Cost-effectiveness of restorative treatments for permanent molars with severe molar incisor hypomineralization: perspectives for the Brazilian public health system.

OBJECTIVES: To undertake a cost-effectiveness analysis of restorative treatments for a first permanent molar with severe molar incisor hypomineralization from the perspective of the Brazilian public system. MATERIALS AND METHODS: Two models were constructed: a one-year decision tree and a ten-year Markov model, each based on a hypothetical cohort of one thousand individuals through Monte Carlo simulation. Eight restorative strategies were evaluated: high viscosity glass ionomer cement (HVGIC); encapsulated GIC; etch and rinse adhesive + composite; self-etch adhesive + composite; preformed stainless steel crown; HVGIC + etch and rinse adhesive + composite; HVGIC + self-etch adhesive + composite, and encapsulated GIC + etch and rinse adhesive + composite. Effectiveness data were sourced from the literature. Micro-costing was applied using 2022 USD market averages with a 5% variation. Incremental cost-effectiveness ratio (ICER), net monetary benefit (%NMB), and the budgetary impact were obtained. RESULTS: Cost-effective treatments included HVGIC (%NMB = 0%/ 0%), encapsulated GIC (%NMB = 19.4%/ 19.7%), and encapsulated GIC + etch and rinse adhesive + composite (%NMB = 23.4%/ 24.5%) at 1 year and 10 years, respectively. The benefit gain of encapsulated GIC + etch and rinse adhesive + composite in relation to encapsulated GIC was small when compared to the cost increase at 1 year (gain of 3.28% and increase of USD 24.26) and 10 years (gain of 4% and increase of USD 15.54). CONCLUSION: Within the horizon and perspective analyzed, the most cost-effective treatment was encapsulated GIC restoration. CLINICAL RELEVANCE: This study can provide information for decision-making.

"It's Like Living with a Sassy Teenager!": A Mixed-Methods Analysis of Owners' Comments about Dogs between the Ages of 12 Weeks and 2 Years.

Owners' understanding of dog behaviour influences dog welfare. This study aimed to investigate owners' experiences of living with dogs and perceptions of dog behaviour/behaviour change. Data from an ongoing UK/ROI longitudinal study of dogs were used. Open-ended survey data (n = 3577 comments, n = 1808 dogs) when dogs were 12/16 weeks (data combined), 6, 12, 18 and 24 months were analysed to cover the dog's puppyhood/adolescence. To evaluate the usefulness of open-ended survey questions, both quantitative textual and qualitative thematic analyses were employed. Textual analysis identified an overall positive sentiment at all timepoints; the proportion of positive: negative sentiments increased with the dog's age. Words related to 'love' were the most frequent descriptors at all but the first timepoint, when 'bite' was the most frequent descriptor. Qualitative analysis helped to identify that owners attribute dog behaviour to 'Dog's biology', 'Personality/deliberate action' and 'External influences'. Analysis of open-ended survey responses helped to identify changes in perception over time. When dogs were young, owners described problematic behaviours as 'mischievous', unintentional and context-specific. Similar behaviours shown by older dogs were seen as 'deliberate'. Both positive and negative experiences of dog ownership were identified. However, as not all respondents answered open-ended questions, the generalisability of our findings is limited.

Comprehension and Decision-Making Capacity Questionnaire About Palliative Care and Advance Care Planning: A Delphi Study.

Objective(s): To develop a questionnaire that assesses the level of comprehension and decision-making capacity of patients with breast cancer about palliative care and advance care planning. Methods: Questionnaire items were based on the scientific literature. Delphi Consensus, a three-round survey with experts (n = 14), evaluated the relevance, clarity, and redundancies of the items. A pretest with breast cancer patients (n = 15) evaluated whether they comprehended each item and identified doubts or discomforts. Results: The initial questionnaire was composed of 38 items. After the Delphi, 18 items were restructured, six were added, and 16 were removed. In the pretest phase, all items with the survey header, guidelines, and Likert model were evaluated. All items accomplished ≥80% cut-off score and were kept as in the original version. The final version of the questionnaire have 28 itens and five domains: determination, responsibility, independence, self-knowledge, and knowledge of reality. Conclusions: This study represents the first step in the development of a questionnaire that may be used in oncology clinical practice. The main findings revealed that Delphi and pretesting increased the quality of the questionnaire, making it compelling to assess breast cancer patients' comprehension and decision-making capacity about PC and ACP.

Odontopediatría en el contexto de la COVID-19: publicaciones científicas y práctica clínica / Odontopediatria no contexto da COVID-19: publicações científicas e prática clínica / Pediatric dentistry in the context of COVID-19: scientific publications and clinical practice

El propósito es analizar las características de los estudios y las tendencias en las publicaciones científicas y las recomendaciones clínicas relacionadas con el COVID-19 en odontopediatría. La búsqueda electrónica se realizó en las bases de datos MEDLINE, Scopus, Web of Science Core Collection y LILACS/BVS, sin restricciones. Se incluyeron estudios que usaron términos referentes a COVID-19, odontología pediátrica y niños en el título, resumen o palabras clave. Se extrajeron datos bibliométricos y características de los estudios. Cada estudio se categorizó de acuerdo con su diseño, muestra y tema principal. Se incluyeron 49 estudios, la mayoría revisiones (n=25; 51,00%), estudios observacionales (n=23; 47,00%) y estudio clínico (n=1; 2%). Los principales temas fueron urgencias odontológicas (n=9; 18,30%), bioseguridad (n= 8; 16,30%) y teleodontología (n=6; 12,20%). Las urgencias odontológicas más reportadas fueron trauma (n=12; 63,10%), edema (n=9; 47,30%) y dolor (n=9; 47,30%). Se concluyó que se realizaron pocos estudios sobre COVID-19 y odontología pediátrica, y la mayoría de las revisiones y estudios observacionales sobre emergencias dentales se publicaron en Asia.

O objetivo é analisar as características dos estudos e tendências nas publicações científicas e recomendações clínicas relacionadas ao COVID-19 em odontopediatria. A busca eletrônica foi realizada nas bases de dados MEDLINE, Scopus, Web of Science Core Collection e LILACS/BVS, sem restrições. Foram incluídos estudos que usaram termos referentes a COVID-19, odontopediatria e crianças no título, resumo ou palavras-chave. Os dados bibliométricos e as características do estudo foram extraídos. Cada estudo foi categorizado de acordo com seu desenho, amostra e tema principal. Quarenta e nove estudos foram incluídos, sendo a maioria revisões (n=25; 51,00%), estudos observacionais (n=23; 47,00%) e estudo clínico (n=1; 2%). Os principais temas foram emergências odontológicas (n=9; 18,30%), biossegurança (n= 8; 16,30%) e teleodontologia (n=6; 12,20%). As emergências odontológicas mais relatadas foram trauma (n=12; 63,10%), edema (n=9; 47,30%) e dor (n=9; 47,30%). Concluiu-se que poucos estudos sobre COVID-19 e odontopediatria foram realizados, com a maioria das revisões e estudos observacionais sobre emergências odontológicas publicados na Ásia

The purpose is to analyze the characteristics of the studies and trends in scientific publications and the clinical recommendations related to COVID-19 in pediatric dentistry. Electronic search was performed on MEDLINE, Scopus, Web of Science Core Collection, and LILACS/VHL databases, without restrictions. Studies that used terms referring to COVID-19, pediatric dentistry, and children in the title, abstract, or keywords were included. Bibliometric data and studies' characteristics were extracted. Each study was categorized according to its design, sample, and main subject. Forty-nine studies were included, most of them reviews (n=25; 51.00%), observational studies (n=23; 47.00%), and clinical study (n=1; 2%). The main topics were dental emergencies (n=9; 18.30%), biosafety (n= 8; 16.30%) and teledentistry (n=6; 12.20%). The most reported dental emergencies were trauma (n=12; 63.10%), edema (n=9; 47.30%), and pain (n=9; 47.30%). It was concluded that few studies on COVID-19 and pediatric dentistry were conducted, and most reviews and observational studies regarding dental emergencies were published in Asia.

Introducing a Puppy to Existing Household Cat(s): Mixed Method Analysis.

Although cats and dogs can live amicably, inter-species conflict can result in poor welfare. Species introduction can impact the development of the cat-dog relationship. This study aimed to identify factors associated with owner reported 'only desirable' puppy behaviour (defined as the puppy being uninterested, ignored the cat and/or interacted in a calm way) following introduction to existing household cats, and to explore perceptions of the emerging cat-dog relationship. Owner-reported data collected as part of a longitudinal study of canine health and behaviour were used. Of 4678 puppies, 26.7% lived with at least one cat. Of the 1211 puppies who had been introduced to the household cat at the time of survey completion, playing (58.9%), being overexuberant or over-excited (56.6%), and chasing (48.6%) were the most common behaviours displayed towards cats. 'Only desirable' behaviours were shown by 7.3% of puppies. Multivariable logistic regression showed early (puppies aged <12 weeks), gradual introductions and living in a multi-dog household increased the odds of 'only desirable' behaviours. Qualitative analysis revealed two styles of introductions­owner-led and pet-led. Owners who led introductions anticipated amicable relationships between pets, whilst owners who let pets introduce themselves did not. Early, gradual, owner-led introductions of puppies to household cats should be encouraged.

Evaluation of a DNA demethylating agent in combination with all-trans retinoic acid for IDH1-mutant gliomas.

BACKGROUND: Isocitrate Dehydrogenase 1/2 (IDH1/2) mutations are diagnostic for Astrocytoma or Oligodendroglioma, IDH-mutant. In these IDH-mutant gliomas, retinoic acid-related gene expression is commonly silenced by DNA hypermethylation. DNA demethylating agents can epigenetically reprogram IDH-mutant cells and reduce proliferation, likely by re-expression of silenced tumor suppressor pathways. We hypothesized that DNA demethylation might restore the retinoic acid pathway and slow tumor growth. This was the rationale for a preclinical evaluation combining the DNA demethylating agent, 5-Azacytidine (5-Aza), and retinoic acid pathway activation with all-trans retinoic acid (atRA) in IDH-mutant glioma. METHODS: In this study, we evaluated the effect of 5-Aza and atRA combination on cell proliferation, apoptosis, and gene expression in human glioma cells. In addition, the efficacy of this combination was tested in patient-derived xenograft (PDX) bearing the IDH1R132H mutation, utilizing subcutaneous and orthotopic models. RESULTS: 5-Aza reduced the DNA methylation profile and increased the gene expression of retinoic acid-related genes. Combination of 5-Aza and atRA reduced cell growth, increased differentiation marker expression, and apoptosis in IDH1R132H glioma cells. Mechanistically, 5-Aza sensitized IDHIR132H glioma cells to atRA via upregulation of the retinoic acid pathway. Importantly, the drug combination reduced significantly the growth rate of subcutaneous tumors, but in an orthotopic mouse model, the combination did not improve survival and 5-Aza alone provided the best survival benefit. CONCLUSION: Use of DNA demethylating agent in combination with retinoids shows promise, but further optimization and preclinical studies are required for treatment of intracranial IDH-mutant gliomas.

Worldwide trends on molar incisor and deciduous molar hypomineralisation research: a bibliometric analysis over a 19-year period.

AIM: To identify the worldwide trends in scientific evidence and gaps in knowledge regarding molar incisor hypomineralisation (MIH) and deciduous molar hypomineralisation/hypomineralised second primary molars (DMH/HSPM), exploring the contribution of authors and countries, possible etiological factors and proposed treatments, in order to guide future research in the area. METHODS: Searches were conducted in MEDLINE, Scopus, Web of Science, Cochrane Library, Lilacs/BBO, Embase and Google Scholar. Studies employing the terms MIH, DMH/HSPM and their linguistic variations were included. The following data were extracted: title, authors, year and journal of publication and first author's affiliation country. Studies were categorized according to topic, dentition, study design, etiological factors and types of treatments. Categories were analysed in relation to their distribution, co-occurrence, cross-correlation and/or autocorrelation. RESULTS: Five hundred and three studies were included. The most published authors were Manton D (n = 47), de Souza JF (n = 22) and Ghanim A (n = 22) and four main collaboration clusters have been identified. Most of the studies were conducted on permanent dentition (MIH) (87.4%); with observational design (57.2%). The "European Archives of Paediatric Dentistry" was the most published journal (13.3%) and a significant increase in the number of publications was observed in the last decade. MIH was most studied in relation to prevalence/incidence, systemic factors involved in its aetiology and treatment with composite restorations, while a gap in knowledge was observed for extraction and sealants. Less studies were published on DMH/HSPM and most of them evaluated risk factors or prevalence/incidence. The gap of knowledge was observed in relation to treatments and patient's quality of life. CONCLUSIONS: This bibliometric review provided a comprehensive overview of research in MIH and DMH/HSPM over the past 19 years. Within the limitations of the present study, the following conclusions can be drawn: global trends point to an increasing peak of scientific publication, especially in the last decade, while there is a shortage of clinical studies on treatments, mainly evaluating tooth extractions. Finally the multifactorial nature should be further explored, considering environmental and systemic factors together.

The use of nutrition support near the end of life for hospitalized patients with advanced cancer at a reference center: Two realities.

OBJECTIVE: To assess the frequency and factors associated of the provision of nutrition support (NS) in the last 30 days of life in patients with advanced cancer in the palliative or non-palliative setting. METHODS: Retrospective cohort study in palliative and non-palliative care units at a specialized cancer center for oncology in Brazil. The use of oral nutrition supplements (ONS) and enteral (EN) and parenteral (PN) nutrition in the 30 days before death were assessed. RESULTS: The 239 patients included were predominantly older (>60 years; 63.2%) and female (61.1%). The use of ONS was lower in palliative than non-palliative care during the last 30 (52% vs. 6%), 7 (42% vs. 4%), and 3 (23% vs. 2%) days before death (all P < .001). The use of EN and PN was lower in palliative care, decreasing with the approach of death. The independent factors associated with ONS in non-palliative care were (odds ratio): breast tumor (3.03), hypoalbuminemia (1.10), and nutrition risk (16.98); in palliative care, only the Karnofsky Performance Status (KPS) ≥40% (1.24) was associated to the use of ONS. The use of EN and PN was associated with head-neck (HN) tumor in both settings (5.41) in non-palliative and (8.74) in palliative. Others independent factors were: hypoalbuminemia (3.12) in non-palliative care and KPS (1.31) in palliative care. CONCLUSIONS: The use of NS near the end of life was high in the non-palliative and less frequent in palliative care setting. The factors associated with NS differed according to the clinical oncology setting, with one of the factors in palliative care being a better prognosis.

Obesity phenotypes are, in part, associated with physical activity in diabetic hemodialysis patients.

PURPOSE: To investigate the prevalence of obesity phenotypes and their association with physical activity levels among diabetic hemodialysis patients. METHODS: This is a cross-sectional study with 84 diabetic hemodialysis patients (63.5 ± 9.4 years, 54.8% of men). Obesity was diagnosed as high body fat (≥ 40% for male and ≥ 30% for female). Sarcopenic obesity was considered if low skeletal muscle mass (< 20.0 kg for males and < 15.0 kg for females) and obesity were combined. Dynapenic obesity was defined in the presence of low handgrip strength (< 27 kg for males and < 16 kg for females) and obesity. Muscle failure obesity was confirmed in the concomitant presence of obesity, sarcopenia, and dynapenia. Physical activity level was assessed by the Baecke questionnaire and patients were classified as low physical activity according to the first tertile for each of and total domains. RESULTS: Fifty-four patients (64%) presented obesity. From these, 5 (6%), 19 (23%) and 8 (10%) were classified as sarcopenic obese, dynapenic obese, and muscle failure obese, respectively, and 22 (26%) were only obese. Patients with sarcopenic obesity and muscle failure obesity had lower leisure and locomotion physical activity scores than non-obese, whereas the total domain score did not differ across the groups. Muscle failure obesity was independently associated with low leisure physical activity (OR 10.8, 95% CI 1.3-88.1). Only sarcopenic obesity was independently associated with the locomotion and total physical activity domains (OR 15.4, 95% CI 1.4-90.2 and OR 17.0, 95% CI 1.5-95.4, respectively). CONCLUSION: Our study found a lower prevalence of sarcopenic obesity compared to dynapenic obesity and muscle failure obesity among diabetic hemodialysis patients. Moreover, sarcopenic obesity and muscle failure obesity, but not dynapenic obesity, were associated with low physical activity levels.

Age of sexual maturity and factors associated with neutering dogs in the UK and the Republic of Ireland.

BACKGROUND: Surgical neutering of dogs is common, however the average age that dogs reach sexual maturity, are neutered, and dog owners' attitudes to neutering in the UK and the Republic of Ireland have not been explored in a longitudinal study. METHODS: Owner-reported data on the timing of the first oestrus, timing of neutering and the reasons given for neutering dogs by 12 and 15 months of age were summarised. Factors associated with neutering at 15 months and factors associated with intention to neuter were quantified using multivariable logistic regression. RESULTS: At 15 months of age, 90.0% (n = 207/230) of unneutered females had had their first oestrus. By 7, 9, 12 and 15 months of age, 22.1% (n = 131/593), 32.2% (197/593), 45.4% (n = 269/593) and 59.9% (n = 352/593) of dogs were neutered, respectively. Breed purity, dog's source, owners' intentions to neuter and the number of dogs in the household were associated with neuter status at age 15 months. Dog's sex, Kennel Club registration, dog's source, dogs intended to be working dogs and previous dog ownership were associated with intentions to neuter. Preventing puppies was the most common reason for neutering. CONCLUSION: Understanding factors that shape owners' intentions to neuter can inform owner-vet discussions regarding whether to neuter a dog and the optimal age for doing so.

Mães com Deficiência e Maternidade: Cotidiano, Redes de Apoio e Relação com a Escola / Mothers with Disabilities and Motherhood: Everyday Life, Support Networks and Relationship with School

RESUMO: Cerca de metade das pessoas com deficiência no Brasil são mulheres e uma parte delas torna-se mãe. Entretanto, não há dados na literatura sobre as necessidades específicas dessa população. Assim sendo, este artigo tem por objetivo apresentar as percepções de mulheres com deficiência física e visual sobre si mesmas, sobre o cotidiano da maternidade, as redes de apoio e a relação da família com a escola. A pesquisa seguiu a metodologia qualitativa e utilizou narrativas como forma de coletar dados. Participaram do estudo seis mulheres, sendo três com deficiência visual e três com deficiência física. Os resultados estão apresentados em duas categorias: 1) concepções das mulheres sobre sua deficiência, que reúne falas sobre como a interação com a sociedade afeta a concepção que elas têm de si mesmas; e 2) cotidiano da maternidade, que discute os relatos sobre o cotidiano e as experiências dessas mulheres como mães, incluindo suas redes de apoio formal e informal, os desafos diários e as adaptações necessárias no cuidado com seus filhos, as relações com a escola e a comunidade e a maneira como as crianças se desenvolvem e se organizam frente às limitações da mãe. As narrativas trouxeram elementos importantes do cotidiano dessas mulheres que são invisíveis perante a sociedade e os profssionais que atuam junto às pessoas com deficiência, indicando a necessidade de fomentar práticas profssionais e mais pesquisas sobre o tema, com a perspectiva de promover uma sociedade mais inclusiva.

ABSTRACT: About half of the people with disabilities in Brazil are women, and some of them become mothers. However, there is no data in literature about the specific needs of this population. Tus, this paper aims to present the perceptions of women with physical and visual disabilities about themselves, about everyday life as mothers, about support networks and the relationship between family and school. The research followed a qualitative methodology and used narratives as a means of data collection. Six women participated in the study, three with visual impairment and three with physical disability. The findings are presented in two categories: 1) women's conceptions of their disability, which summarizes their expressions about interactions with society that affect their self-image; and 2) daily life of motherhood, which addresses the accounts of these women's daily lives and experiences as mothers, including their formal and informal support networks, daily challenges and necessary adjustments in caring for their children, relationships with school and the community, and how the children develop and self-organize in the face of their mother's limitations. The narratives brought to light important elements of these women's daily lives that are invisible to society and to professionals working with people with disabilities. This shows the need to promote professional practices and more research on the subject in order to create a more inclusive society.

The bacterial microbiome and metabolome in caries progression and arrest.

Aim: This in vivo experimental study investigated bacterial microbiome and metabolome longitudinal changes associated with enamel caries lesion progression and arrest. Methods: We induced natural caries activity in three caries-free volunteers prior to four premolar extractions for orthodontic reasons. The experimental model included placement of a modified orthodontic band on smooth surfaces and a mesh on occlusal surfaces. We applied the caries-inducing protocol for 4- and 6-weeks, and subsequently promoted caries lesion arrest via a 2-week toothbrushing period. Lesions were verified clinically and quantitated via micro-CT enamel density measurements. The biofilm microbial composition was determined via 16S rRNA gene Illumina sequencing and NMR spectrometry was used for metabolomics. Results: Biofilm maturation and caries lesion progression were characterized by an increase in Gram-negative anaerobes, including Veillonella and Prevotella. Streptococcus was associated caries lesion progression, while a more equal distribution of Streptococcus, Bifidobacterium, Atopobium, Prevotella, Veillonella, and Saccharibacteria (TM7) characterized arrest. Lactate, acetate, pyruvate, alanine, valine, and sugars were more abundant in mature biofilms compared to newly formed biofilms. Conclusions: These longitudinal bacterial microbiome and metabolome results provide novel mechanistic insights into the role of the biofilm in caries progression and arrest and offer promising candidate biomarkers for validation in future studies.

Prognostic factors in patients with advanced cancer and COVID-19: a cohort from the Palliative Care Unit of the Brazilian National Cancer Institute.

OBJECTIVE: To describe overall survival (OS) in 90 days and to evaluate the prognostic factors in patients with advanced cancer and COVID-19. METHODS: This is a retrospective cohort study carried out at the Palliative Care Unit of the Brazilian National Cancer Institute. Patients with advanced cancer and COVID-19 confirmed by Reverse Transcription Polymerase Chain Reaction were included. Kaplan-Meier's curves, log-rank test, and Cox regression were performed. RESULTS: Eighty-three inpatients were selected. The average age was 61.4 (±12.6) years, with a higher proportion of women (73.4%). The most prevalent tumor type was breast (36.7%), followed by gastrointestinal tract (20.3%). The OS was 32 [interquartile range (IQR): 6-70] days, and at the end of the follow-up period, 17 patients (20.5%) were alive and 66 (79.5%) had died. Patients with advanced cancer and COVID-19 and who were 60-74 years old [hazard ratio (HR): 2.03; 95% confidence interval (CI): 1.09-3.78], with lung tumors (HR: 17.50; 95% CI: 1.70-28.34), with lung metastasis (HR: 4.21; 95% CI: 2.17-8.15), and with chronic obstructive pulmonary disease (HR: 4.92; 95% CI: 1.01-24.69) had higher risk of death in 90 days. CONCLUSION: The age of 60-74 years old, lung tumors (primary or metastases), and the presence of chronic obstructive pulmonary disease were considered independent prognostic factors in patients with advanced cancer and COVID-19.

The glutamine antagonist prodrug JHU-083 slows malignant glioma growth and disrupts mTOR signaling.

BACKGROUND: Metabolic reprogramming is a common feature in cancer, and it is critical to facilitate cancer cell growth. Isocitrate Dehydrogenase 1/2 (IDH1 and IDH2) mutations (IDHmut) are the most common genetic alteration in glioma grade II and III and secondary glioblastoma and these mutations increase reliance on glutamine metabolism, suggesting a potential vulnerability. In this study, we tested the hypothesis that the brain penetrant glutamine antagonist prodrug JHU-083 reduces glioma cell growth. MATERIAL AND METHODS: We performed cell growth, cell cycle, and protein expression in glutamine deprived or Glutaminase (GLS) gene silenced glioma cells. We tested the effect of JHU-083 on cell proliferation, metabolism, and mTOR signaling in cancer cell lines. An orthotopic IDH1R132H glioma model was used to test the efficacy of JHU-083 in vivo. RESULTS: Glutamine deprivation and GLS gene silencing reduced glioma cell proliferation in vitro in glioma cells. JHU-083 reduced glioma cell growth in vitro, modulated cell metabolism, and disrupted mTOR signaling and downregulated Cyclin D1 protein expression, through a mechanism independent of TSC2 modulation and glutaminolysis. IDH1R132H isogenic cells preferentially reduced cell growth and mTOR signaling downregulation. In addition, guanine supplementation partially rescued IDHmut glioma cell growth, mTOR signaling, and Cyclin D1 protein expression in vitro. Finally, JHU-083 extended survival in an intracranial IDH1 mut glioma model and reduced intracranial pS6 protein expression. CONCLUSION: Targeting glutamine metabolism with JHU-083 showed efficacy in preclinical models of IDHmut glioma and measurably decreased mTOR signaling.

'Generation Pup' - protocol for a longitudinal study of dog behaviour and health.

BACKGROUND: Despite extensive research, many questions remain unanswered about common problems that impact dog welfare, particularly where there are multiple contributing factors that can occur months or years before the problem becomes apparent. The Generation Pup study is the first longitudinal study of dogs that recruits pure- and mixed-breed puppies, aiming to investigate the relative influence of environmental and genetic factors on a range of health and behaviour outcomes, (including separation related behaviour, aggression to familiar/unfamiliar people or dogs and obesity). This paper describes the study protocol in detail. METHODS: Prior to commencing recruitment of puppies, the study infrastructure was developed, and subject specialists were consulted to inform data collection methodology. Questionnaire content and timepoint(s) for data collection for outcomes and potential predictors were chosen with the aim of providing the best opportunity of achieving the aims of the study, subject to time and funding constraints. Recruitment of puppies (< 16 weeks, or < 21 weeks of age if entering the United Kingdom or Republic of Ireland through quarantine) is underway. By 23 January 2020, 3726 puppies had been registered, with registration continuing until 10,000 puppies are recruited. Data collection encompasses owner-completed questionnaires issued at set timepoints throughout the dog's life, covering aspects such as training, diet, exercise, canine behaviour, preventative health care, clinical signs and veterinary intervention. Owners can elect to submit additional data (health cards completed by veterinary professionals, canine biological samples) and/or provide consent for access to veterinary clinical notes. Incidence and breed associations will be calculated for conditions for which there is currently limited information (e.g. separation related behaviour). Multivariable statistical analysis will be conducted on a range of outcomes that occur throughout different life stages, with the aim of identifying modifiable risk factors that can be used to improve canine health and welfare. DISCUSSION: The Generation Pup project is designed to identify associations between early-life environment, genotypic make-up and outcomes at different life stages. Modifiable risk factors can be used to improve canine health and welfare. Research collaboration with subject specialists is welcomed and already underway within the fields of orthopaedic research, epilepsy, epigenetics and canine impulsivity.

Puppy acquisition: factors associated with acquiring a puppy under eight weeks of age and without viewing the mother.

BACKGROUND: Puppy acquisition decisions may impact upon the health and behaviour of these dogs in later life. It is widely recommended by welfare organisations and veterinary bodies that puppies should not leave maternal care until at least eight weeks (56 days) of age, and that when acquiring a puppy it should be viewed with its mother. METHODS: Owner-reported prospective data were used to explore risk factors for puppy acquisition age, and whether the mother was viewed during acquisition, within a cohort of dog owners participating in an ongoing longitudinal project. RESULTS: A quarter (461/1844) of puppies were acquired under eight weeks of age and 8.1 per cent were obtained without viewing the mother (n=149). Only 1.6 per cent of puppies were obtained under eight weeks of age and without the mother being seen (n=30). Multivariable logistic regression analysis revealed that owners who intended their puppy to be a working dog, visited their puppy prior to acquisition, and/or obtained a puppy of unknown breed composition had increased odds of acquiring a puppy under eight weeks of age. The odds also increased as the number of dogs in the household increased but decreased as annual income rose. Owners who visited their puppy prior to acquisition, obtained a Kennel Club registered puppy, viewed the puppy's father, and/or collected their puppy from the breeder's home had decreased odds of acquiring a puppy without viewing the mother. CONCLUSION: Targeting interventions towards identified owners who are more likely to acquire a puppy against current recommendations could help reduce these types of acquisitions.

Sleep Duration and Behaviours: A Descriptive Analysis of a Cohort of Dogs up to 12 Months of Age.

Sleep is a vital behaviour that can reflect an animal's adaptation to the environment and their welfare. However, a better understanding of normal age-specific sleep patterns is crucial. This study aims to provide population norms and descriptions of sleep-related behaviours for 16-week-old puppies and 12-month-old dogs living in domestic environments. Participants recruited to a longitudinal study answered questions relating to their dogs' sleep behaviours in surveys issued to them when their dogs reached 16 weeks (n = 2332) and 12 months of age (n = 1091). For the statistical analysis, subpopulations of dogs with data regarding sleep duration at both timepoints were used. Owners of 16-week-old puppies perceived their dogs to sleep longer during the day and over a 24 h period, but for less time during the night than owners of 12-month-old dogs. At both timepoints, dogs were most commonly settled to sleep by being left in a room/area without human company. However, of dogs that had access to people overnight, 86.7% and 86.8% chose to be around people at 16 weeks and 12 months of age, respectively. The most common sleeping place was in a kennel/crate at 16 weeks (49.1%), and a dog bed at 12 months (31.7%). Future research within this longitudinal study will investigate how sleep duration and behaviours change with age and impact on a dog's health and behaviour.

Abortion Services in Humanitarian Contexts.

Conditions prevailing in humanitarian crises often create a coercive environment for women. Material and security needs and pre-exisiting inequalities render women particularly vulnerable to social and contextual coercion in such situations, which can often result in unwanted pregnancies. Some women may resort to unsafe abortions, sometimes resulting in death. Currently, abortion services provided by humanitarian agencies are either unavailable or fail to meet the real need in humanitarian settings. Accessible family planning, contraceptives, and early remedies should all be available, along with counselling. In addition, a pro-choice approach and accompanying abortion services should be a fundamental pillar of health services available to women in emergencies.

Multi-part quality evaluation of a customized mobile application for monitoring elderly patients with functional loss and helping caregivers.

BACKGROUND: The challenges faced by caregivers of the elderly with chronic diseases are always complex. In this context, mobile technologies have been used with promising results, but often have restricted functionality, or are either difficult to use or do not provide the necessary support to the caregiver - which leads to declining usage over time. Therefore, we developed the Mobile System for Elderly Monitoring, SMAI. The purpose of SMAI is to monitor patients with functional loss and to improve the support to caregivers' communication with the health team professionals, informing them the data related to the patients' daily lives, while providing the health team better tools. METHOD: SMAI is composed of mobile applications developed for the caregivers and health team, and a web portal that supports management activities. Caregivers use an Android application to send information and receive care advice and feedback from the health team. The system was constructed using a refinement stage approach. Each stage involved caregivers and the health team in prototype release-test-assessment-refinement cycles. SMAI was evaluated during 18 months. We studied which features were being used the most, and their use pattern throughout the week. We also studied the users' qualitative perceptions. Finally, the caregiver application was also evaluated for usability. RESULTS: SMAI functionalities showed to be very useful or useful to caregivers and health professionals. The Focus Group interviews reveled that among caregivers the use of the application gave them the sensation of being connected to the health team. The usability evaluation identified that the interface design and associated tasks were easy to use and the System Usability Scale, SUS, presented very good results. CONCLUSIONS: In general, the use of SMAI represented a positive change for the family caregivers and for the NAI health team. The overall qualitative results indicate that the approach used to construct the system was appropriate to achieve the objectives.

Demethylation and epigenetic modification with 5-azacytidine reduces IDH1 mutant glioma growth in combination with temozolomide.

BACKGROUND: Isocitrate deyhydrogenase (IDH) mutant glioma comprises the majority of grades II-III gliomas and nearly all secondary glioblastomas. These progressive gliomas arise from mutations in IDH1 or IDH2 that pathologically produce D-2-hydroxyglutarate (2HG), which interferes with cell reactions using alpha ketoglutarate, leading to a hypermethylated genome and epigenetic dysregulation of gene expression initiating tumorigenesis. METHODS: Human IDH1 wild type (wt) and IDH1 R132H cell lines and patient-derived xenografts (PDXs) were used to evaluate the FDA-approved DNA demethylating agent 5-azacytidine (5-aza). Cell growth, protein and gene expression, chromatin immunoprecipitation, and nucleosome position assays were performed in 5-aza treated cells. To evaluate antitumor activity in vivo, 5-aza was administered alone and in combination with temozolomide (TMZ) in a PDX glioma model harboring IDH1 R132H mutation. RESULTS: 5-Aza treatment has been found to reduce cell growth and increase expression of glial fibrillary acid protein (GFAP). Chromatin immunoprecipitation and nucleosome position assay showed that the mechanism of increased GFAP expression induction is associated with histone modification and nucleosome repositioning of the GFAP promoter, respectively. In vivo, 5-aza treatment extended survival in IDH1 R132H mutant but not in an IDH1 wt glioma model. Additionally, 5-aza enhances the therapeutic effect of the DNA damaging agent TMZ in both subcutaneous and orthotopic PDX models of IDH1 R132H mutant glioma. CONCLUSION: 5-Aza provided a survival benefit as a single agent but worked best in combination with TMZ in 2 different IDH1 R132H mutant glioma models.