Amivantamab plus Lazertinib in Previously Untreated EGFR-Mutated Advanced NSCLC.

BACKGROUND: Amivantamab plus lazertinib (amivantamab-lazertinib) has shown clinically meaningful and durable antitumor activity in patients with previously untreated or osimertinib-pretreated EGFR (epidermal growth factor receptor)-mutated advanced non-small-cell lung cancer (NSCLC). METHODS: In a phase 3, international, randomized trial, we assigned, in a 2:2:1 ratio, patients with previously untreated EGFR-mutated (exon 19 deletion or L858R), locally advanced or metastatic NSCLC to receive amivantamab-lazertinib (in an open-label fashion), osimertinib (in a blinded fashion), or lazertinib (in a blinded fashion, to assess the contribution of treatment components). The primary end point was progression-free survival in the amivantamab-lazertinib group as compared with the osimertinib group, as assessed by blinded independent central review. RESULTS: Overall, 1074 patients underwent randomization (429 to amivantamab-lazertinib, 429 to osimertinib, and 216 to lazertinib). The median progression-free survival was significantly longer in the amivantamab-lazertinib group than in the osimertinib group (23.7 vs. 16.6 months; hazard ratio for disease progression or death, 0.70; 95% confidence interval [CI], 0.58 to 0.85; P<0.001). An objective response was observed in 86% of the patients (95% CI, 83 to 89) in the amivantamab-lazertinib group and in 85% of those (95% CI, 81 to 88) in the osimertinib group; among patients with a confirmed response (336 in the amivantamab-lazertinib group and 314 in the osimertinib group), the median response duration was 25.8 months (95% CI, 20.1 to could not be estimated) and 16.8 months (95% CI, 14.8 to 18.5), respectively. In a planned interim overall survival analysis of amivantamab-lazertinib as compared with osimertinib, the hazard ratio for death was 0.80 (95% CI, 0.61 to 1.05). Predominant adverse events were EGFR-related toxic effects. The incidence of discontinuation of all agents due to treatment-related adverse events was 10% with amivantamab-lazertinib and 3% with osimertinib. CONCLUSIONS: Amivantamab-lazertinib showed superior efficacy to osimertinib as first-line treatment in EGFR-mutated advanced NSCLC. (Funded by Janssen Research and Development; MARIPOSA ClinicalTrials.gov number, NCT04487080.).

The 2023 top 10 list of endoscopy topics in medical publishing: an annual review by the American Society for Gastrointestinal Endoscopy Editorial Board.

Using a systematic literature search of original articles published during 2023 in Gastrointestinal Endoscopy (GIE) and other high-impact medical and gastroenterology journals, the GIE Editorial Board of the American Society for Gastrointestinal Endoscopy compiled a list of the top 10 most significant topic areas in general and advanced GI endoscopy during the year. Each GIE Editorial Board member was directed to consider 3 criteria in generating candidate topics-significance, novelty, and impact on global clinical practice-and subject matter consensus was facilitated by the Chair through electronic voting and a meeting of the entire GIE Editorial Board. The 10 identified areas collectively represent advances in the following endoscopic spheres: GI bleeding, endohepatology, endoscopic palliation, artificial intelligence and polyp detection, artificial intelligence beyond the colon, better polypectomy and endoscopic mucosal resection, how to make endoscopy units greener, high quality upper endoscopy, endoscopic tissue apposition/closure devices, and endoscopic submucosal dissection. Each board member was assigned a topic area around which summarized relevant important articles, thereby generating this overview of the "top 10" endoscopic advances of 2023.

Community-Driven Conversations: Partnership Building through CHEC-Ins.

BACKGROUND: Chicago's systemically underserved communities have disproportionately high cancer rates. The Chicago Cancer Health Equity Collaborative (ChicagoCHEC) brings together academic and community partners to address these health inequities. The community conversations known as "CHEC-Ins" provide a space for community members to voice their experiences and needs and for ChicagoCHEC to fulfill its commitment to advancing health equity through collaboration and action. OBJECTIVE: This paper presents a community-generated approach to social networking about cancer health issues known as CHEC-Ins. Through this innovative approach, community members and organizations share cancer related information and experiences, as well as needs and concerns, which are then channeled to ChicagoCHEC academic and administrative members who incorporate them into outreach and research activities. In this way, community members set the agenda and the process and collect the information they deem relevant and important. This paper describes the process of organizing and conducting two pilot CHEC-Ins and the model of this approach, which we intend to employ moving forward to advance partnership building and collaborative research practice between academic institutions and community partners and organizations. This paper contributes a unique model of community-generated and led outreach as a cornerstone of the ChicagoCHEC approach to community engagement. METHODS: The leaders of the ChicagoCHEC Community Steering Committee spearheaded the design and implementation of CHEC-Ins, including developing the question guide and hosting events within their organizations. LESSONS LEARNED: CHEC-Ins proved to be a valuable strategy for defining the role of community partners and establishing the basis for a bi-directional flow of information, resources, and productive action. The two pilot CHEC-Ins revealed important insights related to sources of cancer information, meanings and associated attitudes, barriers to access and use of health services, and social support systems in the communities where ChicagoCHEC works. We will implement this approach and continue to refine it as we conduct CHECIns moving forward.

CDK9 inhibition induces epigenetic reprogramming revealing strategies to circumvent resistance in lymphoma.

Diffuse large B-cell lymphoma (DLBCL) exhibits significant genetic heterogeneity which contributes to drug resistance, necessitating development of novel therapeutic approaches. Pharmacological inhibitors of cyclin-dependent kinases (CDK) demonstrated pre-clinical activity in DLBCL, however many stalled in clinical development. Here we show that AZD4573, a selective inhibitor of CDK9, restricted growth of DLBCL cells. CDK9 inhibition (CDK9i) resulted in rapid changes in the transcriptome and proteome, with downmodulation of multiple oncoproteins (eg, MYC, Mcl-1, JunB, PIM3) and deregulation of phosphoinotiside-3 kinase (PI3K) and senescence pathways. Following initial transcriptional repression due to RNAPII pausing, we observed transcriptional recovery of several oncogenes, including MYC and PIM3. ATAC-Seq and ChIP-Seq experiments revealed that CDK9i induced epigenetic remodeling with bi-directional changes in chromatin accessibility, suppressed promoter activation and led to sustained reprograming of the super-enhancer landscape. A CRISPR library screen suggested that SE-associated genes in the Mediator complex, as well as AKT1, confer resistance to CDK9i. Consistent with this, sgRNA-mediated knockout of MED12 sensitized cells to CDK9i. Informed by our mechanistic findings, we combined AZD4573 with either PIM kinase or PI3K inhibitors. Both combinations decreased proliferation and induced apoptosis in DLBCL and primary lymphoma cells in vitro as well as resulted in delayed tumor progression and extended survival of mice xenografted with DLBCL in vivo. Thus, CDK9i induces reprogramming of the epigenetic landscape, and super-enhancer driven recovery of select oncogenes may contribute to resistance to CDK9i. PIM and PI3K represent potential targets to circumvent resistance to CDK9i in the heterogeneous landscape of DLBCL.

The novel HLA-A*30:172 allele identified in a donor from the Colombian bone marrow donor registry.

HLA-A*30:172 differs from HLA-A*30:01:01:01 by a single nucleotide in codon 153 in exon 3.

Urinary glyphosate concentration in pregnant women in relation to length of gestation.

Human exposure to glyphosate-based herbicides (GBH) is increasing rapidly worldwide. Most existing studies on health effects of glyphosate have focused on occupational settings and cancer outcomes and few have examined this common exposure in relation to the health of pregnant women and newborns in the general population. We investigated associations between prenatal glyphosate exposure and length of gestation in The Infant Development and the Environment Study (TIDES), a multi-center US pregnancy cohort. Glyphosate and its primary degradation product [aminomethylphosphonic acid (AMPA)] were measured in urine samples collected during the second trimester from 163 pregnant women: 69 preterm births (<37 weeks) and 94 term births, the latter randomly selected as a subset of TIDES term births. We examined the relationship between exposure and length of gestation using multivariable logistic regression models (dichotomous outcome; term versus preterm) and with weighted time-to-event Cox proportional hazards models (gestational age in days). We conducted these analyses in the overall sample and secondarily, restricted to women with spontaneous deliveries (n = 90). Glyphosate and AMPA were detected in most urine samples (>94 %). A shortened gestational length was associated with maternal glyphosate (hazard ratio (HR): 1.31, 95 % confidence interval (CI) 1.00-1.71) and AMPA (HR: 1.32, 95%CI: 1.00-1.73) only among spontaneous deliveries using adjusted Cox proportional hazards models. In binary analysis, glyphosate and AMPA were not associated with preterm birth risk (<37 weeks). Our results indicate widespread exposure to glyphosate in the general population which may impact reproductive health by shortening length of gestation. Given the increasing exposure to GBHs and the public health burden of preterm delivery, larger confirmatory studies are needed, especially in vulnerable populations such as pregnant women and newborns.

MARIPOSA: phase 3 study of first-line amivantamab + lazertinib versus osimertinib in EGFR-mutant non-small-cell lung cancer.

Third-generation EGFR tyrosine kinase inhibitors (TKIs), such as osimertinib, have demonstrated efficacy in patients with EGFR-mutant non-small-cell lung cancer; however, almost all patients will eventually relapse. Amivantamab is an EGFR-MET bispecific antibody with immune cell-directing activity that targets activating and resistance EGFR mutations and MET mutations and amplifications. In the ongoing CHRYSALIS study (NCT02609776), amivantamab in combination with lazertinib, a potent, brain-penetrant third-generation EGFR TKI, demonstrated antitumor activity in the treatment-naive and osimertinib-relapsed setting. Here the authors present the methodology for the MARIPOSA study (NCT04487080), a phase 3, multicenter, randomized study designed to compare the efficacy and safety of amivantamab and lazertinib combination therapy versus single-agent osimertinib as first-line treatment for EGFR-mutant non-small-cell lung cancer.

Plain language summary Osimertinib is the standard-of-care treatment for patients with non-small-cell lung cancer caused by mutations in the EGFR. However, patients will eventually see their disease return because their tumors will develop new mutations that are resistant to osimertinib treatment. Amivantamab is a new antibody treatment that blocks the EGFR and another receptor called the MET receptor, to stop the growth of lung tumor cells. In an ongoing clinical trial, called the CHRYSALIS study, when amivantamab was given with lazertinib (another drug that blocks the EGFR), lung tumors shrank in patients whose lung cancer had not been previously treated. A new clinical trial called the MARIPOSA study (NCT04487080) aims to compare the antitumor activity and safety of the amivantamab + lazertinib combination versus osimertinib alone in patients with EGFR-mutant non-small-cell lung cancer who have not received treatment for their lung cancer. Trial registration number: NCT04487080 (ClinicalTrials.gov).

Identification of five novel HLA-B alleles in donors from the Colombian Bone Marrow Donor Registry.

Identification of five novel HLA-B alleles in five samples from Colombian bone marrow donors.

The novel HLA-A*24 allele, HLA-A*24:487, identified in three unrelated bone marrow donors in Colombia.

Identification of the novel HLA-A*24:487 allele, which differs from HLA-A*24:02:01:01 at one position.

Validación de una encuesta para medir la satisfacción de los médicos residentes sobre el programa de especialización en Lima, Perú / Validation of a survey aimed at measuring satisfaction of residents about a specialization program in Lima, Peru

RESUMEN Objetivo: Validar una encuesta para medir el nivel de satisfacción de los médicos residentes sobre el programa de segunda especialización en un hospital público de Lima, Perú. Material y métodos: Estudio transversal. El nuevo constructo se elaboró considerando los requisitos de satisfacción según opinión de los residentes y los 5 componentes de calidad de la encuesta SERVQUAL. Previo a su aplicación, fue sometida a opinión de expertos y prueba piloto para evaluar el grado de entendimiento de las preguntas y tiempo para su aplicación. La confiabilidad se evaluó con el alfa de Cronbach y la validez de constructo mediante análisis factorial. Realizamos estadística descriptiva y Chi cuadrado considerando significativo p<0,05. Resultados : Se analizaron 218 (82,0%) encuestas. 54,1% fueron del sexo femenino, 57,7% tenía edad ≤30 años, 86,2% era de plaza libre. El grado de entendimiento fue 9,98 y el tiempo de aplicación promedio fue 5,45 minutos. El alfa de Cronbach 0,919. Según el análisis factorial los 5 componentes principales de satisfacción explicaron el 65,5 % de la varianza de las 22 preguntas. La satisfacción global fue 71,8 %, fiabilidad 79,2%, capacidad de respuesta 80,2 %, seguridad 60,8%, empatía 82,8% y aspectos tangibles 55,9%. No se encontró diferencia significativa por género, grupo etario, modalidad de ingreso y especialidad. Conclusiones: La validación de la encuesta para medir satisfacción de los médicos residentes sobre el programa de segunda especialización demostró ser válida y confiable, constituyendo una herramienta útil para identificar las oportunidades de mejora para el perfeccionamiento continuo del programa de Residentado Médico.

SUMMARY Objective: To validate a survey aimed at measuring satisfaction of residents about a specialization program in Lima, Peru. Methods: A cross-sectional study was carried-out. The survey was built considering resident´s opinions on the satisfaction requirements of each program and the five components of the SERVQUAL quality survey. A pilot study was undertaken to evaluate the degree of understanding of the questions and an expert evaluation was also performed before applying the survey. Reliability was evaluated with Cronbach´s alpha test and validity was evaluated with a multifactorial analysis. Descriptive statistics was applied, Chi square test with a p value <0.05 was used. Results: 218 (82.0%) surveys were analyzed; 54.1% were females; 57.7% were younger than 30 years of age; 86.2% were of free position. Degree of understanding was 9.98 and time to complete the survey was 5.45 minutes. Cronbach´s alpha was 0.919. The factorial analysis of the five most important components of satisfaction explained 66.5% of the variance of the 22 questions. Overall satisfaction was 71.8%, reliability was 79.2%, ability to respond was 80.2%, security was 60.8%, empathy was 82.8% and tangible aspects was 55.9%. No difference by sex, age group, specialty and modality of admission was found. Conclusions: The survey tested showed to be reliable and valid to evaluate the satisfaction of residents to their programs and it is a useful tool to identify opportunities to improve the residency program.

Stimulation of the human mitochondrial transporter ABCB10 by zinc-mesoporphrin.

Heme biosynthesis occurs through a series of reactions that take place within the cytoplasm and mitochondria, so intermediates need to move across these cellular compartments. However, the specific membrane transport mechanisms involved in the process are not yet identified. The ATP-binding cassette protein ABCB10 is essential for normal heme production, as knocking down this transporter in mice is embryonically lethal and accompanied by severe anemia plus oxidative damage. The role of ABCB10 is unknown, but given its location in the inner mitochondrial membrane, it has been proposed as a candidate to export either an early heme precursor or heme. Alternatively, ABCB10 might transport a molecule important for protection against oxidative damage. To help discern between these possibilities, we decided to study the effect of heme analogs, precursors, and antioxidant peptides on purified human ABCB10. Since substrate binding increases the ATP hydrolysis rate of ABC transporters, we have determined the ability of these molecules to activate purified ABCB10 reconstituted in lipid nanodiscs using ATPase measurements. Under our experimental conditions, we found that the only heme analog increasing ABCB10 ATPase activity was Zinc-mesoporphyrin. This activation of almost seventy percent was specific for ABCB10, as the ATPase activity of a negative control bacterial ABC transporter was not affected. The activation was also observed in cysteine-less ABCB10, suggesting that Zinc-mesoporphyrin's effect did not require binding to typical heme regulatory motifs. Furthermore, our data indicate that ABCB10 was not directly activated by neither the early heme precursor delta-aminolevulinic acid nor glutathione, downsizing their relevance as putative substrates for this transporter. Although additional studies are needed to determine the physiological substrate of ABCB10, our findings reveal Zinc-mesoporphyrin as the first tool compound to directly modulate ABCB10 activity and raise the possibility that some actions of Zinc-mesoporphyrin in cellular and animal studies could be mediated by ABCB10.

Surgery for small asymptomatic abdominal aortic aneurysms.

BACKGROUND: An abdominal aortic aneurysm (AAA) is an abnormal ballooning of the major abdominal artery. Some AAAs present as emergencies and require surgery; others remain asymptomatic. Treatment of asymptomatic AAAs depends on many factors, but the size of the aneurysm is important, as risk of rupture increases with aneurysm size. Large asymptomatic AAAs (greater than 5.5 cm in diameter) are usually repaired surgically; very small AAAs (less than 4.0 cm diameter) are monitored with ultrasonography. Debate continues over the roles of early repair versus surveillance with repair on subsequent enlargement in people with asymptomatic AAAs of 4.0 cm to 5.5 cm diameter. This is the fourth update of the review first published in 1999. OBJECTIVES: To compare mortality and costs, as well as quality of life and aneurysm rupture as secondary outcomes, following early surgical repair versus routine ultrasound surveillance in people with asymptomatic AAAs between 4.0 cm and 5.5 cm in diameter. SEARCH METHODS: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, two other databases, and two trials registers to 10 July 2019. We handsearched conference proceedings and checked reference lists of relevant studies. SELECTION CRITERIA: We included randomised controlled trials where people with asymptomatic AAAs of 4.0 cm to 5.5 cm were randomly allocated to early repair or imaging-based surveillance at least every six months. Outcomes had to include mortality or survival. DATA COLLECTION AND ANALYSIS: Three review authors independently extracted data, which were cross-checked by other team members. Outcomes were mortality, costs, quality of life, and aneurysm rupture. For mortality, we estimated risk ratios (RR) (endovascular aneurysm repair only), hazard ratios (HR) (open repair only), and 95% confidence intervals (CI) based on Mantel-Haenszel Chi2 statistics at one and six years (open repair only) following randomisation. MAIN RESULTS: We found no new studies for this update. Four trials with 3314 participants fulfilled the inclusion criteria. Two trials compared early open repair with surveillance and two trials compared early endovascular repair (EVAR) with surveillance. We used GRADE to access the certainty of the evidence for mortality and cost, which ranged from high to low. We downgraded the certainty in the evidence from high to moderate and low due to risk of bias concerns and imprecision (some outcomes were only reported by one study). All four trials showed an early survival benefit in the surveillance group (due to 30-day operative mortality with repair) but no evidence of differences in long-term survival. One study compared early open repair with surveillance with an adjusted HR of 0.88 (95% CI 0.75 to 1.02, mean follow-up 10 years; HR 1.21, 95% CI 0.95 to 1.54, mean follow-up 4.9 years). Pooled analysis of participant-level data from the two trials comparing early open repair with surveillance (maximum follow-up seven to eight years) showed no evidence of a difference in survival (propensity score-adjusted HR 0.99, 95% CI 0.83 to 1.18; 2226 participants; high-certainty evidence). This lack of treatment effect did not vary to three years by AAA diameter (P = 0.39), participant age (P = 0.61), or for women (HR 0.84, 95% CI 0.62 to 1.11). Two studies compared EVAR with surveillance and there was no evidence of a survival benefit for early EVAR at 12 months (RR 1.92, 95% CI 0.73 to 5.06; 846 participants; low-certainty evidence). Two trials reported costs. The mean UK health service costs per participant over the first 18 months after randomisation were higher in the open repair surgery than the surveillance group (GBP 4978 in the repair group versus GBP 3914 in the surveillance group; mean difference (MD) GBP 1064, 95% CI 796 to 1332; 1090 participants; moderate-certainty evidence). There was a similar difference after 12 years. The mean USA hospital costs for participants at six months after randomisation were higher in the EVAR group than in the surveillance group (USD 33,471 with repair versus USD 5520 with surveillance; MD USD 27,951, 95% CI 25,156 to 30,746; 614 participants; low-certainty evidence). After four years, there was no evidence of a difference in total medical costs between groups (USD 48,669 with repair versus USD 46,112 with surveillance; MD USD 2557, 95% CI -8043 to 13,156; 614 participants; low-certainty evidence). All studies reported quality of life but used different assessment measurements and results were conflicting. All four studies reported aneurysm rupture. There were very few ruptures reported in the trials of EVAR versus surveillance up to three years. In the trials of open surgery versus surveillance, there were ruptures to at least six years and there were more ruptures in the surveillance group, but most of these ruptures occurred in aneurysms that had exceeded the threshold for surgical repair. AUTHORS' CONCLUSIONS: There was no evidence of an advantage to early repair for small AAA (4.0 cm to 5.5 cm), regardless of whether open repair or EVAR is used and, at least for open repair, regardless of patient age and AAA diameter. Thus, neither early open nor early EVAR of small AAAs is supported by currently available evidence. Long-term data from the two trials investigating EVAR are not available, so, we can only draw firm conclusions regarding outcomes after the first few years for open repair. Research regarding the risks related to and management of small AAAs in ethnic minorities and women is urgently needed, as data regarding these populations are lacking.

Ketamina, un nuevo agente terapéutico para la depresión / Ketamine, a New Therapeutic Agent for Depression

Resumen: El trastorno depresivo mayor (TDM) afecta aproximadamente a una de cada 10 personas en México y es una de las primeras 5 causas de discapacidad a nivel global. Las opciones de tratamiento actuales son limitadas debido a que solo actúan en algunos de los factores fisiopatológicos relacionados con esta enfermedad, además de que los efectos sobre la depresión suelen ser retardados. Esto implica una importante limitación en disminuir la discapacidad que origina e impide una acción rápida ante la ideación suicida. Recientemente, la ketamina (un anestésico) ha probado tener propiedades antidepresivas a través de su actividad sobre el sistema de neurotransmisión glutamatérgica (ningún otro tratamiento actúa a este nivel). Logra mejoría de los síntomas depresivos en horas y ha resultado útil en pacientes que no responden a los tratamientos disponibles en la actualidad. Recientemente se aprobó su utilización para el tratamiento de este trastorno. Sin embargo, aún quedan interrogantes sobre sus mecanismos de acción antidepresiva, seguridad y efectos secundarios, entre otros.

Abstract: Major depressive disorder affects about one in every 10 people in Mexico and is one of the first 5 causes of disability worldwide. Current treatment options are limited and only act upon some factors associated in its physiopathology. Moreover, the effects on depression are not immediate, which is a great limitation in obtaining a benefit over disability caused by this disorder and impedes a rapid action in the scenario of suicidality. Recently, ketamine (an anesthetic) has shown to have antidepressant properties by acting in the glutamate neurotransmission system (while no other current treatment acts on this level). It offers benefits in depressive symptoms in a matter of hours and has proven to be useful in patients that do not benefit from current therapeutic options. Recently, it has been approved for the treatment of depression. However, there are still many questions about its antidepressant mechanisms of action, safety, side effects, among others.

Efecto sobre la talla en niñas con pubertad precoz central de diagnóstico tardío tratadas con análogos de GnRH / Effect of GnRH analogs on girls height with late diagnosis central precocious puberty

RESUMEN Objetivo: evaluar el efecto de los análogos de GnRH sobre la predicción de talla final adulta en niñas con pubertad precoz central de diagnóstico tardío. Materiales y métodos: estudio descriptivo, retrospectivo. Se incluyeron niñas atendidas entre 2012 y 2018 en la Unidad de Endocrinología Pediátrica del Hospital Cayetano Heredia con diagnóstico de pubertad precoz central idiopática de diagnóstico tardío. Se realizó evaluación antropométrica, evaluación de estadío Tanner y determinación de edad ósea con el método de Greulich y Pyle, estimando la predicción de talla final adulta mediante el método de Bayley Pinneau antes y después del tratamiento con análogos de GnRH. Se realizó t de student para comparar la predicción de talla antes y después del tratamiento. Se consideró significativo un p< 0,05. Resultados: se incluyeron 23 niñas con edad cronológica media de 8,4 ± 0,4 años y una edad ósea de 10,7 ± 0,8 años al ingreso. El 83,9% de las pacientes tuvieron exceso de peso y el 74,0% estadio Tanner 3 al diagnóstico. El tiempo promedio de tratamiento con análogos de GnRH fue de 20,5 ± 8,4 meses. El efecto del tratamiento calculado con la diferencia de predicción de talla final adulta menos predicción de talla inicial fue de 2,5 ± 4,1 cm (p<0,01). Conclusión: las niñas con diagnóstico de pubertad precoz central de diagnóstico tardío muestran un discreto beneficio sobre la predicción de talla final adulta, por lo que la terapia a esta edad debe ser individualizada.

ABSTRACT Objective: to assess the effect of GnRH analogues on predicted adult final height in girls with a late diagnosis of central precocious puberty. Material and Methods : this is a descriptive and retrospective study. Girls seen between 2012 and 2018 in the Pediatric Endocrinology Unit of Hospital Nacional Cayetano Heredia with a late diagnosis of idiopathic precocious central puberty were included. Anthropometric assessments were performed, Tanner stage assessment and bone age determination using the Greulich and Pyle method were performed, and the final adult height was predicted using the Bailey Pinneau method before and after therapy. A Student-t test was used for comparing the height prediction before and after therapy. A p<0.05 value was considered as significant. Results : twenty-three girls with mean chronological age 8.4 ± 0.4 years were included. Their bone age was 10.7 ± 0.8 on admission. Most of the patients (83.9%) were overweight and 74.3% were Tanner 3 at the time of diagnosis. The average time using GnRH analogues therapy was 20.5 ± 8.4 months. The effect of therapy, which was calculated using the prediction difference for the final adult height minus the initial height prediction was 2.5 ± 4.1 cm (p<0.001). Conclusion : girls with a diagnosis of late diagnosis central precocious puberty show a discrete benefit on the prediction of the final adult height, so therapy at this age should be individualized.

Alanina aminotransferasa como marcador en el diagnóstico de síndrome metabólico y riesgo cardiovascular en niños con obesidad / Alanine aminotransferase as a marker for diagnosing metabolic syndrome and cardiovascular risk in obese children

Objetivo: Evaluar la alanina aminotransferasa (ALT) como marcador en el diagnóstico de síndrome metabólico (SM) y riesgo cardiovascular (RCV) en niños con obesidad exógena. Materiales y métodos: Estudio transversal. Se incluyeron niños con obesidad exógena de 2 a 14 años, atendidos en la Unidad de Endocrinología Pediátrica del Hospital Nacional Cayetano Heredia, entre el 2014 al 2018. Se definió enfermedad hepática no alcohólica (EHNA) considerando dos puntos de corte de ALT; en mujeres: >22,1U/L y >44U/L, en varones: >25,8U/L y >50U/L. Se definió SM según la Academia Americana de Pediatría y RCV con TG/HDL-C ≥3,5. Aplicamos Chi cuadrado, considerándose significativo p<0,05. Estimamos sensibilidad(S), especificidad (E) y likelihood ratios (LR). Resultados: Se incluyeron 347 niños obesos (54,7% varones). La frecuencia de EHNA fue de 23,1%. La sensibilidad y especificidad para el diagnóstico de SM con ALT >22,1U/L y >25,8U/L fue 79,4% y 37,6% respectivamente y, con ALT>44U/L y >50U/L fue 28,6% y 83,3%. La ALT con punto de corte mayor en conjunto con TG/HDL-C≥3,5 mostró una especificidad del 96,9% y un likelihood ratio + (LR+) de 6,7. Conclusión: La ALT con un punto de corte >44U/L en mujeres y >50U/L en varones, es un marcador bioquímico útil en la identificación de SM y riesgo cardiovascular en niños con obesidad exógena desde los primeros años de vida.

Objective: To assess alanine aminotransferase (ALT) as a marker for diagnosing metabolic syndrome (MS) and cardiovascular risk in children with exogenous obesity. Materials and Methods: This is a cross-sectional study. Children with exogenous obesity between 2 and 14 years of age seen in the Pediatric Endocrinology Unit at Cayetano Heredia Hospital between 2014 and 2018 were included. Non alcoholic liver disease was defined considering two ALT cutoff points: >22.1 U/L and >44 U/L in females and >25.8 U/L and >50 U/L in males. MS was defined according to the American Academy of Pediatrics criteria, and cardiovascular risk was defined with TG/HDL-C ratio ³3.5. We used chi-square test, and p<0.05 was deemed as significant. We estimated sensitivity (S), specificity (E) and likelihood ratios (LR). Results: Three-hundred and forty-seven obese children were included (54.7% were male). Non-alcoholic liver disease frequency was 23.1%. Sensitivity and specificity values for diagnosing MS with ALT >22.1 U/L and >25.8 U/L were 79.4% and 37.6%, respectively; and with ALT >44 U/L and 50 U/L these values were 28.6% and 83.3%. ALT levels with higher cutoff values, together with a ³3.5 TG/HDL-C ratio showed 96.9% specificity and 6.7 likelihood ratio (LR+). Conclusion: ALT levels with a >44 U/L cutoff value in females and >50 U/L in males is a useful biochemical marker for identifying MS and determining cardiovascular risk in children with exogen obesity during their early years of life.

Utilidad del índice triglicéridos/HDL-C desde los primeros años de vida en el diagnóstico de síndrome metabólico en niños obesos / Utility of the triglycerides/HDL-C index from the first years of age in the diagnosis of metabolic syndrome in obese children

Objetivo: Determinar la utilidad del índice triglicéridos/HDL-C (TG/HDL-C) para el diagnóstico de síndrome metabólico (SM) en niños obesos de 2 a 14 años. Material y métodos: Estudio transversal tipo prueba de diagnóstico. Fueron incluidos 360 niños obesos exógenos (199M/161F), divididos en tres grupos etarios: 2 a <6 años, 6 a <10 años y 10 a 14 años. Se definió SM según los criterios de la International Diabetes Federation y se evaluó al índice TG/HDL-C como diagnóstico en dos puntos de corte: ≥2,32 y ≥3,5, en cada grupo etario. Se aplicó Chi cuadrado, considerándose significativo p<0,05. Se determinó la sensibilidad, especificidad y valores predictivos positivo y negativo, para cada punto de corte. Resultados: La frecuencia de SM fue 15,79% de 2 a <6 años, 20,25% de 6 a <10 años, 19,63% de 10 a 14 años. En los niños con SM el 97,1% presentó HDL bajo, 83,8% triglicéridos elevados. Se encontró diferencia significativa en la frecuencia del índice TG/HDL-C en ambos puntos de corte, entre los niños con y sin SM en todos los grupos etarios. La sensibilidad para ambos puntos de corte fue alta (86-100%) y la especificidad fue mejor para el punto de corte ≥3,5 (72-80%). Conclusiones: El índice TG/HDL-C ≥3,5 representaría un marcador sensible y específico para el diagnóstico de síndrome metabólico desde los primeros años de vida.

Objective: To determine the utility of the triglycerides/HDL-C index for the diagnosis of metabolic syndrome (MS) in obese 2-14 years of age children. Methods: Cross-sectional diagnostic study. We included 360 exogenous obese children (199M/161F) divided in three age groups: 2 to <6; 6 to <10 and 10-14 years. MS was defined according to the International Diabetes Federation and the TG/HDL-C index was evaluated using two cutoffs by age group, ≥2.32 and ≥3.5. Chi squared was used accepting a p value <0.05 as statistically significant. Fir each cut-off we determined sensitivity, specificity and predictive values. Results: Frequency of MS was 15.79% in the 2 to <6 years age group; 20.25% in the 6 to<10 years age group and 19.63% in the 10-14 years age group. Among children with SM, 97.1% had low HDL and 83.8% had elevated triglycerides. A statistically significant difference was found in the frequency of the TG/HDL-C index in children with or without MS in all age groups. Sensitivity for all cut-offs was high (86-100%) and specificity was best for the cut-off of ≥3.5 (72-80%). Conclusions: The TG/HDL-C index is a sensitive and specific marker of MS from the first years of age.

Discovering human transcription factor physical interactions with genetic variants, novel DNA motifs, and repetitive elements using enhanced yeast one-hybrid assays.

Identifying transcription factor (TF) binding to noncoding variants, uncharacterized DNA motifs, and repetitive genomic elements has been technically and computationally challenging. Current experimental methods, such as chromatin immunoprecipitation, generally test one TF at a time, and computational motif algorithms often lead to false-positive and -negative predictions. To address these limitations, we developed an experimental approach based on enhanced yeast one-hybrid assays. The first variation of this approach interrogates the binding of >1000 human TFs to repetitive DNA elements, while the second evaluates TF binding to single nucleotide variants, short insertions and deletions (indels), and novel DNA motifs. Using this approach, we detected the binding of 75 TFs, including several nuclear hormone receptors and ETS factors, to the highly repetitive Alu elements. Further, we identified cancer-associated changes in TF binding, including gain of interactions involving ETS TFs and loss of interactions involving KLF TFs to different mutations in the TERT promoter, and gain of a MYB interaction with an 18-bp indel in the TAL1 superenhancer. Additionally, we identified TFs that bind to three uncharacterized DNA motifs identified in DNase footprinting assays. We anticipate that these enhanced yeast one-hybrid approaches will expand our capabilities to study genetic variation and undercharacterized genomic regions.

Deep Brain Stimulation Surgery for Parkinson Disease Coexisting With Communicating Hydrocephalus: A Case Report.

We report a successful bilateral globus pallidus internus-deep brain stimulation (GPi-DBS) for a Parkinson disease (PD) patient with idiopathic normal pressure hydrocephalus (INPH) and an unusually long anterior commissure-posterior commissure (AC-PC) line. A 54-year-old man presented with a history of 3 months of severe shuffling gait, rigidity, slow movements of the left side limbs, and difficulty managing finances. A brain MRI revealed marked ventriculomegaly (Evans index = 0.42). The patient was diagnosed with INPH and a ventriculoperitoneal shunt was placed. Cognitive impairment improved, but walking disturbances, slowness, and rigidity persisted. Then treatment with levodopa was added, and the patient experienced a sustained improvement. He was diagnosed with PD. After 7 years, the patient developed gait freezing and severe levodopa-induced dyskinesia. The patient underwent bilateral GPi-DBS. We used MRI/CT fusion techniques for anatomical indirect targeting. Indirect targeting is based on standardized stereotactic atlas and on a formula-derived method based on AC-PC landmarks. The AC-PC line was 40 mm (the usual length is between 19 and 32 mm). Intraoperative microelectrode recording was a non-expendable test, but multiple recordings were avoided to reduce the surgical risk of ventricular involvement. There was a 71% decrease in the UPDRS III score during the on-stimulation state (28 to 8). The patient's dyskinesias resolved dramatically with a UdysRS of 15 (88% improvement) during the on-stimulation condition. The observed motor benefits and the improvement of his daily activities have persisted 6 months after surgery. Deep brain stimulation surgery in PD with ventriculomegaly is a challenge. This procedure can result in a greater chance of breaching the ventricle, with risks of intraventricular hemorrhage and migration of cerebrospinal fluid into the brain parenchyma with target displacement. Furthermore, clinical judgment is paramount when recent onset of shuffling gait coexists with ventriculomegaly because the most common dilemma is differentiating between PD and INPH. For these reasons, neurologists and surgeons may refuse to operate on PD patients with ventriculomegaly. However, DBS should be considered for PD patients with motor complications when responsiveness to levodopa is demonstrated, even in the context of marked ventriculomegaly.

Comparing adult cannabis treatment-seekers enrolled in a clinical trial with national samples of cannabis users in the United States.

BACKGROUND: Cannabis use rates are increasing among adults in the United States (US) while the perception of harm is declining. This may result in an increased prevalence of cannabis use disorder and the need for more clinical trials to evaluate efficacious treatment strategies. Clinical trials are the gold standard for evaluating treatment, yet study samples are rarely representative of the target population. This finding has not yet been established for cannabis treatment trials. This study compared demographic and cannabis use characteristics of a cannabis cessation clinical trial sample (run through National Drug Abuse Treatment Clinical Trials Network) with three nationally representative datasets from the US; 1) National Survey on Drug Use and Health, 2) National Epidemiologic Survey on Alcohol and Related Conditions-III, and 3) Treatment: Episodes Data Set - Admissions. METHODS: Comparisons were made between the clinical trial sample and appropriate cannabis using sub-samples from the national datasets, and propensity scores were calculated to determine the degree of similarity between samples. RESULTS: showed that the clinical trial sample was significantly different from all three national datasets, with the clinical trial sample having greater representation among older adults, African Americans, Hispanic/Latinos, adults with more education, non-tobacco users, and daily and almost daily cannabis users. CONCLUSIONS: These results are consistent with previous studies of other substance use disorder populations and extend sample representation issues to a cannabis use disorder population. This illustrates the need to ensure representative samples within cannabis treatment clinical trials to improve the generalizability of promising findings.

Past and present land use influences on tropical riparian zones: an isotopic assessment with implications for riparian forest width determination / Influências pretéritas e presentes do uso da terra sobre zonas ripárias tropicais: uma avaliação isotópica com implicações para a determinação da largura de florestas ripárias

Abstract In this article, by using carbon stable isotopes, we assessed the past and present land use influences that riparian areas are subject within agricultural landscapes. Emphasis is given to the understanding of the effects of the 2012 Brazilian Forest Act on such areas. We selected five riparian areas within a highly C4 dominated agricultural landscape. Three of them had 30 meters native riparian forest buffer (NRFB) and two of them had 8 meter and no NRFB. We used three 100 meter-transects located 5, 15 and 30 meters relative to stream channel to obtain soil samples (0 - 10 cm). All riparian areas presented soil carbon isotopic signatures that are not C3 (native forests) irrespective of having or not 30 meters NRFB. Two cases presenting less than 30 meters NRFB had higher C4 derived carbon contribution. All of the other three areas that followed the 30 meters NRFB presented, to some degree, C4 derived carbon, which was attributed to C4 organic matter deposition originated from cultivated areas and, in one case, to the persistence of former exotic grasses. With the 2012 Forest Act allowing narrower buffers (< 30 meters), we expect C4 contributions to soil organic matter to remain high in riparian areas and streams within agricultural landscapes dominated by C4 plants where 30 meter NRFB is no longer required. Such contributions will likely continue to have detrimental effects on stream water quality and biota.

Resumo Neste artigo, ao utilizar isótopos estáveis de carbono, nós avaliamos as influências presentes e pretéritas do uso da terra a que as áreas ripárias estão sujeitas quando situadas dentro de paisagens agrícolas. Ênfase é dada ao entendimento dos efeitos do Código Florestal de 2012 em tais áreas. Nós selecionamos cinco áreas ripárias em uma paisagem agrícola altamente dominada por plantas C4. Três delas apresentam faixa ripária de floresta nativa (FRFN) de 30 metros de largura e as outras duas apresentam FRFN de 8 e 0 m (i.e. sem FRFN). Nós utilizamos três transectos de 100 metros localizados a 5, 15 e 30 metros de distância do canal fluvial para obter amostras de solo (0 - 10 cm). Todas as áreas ripárias apresentaram assinaturas isotópicas do carbono do solo que não são C3 (floresta nativa) independentemente de apresentarem ou não FRFN de 30 metros. Os dois casos em que FRFN era menor que 30 m apresentaram maior contribuição de carbono oriundo de plantas C4. Todas as outras três áreas com FRFN de 30 m também apresentaram, em algum grau, carbono oriundo de plantas C4. Todas as outras três áreas com FRFN de 30 m também apresentaram, em algum grau, carbono oriundo de plantas C4 que foi atribuído è deposição de matéria orgânica de plantas C4 originada das áreas cultivadas e, em um caso, è persistência de gramíneas exóticas pré-existentes. Com o Código Florestal de 2012 permitindo FRFN mais estreitas (< 30 metros), nós esperamos que a contribuição de plantas C4 para a matéria orgânica permaneça alta em áreas ripárias e rios dentro de paisagens agrícolas dominadas por plantas C4 onde a FRFN de 30 m não é mais uma obrigação. Tais contribuições irão, provavelmente, continuar a ter efeitos prejudiciais è qualidade de água dos rios e à sua biota.