Evolution and divergence of the genetic lineage Desmodus rotundus/Artibeus lituratus of rabies virus in São Paulo State.

The last record of a rabies case caused by the dog-specific rabies virus (RABV) lineage in dogs or cats in São Paulo State was in 1998. From 2002 to 2021, 57 cases of rabies in these animals were reported, and the vast majority (51) were genetically characterized as belonging to the Desmodus rotundus/Artibeus lituratus RABV lineage. However, it is not currently possible to infer which of these bats is the source of infection by genome sequencing of RABV isolates. The aims of this study were (a) to characterize the Desmodus rotundus/Artibeus lituratus lineage to determine the relationships between the RABV lineages and each reservoir, (b) to assess the phylogeny and common ancestors of the RABV lineages found in D. rotundus and A. lituratus, and (c) to further understand the epidemiology and control of rabies. In this study, we genetically analyzed 70 RABV isolates from São Paulo State that were received by the Virology Laboratory of the Pasteur Institute of São Paulo between 2006 and 2015. Of these isolates, 33 were associated with the hematophagous bat D. rotundus and 37 with the fruit bat A. lituratus. A genomic approach using phylogenetic analysis and nucleotide sequence comparisons demonstrated that these isolates belonged to the same genetic lineage of RABV. We also found that, in São Paulo State, the D. rotundus/A. lituratus lineage could be subdivided into at least four phylogenetic sublineages: two associated with D. rotundus and two with A. lituratus. These results are of importance for the epidemiological surveillance of rabies in São Paulo.

Fire seasonality plays a limited role in the reproduction of Anacardium humile A. St.-Hil. in a tropical savanna.

Anthropogenic fires are an increasing threat to tropical savannas and their plant populations. In the Brazilian Cerrado, human-made fires at the end of the dry season are replacing natural fires at the beginning of the dry season. Critically, these late burns occur under more intense climate variables. Here, we aimed to understand the potential role of fire seasonality on individuals of Anacardium humile, a widespread Cerrado species of cultural and economic importance. We conducted two prescribed burnings, one at the beginning of the dry season (early burning) and one at the end of the dry season (late burning) when climate variables were remarkably different. We assessed the reproductive responses of A. humile individuals over 4 years and compared individuals from the fire treatments with those from an unburned area (control). The reproductive phenology of A. humile varied over time and was influenced by climate variables. The seasons of different burning had similar impacts on the reproductive phenology of A. humile, and this impact lasted for at least 4 years. While A. humile populations do not depend on fire for reproduction, they produced more flowers and fruits for up to 2 years with the fire treatments. We provide empirical evidence of the role of climate variables on the phenology of A. humile and demonstrate the importance of considering the role of time after fire events. The similar responses of A. humile to fire seasonality show that Cerrado fire management can be more complex than previously thought.

[Driving improvement in spinal cord injury patients using virtual reality. Systematic review]. / Mejora de la conducción en pacientes con lesión medular mediante el uso de la realidad virtual. Revisión sistemática.

INTRODUCTION: Spinal cord injury is a pathology which causes motor and sensory impairment under the region damaged by the lesion. This results in limitations in daily activities such as driving. In recent years, improvement in this task has been achieved by means of virtual reality treatment in the rehabilitation of patients with spinal cord injury. The aim of the present study was to analyze, through a systematic review, the effectiveness of using virtual reality on driving skills in patients with spinal cord injury. MATERIALS AND METHODS: The literature search was carried out using the following databases: PubMed, Web of Science, PEDro, Cochrane Central Register of Controlled Trials, Medline, Scopus and CINAHL, including articles published from January 2000 to May 2021. RESULTS: After the research process, out of a total of 51 articles, 7 were included: 2 applied immersive VR and 5 semi-immersive VR. Road driving simulation was addressed by 4 of them: 1 on sailing, 1 on motorbike and 1 on bicycle. CONCLUSIONS: The use of virtual reality in driving skills training has led to improvements in quality of life, driving skills and reduction of fear of driving. Despite these findings, more research, patients, sessions and improvements are needed for a clearer understanding of this topic and its usefulness.

TITLE: Mejora de la conducción en pacientes con lesión medular mediante el uso de la realidad virtual. Revisión sistemática.Introducción. La lesión medular es una patología que provoca afectaciones motoras y sensitivas por debajo de la lesión. Esto da lugar a limitaciones en las actividades de la vida diaria, como en la capacidad de conducción. En los últimos años, la mejora en esta tarea se ha llevado a cabo mediante el tratamiento a través de la realidad virtual (RV) en la rehabilitación de pacientes con lesión medular. El objetivo del presente estudio fue analizar la eficacia del uso de la RV en la capacidad de conducción en pacientes con lesión medular mediante una revisión sistemática. Materiales y métodos. La búsqueda bibliográfica se llevó a cabo en las siguientes bases de datos: PubMed, Web of Science, PEDro, Cochrane Central Register of Controlled Trials, Medline, Scopus y CINAHL, incluyendo los artículos publicados desde enero de 2000 hasta mayo de 2021. Resultados. Tras el proceso de búsqueda, de un total de 51 artículos, se incluyeron siete; dos aplicaron RV inmersiva, y cinco, semiinmersiva. La simulación de conducción en carretera fue abordada por cuatro de ellos, uno de navegación, uno sobre motocicleta y uno en bicicleta. Conclusiones. El uso de la RV en el entrenamiento de la capacidad de conducción ha supuesto mejoras en la calidad de vida, en las habilidades de conducción y en la reducción del miedo a conducir. A pesar de esto, se necesita más investigación, con un mayor número de pacientes, mayor número de sesiones y mejoras en los simuladores de conducción.

Health-related quality of life in T1DM patients after high-dose cholecalciferol supplementation: data from a pilot clinical trial.

BACKGROUND: Type 1 Diabetes Mellitus (T1DM) impacts health-related quality of life (HRQoL). Cross-sectional studies suggest that low levels of vitamin D (VD) may impair HRQoL, however, the effect of VD supplementation on quality of life in T1DM patients has not yet been clarified. Our study evaluated the effects of high-dose VD supplementation on HRQoL in T1DM. METHODS: We performed a prospective study with 64 patients receiving cholecalciferol (4000 IU/day for patients with 25-OH-vitamin D [25(OH)D] between 30 and 60 ng/mL, and 10,000 IU/day for those with 25(OH)D below 30 ng/mL) for 12 weeks, as part of a research protocol. HRQoL was assessed with EuroQol instruments (EQ-5D and EQ-VAS). RESULTS: There was an improvement in global EQ-5D index, and analysing specifically the EQ-5D domains, we observed an improvement in mobility (1.3 ± 0.6 versus 1.1 ± 0.3, p < 0.01). Evaluating possible outcome influencing variables, we detected a reduction in albuminuria at the end of the trial, without changes in BMI, lipids, blood pressure, glycemic control and insulin doses. We found correlations between final albuminuria and the dimensions: mobility (r = 0.6; p < 0.01), personal care (r = 0.7; p < 0.01), pain and discomfort (r = 0.6; p < 0.01) and habitual activities (r = 0.6; p < 0.01), suggesting an association between albuminuria reduction and the impact of VD supplementation on HRQoL. CONCLUSION: Our data showed that high doses of cholecalciferol supplementation can improve HRQoL in patients with T1DM, and the reduction of albuminuria seems to be an important factor in this context. TRIAL REGISTRATION: (ISRCTN32601947), 03/06/2017 retrospectively registered.

High-dose Vitamin D Supplementation on Type 1 Diabetes Mellitus Patients: Is there an Improvement in Glycemic Control?

BACKGROUND: Some authors evaluated the effect of VD on hyperglycemia in T1DM, but the results remain controversial. This study aims to analyze the effects of high-dose VD supplementation on T1DM patients' glycemic levels, maintaining stable doses of insulin. METHODS: Prospective, 12-week clinical trial including 67 T1DM patients, supplemented with high doses of cholecalciferol according to participants' VD value. Patients with VD levels below 30 ng/mL received 10,000 IU/day; those with levels between 30-60 ng/mL received 4,000 IU/day. Patients who had not achieved 25(OH)D levels > 30 ng/ml or presented insulin dose variation during the study were not analyzed. RESULTS: Only 46 out of 67 patients accomplished the criteria at the end of the study. There was no general improvement in the glycemic control evaluated by HbA1c (9.4 ± 2.4 vs 9.4 ± 2.6, p=NS) after VD supplementation. However, a post-hoc analysis, based on HbA1c variation, identified patients who had HbA1c reduced at least 0.6% (group 1, N = 13 (28%)). In addition, a correlation between 25(OH)D levels with HbA1c and total insulin dose at the end of the study was observed (r = -0.3, p<0.05; r=-0.4, p<0.05, respectively), and a regression model demonstrated that 25(OH)D was independent of BMI, duration of T1DM and final total insulin dose, being capable of determining 9.2% of HbA1c final levels (Unstandardized B coefficient = -0.033 (CI 95%: -0.064 to -0.002), r2 = 0.1, p <0.05). CONCLUSION: Our data suggest that VD is not widely recommended for glycemic control. Nevertheless, specific patients might benefit from this approach.

Association Between 25(OH)Vitamin D, HbA1c and Albuminuria in Diabetes Mellitus: Data From a Population-Based Study (VIDAMAZON).

Background: The effect of glycemic control on diabetic kidney disease (DKD) is well known. Recent evidence has suggested that Vitamin D (VD) may have a nephroprotective effect in diabetes, but the relationship between VD, glycemic control, and albuminuria has yet to be clarified. Objective: Evaluate the relationship between 25-hydroxy-vitamin D [25(OH)D], HbA1c, and albuminuria in Diabetes Mellitus (DM). Patients and Methods: Cross-sectional study with 1576 individuals with DM who had 25(OH)D, HbA1c, and albuminuria levels measured. Patients with abnormal creatinine levels were excluded, in order to avoid interference on VD levels by impaired kidney function. Results: Patients with HbA1c ≥7% had lower 25(OH)D when compared to patients with HbA1c <7% (29.7 ± 10.2 vs 28.1 ± 9.9 ng/ml, p = 0.003) and 25(OH)D levels seems to predict 1.5% of HbA1c behavior. The 25(OH)D concentrations in patients with normoalbuminuria were higher than the levels observed in those with micro or macroalbuminuria (29.8 ± 9.0 vs 26.8 ± 8.6 and 25.1 ± 7.6, respectively, p = 0.001), patients who had 25(OH)D <20 ng/ml and 25(OH)D <30 ng/ml were at a higher risk of presenting albuminuria [OR = 2.8 (95% CI = 1.6 - 4.9), p<0.001, and OR = 2.1 (95% CI = 1.3 - 4.6), p<0.001, respectively]. In our regression model, albuminuria was influenced by HbA1c (r² = 0.076, p<0.00001) and 25(OH)D (r² = 0.018, p = 0.002) independently. Conclusion: Our study found an association between vitamin D levels, HbA1c and DKD. Additionally, our data suggest that the association between urinary albumin excretion and vitamin D levels is independent of glycemic control in patients with diabetes. Even though our patients presented normal creatinine levels, it is necessary further prospective studies to confirm if this association precedes or not the loss of renal function.

Transcriptome of iPSC-derived neuronal cells reveals a module of co-expressed genes consistently associated with autism spectrum disorder.

Evaluation of expression profile in autism spectrum disorder (ASD) patients is an important approach to understand possible similar functional consequences that may underlie disease pathophysiology regardless of its genetic heterogeneity. Induced pluripotent stem cell (iPSC)-derived neuronal models have been useful to explore this question, but larger cohorts and different ASD endophenotypes still need to be investigated. Moreover, whether changes seen in this in vitro model reflect previous findings in ASD postmortem brains and how consistent they are across the studies remain underexplored questions. We examined the transcriptome of iPSC-derived neuronal cells from a normocephalic ASD cohort composed mostly of high-functioning individuals and from non-ASD individuals. ASD patients presented expression dysregulation of a module of co-expressed genes involved in protein synthesis in neuronal progenitor cells (NPC), and a module of genes related to synapse/neurotransmission and a module related to translation in neurons. Proteomic analysis in NPC revealed potential molecular links between the modules dysregulated in NPC and in neurons. Remarkably, the comparison of our results to a series of transcriptome studies revealed that the module related to synapse has been consistently found as upregulated in iPSC-derived neurons-which has an expression profile more closely related to fetal brain-while downregulated in postmortem brain tissue, indicating a reliable association of this network to the disease and suggesting that its dysregulation might occur in different directions across development in ASD individuals. Therefore, the expression pattern of this network might be used as biomarker for ASD and should be experimentally explored as a therapeutic target.

High-dose Cholecalciferol Supplementation Reducing Morning Blood Pressure in Normotensive DM1 Patients.

BACKGROUND: Vitamin D (VD) deficiency has been related to several endocrine metabolic and cardiovascular diseases. The effect of VD supplementation on blood pressure (BP) in patients with diabetes is controversial. OBJECTIVE: The aim of this study was to evaluate high-dose vitamin D supplementation effects on blood pressure of normotensive patients with diabetes mellitus 1 (DM1) patients by 24-hour ambulatory blood pressure monitoring (ABPM). METHODS: We performed a clinical trial including 35 DM1 normotensive patients, who received doses of 4,000 or 10,000 IU/day of cholecalciferol for 12 weeks according to previous VD levels. They underwent 24-hour ABPM, along with glycated hemoglobin, creatine, lipids profile and PCRus dosage before and after VD supplementation. RESULTS: We found an expressive reduction of systolic and diastolic morning blood pressures (117±14 vs 112±14, p<0,05; 74±9 vs 70±10 mmHg, p<0,05, respectively) with no changes in other pressoric markers. Besides, we noticed a relationship between levels of VD after supplementation and diastolic morning blood pressure (r= -0,4; p<0.05). CONCLUSION: Our study suggests an association between supplementation of high doses of vitamin D and the reduction of morning blood pressure in normotensive DM1 patients.

Improvement in Cardiovascular Autonomic Neuropathy After High-Dose Vitamin D Supplementation in Patients With Type 1 Diabetes.

Background: Cardiovascular autonomic neuropathy (CAN) is associated with diabetes mellitus, increasing morbidity and mortality. Some cross-sectional studies associated CAN with low 25-hydroxyvitamin D levels. The aim of our study was to evaluate the effect of high-dose vitamin D (VD) supplementation on CAN in Type 1 Diabetes Mellitus (T1DM) patients. Methods: We performed a prospective study with 23 patients diagnosed with T1DM and CAN. Subjects with VD levels <30 ng/ml received 10,000 IU/day; the ones with VD levels between 30-60 ng/ml were given 4,000 IU/day for 12 weeks. Results: There was an improvement in CAN parameters related to resting heart rate variability, such as time domain parameters [Maximum RR interval (0.77 ± 0.11 vs 0.94 ± 0.51 s, p <0.05), Mean length of regular RR intervals (0.71 ± 0.10 vs 0.76 ± 0.09 s, p <0.05) and Standard deviation of all NN intervals (0.02 ± 0.01 vs 0.03 ± 0.02 s; p <0.01)] and frequency domain parameters [Low Frequency (1.9 ± 0.5 vs 2.5 ± 0.9 s, p < 0.001), Total Power (2.5 ± 0.4 vs 2.8 ± 0.6 s, p <0.05)]. In addition, there was a correlation between absolute VD level variation and posttreatment High Frequency (%), as well as among percent variation in VD level and end-of-study Low Frequency/High Frequency ratio (r=0.6, p<0.01; r= -0.5, p<0.05, respectively). Conclusion: Our pilot study is the first to suggest a strong association between high-dose vitamin D supplementation and improved cardiovascular autonomic neuropathy in T1DM patients. It occurred without any variation in HbA1C, blood pressure levels, lipids, and insulin dose. Clinical Trial Registration: http://www.isrctn.com/ISRCTN32601947, identifier ISRCTN32601947.

A critical realist evaluation of an integrated care project for vulnerable families in Sydney, Australia.

BACKGROUND: Healthy Homes and Neighbourhoods (HHAN) Integrated Care Initiative was established to improve the care of families with complex health and social needs who reside in Sydney Local Health District. HHAN seeks to provide long-term multi-disciplinary care coordination as well as enhance capacity building and promote integrated care. The critical realist study reported here is part of the longitudinal development and evaluation of complex integrated health and social care interventions in Sydney, Australia. METHODS: We describe the qualitative component of a critical realist pilot case study aimed at exploring, explaining and refining emerging HHAN programme theories in relation to care coordination. Qualitative interviews were undertaken with HHAN clients (n = 12), staff and other stakeholders (n = 21). Interviews and coding used a context (C), mechanism (M) and outcome (O) framework. Inductive, deductive, retroductive and abductive modes of reasoning were used with the CMO heuristic tool to inform the developing programme theory. RESULTS: The mechanisms underpinning effective engagement of clients by care coordinators included: building trust, leveraging other family, social and organisational relationships, meeting clients on their own terms, demonstrating staff effectiveness as quickly as possible, and client empowerment. Mechanisms for enhancing care integration included knowledge transfer activities and shared learning among collaborators, structural and cultural changes, enhancing mutual respect, co-location of multidisciplinary and/or interagency staff and cultivating faith in positive change among staff. CONCLUSIONS: Use of a critical realism case study approach served to elucidate the varied influences of contexts and mechanisms on programme outcomes, to highlight what works for whom and in what context. Findings supported the initial programme theory that engagement and trust building with clients, alongside enhanced collaboration and integration of services, improved outcomes for vulnerable families with complex needs. Further research is needed to explore the cost-effectiveness of integrated care initiatives, in view of the long term nature of service provision and the risk of staff burnout.

Modulation of cognition and neuronal plasticity in gain- and loss-of-function mouse models of the schizophrenia risk gene Tcf4.

The transcription factor TCF4 was confirmed in several large genome-wide association studies as one of the most significant schizophrenia (SZ) susceptibility genes. Transgenic mice moderately overexpressing Tcf4 in forebrain (Tcf4tg) display deficits in fear memory and sensorimotor gating. As second hit, we exposed Tcf4tg animals to isolation rearing (IR), chronic social defeat (SD), enriched environment (EE), or handling control (HC) conditions and examined mice with heterozygous deletion of the exon 4 (Tcf4Ex4δ+/-) to unravel gene-dosage effects. We applied multivariate statistics for behavioral profiling and demonstrate that IR and SD cause strong cognitive deficits of Tcf4tg mice, whereas EE masked the genetic vulnerability. We observed enhanced long-term depression in Tcf4tg mice and enhanced long-term potentiation in Tcf4Ex4δ+/- mice indicating specific gene-dosage effects. Tcf4tg mice showed higher density of immature spines during development as assessed by STED nanoscopy and proteomic analyses of synaptosomes revealed concurrently increased levels of proteins involved in synaptic function and metabolic pathways. We conclude that environmental stress and Tcf4 misexpression precipitate cognitive deficits in 2-hit mouse models of relevance for schizophrenia.

Microbial Control of Leptopharsa heveae Drake & Poor (Hemiptera: Tingidae) in Brazilian Rubber Tree Plantations: a Brief Historical Account and Identification of Entomopathogenic Fungi by Means of Multigene Phylogeny.

Over the last decades, a few fungal species have been mentioned in the literature associated with the rubber tree lace bug, Leptopharsa heveae Drake & Poor (Hemiptera: Tingidae). The rubber plantation area treated with these biocontrol agents has been steady since the 1990s, estimated in 10,000-15,000 ha per year. A few large-scale rubber operations, one biocontrol company, and three government-owned laboratories were, and currently one still is, involved in their commercialization. One species, currently referred to as Sporothrix insectorum, has been historically deployed in biocontrol applications in Brazilian rubber farms. However, L. heveae-infecting isolates have only been identified through morphological examinations; therefore, proper molecular assessments are needed for accurate identifications. Hence, DNA of six L. heveae-infecting isolates (five of which have been deployed in field applications) were extracted and sequenced. Multigene phylogeny found that both Simplicillium lanosoniveum and Cordyceps (formerly Isaria) sp. have been sprayed on rubber plantations to manage L. heveae populations, although the former is the only one currently applied. Simplicillium lanosoniveum and Cordyceps sp. have no relation whatsoever to true Sporothrix species associated with human and animal diseases. Therefore, our molecular data may encourage biocontrol companies to register mycoinsecticides targeting L. heveae. We also added unpublished historical accounts after contacting key contributors to the launching of this not so well-known biocontrol program in the 1980s.

Evidence of macrophage modulation in the mouse pubic symphysis remodeling during the end of first pregnancy and postpartum.

In mouse pregnancy, pubic symphysis (PS) remodels into an elastic interpubic ligament (IpL) in a temporally regulated process to provide safe delivery. It restores at postpartum to assure reproductive tract homeostasis. Recently, macrophage localization in the IpL and dynamic changes in the expression of inflammatory mediators observed from the end of pregnancy (D18, D19) to early days postpartum (1dpp, 3dpp) highlighted the necessity of the identification of the key molecules involved in innate immune processes in PS remodeling. Therefore, this study uses morphological and high-sensitivity molecular techniques to identify both macrophage association with extracellular matrix (ECM) remodeling and the immunological processes involved in PS changes from D18 to 3dpp. Results showed macrophage association with active gelatinases and ECM components and 25 differentially expressed genes (DEGs) related to macrophage activities in interpubic tissues from D18 to 3dpp. Additionally, microarray and proteomic analysis showed a significant association of interpubic tissue DEGs with complement system activation and differentially expressed proteins (DEPs) with phagocytosis, highlighting the involvement of macrophage-related activities in mouse PS remodeling. Therefore, the findings suggest that PS ECM remodeling is associated with evidence of macrophage modulation that ensures both IpL relaxation and fast PS recovery postpartum for first labor.

Digging deeper in the proteome of different regions from schizophrenia brains.

Schizophrenia is a psychiatric disorder that affects 21 million people worldwide. Despite several studies having been shown that some brain regions may play a critical role in the pathophysiology of schizophrenia, the molecular basis to explain this diversity is still lacking. The cerebellum (CER), caudate nucleus (CAU), and posterior cingulate cortex (PCC) are areas associated with negative and cognitive symptoms in schizophrenia. In this study, we performed shotgun proteomics of the aforementioned brain regions, collected postmortem from patients with schizophrenia and compared with the mentally healthy group. In addition, we performed a proteomic analysis of nuclear and mitochondrial fractions of these same regions. Our results presented 106, 727 and 135 differentially regulated proteins in the CAU, PCC, and CER, respectively. Pathway enrichment analysis revealed dysfunctions associated with synaptic processes in the CAU, transport in the CER, and in energy metabolism in the PCC. In all brain areas, we found that proteins related to oligodendrocytes and the metabolic processes were dysregulated in schizophrenia. SIGNIFICANCE: Schizophrenia is a complex and heterogeneous psychiatric disorder. Despite much research having been done to increase the knowledge about the role of each region in the pathophysiology of this disorder, the molecular mechanisms underlying it are still lacking. We performed shotgun proteomics in the postmortem cerebellum (CER), caudate nucleus (CAU) and posterior cingulate cortex (PCC) from patients with schizophrenia and compared with healthy controls. Our findings suggest that each aforementioned region presents dysregulations in specific molecular pathways, such as energy metabolism in the PCC, transport in the CER, and synaptic process in the CAU. Additionally, these areas presented dysfunctions in oligodendrocytes and metabolic processes. Our results may highlight future directions for the development of novel clinical approaches for specific therapeutic targets.

Diagnosis of Idiopathic GHD in Children Based on Response to rhGH Treatment: The Importance of GH Provocative Tests and IGF-1.

Purpose: Serum IGF-1 (Insulin like growth factor 1) and Growth Hormone (GH) provocative tests are reasonable tools for screening and diagnosis of idiopathic GH Deficiency (IGHD). However, the average cut-off points applied on these tests have a lower level of evidence and produce large amounts of false results. The aim of this study is to evaluate the sensitivity, specificity, and accuracy of IGF-1 and GH stimulation tests as diagnostic tools for IGHD, using clinical response to recombinant human GH (rhGH) treatment as diagnostic standard [increase of at least 0.3 in height standard deviation (H-SD) in 1 year]. Methods: We performed a prospective study with 115 children and adolescents presenting short stature (SS), without secondary SS etiologies such as organic lesions, genetic syndromes, thyroid disorders. They were separated into Group 1 [patients with familial SS or constitutional delay of growth and puberty (CDGP), not treated with rhGH], Group 2 (patients with suspicion of IGHD with clinical response to rhGH treatment), and Group 3 (patients with suspicion of IGHD without growth response to rhGH treatment). Then, they were assessed for diagnostic performance of IGF-1, Insulin Tolerance Test (ITT) and clonidine test (CT) alone and combined at different cut-off points. Results: Based on the ROC curve, the best cut-off points found for IGF-1, ITT, and CT when they were used isolated were -0.492 SDS (sensitivity: 50%; specificity: 53.8%; accuracy: 46.5%), 4.515 µg/L (sensitivity: 75.5%; specificity: 45.5%; accuracy: 52.7%), and 4.095 µg/L (sensitivity: 54.5%; specificity: 52.6%; accuracy: 56.9%), respectively. When we had combined IGF-1 with-2SD as cut-off alongside ITT or CT, we found 7 µg/L as the best cut-off point. In this situation, ITT had sensitivity, specificity and accuracy of 93.9, 81.8, and 90.1%, while CT had 93.2, 68.4, and 85.7%, respectively. Conclusion: Our data suggest that diagnosis of IGHD should be established based on a combination of clinical expertise, auxologic, radiologic, and laboratorial data, using IGF-1 at the -2SD threshold combined, with ITT or CT at the cut-off point of 7 µg/L. Additional studies, similar to ours, are imperative to establish cut-off points based on therapeutic response to rhGH in IGHD, which would be directly related to a better treatment outcome.

Rapid advances in auto-segmentation of organs at risk and target volumes in head and neck cancer.

Advances in technical radiotherapy have resulted in significant sparing of organs at risk (OARs), reducing radiation-related toxicities for patients with cancer of the head and neck (HNC). Accurate delineation of target volumes (TVs) and OARs is critical for maximising tumour control and minimising radiation toxicities. When performed manually, variability in TV and OAR delineation has been shown to have significant dosimetric impacts for patients on treatment. Auto-segmentation (AS) techniques have shown promise in reducing both inter-practitioner variability and the time taken in TV and OAR delineation in HNC. Ultimately, this may reduce treatment planning and clinical waiting times for patients. Adaptation of radiation treatment for biological or anatomical changes during therapy will also require rapid re-planning; indeed, the time taken for manual delineation currently prevents adaptive radiotherapy from being implemented optimally. We are therefore standing on the threshold of a transformation of routine radiotherapy planning via the use of artificial intelligence. In this article, we outline the current state-of-the-art for AS for HNC radiotherapy in order to predict how this will rapidly change with the introduction of artificial intelligence. We specifically focus on delineation accuracy and time saving. We argue that, if such technologies are implemented correctly, AS should result in better standardisation of treatment for patients and significantly reduce the time taken to plan radiotherapy.

Cochlear dysfunction and microvascular complications in patients with type 1 diabetes mellitus.

Sensorineural hearing impairment has been associated with DM, and it is probably linked to the same pathophysiological mechanisms as well-established in microvascular diabetes complications. The study of otoacoustic emissions (OAEs) is useful to identify subclinical cochlear dysfunction. Therefore, the aim of this study was to evaluate the association between abnormal OAEs responses, diabetic kidney disease (DKD) and diabetic cardiac autonomic neuropathy (CAN). We performed a cross-sectional study with 37 type 1 DM patients without auditory symptoms, submitted to the study of Distortion Product Otoacoustic Emissions (DPOAEs) and screened for DKD and CAN. The otoacoustic emissions responses were considered abnormal in 27/37 (73%) patients. A correlation was found between abnormal OAEs responses and presence of DKD (r = 0.36, p < 0.05), and 14/16 (88%) patients with a lower amplitude of OAEs in 8 kHz frequency band presented DKD. Abnormal OAEs responses in the 6 kHz frequency band were correlated with the presence (r = 0.41, p = 0.01) and severity of CAN (r = 0.44, p < 0.001). Additionally, 7/9 (78%) patients with abnormal OAE responses in this frequency also presented abnormal CAN scores. Our results suggest that abnormal otoacoustic emissions responses in high frequency bands are associated with diabetes microvascular complications and could be a risk marker for DKD and CAN, presenting low sensitivity and high specificity. Therefore, assuming that hearing impairment is a pre-clinical stage of hearing loss, performing distortion product otoacoustic emissions in T1DM patients with microvascular complications could be useful to identify those who would be benefit with regular audiologic follow up and tighter diabetes control.

Congenital bilateral absence of the vas deferens as an atypical form of cystic fibrosis: reproductive implications and genetic counseling.

Congenital bilateral absence of the vas deferens (CBAVD) is found in 1% to 2% of males with infertility and is present in 6% of obstructive azoospermia cases. Nearly 95% of men with cystic fibrosis (CF, an autosomal recessive disorder) have CBAVD. There are genetic links between CBAVD and CF. Some mutations in the gene encoding cystic fibrosis transmembrane conductance regulator (CFTR) can lead to CBAVD as a monosymptomatic form of CF. With the use of assisted reproductive techniques (ART), especially testicular or epididymal sperm aspiration, intracytoplasmic sperm injection, and in vitro fertilization, it is possible that men with CBAVD can produce offspring. Therefore, genetic counseling should be offered to couples undergoing ART to discuss the probability of having offspring that carry CFTR gene mutations. The aim of this review was to present the main cause of CBAVD, to call attention to its implications for assisted reproduction, and to show the importance of genetic counseling for couples where men have CBAVD, as they can have offspring with a lethal disease.

Comparative Metabolomics of Mycoplasma bovis and Mycoplasma gallisepticum Reveals Fundamental Differences in Active Metabolic Pathways and Suggests Novel Gene Annotations.

Mycoplasmas are simple, but successful parasites that have the smallest genome of any free-living cell and are thought to have a highly streamlined cellular metabolism. Here, we have undertaken a detailed metabolomic analysis of two species, Mycoplasma bovis and Mycoplasma gallisepticum, which cause economically important diseases in cattle and poultry, respectively. Untargeted gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry analyses of mycoplasma metabolite extracts revealed significant differences in the steady-state levels of many metabolites in central carbon metabolism, while 13C stable isotope labeling studies revealed marked differences in carbon source utilization. These data were mapped onto in silico metabolic networks predicted from genome wide annotations. The analyses elucidated distinct differences, including a clear difference in glucose utilization, with a marked decrease in glucose uptake and glycolysis in M. bovis compared to M. gallisepticum, which may reflect differing host nutrient availabilities. The 13C-labeling patterns also revealed several functional metabolic pathways that were previously unannotated in these species, allowing us to assign putative enzyme functions to the products of a number of genes of unknown function, especially in M. bovis. This study demonstrates the considerable potential of metabolomic analyses to assist in characterizing significant differences in the metabolism of different bacterial species and in improving genome annotation. IMPORTANCE Mycoplasmas are pathogenic bacteria that cause serious chronic infections in production animals, resulting in considerable losses worldwide, as well as causing disease in humans. These bacteria have extremely reduced genomes and are thought to have limited metabolic flexibility, even though they are highly successful persistent parasites in a diverse number of species. The extent to which different Mycoplasma species are capable of catabolizing host carbon sources and nutrients, or synthesizing essential metabolites, remains poorly defined. We have used advanced metabolomic techniques to identify metabolic pathways that are active in two species of Mycoplasma that infect distinct hosts (poultry and cattle). We show that these species exhibit marked differences in metabolite steady-state levels and carbon source utilization. This information has been used to functionally characterize previously unknown genes in the genomes of these pathogens. These species-specific differences are likely to reflect important differences in host nutrient levels and pathogenic mechanisms.

Selection of experimental strawberry (Fragaria x ananassa) hybrids based on selection indices.

The strawberry (Fragaria x ananassa Dutch.), is the only vegetable belonging to the rosacea family. All strawberry species have now emerged from wild species and belong to the genus Fragaria, being that this genus presents more than 45 described species, and only 11 are considered natural species. Due to the octoploid nature of strawberry and its variability after hybridization, selecting one or more characters may result in unfavorable genotypes and even the exclusion of promising ones, because negative genetic correlations have been observed among them that cause inefficient selection. Therefore, the objective of this study was to verify the efficiency of selection indices in selecting experimental strawberry hybrids for in natura consumption and processing. Seven commercial cultivars and 103 hybrids were used, which were obtained from populations derived from their crossings. The experiment was conducted in augmented blocks, in which four agronomical traits (total mass, amount of commercial fruit, amount of noncommercial fruit, and average fruit mass) and seven physical-chemical traits (soluble solids, soluble solids:titratable acidity ratio, total sugars, total pectin, vigor, and internal and external coloration) were evaluated. For hybrid selection, the following indices were used: Mulamba and Mock (1978), Smith (1936), Hazel (1943), and genotype-ideotype, which selected 20% of the genotypes evaluated. The three indices selected about 9% of the hybrids. The selection of two experimental hybrids (89 and 495) and the use of selection indices resulted in larger estimates of selection gains. The Mulamba and Mock (1978), Smith (1936), and Hazel (1943) indices had the highest percentage of gains on selection, and are therefore recommended for the selection of strawberry clones.