Non-continuous and variable rate processes: Optimisation for energy use

The need to develop new and improved ways of reducing energy use and increasing energy intensity in industrial processes is currently a major issue in New Zealand. Little attention has been given to optimisation of non-continuous processes in the past, due to their complexity, yet they remain an essential and often energy intensive component of many industrial sites. Novel models based on pinch analysis that aid in minimising utility usage have been constructed here through the adaptation of proven continuous techniques. The knowledge has been integrated into a user friendly software package, and allows the optimisation of processes under variable operating rates and batch conditions. An example problem demonstrates the improvements in energy use that can be gained when using these techniques to analyse non-continuous data. A comparison with results achieved using a pseudo-continuous method show that the method described can provide simultaneous reductions in capital and operating costs

The use (and misuse) of phylogenetic trees in comparative behavioral analyses

Abstract Phylogenetic comparative methods play a critical role in our understanding of the adaptive origin of primate behaviors. To incorporate evolutionary history directly into comparative behavioral research, behavioral ecologists rely on strong, wellresolved phylogenetic trees. Phylogenies provide the framework on which behaviors can be compared and homologies can be distinguished from similarities due to convergent or parallel evolution. Phylogenetic reconstructions are also of critical importance when inferring the ancestral state of behavioral patterns and when suggesting the evolutionary changes that behavior has undergone. Improvements in genome sequencing technologies have increased the amount of data available to researchers. Recently, several primate phylogenetic studies have used multiple loci to produce robust phylogenetic trees that include hundreds of primate species. These trees are now commonly used in comparative analyses and there is a perception that we have a complete picture of the primate tree. But how confident can we be in those phylogenies? And how reliable are comparative analyses based on such trees? Herein, we argue that even recent molecular phylogenies should be treated cautiously because they rely on many assumptions and have many shortcomings. Most phylogenetic studies do not model gene tree diversity and can produce misleading results, such as strong support for an incorrect species tree, especially in the case of rapid and recent radiations. We discuss implications that incorrect phylogenies can have for reconstructing the evolution of primate behaviors and we urge primatologists to be aware of the current limitations of phylogenetic reconstructions when applying phylogenetic comparative methods

Surgical management of ductal carcinoma in situ of the breast: A large retrospective study from a single institution

Background: Management of breast ductal carcinoma in situ (DCIS) has various approaches with distinct institutional specific practice. Here, we review DCIS management in a single institution with emphasise on re-operation rates and outcome. Methods: DCIS cases diagnosed at the Nottingham Breast Institute between 1987 and 2017 were identified (n=1,249). Clinicopathological data was collected. Cases were histologically reviewed, and different factors associated with primary operation selection, re-excision, presence of residual tumour in the re-excision specimens, use of radiotherapy and ipsilateral recurrences were analysed. Results: 34% of DCIS patients were initially treated by mastectomy and were more frequently symptomatic, of high nuclear tumour grade, size >40mm, and associated with comedo necrosis and Paget’s disease of the nipple. Further surgery was due to involved or narrow surgical margins. Residual tumour tissue was detected in 53% of the re-excision specimens. Re-excision rates of patients treated with breast conserving surgery (BCS) were reduced from approximately 70% to 23% and the final mastectomy rates decreased from 60% to 20%. Changes in surgical practice with acceptance of smaller excision margins and more frequent use of local radiotherapy have led to a significant decrease not only in the re-excision rate but also in the final mastectomy rate together with non-significant reduction in 5- and 10-year local recurrence rates. Conclusion: Although BCS is increasingly the preferred primary surgical option for DCIS management, a proportion of low-risk DCIS patients continue to undergo re-excision surgery or completion mastectomy. Despite acceptance of smaller margins, recurrence rate is decreasing

Lesula: A New Species of Cercopithecus Monkey Endemic to the Democratic Republic of Congo and Implications for Conservation of Congo’s Central Basin

In June 2007, a previously undescribed monkey known locally as “lesula” was found in the forests of the middle Lomami Basin in central Democratic Republic of Congo (DRC). We describe this new species as Cercopithecus lomamiensis sp. nov., and provide data on its distribution, morphology, genetics, ecology and behavior. C. lomamiensis is restricted to the lowland rain forests of central DRC between the middle Lomami and the upper Tshuapa Rivers. Morphological and molecular data confirm that C. lomamiensis is distinct from its nearest congener, C. hamlyni, from which it is separated geographically by both the Congo (Lualaba) and the Lomami Rivers. C. lomamiensis, like C. hamlyni, is semi-terrestrial with a diet containing terrestrial herbaceous vegetation. The discovery of C. lomamiensis highlights the biogeographic significance and importance for conservation of central Congo’s interfluvial TL2 region, defined from the upper Tshuapa River through the Lomami Basin to the Congo (Lualaba) River. The TL2 region has been found to contain a high diversity of anthropoid primates including three forms, in addition to C. lomamiensis, that are endemic to the area. We recommend the common name, lesula, for this new species, as it is the vernacular name used over most of its known range

HIV Risk and Associations of HIV Infection among men who have sex with men in Peri-Urban Cape Town, South Africa

<p>Abstract</p> <p>Background</p> <p>The HIV epidemic in Sub Saharan Africa has been traditionally assumed to be driven by high risk heterosexual and vertical transmission. However, there is an increasing body of data highlighting the disproportionate burden of HIV infection among MSM in the generalized HIV epidemics across of Southern Africa. In South Africa specifically, there has been an increase in attention focused on the risk status and preventive needs of MSM both in urban centers and peri-urban townships. The study presented here represents the first evaluation of HIV prevalence and associations of HIV infection among MSM in the peri-urban townships of Cape Town.</p> <p>Methods</p> <p>The study consisted of an anonymous probe of 200 men, reporting ever having had sex with another man, recruited through venue-base sampling from January to February, 2009.</p> <p>Results</p> <p>Overall, HIV prevalence was 25.5% (n = 51/200). Of these prevalent HIV infections, only 6% of HIV-1 infected MSM were aware of their HIV status (3/50). 0% of men reported always having safe sex as defined by always wearing condoms during sex and using water-based lubricants. Independent associations with HIV infection included inconsistent condom use with male partners (aOR 2.3, 95% CI 1.0-5.4), having been blackmailed (aOR 4.4, 95% CI 1.6-20.2), age over 26 years (aOR 4.2, 95% CI 1.6-10.6), being unemployed (aOR 3.7, 95% CI 1.5-9.3), and rural origin (aOR 6.0, 95% CI 2.2-16.7). Bisexual activity was reported by 17.1% (34/199), and a total of 8% (16/200) reported having a regular female partner. Human rights violations were common with 10.5% (n = 21/200) reporting having been blackmailed and 21.0% (n = 42/200) reporting being afraid to seek health care.</p> <p>Conclusions</p> <p>The conclusions from this study include that a there is a high risk and underserved population of MSM in the townships surrounding Cape Town. The high HIV prevalence and high risk sexual practices suggest that prevalence will continue to increase among these men in the context of an otherwise slowing epidemic. These data further highlight the need to better characterize risk factors for HIV prevention and appropriate targeted combination packages of HIV interventions including biomedical, behavioural, and structural approaches to mitigate HIV risk among these men.</p

Dose-dependent effect and pharmacokinetics of fexinidazole and its metabolites in a mouse model of human African trypanosomiasis.

Human African trypanosomiasis (HAT) is a neglected tropical disease, with a population of 70 million at risk. Current treatment options are limited. In the search for new therapeutics, the repurposing of the broad-spectrum antiprotozoal drug fexinidazole has completed Phase III trials with the anticipation that it will be the first oral treatment for HAT. This study used the recently validated bioluminescence imaging model to assess the dose and rate of kill effect of fexinidazole in infected mice, and the dose-dependent effect of fexinidazole on trypanosome infection. Pharmacokinetics of fexinidazole in plasma and central nervous system (CNS) compartments were similar in both infected and uninfected mice. Drug distribution within the CNS was further examined by microdialysis, showing similar levels in the cortex and hippocampus. However, high variability in drug distribution and exposure was found between mice

Establishing a Pragmatic Framework to Optimise Health Outcomes in Heart Failure and Multimorbidity (ARISE-HF): A Multidisciplinary Position Statement

Background Multimorbidity in heart failure (HF), defined as HF of any aetiology and multiple concurrent conditions that require active management, represents an emerging problem within the ageing HF patient population worldwide. Methods To inform this position paper, we performed: 1) an initial review of the literature identifying the ten most common conditions, other than hypertension and ischaemic heart disease, complicating the management of HF (anaemia, arrhythmias, cognitive dysfunction, depression, diabetes, musculoskeletal disorders, renal dysfunction, respiratory disease, sleep disorders and thyroid disease) and then 2) a review of the published literature describing the association between HF with each of the ten conditions. From these data we describe a clinical framework, comprising five key steps, to potentially improve historically poor health outcomes in this patient population. Results We identified five key steps (ARISE-HF) that could potentially improve clinical outcomes if applied in a systematic manner: 1) Acknowledge multimorbidity as a clinical syndrome that is associated with poor health outcomes, 2) Routinely profile (using a standardised protocol — adapted to the local health care system) all patients hospitalised with HF to determine the extent of concurrent multimorbidity, 3) Identify individualised priorities and person-centred goals based on the extent and nature of multimorbidity, 4) Support individualised, home-based, multidisciplinary, case management to supplement standard HF management, and 5) Evaluate health outcomes well beyond acute hospitalisation and encompass all-cause events and a person-centred perspective in affected individuals. Conclusions We propose ARISE-HF as a framework for improving typically poor health outcomes in those affected by multimorbidity in HF

Aurora kinase A drives the evolution of resistance to third-generation EGFR inhibitors in lung cancer.

Although targeted therapies often elicit profound initial patient responses, these effects are transient due to residual disease leading to acquired resistance. How tumors transition between drug responsiveness, tolerance and resistance, especially in the absence of preexisting subclones, remains unclear. In epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma cells, we demonstrate that residual disease and acquired resistance in response to EGFR inhibitors requires Aurora kinase A (AURKA) activity. Nongenetic resistance through the activation of AURKA by its coactivator TPX2 emerges in response to chronic EGFR inhibition where it mitigates drug-induced apoptosis. Aurora kinase inhibitors suppress this adaptive survival program, increasing the magnitude and duration of EGFR inhibitor response in preclinical models. Treatment-induced activation of AURKA is associated with resistance to EGFR inhibitors in vitro, in vivo and in most individuals with EGFR-mutant lung adenocarcinoma. These findings delineate a molecular path whereby drug resistance emerges from drug-tolerant cells and unveils a synthetic lethal strategy for enhancing responses to EGFR inhibitors by suppressing AURKA-driven residual disease and acquired resistance

The Microphenotron: a robotic miniaturized plant phenotyping platform with diverse applications in chemical biology

Background Chemical genetics provides a powerful alternative to conventional genetics for understanding gene function. However, its application to plants has been limited by the lack of a technology that allows detailed phenotyping of whole-seedling development in the context of a high-throughput chemical screen. We have therefore sought to develop an automated micro-phenotyping platform that would allow both root and shoot development to be monitored under conditions where the phenotypic effects of large numbers of small molecules can be assessed. Results The ‘Microphenotron’ platform uses 96-well microtitre plates to deliver chemical treatments to seedlings of Arabidopsis thaliana L. and is based around four components: (a) the ‘Phytostrip’, a novel seedling growth device that enables chemical treatments to be combined with the automated capture of images of developing roots and shoots; (b) an illuminated robotic platform that uses a commercially available robotic manipulator to capture images of developing shoots and roots; (c) software to control the sequence of robotic movements and integrate these with the image capture process; (d) purpose-made image analysis software for automated extraction of quantitative phenotypic data. Imaging of each plate (representing 80 separate assays) takes 4 min and can easily be performed daily for time-course studies. As currently configured, the Microphenotron has a capacity of 54 microtitre plates in a growth room footprint of 2.1 m², giving a potential throughput of up to 4320 chemical treatments in a typical 10 days experiment. The Microphenotron has been validated by using it to screen a collection of 800 natural compounds for qualitative effects on root development and to perform a quantitative analysis of the effects of a range of concentrations of nitrate and ammonium on seedling development. Conclusions The Microphenotron is an automated screening platform that for the first time is able to combine large numbers of individual chemical treatments with a detailed analysis of whole-seedling development, and particularly root system development. The Microphenotron should provide a powerful new tool for chemical genetics and for wider chemical biology applications, including the development of natural and synthetic chemical products for improved agricultural sustainability

Clinical characteristics, risk factors and outcomes in patients with severe COVID-19 registered in the International Severe Acute Respiratory and Emerging Infection Consortium WHO clinical characterisation protocol: a prospective, multinational, multicentre, observational study

Due to the large number of patients with severe coronavirus disease 2019 (COVID-19), many were treated outside the traditional walls of the intensive care unit (ICU), and in many cases, by personnel who were not trained in critical care. The clinical characteristics and the relative impact of caring for severe COVID-19 patients outside the ICU is unknown. This was a multinational, multicentre, prospective cohort study embedded in the International Severe Acute Respiratory and Emerging Infection Consortium World Health Organization COVID-19 platform. Severe COVID-19 patients were identified as those admitted to an ICU and/or those treated with one of the following treatments: invasive or noninvasive mechanical ventilation, high-flow nasal cannula, inotropes or vasopressors. A logistic generalised additive model was used to compare clinical outcomes among patients admitted or not to the ICU. A total of 40 440 patients from 43 countries and six continents were included in this analysis. Severe COVID-19 patients were frequently male (62.9%), older adults (median (interquartile range (IQR), 67 (55-78) years), and with at least one comorbidity (63.2%). The overall median (IQR) length of hospital stay was 10 (5-19) days and was longer in patients admitted to an ICU than in those who were cared for outside the ICU (12 (6-23) days versus 8 (4-15) days, p<0.0001). The 28-day fatality ratio was lower in ICU-admitted patients (30.7% (5797 out of 18 831) versus 39.0% (7532 out of 19 295), p<0.0001). Patients admitted to an ICU had a significantly lower probability of death than those who were not (adjusted OR 0.70, 95% CI 0.65-0.75; p<0.0001). Patients with severe COVID-19 admitted to an ICU had significantly lower 28-day fatality ratio than those cared for outside an ICU