The response to metformin, the most commonly used drug for the treatment of type 2 diabetes (T2D), is highly variable. The common variant rs7903146 C>T within the transcription factor 7 like 2 gene (TCF7L2) is the strongest genetic risk factor associated with T2D to date. In this study we explored the effects of TCF7L2 rs7903146 genotype on metformin response in T2D. The study included 86 newly diagnosed patients with T2D, incident users of metformin. Levels of fasting glucose, insulin, HbA1c, total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, and anthropometric parameters were measured prior to metformin therapy, and 6 and 12 months after the treatment. Genotyping of TCF7L2 rs7903146 was performed by the Sequenom MassARRAY® iPLEX® platform. At baseline, the diabetes risk allele (T) showed an association with lower triglyceride levels (p = 0.037). After 12 months of metformin treatment, the T allele was associated with 25.9% lower fasting insulin levels (95% CI 10.9-38.3%, p = 0.002) and 29.1% lower HOMA-IR index (95% CI 10.1-44.1%, p = 0.005), after adjustment for baseline values. Moreover, the T allele was associated with 6.7% lower fasting glucose levels (95% CI 1.1-12.0%, p = 0.021), adjusted for baseline glucose and baseline HOMA-%B levels, after 6 months of metformin treatment. This effect was more pronounced in TT carriers who had 16.8% lower fasting glucose levels (95% CI 7.0-25.6%, p = 0.002) compared to the patients with CC genotype. Our results suggest that TCF7L2 rs7903146 variant affects markers of insulin resistance and glycemic response to metformin in newly diagnosed patients with T2D within the first year of metformin treatment.

A tuberculose é uma importante causa de adoecimento e morte no mundo. O trato geniturinário circula entre os sítios extrapulmonares mais acometidos e, muitas vezes, tem diagnóstico tardio. Realizou-se um estudo de caso com objetivo de apresentar os principais Diagnósticos de Enfermagem relativos ao paciente em tratamento de tuberculose renal. O estudo foi realizado no âmbito da Atenção Primária à Saúde, onde as ações de Enfermagem, juntamente aos demais integrantes da equipe multiprofissional, podem propiciar um desfecho do tratamento favorável para esse paciente.Palavras-chave: diagnóstico de enfermagem, tuberculose renal, cuidados de enfermagem.

Taking advantage of the flexibility of the apatite structure, nano- and micro-particles of hydroxyapatite (HAp) were doped with different combinations of rare earth ions (RE3+ = Gd, Eu, Yb, Tm) to achieve a synergy among their magnetic and optical properties and to enable their application in preventive medicine, particularly diagnostics based on multimodal imaging. All powders were synthesized through hydrothermal processing at T ≤ 200 °C. An X-ray powder diffraction analysis showed that all powders crystallized in P63/m space group of the hexagonal crystal structure. The refined unit-cell parameters reflected a decrease in the unit cell volume as a result of the partial substitution of Ca2+ with smaller RE3+ ions at both cation positions. The FTIR analysis additionally suggested that a synergy may exist solely in the triply doped system, where the lattice symmetry and vibration modes become more coherent than in the singly or doubly doped systems. HAp:RE3+ optical characterization revealed a change in the energy band gap and the appearance of a weak blue luminescence (λex = 370 nm) due to an increased concentration of defects. The “up”- and the “down”-conversion spectra of HAp:Gd/Yb/Tm and HAp:Gd/Eu powders showed characteristic transitions of Tm3+ and Eu3+, respectively. Furthermore, in contrast to diamagnetic HAp, all HAp:RE3+ powders exhibited paramagnetic behavior. Cell viability tests of HAp:Gd/Yb/Tm and HAp:Gd/Eu powders in human dental pulp stem cell cultures indicated their good biocompatibility.

In this manuscript we describe how, by taking a systems approach, complex energy landscapes of supramolecular assemblies can be navigated using stoichiometry to control, with remarkable selectivity, which assembly gets populated. The perhaps counterintuitive finding is that it is not necessarily the assembly that, in a one-to-one comparison, is the most stable that wins the competition for common building blocks, even though the system is under thermodynamic control. Instead, an individually less stable assembly may completely dominate the system. This domination is possible when the building block stoichiometry in the system matches the stoichiometry of this specific assembly, allowing the system to maximize binding energy by making a large number of assemblies of moderate stability as opposed to a small number of more stable assemblies.

Frameshift insertion/deletions (fs-indels) are an infrequent but highly immunogenic mutation subtype. Although fs-indels are degraded through the nonsense-mediated decay (NMD) pathway, we hypothesise that some fs-indels escape degradation and elicit anti-tumor immune responses. Using allele-specific expression analysis, expressed fs-indels are enriched in genomic positions predicted to escape NMD, and associated with higher protein expression, consistent with degradation escape (NMD-escape). Across four independent melanoma cohorts, NMD-escape mutations are significantly associated with clinical-benefit to checkpoint inhibitor (CPI) therapy (Pmeta = 0.0039). NMD-escape mutations are additionally found to associate with clinical-benefit in the low-TMB setting. Furthermore, in an adoptive cell therapy treated melanoma cohort, NMD-escape mutation count is the most significant biomarker associated with clinical-benefit. Analysis of functional T cell reactivity screens from personalized vaccine studies shows direct evidence of fs-indel derived neoantigens eliciting immune response, particularly those with highly elongated neo open reading frames. NMD-escape fs-indels represent an attractive target for biomarker optimisation and immunotherapy design. The transcripts generated by frameshifts and indels in cancer are frequently degraded by nonsense mediated decay. Here, the authors show that some of these transcripts can escape this degradation mechanism and their prevalence correlates with tumour response to immunotherapy.

This paper presents enhanced coordination between TSOs and DSOs with regard to market related information and data infrastructures that can be developed using a cloud-based approach. The definition of use cases with regard to the levels of portal access is proposed and particular attention is given to the different time and space scales of data that is needed to provide harmonised access. The attributes of the information layer as defined in the Smart Grid Architecture Model (SGAM) are reflected in the formally defined use cases. Different access levels are demonstrated via the definition of use cases for a trusted cloud platform by considering harmonised access processes and role-based access control for security.

Ambroise Paré was celebrated surgeon of the 16th Century whose practical accomplishments, books, and ideas transformed surgery and was a precursor for the later development of neurosurgery. He developed many surgical innovations related to wound management, arterial ligation for the prevention of hemorrhage during limb amputations, and the treatment of war-related head and spine injuries. He maintained that a surgeon should operate gently to reduce pain and improve outcome, and he dedicated his career to the wounded, sick and poor. He also served four consecutive French monarchs-Henri II and his three sons François II, Charles IX, and Henri III. As a Huguenot (a Reformed Protestant) by faith, he lived in an environment dominated by Catholicism. Hence, his practice and life were sometimes hindered by political circumstances and religious prejudice. In this historical vignette, we will discuss the professional accomplishments of Ambroise Paré that influenced the future development of neurosurgery, including his descriptions of phantom-limb pain and peripheral nerve injury, his innovations in neurotraumatology, and the saws he invented for use in skull surgery. We will also highlight Paré's broad neurosurgical contributions to the field. Finally, we will discuss his personal life during the difficult and dangerous political circumstances of 16th Century France.

Two commercial tomato cultivars were used to determine whether grafting could prevent decrease of Ca2+ concentration under salt stress conditions. The cultivars Buran F1 and Berberana F1 were grafted onto rootstock "Maxifort" and grown under three levels of the elevated soil salinity (S1 EC 3.80 dS m-1, S2 6.95 dS m-1 and S3 9.12 dS m-1). Ca2+ concentration of non-grafted plants of both examined hybrids was lower at all salinity levels in comparison to the control. In the fruits of grafted plants salt stress significantly decreased Ca2+ concentration only at the third salinity level (EC 9.12 dS m-1). The possibility of grafting tomato plants to improve influx of Ca2+ under salt stress conditions is discussed.

Once coined the neglected stepchild of global health, surgical care has become an integral part of healthcare.1 Five billion people worldwide lack access to safe, timely, and affordable surgery, obstetrics, and anesthesia, causing over 18 million preventable deaths each year.2 To systematically address infrastructural and workforce shortages, and increase the accessibility of safe surgical care, National Surgical, Obstetric, and Anesthesia Plans (NSOAPs) are being developed around the world.3 As strategic plans embedded within countries' national health plans, NSOAPs allow for comprehensive health system strengthening across workforce, infrastructure, service delivery, financing, information management, and governance.4