MicroRNA-124-3p Modulates Alpha-Synuclein Expression Levels in a Paraquat-Induced in vivo Model for Parkinson's Disease.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease and the most common movement disorder. Although PD etiology is not fully understood, alpha (α)-synuclein is a key protein involved in PD pathology. MicroRNAs (miRNA), small gene regulatory RNAs that control gene expression, have been identified as biomarkers and potential therapeutic targets for brain diseases, including PD. In particular, miR-124 is downregulated in the plasma and brain samples of PD patients. Recently we showed that the brain delivery of miR-124 counteracts 6-hydroxydopamine-induced motor deficits. However, its role in α-synuclein pathology has never been addressed. Here we used paraquat (PQ)-induced rat PD model to evaluate the role of miR-124-3p in α-synuclein accumulation and dopaminergic neuroprotection. Our results showed that an intranigral administration of miR-124-3p reduced the expression and aggregation of α-synuclein in the substantia nigra (SN) of rats exposed to PQ. NADPH oxidases (NOX), responsible for reactive oxygen species generation, have been considered major players in the development of α-synuclein pathology. Accordingly, miR-124-3p decreased protein expression levels of NOX1 and its activator, small GTPase Rac1, in the SN of PQ-lesioned rats. Moreover, miR-124-3p was able to counteract the reduced levels of pituitary homeobox 3 (PITX3), a protein required for the dopaminergic phenotype, induced by PQ in the SN. This is the first study showing that miR-124-3p decreases PQ-induced α-synuclein levels and the associated NOX1/Rac1 signaling pathway, and impacts PITX3 protein levels, supporting the potential of miR-124-3p as a disease-modifying agent for PD and related α-synucleinopathies.

Efficacy of a novel three-step decontamination protocol for titanium-based dental implants: An in vitro and in vivo study.

AIM: The aim of the study was to evaluate several mechanical and chemical decontamination methods associated with a newly introduced biofilm matrix disruption strategy for biofilm cleaning and preservation of implant surface features. MATERIALS AND METHODS: Titanium (Ti) discs were obtained by additive manufacturing. Polymicrobial biofilm-covered Ti disc surfaces were decontaminated with mechanical [Ti curette, Teflon curette, Ti brush, water-air jet device, and Er:YAG laser] or chemical [iodopovidone (PVPI) 0.2% to disrupt the extracellular matrix, along with amoxicillin; minocycline; tetracycline; H2 O2 3%; chlorhexidine 0.2%; NaOCl 0.95%; hydrocarbon-oxo-borate-based antiseptic] protocols. The optimal in vitro mechanical/chemical protocol was then tested in combination using an in vivo biofilm model with intra-oral devices. RESULTS: Er:YAG laser treatment displayed optimum surface cleaning by biofilm removal with minimal deleterious damage to the surface, smaller Ti release, good corrosion stability, and improved fibroblast readhesion. NaOCl 0.95% was the most promising agent to reduce in vitro and in vivo biofilms and was even more effective when associated with PVPI 0.2% as a pre-treatment to disrupt the biofilm matrix. The combination of Er:YAG laser followed by PVPI 0.2% plus NaOCl 0.95% promoted efficient decontamination of rough Ti surfaces by disrupting the biofilm matrix and killing remnants of in vivo biofilms formed in the mouth (the only protocol to lead to ~99% biofilm eradication). CONCLUSION: Er:YAG laser + PVPI 0.2% + NaOCl 0.95% can be a reliable decontamination protocol for Ti surfaces, eliminating microbial biofilms without damaging the implant surface.

Do binge drinking adolescents have a greater number of traumatised teeth? A longitudinal study with 12-year-olds in Brazil.

BACKGROUND: Binge drinking has been linked to traumatic dental injury (TDI). Once drunk, adolescents are more prone to accidents, which may result in orofacial injury. AIM: This study evaluated the possible association of binge drinking with a number of traumatised teeth in a population of 12-year-old Brazilian adolescents in 2013 and 2015. DESIGN: This study was longitudinal, carried out with 588 adolescents at two moments, 2013 and 2015. TDI, overjet and lip protection were assessed by calibrated examiners. Binge drinking data were collected through the Alcohol Use Disorders Identification Test. Sociodemographic indicators were obtained through a questionnaire answered by the parents/guardians. The Poisson regression model with a random effects intercept was estimated. RESULTS: A higher prevalence of traumatised teeth was observed among adolescents who binge drink (IRR = 1.37; 95% CI: 1.05-1.80; p < .05). The prevalence was also significantly higher among adolescents in this age range with a ≥ 3-mm overjet and those with inadequate lip protection (IRR = 1.99; 95% CI: 1.44-2.76; p < .001 and IRR = 3.41; 95% CI: 2.57-4.53; p < .001, respectively). CONCLUSION: A greater number of traumatised teeth were found among adolescents who reported binge drinking and had severe overjet and inadequate lip coverage.

Association between shortened dental configurations and health outcomes: a scoping review.

This study mapped definitions of shortened dental configurations and health outcomes employed in association studies. A scoping review was conducted using the PubMed/Medline, Scopus, Web of Science, SciELO and Cochrane databases. Two trained researchers selected studies and extracted data. Studies that investigated the association between shortened dental configurations (exposure) and person-centered outcomes (general and oral health) related to health behavior (dietary patterns). Clinical outcomes were classified according to the International Classification of Functioning, Disability and Health and the International Classification of Diseases of the World Health Organization (WHO). Shortened dental configurations were defined as at least 20/21 teeth or the position of the teeth, including esthetics, dental occlusion and periodontal status (Eichner Index, Shortened Dental Arches, Functional Dentition Classification System, Posterior Occluding Pairs, Functional Tooth Units). The initial search resulted in 12,525 records in English, Portuguese and Spanish, 432 of which addressed the association of interest. General health (n = 203) and oral health (n = 201) were addressed in a similar number of studies. Most outcomes were related to general health (n = 184), the most frequent of which were endocrine, nutritional or metabolic diseases (n = 57) and mental functions (n = 26). Person-centered measures were addressed in 153 studies, most of which were about oral health and oral health-related quality of life (n = 62). Oral health outcomes were predominantly related to intake functions (n = 44) and diseases or disorders of the orofacial complex (n = 24). Dietary patterns (n = 43) and mortality (n = 38) were also studied. The cross-sectional design (n = 257) and non-probabilistic sampling (n = 218) were more frequent. The shortened dental configurations defined by the WHO were the most frequent in the studies (n = 206). The effects of shortened dental configurations have been investigated mainly in relation to endocrine, nutritional or metabolic diseases and measures of oral health-related quality of life. The findings point to a diversity of health outcomes assessed and substantial methodological variability.

Challenges to conducting research on oral health with older adults living in long-term care facilities.

BACKGROUND: The challenges to conducting oral health studies involving older people in long-term care facilities (LTCFs) must be debated. OBJECTIVE: This study aimed to investigate researchers' perceptions and experiences while conducting an epidemiological survey on oral health among older individuals residing in LTCFs. METHODS: A qualitative study was conducted involving six researchers who utilized field diaries to record their impressions during data collection through interviews (older individuals (or their proxies), caregivers, and LTCF coordinators) and oral examinations of the older people participants. Additionally, researchers responded to open-ended questions about their experiences. The collected material was subjected to content analysis by two researchers. RESULTS: The themes that emerged from the analysis were institutional context, aspects affecting the operationalization of the study, and data collection oriented by the clinical-functional profile of the older people. According to the researchers' perceptions, LTCF coordinators demonstrated concern for the study's benefits for older adults and the preservation of institutional routines during the research process. Caregivers emerged as vital sources of information, guiding researchers in navigating the challenges posed by the physical and mental complexities of the older people participants, necessitating empathy, sensitivity, and attentive listening from the researchers. The organization of materials and a streamlined data collection process proved essential for optimizing time efficiency and reducing stress for participants and researchers. CONCLUSION: The researchers recognized the important role played by LTCF coordinators and formal caregivers, underscoring the significance of empathetic methodologies and streamlined data collection processes in mitigating the challenges inherent to research conducted within LTCFs.

Inpatient Screening for Early Identification of Developmental Risk in Infants with Congenital Heart Defects.

OBJECTIVE: To assess the utility of an inpatient standardized developmental screener for early identification of developmental risk in infants with a congenital heart defect (CHD). STUDY DESIGN: This was a retrospective, observational study with convenience sample of postoperative infants with CHD (aged 3-12 months) who underwent neurodevelopmental screening with the Bayley Scales of Infant and Toddler Development Screening Test, Third Edition (Bayley-III Screener) just before discharge. Follow-up testing included outpatient Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) (12-42 mo). RESULTS: The Bayley-III Screener was administered to 325 infants at a median of 5 months, 8 days (IQR 3 months, 28 days, to 7 months, 17 days). Infants scored below age expectations on the Gross Motor (79%), Fine Motor (63%), Receptive Communication (50%), Expressive Communication (38%), and Cognitive (38%) domains. In each domain, children with CHD had greater rates of scores below expectations than the normative sample (each P <.001). The odds of scoring in a greater risk category were increased for infants with genetic syndromes and longer length of hospital stay across all domains. The outpatient Bayley-III (n = 74, 23% follow-up) was completed at a median of 19 months, 9 days (IQR: 17 months, 3 days, to 23 months, 37 days). Individuals falling in greater-risk categories on their initial Bayley-III Screener were significantly more likely to have worse performance on their follow-up outpatient Bayley-III (each domain P < .01). CONCLUSIONS: Inpatient standardized neurodevelopmental screening provides important clinical utility in identifying infants at risk for developmental concern, allows for provision of recommendations for developmental services, and potentially overcomes barriers often noted in returning for outpatient post-discharge assessments.

MicroRNA-124-3p-enriched small extracellular vesicles as a therapeutic approach for Parkinson's disease.

Parkinson's disease is a neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra with no effective cure available. MicroRNA-124 has been regarded as a promising therapeutic entity for Parkinson's disease due to its pro-neurogenic and neuroprotective roles. However, its efficient delivery to the brain remains challenging. Here, we used umbilical cord blood mononuclear cell-derived extracellular vesicles as a biological vehicle to deliver microRNA (miR)-124-3p and evaluate its therapeutic effects in a mouse model of Parkinson's disease. In vitro, miR-124-3p-loaded small extracellular vesicles induced neuronal differentiation in subventricular zone neural stem cell cultures and protected N27 dopaminergic cells against 6-hydroxydopamine-induced toxicity. In vivo, intracerebroventricularly administered small extracellular vesicles were detected in the subventricular zone lining the lateral ventricles and in the striatum and substantia nigra, the brain regions most affected by the disease. Most importantly, although miR-124-3p-loaded small extracellular vesicles did not increase the number of new neurons in the 6-hydroxydopamine-lesioned striatum, the formulation protected dopaminergic neurons in the substantia nigra and striatal fibers, which fully counteracted motor behavior symptoms. Our findings reveal a novel promising therapeutic application of small extracellular vesicles as delivery agents for miR-124-3p in the context of Parkinson's disease.

Bleaching effectiveness and cytotoxicity of new experimental formulation of niobium-based bleaching gel.

OBJECTIVES: The development of new bleaching agents with minimum concentration of hydrogen peroxide (HP), without adverse effects, and with bleaching effectiveness, has great clinical relevance. The aim of this study was to evaluate the bleaching efficacy and cytotoxicity of a new niobium-based bleaching gel, compared to already available HP-based gels. MATERIALS AND METHODS: For the bleaching efficacy analysis, 40 bovine incisors were randomly divided into 4 groups according to the established bleaching protocol: control, untreated; 35HP, 35% HP bleaching gel; 6HP, 6% HP bleaching gel; NbHP, niobium gel associated with 3% HP gel. The color variation was measured in a spectrophotometer and the values of ΔL, Δa, Δb, and ΔE obtained. For the cell viability assay by MTT, MC3T3 cells were exposed to bleaching gel extracts (1:500, 1:250, 1:125 dilutions; immediately and 24 h). Statistical tests were performed (P < 0.05). RESULTS: The color alteration for all bleaching gels was significant compared to control (P < 0.05), but the NbHP gel showed a significant ΔE than other gels, with expressive color alteration at 14 days (P < 0.05). The 35HP showed high cytotoxicity regarding control and the most groups in all periods and extracts analyzed (P < 0.05), while the NbHP showed greater cell viability than control in the immediate period, dilution of the 1:500 and superior to 6HP in the most extracts at 24 h. CONCLUSION: The new experimental niobium-based gel has bleaching efficacy similar to that of gels with a high concentration of HP, and it has high cytocompatibility. CLINICAL RELEVANCE: The use of this new generation of niobium-based whitening gel associated with a low concentration of hydrogen peroxide represents the possibility of a tooth whitening with lower dentin sensitivity.

Unraveling the signs and symptoms of oral conditions that affect daily life activities and oral health-related quality of life.

OBJECTIVES: Since oral conditions negatively affect oral health-related quality of life (OHRQoL), this study evaluated which oral clinical condition, signs, and symptoms are associated with the impact on OHRQoL, its domains, and specific daily life activities among adults. MATERIALS AND METHODS: Data from a probabilistic sample of adults (35-44 years old) was used. The Oral Impacts on Daily Performance (OIDP) was used to evaluate OHRQoL, its domains (physical, psychological, and social), and nine daily life activities. Signs and symptoms of oral diseases (dental caries, periodontal disease, need for dental prothesis, and tooth loss) and oral self-perception were considered. Descriptive, bivariate, and multi-level analyses were conducted. RESULTS: A total of 5,834 adults were included, of which 52.9% had some negative impact of oral conditions on OHRQoL. Difficulty in eating was the most affected daily life activity. For multiple models, dental caries lesions (cavities), filled teeth with caries, gingival bleeding, periodontal pocket, dental pain, need for upper or lower dental prosthesis, and oral health self-perception were associated (p < 0.05) with overall OHRQoL or at least one of its domains. The impact on daily life activities of each individual was associated with at least one oral condition. Dental caries lesions (cavity) and dental pain were associated (p < 0.05) with the impact on most daily life activities evaluated. CONCLUSIONS: Different signs and symptoms of prevalent oral diseases are associated with the impact on specific daily life activities among adults, which may compromise the OHRQoL. CLINICAL RELEVANCE: Knowledge of how signs, symptoms, and oral conditions affect OHRQoL and daily life activities can provide essential information for clinicians to establish proper disease management and preventive strategies focusing on improving patients' lives.

Intersectoral Collaboration to Promote Child Development: The Contributions of the Actor-Network Theory.

An integrated intersectoral care model promises to meet complex needs to promote early child development and address health determinants and inequities. Nevertheless, there is a lack of understanding of actors' interactions in producing intersectoral collaboration networks. The present study aimed to analyze the intersectoral collaboration in the social protection network involved in promoting early child growth and development in Brazilian municipalities. Underpinned by the tenets of actor-network theory, a case study was conducted with data produced from an educational intervention, entitled "Projeto Nascente." Through document analysis (ecomaps), participant observation (in Projeto Nascente seminars), and interviews (with municipal management representatives), our study explored and captured links among actors; controversies and resolution mechanisms; the presence of mediators and intermediaries; and an alignment of actors, resources, and support. The qualitative analysis of these materials identified three main themes: (1) agency fragility for intersectoral collaboration, (2) attempt to form networks, and (3) incorporation of fields of possibilities. Our findings revealed that intersectoral collaboration for promoting child growth and development is virtually non-existent or fragile, and local potential is missed or underused. These results emphasized the scarcity of action by mediators and intermediaries to promote enrollment processes to intersectoral collaboration. Likewise, existing controversies were not used as a mechanism for triggering changes. Our research supports the need to mobilize actors, resources, management, and communication tools that promote processes of interessement and enrollment in favor of intersectoral collaboration policies and practices for child development.

A systematic review of measurement instruments for oral health assessment of older adults in long-term care facilities by nondental professionals.

BACKGROUND: Regular oral health assessment of older adults living in Long-term Care Facilities (LTCF) can improve their oral health. AIMS: This study aimed to systematically review studies describing the development of instruments employed by nondental professionals to assess the oral health of older adults in LTCF and to evaluate their measurement properties. MATERIAL & METHODS: Electronic searches were conducted in the MEDLINE (PubMed), Embase, Web of Science, Scopus, and LILACS databases. Measurement properties of the identified instruments were evaluated using the Consensus-based Standards to select health Measurement Instruments (COSMIN) checklist. Studies assessing at least one measurement property (validity, reliability, or responsiveness) of instruments used to assess oral health of older adults living in LTCF by nondental professionals were considered. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) checklist was used to evaluate the quality of evidence. RESULTS: Fifteen studies reporting measurement properties of seven instruments were selected. The ohr-interRAI and the OHAT were considered to have sufficient content validity, with high and moderate evidence quality, respectively. OHAT, BOHSE, and DHI showed acceptable results on reliability but with very low quality of evidence. DHI and OHSTNP also showed acceptable results for criterion validity, but, with low quality of evidence, insufficient or unclear results were observed for the remaining measurement properties. Studies evaluating the validity criteria of BOHSE and hypotheses testing of ohr-MDS were considered to have high evidence quality. DISCUSSION AND CONCLUSION: The ohr-interRAI can be provisionally recommended for use until further evidence is provided. Further methodologically rigorous studies are needed to assess the measurement properties of the existing instruments.

Medial Entorhinal Cortex Excitatory Neurons Are Necessary for Accurate Timing.

The hippocampal region has long been considered critical for memory of time, and recent evidence shows that network operations and single-unit activity in the hippocampus and medial entorhinal cortex (MEC) correlate with elapsed time. However, whether MEC activity is necessary for timing remains largely unknown. Here we expressed DREADDs (designer receptors exclusively activated by designer drugs) under the CaMKIIa promoter to preferentially target MEC excitatory neurons for chemogenetic silencing, while freely moving male rats reproduced a memorized time interval by waiting inside a region of interest. We found that such silencing impaired the reproduction of the memorized interval and led to an overestimation of elapsed time. Trial history analyses under this condition revealed a reduced influence of previous trials on current waiting times, suggesting an impairment in maintaining temporal memories across trials. Moreover, using GLM (logistic regression), we show that decoding behavioral performance from preceding waiting times was significantly compromised when MEC was silenced. In addition to revealing an important role of MEC excitatory neurons for timing behavior, our results raise the possibility that these neurons contribute to such behavior by holding temporal information across trials.SIGNIFICANCE STATEMENT Medial temporal lobe (MTL) structures are implicated in processing temporal information. However, little is known about the role MTL structures, such as the hippocampus and the entorhinal cortex, play in perceiving or reproducing temporal intervals. By chemogenetically silencing medial entorhinal cortex (MEC) excitatory activity during a timing task, we show that this structure is necessary for the accurate reproduction of temporal intervals. Furthermore, trial history analyses suggest that silencing MEC disrupts memory mechanisms during timing. Together, these results suggest that MEC is necessary for timing behavior, possibly by representing the target interval in memory.

Argonaute-2 protects the neurovascular unit from damage caused by systemic inflammation.

BACKGROUND: The brain vasculature plays a pivotal role in the inflammatory process by modulating the interaction between blood cells and the neurovascular unit. Argonaute-2 (Ago2) has been suggested as essential for endothelial survival but its role in the brain vasculature or in the endothelial-glial crosstalk has not been addressed. Thus, our aim was to clarify the significance of Ago2 in the inflammatory responses elicited by these cell types. METHODS: Mouse primary cultures of brain endothelial cells, astrocytes and microglia were used to evaluate cellular responses to the modulation of Ago2. Exposure of microglia to endothelial cell-conditioned media was used to assess the potential for in vivo studies. Adult mice were injected intraperitoneally with lipopolysaccharide (LPS) (2 mg/kg) followed by three daily intraperitoneal injections of Ago2 (0.4 nM) to assess markers of endothelial disruption, glial reactivity and neuronal function. RESULTS: Herein, we demonstrated that LPS activation disturbed the integrity of adherens junctions and downregulated Ago2 in primary brain endothelial cells. Exogenous treatment recovered intracellular Ago2 above control levels and recuperated vascular endothelial-cadherin expression, while downregulating LPS-induced nitric oxide release. Primary astrocytes did not show a significant change in Ago2 levels or response to the modulation of the Ago2 system, although endogenous Ago2 was shown to be critical in the maintenance of tumor necrosis factor-α basal levels. LPS-activated primary microglia overexpressed Ago2, and Ago2 silencing contained the inflammatory response to some extent, preventing interleukin-6 and nitric oxide release. Moreover, the secretome of Ago2-modulated brain endothelial cells had a protective effect over microglia. The intraperitoneal injection of LPS impaired blood-brain barrier and neuronal function, while triggering inflammation, and the subsequent systemic administration of Ago2 reduced or normalized endothelial, glial and neuronal markers of LPS damage. This outcome likely resulted from the direct action of Ago2 over the brain endothelium, which reestablished glial and neuronal function. CONCLUSIONS: Ago2 could be regarded as a putative therapeutic agent, or target, in the recuperation of the neurovascular unit in inflammatory conditions.

Sintra Grows Healthy: development and implementation of a food literacy curriculum for primary schools.

OBJECTIVE: Describe the process of development and implementation of Health at the Table - a food literacy curriculum for primary school aged children. DESIGN: Through a community-based research process, Health at the Table development and implementation took place in four stages: exploratory study, production, implementation and monitoring. SETTING: Primary schools of Sintra's municipality, Portugal. PARTICIPANTS: Children (6-10 years), teachers, school staff and children's legal guardians of three primary schools during the pilot project and eight primary schools in the second year. RESULTS: During the needs assessment phase, 99·1 % (n 341) of the children's legal guardians, 100 % (n 34) of the teachers and 100 % (n 19) of the school staff considered that the school plays an important or very important role in children's food literacy (stage 1). During the pilot project, a manual with sixty session plans was developed (stage 2). In the second year, Health at the Table was implemented by seventy-two trained teachers during one school year (stage 3). Most of the teachers agreed that the curriculum was appropriate (69·2 %) and that children developed health, wellness/well-being and environmental skills (83·1 %). Most of the children said they had learned about healthy eating (86·3 %) and claimed to eat healthier since the Health at the Table implementation (58·9 %) (stage 4). CONCLUSIONS: Health at the Table is a food literacy curriculum that can be reproduced in similar contexts in a sustainable way. The need to combine educational strategies with a healthy school food environment is reinforced to increase effectiveness in tackling childhood obesity.

Is Binge Drinking Associated with Suicidal Behaviors among Brazilian Adolescents?

OBJECTIVE: To evaluate the association between suicidal behaviors and binge drinking among Brazilian adolescents. METHODS: A cross-sectional study was conducted with 2,476 students 14 to 19 years of age from 26 public high schools in the city of Olinda, Brazil. Data collection occurred between March and June 2018 through the self-administered Youth Risk Behavior Survey. Descriptive analysis and Poisson regression (p < 0.05, 95%CI) were performed. RESULTS: The prevalence of suicidal ideation, planning and attempt in the previous 12 months was 23.7%, 17.4% and 13.5%, respectively. Suicidal ideation was associated with binge drinking one to two days (PR:1.053, 95%CI:1.011-1.096) and ≥ three days in the previous 30 days (PR:1.069, 95%CI:1.016-1.125), sadness/hopelessness in the previous 12 months (PR:1.313, 95%CI:1.267-1.360), a report of family physical aggression in the previous 12 months (PR:1.111, 95%CI:1.068-1.155), the female sex (PR:1.082, 95%CI:1.049-1.115) and a non-nuclear family (PR:1.037, 95%CI:1.004-1.071). Suicidal planning was associated with sadness/hopelessness in the previous 12 months (PR:1.257, 95%CI:1.214-1.302), report of family physical aggression in the previous 12 months (PR:1.110, 95%CI:1.065-1.156) and the female sex (PR:1.072, 95%CI:1.041-1.104). Suicide attempt was associated with binge drinking ≥ three days in the previous 30 days (PR:1.062, 95%CI:1.008-1.119), sadness/hopelessness in the previous 12 months (PR:1.202, 95%CI:1.161-1.244), report of family physical aggression in the previous 12 months (PR:1.105, 95%CI:1.060-1.153) and the female sex (PR:1.064, 95%CI:1.034-1.095). The Catholic (PR:0.938, 95%CI:0.899-0.979; PR:0.925, 95%CI:0.888-0.9865; PR:0.937, 95%CI:0.899-0.977) and Evangelical (PR:0.956, 95%CI:0.922-0.992; PR:0.954, 95%CI:0.919-0.991) religions acted as a possible protective factor against suicidal behaviors. CONCLUSIONS: Suicidal ideation and attempt were associated with binge drinking.

Increased Co-Occurrence of Pathogenic Variants in Hereditary Breast and Ovarian Cancer and Lynch Syndromes: A Consequence of Multigene Panel Genetic Testing?

The probability of carrying two pathogenic variants (PVs) in dominant cancer-predisposing genes for hereditary breast and ovarian cancer and lynch syndromes in the same patient is uncommon, except in populations where founder effects exist. Two breast cancer women that are double heterozygotes (DH) for both BRCA1/BRCA2, one ovarian cancer case DH for BRCA1/RAD51C, and another breast and colorectal cancer who is DH for BRCA2/PMS2 were identified in our cohort. Ages at diagnosis and severity of disease in BRCA1/BRCA2 DH resembled BRCA1 single-carrier features. Similarly, the co-existence of the BRCA2 and PMS2 mutations prompted the development of breast and colorectal cancer in the same patient. The first BRCA1/BRCA2 DH was identified by HA-based and Sanger sequencing (1 of 623 families with BRCA PVs). However, this ratio has increased up to 2.9% (1 DH carrier vs. 103 single PV carriers) since using a custom 35-cancer gene on-demand panel. The type of cancer developed in each DH patient was consistent with the independently inherited condition, and the clinical outcome was no worse than in patients with single BRCA1 mutations. Therefore, the clinical impact, especially in patients with two hereditary syndromes, lies in genetic counseling tailor-made for each family based on the clinical guidelines for each syndrome. The number of DH is expected to be increased in the future as a result of next generation sequencing routines.

Protective measures feasibility for infants of low income SARS-CoV-2 positive breastfeeding mothers: a prospective multicenter cohort study.

AIM: The aim was to evaluate the feasibility of protective measures for infants of low-income SARS-CoV-2 positive breastfeeding mothers. BACKGROUND: Breastfeeding mothers with SARS-CoV-2 positive should avoid exposing the infant through protective measures (PM), but it could be challenging in a low-income population. METHODS: A prospective, multicenter study was conducted between July and October 2020 (BRACOVID). The participants were recruited at birth and interviewed through a structured questionnaire at seven and 14 days in the home environment. The feasibility of PM during breastfeeding at home was defined by guidelines recommendations (mask using, handwashing, and distancing from newborn when not breastfeeding). Three groups according to the feasibility of guidelines: complete guidelines feasibility (CG): all PM; partial guidelines feasibility (PG): at least one PM feasible; no guidelines (NG): infeasibility to all of PM. Flu-like neonatal symptoms, mothers' breastfeeding practices. We evaluated the association between PM feasibility and socioeconomic factors. RESULTS: 117 infected mothers from 17 Brazilian hospitals were enrolled. 47 (40%) mothers followed all recommendations, 14 (11.9%) could not practice at least one recommendation, and 50 (42.7%) did not execute any of them. The breastfeeding rate was 98%. Factors associated with infeasibility were monthly family income < 92.7 dollars/person, high housing density (>1 inhabitant/room), teenage mothers, responsive feeding, and poor schooling. Regarding infants' flu-like symptoms, 5% presented symptoms at fourteen days (NG group). CONCLUSION: The guidelines were not applied to infants of SARs-CoV-positive mothers in 54.6% of the dyads since the recommendations were unviable in their environments. During pandemics, we should look for feasible and effective guidelines to protect neonates from low-income populations. IMPLICATIONS FOR NURSING MANAGEMENT: Poor socioeconomic conditions lead to the unfeasibility of protective measures for infants of low-income SARS-CoV-2 positive breastfeeding mothers during the isolation period in the pandemics. The orientations and the support provided to dyad should consider the socioeconomic factors to guide feasible measures in the home environment and promote adequate protections; only an individual approach will allow a safe environment for low-income infants.

Salt concentration modulates the DNA target search strategy of NdeI.

DNA target search is a key step in cellular transactions that access genomic information. How DNA binding proteins combine 3D diffusion, sliding and hopping into an overall search strategy remains poorly understood. Here we report the use of a single molecule DNA tethering method to characterize the target search kinetics of the type II restriction endonuclease NdeI. The measured search rate depends strongly on DNA length as well as salt concentration. Using roadblocks, we show that there are significant changes in the DNA sliding length over the salt concentrations in our study. To explain our results, we propose a model including cycles of 3D and 1D search in which salt concentration modulates the strategy by varying the length of DNA probed per 1D scan. At low salt NdeI makes a single non-specific encounter with DNA followed by an effective and complete 1D scan. At higher salt, NdeI must execute multiple cycles of target search due to the reduced efficacy of 1D search.

Happiness, quality of life and their determinants among people with systemic sclerosis: a structural equation modelling approach.

BACKGROUND: Patients' objectives and experiences must be core to the study and management of chronic diseases, such as SSc. Although patient-reported outcomes are attracting increasing attention, evaluation of the impact of disease on the overall subjective well-being, equivalent to 'happiness', is remarkably lacking. OBJECTIVES: To examine the determinants of happiness and quality of life in patients with SSc, with emphasis on disease features and personality traits. METHODS: Observational, cross-sectional multicentre study, including 142 patients, with complete data regarding disease activity, disease impact, personality, health-related quality of life (HR-QoL) and happiness. Structural equation modelling was used to evaluate the association between the variables. RESULTS: The results indicated an acceptable fit of the model to the data. Perceived disease impact had a significant negative direct relation with HR-QoL (ß = -0.79, P < 0.001) and with happiness (ß = -0.52, P < 0.001). Positive personality traits had a positive relation with happiness (ß = 0.36, P = 0.002) and an important indirect association upon QoL (ß = 0.43) and happiness (ß = 0.23). Perceived disease impact is influenced by body image, fatigue and SSc-related disability to a higher degree (ß = 0.6-0.7) than by disease activity (ß = 0.28) or form (ß = 0.17). Impact of disease had a much stronger relation with HR-QoL than with happiness. CONCLUSIONS: The results suggest that treatment strategies targeting not only disease control but also the mitigation of relevant domains of disease impact (body image, fatigue, global disability) may be important to improve patients' experience of the disease. The reinforcement of resilience factors, such as positive psychological traits, may also play a contributory role towards better patient outcomes.

Value-based care in obstetrics: comparison between vaginal birth and caesarean section.

BACKGROUND: Healthcare costs have substantially increased in recent years, threatening the population health. Obstetric care is a significant contributor to this scenario since it represents 20% of healthcare. The rate of cesarean sections (C-sections) has escalated worldwide. Evidence shows that cesarean delivery is not only more expensive, but it is also linked to poorer maternal and neonatal outcomes. This study assesses which type of delivery is associated with a higher healthcare value in low-risk pregnancies. RESULTS: A total of 9345 deliveries were analyzed. The C-section group had significantly worse rates of breastfeeding in the first hour after delivery (92.57% vs 88.43%, p < 0.001), a higher rate of intensive unit care (ICU) admission both for the mother and the newborn (0.8% vs 0.3%, p = 0.001; 6.7% vs 4.5%, p = 0.0078 respectively), and a higher average cost of hospitalization (BRL14,342.04 vs BRL12,230.03 considering mothers and babies). CONCLUSION: Cesarean deliveries in low-risk pregnancies were associated with a lower value delivery because in addition to being more expensive, they had worse perinatal outcomes.