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Abstract Lin28 is a key regulator of cancer stem cell gene network that promotes therapy-resistant tumor progression in various tumors. However, no Lin28 inhibitor has been approved to treat cancer patients, urging exploration of novel compounds as candidates to be tested for clinical trials. In this contribution, we applied computer-aided drug design (CADD) in combination with quantitative biochemical and biological assays. These efforts led to the discovery of Ln268 as a drug candidate that can block Lin28 from binding to its RNA substrates and inhibit Lin28 activities. Ln268 suppressed Lin28-mediated cancer cell proliferation and spheroid growth. Results from nuclear magnetic resonance spectroscopy confirmed that Ln268 perturbs the conformation of the zinc knuckle domain of Lin28, validating the rational drug design by CADD. The inhibitory effects of Ln268 are dependent on Lin28 protein expression in cancer cells, highlighting limited off-target effects of Ln268. Moreover, Ln268 synergizes with several chemotherapy drugs to suppress tumor cell growth. In summary, Ln268 is a promising candidate for further development to target Lin28 as a cancer therapy.

Abstract Up to 40% of patients with estrogen receptor (ER)-positive breast cancer will develop resistance against the majority of current ER-directed therapies. Resistance can arise through various mechanisms such as increased expression levels of coregulators, and key mutations acquired in the receptor’s ligand binding domain rendering it constitutively active. To overcome these resistance mechanisms, we explored targeting the ER Activation Function 2 (AF2) site, which is essential for coactivator binding and activation. Using artificial intelligence and the deep docking methodology, we virtually screened > 1 billion small molecules and identified 290 potential AF2 binders that were then characterized and validated through an iterative screening pipeline of cell-based and cell-free assays. We ranked the compounds based on their ability to reduce the transcriptional activity of the estrogen receptor and the viability of ER-positive breast cancer cells. We identified a lead compound, VPC-260724, which inhibits ER activity at low micromolar range. We confirmed its direct binding to the ER-AF2 site through a PGC1α peptide displacement experiment. Using proximity ligation assays, we showed that VPC-260724 disrupts the interaction between ER-AF2 and the coactivator SRC-3 and reduces the expression of ER target genes in various breast cancer models including the tamoxifen resistant cell line TamR3. In conclusion, we developed a novel ER-AF2 binder, VPC-260724, which shows antiproliferative activity in ER-positive breast cancer models. The use of an ER-AF2 inhibitor in combination with current treatments may provide a novel complementary therapeutic approach to target treatment resistance in ER-positive breast cancer.

BackgroundThe spleen is commonly injured in trauma and this may be managed with a conservative approach, embolisation or splenectomy. There is uncertainty how splenic embolisation fits into the treatment paradigm and the delivery of IR services remains variable.Aims and objectivesThe primary objectives are to determine if service design significantly affects splenic embolisation (SE) rates in AAST grade 2-5 acute traumatic splenic injuries (ATSI) across the Major Trauma Centres (MTCs) in England and to determine if variation in treatment affects SE outcomes in ATSI.MethodsWe will include 5 years of data from traumatic splenic injury patients in the MTCs from 01/01/2016 to 31/12/2020 available from the Trauma Audit and Research Network (TARN) database. Inclusion Criteria will be all patients with ATSI registered with TARN. Those without a CT available to grade radiologically will be excluded. Data available from the TARN database and then correlated with data that will be collected at each MTC, where detail as to the embolisation technique, specific injury pattern, imaging based follow up and patient survival will be available. A short service-based questionnaire will be sent to each centre to establish centre-specific details such as on call rota, IR response activation, reporting practices and capture data around routine decision-making at that site. Data will be collected on an anonymised (REDCap) database. This project will evaluate the impact of service design on embolisation rates and outcomes, as well as evaluating the impact of the variation upon treatment selection and outcomes. Logistic regression will be used to identify factors associated with treatment selection and mortality at 30 days.

Introduction: The seemingly inexorable rise of opioid-related overdose deaths despite the reduced number of COVID-19 pandemic deaths demands novel responses and partnerships in our public health system’s response. Addiction medicine is practiced in a broad range of siloed clinical environments that need to be included in addiction medicine training beyond the traditional fellowship programs. Our objective in this project was to implement a knowledge-based, live virtual training program that would provide clinicians and other healthcare professionals with an overview of addiction, substance use disorders (SUD), and clinical diagnosis and management of opioid use disorder (OUD). Methods: The Veterans Health Administration (VHA) Emergency Department Opioid Safety Initiative (ED OSI) offered a four-day course for healthcare professionals interested in gaining knowledge and practical skills to improve VHA-based SUD care. The course topics centered around the diagnosis and treatment of SUD, with a focus on OUD. Additionally, trainees received six months of support to develop addiction medicine treatment programs. Evaluations of the course were performed immediately after completion of the program and again at the six-month mark to assess its effectiveness. Results: A total of 56 clinicians and other healthcare professionals participated in the Addiction Scholars Program (ASP). The participants represented nine Veteran Integrated Service Networks and 21 different VHA medical facilities. Nearly 70% of participants completed the initial post-survey. Thirty-eight respondents (97.4%) felt the ASP series contained practical examples and useful information that could be applied in their work. Thirty-eight respondents (97.4%) felt the workshop series provided new information or insights into the diagnosis and treatment of SUD. Eleven capstone projects based on the information acquired during the ASP were funded (a total of $407,178). Twenty participants (35.7%) completed the six-month follow-up survey. Notably, 90% of respondents reported increased naloxone prescribing and 50% reported increased prescribing of buprenorphine to treat patients with OUD since completing the course. Conclusion: The ASP provided healthcare professionals with insight into managing SUD and equipped them with practical clinical skills. The students translated the information from the course to develop medication for opioid use disorder (M-OUD) programs at their home institutions.

The loss of upper and lower motor neurons, and their axons is central to the loss of motor function and death in amyotrophic lateral sclerosis (ALS). Due to the diverse range of genetic and environmental factors that contribute to the pathogenesis of ALS, there have been difficulties in developing effective therapies for ALS. One emerging dichotomy is that protection of the neuronal cell soma does not prevent axonal vulnerability and degeneration, suggesting the need for targeted therapeutics to prevent axon degeneration. Post-translational modifications of protein acetylation can alter the function, stability and half-life of individual proteins, and can be enzymatically modified by histone acetyltransferases (HATs) and histone deacetyltransferases (HDACs), which add, or remove acetyl groups, respectively. Maintenance of post-translational microtubule acetylation has been suggested as a mechanism to stabilize axons, prevent axonal loss and neurodegeneration in ALS. This study used an orally dosed potent HDAC6 inhibitor, ACY-738, prevent deacetylation and stabilize microtubules in the mSOD1G93A mouse model of ALS. Co-treatment with riluzole was performed to determine any effects or drug interactions and potentially enhance preclinical research translation. This study shows ACY-738 treatment increased acetylation of microtubules in the spinal cord of mSOD1G93A mice, reduced lower motor neuron degeneration in female mice, ameliorated reduction in peripheral nerve axon puncta size, but did not prevent overt motor function decline. The current study also shows peripheral nerve axon puncta size to be partially restored after treatment with riluzole and highlights the importance of co-treatment to measure the potential effects of therapeutics in ALS.

Introduction Uncontrolled bleeding is a major cause of death for patients with major trauma. Current transfusion practices vary, and there is uncertainty about the optimal strategy. Whole blood (WB) transfusion, which contains all components in one bag, is considered potentially advantageous, particularly for resuscitating patients with major bleeding in the prehospital setting. It could potentially improve survival, reduce donor risk and simplify the processes of delivering blood transfusions outside hospitals. However, the evidence supporting the effectiveness and safety of WB compared with the standard separate blood component therapy is limited. A multicentre randomised controlled trial will be conducted, alongside an implementation study, to assess the efficacy, cost-effectiveness and implementation of prehospital WB transfusion in the prehospital environment. The implementation study will focus on evaluating the acceptability and integration of the intervention into clinical settings and on addressing broader contextual factors that may influence its success or failure.Methods and analysis A type 1 effectiveness–implementation hybrid design will be employed. The implementation study will use qualitative methods, encompassing comprehensive interviews and focus groups with operational staff, patients and blood donor representatives. Staff will be purposefully selected to ensure a wide range of perspectives based on their professional background and involvement in the WB pathway. The study design includes: (1) initial assessment of current practice and processes in the WB pathway; (2) qualitative interviews with up to 40 operational staff and (3) five focus groups with staff and donor representatives. Data analysis will be guided by the theoretical lenses of the Normalisation Process Theory and the Theoretical Framework of Acceptability.Ethics and dissemination The study was prospectively registered and approved by the South Central—Oxford C Research Ethics Committee and the Health Research Authority and Health and Care Research Wales. The results will be published in peer-reviewed journals and provided to all relevant stakeholders.Trial registration number ISRCTN23657907; EudraCT: 2021-006876-18; IRAS Number: 300414; REC: 22/SC/0072.

Diverse microbial ecosystems underpin life in the sea. Among these microbes are many unicellular eukaryotes that span the diversity of the eukaryotic tree of life. However, genetic tractability has been limited to a few species, which do not represent eukaryotic diversity or environmentally relevant taxa. Here, we report on the development of genetic tools in a range of protists primarily from marine environments. We present evidence for foreign DNA delivery and expression in 13 species never before transformed and for advancement of tools for eight other species, as well as potential reasons for why transformation of yet another 17 species tested was not achieved. Our resource in genetic manipulation will provide insights into the ancestral eukaryotic lifeforms, general eukaryote cell biology, protein diversification and the evolution of cellular pathways.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Abstract Background and Aims Skin substitutes, essential tools for helping close full thickness wounds with minimal scarring, are available in both collagen‐based and synthetic polyurethane constructions. Here we explore fundamental differences between two frequently used skin substitutes and discuss how these differences may impact in vivo performance. Methods Polyurethane‐ and collagen‐based matrices were characterized in vitro for pore size via scanning electron microscopy, hydrophobicity via liquid contact angle, conformability via bending angle, and biocompatibility via fibroblast and keratinocyte adhesion and proliferation. These matrices were then evaluated in a full‐thickness excisional pig wound study followed by histological analysis. Statistical analysis was performed using t‐tests or one‐way analysis of variances with Tukey's multiple post hoc comparisons, where appropriate. Results Average pore diameter in the tested polyurethane matrix was over four times larger than that of the collagen matrix (589 ± 297 µm vs. 132 ± 91 µm). Through liquid contact angle measurement, the collagen matrix (not measurable) was found to be hydrophilic compared to the hydrophobic polyurethane matrix (>90°). The collagen matrix was significantly more conformable than the polyurethane matrix (9 ± 2° vs. 84 ± 5° bending angle, respectively). Fibroblast and keratinocyte adhesion and proliferation assays elucidated a significantly greater ability of both cell types to attach and proliferate on collagen versus polyurethane. While the porcine study showed minimal contraction of either matrix material, histological findings between the two treatments were markedly different. Collagen matrices were associated with early fibroblast infiltration and fibroplasia, whereas polyurethane matrices elicited a strong multinucleated giant cell response and produced a network of comparatively aligned collagen fibrils. Conclusions The more favorable in vitro properties of the collagen matrix led to less inflammation and better overall tissue response in vivo. Overall, our findings demonstrate how the choice of biomaterial and its design directly translate to differing in vivo mechanisms of action and overall tissue quality.

The sport of fly-fishing has experienced significant growth since the start of the COVID-19 pandemic. There is very little literature available to quantify injuries associated with the sport of fly-fishing. Previous injury surveillance studies demonstrated certain casting styles and equipment may lead to upper extremity pain or injury. The purpose of this study was to evaluate factors that can contribute to injuries that occur while participating in the sport of fly-fishing.

Abstract Background Motor vehicle collisions (MVCs), particularly those associated with entrapment, are a common cause of major trauma. Current extrication methods are focused on spinal movement minimisation and mitigation, but for many patients self-extrication may be an appropriate alternative. Older drivers and passengers are increasingly injured in MVCs and may be at an increased risk of entrapment and its deleterious effects. The aim of this study is to describe the injuries, trapped status, outcomes, and potential for self-extrication for patients following an MVC across a range of age groups. Methods This is a retrospective study using the Trauma Audit and Research Network (TARN) database. Patients were included if they were admitted to an English hospital following an MVC from 2012 to 2019. Patients were excluded when their outcomes were not known or if they were secondary transfers. Simple descriptive analysis was used across the age groups: 16–59, 60–69, 70–79 and 80+ years. Logistic regression was performed to develop a model with known confounders, considering the odds of death by age group, and examining any interaction between age and trapped status with mortality. Results 70,027 patients met the inclusion criteria. Older patients were more likely to be trapped and to die following an MVC (p

ABSTRACT Viruses have brought humanity many challenges: respiratory infection, cancer, neurological impairment and immunosuppression to name a few. Virology research over the last 60+ years has responded to reduce this disease burden with vaccines and antivirals. Despite this long history, the COVID-19 pandemic has brought unprecedented attention to the field of virology. Some of this attention is focused on concern about the safe conduct of research with human pathogens. A small but vocal group of individuals has seized upon these concerns – conflating legitimate questions about safely conducting virus-related research with uncertainties over the origins of SARS-CoV-2. The result has fueled public confusion and, in many instances, ill-informed condemnation of virology. With this article, we seek to promote a return to rational discourse. We explain the use of gain-of-function approaches in science, discuss the possible origins of SARS-CoV-2 and outline current regulatory structures that provide oversight for virological research in the United States. By offering our expertise, we – a broad group of working virologists – seek to aid policy makers in navigating these controversial issues. Balanced, evidence-based discourse is essential to addressing public concern while maintaining and expanding much-needed research in virology.

To sustainably adapt viticultural production to drought, the planting of rootstock genotypes adapted to a changing climate is a promising means. Rootstocks contribute to the regulation of scion vigor and water consumption, modulate scion phenological development and determine resource availability by root system architecture development. There is, however, a lack of knowledge on spatio-temporal root system development of rootstock genotypes and its interactions with environment and management that prevents efficient knowledge transfer into practice. Hence, winegrowers take only limited advantage of the large variability of existing rootstock genotypes. Models of vineyard water balance combined with root architectural models, using both static and dynamic representations of the root system, seem promising tools to match rootstock genotypes to frequently occurring future drought stress scenarios and address scientific knowledge gaps. In this perspective, we discuss how current developments in vineyard water balance modeling may provide the background for a better understanding of the interplay of rootstock genotypes, environment and management. We argue that root architecture traits are key drivers of this interplay, but our knowledge on rootstock architectures in the field remains limited both qualitatively and quantitatively. We propose phenotyping methods to help close current knowledge gaps and discuss approaches to integrate phenotyping data into different models to advance our understanding of rootstock x environment x management interactions and predict rootstock genotype performance in a changing climate. This could also provide a valuable basis for optimizing breeding efforts to develop new grapevine rootstock cultivars with optimal trait configurations for future growing conditions.

Abstract Background Motor vehicle collisions remain a common cause of spinal cord injury. Biomechanical studies of spinal movement often lack “real world” context and applicability. Additional data may enhance our understanding of the potential for secondary spinal cord injury. We propose the metric ‘travel’ (total movement) and suggest that our understanding of movement related risk of injury could be improved if travel was routinely reported. We report maximal movement and travel for collar application in vehicle and subsequent self-extrication. Methods Biomechanical data on application of cervical collar with the volunteer sat in a vehicle were collected using Inertial Measurement Units on 6 healthy volunteers. Maximal movement and travel are reported. These data and a re-analysis of previously published work is used to demonstrate the utility of travel and maximal movement in the context of self-extrication. Results Data from a total of 60 in-vehicle collar applications across three female and three male volunteers was successfully collected for analysis. The mean age across participants was 50.3 years (range 28–68) and the BMI was 27.7 (range 21.5–34.6). The mean maximal anterior–posterior movement associated with collar application was 2.3 mm with a total AP travel of 4.9 mm. Travel (total movement) for in-car application of collar and self-extrication was 9.5 mm compared to 9.4 mm travel for self-extrication without a collar. Conclusion We have demonstrated the application of ‘travel’ in the context of self-extrication. Total travel is similar across self-extricating healthy volunteers with and without a collar. We suggest that where possible ‘travel’ is collected and reported in future biomechanical studies in this and related areas of research. It remains appropriate to apply a cervical collar to self-extricating casualties when the clinical target is that of movement minimisation.

Objectives To identify the differences between women and men in the probability of entrapment, frequency of injury and outcomes following a motor vehicle collision. Publishing sex-disaggregated data, understanding differential patterns and exploring the reasons for these will assist with ensuring equity of outcomes especially in respect to triage, rescue and treatment of all patients.Design We examined data from the Trauma Audit and Research Network (TARN) registry to explore sex differences in entrapment, injuries and outcomes. We explored the relationship between age, sex and trapped status using multivariate logistical regression.Setting TARN is a UK-based trauma registry covering England and Wales.Participants We examined data for 450 357 patients submitted to TARN during the study period (2012–2019), of which 70 027 met the inclusion criteria. There were 18 175 (26%) female and 51 852 (74%) male patients.Primary and secondary outcome measures We report difference in entrapment status, injury and outcome between female and male patients. For trapped patients, we examined the effect of sex and age on death from any cause.Results Female patients were more frequently trapped than male patients (female patients (F) 15.8%, male patients (M) 9.4%; p

Abstract Metastasis is the leading cause of mortalities in cancer patients due to the spreading of cancer cells to various organs. Detecting cancer and identifying its metastatic potential at the early stage is important. This may be achieved based on the quantification of the key biomolecular components within tissues and cells using recent optical spectroscopic techniques. The aim of this study was to develop a noninvasive label-free optical biopsy technique to retrieve the characteristic molecular information for detecting different metastatic potentials of prostate cancer cells. Herein we report using native fluorescence (NFL) spectroscopy along with machine learning (ML) to differentiate prostate cancer cells with different metastatic abilities. The ML algorithms including principal component analysis (PCA) and nonnegative matrix factorization (NMF) were used for dimension reduction and feature detection. The characteristic component spectra were used to identify the key biomolecules that are correlated with metastatic potentials. The relative concentrations of the molecular spectral components were retrieved and used to classify the cancer cells with different metastatic potentials. A multi-class classification was performed using support vector machines (SVMs). The NFL spectral data were collected from three prostate cancer cell lines with different levels of metastatic potentials. The key biomolecules in the prostate cancer cells were identified to be tryptophan, reduced nicotinamide adenine dinucleotide (NADH) and hypothetically lactate as well. The cancer cells with different metastatic potentials were classified with high accuracy using the relative concentrations of the key molecular components. The results suggest that the changes in the relative concentrations of these key fluorophores retrieved from NFL spectra may present potential criteria for detecting prostate cancer cells of different metastatic abilities.

Abstract Background Motor vehicle collisions (MVCs) are a common cause of major trauma and death. Following an MVC, up to 40% of patients will be trapped in their vehicle. Extrication methods are focused on the prevention of secondary spinal injury through movement minimisation and mitigation. This approach is time consuming and patients may have time-critical injuries. The purpose of this study is to describe the outcomes and injuries of those trapped following an MVC: this will help guide meaningful patient-focused interventions and future extrication strategies. Methods We undertook a retrospective database study using the Trauma Audit and Research Network database. Patients were included if they were admitted to an English hospital following an MVC from 2012 to 2018. Patients were excluded when their outcomes were not known or if they were secondary transfers. Results This analysis identified 426,135 cases of which 63,625 patients were included: 6983 trapped and 56,642 not trapped. Trapped patients had a higher mortality (8.9% vs 5.0%, p

Background It is unclear whether the recent increase in the number of heart transplants performed annually in the United States is only because of higher availability of donors and if it affected recipients’ survival. Methods and Results We examined characteristics of donors and recipients from 2008 to 2012 (n=11 654) and 2013 to 2017 (n=14 556) and compared them with 2003 to 2007 (n=10 869). Cox models examined 30‐day and 1‐year risk of recipients’ death post transplant. From 2013 to 2017, there was an increase in the number of transplanted hearts and number of donor offers but an overall decline in the ratio of hearts transplanted to available donors. Donors between 2013 and 2017 were older, heavier, more hypertensive, diabetic, and likely to have abused illicit drugs compared with previous years. Drug overdose and hepatitis C positive donors were additional contributors to donor risk in recent years. In Cox models, risk of death post transplant between 2013 and 2017 was 15% lower at 30 days (hazard ratio [HR] 0.85; 95% CI, 0.74–0.98) and 21% lower at 1 year (HR, 0.79; 95% CI, 0.73–0.87) and between 2008 and 2012 was 9% lower at 30 days (HR, 0.91; 95% CI, 0.79–1.05) and 14% lower at 1 year (HR, 0.86; 95% CI, 0.79–0.94) compared with 2003 to 2007. Conclusions Despite a substantial increase in heart donor offers in recent years, the ratio of transplants performed to available donors has decreased. Even though hearts from donors who are older, more hypertensive, and have diabetes mellitus are being used, overall recipient survival continues to improve. Broader acceptance of drug overdose and hepatitis C positive donors may increase the number and percentage of heart transplants further without jeopardizing short‐term outcomes.

BackgroundGray-scale, B-mode ultrasound (US) imaging is part of the standard clinical procedure for evaluating thyroid nodules (TNs). It is limited by its instrument- and operator-dependence and inter-observer variability. In addition, the accepted high-risk B-mode US TN features are more specific for detecting classic papillary thyroid cancer rather than the follicular variant of papillary thyroid cancer or follicular thyroid cancer. Quantitative ultrasound (QUS) is a technique that can non-invasively assess properties of tissue microarchitecture by exploiting information contained in raw ultrasonic radiofrequency (RF) echo signals that is discarded in conventional B-mode imaging. QUS provides quantitative parameter-value estimates that are a function of the properties of US scatterers and microarchitecture of the tissue. The purpose of this preliminary study was to assess the performance of QUS parameters in evaluating benign and malignant thyroid nodules.MethodsPatients from the Thyroid Health Center at the Boston Medical Center were recruited to participate. B-mode and RF data were acquired and analyzed in 225 TNs (24 malignant and 201 benign) from 208 patients. These data were acquired either before (167 nodules) or after (58 nodules) subjects underwent fine-needle biopsy (FNB). The performance of a combination of QUS parameters (CQP) was assessed and compared with the performance of B-mode risk-stratification systems.ResultsCQP produced an ROC AUC value of 0.857 ± 0.033 compared to a value of 0.887 ± 0.033 (p=0.327) for the American College of Radiology Thyroid Imaging, Reporting and Data System (ACR TI-RADS) and 0.880 ± 0.041 (p=0.367) for the American Thyroid Association (ATA) risk-stratification system. Furthermore, using a CQP threshold of 0.263 would further reduce the number of unnecessary FNBs in 44% of TNs without missing any malignant TNs. When CQP used in combination with ACR TI-RADS, a potential additional reduction of 49 to 66% in unnecessary FNBs was demonstrated.ConclusionThis preliminary study suggests that QUS may provide a method to classify TNs when used by itself or when combined with a conventional gray-scale US risk-stratification system and can potentially reduce the need to biopsy TNs.

Background Incidental gallbladder cancer is relatively rare, with an incidence ranging between 0.19 and 5.5% of all the cholecystectomies for benign disease, and carries a poor prognosis. Currently, in the literature, there appears to be some controversy about whether all gallbladder specimens should be sent for routine histopathology. The aim of this study was to investigate the need for either routine or selective histopathological evaluation of all gallbladder specimens following cholecystectomy in our institution. Methods The records of all patients who underwent a cholecystectomy (laparoscopic and open) for gallstone disease over a 5-year period (between January 2011 and January 2016) were reviewed retrospectively in a single university teaching hospital. Patients with radiological evidence of gallbladder cancer preoperatively were excluded. The notes of patients with incidental gallbladder cancer were reviewed and data were collected for clinical presentation and preoperative investigations including blood tests and radiological imaging. Results A total of 1,473 specimens were sent for histopathological evaluation, with two patients being diagnosed with an incidental gallbladder cancer (papillary adenocarcinoma in situ and moderately differentiated invasive adenocarcinoma [stage IIIa]). The incidence rate was 0.14%. All patients with incidental gallbladder cancer had macroscopically abnormal specimens. Conclusion Both patients in our study who were diagnosed with incidental gallbladder cancer had macroscopic abnormalities. A selective rather than routine approach to histological evaluation of gallbladder specimens especially in those with macroscopic abnormalities should be employed. This will reduce the burden on the pathology department with potential cost savings.

Innovation in agricultural biotechnology seed products can be characterized as a non-drastic innovative process with product differentiation. We model this innovation and examine the pricing and purchase decisions for experimental use licensing. In equilibrium, a technologically advantaged firm will purchase a license, while a technologically disadvantaged firm will not. This is the case regardless of the order of pricing decisions.

Abstract Background Malaria control remains a significant challenge in the Solomon Islands. Despite progress made by local malaria control agencies over the past decade, case rates remain high in some areas of the country. Studies from around the world have confirmed important links between climate and malaria transmission. This study focuses on understanding the links between malaria and climate in Guadalcanal, Solomon Islands, with a view towards developing a climate-based monitoring and early warning for periods of enhanced malaria transmission. Methods Climate records were sourced from the Solomon Islands meteorological service (SIMS) and historical malaria case records were sourced from the National Vector-Borne Disease Control Programme (NVBDCP). A declining trend in malaria cases over the last decade associated with improved malaria control was adjusted for. A stepwise regression was performed between climate variables and climate-associated malaria transmission (CMT) at different lag intervals to determine where significant relationships existed. The suitability of these results for use in a three-tiered categorical warning system was then assessed using a Mann–Whitney U test. Results Of the climate variables considered, only rainfall had a consistently significant relationship with malaria in North Guadalcanal. Optimal lag intervals were determined for prediction using R2 skill scores. A highly significant negative correlation (R = − 0.86, R2 = 0.74, p

Epilepsy has many causes and comorbidities affecting as many as 4% of people in their lifetime. Both idiopathic and symptomatic epilepsies are highly heritable, but genetic factors are difficult to characterize among humans due to complex disease etiologies. Rodent genetic studies have been critical to the discovery of seizure susceptibility loci, including Kcnj10 mutations identified in both mouse and human cohorts. However, genetic analyses of epilepsy phenotypes in mice to date have been carried out as acute studies in seizure-naive animals or in Mendelian models of epilepsy, while humans with epilepsy have a history of recurrent seizures that also modify brain physiology. We have applied a repeated seizure model to a genetic reference population, following seizure susceptibility over a 36-d period. Initial differences in generalized seizure threshold among the Hybrid Mouse Diversity Panel (HMDP) were associated with a well-characterized seizure susceptibility locus found in mice: Seizure susceptibility 1. Remarkably, Szs1 influence diminished as subsequent induced seizures had diminishing latencies in certain HMDP strains. Administration of eight seizures, followed by an incubation period and an induced retest seizure, revealed novel associations within the calmodulin-binding transcription activator 1, Camta1. Using systems genetics, we have identified four candidate genes that are differentially expressed between seizure-sensitive and -resistant strains close to our novel Epileptogenesis susceptibility factor 1 (Esf1) locus that may act individually or as a coordinated response to the neuronal stress of seizures.

Recurrent blooms of harmful algae and cyanobacteria (HABs) plague many coastal and inland waters throughout the United States and have significant socioeconomic impacts to the adjacent communities. Notable HAB events in recent years continue to underscore the many remaining gaps in knowledge and increased needs for technological advances leading to early detection. This review summarizes the main research and management priorities that can be addressed through ocean observation-based approaches and technological solutions for harmful algal blooms, provides an update to the state of the technology to detect HAB events based on recent activities of the Alliance for Coastal Technologies (ACT), offers considerations for ensuring data quality, and highlights both ongoing challenges and opportunities for solutions in integrating HAB-focused technologies in research and management. Specifically, technological advances are discussed for remote sensing (both multispectral satellite and hyperspectral); deployable in situ detection of HAB species on fixed or mobile platforms (based on bulk or taxa-specific biomass, images, or molecular approaches); and field-based and/or rapid quantitative detection of HAB toxins (via molecular and analytical chemistry methods). Suggestions for addressing challenges to continued development and adoption of new technologies are summarized, based on a consensus-building workshop hosted by ACT, including dealing with the uncertainties in investment for HAB research, monitoring, and management. Challenges associated with choosing appropriate technologies for a given ecosystem and/or management concern are also addressed, and examples of programs that are leveraging and combining complementary approaches are highlighted.

Aim: The aim of the study was to test the effect of a single heat event (HE), and the additive effects of repeated HEs at whole-vine level, on Shiraz berry composition, including detailed tannins. Methods and results: In a UV-transparent glasshouse, a system was developed to individually heat the above-ground parts of well-irrigated potted Shiraz vines without changing fruit and canopy light exposure. At the end of fruit set, and again prior to véraison, selected vines were heated to + 6 °C above ambient temperature for three consecutive days and nights in a combination of treatments to test the effect of a single HE and the additive effects of repeated HEs. A factorial design was used with four treatments (n=6): Control (C), heated at E-L 31 (HW1), heated at E-L 32 (HW2) and heated twice (HW1&2). Berries were sampled from fruit set until maturity at regular intervals, and primary and secondary metabolites, including detailed tannin composition, were analysed by GC-MS and LC-MS/MS, respectively. Temperatures (mean and maximum) inside the glasshouse were influenced by outside weather conditions and the 1st HE (HE1) was more intense than the 2nd (HE2). Photosynthesis was significantly decreased for the heated vines during HE1 where maximum temperature reached 45 °C, affecting both berry weight and titratable acidity (TA). HE2 was less intense with maximum temperature only reaching 40 °C, and had no effect on photosynthesis and less direct impact on composition. A few primary metabolites were affected by either HE1 or HE2 such as valine, leucine, pyruvic and lactic acids. Interactions between the two HEs were found for TA, malic acid and glucose at harvest. Skin tannin composition was significantly impacted by HE1, applied during the main biosynthesis period, but not by HE2. Epicatechin gallate terminal subunit concentration was the most impacted by heat. Seed physiology was also affected by HE1 and HE2 as well as seed tannin composition right after HE1. A small decrease in both total anthocyanins and total soluble solids at the end of véraison suggested that ripening was slightly delayed for HW1&2. Conclusions: Shiraz grapevines showed an elastic response to short heat stress between fruit set and véraison, with most impacts on physiology and composition observed during early post-treatment no longer evident by harvest. Significance and impact of the study: Increasing climate variability, with more frequent heatwaves, is a threat for viticulture in Australia where a large proportion of vineyards are located in already warm and hot regions. As grapevines may be exposed to abnormal high temperatures prior to véraison, knowledge on the effect of heat on metabolite biosynthesis occurring during this phase, such as tannins, is needed.