Genotypic and phenotypic characterisation of a nosocomial outbreak of Candida auris in Spain during 5 years.

OBJECTIVES: The investigation of Candida auris outbreaks is needed to provide insights into its population structure and transmission dynamics. We genotypically and phenotypically characterised a C. auris nosocomial outbreak occurred in Consorcio Hospital General Universitario de Valencia (CHGUV), Spain. METHODS: Data and isolates were collected from CHGUV from September 2017 (first case) until September 2021. Thirty-five isolates, including one from an environmental source, were randomly selected for whole genome sequencing (WGS), and the genomes were analysed along with a database with 335 publicly available genomes, assigning them to one of the five major clades. In order to identify polymorphisms associated with drug resistance, we used the fully susceptible GCA_003014415.1 strain as reference sequence. Known mutations in genes ERG11 and FKS1 conferring resistance to fluconazole and echinocandins, respectively, were investigated. Isolates were classified into aggregating or non-aggregating. RESULTS: All isolates belonged to clade III and were from an outbreak with a single origin. They clustered close to three publicly available genomes from a hospital from where the first patient was transferred, being the probable origin. The mutation VF125AL in the ERG11 gene, conferring resistance to fluconazole, was present in all the isolates and one isolate also carried the mutation S639Y in the FKS1 gene. All the isolates had a non-aggregating phenotype (potentially more virulent). CONCLUSIONS: Isolates are genotypically related and phenotypically identical but one with resistance to echinocandins, which seems to indicate that they all belong to an outbreak originated from a single isolate, remaining largely invariable over the years. This result stresses the importance of implementing infection control practices as soon as the first case is detected or when a patient is transferred from a setting with known cases.

LINE-1 RNA triggers matrix formation in bone cells via a PKR-mediated inflammatory response.

Transposable elements (TEs) are mobile genetic modules of viral derivation that have been co-opted to become modulators of mammalian gene expression. TEs are a major source of endogenous dsRNAs, signaling molecules able to coordinate inflammatory responses in various physiological processes. Here, we provide evidence for a positive involvement of TEs in inflammation-driven bone repair and mineralization. In newly fractured mice bone, we observed an early transient upregulation of repeats occurring concurrently with the initiation of the inflammatory stage. In human bone biopsies, analysis revealed a significant correlation between repeats expression, mechanical stress and bone mineral density. We investigated a potential link between LINE-1 (L1) expression and bone mineralization by delivering a synthetic L1 RNA to osteoporotic patient-derived mesenchymal stem cells and observed a dsRNA-triggered protein kinase (PKR)-mediated stress response that led to strongly increased mineralization. This response was associated with a strong and transient inflammation, accompanied by a global translation attenuation induced by eIF2α phosphorylation. We demonstrated that L1 transfection reshaped the secretory profile of osteoblasts, triggering a paracrine activity that stimulated the mineralization of recipient cells.

Identification of Transcripts with Shared Roles in the Pathogenesis of Postmenopausal Osteoporosis and Cardiovascular Disease.

Epidemiological evidence suggests existing comorbidity between postmenopausal osteoporosis (OP) and cardiovascular disease (CVD), but identification of possible shared genes is lacking. The skeletal global transcriptomes were analyzed in trans-iliac bone biopsies (n = 84) from clinically well-characterized postmenopausal women (50 to 86 years) without clinical CVD using microchips and RNA sequencing. One thousand transcripts highly correlated with areal bone mineral density (aBMD) were further analyzed using bioinformatics, and common genes overlapping with CVD and associated biological mechanisms, pathways and functions were identified. Fifty genes (45 mRNAs, 5 miRNAs) were discovered with established roles in oxidative stress, inflammatory response, endothelial function, fibrosis, dyslipidemia and osteoblastogenesis/calcification. These pleiotropic genes with possible CVD comorbidity functions were also present in transcriptomes of microvascular endothelial cells and cardiomyocytes and were differentially expressed between healthy and osteoporotic women with fragility fractures. The results were supported by a genetic pleiotropy-informed conditional False Discovery Rate approach identifying any overlap in single nucleotide polymorphisms (SNPs) within several genes encoding aBMD- and CVD-associated transcripts. The study provides transcriptional and genomic evidence for genes of importance for both BMD regulation and CVD risk in a large collection of postmenopausal bone biopsies. Most of the transcripts identified in the CVD risk categories have no previously recognized roles in OP pathogenesis and provide novel avenues for exploring the mechanistic basis for the biological association between CVD and OP.

Systematic review of cognitive and behavioral strategies used in effective harm reduction interventions for people who use cocaine.

OBJECTIVE: The aim of this systematic review is to identify cognitive and behavioral strategies that have been used in effective harm reduction interventions for people who use cocaine. METHOD: Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed, and the search was performed on February 26, 2023 across databases including PsycInfo, PubMed, Scopus, and Web of Science. Studies were included if they (1) report the use of one cognitive or behavioral strategy, (2) have harm reduction as the objective, (3) involve participants who used cocaine as at least one of their substances, (4) be published within the last 10 years, and (5) have a randomized controlled trial design. The Cochrane RoB 2.0 Tool was used to assess risk of bias. The cognitive and behavioral strategies were extracted and organized based on their frequency of use in the studies and their corresponding outcomes. RESULTS: The final synthesis included k = 10 studies with N = 3,567 participants. Psychoeducation strategies, influence on social norms, personalized feedback, increased self-efficacy and motivational interviewing were the most frequently used promising strategies across studies. CONCLUSIONS: This review underscores the significance of incorporating cognitive and behavioral strategies within harm reduction interventions, as they represent a promising domain that could enhance the effectiveness of addressing cocaine use.

A perspective on muscle phenotyping in musculoskeletal research.

Musculoskeletal research should synergistically investigate bone and muscle to inform approaches for maintaining mobility and to avoid bone fractures. The relationship between sarcopenia and osteoporosis, integrated in the term 'osteosarcopenia', is underscored by the close association shown between these two conditions in many studies, whereby one entity emerges as a predictor of the other. In a recent workshop of Working Group (WG) 2 of the EU Cooperation in Science and Technology (COST) Action 'Genomics of MusculoSkeletal traits Translational Network' (GEMSTONE) consortium (CA18139), muscle characterization was highlighted as being important, but currently under-recognized in the musculoskeletal field. Here, we summarize the opinions of the Consortium and research questions around translational and clinical musculoskeletal research, discussing muscle phenotyping in human experimental research and in two animal models: zebrafish and mouse.

Association between BMD and coronary artery calcification: an observational and Mendelian randomization study.

Observational studies have reported inconsistent associations between bone mineral density (BMD) and coronary artery calcification (CAC). We examined the observational association of BMD with CAC in 2 large population-based studies and evaluated the evidence for a potential causal relation between BMD and CAC using polygenic risk scores (PRS), 1- and 2-sample Mendelian randomization (MR) approaches. Our study populations comprised 1414 individuals (mean age 69.9 yr, 52.0% women) from the Rotterdam Study and 2233 individuals (mean age 56.5 yr, 50.9% women) from the Framingham Heart Study with complete information on CAC and BMD measurements at the total body (TB-), lumbar spine (LS-), and femoral neck (FN-). We used linear regression models to evaluate the observational association between BMD and CAC. Subsequently, we compared the mean CAC across PRSBMD quintile groups at different skeletal sites. In addition, we used the 2-stage least squares regression and the inverse variance weighted (IVW) model as primary methods for 1- and 2-sample MR to test evidence for a potentially causal association. We did not observe robust associations between measured BMD levels and CAC. These results were consistent with a uniform random distribution of mean CAC across PRSBMD quintile groups (P-value > .05). Moreover, neither 1- nor 2-sample MR supported the possible causal association between BMD and CAC. Our results do not support the contention that lower BMD is (causally) associated with an increased CAC risk. These findings suggest that previously reported epidemiological associations of BMD with CAC are likely explained by unmeasured confounders or shared etiology, rather than by causal pathways underlying both osteoporosis and vascular calcification processes.

Decreased bone mineral density, the determinant of osteoporosis, and increased coronary artery calcification are common in people at an advanced age and share some common risk factors. Some studies have reported a higher risk for coronary artery calcification in people with osteoporosis than in people without, whereas others failed to find evidence for this relationship. Recently, Mendelian randomization has emerged as an important epidemiological tool that offers a simple way to distinguish causation, minimizing the confounding present in observational studies, leveraging individual genetic data and the findings from robust genome-wide association studies. We combined data from the participants of both the Rotterdam Study and the Framingham Heart Study, and did not observe sufficient evidence for the association between bone mineral density at different skeletal sites and coronary artery calcification. Also, when using Mendelian randomization, we concluded there was no causal relation between bone deterioration and the build-up of calcium in the coronary arteries. Although more research is needed, we conclude that the associations between decreased bone mineral density and increased coronary artery calcification reported in previous studies are likely attributed to other confounders rather than a causal relationship between these traits.

Oral microbiota of adolescents with dental caries: A systematic review.

OBJECTIVE: This systematic review summarizes the current knowledge on the association between the oral microbiota and dental caries in adolescents. DESIGN: An electronic search was carried out across five databases. Studies were included if they conducted research on generally healthy adolescents, applied molecular-based microbiological analyses and assessed caries status. Data extraction was performed by two reviewers and the Newcastle-Ottawa Scale was applied for quality assessment. RESULTS: In total, 3935 records were reviewed which resulted in a selection of 20 cross-sectional studies (published 2005-2022) with a sample size ranging from 11 to 614 participants including adolescents between 11 and 19 years. The studies analyzed saliva, dental biofilm or tongue swabs with Checkerboard DNA-DNA hybridization, (q)PCR or Next-Generation Sequencing methods. Prevotella denticola, Scardoviae Wiggsiae, Streptococcus sobrinus and Streptococcus mutans were the most frequently reported species presenting higher abundance in adolescents with caries. The majority of the studies reported that the microbial diversity was similar between participants with and without dental caries. CONCLUSION: This systematic review is the first that shows how the oral microbiota composition in adolescents appears to differ between those with and without dental caries, suggesting certain taxa may be associated with increased caries risk. However, there is a need to replicate and expand these findings in larger, longitudinal studies that also focus on caries severity and take adolescent-specific factors into account.

Bone health index in the assessment of bone health: The Generation R Study.

Bone Health Index (BHI) has been proposed as a useful instrument for assessing bone health in children. However, its relationship with fracture risk remains unknown. We aimed to investigate whether BHI is associated with bone mineral density (BMD) and prevalent fracture odds in children from the Generation R Study. We also implemented genome-wide association study (GWAS) and polygenic score (PGS) approaches to improve our understanding of BHI and its potential. In total, 4150 children (49.4 % boys; aged 9.8 years) with genotyped data and bone assessments were included in this study. BMD was measured across the total body (less head following ISCD guidelines) using a GE-Lunar iDXA densitometer; and BHI was determined from the hand DXA scans using BoneXpert®. Fractures were self-reported collected with home questionnaires. The association of BHI with BMD and fractures was evaluated using linear models corrected for age, sex, ethnicity, height, and weight. We observed a positive correlation between BHI and BMD (ρ = 0.32, p-value<0.0001). Further, every SD decrease in BHI was associated with an 11 % increased risk of prevalent fractures (OR:1.11, 95 % CI 1.00-1.24, p-value = 0.05). Our BHI GWAS identified variants (lead SNP rs1404264-A, p-value = 2.61 × 10-14) mapping to the ING3/CPED1/WNT16 locus. Children in the extreme tails of the BMD PGS presented a difference in BHI values of -0.10 standard deviations (95% CI -0.14 to -0.07; p-value<0.0001). On top of the demonstrated epidemiological association of BHI with both BMD and fracture risk, our results reveal a partially shared biological background between BHI and BMD. These findings highlight the potential value of using BHI to screen children at risk of fracture.

Glaucoma Patients Have a Lower Abundance of Butyrate-Producing Taxa in the Gut.

Purpose: Glaucoma is an eye disease that is the most common cause of irreversible blindness worldwide. It has been suggested that gut microbiota can produce reactive oxygen species and pro-inflammatory cytokines that may travel from the gastric mucosa to distal sites, for example, the optic nerve head or trabecular meshwork. There is evidence for a gut-eye axis, as microbial dysbiosis has been associated with retinal diseases. We investigated the microbial composition in patients with glaucoma and healthy controls. Moreover, we analyzed the association of the gut microbiome with intraocular pressure (IOP; risk factor of glaucoma) and vertical cup-to-disc ratio (VCDR; quantifying glaucoma severity). Methods: The discovery analyses included participants of the Rotterdam Study and the Erasmus Glaucoma Cohort. A total of 225 patients with glaucoma and 1247 age- and sex-matched participants without glaucoma were included in our analyses. Stool samples were used to generate 16S rRNA gene profiles. We assessed associations with 233 genera and species. We used data from the TwinsUK and the Study of Health in Pomerania (SHIP) to replicate our findings. Results: Several butyrate-producing taxa (e.g. Butyrivibrio, Caproiciproducens, Clostridium sensu stricto 1, Coprococcus 1, Ruminococcaceae UCG 007, and Shuttleworthia) were less abundant in people with glaucoma compared to healthy controls. The same taxa were also associated with lower IOP and smaller VCDR. The replication analyses confirmed the findings from the discovery analyses. Conclusions: Large human studies exploring the link between the gut microbiome and glaucoma are lacking. Our results suggest that microbial dysbiosis plays a role in the pathophysiology of glaucoma.

Early-life stress and the gut microbiome: A comprehensive population-based investigation.

Early-life stress (ELS) has been robustly associated with a range of poor mental and physical health outcomes. Recent studies implicate the gut microbiome in stress-related mental, cardio-metabolic and immune health problems, but research on humans is scarce and thus far often based on small, selected samples, often using retrospective reports of ELS. We examined associations between ELS and the human gut microbiome in a large, population-based study of children. ELS was measured prospectively from birth to 10 years of age in 2,004 children from the Generation R Study. We studied overall ELS, as well as unique effects of five different ELS domains, including life events, contextual risk, parental risk, interpersonal risk, and direct victimization. Stool microbiome was assessed using 16S rRNA sequencing at age 10 years and data were analyzed at multiple levels (i.e. α- and ß-diversity indices, individual genera and predicted functional pathways). In addition, we explored potential mediators of ELS-microbiome associations, including diet at age 8 and body mass index at 10 years. While no associations were observed between overall ELS (composite score of five domains) and the microbiome after multiple testing correction, contextual risk - a specific ELS domain related to socio-economic stress, including risk factors such as financial difficulties and low maternal education - was significantly associated with microbiome variability. This ELS domain was associated with lower α-diversity, with ß-diversity, and with predicted functional pathways involved, amongst others, in tryptophan biosynthesis. These associations were in part mediated by overall diet quality, a pro-inflammatory diet, fiber intake, and body mass index (BMI). These results suggest that stress related to socio-economic adversity - but not overall early life stress - is associated with a less diverse microbiome in the general population, and that this association may in part be explained by poorer diet and higher BMI. Future research is needed to test causality and to establish whether modifiable factors such as diet could be used to mitigate the negative effects of socio-economic adversity on the microbiome and related health consequences.

Defining type 2 diabetes polygenic risk scores through colocalization and network-based clustering of metabolic trait genetic associations.

BACKGROUND: Type 2 diabetes (T2D) is a heterogeneous and polygenic disease. Previous studies have leveraged the highly polygenic and pleiotropic nature of T2D variants to partition the heterogeneity of T2D, in order to stratify patient risk and gain mechanistic insight. We expanded on these approaches by performing colocalization across GWAS traits while assessing the causality and directionality of genetic associations. METHODS: We applied colocalization between T2D and 20 related metabolic traits, across 243 loci, to obtain inferences of shared casual variants. Network-based unsupervised hierarchical clustering was performed on variant-trait associations. Partitioned polygenic risk scores (PRSs) were generated for each cluster using T2D summary statistics and validated in 21,742 individuals with T2D from 3 cohorts. Inferences of directionality and causality were obtained by applying Mendelian randomization Steiger's Z-test and further validated in a pediatric cohort without diabetes (aged 9-12 years old, n = 3866). RESULTS: We identified 146 T2D loci that colocalized with at least one metabolic trait locus. T2D variants within these loci were grouped into 5 clusters. The clusters corresponded to the following pathways: obesity, lipodystrophic insulin resistance, liver and lipid metabolism, hepatic glucose metabolism, and beta-cell dysfunction. We observed heterogeneity in associations between PRSs and metabolic measures across clusters. For instance, the lipodystrophic insulin resistance (Beta - 0.08 SD, 95% CI [- 0.10-0.07], p = 6.50 × 10-32) and beta-cell dysfunction (Beta - 0.10 SD, 95% CI [- 0.12, - 0.08], p = 1.46 × 10-47) PRSs were associated to lower BMI. Mendelian randomization Steiger analysis indicated that increased T2D risk in these pathways was causally associated to lower BMI. However, the obesity PRS was conversely associated with increased BMI (Beta 0.08 SD, 95% CI 0.06-0.10, p = 8.0 × 10-33). Analyses within a pediatric cohort supported this finding. Additionally, the lipodystrophic insulin resistance PRS was associated with a higher odds of chronic kidney disease (OR 1.29, 95% CI 1.02-1.62, p = 0.03). CONCLUSIONS: We successfully partitioned T2D genetic variants into phenotypic pathways using a colocalization first approach. Partitioned PRSs were associated to unique metabolic and clinical outcomes indicating successful partitioning of disease heterogeneity. Our work expands on previous approaches by providing stronger inferences of shared causal variants, causality, and directionality of GWAS variant-trait associations.

Effect of aging on the human myometrium at single-cell resolution.

Age-associated myometrial dysfunction can prompt complications during pregnancy and labor, which is one of the factors contributing to the 7.8-fold increase in maternal mortality in women over 40. Using single-cell/single-nucleus RNA sequencing and spatial transcriptomics, we have constructed a cellular atlas of the aging myometrium from 186,120 cells across twenty perimenopausal and postmenopausal women. We identify 23 myometrial cell subpopulations, including contractile and venous capillary cells as well as immune-modulated fibroblasts. Myometrial aging leads to fewer contractile capillary cells, a reduced level of ion channel expression in smooth muscle cells, and impaired gene expression in endothelial, smooth muscle, fibroblast, perivascular, and immune cells. We observe altered myometrial cell-to-cell communication as an aging hallmark, which associated with the loss of 25 signaling pathways, including those related to angiogenesis, tissue repair, contractility, immunity, and nervous system regulation. These insights may contribute to a better understanding of the complications faced by older individuals during pregnancy and labor.

Hydrogen sulfide ameliorates hypertension and vascular dysfunction induced by insulin resistance in rats by reducing oxidative stress and activating eNOS.

Hydrogen sulfide (H2S) is a gasotransmitter implied in metabolic diseases, insulin resistance, obesity, and type 2 Diabetes Mellitus. This study aimed to determine the effect of chronic administration of sodium hydrosulfide (NaHS; inorganic H2S donor), L-Cysteine (L-Cys; substrate of H2S producing enzymes) and DL-Propargylglycine (DL-PAG; cystathionine-gamma-lyase inhibitor) on the vascular dysfunction induced by insulin resistance in rat thoracic aorta. For this purpose, 72 animals were divided into two main sets that received: 1) tap water (control group; n = 12); and 2) fructose 15% w/v in drinking water [insulin resistance group (IR); n = 60] for 20 weeks. After 16 weeks, the group 2 was divided into five subgroups (n = 12 each), which received daily i. p. injections during 4 weeks of: 1) non-treatment (control); 2) vehicle (phosphate buffer saline; PBS, 1 ml/kg); 3) NaHS (5.6 mg/kg); 4) L-Cys (300 mg/kg); and (5) DL-PAG (10 mg/kg). Hemodynamic variables, metabolic variables, vascular function, ROS levels and the expression of p-eNOS and eNOS were determined. IR induced: 1) hyperinsulinemia; 2) increased HOMA-index; 3) decreased Matsuda index; 4) hypertension, vascular dysfunction, increased ROS levels; 5) increased iNOS, and 6) decreased CSE, p-eNOS and eNOS expression. Furthermore, IR did not affect contractile responses to norepinephrine. Interestingly, NaHS and L-Cys treatment, reversed IR-induced impairments and DL-PAG treatment decreased and increased the HOMA and Matsuda index, respectively. Taken together, these results suggest that NaHS and L-Cys decrease the metabolic and vascular alterations induced by insulin resistance by reducing oxidative stress and activating eNOS. Thus, hydrogen sulfide may have a therapeutic application.

European and multi-ancestry genome-wide association meta-analysis of atopic dermatitis highlights importance of systemic immune regulation.

Atopic dermatitis (AD) is a common inflammatory skin condition and prior genome-wide association studies (GWAS) have identified 71 associated loci. In the current study we conducted the largest AD GWAS to date (discovery N = 1,086,394, replication N = 3,604,027), combining previously reported cohorts with additional available data. We identified 81 loci (29 novel) in the European-only analysis (which all replicated in a separate European analysis) and 10 additional loci in the multi-ancestry analysis (3 novel). Eight variants from the multi-ancestry analysis replicated in at least one of the populations tested (European, Latino or African), while two may be specific to individuals of Japanese ancestry. AD loci showed enrichment for DNAse I hypersensitivity and eQTL associations in blood. At each locus we prioritised candidate genes by integrating multi-omic data. The implicated genes are predominantly in immune pathways of relevance to atopic inflammation and some offer drug repurposing opportunities.

La dieta como fuente de sulfuro de hidrógeno y sus efectos en la salud y la enfermedad / Diet as a source of hydrogen sulfide and its effects on health and disease

Conocido originalmente por sus efectos deletéreos en la salud, recientemente se ha reconocido al sulfuro de hidrógeno (H2S) como un gasotransmisor de importancia biológica, al igual que el óxido nítrico y el monóxido de carbono. El H2S puede producirse de forma endógena en lascélulas de mamíferos por dos vías: la vía enzimática y la vía no enzimática. Cuando se produce por la vía enzimática, su síntesis se lleva a cabo apartir de los aminoácidos L-cisteína o metionina mediante transulfuración y transmetilación. También se puede producir el H2S a partir donadores de grupos sulfuro como, por ejemplo, compuestos orgánicos que se encuentran presentes en algunos vegetales. Actualmente es bien conocido el papel del H2S como protector a nivel cerebral y cardiaco, y cada vez adquiere mayor relevancia su estudio como coadyuvante terapéutico en padecimientos metabólicos como la obesidad y la diabetes mellitus de tipo 2. El objetivo de esta revisión es examinar cómo impacta el aporte de donadores y precursores del sulfuro de hidrógeno por la dieta en la salud y la enfermedad. (AU)

Initially known for its deleterious health effects, hydrogen sulfide (H2S) has recently been recognized as a biologically important gas carrier, likenitric oxide and carbon monoxide. H2S is produced endogenously in mammalian cells by enzymatic and non-enzymatic pathways. When it isproduced by the enzymatic pathway, its synthesis is carried out from the amino acid L-cysteine through the transsulfuration pathway. It can alsobe produced endogenously from exogenous compounds that function as H2S donors as, for example, the naturally occurring organic donors foundin some plants. Currently, the role of H2S is well known as brain and cardiac protector, and its research as a therapeutic adjuvant in metabolicdiseases such as obesity and type-2 diabetes is becoming increasingly important. The objective of this review is to examine how the contributionof donors and precursors of hydrogen sulfide by the diet impacts health and disease. (AU)

Bi-Directional Interactions between Glucose-Lowering Medications and Gut Microbiome in Patients with Type 2 Diabetes Mellitus: A Systematic Review.

Background: Although common drugs for treating type 2 diabetes (T2D) are widely used, their therapeutic effects vary greatly. The interaction between the gut microbiome and glucose-lowering drugs is one of the main contributors to the variability in T2D progression and response to therapy. On the one hand, glucose-lowering drugs can alter gut microbiome components. On the other hand, specific gut microbiota can influence glycemic control as the therapeutic effects of these drugs. Therefore, this systematic review assesses the bi-directional relationships between common glucose-lowering drugs and gut microbiome profiles. Methods: A systematic search of Embase, Web of Science, PubMed, and Google Scholar databases was performed. Observational studies and randomised controlled trials (RCTs), published from inception to July 2023, comprising T2D patients and investigating bi-directional interactions between glucose-lowering drugs and gut microbiome, were included. Results: Summarised findings indicated that glucose-lowering drugs could increase metabolic-healthy promoting taxa (e.g., Bifidobacterium) and decrease harmful taxa (e.g., Bacteroides and Intestinibacter). Our findings also showed a significantly different abundance of gut microbiome taxa (e.g., Enterococcus faecium (i.e., E. faecium)) in T2D patients with poor compared to optimal glycemic control. Conclusions: This review provides evidence for glucose-lowering drug and gut microbiome interactions, highlighting the potential of gut microbiome modulators as co-adjuvants for T2D treatment.

Deep Brain Stimulation of the Globus Pallidus Internus and Externus in Multiple System Atrophy.

BACKGROUND: Multiple system atrophy with parkinsonism (MSA-P) is a progressive condition with no effective treatment. OBJECTIVE: The aim of this study was to describe the safety and efficacy of deep brain stimulation (DBS) of globus pallidus pars interna and externa in a cohort of patients with MSA-P. METHODS: Six patients were included. Changes in Movement Disorders Society Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS III), Parkinson's Disease Questionnaire (PDQ-39) scores, and levodopa equivalent daily dose were compared before and after DBS. Electrode localization and volume tissue activation were calculated. RESULTS: DBS surgery did not result in any major adverse events or intraoperative complications. Overall, no differences in MDS-UPDRS III scores were demonstrated (55.2 ± 17.6 preoperatively compared with 67.3 ± 19.2 at 1 year after surgery), although transient improvement in mobility and dyskinesia was reported in some subjects. CONCLUSIONS: Globus pallidus pars interna and externa DBS for patients with MSA-P did not result in major complications, although it did not provide significant clinical benefit as measured by MDS-UPDRS III. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

From private incentives to public health need: rethinking research and development for pandemic preparedness.

Pandemic preparedness and response have relied primarily on market dynamics to drive development and availability of new health products. Building on calls for transformation, we propose a new value proposition that instead prioritises equity from the research and development (R&D) stage and that strengthens capacity to control outbreaks when and where they occur. Key elements include regional R&D hubs free to adapt well established technology platforms, and independent clinical trials networks working with researchers, regulators, and health authorities to better study questions of comparative benefit and real-world efficacy. Realising these changes requires a shift in emphasis: from pandemic response to outbreak control, from one-size-fits-all economies of scale to R&D and manufacture for local need, from de novo product development to last-mile innovation through adaptation of existing technologies, and from proprietary, competitive R&D to open science and financing for the common good that supports collective management and sharing of technology and know-how.

[Diet as a source of hydrogen sulfide and its effects on health and disease]. / La dieta como fuente de sulfuro de hidrógeno y sus efectos en la salud y la enfermedad.

Introduction: Initially known for its deleterious health effects, hydrogen sulfide (H2S) has recently been recognized as a biologically important gas carrier, like nitric oxide and carbon monoxide. H2S is produced endogenously in mammalian cells by enzymatic and non-enzymatic pathways. When it is produced by the enzymatic pathway, its synthesis is carried out from the amino acid L-cysteine through the transsulfuration pathway. It can also be produced endogenously from exogenous compounds that function as H2S donors as, for example, the naturally occurring organic donors found in some plants. Currently, the role of S2H is well known as brain and cardiac protector, and its research as a therapeutic adjuvant in metabolic diseases such as obesity and type-2 diabetes is becoming increasingly important. The objective of this review is to examine how the contribution of donors and precursors of hydrogen sulfide by the diet impacts health and disease.

Introducción: Conocido originalmente por sus efectos deletéreos en la salud, recientemente se ha reconocido al sulfuro de hidrógeno (H2S) como un gasotransmisor de importancia biológica, al igual que el óxido nítrico y el monóxido de carbono. El H2S puede producirse de forma endógena en las células de mamíferos por dos vías: la vía enzimática y la vía no enzimática. Cuando se produce por la vía enzimática, su síntesis se lleva a cabo a partir de los aminoácidos L-cisteína o metionina mediante transulfuración y transmetilación. También se puede producir el H2S a partir donadores de grupos sulfuro como, por ejemplo, compuestos orgánicos que se encuentran presentes en algunos vegetales. Actualmente es bien conocido el papel del H2S como protector a nivel cerebral y cardiaco, y cada vez adquiere mayor relevancia su estudio como coadyuvante terapéutico en padecimientos metabólicos como la obesidad y la diabetes mellitus de tipo 2. El objetivo de esta revisión es examinar cómo impacta el aporte de donadores y precursores del sulfuro de hidrogeno por la dieta en la salud y la enfermedad.