Combination therapy of Epidermal Growth Factor and Growth Hormone-Releasing Hexapeptide in acute ischemic stroke: a phase I/II non-blinded, randomized clinical trial.

Objective: This study tested the hypothesis that a neuroprotective combined therapy based on epidermal growth factor (EGF) and growth hormone-releasing hexapeptide (GHRP6) could be safe for acute ischemic stroke patients, admitting up to 30% of serious adverse events (SAE) with proven causality. Methods: A multi-centric, randomized, open-label, controlled, phase I-II clinical trial with parallel groups was conducted (July 2017 to January 2018). Patients aged 18-80 years with a computed tomography-confirmed ischemic stroke and less than 12 h from the onset of symptoms were randomly assigned to the study groups I (75 µg rEGF + 3.5 mg GHRP6 i.v., n=10), II (75 µg rEGF + 5 mg GHRP6 i.v., n=10), or III (standard care control, n=16). Combined therapy was given BID for 7 days. The primary endpoint was safety over 6 months. Secondary endpoints included neurological (NIHSS) and functional [Barthel index and modified Rankin scale (mRS)] outcomes. Results: The study population had a mean age of 66 ± 11 years, with 21 men (58.3%), a baseline median NIHSS score of 9 (95% CI: 8-11), and a mean time to treatment of 7.3 ± 2.8 h. Analyses were conducted on an intention-to-treat basis. SAEs were reported in 9 of 16 (56.2%) patients in the control group, 3 of 10 (30%) patients in Group I (odds ratio (OR): 0.33; 95% CI: 0.06-1.78), and 2 of 10 (20%) patients in Group II (OR: 0.19; 95% CI: 0.03-1.22); only two events in one patient in Group I were attributed to the intervention treatment. Compliance with the study hypothesis was greater than 0.90 in each group. Patients treated with EGF + GHRP6 had a favorable neurological and functional evolution at both 90 and 180 days, as evidenced by the inferential analysis of NIHSS, Barthel, and mRS and by their moderate to strong effect size. At 6 months, proportion analysis evidenced a higher survival rate for patients treated with the combined therapy. Ancillary analysis including merged treated groups and utility-weighted mRS also showed a benefit of this combined therapy. Conclusion: EGF + GHRP6 therapy was safe. The functional benefits of treatment in this study supported a Phase III study. Clinical Trial Registration: RPCEC00000214 of the Cuban Public Registry of Clinical Trials, Unique identifier: IG/CIGB-845I/IC/1601.

Modification of Mesenchymal Stem/Stromal Cell-Derived Small Extracellular Vesicles by Calcitonin Gene Related Peptide (CGRP) Antagonist: Potential Implications for Inflammation and Pain Reversal.

During the progression of knee osteoarthritis (OA), the synovium and infrapatellar fat pad (IFP) can serve as source for Substance P (SP) and calcitonin gene-related peptide (CGRP), two important pain-transmitting, immune, and inflammation modulating neuropeptides. Our previous studies showed that infrapatellar fat pad-derived mesenchymal stem/stromal cells (MSC) acquire a potent immunomodulatory phenotype and actively degrade Substance P via CD10 both in vitro and in vivo. On this basis, our hypothesis is that CD10-bound IFP-MSC sEVs can be engineered to target CGRP while retaining their anti-inflammatory phenotype. Herein, human IFP-MSC cultures were transduced with an adeno-associated virus (AAV) vector carrying a GFP-labelled gene for a CGRP antagonist peptide (aCGRP). The GFP positive aCGRP IFP-MSC were isolated and their sEVs' miRNA and protein cargos were assessed using multiplex methods. Our results showed that purified aCGRP IFP-MSC cultures yielded sEVs with cargo of 147 distinct MSC-related miRNAs. Reactome analysis of miRNAs detected in these sEVs revealed strong involvement in the regulation of target genes involved in pathways that control pain, inflammation and cartilage homeostasis. Protein array of the sEVs cargo demonstrated high presence of key immunomodulatory and reparative proteins. Stimulated macrophages exposed to aCGRP IFP-MSC sEVs demonstrated a switch towards an alternate M2 status. Also, stimulated cortical neurons exposed to aCGRP IFP-MSC sEVs modulate their molecular pain signaling profile. Collectively, our data suggest that yielded sEVs can putatively target CGRP in vivo, while containing potent anti-inflammatory and analgesic cargo, suggesting the promise for novel sEVs-based therapeutic approaches to diseases such as OA.

Neurodevelopmental assessment of normocephalic children born to Zika virus exposed and unexposed pregnant people.

BACKGROUND: Studies examining the association between in utero Zika virus (ZIKV) exposure and child neurodevelopmental outcomes have produced varied results. METHODS: We aimed to assess neurodevelopmental outcomes among normocephalic children born from pregnant people enrolled in the Zika in Pregnancy in Honduras (ZIPH) cohort study, July-December 2016. Enrollment occurred during the first prenatal visit. Exposure was defined as prenatal ZIKV IgM and/or ZIKV RNA result at enrollment. Normocephalic children, >6 months old, were selected for longitudinal follow-up using the Bayley Scales of Infant and Toddler Development (BSID-III) and the Ages & Stages Questionnaires: Social-Emotional (ASQ:SE-2). RESULTS: One hundred fifty-two children were assessed; after exclusion, 60 were exposed and 72 were unexposed to ZIKV during pregnancy. Twenty children in the exposed group and 21 children in the unexposed group had a composite score <85 in any of the BSID-III domains. Although exposed children had lower cognitive and language scores, differences were not statistically significant. For ASQ:SE-2 assessment, there were not statistically significant differences between groups. CONCLUSIONS: This study found no statistically significant differences in the neurodevelopment of normocephalic children between in utero ZIKV exposed and unexposed. Nevertheless, long-term monitoring of children with in utero ZIKV exposure is warranted. IMPACT: This study found no statistically significant differences in the neurodevelopment in normocephalic children with in utero Zika virus exposure compared to unexposed children, although the exposed group showed lower cognitive and language scores that persisted after adjustment by maternal age and education and after excluding children born preterm and low birth weight from the analysis. Children with prenatal Zika virus exposure, including those normocephalic and have no evidence of abnormalities at birth, should be monitored for neurodevelopmental delays. Follow-up is important to be able to detect developmental abnormalities that might not be detected earlier in life.

Recent parallel speciation in Antirrhinum involved complex haplotypes and multiple adaptive characters.

A role of ecological adaptation in speciation can be obscured by stochastic processes and differences that species accumulate after genetic isolation. One way to identify adaptive characters and their underlying genes is to study cases of speciation involving parallel adaptations. Recently resolved phylogenies reveal that alpine morphology has evolved in parallel in the genus Antirrhinum (snapdragons): first in an early split of an alpine from a lowland lineage and, more recently, from within the lowland lineage to produce closely related sympatric species with contrasting alpine and lowland forms. Here, we find that two of these later diverged sympatric species are differentiated by only around 2% of nuclear loci. Though showing evidence of recent gene flow, the species remain distinct for a suite of morphological characters typical of earlier-diverged alpine or lowland lineages and their morphologies correlate with features of the local landscape, as expected of ecological adaptations. Morphological differences between the two species involve multiple, unlinked genes so that parental character combinations are readily broken up by recombination in hybrids. We detect little evidence for post-pollination barriers to gene flow or recombination, suggesting that genetic isolation related to ecological adaptation is important in maintaining character combinations and might have contributed to parallel speciation. We also find evidence that genes involved in the earlier alpine-lowland split were reused in parallel evolution of alpine species, consistent with introgressive hybridisation, and speculate that many non-ecological barriers to gene flow might have been purged during the process.

Improving Extracorporeal Membrane Oxygenation Survival in COVID-19. Effect of a Bundle of Care.

Veno-venous extracorporeal membrane oxygenation (ECMO) support surged during the COVID-19 pandemic. Our program changed the model of care pursuing to protect the multidisciplinary team from the risk of infection and to serve as many patients as possible. Patient-healthcare interactions were restricted, and the ECMO bed capacity was increased by reducing the ECMO specialist-patient ratio to 1:4 with non-ECMO trained nurses support. The outcomes worsened and we paused while we evaluated and modified our model of care. The ECMO bed capacity was reduced to allow a nurse ECMO-specialist nurse ratio 2:1 with an ECMO trained nurse assistant's support. Intensivists, general practitioners, nurse assistants, and physical and respiratory therapists were trained on ECMO. Tracheostomy, bronchoscopy, and microbiological molecular diagnosis were done earlier, and family visits and rehabilitation were allowed in the first 48 hours of ECMO cannulation. There were 35 patients in the preintervention cohort and 66 in the postintervention cohort. Ninety days mortality was significantly lower after the intervention (62.9% vs. 31.8%, p = 0.003). Factors associated with increased risk of death were the need for cannulation or conversion to veno arterial or veno arterio venous ECMO, hemorrhagic stroke, and renal replacement therapy during ECMO. The interventions associated with a decrease in the risk of death were the following: early fiberoptic bronchoscopy and microbiological molecular diagnostic tests. Increasing the ECMO multidisciplinary team in relation to the number of patients and the earlier performance of diagnostic and therapeutic interventions, such as tracheostomy, fiberoptic bronchoscopy, molecular microbiological diagnosis of pneumonia, rehabilitation, and family support significantly decreased mortality of patients on ECMO due to COVID-19.

A phylogeny of Antirrhinum reveals parallel evolution of alpine morphology.

Parallel evolution of similar morphologies in closely related lineages provides insight into the repeatability and predictability of evolution. In the genus Antirrhinum (snapdragons), as in other plants, a suite of morphological characters are associated with adaptation to alpine environments. We tested for parallel trait evolution in Antirrhinum by investigating phylogenetic relationships using restriction-site associated DNA (RAD) sequencing. We then associated phenotypic information to our phylogeny to reconstruct the patterns of morphological evolution and related this to evidence for hybridisation between emergent lineages. Phylogenetic analyses showed that the alpine character syndrome is present in multiple groups, suggesting that Antirrhinum has repeatedly colonised alpine habitats. Dispersal to novel environments happened in the presence of intraspecific and interspecific gene flow. We found support for a model of parallel evolution in Antirrhinum. Hybridisation in natural populations, and a complex genetic architecture underlying the alpine morphology syndrome, support an important role of natural selection in maintaining species divergence in the face of gene flow.

Características epidemiológicas de los 190 pacientes internados con SARS-CoV2 en el Hospital General de Barrio Obrero periodo junio-diciembre 2020

RESUMEN El Hospital General de Barrio Obrero no es ajeno a la pandemia, teniendo pacientes hospitalizados con COVID-19 desde inicios de junio de 2020 con un impacto alto en los servicios. Se analizaron 190 pacientes internados en los distintos servicios. Se encontró predominio del sexo masculino 52%. En cuanto a la edad, se observó un claro predominio de gerontes con el 51% del total de pacientes170 (89%) fueron internados en el servicio de clínica médica, a pesar de eso, aún un bajo porcentaje se detectó en servicios como gineco-obstetricia y cirugía general. Según la evolución clínica de los pacientes, 138 (73%) fueron dados de alta, 29 (15%) fueron trasladados a un centro de mayor complejidad por complicación de la enfermedad y 23 (12%) fallecieron, 16 (70%) eran de sexo masculino, según el rango etario, los pacientes que obitaron eran gerontes 17 (74%), adultos mayores 4 (17%) y adultos jóvenes 2 (9%). Octubre fue el mes con más muertes en pacientes internados con SARS-CoV-2. .En cuanto a la comorbilidad, 91% presentaba al menos una comorbilidad, entre las que predominó la hipertensión arterial (25%)

ABSTRACT The Barrio Obrero General Hospital is no stranger to the pandemic, having hospitalized patients with COVID-19 since the beginning of June 2020 with a high impact on services. 190 patients admitted to the different services were analyzed. 52% male predominance was found. Regarding age, a clear predominance of elderly was observed with 51% of all patients170 (89%) were admitted to the medical clinic service, despite this, a low percentage was still detected in services such as gynecology. obstetrics and general surgery. According to the clinical evolution of the patients, 138 (73%) were discharged, 29 (15%) were transferred to a more complex center due to complications of the disease and 23 (12%) died, 16 (70%) were of male sex, according to age range, the patients who obtained were elderly 17 (74%), older adults 4 (17%) and young adults 2 (9%). October was the month with the most deaths in patients hospitalized with SARS-CoV-2. Regarding comorbidity, 91% had at least one comorbidity, among which arterial hypertension predominated (25%).

Microcephaly Outcomes among Zika Virus-Infected Pregnant Women in Honduras.

The impact of Zika virus (ZIKV) infection on pregnancies shows regional variation emphasizing the importance of studies in different geographical areas. We conducted a prospective study in Tegucigalpa, Honduras, recruiting 668 pregnant women between July 20, 2016, and December 31, 2016. We performed Trioplex real-time reverse transcriptase-PCR (rRT-PCR) in 357 serum samples taken at the first prenatal visit. The presence of ZIKV was confirmed in seven pregnancies (7/357, 2.0%). Nine babies (1.6%) had microcephaly (head circumference more than two SDs below the mean), including two (0.3%) with severe microcephaly (head circumference [HC] more than three SDs below the mean). The mothers of both babies with severe microcephaly had evidence of ZIKV infection. A positive ZIKV Trioplex rRT-PCR was associated with a 33.3% (95% CI: 4.3-77.7%) risk of HC more than three SDs below the mean.

Psychogenic nonepileptic seizures in Latin America: A survey describing current practices.

OBJECTIVE: Psychogenic nonepileptic seizures (PNES) are one of the most common differential diagnoses of epilepsy. This study provides an overview of diagnostic and treatment services for patients with PNES across Latin America. METHODS: In 2017-2018, clinicians practicing in Latin America with responsibilities for patients with PNES were contacted to respond to a survey regarding the management of this disorder developed by the International League Against Epilepsy (ILAE) PNES Task Force. RESULTS: Three hundred and sixty responses from 17 Latin American countries were analyzed. Most respondents were neurologists (81%) under 40 years of age (61%). Fifty-seven percent of professionals stated that they personally diagnose PNES, but only 33% stated that they provide follow-up, and only 20% that they recommend treatment. Many participants (54%) characterized themselves as either unfamiliar with the diagnosis or inexperienced in arranging treatment. Most respondents reported having access to brain magnetic resonance imaging (MRI; 88%) and routine electroencephalogram (EEG; 71%), 64% have the access to video-EEG longer than 8 h, and 54% of professionals performed video-EEG to confirm PNES diagnoses. Although cognitive-behavioral therapy was recognized as the treatment of choice (by 82% of respondents), there was little access to it (60%). In contrast, a high proportion of respondents reported using antidepressant (67%), antiseizure (57%), and antipsychotic medications (54%) as treatments for PNES. SIGNIFICANCE: This study reveals several deficiencies in the diagnosis and treatment of patients with PNES in Latin America. The barriers are reinforced by lack of knowledge among the specialists and poor healthcare system support. There is inadequate access to prolonged video-EEG and psychotherapy. An inappropriate use of antiseizure medicines seems commonplace, and there are low follow-up rates by neurologists after the diagnosis. Multidisciplinary guidelines are required to improve the approach of patients with PNES.

Incidencia de neoplasias en una cohorte española de pacientes con infección por el virus de la inmunodeficiencia humana / Incidence of malignancy in a Spanish cohort of patients infected by the human immunodeficiency virus

INTRODUCCIÓN: Se ha descrito una mayor incidencia de neoplasias en los pacientes con infección por VIH en comparación con la población general. PACIENTES Y MÉTODOS: Estudio observacional retrospectivo de la población infectada por VIH en seguimiento en el Hospital Vall d'Hebron (Barcelona) entre 2009 y 2017. El objetivo de este estudio fue estimar la incidencia de neoplasias en estos pacientes con infección por VIH y su supervivencia. Se comparó la incidencia ajustada por edad y sexo en dicha población con la calculada por la Red Española de Registros de Cáncer (REDECAN) en 2015. RESULTADOS: Se incluyeron 2.773 pacientes (41.238 pacientes-año). Se diagnosticaron 211 cánceres en 182 pacientes. El 78,2% de las neoplasias fueron no definitorias de sida (NNDS). La tasa global de incidencia de cáncer fue 485 neoplasias por 100.000 pacientes-año. La mortalidad a 20años en pacientes con cáncer fue del 31,2%, y del 7,8% en pacientes sin cáncer. En varones, ajustada por edad, la incidencia de neoplasias fue mayor que en la población general (978,4 vs. 641 por 100.000 pacientes-año, p < 0,001); las más frecuentes fueron carcinomas de pulmón, sarcoma de Kaposi y linfoma no Hodgkin. En mujeres, la incidencia no fue mayor a la de la población general (340,6 vs. 404,7 por 100.000 pacientes-año, p = 0,27). Las neoplasias más frecuentes fueron carcinomas pulmonares, carcinomas de cabeza y cuello, cérvix y linfoma Hodgkin. CONCLUSIONES: Los varones con infección por VIH presentaron una incidencia significativamente mayor de cáncer que la población española del mismo sexo. Los carcinomas pulmonares fueron las NNDS más frecuentes

INTRODUCTION: A higher incidence of malignancies has been described in patients with HIV infection compared to the general population. PATIENTS AND METHODS: Observational retrospective study in patients with HIV infection followed up at the Vall d'Hebron University Hospital (Barcelona, Spain) between 2009 and 2017. The objective of this research was to estimate the incidence of malignancies in HIV patients and their surveillance. Age and sex-adjusted incidence was compared to the incidence calculated by the Spanish Cancer Registry network (REDECAN) in 2015. RESULTS: We included 2,773 patients (41,238 patients-year). Two hundred and eleven malignancies were diagnosed in 182 patients. Non-AIDS defining cancers accounted for 78.2% of the malignancies. The global incidence of cancer was 485 cases per 100,000 person-years. Twenty-year mortality rate was 31.2% in patients with cancer and 7.8% in patients without cancer. In men, adjusted for age, the incidence of malignancies was higher than the incidence in the general population (978.4 vs. 641 cases per 100,000 person-years, P<.001). The most common malignancies in men were lung cancer, Kaposi sarcoma and Hodgkin lymphoma. In women, the incidence of malignancies was not higher than in the general population (340.6 vs. 404.7 cases per 100,000 person-years, P=.27). The most common malignancies among women were lung cancer, head and neck cancer, cervical cancer and Hodgkin's lymphoma. CONCLUSIONS: Men with HIV infection showed a statistically significant higher incidence of malignancies compared to the general Spanish population. Lung cancer was the most common non-AIDS defining cancer

Lipidomics Reveals Reduced Inflammatory Lipid Species and Storage Lipids after Switching from EFV/FTC/TDF to RPV/FTC/TDF: A Randomized Open-Label Trial.

HIV and antiretroviral therapy affect lipid metabolism. Lipidomics quantifies several individual species that are overlooked using conventional biochemical analyses, outperforming traditional risk equations. We aimed to compare the plasma lipidomic profile of HIV patients taking efavirenz (EFV) or rilpivirine (RPV). Patients ≥ 18 years old on EFV co-formulated with emtricitabine and tenofovir disoproxil fumarate (FTC/TDF) with HIV-RNA < 50 copies/mL for ≥6 months were randomized to continue EFV/FTC/TDF (n = 14) or switch to RPV/FTC/TDF (n =15). Lipidomic analyses conducted by mass spectrometry (MS) were performed at baseline and after 12 and 24 weeks. OWLiver® Care and OWLiver® tests were performed to estimate the presence of fatty liver disease (NAFLD). No significant differences (83% male, median age 44 years, 6 years receiving EFV/FTC/TDF, CD4+ count 740 cells/mm3, TC 207 [57 HDL-C/133 LDL-C] mg/dL, TG 117 mg/dL) were observed between the groups at baseline. Significant reductions in plasma lipids and lipoproteins but increased circulating bilirubin concentrations were observed in patients who switched to RPV/FTC/TDF. Patients on RPV/FTC/TDF showed a decrease in the global amount of storage lipids (-0.137 log2 [fold-change] EFV vs. 0.059 log2 [fold-change] RPV) but an increase in lysophosphatidylcholines (LPCs) and total steroids. Compared with EFV, RPV increased metabolites with anti-inflammatory properties and reduced the repository of specific lipotoxic lipids.

Invasion, isolation and evolution shape population genetic structure in Campanula rotundifolia.

The distribution and genetic structure of most plant species in Britain and Ireland bear the imprint of the last ice age. These patterns were largely shaped by random processes during recolonization but, in angiosperms, whole-genome duplication may also have been important. We investigate the distribution of cytotypes of Campanula rotundifolia, considering DNA variation, postglacial colonization, environmental partitioning and reproductive barriers. Cytotypes and genome size variation from across the species' range were determined by flow cytometry and genetic variation was assessed using cpDNA markers. A common garden study examined growth and flowering phenology of tetraploid, pentaploid and hexaploid cytotypes and simulated a contact zone for investigation of reproductive barriers. Irish populations were entirely hexaploid. In Britain, hexaploids occurred mostly in western coastal populations which were allopatric with tetraploids, and in occasional sympatric inland populations. Chloroplast markers resolved distinct genetic groups, related to cytotype and geographically segregated; allopatric hexaploids were distinct from tetraploids, whereas sympatric hexaploids were not. Genome downsizing occurred between cytotypes. Progeny of open-pollinated clones from the contact zone showed that maternal tetraploids rarely produced progeny of other cytotypes, whereas the progeny of maternal hexaploids varied, with frequent pentaploids and aneuploids. The presence of distinctive hexaploid chloroplast types in Ireland, Scottish islands and western mainland Britain indicates that its establishment preceded separation of these land masses by sea-level rise c. 16 000 years BP. This group did not originate from British tetraploids and probably diverged before postglacial invasion from mainland Europe. The combination of cytotype, molecular, contact zone and common garden data shows an overall pattern reflecting postglacial colonization events, now maintained by geographic separation, together with more recent occasional local in situ polyploidisation. Reproductive barriers favour the persistence of the tetraploid to the detriment of the hexaploid.

Exploration of clients living with HIV needs for reporting on experiences with sex.

Talking about sex with people living with HIV receives insufficient attention in health care. A cross-sectional and exploratory study describes the preferences of people living with HIV to talk about sex with specialized HIV physicians and nurses in a clinic in Barcelona (Spain). A 27-item self-administered questionnaire was used between June 2017 and May 2018. One hundred fourteen people agreed to participate. Data were analyzed using multivariate logistic regression. Most of the participants reported "never or almost never" having been asked about sex practices in visits with the HIV specialist physician (n = 65 [57.0%]) or nurse (n = 74 [64.9%]). Older participants stated that neither physicians nor nurses talked about sex during visits. Women felt that physicians hardly ever asked about their sexual practices. Men who had sex with other men indicated that their physicians always asked about their sex practices compared with heterosexuals living with HIV. Health professionals should reformulate how to talk about sex with people living with HIV to facilitate communication and provide adequate care.

Incidence of malignancy in a Spanish cohort of patients infected by the human immunodeficiency virus. / Incidencia de neoplasias en una cohorte española de pacientes con infección por el virus de la inmunodeficiencia humana.

INTRODUCTION: A higher incidence of malignancies has been described in patients with HIV infection compared to the general population. PATIENTS AND METHODS: Observational retrospective study in patients with HIV infection followed up at the Vall d'Hebron University Hospital (Barcelona, Spain) between 2009 and 2017. The objective of this research was to estimate the incidence of malignancies in HIV patients and their surveillance. Age and sex-adjusted incidence was compared to the incidence calculated by the Spanish Cancer Registry network (REDECAN) in 2015. RESULTS: We included 2,773 patients (41,238 patients-year). Two hundred and eleven malignancies were diagnosed in 182 patients. Non-AIDS defining cancers accounted for 78.2% of the malignancies. The global incidence of cancer was 485 cases per 100,000 person-years. Twenty-year mortality rate was 31.2% in patients with cancer and 7.8% in patients without cancer. In men, adjusted for age, the incidence of malignancies was higher than the incidence in the general population (978.4 vs. 641 cases per 100,000 person-years, P<.001). The most common malignancies in men were lung cancer, Kaposi sarcoma and Hodgkin lymphoma. In women, the incidence of malignancies was not higher than in the general population (340.6 vs. 404.7 cases per 100,000 person-years, P=.27). The most common malignancies among women were lung cancer, head and neck cancer, cervical cancer and Hodgkin's lymphoma. CONCLUSIONS: Men with HIV infection showed a statistically significant higher incidence of malignancies compared to the general Spanish population. Lung cancer was the most common non-AIDS defining cancer.

Measurement of Head Circumference: Implications for Microcephaly Surveillance in Zika-Affected Areas.

Worldwide recognition of the Zika virus outbreak in the Americas was triggered by an unexplained increase in the frequency of microcephaly. While severe microcephaly is readily identifiable at birth, diagnosing less severe cases requires comparison of head circumference (HC) measurement to a growth chart. We examine measured values of HC and digit preference in those values, and, by extension, the prevalence of microcephaly at birth in two data sources: a research study in Honduras and routine surveillance data in Uruguay. The Zika in Pregnancy in Honduras study enrolled pregnant women prenatally and followed them until delivery. Head circumference was measured with insertion tapes (SECA 212), and instructions including consistent placement of the tape and a request to record HC to the millimeter were posted where newborns were examined. Three indicators of microcephaly were calculated: (1) HC more than 2 standard deviations (SD) below the mean, (2) HC more than 3 SD below the mean (referred to as "severe microcephaly") and (3) HC less than the 3rd percentile for sex and gestational age, using the INTERGROWTH-21st growth standards. We compared these results from those from a previous analysis of surveillance HC data from the Uruguay Perinatal Information System (Sistema Informático Perinatal (SIP). Valid data on HC were available on 579 infants, 578 with gestational age data. Nine babies (1.56%, 95% CI 0.71-2.93) had HC < 2SD, including two (0.35%, 95% CI 0.04-1.24) with HC < 3SD, and 11 (1.9%, 95% CI, 0.79-3.02) were below the 3rd percentile. The distribution of HC showed strong digit preference: 72% of measures were to the whole centimeter (cm) and 19% to the half-cm. Training and use of insertion tapes had little effect on digit preference, nor were overall HC curves sufficient to detect an increase in microcephaly during the Zika epidemic in Honduras. When microcephaly prevalence needs to be carefully analyzed, such as during the Zika epidemic, researchers may need to interpret HC data with caution.

Latency reversal agents affect differently the latent reservoir present in distinct CD4+ T subpopulations.

Latency reversal agents (LRAs) have proven to induce HIV-1 transcription in vivo but are ineffective at decreasing the size of the latent reservoir in antiretroviral treated patients. The capacity of the LRAs to perturb the viral reservoir present in distinct subpopulations of cells is currently unknown. Here, using a new RNA FISH/flow ex vivo viral reactivation assay, we performed a comprehensive assessment of the viral reactivation capacity of different families of LRAs, and their combinations, in different CD4+ T cell subsets. We observed that a median of 16.28% of the whole HIV-reservoir induced HIV-1 transcripts after viral reactivation, but only 10.10% of these HIV-1 RNA+ cells produced the viral protein p24. Moreover, none of the LRAs were powerful enough to reactivate HIV-1 transcription in all CD4+ T cell subpopulations. For instance, the combination of Romidepsin and Ingenol was identified as the best combination of drugs at increasing the proportion of HIV-1 RNA+ cells, in most, but not all, CD4+ T cell subsets. Importantly, memory stem cells were identified as highly resistant to HIV-1 reactivation, and only the combination of Panobinostat and Bryostatin-1 significantly increased the number of cells transcribing HIV within this subset. Overall, our results validate the use of the RNA FISH/flow technique to assess the potency of LRAs among different CD4+ T cell subsets, manifest the intrinsic differences between cells that encompass the latent HIV reservoir, and highlight the difficulty to significantly impact the latent infection with the currently available drugs. Thus, our results have important implications for the rational design of therapies aimed at reversing HIV latency from diverse cellular reservoirs.

National Clinical Practice Guidelines for the management of non-small cell lung cancer in early, locally advanced and metastatic stages. Extended version. / Guía de Práctica Clínica Nacional para el manejo del cáncer de pulmón de células no pequeñas en estadios tempranos, localmente avanzados y metastásicos.

OBJECTIVE: Lung cancer is one the leading causes of mortality worldwide. Symptomatic manifestations of the disease generally occur in the advanced-stage setting, and therefore an important number of patients have advanced or metastatic disease by the time they are diagnosed. This situation contributes to a poor prognosis in the treatment of lung cancer. Evidencebased clinical recommendations are of great value to support decision-making for daily practice, and thus improving health care quality and patient outcomes. MATERIALS AND METHODS: This document was an initiative of the Mexican Society of Oncology (SMEO) in collaboration with Mexican Center of Clinical Excellence (Cenetec) according to Interna- tional Standards. Such standards included those described by the IOM, NICE, SIGN and GI-N. An interdisciplinary Guideline Development Group (GDG) was put together which included medical oncologists, surgical oncologistsc, radiation therapists, and methodologists with expertise in critical appraisal, sys- tematic reviews and clinical practice guidelines development. RESULTS: 62 clinical questions were agreed among members of the GDG. With the evidence identified from systematic reviews, the GDG developed clinical recommendations using a Modified Delphi Panel technique. Patients' representatives validated them. CONCLUSIONS: These Clinical Practice Guideline aims to support the shared decision-making process for patients with different stages of non-small cell lung cancer. Our goal is to improve health-care quality on these patients.

OBJETIVO: El cáncer de pulmón es una de las principales causas de mortalidad alrededor del mundo. Su historia natural, con la manifestación de síntomas en etapas avanzadas y el retraso en su diagnóstico hacen que una gran proporción de pacientes se diagnostiquen en estadios tardíos de la enfermedad, lo que hace muy complicado el tratamiento exitoso de la misma. De esto deriva la importancia de dar origen a recomendaciones basadas en evidencia para soportar la toma de decisiones clínicas por parte de los grupos interdisicplinarios que se encargan del manejo de este padecimiento. MATERIAL Y MÉTODOS: Este documento se desarrolló por parte de la Sociedad Mexicana de Oncología en colaboración con el Centro Nacional de Excelencia Tec- nológica de México (Cenetec) a través de la dirección de integración de Guías de Práctica Clínica en cumplimiento a estándares internacionales como los descritos por el Ins- tituto de Medicina de EUA (IOM, por sus siglas en inglés), el Instituto de Excelencia Clínica de Gran Bretaña (NICE, por sus siglas en inglés), la Red Colegiada para el Desarrollo de Guías de Escocia (SIGN, por sus siglas en inglés), la Red Internacional de Guías (G-I-N, por sus siglas en inglés); entre otros. Se integró en representación de la Sociedad Mexicana de Oncología un Grupo de Desarrollo de la Guía (GDG) de manera interdisciplinaria, considerando oncólogos médicos, cirujanos oncólogos, cirujanos de tórax, radio-oncólogos, y metodólogos con experiencia en revisiones sistemáticas de la literatura y guías de práctica clínica. RESULTADOS: Se consensuaron 62 preguntas cllínicas que abarcaron lo establecido previamente por el GDG en el documento de alcances de la Guía. Se identificó la evidencia científica que responde a cada una de estas preguntas clínicas y se evaluó críticamente la misma, antes de ser incorporada en el cuerpo de evidencia de la Guía. El GDG acordó mediante la técnica de consenso formal de expertos Panel Delphi la redacción final de las recomendaciones clínicas. C. CONCLUSIONES: Esta Guía de Práctica Clínica pretende proveer recomendaciones clínicas para el manejo de los distintos estadios de la enfermedad y que asistan en el proceso de toma de decisiones compartida. El GDG espera que esta guía contribuya a mejorar la calidad de la atención clínica en las pacientes con cáncer de pulmón de células no pequeñas.