The relationship between pain, analgesics and survival in patients with advanced cancer; a secondary data analysis of the international European palliative care Cancer symptom study.

PURPOSE: Opioids reduce cancer-related pain but an association with shorter survival is variably reported. AIM: To investigate the relationship between pain, analgesics, cancer and survival within the European Palliative Care Cancer Symptom (EPCCS) study to help inform clinical decision making. METHODS: Secondary analysis of the international prospective, longitudinal EPCCS study which included 1739 adults with advanced, incurable cancer receiving palliative care. In this secondary analysis, for all participants with date of death or last follow up, a multilevel Weibull survival analysis examined whether pain, analgesics, and other relevant variables are associated with time to death. RESULTS: Date of death or last follow-up was available for 1404 patients (mean age 65.7 [SD:12.3];men 50%). Secondary analysis of this group showed the mean survival from baseline was 46.5 (SD:1.5) weeks (95% CI:43.6-49.3). Pain was reported by 76%; 60% were taking opioids, 51% non-opioid analgesics and 24% co-analgesics. Opioid-use was associated with decreased survival in the multivariable model (HR = 1.59 (95% CI:1.38-1.84), p < 0.001). An exploratory subgroup analysis of those with C-reactive protein (CRP) measures (n = 219) indicated higher CRP was associated with poorer survival (p = 0.001). In this model, the strength of relationship between survival and opioid-use weakened (p = 0.029). CONCLUSION: Opioid-use and survival were associated; this relationship weakened in a small sensitivity-testing subgroup analysis adjusting for CRP. Thus, the observed relationship between survival and opioid-use may partly be due to tumour-related inflammation. Larger studies, measuring disease activity, are needed to confirm this finding to more accurately judge the benefits and risks of opioids in advanced progressive disease.

"How Long Have I Got?"-A Prospective Cohort Study Comparing Validated Prognostic Factors for Use in Patients with Advanced Cancer.

BACKGROUND: The optimal prognostic factors in patients with advanced cancer are not known, as a comparison of these is lacking. The aim of the present study was to determine the optimal prognostic factors by comparing validated factors. MATERIALS AND METHODS: A multicenter, prospective observational cohort study recruited patients over 18 years with advanced cancer. The following were assessed: clinician-predicted survival (CPS), Eastern Cooperative Oncology Group performance status (ECOG-PS), patient reported outcome measures (anorexia, cognitive impairment, dyspnea, global health), metastatic disease, weight loss, modified Glasgow Prognostic Score (mGPS) based on C-reactive protein and albumin, lactate dehydrogenase (LDH), and white (WCC), neutrophil (NC), and lymphocyte cell counts. Survival at 1 and 3 months was assessed using area under the receiver operating curve and logistic regression analysis. RESULTS: Data were available on 478 patients, and the median survival was 4.27 (1.86-7.03) months. On univariate analysis, the following factors predicted death at 1 and 3 months: CPS, ECOG-PS, mGPS, WCC, NC (all p < .001), dyspnea, global health (both p ≤ .001), cognitive impairment, anorexia, LDH (all p < .01), and weight loss (p < .05). On multivariate analysis ECOG-PS, mGPS, and NC were independent predictors of survival at 1 and 3 months (all p < .01). CONCLUSION: The simple combination of ECOG-PS and mGPS is an important novel prognostic framework which can alert clinicians to patients with good performance status who are at increased risk of having a higher symptom burden and dying at 3 months. From the recent literature it is likely that this framework will also be useful in referral for early palliative care with 6-24 months survival. IMPLICATIONS FOR PRACTICE: This large cohort study examined all validated prognostic factors in a head-to-head comparison and demonstrated the superior prognostic value of the Eastern Cooperative Oncology Group performance status (ECOG-PS)/modified Glasgow Prognostic Score (mGPS) combination over other prognostic factors. This combination is simple, accurate, and also relates to quality of life. It may be useful in identifying patients who may benefit from early referral to palliative care. It is proposed ECOG-PS/mGPS as the new prognostic domain in patients with advanced cancer.

Turning the tables of sex distinction in craniofacial identification: Why females possess thicker facial soft tissues than males, not vice versa.

Males are universally reported to possess larger facial soft-tissue thickness (FSTT) than females, however, this observation oversimplifies the raw data yielding an underpowered assessment of FSTT sex-patterning where: differences are small (η(2) < 5%) and inconsistent (females are routinely larger than males at the cheeks). Here we investigate body-size normalized data to assess whether more general and improved understanding of FSTT sex-variation in humans is possible. FSTTs were measured in 52 healthy living Australians aged 18 to 30 years using B-mode ultrasound. Participants' stature and body mass were also measured. Sex differences were calculated before and after normalization by the aforementioned body-composition variables. Methods were repeated in three other independent samples to evaluate reproducibility: 100 American Whites and 60 American Blacks measured by B-mode ultrasound; and 50 Turkish residents measured by regular supine CT. Compared to raw mean differences (F < M, by -6%), females displayed much thicker FSTTs than males when normalized for body mass (F > M, by +16%). Consequently, while the sexes share similar raw values, females possess much larger FSTTs for their relatively lighter bodies. The relative FSTT difference was 2.7× larger than the raw mean difference. Sex differences in FSTT are of larger magnitude and reversed direction in mass normalized data. Contrary to popular thought, females possess much larger FSTTs than males owing to their generically lighter bodies (-18 kg). These data patterns help explain why the pooling of sex-categorized FSTT does not jeopardize the sex-difference-it is encoded more strongly in terms relative to body mass.

Non-medical prescribing in palliative care: a regional survey.

BACKGROUND: The United Kingdom is considered to be the world leader in nurse prescribing, no other country having the same extended non-medical prescribing rights. Arguably, this growth has outpaced research to evaluate the benefits, particularly in areas of clinical practice where patients have complex co-morbid conditions such as palliative care. This is the first study of non-medical prescribing in palliative care in almost a decade. AIM: To explore the current position of nurse prescribing in palliative care and establish the impact on practice of the 2012 legislative changes. DESIGN: An online survey circulated during May and June 2013. PARTICIPANTS: Nurse members (n = 37) of a regional cancer network palliative care group (61% response rate). RESULTS: While this survey found non-medical prescribers have embraced the 2012 legislative changes and prescribe a wide range of drugs for cancer pain, we also identified scope to improve the transition from qualified to active non-medical prescriber by reducing the time interval between the two. CONCLUSION: To maximise the economic and clinical benefit of non-medical prescribing, the delay between qualifying as a prescriber and becoming an active prescriber needs to be reduced. Nurses who may be considering training to be a non-medical prescriber may be encouraged by the provision of adequate study leave and support to cover clinical work. Further research should explore the patients' perspective of non-medical prescribing.

Lineage tree for the venous pole of the heart: clonal analysis clarifies controversial genealogy based on genetic tracing.

RATIONALE: Genetic tracing experiments and cell lineage analyses are complementary approaches that give information about the progenitor cells of a tissue. Approaches based on gene expression have led to conflicting views about the origin of the venous pole of the heart. Whereas the heart forms from 2 sources of progenitor cells, the first and second heart fields, genetic tracing has suggested a distinct origin for caval vein myocardium, from a proposed third heart field. OBJECTIVE: To determine the cell lineage history of the myocardium at the venous pole of the heart. METHODS AND RESULTS: We used retrospective clonal analyses to investigate lineage segregation for myocardium at the venous pole of the mouse heart, independent of gene expression. CONCLUSIONS: Our lineage analysis unequivocally shows that caval vein and atrial myocardium share a common origin and demonstrates a clonal relationship between the pulmonary vein and progenitors of the left venous pole. Clonal characteristics give insight into the development of the veins. Unexpectedly, we found a lineage relationship between the venous pole and part of the arterial pole, which is derived exclusively from the second heart field. Integration of results from genetic tracing into the lineage tree adds a further temporal dimension to this reconstruction of the history of venous myocardium and the arterial pole.

Exploring interference from analgesia in patients with cancer pain: a longitudinal qualitative study.

AIMS AND OBJECTIVES: To increase understanding of the impact of analgesic side effects in patients with cancer pain. BACKGROUND: Studies in the area of cancer pain often refer to the need to find a satisfactory balance between analgesics and side effects as the key to cancer pain management. We explore how patients achieve this balance, its components and how it affects pain treatment adherence. DESIGN: An exploratory longitudinal study using qualitative research methodology. METHODS: Twenty-five semi-structured face-to-face interviews with patients with advanced cancer and their caregivers. Longitudinal interviews were conducted with patients (n = 11) at six-week intervals over three months. Eleven first interviews, eight second interviews and six third interviews were completed with attrition due to death or ill health. Ten of the 25 interviews included caregivers. RESULTS: How cancer pain analgesics interfere with patients' life determines their adherence to the prescribed treatment. Compromises were made to manage three elements: pain, cognitive adverse effects of analgesics and physical activity. Negotiations and choices within this triad fluctuated and were determined by multiple psychosocial circumstances affecting patients and their caregivers varying from simple to complex. Patients with cancer and their caregivers actively managed the interference of analgesic drugs in their cognitive abilities and displayed a variety of nonadherence behaviours. CONCLUSION: Further understanding of the role of analgesic side effects in the success of cancer pain management in patients is needed. This would enable clinicians to frame an optimal pain management plan. RELEVANCE TO CLINICAL PRACTICE: Clinicians should advise their patients about side effects of analgesic drugs, specifically the impact that cognitive alterations might have on their lives and subsequent adherence behaviour. Helping patients to achieve a balance between pain, adverse effects and physical function should have a key place in pain management strategies with advanced cancer.

Extent of palliative care need in the acute hospital setting: a survey of two acute hospitals in the UK.

BACKGROUND: In common with international health policy, The End of Life Care Strategy for England has highlighted the delivery of high quality palliative care in the acute hospital setting as an area of priority. AIM: The aim of this study was to explore the extent of palliative care need in the acute hospital setting, and to explore agreement between different sources in the identification of patients with palliative care need. DESIGN: A cross-sectional survey of palliative care need was undertaken in two UK acute hospitals. Hospital case notes were examined for evidence of palliative care need according to Gold Standards Framework (GSF) prognostic indicator criteria. Medical and nursing staff were asked to identify patients with palliative care needs. Patients (or consultees) completed assessments of palliative care need. PARTICIPANTS: Of a total in-patient population of 1359, complete datasets were collected for 514 patients/consultees. RESULTS: 36.0% of patients were identified as having palliative care needs according to GSF criteria. Medical staff identified 15.5% of patients as having palliative care needs, and nursing staff 17.4% of patients. Patient self-report data indicated that 83.2% of patients meeting GSF criteria had palliative care needs. CONCLUSION: The results reveal that according to the GSF prognostic guide, over a third of hospital in-patients meet the criteria for palliative care need. Consensus between medical staff, nursing staff and the GSF was poor regarding the identification of patients with palliative care needs. This has significant implications for patient care, and draws into question the utility of the GSF in the hospital setting.

Retrospective genomics highlights changes in genetic composition of tiger sharks (Galeocerdo cuvier) and potential loss of a south-eastern Australia population.

Over the last century, many shark populations have declined, primarily due to overexploitation in commercial, artisanal and recreational fisheries. In addition, in some locations the use of shark control programs also has had an impact on shark numbers. Still, there is a general perception that populations of large ocean predators cover wide areas and therefore their diversity is less susceptible to local anthropogenic disturbance. Here we report on temporal genomic analyses of tiger shark (Galeocerdo cuvier) DNA samples that were collected from eastern Australia over the past century. Using Single Nucleotide Polymorphism (SNP) loci, we documented a significant change in genetic composition of tiger sharks born between ~1939 and 2015. The change was most likely due to a shift over time in the relative contribution of two well-differentiated, but hitherto cryptic populations. Our data strongly indicate a dramatic shift in the relative contribution of these two populations to the overall tiger shark abundance on the east coast of Australia, possibly associated with differences in direct or indirect exploitation rates.

Diving into the vertical dimension of elasmobranch movement ecology.

Knowledge of the three-dimensional movement patterns of elasmobranchs is vital to understand their ecological roles and exposure to anthropogenic pressures. To date, comparative studies among species at global scales have mostly focused on horizontal movements. Our study addresses the knowledge gap of vertical movements by compiling the first global synthesis of vertical habitat use by elasmobranchs from data obtained by deployment of 989 biotelemetry tags on 38 elasmobranch species. Elasmobranchs displayed high intra- and interspecific variability in vertical movement patterns. Substantial vertical overlap was observed for many epipelagic elasmobranchs, indicating an increased likelihood to display spatial overlap, biologically interact, and share similar risk to anthropogenic threats that vary on a vertical gradient. We highlight the critical next steps toward incorporating vertical movement into global management and monitoring strategies for elasmobranchs, emphasizing the need to address geographic and taxonomic biases in deployments and to concurrently consider both horizontal and vertical movements.

Novel signature fatty acid profile of the giant manta ray suggests reliance on an uncharacterised mesopelagic food source low in polyunsaturated fatty acids.

Traditionally, large planktivorous elasmobranchs have been thought to predominantly feed on surface zooplankton during daytime hours. However, the recent application of molecular methods to examine long-term assimilated diets, has revealed that these species likely gain the majority from deeper or demersal sources. Signature fatty acid analysis (FA) of muscle tissue was used to examine the assimilated diet of the giant manta ray Mobula birostris, and then compared with surface zooplankton that was collected during feeding and non-feeding events at two aggregation sites off mainland Ecuador. The FA profiles of M. birostris and surface zooplankton were markedly different apart from similar proportions of arachidonic acid, which suggests daytime surface zooplankton may comprise a small amount of dietary intake for M. birostris. The FA profile of M. birostris muscle was found to be depleted in polyunsaturated fatty acids, and instead comprised high proportions of 18:1ω9 isomers. While 18:1ω9 isomers are not explicitly considered dietary FAs, they are commonly found in high proportions in deep-sea organisms, including elasmobranch species. Overall, the FA profile of M. birostris suggests a diet that is mesopelagic in origin, but many mesopelagic zooplankton species also vertically migrate, staying deep during the day and moving to shallower waters at night. Here, signature FA analysis is unable to resolve the depth at which these putative dietary items were consumed and how availability of this prey may drive distribution and movements of this large filter-feeder.

Lack of multiple paternity in the oceanodromous tiger shark (Galeocerdo cuvier).

Multiple paternity has been documented as a reproductive strategy in both viviparous and ovoviviparous elasmobranchs, leading to the assumption that multiple mating may be ubiquitous in these fishes. However, with the majority of studies conducted on coastal and nearshore elasmobranchs that often form mating aggregations, parallel studies on pelagic, semi-solitary species are lacking. The tiger shark (Galeocerdo cuvier) is a large pelagic shark that has an aplacental viviparous reproductive mode which is unique among the carcharhinids. A total of 112 pups from four pregnant sharks were genotyped at nine microsatellite loci to assess the possibility of multiple paternity or polyandrous behaviour by female tiger sharks. Only a single pup provided evidence of possible multiple paternity, but with only seven of the nine loci amplifying for this individual, results were inconclusive. In summary, it appears that the tiger sharks sampled in this study were genetically monogamous. These findings may have implications for the genetic diversity and future sustainability of this population.

Managing the symptoms of neuropathic pain: an exploration of patients' experiences.

The debilitating effects of chronic neuropathic pain on everyday life are considerable, but little is known about how individual sufferers manage these effects. Virtually nothing is known about what patients prefer, what measures they take themselves and when, or in what combinations. The aim of this study was to explore patients' reports of how they managed their neuropathic pain symptoms. Three focus groups (10 participants in total) were used to generate qualitative data on both individual and shared experiences of managing symptoms of neuropathic pain. Discussions were recorded and transcribed verbatim. Data were analyzed using thematic analysis, identifying categories and broader themes of importance to patients. The most common management strategy was the use of conventional medications, often associated with poor effectiveness and unpleasant side effects. Complementary and alternative medicine was ineffective, but many found resting or retreating helpful. They exhibited a repeated cycle of seeking help to manage the pain, with each unsuccessful attempt followed by new attempts. Some had tried to accept their pain, but there was insufficient psychological, social, emotional, and practical support to allow them to do this successfully. This exploratory study provides a basis from which to develop a larger study to validate and extend the findings. Other issues meriting research are the effectiveness of cognitive-behavioral therapies for those with neuropathic pain, and an exploration and subsequent evaluation of different types of social, practical, and emotional support needed to help live with neuropathic pain.

Survey of blood transfusion practice for palliative care patients in Yorkshire: implications for clinical care.

Blood transfusions can be used to palliate the symptoms of fatigue or dyspnea in the presence of anemia. We studied the transfusion practices of 8 hospices in our cancer network over a 1-year period. We identified 164 patients who received 650 units of blood in 230 transfusions. The majority of patients received a single transfusion (71%), of 2 or 3 units of blood (76%), as an inpatient (83%). Blood transfusions occurred in 140 (5.7%) of 2460 hospice admissions. Median survival following first transfusion was 42 days and significantly longer for outpatients compared to inpatients (median of 104 days and 36 days, respectively, p = 0.006).

Pain and Opioids in Cancer Care: Benefits, Risks, and Alternatives.

Pain remains common in the setting of malignancy, occurring as a consequence of cancer and its treatment. Several high-quality studies confirm that more than 50% of all patients with cancer experience moderate to severe pain. The prevalence of pain in cancer survivors is estimated to be 40%, while close to two-thirds of those with advanced disease live with pain. Progress has occurred in the management of cancer pain, yet undertreatment persists. Additionally, new challenges are threatening these advances. These challenges are numerous and include educational deficits, time restraints, and limited access to all types of care. New challenges to access are occurring as a result of interventions designed to combat the prescription drug abuse epidemic, with fewer clinicians willing to prescribe opioids, pharmacies reluctant to stock the medications, and payers placing strict limits on reimbursement. A related challenge is our evolving understanding of the risks of long-term adverse effects associated with opioids. And reflective of the opioid abuse epidemic affecting the general population, the potential for misuse or abuse exists in those with cancer. Guidelines have been developed to support oncologists when prescribing the long-term use of opioids for cancer survivors. The challenges surrounding the use of opioids, and the need for safe and effective alternative analgesics, are leading to intense interest in the potential benefits of cannabis for cancer-related pain. Oncologists are faced with questions regarding the types of cannabis available, differences between routes of administration, data concerning safety and efficacy, and legal and regulatory dynamics.

Population structure and connectivity of tiger sharks (Galeocerdo cuvier) across the Indo-Pacific Ocean basin.

Population genetic structure using nine polymorphic nuclear microsatellite loci was assessed for the tiger shark (Galeocerdo cuvier) at seven locations across the Indo-Pacific, and one location in the southern Atlantic. Genetic analyses revealed considerable genetic structuring (FST > 0.14, p < 0.001) between all Indo-Pacific locations and Brazil. By contrast, no significant genetic differences were observed between locations from within the Pacific or Indian Oceans, identifying an apparent large, single Indo-Pacific population. A lack of differentiation between tiger sharks sampled in Hawaii and other Indo-Pacific locations identified herein is in contrast to an earlier global tiger shark nDNA study. The results of our power analysis provide evidence to suggest that the larger sample sizes used here negated any weak population subdivision observed previously. These results further highlight the need for cross-jurisdictional efforts to manage the sustainable exploitation of large migratory sharks like G. cuvier.

Prey Density Threshold and Tidal Influence on Reef Manta Ray Foraging at an Aggregation Site on the Great Barrier Reef.

Large tropical and sub-tropical marine animals must meet their energetic requirements in a largely oligotrophic environment. Many planktivorous elasmobranchs, whose thermal ecologies prevent foraging in nutrient-rich polar waters, aggregate seasonally at predictable locations throughout tropical oceans where they are observed feeding. Here we investigate the foraging and oceanographic environment around Lady Elliot Island, a known aggregation site for reef manta rays Manta alfredi in the southern Great Barrier Reef. The foraging behaviour of reef manta rays was analysed in relation to zooplankton populations and local oceanography, and compared to long-term sighting records of reef manta rays from the dive operator on the island. Reef manta rays fed at Lady Elliot Island when zooplankton biomass and abundance were significantly higher than other times. The critical prey density threshold that triggered feeding was 11.2 mg m-3 while zooplankton size had no significant effect on feeding. The community composition and size structure of the zooplankton was similar when reef manta rays were feeding or not, with only the density of zooplankton changing. Higher zooplankton biomass was observed prior to low tide, and long-term (~5 years) sighting data confirmed that more reef manta rays are also observed feeding during this tidal phase than other times. This is the first study to examine prey availability at an aggregation site for reef manta rays and it indicates that they feed in locations and at times of higher zooplankton biomass.

Morphology of the ampullae of Lorenzini in juvenile freshwater Carcharhinus leucas.

Ampullae of Lorenzini were examined from juvenile Carcharhinus leucas (831-1,045 mm total length) captured from freshwater regions of the Brisbane River. The ampullary organ structure differs from all other previously described ampullae in the canal wall structure, the general shape of the ampullary canal, and the apically nucleated supportive cells. Ampullary pores of 140-205 µm in diameter are distributed over the surface of the head region with 2,681 and 2,913 pores present in two sharks that were studied in detail. The primary variation of the ampullary organs appears in the canal epithelial cells which occur as either flattened squamous epithelial cells or a second form of pseudostratified contour-ridged epithelial cells; both cell types appear to release material into the ampullary lumen. Secondarily, this ampullary canal varies due to involuted walls that form a clover-like canal wall structure. At the proximal end of the canal, contour-ridged cells abut a narrow region of cuboidal epithelial cells that verge on the constant, six alveolar sacs of the ampulla. The alveolar sacs contain numerous receptor and supportive cells bound by tight junctions and desmosomes. Pear-shaped receptor cells that possess a single apical kinocilium are connected basally by unmyelinated neural boutons. Opposed to previously described ampullae of Lorenzini, the supportive cells have an apical nucleus, possess a low number of microvilli, and form a unique, jagged alveolar wall. A centrally positioned centrum cap of cuboidal epithelial cells overlies a primary afferent lateral line nerve.

A comparative analysis of feeding and trophic level ecology in stingrays (Rajiformes; Myliobatoidei) and electric rays (Rajiformes: Torpedinoidei).

Standardised diets and trophic level (T L) estimates were calculated for 75 ray species from the suborders Myliobatoidei (67 spp.) and Torpedinoidei (8 spp.). Decapod crustaceans (31.71 ± 3.92%) and teleost fishes (16.45 ± 3.43%) made the largest contribution to the standardised diet of the Myliobatoidei. Teleost fishes (37.40 ± 16.09%) and polychaete worms (31.96 ± 14.22%) were the most prominent prey categories in the standardised diet of the suborder Torpedinoidei. Cluster analysis identified nine major trophic guilds the largest of which were decapod crustaceans (24 species), teleost fishes (11 species) and molluscs (11 species). Trophic level estimates for rays ranged from 3.10 for Potamotrygon falkneri to 4.24 for Gymnura australis, Torpedo marmorata and T. nobiliana. Secondary consumers with a T L <4.00 represented 84% of the species examined, with the remaining 12 species (16%) classified as tertiary consumers (T L ≥ 4.00). Tertiary consumers included electric rays (Torpedo, 3 spp. and Hypnos, 1 sp.), butterfly rays (Gymnura, 4 spp.), stingrays (2 spp.) and Potamotrygonid stingrays (2 spp.). Feeding strategies were identified as the primary factor of influence with respect to Myliobatoidei and Torpedinoidei T L estimates with inter-family comparisons providing the greatest insight into Myliobatoidei and Torpedinoidei relationships.

Down's syndrome-like cardiac developmental defects in embryos of the transchromosomic Tc1 mouse.

AIMS: Cardiac malformations are prevalent in trisomies of human chromosome 21 [Down's syndrome (DS)], affecting normal chamber separation in the developing heart. Efforts to understand the aetiology of these defects have been severely hampered by the absence of an accurate mouse model. Such models have proved challenging to establish because synteny with human chromosome Hsa21 is distributed across three mouse chromosomes. None of those engineered so far accurately models the full range of DS cardiac phenotypes, in particular the profound disruptions resulting from atrioventricular septal defects (AVSDs). Here, we present analysis of the cardiac malformations exhibited by embryos of the transchromosomic mouse line Tc(Hsa21)1TybEmcf (Tc1) which contains more than 90% of chromosome Hsa21 in addition to the normal diploid mouse genome. METHODS AND RESULTS: Using high-resolution episcopic microscopy and three-dimensional (3D) modelling, we show that Tc1 embryos exhibit many of the cardiac defects found in DS, including balanced AVSD with single and separate valvar orifices, membranous and muscular ventricular septal defects along with outflow tract and valve leaflet abnormalities. Frequencies of cardiac malformations (ranging from 38 to 55%) are dependent on strain background. In contrast, no comparable cardiac defects were detected in embryos of the more limited mouse trisomy model, Dp(16Cbr1-ORF9)1Rhr (Ts1Rhr), indicating that trisomy of the region syntenic to the Down's syndrome critical region, including the candidate genes DSCAM and DYRK1A, is insufficient to yield DS cardiac abnormalities. CONCLUSION: The Tc1 mouse line provides a suitable model for studying the underlying genetic causes of the DS AVSD cardiac phenotype.