Academic, socioeconomic and interpersonal consequences of cannabis use : a narrative review

This article reviews the literature on the association between cannabis use (CU) and psychosocial functioning, operationalized here as academic achievement, economic prospects, social relationships and quality of life. So far, study results have been inconsistent. To clarify whether CU has an impact on psychosocial functioning, this article mainly reviewed prospective and longitudinal studies published since 2000 and examined whether studies controlled for confounding factors (e.g. socio-demographics, other substance use, psychopathology, social environment). The review suggested that when confounding variables are controlled for, the association between CU and psychosocial outcomes is generally small or non-significant. When significant associations remain, they are for chronic, dependent or early onset CU specifically, suggesting that the frequency of use and age of onset may be necessary elements to detect persistent, however small, psychosocial consequences. These results illustrate the importance of controlling for intra- and inter-individual differences to examine the link between CU and later psychosocial functioning. Results also suggest that policy and prevention efforts should consider targeting the individual and environmental factors (e.g. early academic and cognitive functioning, social disadvantage, family functioning, personality, smoking) that account for much of the association between CU and later psychosocial problems, rather than, or in addition to, CU itself

Verrucous epidermal nevus as a manifestation of a type 2 mosaic PTEN mutation in Cowden syndrome

Altres ajuts: Acord transformatiu CRUE-CSICUTP en procés de revisióLinear Cowden nevus, also known as linear PTEN nevus, is a type of epidermal nevus, first described in 2007, which is seen in patients with PTEN hamartoma tumor syndrome. It is considered to be a type 2 form of segmental mosaicism, and we suggest that it has certain clinical features that distinguish it from epidermal nevi seen in similar conditions, such as Proteus syndrome. We present a case of linear Cowden nevus in a 4-year-old boy and review the literature

Skin lesions in neurofibromatosis type 2 : diagnostic and prognostic significance of cutaneous (plexiform) schwannomas

Acord transformatiu CRUE-CSICBackground: Neurofibromatosis type 2 (NF2) is a genetic disease characterized by the appearance of multiple tumours in the nervous system. Cutaneous lesions are common and may provide useful diagnostic and prognostic information, but they have not been widely studied. Objectives: To characterize cutaneous lesions in a Spanish cohort of patients with NF2 and investigate associations with clinical and genetic severity. Methods: We studied the clinical and histologic characteristics of cutaneous lesions in 49 patients with NF2 and analysed correlations with phenotype- and genotype-based severity scores. We collected information on the presence/absence of cutaneous lesions, location, age at onset, type of lesion, and histologic features. We also studied level of systemic involvement and genetic mutations involved. Results: Forty-nine patients (31 women [63.3%] and 18 men [36.7%]) were analysed, and 33 (67.3%) had cutaneous lesions presumed to be schwannomas. According to their clinical form, they were distributed as follows: 24 patients (48%) had deep tumours, 21 (42%) had plaque-like lesions, and 3 (6%) had superficial tumours. Histologic examination from 27 lesions analysed out 23 patients showed classic schwannoma or hybrid schwannoma-neurofibroma features in the 8 deep tumours biopsied and plexiform schwannoma features in the 17 plaque-like lesions and the 2 superficial tumours analysed. Early onset (first 2 decades of life) was reported by all patients with plaques and superficial tumours. In our cohort, 100% of the patients with plaque-like lesions and superficial tumours with microscopic features of plexiform schwannoma were in the 2 groups with the most severe clinical phenotypes, and 82.6% of them were in the 3 most severe genotype-based classes. Conclusions and Relevance: Cutaneous lesions, specially plexiform schwannomas, are common in NF2, and they usually appear at an early age providing useful diagnostic and prognostic information. These tumours are part of the spectrum of cutaneous manifestations in this disease. Although its diagnostic and prognostic value has been pointed out, there are few studies focussed on their analysis

Unbalancing cAMP and Ras/MAPK pathways as a therapeutic strategy for cutaneous neurofibromas

Cutaneous neurofibromas (cNFs) are benign Schwann cell (SC) tumors arising from subepidermal glia. Individuals with neurofibromatosis type 1 (NF1) may develop thousands of cNFs, which greatly affect their quality of life. cNF growth is driven by the proliferation of NF1-/- SCs and their interaction with the NF1+/- microenvironment. We analyzed the crosstalk between human cNF-derived SCs and fibroblasts (FBs), identifying an expression signature specific to the SC-FB interaction. We validated the secretion of proteins involved in immune cell migration, suggesting a role of SC-FB crosstalk in immune cell recruitment. The signature also captured components of developmental signaling pathways, including the cAMP elevator G protein-coupled receptor 68 (GPR68). Activation of Gpr68 by ogerin in combination with the MEK inhibitor (MEKi) selumetinib reduced viability and induced differentiation and death of human cNF-derived primary SCs, a result corroborated using an induced pluripotent stem cell-derived 3D neurofibromasphere model. Similar results were obtained using other Gpr68 activators or cAMP analogs/adenylyl cyclase activators in combination with selumetinib. Interestingly, whereas primary SC cultures restarted their proliferation after treatment with selumetinib alone was stopped, the combination of ogerinselumetinib elicited a permanent halt on SC expansion that persisted after drug removal. These results indicate that unbalancing the Ras and cAMP pathways by combining MEKi and cAMP elevators could be used as a potential treatment for cNFs

Patient Frailty: Key Considerations, Definitions and Practical Implications

By 2020, the elderly (≥65-year-old) world population is projected to exceed one billion individuals. This demographic megatrend has brought topics such as physiological age and frailty to the forefront of medical research efforts around the globe. The concept of frailty has evolved significantly since the mid-twentieth century. The outdated stereotype of a “thin, stooped, slow octogenarian” has transitioned to a more scientific and objective understanding of the problem. Still, a comprehensive and concise definition of “frailty” remains elusive. Until such a definition is firmly established and universally agreed upon, clinicians continue to rely on the somewhat subjective conceptual framework of today. In this chapter, the authors review key issues pertaining to clinical management of frail patients, including diagnosis/identification, preventive strategies, therapeutic approaches, and common pitfalls. The relationship between frailty, various domains of life, and functional status is also discussed. Finally, we will touch upon the concepts of end-of-life and goals of care, focusing on their relationship to frailty

CNVfilteR: an R/bioconductor package to identify false positives produced by germline NGS CNV detection tools.

Germline copy-number variants (CNVs) are relevant mutations for multiple genetics fields, such as the study of hereditary diseases. However, available benchmarks show that all next-generation sequencing (NGS) CNV calling tools produce false positives. We developed CNVfilteR, an R package that uses the single nucleotide variant calls usually obtained in germline NGS pipelines to identify those false positives. The package can detect both false deletions and false duplications. We evaluated CNVfilteR performance on callsets generated by 13 CNV calling tools on 3 whole-genome sequencing and 541 panel samples, showing a decrease of up to 44.8% in false positives and consistent F1-score increase. Using CNVfilteR to detect false-positive calls can improve the overall performance of existing CNV calling pipelines. Availability: CNVfilteR is released under Artistic-2.0 License. Source code and documentation are freely available at Bioconductor (http://www.bioconductor.org/packages/CNVfilteR). Supplementary information: Supplementary data are available at Bioinformatics online

Using antisense oligonucleotides for the physiological modulation of the alternative splicing of NF1 exon 23a during PC12 neuronal differentiation

Neurofibromatosis Type 1 (NF1) is a genetic condition affecting approximately 1:3500 persons worldwide. The NF1 gene codes for neurofibromin protein, a GTPase activating protein (GAP) and a negative regulator of RAS. The NF1 gene undergoes alternative splicing of exon 23a (E23a) that codes for 21 amino acids placed at the center of the GAP related domain (GRD). E23a-containing type II neurofibromin exhibits a weaker Ras-GAP activity compared to E23a-less type I isoform. Exon E23a has been related with the cognitive impairment present in NF1 individuals. We designed antisense Phosphorodiamidate Morpholino Oligomers (PMOs) to modulate E23a alternative splicing at physiological conditions of gene expression and tested their impact during PC12 cell line neuronal differentiation. Results show that any dynamic modification of the natural ratio between type I and type II isoforms disturbed neuronal differentiation, altering the proper formation of neurites and deregulating both the MAPK/ERK and cAMP/PKA signaling pathways. Our results suggest an opposite regulation of these pathways by neurofibromin and the possible existence of a feedback loop sensing neurofibromin-related signaling. The present work illustrates the utility of PMOs to study alternative splicing that could be applied to other alternatively spliced genes in vitro and in vivo

The vestibular calyceal junction is dismantled following subchronic streptomycin in rats and sensory epithelium stress in humans

Hair cell (HC) loss by epithelial extrusion has been described to occur in the rodent vestibular system during chronic 3,3'-iminodipropionitrile (IDPN) ototoxicity. This is preceded by dismantlement of the calyceal junction in the contact between type I HC (HCI) and calyx afferent terminals. Here, we evaluated whether these phenomena have wider significance. First, we studied rats receiving seven different doses of streptomycin, ranging from 100 to 800 mg/kg/day, for 3 to 8 weeks. Streptomycin caused loss of vestibular function associated with partial loss of HCI and decreased expression of contactin-associated protein (CASPR1), denoting calyceal junction dismantlement, in the calyces encasing the surviving HCI. Additional molecular and ultrastructural data supported the conclusion that HC-calyx detachment precede HCI loss by extrusion. Animals allowed to survive after the treatment showed functional recuperation and rebuilding of the calyceal junction. Second, we evaluated human sensory epithelia obtained during therapeutic labyrinthectomies and trans-labyrinthine tumour excisions. Some samples showed abnormal CASPR1 label strongly suggestive of calyceal junction dismantlement. Therefore, reversible dismantlement of the vestibular calyceal junction may be a common response triggered by chronic stress, including ototoxic stress, before HCI loss. This may partly explain clinical observations of reversion in function loss after aminoglycoside exposure

Evaluation of CNV detection tools for NGS panel data in genetic diagnostics

Although germline copy-number variants (CNVs) are the genetic cause of multiple hereditary diseases, detecting them from targeted next-generation sequencing data (NGS) remains a challenge. Existing tools perform well for large CNVs but struggle with single and multi-exon alterations. The aim of this work is to evaluate CNV calling tools working on gene panel NGS data and their suitability as a screening step before orthogonal confirmation in genetic diagnostics strategies. Five tools (DECoN, CoNVaDING, panelcn.MOPS, ExomeDepth, and CODEX2) were tested against four genetic diagnostics datasets (two in-house and two external) for a total of 495 samples with 231 single and multi-exon validated CNVs. The evaluation was performed using the default and sensitivity-optimized parameters. Results showed that most tools were highly sensitive and specific, but the performance was dataset dependant. When evaluating them in our diagnostics scenario, DECoN and panelcn.MOPS detected all CNVs with the exception of one mosaic CNV missed by DECoN. However, DECoN outperformed panelcn.MOPS specificity achieving values greater than 0.90 when using the optimized parameters. In our in-house datasets, DECoN and panelcn.MOPS showed the highest performance for CNV screening before orthogonal confirmation. Benchmarking and optimization code is freely available at https://github.com/TranslationalBioinformaticsIGTP/CNVbenchmarkeR

Percepción del comportamiento alimentario en los hogares de Cali para el primer trimestre de la cuarentena por COVID 19 en 2020

Introducción: en 2020, la Organización Mundial de la Salud (OMS) declaró la emergencia de salud pública por SARS-CoV-21; el 11 de marzo de 2020 se notificó la pandemia global por COVID-19 y el gobierno colombiano decretó para todas las ciudades el aislamiento preventivo obligatorio2. Para el mes de mayo, Cali reportó 1635 casos de COVID confirmados y 85 fallecidos por un virus con un 4,95% de letalidad3. Lo anterior influenció de forma importante las rutinas alimentarias de las familias durante el primer trimestre del periodo de confinamiento. Considerando que esta situación era atípica en el país, era necesario describir la percepción del comportamiento alimentario durante este primer trimestre de aislamiento preventivo obligatorio en la ciudad de Cali, considerandolas normas de bioseguridad establecidas para el periodo mencionado. Objetivo: describir el comportamiento alimentario de 1814 familias en Cali durante el primer trimestre de aislamiento preventivo obligatorio. Metodología: estudio cuantitativo, descriptivo transversal, con técnica de encuesta. Se aplicó un instrumento virtual compuesto por 28 ítems, que indagó el comportamiento alimentario de las familias. Discusión: se encontró que el 95,1% de los hogares percibió escasez y aumento de precios en alimentos que componen la canasta alimentaria familiar, y el 67,2% de las familias estuvieron preocupadas por la alimentación. Hubo un aumento en el consumo de alimentos y se modificó el número de tiempos de comida/día. Los hábitos alimentarios, ingesta de refrescos y consumo de alcohol también se modificaron durante confinamiento. Conclusiones: se puede afirmar que durante el primer trimestre de cuarentena por COVID-19 en Cali se modificó el comportamiento alimentario de las familias encuestadas, una de las razones estuvo relacionada con un cambio en los ingresos económicos, que afectó la cantidad de dinero disponible para alimentos. Durante este periodo se modificaron también los tiempos de comida y la variedad en la ingesta de alimentos. En general, se describieron aspectos que afectaron la seguridad alimentaria de las familias.Introducción: en 2020, la Organización Mundial de la Salud (OMS) declaró la emergencia de salud pública por SARS-CoV-21; el 11 de marzo de 2020 se notificó la pandemia global por COVID-19 y el gobierno colombiano decretó para todas las ciudades el aislamiento preventivo obligatorio2. Para el mes de mayo, Cali reportó 1635 casos de COVID confirmados y 85 fallecidos por un virus con un 4,95% de letalidad3. Lo anterior influenció de forma importante las rutinas alimentarias de las familias durante el primer trimestre del periodo de confinamiento. Considerando que esta situación era atípica en el país, era necesario describir la percepción del comportamiento alimentario durante este primer trimestre de aislamiento preventivo obligatorio en la ciudad de Cali, considerando las normas de bioseguridad establecidas para el periodo mencionado. Objetivo: describir el comportamiento alimentario de 1814 familias en Cali durante el primer trimestre de aislamiento preventivo obligatorio. Metodología: estudio cuantitativo, descriptivo transversal, con técnica de encuesta. Se aplicó un instrumento virtual compuesto por 28 ítems, que indagó el comportamiento alimentario de las familias. Discusión: se encontró que el 95,1% de los hogares percibió escasez y aumento de precios en alimentos que componen la canasta alimentaria familiar, y el 67,2% de las familias estuvieron preocupadas por la alimentación. Hubo un aumento en el consumo de alimentos y se modificó el número de tiempos de comida/día. Los hábitos alimentarios, ingesta de refrescos y consumo de alcohol también se modificaron durante confinamiento. Conclusiones: se puede afirmar que durante el primer trimestre de cuarentena por COVID-19 en Cali se modificó el comportamiento alimentario de las familias encuestadas, una de las razones estuvo relacionada con un cambio en los ingresos económicos, que afectó la cantidad de dinero disponible para alimentos. Durante este periodo se modificaron también los tiempos de comida y la variedad en la ingesta de alimentos. En general, se describieron aspectos que afectaron la seguridad alimentaria de las familias.Introduction: In 2020, the World Health Organization (WHO) declared a public health emergency due to SARSCoV-21. On March 11, 2020, the global pandemic due to COVID-19 was declared, with which the Colombiangovernment decreed mandatory preventive isolation in the country2. In May, Cali reported 1,635 confirmed COVIDcases and 85 deaths from a virus with a 4.95 % case fatality rate3. This situation affected families eating routines during this period. Considering that this situation was atypical in the country, it was necessary to describe the perception of feeding behavior during this first trimester of mandatory preventive isolation in the city of Cali, considering the biosafety standards established by the national government. Objetive: To describe the feeding behavior of 1,814 families in Cali during the first trimester of mandatory preventive isolation. Methodology: Cross-sectional, descriptive and quantitative study. A virtual instrument composed of 28 items was applied, which investigated the feeding behavior of the families. Convenience sampling. Results: The results show that the economic income of families, as well as the distribution of expenses within the home, were affected in the evaluated period. In addition, it was found that 95.1 % of households perceived shortages and price increases in foods that make up the family food basket; 67.2% of families were concerned about food. There was an increase in food consumption and the number of perhaps consider, meals per day was modified. Eating habits, soft drink intake and alcohol consumption also changed during confinement in the evaluated time. Conclusions: It can be affirmed families modified their feeding behaviors during the first quarter of quarantine due to COVID-19. Because the economic income of families was affected, the money available for food purchases was affected as well. During this time, perhaps consider: meal frequencies and, in general, the variety in food intake was also modified. Finally, the results suggest perhaps consider: a negative effect in the food security of families