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BACKGROUND: Perinatal Palliative Care (PPC) is individualized medical-nursing care aimed at improving the quality of life of newborns with life-limiting conditions and to support their families. This study draws on the analysis of the experience gained over ten years by a service of PPC called the "Percorso Giacomo" (PG). METHODS: We employed a SWOT analysis to identify the strengths, weaknesses, opportunities, and threats of the PG through a systematic retrospective review of 48 cases followed by the program over the course of 10 years, 21 unsolicited parents' narrative and 27 experts' point of view. RESULTS: Main strengths of the program were communication and parents' involvement in shared decision-making. Main weaknesses included lack of knowledge of the presence and the role of the PG and lack of resources. For opportunities, the PG proved to be an innovative choice for pregnancies with a fetal life-limiting diagnosis, however threats were identified such as lack of knowledge of PPC and delayed referrals. CONCLUSION: The analysis by SWOT method of the 10-year experience of the PG allowed the identification of limitations and areas of improvement, however demonstrated that the PG provided beneficial services to women faced with fetal life-limiting diagnoses. IMPACT: Perinatal Palliative Care (PPC) practice and literature on this subject is still limited. This study offers features of the 10-year experience of the Percorso Giacomo (PG), a service of PPC, through a SWOT analysis. By identifying strengths, weaknesses, opportunities and threats of the PG, the study shows limitations and areas of improvement but also benefits of a PPC service to women with fetal diagnosis of life-limiting condition and may allow replication in other institutions.

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[This corrects the article DOI: 10.3389/fmed.2022.1006891.].

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Taurine deficiency predisposes to the development of nutritional dilated cardiomyopathy and is widespread in dogs fed with non-traditional diets. However, Golden retrievers show lower plasma taurine concentration and an impaired systolic function compared to breeds of the same size and morphotype. For these reasons, it can be difficult to classify a subject from a cardiological point of view, with the risk of considering as pathological characteristics that can be completely normal in this breed. This is a cross-sectional multicenter study. The aims were 1) to identify breed-specific range of serum taurine concentration, 2) to describe a correlation between serum taurine concentration and echocardiographic parameters of systolic function in clinically healthy Golden retrievers fed with traditional diet, 3) to identify a correlation between thyroid hormones, serum taurine concentration and echocardiographic indices. Sixty clinically healthy Golden retrievers (33% males, 67% females) were included. Fifty-three dogs were fed with traditional diets and their range of serum taurine concentration was 398.2 (31.8-430) nmol/ml. Serum taurine concentration was found to be negatively correlated to systolic internal diameter of the left ventricle and systolic and diastolic left ventricular indices and volumes obtained with different methods, whereas was positively correlated to the left ventricle ejection and shortening fractions but difference was not statistically significative. A weak but significant correlation between serum taurine and T4 was demonstrated. Serum taurine median values in dogs with normal systolic function were higher than in dogs with impaired systolic function. A cut-off of serum taurine concentration of 140.6 nmol/ml had a moderate sensitivity and specificity in the identification of an impaired left ventricular systolic function (AUC 0.6, Se 78%, Sp 44%). This study showed that the median serum taurine concentration was significantly lower in dogs with impaired systolic function. Therefore, echocardiographic monitoring is recommended in all dogs with serum taurine concentration lower than 140.6 nmol/ml.

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Introduction: Trisomy 21 (T21), which causes Down syndrome (DS), is the most common chromosomal aneuploidy in humankind and includes different clinical comorbidities, among which the alteration of the immune system has a heavy impact on patient's lives. A molecule with an important role in immune response is zinc and it is known that its concentration is significantly lower in children with T21. Different hypotheses were made about this metabolic alteration and one of the reasons might be the overexpression of superoxide dismutase 1 (SOD1) gene, as zinc is part of the SOD1 active enzymatic center. Methods: The aim of our work is to explore if there is a linear correlation between zinc level and immune cell levels measured in a total of 217 blood samples from subjects with T21. Furthermore, transcriptome map analyses were performed using Transcriptome Mapper (TRAM) software to investigate whether a difference in gene expression is detectable between subjects with T21 and euploid control group in tissues and cells involved in the immune response such as lymphoblastoid cells, thymus and white blood cells. Results: Our results have confirmed the literature data stating that the blood zinc level in subjects with T21 is lower compared to the general population; in addition, we report that the T21/control zinc concentration ratio is 2:3, consistent with a chromosomal dosage effect due to the presence of three copies of chromosome 21. The transcriptome map analyses showed an alteration of some gene's expression which might explain low levels of zinc in the blood. Discussion: Our data suggest that zinc level is not associated with the levels of immunity cells or proteins analyzed themselves and rather the main role of this ion might be played in altering immune cell function.

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BACKGROUND: Pallister-Killian syndrome (PKS) is a rare genetic disorder caused by mosaic tetrasomy of 12p with wide neurological involvement. Intellectual disability, developmental delay, behavioral problems, epilepsy, sleep disturbances, and brain malformations have been described in most individuals, with a broad phenotypic spectrum. This observational study, conducted through brain MRI scan analysis on a cohort of patients with genetically confirmed PKS, aims to systematically investigate the neuroradiological features of this syndrome and identify the possible existence of a typical pattern. Moreover, a literature review differentiating the different types of neuroimaging data was conducted for comparison with our population. RESULTS: Thirty-one individuals were enrolled (17 females/14 males; age range 0.1-17.5 years old at first MRI). An experienced pediatric neuroradiologist reviewed brain MRIs, blindly to clinical data. Brain abnormalities were observed in all but one individual (compared to the 34% frequency found in the literature review). Corpus callosum abnormalities were found in 20/30 (67%) patients: 6 had callosal hypoplasia; 8 had global hypoplasia with hypoplastic splenium; 4 had only hypoplastic splenium; and 2 had a thin corpus callosum. Cerebral hypoplasia/atrophy was found in 23/31 (74%) and ventriculomegaly in 20/31 (65%). Other frequent features were the enlargement of the cisterna magna in 15/30 (50%) and polymicrogyria in 14/29 (48%). Conversely, the frequency of the latter was found to be 4% from the literature review. Notably, in our population, polymicrogyria was in the perisylvian area in all 14 cases, and it was bilateral in 10/14. CONCLUSIONS: Brain abnormalities are very common in PKS and occur much more frequently than previously reported. Bilateral perisylvian polymicrogyria was a main aspect of our population. Our findings provide an additional tool for early diagnosis.Further studies to investigate the possible correlations with both genotype and phenotype may help to define the etiopathogenesis of the neurologic phenotype of this syndrome.

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The one-carbon metabolism pathway is involved in critical human cellular functions such as cell proliferation, mitochondrial respiration, and epigenetic regulation. In the homocysteine-methionine cycle S-adenosyl-methionine (SAM) and S-adenosyl-homocysteine (SAH) are synthetized, and their levels are finely regulated to ensure proper functioning of key enzymes which control cellular growth and differentiation. Here we review the main biological mechanisms involving SAM and SAH and the known related human diseases. It was recently demonstrated that SAM and SAH levels are altered in plasma of subjects with trisomy 21 (T21) but how this metabolic dysregulation influences the clinical manifestation of T21 phenotype has not been previously described. This review aims at providing an overview of the biological mechanisms which are altered in response to changes in the levels of SAM and SAH observed in DS.

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BACKGROUND: Hydrogen sulfide (H2S) is established as the third gaseous signaling molecule and is known to be overproduced in down syndrome (DS) due to the extra copy of the CBS gene on chromosome 21, which has been suggested to contribute to the clinical manifestation of this condition. We recently discovered trimethylsulfonium (TMS) in human urine and highlighted its potential as a selective methylation metabolite of endogenously produced H2S, but the clinical utility of this novel metabolite has not been previously investigated. We hypothesize that the elevation of H2S production in DS would be reflected by an elevation in the methylation product TMS. METHODS: To test this hypothesis, a case-control study was performed and the urinary levels of TMS were found to be higher in the DS group (geo. mean 4.5 nM, 95 % CI 2.4-3.9) than in the control (N) group (3.1 nM, 3.5-6.0), p-value 0.01, whereas the commonly used biomarker of hydrogen sulfide, thiosulfate, failed to reflect this alteration in H2S production (15 µM (N) vs. 13 µM (DS), p-value 0.24. RESULTS: The observed association is in line with the proposed hypothesis and provides first clinical evidence of the utility of TMS as a novel and more sensitive biomarker for the endogenous production of the third gaseous signaling molecule than the conventionally used biomarker thiosulfate, which is heavily dependent on bacterial hydrogen sulfide production. CONCLUSION: This work shows that TMS must be explored in clinical conditions where altered metabolism of hydrogen sulfide is implicated.

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BACKGROUND: Persons with Down syndrome (DS) reveal adaptive functioning (AF) difficulties. Studies on AF in DS have focused mainly on describing the profile (i.e., strengths in socialization, and weaknesses in communication), while less is known about age-related differences. This study aimed to elucidate how AF changes with age in children and adolescents with DS, taking a cross-sectional developmental trajectory approach. Moreover, the contribution of both chronological age (CA) and mental age (MA) on AF development was explored. METHOD: This study involved 115 children and adolescents (between 3 and 16 years old) with DS. Parents were interviewed about their children's AF on communication, daily living and socialization skills. Children and adolescents with DS were assessed on their developmental level. RESULTS: While participants' standard scores on AF decreased linearly over time, their age-equivalent scores increased with linear or segmented patterns, depending on the skill considered. CA and MA were related to daily living skills and socialization to much the same degree, while MA correlated more strongly than CA with communication. CONCLUSION: This study contributes to the understanding of how AF develops in children and adolescents with DS, showing that CA and MA both contribute to shaping the skills involved.

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Down syndrome (DS) or trisomy 21 is the most common genetic cause of intellectual disability (ID), but a pathogenic mechanism has not been identified yet. Studying a complex and not monogenic condition such as DS, a clear correlation between cause and effect might be difficult to find through classical analysis methods, thus different approaches need to be used. The increased availability of big data has made the use of artificial intelligence (AI) and in particular machine learning (ML) in the medical field possible. The purpose of this work is the application of ML techniques to provide an analysis of clinical records obtained from subjects with DS and study their association with ID. We have applied two tree-based ML models (random forest and gradient boosting machine) to the research question: how to identify key features likely associated with ID in DS. We analyzed 109 features (or variables) in 106 DS subjects. The outcome of the analysis was the age equivalent (AE) score as indicator of intellectual functioning, impaired in ID. We applied several methods to configure the models: feature selection through Boruta framework to minimize random correlation; data augmentation to overcome the issue of a small dataset; age effect mitigation to take into account the chronological age of the subjects. The results show that ML algorithms can be applied with good accuracy to identify variables likely involved in cognitive impairment in DS. In particular, we show how random forest and gradient boosting machine produce results with low error (MSE <0.12) and an acceptable R2 (0.70 and 0.93). Interestingly, the ranking of the variables point to several features of interest related to hearing, gastrointestinal alterations, thyroid state, immune system and vitamin B12 that can be considered with particular attention for improving care pathways for people with DS. In conclusion, ML-based model may assist researchers in identifying key features likely correlated with ID in DS, and ultimately, may improve research efforts focused on the identification of possible therapeutic targets and new care pathways. We believe this study can be the basis for further testing/validating of our algorithms with multiple and larger datasets.

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BACKGROUND: Aldosterone represents an important target of heart failure therapy and may be a valuable indicator of the renin-angiotensin-aldosterone system activity. However, its assessment might be challenging because of the effect of individual factors. In a recent study, intact female dogs showed the highest value of urinary aldosterone-to-creatinine ratio (UAldo:C) compared to other sex categories. In humans and rodents, an influence of progesterone has been reported by several studies. To our knowledge, the relationship between aldosterone and progesterone has not yet been investigated in dogs. The aim of this prospective study was to investigate this relationship in sexually intact Chihuahua females, measuring both hormones twice in the same bitch, that is in anoestrus when progesterone concentrations are baseline and in dioestrus when they are high. RESULTS: The study population consisted of 14 sexually intact Chihuahua bitches. Serum progesterone (34.06 (21.17-44.90) vs. 0.19 [0.13-0.38] ng/ml; P < 0.001) and urinary aldosterone (9886.98 ± 5735.22 vs. 5005.72 ± 2127.73 pg/ml; P = 0.01) were significantly higher in dioestrus compared to anoestrous. Urinary aldosterone-to-creatinine ratio was higher in dioestrus compared to anoestrus (4.16 [3.17-6.80] vs. 3.39 ± 1.64 µg/g), but it did not reach the statistical significance (P = 0.056). Serum progesterone showed a moderate positive correlation with urinary aldosterone (ρ = 0.638, P < 0.001) and UAldo:C (ρ = 0.516, P = 0.005). CONCLUSIONS: The results of the present study suggest the existence of a progesterone-aldosterone relationship in canine species, indicating that sex and phase of reproductive cycle should be taken into account when interpreting aldosterone concentrations. Further studies are needed to confirm these results on a larger canine population and to identify the underlying mechanisms in this species.

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OBJECTIVES: To evaluate if the functional grading system (Cambridge classification) of brachycephalic obstructive airways syndrome (BOAS) and the temperament score can be useful tools in predicting the feasibility of echocardiographic examination in lateral recumbency. The hypothesis is that the temperament of the dog, rather than the severity of BOAS alone, can exacerbate respiratory symptoms (dyspnea, stertor, stridor and/or cyanosis) during lateral containment. METHODS: Prospective cross-sectional study. Twenty-nine French Bulldogs were included and classified according to the Cambridge classification for the BOAS and to the Maddern score for the temperament. Receiver operating characteristic analysis was used to evaluate the sensitivity (Se) and specificity (Sp) of the Cambridge classification, of the temperament score and their sum to predict the feasibility of the echocardiography in lateral recumbency without dyspnea/cyanosis. RESULTS: 8 females (27.59%) and 21 (72.41%) males French Bulldogs of 3 years (IQR25-75 1-4), and 12.45 kg (IQR25-7511.5-13.25) were included. The Cambridge classification alone was not predictive for the possibility of performing the echocardiography in lateral recumbency, unlike temperament score and the sum of the two classification indices. The diagnostic accuracy of Cambridge classification (AUC 0.81, Se 50%, Sp 100%), temperament score (AUC 0.73, Se 75%, Sp 69%), and their sum (AUC 0.83, Se 75%, Sp 85%) cut-offs was moderate for each score. CLINICAL SIGNIFICANCE: The dog's temperament, and therefore its susceptibility to stress, rather than the severity of BOAS (Cambridge classification) alone, is a good predictor of the possibility of performing the echocardiographic examination in standing instead of lateral recumbency.

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Echocardiography is the most widely accepted diagnostic tool for assessment of cardiac function and morphology in dogs and is usually performed in lateral recumbency. However, in some situations or in stressed patients, it is necessary to perform it in a standing position. Only one study evaluated the effects of animal position on selected two-dimensional and M-mode echocardiographic variables in four healthy dogs of different breeds, but not in brachycephalic breeds. In these breeds echocardiographic evaluation is sometimes needed in standing position due to the severity of brachycephalic obstructive airway syndrome and the impossibility of managing them in lateral recumbency without causing stress and choking danger. The objectives of this prospective, observational study were to (a) evaluate the effects of lateral recumbency versus standing positions on echocardiographic M-mode, two-dimensional, Doppler flow measurements, and Tissue Doppler imaging in healthy French bulldogs (FBs); (b) assess the intra- and interoperator variability of the standing echocardiographic examination; and (c) compare the obtained results with the available data from the literature. Forty healthy FBs (20 females/20 males) were sampled. The median age and weight were 2.45 years (IQR25-75 , 1.18-4.16) and 12.7 kg (IQR25-75 , 10.88-13.46). There were no differences between lateral recumbency and standing position measurements (P > 0.05). Intraoperator coefficients of variation (CVs) ranged from 0.5% to 10.1%, whereas interoperator CVs ranged from 1% to 14.2%. Only E wave peak velocity, aortic, and pulmonary flows were consistent with the previously published reference ranges in lateral recumbency. In conclusion, echocardiography in a standing position could be a useful tool in FBs.

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OBJECTIVES: The aims of this study were to compare the sedative effect, feasibility of venous angiocatheter placement and influence on heart rate (HR), systemic blood pressure (SBP) and echocardiographic variables of two multimodal anaesthetic protocols in uncooperative cats; and to compare their influence on HR, SBP and echocardiographic variables 20 mins after sedation and after elective ovariectomy. METHODS: Eighteen stray female cats randomly received intramuscular (IM) ketamine (2 mg/kg) and methadone (0.3 mg/kg) plus dexmedetomidine (7 µg/kg; group D, n = 9) or alfaxalone (2 mg/kg; group A, n = 9). A sedation score (0-15 [from none to good sedation]) was assigned at 5 mins, 10 mins, 15 mins and 20 mins after IM injection. Venous angiocatheter placement and echocardiographic examination feasibility scores (both from 0 to 3 [from very difficult to very easy]) were recorded at 20 mins. Echocardiography, HR and blood pressure measurements (Doppler and oscillometric methods) were performed at 20 mins and at the end of surgery. RESULTS: Sedation and angiocatheter feasibility scores did not differ significantly between groups (P >0.05); the feasibility score of echocardiographic examination was higher in cats in group D (P = 0.01). HR was higher in group A at 20 mins and after surgery (P <0.05). The systolic arterial pressure obtained with the Doppler method was statistically significantly higher in cats in group D than in group A at 20 mins (P = 0.01), while postoperatively there were no differences between groups. Cats in group D showed significantly higher atrial diameters (P <0.05) and slower atrial flows (P = 0.04) compared with group A; ventricular thickness and atrial function did not differ between groups (P >0.05). Most echocardiographic variables were not different at 20 mins vs postoperatively. CONCLUSIONS AND RELEVANCE: Both protocols allowed for effective sedation; however, cats in group D presented alterations in some echocardiographic measurements; the use of alfaxalone, combined with ketamine and methadone, is recommended to obtain a reliable echocardiographic evaluation in uncooperative cats.

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Communicating the diagnosis of Down Syndrome to a couple of parents is never easy, whether before or after birth. As doctors, we must certainly rely on our own relational skills, but it is also necessary to be confident in some general indications, which are often overlooked in the strict hospital routine. This article is intended as a summary of the main articles published on this subject in the international literature, collecting and summarising the most important indications that have emerged in years of medical practice all over the world as well as in our personal experience. The diffusion of these guidelines is essential to help the doctor in this difficult task, on which there is often little training, and above all to guarantee to the parents the least traumatic communication possible.

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Introduction: Down syndrome (DS) is the most common chromosomal disorder and it is caused by trisomy of chromosome 21 (Hsa21). Subjects with DS show a large heterogeneity of phenotypes and the most constant clinical features present are typical facies and intellectual disability (ID). Several studies demonstrated that trisomy 21 causes an alteration in the metabolic profile, involving among all the one-carbon cycle. Methods: We performed enzyme-linked immunosorbent assays (ELISAs) to identify the concentration of 5 different intermediates of the one-carbon cycle in plasma samples obtained from a total of 164 subjects with DS compared to 54 euploid subjects. We investigated: tetrahydrofolate (THF; DS n = 108, control n = 41), 5-methyltetrahydrofolate (5-methyl-THF; DS n = 140, control n = 34), 5-formyltetrahydrofolate (5-formyl-THF; DS n = 80, control n = 21), S-adenosyl-homocysteine (SAH; DS n = 94, control n = 20) and S-adenosyl-methionine (SAM; DS n = 24, control n = 15). Results: Results highlight specific alterations of THF with a median concentration ratio DS/control of 2:3, a decrease of a necessary molecule perfectly consistent with a chromosomal dosage effect. Moreover, SAM and SAH show a ratio DS/control of 1.82:1 and 3.6:1, respectively. Discussion: The relevance of these results for the biology of intelligence and its impairment in trisomy 21 is discussed, leading to the final proposal of 5-methyl-THF as the best candidate for a clinical trial aimed at restoring the dysregulation of one-carbon cycle in trisomy 21, possibly improving cognitive skills of subjects with DS.

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BACKGROUND: Down syndrome (DS) is caused by the presence of an extra copy of full or partial human chromosome 21 (Hsa21). Partial (segmental) trisomy 21 (PT21) is the duplication of only a delimited region of Hsa21 and can be associated or not to DS: the study of PT21 cases is an invaluable model for addressing genotype-phenotype correlation in DS. Previous works reported systematic reanalyses of 132 subjects with PT21 and allowed the identification of a 34-kb highly restricted DS critical region (HR-DSCR) as the minimal region whose duplication is shared by all PT21 subjects diagnosed with DS. METHODS: We report clinical data and cytogenetic analysis of two children with PT21, one with DS and the other without DS. Moreover, we performed a systematic bibliographic search for any new PT21 report. RESULTS: Clinical and cytogenetic analyses of the two PT21 children have been reported: in Case 1 the duplication involves the whole long arm of Hsa21, except for the last 2.7 Mb, which are deleted as a consequence of an isodicentric 21: the HR-DSCR is within the duplicated regions and the child is diagnosed with DS. In Case 2 the duplication involves 7.1 Mb of distal 21q22, with a deletion of 2.1 Mb of proximal 20p, as a consequence of an unbalanced translocation: the HR-DSCR is not duplicated and the child presents with psychomotor development delay but no clinical signs of DS. Furthermore, two PT21 reports recently published (named Case 3 and 4) have been discussed: Case 3 has DS diagnosis, nearly full trisomy for Hsa21 and a monosomy for the 21q22.3 region. Case 4 is a baby without DS and a 0.56-Mb duplication of 21q22.3. Genotype-phenotype correlation confirmed the presence of three copies of the HR-DSCR in all DS subjects and two copies in all non-DS individuals. CONCLUSIONS: The results presented here are fully consistent with the hypothesis that the HR-DSCR is critically associated with DS diagnosis. No exception to this pathogenetic model was found. Further studies are needed to detect genetic determinants likely located in the HR-DSCR and possibly responsible for core DS features, in particular intellectual disability.

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BACKGROUND: The gold standard in canine blood pressure (BP) measurement is the invasive method; however, non-invasive blood pressure measurement techniques (NIBP) are more commonly used. The lack of small, lightweight, cheap, fast and portable NIBP still remains a point to improve in the emergency setting. KEY FINDINGS: A human wrist blood pressure (WBP) device was evaluated in comparison with the veterinary high-definition oscillometry (HDO) in conscious normotensive dogs. Systolic and diastolic BPs were evaluated in two groups of dogs. The bias, the limits of agreement and correlation between variables were calculated. Twenty-five and 36 dogs were, respectively, included in Study No. 1 (dogs weighting ≥10 kg) and 2 (dogs weighting ≥20 kg). In both studies, correlation between the two devices was moderate. A better agreement was displayed for diastolic pressure and poor precision for both systolic and diastolic pressures measurements (as determined by wide limits of agreement). The WBP method underestimated both the systolic and diastolic BP with respect to the HDO method. The inclusion of bigger dogs (Study No. 2) with limb circumference more like to human limb dimension did not improve the agreement between considered methods. SIGNIFICANCE: The human WBP monitor considered is not suitable to replace the commonly used veterinary HDO for in-clinic BP monitoring in normotensive conscious dogs.

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The Down syndrome (DS) phenotype is usually characterized by relative strengths in non-verbal skills and deficits in verbal processing, but high interindividual variability has been registered in the syndrome. The goal of this study was to explore the cognitive profile, considering verbal and non-verbal intelligence, of children and adolescents with DS, also taking into account interindividual variability. We particularly aimed to investigate whether this variability means that we should envisage more than one cognitive profile in this population. The correlation between cognitive profile and medical conditions, parents' education levels and developmental milestones was also explored. Seventy-two children/adolescents with DS, aged 7-16 years, were assessed with the Wechsler Preschool and Primary Scale of Intelligence-III. Age-equivalent scores were adopted, and Verbal and Non-Verbal indices were obtained for each individual. The cognitive profile of the group as a whole was characterized by similar scores in the verbal and non-verbal domain. Cluster analysis revealed three different profiles, however: one group, with the lowest scores, had the typical profile associated with DS (with higher non-verbal than verbal intelligence); one, with intermediate scores, had greater verbal than non-verbal intelligence; and one, with the highest scores, fared equally well in the verbal and non-verbal domain. Three cognitive profiles emerged, suggesting that educational support for children and adolescents with DS may need to be more specific.

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Down syndrome (DS) is characterised by several clinical features including intellectual disability (ID) and craniofacial dysmorphisms. In 1976, Jackson and coll. identified a checklist of signs for clinical diagnosis of DS; the utility of these checklists in improving the accuracy of clinical diagnosis has been recently reaffirmed, but they have rarely been revised. The purpose of this work is to reassess the characteristic phenotypic signs and their frequencies in 233 DS subjects, following Jackson's checklist. 63.77% of the subjects showed more than 12 signs while none showed less than 5, confirming the effectiveness of Jackson's checklist for the clinical diagnosis of DS. An association between three phenotypic signs emerged, allowing us to distinguish two sub-phenotypes: Brachycephaly, short and broad Hands, short Neck (BHN), which is more frequent, and "non-BHN". The strong association of these signs might be interpreted in the context of the growth defects observed in DS children suggesting decreased cell proliferation. Lastly, cognitive assessments were investigated for 114 subjects. The lack of association between the presence of a physical sign or the number of signs present in a subject and cognitive skills disproves the stereotype that physical characteristics are predictive of degree of ID.

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The aim of this work was to retrospectively evaluate the influence of pimobendan on the survival time (ST) of dogs with myxomatous mitral valve disease at different stages using an Inverse Probability Weighting (IPW) analysis. An IPW method was used to minimize confounding and IPW weighted time-repeated logistic model was used to approximate survival curves (SCs) and calculate survival differences. Subjects were allocated into exposed (E) and unexposed (U). Dogs in the American College of Veterinary Internal Medicine (ACVIM) B2 class treated with pimobendan (± ACE-inhibitors) were selected for the E group, as well as symptomatic patients (ACVIM class C) treated with triple (furosemide, ACE-inhibitor, pimobendan) or quadruple (furosemide, ACE-inhibitor, pimobendan and spironolactone) therapy. The U group included ACVIM class B2 dogs not treated with any medication and ACVIM C dogs treated with a combination of furosemide and ACE-inhibitor/spironolactone without pimobendan. The survival curve (SC) of the E group crossed the U group at 1634 days. The difference between the two SCs at the time of maximum survival difference in favor of the U group was 11.3% (CI 1.7%-20.9%) (significant), in favor of the E group was 3.9% (CI -8.6%-16.4%) (not significant) and at the mean ST was 3.6% (CI -8.5%-15.7%) (not significant) in favor of the E group. For times greater than 1634 days the survival was in favor of the E group, but there were no statistically significant differences in survival in favor of the E group in this clinical population.

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