Connecting genomic and proteomic signatures of amyloid burden in the brain.

Background: Alzheimer's disease (AD) has a high heritable component characteristic of complex diseases, yet many of the genetic risk factors remain unknown. We combined genome-wide association studies (GWAS) on amyloid endophenotypes measured in cerebrospinal fluid (CSF) and positron emission tomography (PET) as surrogates of amyloid pathology, which may be helpful to understand the underlying biology of the disease. Methods: We performed a meta-analysis of GWAS of CSF Aß42 and PET measures combining six independent cohorts (n=2,076). Due to the opposite effect direction of Aß phenotypes in CSF and PET measures, only genetic signals in the opposite direction were considered for analysis (n=376,599). Polygenic risk scores (PRS) were calculated and evaluated for AD status and amyloid endophenotypes. We then searched the CSF proteome signature of brain amyloidosis using SOMAscan proteomic data (Ace cohort, n=1,008) and connected it with GWAS results of loci modulating amyloidosis. Finally, we compared our results with a large meta-analysis using publicly available datasets in CSF (n=13,409) and PET (n=13,116). This combined approach enabled the identification of overlapping genes and proteins associated with amyloid burden and the assessment of their biological significance using enrichment analyses. Results: After filtering the meta-GWAS, we observed genome-wide significance in the rs429358-APOE locus and nine suggestive hits were annotated. We replicated the APOE loci using the large CSF-PET meta-GWAS and identified multiple AD-associated genes as well as the novel GADL1 locus. Additionally, we found a significant association between the AD PRS and amyloid levels, whereas no significant association was found between any Aß PRS with AD risk. CSF SOMAscan analysis identified 1,387 FDR-significant proteins associated with CSF Aß42 levels. The overlap among GWAS loci and proteins associated with amyloid burden was very poor (n=35). The enrichment analysis of overlapping hits strongly suggested several signalling pathways connecting amyloidosis with the anchored component of the plasma membrane, synapse physiology and mental disorders that were replicated in the large CSF-PET meta-analysis. Conclusions: The strategy of combining CSF and PET amyloid endophenotypes GWAS with CSF proteome analyses might be effective for identifying signals associated with the AD pathological process and elucidate causative molecular mechanisms behind the amyloid mobilization in AD.

An artificial intelligence-assisted system versus white light endoscopy alone for adenoma detection in individuals with Lynch syndrome (TIMELY): an international, multicentre, randomised controlled trial.

BACKGROUND: Computer-aided detection (CADe) systems for colonoscopy have been shown to increase small polyp detection during colonoscopy in the general population. People with Lynch syndrome represent an ideal target population for CADe-assisted colonoscopy because adenomas, the primary cancer precursor lesions, are characterised by their small size and higher likelihood of showing advanced histology. We aimed to evaluate the performance of CADe-assisted colonoscopy in detecting adenomas in individuals with Lynch syndrome. METHODS: TIMELY was an international, multicentre, parallel, randomised controlled trial done in 11 academic centres and six community centres in Belgium, Germany, Italy, and Spain. We enrolled individuals aged 18 years or older with pathogenic or likely pathogenic MLH1, MSH2, MSH6, or EPCAM variants. Participants were consecutively randomly assigned (1:1) to either CADe (GI Genius) assisted white light endoscopy (WLE) or WLE alone. A centre-stratified randomisation sequence was generated through a computer-generated system with a separate randomisation list for each centre according to block-permuted randomisation (block size 26 patients per centre). Allocation was automatically provided by the online AEG-REDCap database. Participants were masked to the random assignment but endoscopists were not. The primary outcome was the mean number of adenomas per colonoscopy, calculated by dividing the total number of adenomas detected by the total number of colonoscopies and assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT04909671. FINDINGS: Between Sept 13, 2021, and April 6, 2023, 456 participants were screened for eligibility, 430 of whom were randomly assigned to receive CADe-assisted colonoscopy (n=214) or WLE (n=216). 256 (60%) participants were female and 174 (40%) were male. In the intention-to-treat analysis, the mean number of adenomas per colonoscopy was 0·64 (SD 1·57) in the CADe group and 0·64 (1·17) in the WLE group (adjusted rate ratio 1·03 [95% CI 0·72-1·47); p=0·87). No adverse events were reported during the trial. INTERPRETATION: In this multicentre international trial, CADe did not improve the detection of adenomas in individuals with Lynch syndrome. High-quality procedures and thorough inspection and exposure of the colonic mucosa remain the cornerstone in surveillance of Lynch syndrome. FUNDING: Spanish Gastroenterology Association, Spanish Society of Digestive Endoscopy, European Society of Gastrointestinal Endoscopy, Societat Catalana de Digestologia, Instituto Carlos III, Beca de la Marato de TV3 2020. Co-funded by the European Union.

Huntingtin CAG repeats in neuropathologically confirmed tauopathies: Novel insights.

Previous studies have suggested a relationship between the number of CAG triplet repeats in the HTT gene and neurodegenerative diseases not related to Huntington's disease (HD). This study seeks to investigate whether the number of CAG repeats of HTT is associated with the risk of developing certain tauopathies and its influence as a modulator of the clinical and neuropathological phenotype. Additionally, it aims to evaluate the potential of polyglutamine staining as a neuropathological screening. We genotyped the HTT gene CAG repeat number and APOE-ℰ isoforms in a cohort of patients with neuropathological diagnoses of tauopathies (n=588), including 34 corticobasal degeneration (CBD), 98 progressive supranuclear palsy (PSP) and 456 Alzheimer's disease (AD). Furthermore, we genotyped a control group of 1070 patients, of whom 44 were neuropathologic controls. We identified significant differences in the number of patients with pathological HTT expansions in the CBD group (2.7%) and PSP group (3.2%) compared to control subjects (0.2%). A significant increase in the size of the HTT CAG repeats was found in the AD compared to the control group, influenced by the presence of the Apoliprotein E (APOE)-ℰ4 isoform. Post-mortem assessments uncovered tauopathy pathology with positive polyglutamine aggregates, with a slight predominance in the neostriatum for PSP and CBD cases and somewhat greater limbic involvement in the AD case. Our results indicated a link between HTT CAG repeat expansion with other non-HD pathology, suggesting they could share common neurodegenerative pathways. These findings support that genetic or histological screening for HTT repeat expansions should be considered in tauopathies.

Establishing an online resource to facilitate global collaboration and inclusion of underrepresented populations: Experience from the MJFF Global Genetic Parkinson's Disease Project.

Parkinson's disease (PD) is the fastest-growing neurodegenerative disorder, currently affecting ~7 million people worldwide. PD is clinically and genetically heterogeneous, with at least 10% of all cases explained by a monogenic cause or strong genetic risk factor. However, the vast majority of our present data on monogenic PD is based on the investigation of patients of European White ancestry, leaving a large knowledge gap on monogenic PD in underrepresented populations. Gene-targeted therapies are being developed at a fast pace and have started entering clinical trials. In light of these developments, building a global network of centers working on monogenic PD, fostering collaborative research, and establishing a clinical trial-ready cohort is imperative. Based on a systematic review of the English literature on monogenic PD and a successful team science approach, we have built up a network of 59 sites worldwide and have collected information on the availability of data, biomaterials, and facilities. To enable access to this resource and to foster collaboration across centers, as well as between academia and industry, we have developed an interactive map and online tool allowing for a quick overview of available resources, along with an option to filter for specific items of interest. This initiative is currently being merged with the Global Parkinson's Genetics Program (GP2), which will attract additional centers with a focus on underrepresented sites. This growing resource and tool will facilitate collaborative research and impact the development and testing of new therapies for monogenic and potentially for idiopathic PD patients.

Úlceras de pie diabético infectadas con bacterias multirresistentes a los antimicrobianos en pacientes venezolanos / Diabetic Foot Ulcers Infected with Bacteria Multiresistant to Antimicrobials in Venezuelan patients

Introducción: Las úlceras de pie diabético tienen una importante morbimortalidad, más aun, si están asociadas a bacterias multirresistentes a los antimicrobianos. Objetivo: Analizar las características de las úlceras de pie diabético infectadas con bacterias multirresistentes a los antimicrobianos. Métodos: Se realizó una investigación descriptiva, no experimental y transversal, en 87 pacientes con úlceras de pie diabético infectadas, atendidos en una consulta especializada del estado Zulia, Venezuela. Se realizó la anamnesis y exploración física, especialmente centrada en las características de las úlceras de pie diabético. Se obtuvieron muestras de tejido ulceroso para identificar las bacterias presentes y el antimicrobiano correspondiente. Resultados: Todos los pacientes tenían úlcera previa, con agudización de la infección (75,86 por ciento), rehospitalización (59,77 por ciento), amputación previa (36,78 por ciento), úlceras de pie diabético infectadas de larga duración (86,21 por ciento). El 95,40 por ciento recibieron antibióticos previos y 57,62 por ciento habían sido hospitalizados, la antigüedad de la enfermedad fue 16,17 ± 8,41 años y la HbA1c 8,87 ± 1,23. Las úlceras de pie diabético infectadas más frecuente fue neuroisquémica (71,26 por ciento). Predominó la flora monomicrobiana con un (62,07 por ciento) y bacterias gramnegativas (87,36 por ciento). El 79,3 por ciento presentaron bacterias multirresistentes a los antimicrobianos y el 20,69 por ciento panresistencia. Las bacterias multirresistentes fueron predominantemente gramnegativas, y para las grampositivas solo estuvo el Staphylococcus aureus. Conclusiones: Se presenció una alta frecuencia de úlceras de pie diabético infectadas con multirresistencia, predominantemente monomicrobianas y todas con resistencia a betalactámicos y fluoroquinolonas(AU)

Introduction: Diabetic foot ulcers have significant morbidity and mortality, even more so if they are associated with multi-resistant bacteria to antimicrobials. Objective: To analyze the characteristics of diabetic foot ulcers infected with bacteria multi-resistant to antimicrobials. Methods: A descriptive, non-experimental and cross-sectional investigation was carried out in 87 patients with infected diabetic foot ulcers. They were treated in a specialized clinic in Zulia state, Venezuela. Anamnesis and physical examination were performed, especially focused on the characteristics of diabetic foot ulcers. Ulcer tissue samples were obtained to identify the bacteria existing and the corresponding antimicrobial. Results: All the patients had previous ulcer, with exacerbation of the infection (75.86percent), rehospitalization (59.77percent), previous amputation (36.78percent), long-lasting infected diabetic foot ulcers (86.21percent). 95.40percent received previous antibiotics and 57.62percent had been hospitalized, the disease age was 16.17 ± 8.41 years and Hb A1c was 8.87 ± 1.23. The most frequent infected diabetic foot ulcers were neuroischemic (71.26percent). The monomicrobial flora (62.07percent) and gram-negative bacteria (87.36percent) predominated. 79.3percent had multi-resistant bacteria to antimicrobials and 20.69percent pan-resistance. Multi-resistant bacteria were predominantly gram-negative and for gram-positive only staphylococcus aureus. Conclusions: High frequency of multidrug-resistant infected diabetic foot ulcers was found, predominantly monomicrobial and all with resistance to beta-lactams and fluoroquinolones(AU)

Age-dependent effect of the IFIH1/MDA5 gene variants on the risk of critical COVID-19.

MDA5, encoded by the IFIH1gene, is a cytoplasmic sensor of viral RNAs that triggers interferon (IFN) antiviral responses. Common and rare IFIH1 variants have been associated with the risk of type 1 diabetes and other immune-mediated disorders, and with the outcome of viral diseases. Variants associated with reduced IFN expression would increase the risk for severe viral disease. The MDA5/IFN pathway would play a critical role in the response to SARS-CoV-2 infection mediating the extent and severity of COVID-19. Here, we genotyped a cohort of 477 patients with critical ICU COVID-19 (109 death) for three IFIH1 functional variants: rs1990760 (p.Ala946Thr), rs35337543 (splicing variant, intron 8 + 1G > C), and rs35744605 (p.Glu627Stop). The main finding of our study was a significant increased frequency of rs1990760 C-carriers in early-onset patients (< 65 years) (p = 0.01; OR = 1.64, 95%CI = 1.18-2.43). This variant was also increased in critical vs. no-ICU patients and in critical vs. asymptomatic controls. The rs35744605 C variant was associated with increased blood IL6 levels at ICU admission. The rare rs35337543 splicing variant showed a trend toward protection from early-onset critical COVID-19. In conclusion, IFIH1 variants associated with reduced gene expression and lower IFN response might contribute to develop critical COVID-19 with an age-dependent effect.

IL-1 ß gene (+3954 C/T, exon 5, rs1143634) and NOS2 (exon 22) polymorphisms associate with early aseptic loosening of arthroplasties.

Aseptic prosthetic loosening (APL) and prosthetic joint infections (PJI) are frequent complications of hip and knee implants. Polymorphisms of cytokines and nitric oxide (NO), key inflammatory molecules in APL and PJI pathogenesis, could explain individual susceptibility to these complications. Three cytokines (IL-1-a, IL-1-ß, TNF-α) and two nitric oxide synthase (NOS2, NOS3) genes polymorphisms were genotyped in 77 APL and 117 PJI patients and 145 controls with aseptic hip or knee implants that were implanted for > 16 years. Plasma cytokines and nitrate-nitrite (NOx) levels also were measured. The TT genotype and T allele of (+3954 C/T, exon 5, rs1143634) IL-1ß polymorphism were more frequent in APL patients compared to controls (P = 0.03 and P = 0.02, respectively). No genotypic associations in PJI patients were observed. Plasma IL-6, TNF-α and NOx were significantly different between APL and controls (P < 0.0001). Plasma IL-1ß and IL-6 were significantly higher in APL T allele carriers vs. non-carriers (P < 0.03). Knee implant (HR 2.488, 95% CI 1.307-4.739, P = 0.005), male gender (HR 2.252, 95% CI 1.121-4.525, P = 0.023), carriages of the TT genotype of the (+3954 C/T) IL-1ß polymorphism (HR 3.704, 95% CI 1.274-10.753, P = 0.016) and AA genotype of the (exon 22) NOS2 polymorphism (HR 3.509, 95% CI 1.266-9.709, P = 0.016) were independently associated with a shorter implant survival by Cox regression. No genotypic associations in PJI patients were observed. Genotyping of IL-1ß (+3954 C/T, exon 5, rs1143634) and NOS2 (exon 22) polymorphisms could be useful as predictors of early hip or knee APL.

Smoking is associated with age at disease onset in Parkinson's disease.

BACKGROUND: Previous studies linked disease-progression variables such as age at onset or survival to both genetic, and non-genetic factors in Parkinson's disease (PD) patients. OBJECTIVE: The aim of this study was to assess how genetic and non genetic factors act as modifiers of age at onset and survival and in a cohort of 753 PD patients, and to determine how these variables interact to define the overall risk. METHODS: We analyzed the effect of gender, tobacco, alcohol, type of PD (genetic, gPD or idiopathic, iPD) and three genetic variants rs5848- GRN, rs1042522- TP53 and APOE. We studied two cohorts (PPMI and IPDGC) to replicate positive results. RESULTS: Regarding age at onset, male smokers PD had a significantly lower mean age compared to non-smoker (p = 0.001). APOE-Ɛ4 carriers had a younger onset-age compared to non-carriers (p = 0.03) in the Spanish cohort, but these results were not replicated in the other cohorts. Concerning survival, PD patients with an early onset (below 50 years) had an increased survival rate (p < 0.001). CONCLUSIONS: Our study showed how several genetic and non-genetic risk factors influenced the age at onset and survival in PD.

New insights into the genetic etiology of Alzheimer's disease and related dementias.

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.

A Refined Minimally Invasive Distal First Metatarsal Osteotomy for Moderate Hallux Valgus Treatment: The BC Procedure.

During the last 2 decades, there was an increasing interest in mini-invasive procedures for hallux valgus correction. In this scenario the Bösch technique appears to be a reproducible distal metatarsal osteotomy (DMO) to achieve a proper correction. Our DMO variant, called BC, was planned to combine the stability and predictability of the chevron osteotomy, with the power of correction, low surgical time and mini-invasive approach of the Bösch-SERI technique. The purpose of this investigation is to describe the surgical technique and report the results of this modified procedure at a minimum 2-year follow-up. Sixty-three patients who underwent the BC technique for mild and moderate hallux valgus were prospectively evaluated. Mean follow-up was 36.5 (range 23.4-59.8) months, the mean American Orthopedic Foot and Ankle Society score improved from a median of 47.4 points preoperatively to a median of 88 points postoperatively (p < .05). First MTPJ ROM did not change from preoperative period (mean 32.5°) to the postoperative period (mean 31.8°) (p > .65). All osteotomies went on to bony healing in the 6-week follow-up visit. Fifty-two (82%) of patients were either very satisfied or satisfied with the procedure (p < .05). With our numbers, BC osteotomy is shown to be a technique that can treat both mild and moderate deformities, achieving correction that is maintained over the follow-up evaluated, with a 24 relatively simple procedure and short operative time.

The "diagnose and leave in" strategy for diminutive rectosigmoid polyps in Lynch syndrome: a post hoc analysis from a randomized controlled trial.

BACKGROUND: The "diagnose-and-leave-in" policy has been established to reduce the risks and costs related to unnecessary polypectomies in the average-risk population. In individuals with Lynch syndrome, owing to accelerated carcinogenesis, the general recommendation is to remove all polyps, irrespective of size, location, and appearance. We evaluated the feasibility and safety of the diagnose-and-leave-in strategy in individuals with Lynch syndrome. METHODS : We performed a post hoc analysis based on per-polyp data from a randomized, clinical trial conducted by 24 dedicated colonoscopists at 14 academic centers, in which 256 patients with confirmed Lynch syndrome underwent surveillance colonoscopy from July 2016 to January 2018. In vivo optical diagnosis with confidence level for all detected lesions was obtained before polypectomy using virtual chromoendoscopy alone or with dye-based chromoendoscopy. Primary outcome was the negative predictive value (NPV) for neoplasia of high-confidence optical diagnosis among diminutive (≤ 5 mm) rectosigmoid lesions. Histology was the reference standard. RESULTS: Of 147 rectosigmoid lesions, 128 were diminutive. In 103 of the 128 lesions (81 %), the optical diagnostic confidence was high and showed an NPV of 96.0 % (95 % confidence interval [CI] 88.9 %-98.6 %) and accuracy of 89.3 % (95 %CI 81.9 %-93.9 %). By following the diagnose-and-leave-in policy, we would have avoided 59 % (75/128) of polypectomies at the expense of two diminutive low grade dysplastic adenomas and one diminutive sessile serrated lesion that would have been left in situ. CONCLUSION: In patients with Lynch syndrome, the diagnose-and-leave-in strategy for diminutive rectosigmoid polyps would be feasible and safe.

Cancer in Parkinson's Disease: An Approximation to the Main Risk Factors.

BACKGROUND: Many evidences suggest a pathological link between neurodegenerative diseases and cancer. In fact, several epidemiologic studies indicate a decreased incidence of most cancer types in Parkinson's disease (PD) patients and some PD genes are involved in cancer networks. OBJECTIVE: The aim of this study is to assess the influence of several factors in the risk of cancer in a cohort of 753 PD patients and to study how these variables interact with each other. METHODS: We analyzed the effect of gender, tobacco, alcohol, type of PD (genetic or idiopathic PD), and two genetic variants, previously associated with cancer, rs5848-GRN and rs1042522-TP53. RESULTS: A higher age at PD onset was observed in patients who develop cancer before PD (p < 0.001). Alcohol consumption was a risk factor to develop cancer in PD patients (p = 0.011), while smoking was not a cancer risk factor in our cohort (p = 0.098). Among the genetic factors, the genotype TT GRN-rs5848 was statistically more frequent in PD patients without cancer (p = 0.05). CONCLUSIONS: Our study identified several factors, genetic and nongenetic, which contribute to the risk for cancer in PD.

The TNF-α (-238 G/A) polymorphism could protect against development of severe sepsis.

Primary responses in sepsis-mediated inflammation are regulated by pro-inflammatory cytokines. Variations in the cytokine genes might modify their transcription or expression, plasma cytokines levels and response to sepsis. Activation protein-1 (AP-1) and NF-κB regulate cytokines gene expression in sepsis. A total of 90 severely septic and 91 non-infected patients were prospectively studied. IL-1α (-889 C/T), IL-1ß (+3954 C/T), IL-6 (-174 G/C), TNF-α (-238 G/A), TNF-α (-308G/A), IL-8 (-251A/T) and IL-10 (-1082 G/A) SNPs, plasma IL-1ß, IL-4, IL-6, IL-8, IL-10, IL-13, IFN-γ, TNF-α and monocyte chemoattractant protein 1 (MCP-1) levels, and AP-1 and NF-κB gene expression by neutrophils were assessed. A allele carriers of TNF-α (-238 G/A) SNP were less frequent among septic patients. IL-6, IL-8, IL-10, TNF-α and MCP-1 levels were higher, and AP-1 and NF-κB gene expressions lower in septic patients. Sepsis was independently associated with higher fibrinogen, neutrophils counts and IL-8 levels, lower prothrombin, absence of the variant A allele of the TNF-α (-238 G/A) SNP, and haemodynamic failure. Death was independently associated with a higher APACHE II score, higher IL-8 levels, and the diagnosis of sepsis. TNF-a (-238 G/A) SNP could protect against sepsis development. Higher IL-8 levels are predictive of sepsis and mortality.

Infecciones asociadas a la atención sanitaria en el Instituto Nacional de Angiología y Cirugía Vascular / Infections associated with health care at the National Institute of Angiology and Vascular Surgery

Introducción: Las infecciones asociadas a la asistencia sanitaria constituyen un problema de salud. Objetivo: Caracterizar las infecciones asociadas a la asistencia sanitaria en los tres servicios del Instituto Nacional de Angiología y Cirugía Vascular durante 2019. Métodos: Estudio longitudinal de epidemiología clínica en 89 pacientes ingresados en 2019, a los que se les diagnosticó una infección asociada a la asistencia sanitaria. Las variables de estudio fueron: edad, sexo, meses del año, servicio asistencial, enfermedades asociadas, gérmenes más frecuentes y principales localizaciones. Se calcularon las frecuencias absolutas y relativas. Resultados: Se encontró una tasa porcentual acumulada de 6,6 por cada 100 egresos, con predominio del sexo masculino y mayor frecuencia en los pacientes de la quinta década de vida. La herida quirúrgica contribuyó con 43 casos de los 89 reportados, seguida por la bronconeumonía bacteriana con 18. La principal enfermedad asociada fue la diabetes mellitus y los gérmenes más frecuentes aislados resultaron Stafilococus aureus, Pseudomona sp y Acinetobacter bawmani. Conclusiones: La tasa de incidencia de infecciones asociadas a la asistencia sanitaria en el Instituto Nacional de Angiología y Cirugía Vascular durante 2019 no difiere de las presentadas en años anteriores y se corresponden con los reportes internacionales(AU)

Introduction: Health care associated infections are a health problem. Objective: Characterize healthcare associated infections in the three services of the National Institute of Angiology and Vascular Surgery during 2019. Methods: Longitudinal study of clinical epidemiology in 89 patients admitted in 2019, who were diagnosed with an infection associated with health care. The study variables were: age, sex, months of the year, care service, associated diseases, more frequent germs and main locations. Absolute and relative frequencies were calculated. Results: A cumulative percentage rate of 6.6 per 100 discharges was found, with male predominance and higher frequency in patients in the fifth decade of life. The surgical wound was present in 43 of the 89 cases reported, followed by bacterial bronchopneumonie with 18. The main associated disease was diabetes mellitus and the most common isolated germs were Stafilococus aureus, Pseudomonasp and Acinetobacter baumannii. Conclusions: The incidence rate of healthcare associated infections at the National Institute of Angiology and Vascular Surgery during 2019 does not differ from those presented in previous years and corresponds to international reports(AU)

Genetic variation in APOE, GRN, and TP53 are phenotype modifiers in frontotemporal dementia.

Frontotemporal dementia (FTD) is a clinical, genetic, and pathologic heterogeneous group of neurodegenerative diseases. In this study, we investigated the role of APOƐ4, rs5848 in GRN, and rs1042522 in TP53 gene as disease risk factors and/or phenotype modifiers in 440 FTD patients, including 175 C9orf72 expansion carriers. We found that the C9orf72 expansion carriers showing an earlier age at onset (p < 0.001). Among the clinical groups, the FTD-MND (motoneuron disease) showed the lowest survival (hazard ratio [HR] = 4.12), and the progressive nonfluent aphasia group showed the highest onset age (p = 0.03). In our cohort, the rs1042522 in TP53 was associated with disease onset (p = 0.02) and survival (HR = 1.73) and rs5848 GRN with a significantly shorter survival in CC homozygous patients (HR = 1.98). The frequency of APOƐ4 carriers was significantly increased in the C9orf72 noncarriers (p = 0.022). Although validation of our findings is necessary, our results suggest that TP53, GRN, and APOE genes may act as phenotype modifiers in FTD and should be considered in future clinical trials.

Factores asociados con dolor severo en pacientes con fascitis plantar: Un análisis de relaciones / Factors associated with severe pain in patients with plantar fasciitis: An association analysis

Objetivo: Describir los factores asociados con niveles de dolor mas severo en una cohorte de pacientes con fascitis plantar. El objetivo secundario fue analizar cuales de estos factores estaban asociados con niveles mas altos de mejoria clinica luego del tratamiento conservador. Materiales y Métodos: Se evaluo a una cohorte prospectiva de pacientes con diagnostico de fascitis plantar. Cada participante completo una escala ordinal visual de dolor (del 1 al 10) para dolor del primer paso y dolor al final del dia y encuestas FFI-R (Foot Function Index-Revised). Tambien se realizo una evaluacion demografica. La dorsiflexion de la articulacion del tobillo, el rango de movilidad de la primera articulacion metatarsofalangica, la rigidez del gastrocnemio y el angulo popliteo tambien se evaluaron de manera estandar. Resultados: Se incluyo a 214 pacientes. El 64% eran hombres (118 pacientes), la media de la edad era de 49.67 anos (DE 13.16) y el indice de masa corporal promedio, de 28,53 (DE 5,18). En el analisis multivariado, se observo que el riesgo de un puntaje ≥8 en la escala de dolor aumento cuando el paciente refirio estar de pie por mas de 6 h (OR 1,17; p = 0,03; IC95% 1,02-1,35). El riesgo de un puntaje >8 fue mayor cuando el grado de dorsiflexion del tobillo fue <0° (OR 1,20; p = 0,03; IC95% 1,02-1,41). Conclusión: Nuestros hallazgos apoyan indirectamente la hipotesis de que la dorsiflexion limitada del tobillo juega un papel como factor de riesgo asociado a un puntaje ≥8 en la escala de dolor, en los casos de fascitis plantar. Nivel de Evidencia: IV

Objective: The main purpose of our study was to describe the factors associated with more severe pain levels in a cohort of patients with plantar fasciitis (PF). The secondary purpose of this study was to determine which of these factors were associated with higher levels of clinical improvement after conservative therapy. Materials and Methods: We conducted a prospective study in a cohort of patients with PF. Each participant completed an ordinal pain scale (1-10) for first-step pain and end-of-day pain, and Foot Function Index-Revised (FFI-R) surveys at enrollment. Also, patient demographics were evaluated. The ankle joint dorsiflexion, the range of motion (ROM) for the first metatarsophalangeal joint (MTPJ), the gastrocnemius tightness, and the popliteal angle were evaluated through standard tests. Results: Our study included 214 participants, of which 64% (118 patients) were males, the average age was 49.67 years (SD 13.16) and the average BMI was 28.53 (SD 5.18). The multivariate analysis showed that the risk of having a Visual Analog Scale (VAS) score ≥8 increased when the patient reported standing for more than 6 hours (OR=1.17; P=0.03; CI95%: 1.02-1.359). The risk of a >8-VAS score was higher when the level of ankle dorsiflexion was <0 (OR=1.20; P=0.03; CI95%: 1.02-1.41). Conclusion: Our findings indirectly support the hypothesis that limited ankle dorsiflexion ROM plays a role as a risk factor associated with VAS scores ≥8 in PF patients. Level of Evidence: IV

White-Light Endoscopy Is Adequate for Lynch Syndrome Surveillance in a Randomized and Noninferiority Study.

BACKGROUND & AIMS: Dye-based pancolonic chromoendoscopy is recommended for colorectal cancer surveillance in patients with Lynch syndrome. However, there is scarce evidence to support its superiority to high-definition white-light endoscopy. We performed a prospective study assess whether in the hands of high detecting colonoscopists, high-definition, white-light endoscopy is noninferior to pancolonic chromoendoscopy for detection of adenomas in patients with Lynch syndrome. METHODS: We conducted a parallel controlled study, from July 2016 through January 2018 at 14 centers in Spain of adults with pathogenic germline variants in mismatch repair genes (60% women; mean age, 47 ± 14 years) under surveillance. Patients were randomly assigned to groups that underwent high-definition white-light endoscopy (n = 128) or pancolonic chromoendoscopy (n = 128) evaluations by 24 colonoscopists who specialized in detection of colorectal lesions in high-risk patients for colorectal cancer. Adenoma detection rates (defined as the proportion of patients with at least 1 adenoma) were compared between groups, with a noninferiority margin (relative difference) of 15%. RESULTS: We found an important overlap of confidence intervals (CIs) and no significant difference in adenoma detection rates by pancolonic chromoendoscopy (34.4%; 95% CI 26.4%-43.3%) vs white-light endoscopy (28.1%; 95% CI 21.1%-36.4%; P = .28). However, pancolonic chromoendoscopy detected serrated lesions in a significantly higher proportion of patients (37.5%; 95% CI 29.5-46.1) than white-light endoscopy (23.4%; 95% CI 16.9-31.4; P = .01). However, there were no significant differences between groups in proportions of patients found to have serrated lesions of 5 mm or larger (9.4% vs 7.0%; P = .49), of proximal location (11.7% vs 10.2%; P = .68), or sessile serrated lesions (3.9% vs 5.5%; P = .55), respectively. Total procedure and withdrawal times with pancolonic chromoendoscopy (30.7 ± 12.8 minutes and 18.3 ± 7.6 minutes, respectively) were significantly longer than with white-light endoscopy (22.4 ± 8.7 minutes and 13.5 ± 5.6 minutes; P < .001). CONCLUSIONS: In a randomized parallel trial, we found that for Lynch syndrome surveillance, high-definition white-light endoscopy is not inferior to pancolonic chromoendoscopy if performed by experienced and dedicated endoscopists. ClinicalTrials.gov no: NCT02951390.

Prevalencia de prediabetes y diabetes mellitus en la región de Zulia, Venezuela: resultados preliminares del estudio EVESCAM / Prevalence of prediabetes and diabetes mellitus in the Zulia region, Venezuela: preliminary results of the EVESCAM study

Determinar la prevalencia de prediabetes y de Diabetes Mellitus (DM) en el estado Zulia, Venezuela. Métodos: se realizó un estudio poblacional, aleatorio, descriptivo utilizando los datos del Estudio Venezolano de la Salud Cardiometabólica (EVESCAM) de la región zuliana incluyendo 525 sujetos adultos de ambos géneros. Se aplicó una encuesta sobre factores de riesgo, antecedentes de DM, se registró peso, talla, índice de masa corporal (IMC) kg/m2, circunferencia de cintura en cm (CC) y presión arterial. Se les tomó muestra de sangre para determinación de glucemia, perfil lipídico y prueba de tolerancia a la glucosa (PTG). Los resultados presentados en tablas y figuras utilizando promedios y desviación estándar, procesados con programa estadístico SSPS, la prevalencia fue calculada y ajustada por edad y sexo, fijando un valor alfa menor de 0,05 (P<0,05) como significativo. Resultados: En total 404 sujetos completaron la evaluación: 126 (31,1%) hombres y 278 (68,8 %) mujeres, con edad promedio de 49,6 ± 15,8 años, Glucemia basal: 108,5 ± 28,9 y PTG a las 2 horas 120,6 ± 37,2 mg/dl. La prevalencia de diabetes ajustada por edad y sexo resultó de 16,0%; 19,9% en hombres y 12,1% en mujeres (P = 0,029) y para Prediabetes 58,5%; 65,8% en hombres y 51,3% en mujeres (P= 0,005). Conclusiones: La población zuliana presentó elevada prevalencia de prediabetes y diabetes mellitus. Urge la necesidad de intervención a través de programas de prevención que detengan su avance(AU)

To determine the prevalence of prediabetes and Diabetes Mellitus (DM) in the State of Zulia, Venezuela. Methods: A clinical, randomized, descriptive study was conducted using data from the Venezuelan Cardio-Metabolic Health Study (EVESCAM) of the Zulian region, including 525 adults of both genders. A risk factors questionnaire, history of DM, weight, height, body mass index (BMI) kg/m2, waist circumference in cm (CC), and blood pressure were measured. Blood samples were taken to determine of Glycaemia, lipid profile, and glucose tolerance test (GTT). Results were presented in tables and figures using averages and standard deviation, analyzed with the software SSPS statistical program, prevalence was calculated and adjusted by age and sex, alpha value lower than 0.05 (P <0.05) was considered significant. Results: A total of 404 subjects completed the evaluation: 126 (31.1%) men and 278 (68.8%) women, with a mean age of 49.6 ± 15.8 years; baseline glycaemia were 108.5 ± 28,9 and GTT 120.6 ± 37.2 mg/dl. The age-standardized diabetes prevalence was 16.0%; 19.9% in men and 12.1% in women (P = 0.029); and the age-standarized prevalence of prediabetes was 58.5%; 65.8 in men and 51.3 in women (P =0.005). Conclusions: Zulia´s population presented a high prevalence of prediabetes and diabetes mellitus. To implement an intervention program to halt it´s progress is of urgent need(AU)

Tenodesis del biceps: comparación de técnica supra-pectoral artroscópica versus sub-pectoral abierta / Biceps tenodesis. Arthroscopic supra-pectoral versus mini-open sub-pectoral technique

Introducción: La biotenodesis es la técnica preferida para el manejo de la patología del tendón de la porción larga del bíceps en personas jóvenes, deportistas, trabajadores, y aquellos que desean evitar alguna deformidad estética. El objetivo de nuestro trabajo es evaluar los resultados clínico funcionales, la satisfacción personal del paciente, y las posibles complicaciones de dos técnicas diferentes de tenodesis: Supra-pectoral Artroscopica y Sub-pectoral Abierta Materiales y Métodos: De enero de 2009 a enero de 2012 evaluamos en forma retrospectiva 81 pacientes con patología del tendón largo del biceps tratados con dos técnicas de tenodesis diferentes. Grupo A: 61 pacientes con técnica de biotenodesis artroscópica suprapectoral y Grupo B: 20 pacientes con técnica mini abierta subpectoral utilizando tornillo interferencial. Utilizamos los escores de ASES, Rowe, Simple Shoulder Test, Constant Murley y VAS, y el grado de satisfacción personal en cuanto a estética y dolor local en la cicatriz se evaluo mediante entrevistas personales y telefónicas. El tiempo promedio de seguimiento fue de 12 meses. Resultados: Grupo A: Rowe de 86 puntos, ASES de 81 puntos, el SST de 9 puntos, y Constant Murley de 87 puntos. VAS: escaso dolor post quirúrgico (2/10). El grado de satisfacción fue muy bueno. Grupo B: Rowe de 85 puntos, ASES de 82 puntos, el SST de 8,5 puntos, y el Constant Murley de 85 puntos. VAS: 3/10, mayor en el sitio del abordaje subpectoral. Molestias estéticas sobre la cicatriz en 4 casos, todos estos de sexo femenino. Conclusión: Una tenodesis íntegramente artroscópica es técnicamente mas desafiante y requiere inicialmente una curva de aprendizaje de mayor duración para realizar con éxito este procedimiento. La tenodesis subpectoral es un procedimiento más rápido, sencillo pero su elección estaría únicamente ligada a una cuestión de ahorro de tiempo quirúrgico...

Introduction: The biotenodesis is the preferred technique for handling the pathology of the long head of the biceps tendon in younger people, athletes, workers, and those wishing to avoid any cosmetic deformity. The aim of our study was to evaluate the functional clinical outcomes, patient satisfaction, staff, and possible complications of two different tenodesis techniques: Supra pectoral pectoral Sub Arthroscopic and Open. Materials and methods: From January 2009 to January 2012 retrospectively evaluated 81 patients with pathology of the long biceps tendon treated with two different tenodesis techniques. Group A: 61 patients with arthroscopic technique suprapectoral biotenodesis and Group B: 20 patients with mini open technique using subpectoral interference screw. We used the scores of ASES , Rowe, Simple Shoulder Test , Constant Murley and VAS , and the degree of personal satisfaction in terms of aesthetics and local pain at the scar was assessed through personal and telephone interviews. The average follow-up time was 12 months. Results: Group A: 86 points Rowe, ASES 81 points, 9 points SST , Constant and Murley 87 puntos.VAS : poor postsurgical pain (2/10). The degree of satisfaction was very good...

Relación entre laxitud articular e inestabilidad glenohumeral. Un meta-análisis de la literatura / Relationship between articular laxity and shoulder instability. A meta-analysis

El objetivo de esta revisión sistemática fue establecer si existe alguna relación entre la inestabilidad glenohumeral y cualquier forma de laxitud articular. Se realizó un algoritmo de búsqueda de acuerdo a las guías de PRISMA en las bases de datos de PubMed, OVID, Sport Discus, Scopus y Web of Science usando las palabras clave “(Ligament Laxity OR ligamentous Laxity OR generalized joint laxity) AND (shoulder dislocation OR shoulder subluxation OR shoulder luxation OR Shoulder instability) hasta Diciembre de 2013. Se incluyeron los artículos en lengua inglesa que describan algún tipo de relación objetiva, entre inestabilidad glenohumeral y laxitud articular focal o generalizada. Fueron excluidos estudios en cadáveres, o in vitro, o que contengan pacientes con enfermedades del tejido conectivo, reportes de casos, reportes biomecánicos, revisiones, cartas de editores y notas técnicas. La búsqueda arrojó un total de 603 artículos de los cuales 15 cumplían los criterios de inclusión. Según la evidencia encontrada la laxitud articular podría influir en la inestabilidad glenohumeral, pero debido a la gran diversidad de formas en que ambas se relacionan y las diferentes maneras de diagnosticarlas es imposible obtener un análisis estadístico que provea información confiable. Los cirujanos ortopedistas debemos unificar criterios en relación a la definición y a los test para evaluar laxitud articular e inestabilidad glenohumeral y, así de esta manera, poder obtener información más confiable y objetiva. Nivel de Evidencia: IV. Tipo de Estudio: Revisión Sistemática...

The aim of this meta-analisis was to establish whether there is a relationship between any kind of articular laxity and shoulder instability. The search algorithm according to the PRISMA guidelines of PubMed, OVID, Sport Discus, Scopus and Web of Science databases using the keywords “(Ligament laxity OR ligamentous laxity OR generalized joint laxity) AND (shoulder dislocation OR shoulder subluxation OR shoulder luxation OR shoulder instability) until December of 2013 was done. Inclusion Criteria: articles in English showing relationship between any types of glenohumeral instability with focal or generalized joint laxity. Studies on cadavers, or in vitro, involving patients with connective tissue diseases, case reports, biomechanical reports, revisions, letters to editors and technical notes were excluded. Fifteen articles of 603 reference of the search were included. Joint laxity may influence shoulder instability. We found diversity not only in how to relate joint laxity and glenohumeral instability buy also different ways of diagnosing. This makes it difficult to obtain statistical analysis that can provide reliable data. Additional efforts aiming to provide consensus are required to clarify this subject. Orthopedics surgeons must unify criteria regarding lax shoulder as well as glenohumeral instability and thus can get more objective and reliable data. Level of Evidence: IV. Study design: Systematic Review...