relative weight loss after 12 weeks was 5.1% (range 1.7 to 8.4%) in the exenatide group versus 3.2% (range -5.3 to 5.7%) in the placebo group (P = 0.10). Body composition and adipokine levels were unaffected by exenatide (P>0.05). Twelve weeks of exenatide was well-tolerated, with only two cases of mild, self-limiting gastrointestinal signs and a single case of mild hypoglycemia. The long-term insulinotropic effect of exenatide appeared less pronounced in obese cats compared to previous short-term studies in lean cats. Further investigations are required to fully elucidate the effect on insulin secretion, glucose tolerance and body weight in obese cats.

CYP1A2 in a smoking and a non-smoking population; correlation of urinary and salivary phenotypic ratios.

The use of caffeine as a probe for CYP1A2 phenotyping has been extensively investigated over the last 25 years. Numerous metabolic ratios have been employed and various biological fluids analysed for caffeine and its metabolites. These investigations have used non-smoking, smoking and numerous disease populations to investigate the role of CYP1A2 in possible disease aetiology and for induction and inhibition studies in vivo using dietary, environmental and pharmaceutical compounds. This investigation found that the 17X/137X CYP1A2 metabolic ratio in a 5 h saliva sample and 0-5 h urine collection was not normally distributed in both a non-smoking and a smoking population. The urinary and salivary CYP1A2 metabolic ratio was log normally distributed in the non-smoking population but the smoking population showed a bi- (or tri-)modal distribution on log transformation of both the urinary and salivary CYP1A2 metabolic ratios. The CYP1A2 metabolic ratios were significantly higher in the smoking population compared to the non-smoking population when both the urinary and salivary CYP1A2 metabolic ratios were analysed. These results indicate that urinary flow rate was not a factor in the variation in CYP1A2 phenotype in the non-smoking and smoking populations studied here. The increased CYP1A2 activity in the smoking population was probably due to induction of the CYP1A2 gene via the Ah receptor causing an increase in the concentration of CYP1A2 protein.

Discovery of 4-{4-[(3R)-3-Methylmorpholin-4-yl]-6-[1-(methylsulfonyl)cyclopropyl]pyrimidin-2-yl}-1H-indole (AZ20): a potent and selective inhibitor of ATR protein kinase with monotherapy in vivo antitumor activity.

ATR is an attractive new anticancer drug target whose inhibitors have potential as chemo- or radiation sensitizers or as monotherapy in tumors addicted to particular DNA-repair pathways. We describe the discovery and synthesis of a series of sulfonylmorpholinopyrimidines that show potent and selective ATR inhibition. Optimization from a high quality screening hit within tight SAR space led to compound 6 (AZ20) which inhibits ATR immunoprecipitated from HeLa nuclear extracts with an IC50 of 5 nM and ATR mediated phosphorylation of Chk1 in HT29 colorectal adenocarcinoma tumor cells with an IC50 of 50 nM. Compound 6 potently inhibits the growth of LoVo colorectal adenocarcinoma tumor cells in vitro and has high free exposure in mouse following moderate oral doses. At well tolerated doses 6 leads to significant growth inhibition of LoVo xenografts grown in nude mice. Compound 6 is a useful compound to explore ATR pharmacology in vivo.

Neurotrophic effects of BDNF on embryonic gonadotropin-releasing hormone (GnRH) neurons.

Secretion of gonadotropin-releasing hormone (GnRH) at the median eminence is the essential activator of the reproductive axis. The mechanisms by which embryonic GnRH neurons migrate from the olfactory placode to the preoptic area and then elaborate neurites that course through the hypothalamus to terminate at the median eminence are largely unknown. We investigated the hypothesis that GnRH neurite outgrowth is promoted by brain-derived neurotrophic factor (BDNF) because GnRH neurites course through BDNF-rich areas of the forebrain during their development. Confocal microscopy revealed that most (86%) cultured embryonic GnRH cells tagged with a green fluorescent protein reporter were immunoreactive for TrkB. In primary cultures of E12.5 olfactory tissue, treatment with BDNF induced a dose-dependent increase in neurite outgrowth, but had no discernible effect on branching. BDNF induced phosphorylation of Ca(2+)/cAMP response element-binding protein (pCREB) in both GnRH and non-GnRH cells in these cultures. This was not associated with phosphorylation of ERK in GnRH-immunoreactive cells, though BDNF treatment did stimulate pERK in neighbouring non-GnRH cells. Promotion of neurite outgrowth is unlikely therefore to result from activation of the Ras-MAPK/ERK pathway. We conclude that the developing GnRH secretory system is directly sensitive to BDNF and that this polypeptide functions as a neurotrophic factor for GnRH neurons.