Non-conventional Technologies as Alternative Solutions to the Proposed Whakamaru-Otahuhu Transmission Upgrade

This commentary brings together a preliminary view of the potential of non-conventional generation as a comprehensive alternative solution to the proposed Auckland transmission upgrade

Social Freedom and Self-Actualization: “Normative Reconstruction” as a Theory of Justice

In Freedom's Right Axel Honneth seeks to provide a theory of justice by appropriatingHegel's account of ethical substance in the Philosophy of Right, but hewants to do sowithout endorsingHegel'smore robust idealist commitments. I argue that this project can only succeed if Honneth can offer an alternative, comparatively robust demonstration of the rationality and normative coherence of existing social institutions. I contend that the grounds Honneth provides for this claimare insufficient for his purposes. In particular, I argue that Honneth's claim that "justice and individual self-determination are mutually referential," even were it to be accepted, would be insufficient to underwrite hismore robust identification between the normative foundations of justice, autonomy and reciprocal self-realization. In the final section of the paper, I turn to Honneth's analysis of the "social institution" of friendship,which he, followingHegel, holds up as a paradigmatic instantiation of social freedom understood as, in Hegel's words, "being with oneself in another" (Beisichselbstsein in einem Anderen). I argue that an analysis of the normative import of friendship wholly in terms of mutual recognition misses an important aspect of the kind of self-realization that friendship makes possible

Determination of the physiological and pathological roles of E2F3 in adult tissues

While genetically engineered mice have made an enormous contribution towards the elucidation of human disease, it has hitherto not been possible to tune up or down the level of expression of any endogenous gene. Here we describe compound genetically modified mice in which expression of the endogenous E2f3 gene may be either reversibly elevated or repressed in adult animals by oral administration of tetracycline. This technology is, in principle, applicable to any endogenous gene, allowing direct determination of both elevated and reduced gene expression in physiological and pathological processes. Applying this switchable technology to the key cell cycle transcription factor E2F3, we demonstrate that elevated levels of E2F3 drive ectopic proliferation in multiple tissues. By contrast, E2F3 repression has minimal impact on tissue proliferation or homeostasis in the majority of contexts due to redundancy of adult function with E2F1 and E2F2. In the absence of E2F1 and E2F2, however, repression of E2F3 elicits profound reduction of proliferation in the hematopoietic compartments that is rapidly lethal in adult animals.This work was supported by CRUK (Programme Grant A12077), the ERC (Advanced Investigator Award 294851), and the NCI (grants CA98018, CA100193) (all to G.I.E.). D.G. was supported by NIGMS grant #1 R25 GM56847. MB was funded by an EMBO Long-term fellowship and an Australian NHMRC Early Career Fellowship

Análise técnica e econômica do equipamento Stump Harvester

Orientador: Prof. Dr. Ricardo Anselmo MalinovskiMonografia (graduação) - Universidade Federal do Paraná,Setor de Ciências Agrárias, Curso de Engenharia Florestal.Resumo: As atividades de colheita florestal comumente geram uma grande quantidade de resíduos em plantios florestais de Pinus spp. e Eucalyptus spp, prejudicando as operações silviculturais. Dentre todos os tipos de resíduos florestais, os tocos constituem um grande dificultador das operações de implantação florestal como subsolagem, fertilização, plantio e manutenção. A redução da qualidade das operações pode levar à uma redução na área de efetivo plantio, reduzindo o número de árvores plantadas por hectare e subutilizando o sítio. Diante disso, buscam-se alternativas para remoção e aproveitamento de resíduos florestais. Quanto a remoção de tocos, uma alternativa atual é o equipamento stump harvester que consiste em um implemento específico para a remoção de tocos montado em uma escavadeira hidráulica. Diante disso, o presente trabalho avaliou técnica e economicamente o equipamento stump harvester para a reforma e realinhamento de plantios de Pinus taeda e Eucalyptus dunnii em uma empresa florestal do norte de Santa Catarina. Foram avaliados a produtividade, custos, receitas e indicadores econômicos no intuito de avaliar a viabilidade do investimento no equipamento. Como resultado de produtividade obteve-se uma média de 3,88 e 3,19 tocos/min para o Pinus taeda e Eucalyptus dunnii, respectivamente. O custo de remoção foi calculado em 1.521,47 R$/ha para o Pinus taeda e 1.778,72 R$/ha para o Eucalyptus dunnii. Foram estimadas diversas situações de aumento de receitas com a utilização do equipamento. Quando utilizado somente para fins de reforma e realinhamento o uso do equipamento é inviável a uma taxa mínima de atratividade de 10%. Recomenda-se, entretanto, a quantificação e qualificação do material extraído para a produção de biomassa, pois, segundo literatura especializada, existe um grande potencial energético nesse material

Reactivation of Myc transcription in the mouse heart unlocks its proliferative capacity

Abstract: It is unclear why some tissues are refractory to the mitogenic effects of the oncogene Myc. Here we show that Myc activation induces rapid transcriptional responses followed by proliferation in some, but not all, organs. Despite such disparities in proliferative response, Myc is bound to DNA at open elements in responsive (liver) and non-responsive (heart) tissues, but fails to induce a robust transcriptional and proliferative response in the heart. Using heart as an exemplar of a non-responsive tissue, we show that Myc-driven transcription is re-engaged in mature cardiomyocytes by elevating levels of the positive transcription elongation factor (P-TEFb), instating a large proliferative response. Hence, P-TEFb activity is a key limiting determinant of whether the heart is permissive for Myc transcriptional activation. These data provide a greater understanding of how Myc transcriptional activity is determined and indicate modification of P-TEFb levels could be utilised to drive regeneration of adult cardiomyocytes for the treatment of heart myopathies

Modeling of Human Prokineticin Receptors: Interactions with Novel Small-Molecule Binders and Potential Off-Target Drugs

The Prokineticin receptor (PKR) 1 and 2 subtypes are novel members of family A GPCRs, which exhibit an unusually high degree of sequence similarity. Prokineticins (PKs), their cognate ligands, are small secreted proteins of ∼80 amino acids; however, non-peptidic low-molecular weight antagonists have also been identified. PKs and their receptors play important roles under various physiological conditions such as maintaining circadian rhythm and pain perception, as well as regulating angiogenesis and modulating immunity. Identifying binding sites for known antagonists and for additional potential binders will facilitate studying and regulating these novel receptors. Blocking PKRs may serve as a therapeutic tool for various diseases, including acute pain, inflammation and cancer.Ligand-based pharmacophore models were derived from known antagonists, and virtual screening performed on the DrugBank dataset identified potential human PKR (hPKR) ligands with novel scaffolds. Interestingly, these included several HIV protease inhibitors for which endothelial cell dysfunction is a documented side effect. Our results suggest that the side effects might be due to inhibition of the PKR signaling pathway. Docking of known binders to a 3D homology model of hPKR1 is in agreement with the well-established canonical TM-bundle binding site of family A GPCRs. Furthermore, the docking results highlight residues that may form specific contacts with the ligands. These contacts provide structural explanation for the importance of several chemical features that were obtained from the structure-activity analysis of known binders. With the exception of a single loop residue that might be perused in the future for obtaining subtype-specific regulation, the results suggest an identical TM-bundle binding site for hPKR1 and hPKR2. In addition, analysis of the intracellular regions highlights variable regions that may provide subtype specificity

Elective surgery system strengthening: development, measurement, and validation of the surgical preparedness index across 1632 hospitals in 119 countries

Background: The 2015 Lancet Commission on global surgery identified surgery and anaesthesia as indispensable parts of holistic health-care systems. However, COVID-19 exposed the fragility of planned surgical services around the world, which have also been neglected in pandemic recovery planning. This study aimed to develop and validate a novel index to support local elective surgical system strengthening and address growing backlogs. Methods: First, we performed an international consultation through a four-stage consensus process to develop a multidomain index for hospital-level assessment (surgical preparedness index; SPI). Second, we measured surgical preparedness across a global network of hospitals in high-income countries (HICs), middle-income countries (MICs), and low-income countries (LICs) to explore the distribution of the SPI at national, subnational, and hospital levels. Finally, using COVID-19 as an example of an external system shock, we compared hospitals' SPI to their planned surgical volume ratio (SVR; ie, operations for which the decision for surgery was made before hospital admission), calculated as the ratio of the observed surgical volume over a 1-month assessment period between June 6 and Aug 5, 2021, against the expected surgical volume based on hospital administrative data from the same period in 2019 (ie, a pre-pandemic baseline). A linear mixed-effects regression model was used to determine the effect of increasing SPI score. Findings: In the first phase, from a longlist of 103 candidate indicators, 23 were prioritised as core indicators of elective surgical system preparedness by 69 clinicians (23 [33%] women; 46 [67%] men; 41 from HICs, 22 from MICs, and six from LICs) from 32 countries. The multidomain SPI included 11 indicators on facilities and consumables, two on staffing, two on prioritisation, and eight on systems. Hospitals were scored from 23 (least prepared) to 115 points (most prepared). In the second phase, surgical preparedness was measured in 1632 hospitals by 4714 clinicians from 119 countries. 745 (45·6%) of 1632 hospitals were in MICs or LICs. The mean SPI score was 84·5 (95% CI 84·1–84·9), which varied between HIC (88·5 [89·0–88·0]), MIC (81·8 [82·5–81·1]), and LIC (66·8 [64·9–68·7]) settings. In the third phase, 1217 (74·6%) hospitals did not maintain their expected SVR during the COVID-19 pandemic, of which 625 (51·4%) were from HIC, 538 (44·2%) from MIC, and 54 (4·4%) from LIC settings. In the mixed-effects model, a 10-point increase in SPI corresponded to a 3·6% (95% CI 3·0–4·1; p<0·0001) increase in SVR. This was consistent in HIC (4·8% [4·1–5·5]; p<0·0001), MIC (2·8 [2·0–3·7]; p<0·0001), and LIC (3·8 [1·3–6·7%]; p<0·0001) settings. Interpretation: The SPI contains 23 indicators that are globally applicable, relevant across different system stressors, vary at a subnational level, and are collectable by front-line teams. In the case study of COVID-19, a higher SPI was associated with an increased planned surgical volume ratio independent of country income status, COVID-19 burden, and hospital type. Hospitals should perform annual self-assessment of their surgical preparedness to identify areas that can be improved, create resilience in local surgical systems, and upscale capacity to address elective surgery backlogs. Funding: National Institute for Health Research (NIHR) Global Health Research Unit on Global Surgery, NIHR Academy, Association of Coloproctology of Great Britain and Ireland, Bowel Research UK, British Association of Surgical Oncology, British Gynaecological Cancer Society, and Medtronic

Global wealth disparities drive adherence to COVID-safe pathways in head and neck cancer surgery

Peer reviewe

The impact of surgical delay on resectability of colorectal cancer: An international prospective cohort study

AIM: The SARS-CoV-2 pandemic has provided a unique opportunity to explore the impact of surgical delays on cancer resectability. This study aimed to compare resectability for colorectal cancer patients undergoing delayed versus non-delayed surgery. METHODS: This was an international prospective cohort study of consecutive colorectal cancer patients with a decision for curative surgery (January-April 2020). Surgical delay was defined as an operation taking place more than 4 weeks after treatment decision, in a patient who did not receive neoadjuvant therapy. A subgroup analysis explored the effects of delay in elective patients only. The impact of longer delays was explored in a sensitivity analysis. The primary outcome was complete resection, defined as curative resection with an R0 margin. RESULTS: Overall, 5453 patients from 304 hospitals in 47 countries were included, of whom 6.6% (358/5453) did not receive their planned operation. Of the 4304 operated patients without neoadjuvant therapy, 40.5% (1744/4304) were delayed beyond 4 weeks. Delayed patients were more likely to be older, men, more comorbid, have higher body mass index and have rectal cancer and early stage disease. Delayed patients had higher unadjusted rates of complete resection (93.7% vs. 91.9%, P = 0.032) and lower rates of emergency surgery (4.5% vs. 22.5%, P < 0.001). After adjustment, delay was not associated with a lower rate of complete resection (OR 1.18, 95% CI 0.90-1.55, P = 0.224), which was consistent in elective patients only (OR 0.94, 95% CI 0.69-1.27, P = 0.672). Longer delays were not associated with poorer outcomes. CONCLUSION: One in 15 colorectal cancer patients did not receive their planned operation during the first wave of COVID-19. Surgical delay did not appear to compromise resectability, raising the hypothesis that any reduction in long-term survival attributable to delays is likely to be due to micro-metastatic disease

Statistical design and analysis in trials of proportionate interventions: a systematic review

Background: In proportionate or adaptive interventions, the dose or intensity can be adjusted based on individual need at predefined decision stages during the delivery of the intervention. The development of such interventions may require an evaluation of the effectiveness of the individual stages in addition to the whole intervention. However, evaluating individual stages of an intervention has various challenges, particularly the statistical design and analysis. This review aimed to identify the use of trials of proportionate interventions and how they are being designed and analysed in current practice. Methods: We searched MEDLINE, Web of Science and PsycINFO for articles published between 2010 and 2015 inclusive. We considered trials of proportionate interventions in all fields of research. For each trial, its aims, design and analysis were extracted. The data synthesis was conducted using summary statistics and a narrative format. Results: Our review identified 44 proportionate intervention trials, comprising 28 trial results, 13 protocols and three secondary analyses. These were mostly described as stepped care (n=37) and mainly focussed on mental health research (n=30). The other studies were aimed at finding an optimal adaptive treatment strategy (n=7) in a variety of therapeutic areas. Further terminology used included adaptive intervention, staged intervention, sequentially multiple assignment trial or a two-phase design. The median number of decision stages in the interventions was two and only one study explicitly evaluated the effect of the individual stages. Conclusions: Trials of proportionate staged interventions are being used predominantly within the mental health field. However, few studies consider the different stages of the interventions, either at the design or the analysis phase, and how they may interact with one another. There is a need for further guidance on the design, analyses and reporting across trials of proportionate interventions