Genetic Study of SARS-CoV-2 Non Structural Protein 12 in COVID-19 Patients Non Responders to Remdesivir.

Remdesivir (RDV) was the first antiviral drug approved by the FDA to treat severe coronavirus disease-2019 (COVID-19) patients. RDV inhibits SARS-CoV-2 replication by stalling the non structural protein 12 (nsp12) subunit of the RNA-dependent RNA polymerase (RdRp). No evidence of global widespread RDV-resistance mutations has been reported, however, defining genetic pathways to RDV resistance and determining emergent mutations prior and subsequent antiviral therapy in clinical settings is necessary. This study identified 57/149 (38.3%) patients who did not respond to one course (5-days) (n = 36/111, 32.4%) or prolonged (5 to 20 days) (n = 21/38, 55.3%) RDV therapy by subgenomic RNA detection. Genetic variants in the nsp12 gene were detected in 29/49 (59.2%) non responder patients by Illumina sequencing, including the de novo E83D mutation that emerged in an immunosuppressed patient after receiving 10 + 8 days of RDV, and the L838I detected at baseline and/or after prolonged RDV treatment in 9/49 (18.4%) non responder subjects. Although 3D protein modeling predicted no interference with RDV, the amino acid substitutions detected in the nsp12 involved changes on the electrostatic outer surface and in secondary structures that may alter antiviral response. It is important for health surveillance to study potential mutations associated with drug resistance as well as the benefit of RDV retreatment, especially in immunosuppressed patients and in those with persistent replication. IMPORTANCE This study provides clinical and microbiologic data of an extended population of hospitalized patients for COVID-19 pneumonia who experienced treatment failure, detected by the presence of subgenomic RNA (sgRNA). The genetic variants found in the nsp12 pharmacological target of RDV bring into focus the importance of monitoring emergent mutations, one of the objectives of the World Health Organization (WHO) for health surveillance. These mutations become even more crucial as RDV keeps being prescribed and new molecules are being repurposed for the treatment of COVID-19. The present article offers new perspectives for the clinical management of non responder patients treated and retreated with RDV and emphasizes the need of further research of the benefit of combinatorial therapies and RDV retreatment, especially in immunosuppressed patients with persistent replication after therapy.

Suggestions for Improvements in National Radon Control Strategies of Member States Which Were Developed as a Requirement of EU Directive 2013/59 EURATOM.

Exposure to the indoor air pollutant radon is considered to be a significant health risk globally, as has been demonstrated by many studies over time. A recent WHO statement on radon estimates that, worldwide, approximately 80,000 people may die every year due to lung cancer associated with radon exposure. The recent years have also seen huge improvements in radon policies in European countries, as a consequence of the issuing, in 2013, of the Council Directive 2013/59/Euratom. Although the protection of workers from radon exposure is well established, the protection of the general public needs more improvements. The main objective of this paper is, first, to acknowledge and recognise the improvements in radon protection policies, but also to show that there are many areas where improvements are desirable and possible. The final goal is to suggest better ways to protect the general population from exposure to radon gas. The suggestions are based on the experiences of the co-authors, who come from different disciplines related to radon management. The following fields or areas where improvements are possible are identified: risk communication, building codes, radon policies, including funding, research and protection of children. We describe the work that has been conducted, and the possible improvements and solutions in these fields.

Long-term efficacy and safety profiles following small incision lenticule extraction in eyes with ≥ 5-year follow-up.

PURPOSE: To evaluate long-term efficacy, safety, predictability and stability (refractive and keratometric) of myopic and myopic astigmatism correction with Small Incision Lenticule Extraction (SMILE). METHODS: Single center retrospective review of eyes undergoing SMILE from 2012-2015. Forty-two eyes (23 patients) with ≥ 5-year follow-up. Variables analyzed were preoperative, 3-month, 1-year and last follow-up uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), manifest refraction, spherical equivalent (SE) and mean keratometry. Descriptive statistics were performed and results reported following the Standard for Reporting Astigmatism Outcomes. RESULTS: Mean follow-up of 5.98 ± 0.90 years. Mean preoperative SE was -5.26 ± 1.22D (range -2.50 to -8.12D). Mean preoperative cylinder was -0.66 ± 0.61D (range 0.00 to -2.25D). Efficacy and safety indices were 0.86 and 0.98, respectively. In total, 81% of operated eyes achieved an UDVA of ≥ 0.09 logMar (20/25 Snellen). At the last follow-up, ≥1 line of CDVA was gained in 14% of eyes. Five percent lost 1 line of CDVA, and no eye loss ≥2 lines of CDVA. Sixty-nine percent of eyes were within ± 0.50D and 86% within ± 1.00D of the attempted SE correction. Ninety-one percent of eyes had ≤0.50D of postoperative astigmatism and 71% were within ± 15° from the intended correction axis. At the final follow-up, a statistically significant myopic regression of 0.19 ± 0.50D was observed (p = 0.01). CONCLUSIONS: Long-term results demonstrate that SMILE is effective, predictable and safe. SMILE has good stability, low regression compared to LASIK, and no signs of corneal ectasia staging within our standard criteria.

Chromatin topology defines estradiol-primed progesterone receptor and PAX2 binding in endometrial cancer cells.

Estrogen (E2) and Progesterone (Pg), via their specific receptors (ERalpha and PR), are major determinants in the development and progression of endometrial carcinomas, However, their precise mechanism of action and the role of other transcription factors involved are not entirely clear. Using Ishikawa endometrial cancer cells, we report that E2 treatment exposes a set of progestin-dependent PR binding sites which include both E2 and progestin target genes. ChIP-seq results from hormone-treated cells revealed a non-random distribution of PAX2 binding in the vicinity of these estrogen-promoted PR sites. Altered expression of hormone regulated genes in PAX2 knockdown cells suggests a role for PAX2 in fine-tuning ERalpha and PR interplay in transcriptional regulation. Analysis of long-range interactions by Hi-C coupled with ATAC-seq data showed that these regions, that we call 'progestin control regions' (PgCRs), exhibited an open chromatin state even before hormone exposure and were non-randomly associated with regulated genes. Nearly 20% of genes potentially influenced by PgCRs were found to be altered during progression of endometrial cancer. Our findings suggest that endometrial response to progestins in differentiated endometrial tumor cells results in part from binding of PR together with PAX2 to accessible chromatin regions. What maintains these regions open remains to be studied.

Participación en el sector no agropecuario en el México rural: una perspectiva de género / Participação no setor não agrícola no México rural: uma perspectiva de gênero / Participation in the non-agricultural sector in rural Mexico: a gender perspective

Los hogares rurales diversifican sus ingresos como estrategia para minimizar los riesgos, reducir la variabilidad y asegurar un nivel mínimo de ingreso. Con información panel de la Encuesta Nacional a Hogares Rurales de México, el presente estudio examina, bajo una perspectiva de género, los factores que determinan la participación en el sector no agropecuario. Los resultados señalan que en las ocupaciones asalariadas no agropecuarias, los hombres participan con menores niveles de escolaridad y la condición de indígena limita la incorporación de ambos géneros. En actividades no agropecuarias por cuenta propia son esenciales la riqueza acumulada del hogar y los servicios financieros, de comunicación y transporte.

As famílias rurais diversificam sua renda como estratégia para minimizar o risco, reduzir a variabilidade e garantir um nível mínimo de renda. Com informações da Encuesta Nacional a Hogares Rurales de México, o presente estudo examinou, sob uma perspectiva de gênero, os fatores que determinam a participação no setor não agrícola. Os resultados indicam que, nas ocupações assalariadas não agrícolas, os homens participam com baixos níveis de escolaridade e a situação indígena limita a incorporação de ambos os sexos. Em atividades de autoemprego não agrícola, são essenciais a riqueza acumulada das famílias e serviços financeiros, de comunicação e transporte.

Rural households diversify their income as a strategy to minimize risk, reduce variability and ensure a minimum level of income. With information panel of the National Rural Household Survey of Mexico, this study examined under a gender perspective, the factors that determine participation in the non-agricultural sector. The results indicate that employed in non-agricultural occupations, men participate with lower levels of education and indigenous status limits the incorporation of both genders. In non-agricultural self-employment activities are essential household accumulated wealth and financial services, communication and transportation.

Como lograr mayor prosperidad en tierras forestales en tierras fragmentadas / How to get greater prosperity in fragmented forest lands

La prosperidad de los dueños de tierras forestales y la calidad del medio ambiente asociada al uso de estas tierras dependen del éxito de los negocios forestales que sus dueños puedan realizar en ellas. Los negocios forestales en propiedades fragmentadas son menos competitivos, lo que lleva frecuentemente a la conversión de tales tierras a usos no sostenibles. Una de las formas de enfrentar los problemas de las tierras forestales fragmentadas es integrarlas en unidades productivas mayores que permitan la utilización de tecnologías más adecuadas para propiedades mayores. Con la integración, los pequeños propietarios pueden adoptar tecnologías más productivas, aprovechar precios de insumos o productos más favorables, ser más competitivos, mejorar los ingresos, y generar externalidades positivas para la sociedad. Consecuentemente, podrán ser más prósperos. Por su lado, la industria forestal competitiva depende de insumos de calidad, en la cantidad y oportunidad adecuadas, a precios competitivos. Tradicionalmente, la industria utiliza su limitado capital para comprar tierras para producir la madera que necesita o depende de proveedores inciertos. En ambos casos, su capacidad de crecer y competir es sacrificada. El artículo discute el caso de la integración vertical entre pequeños dueños de tierra y la industria para el beneficio mutuo; se identifica y discute los principales instrumentos legales, institucionales y financieros necesarios para promover la integración vertical. También se presentan cuatro tipos de apoyos que los gobiernos pueden adoptar: 1) crear las condiciones previas a la integración, 2) aclarar las reglas del juego, 3) apoyar la integración, y 4) disminuir costos de transacción

Corynebacterium macginleyi isolated from urine in a patient with a permanent bladder catheter.

An 82-y-old male patient with a neurogenic bladder and vesical stones presented with a urinary tract infection caused by Corynebacterium macginleyi. This is the first case of isolation of C. macginleyi from a non-conjunctival specimen. The patient recovered fully with antimicrobial treatment.