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Infection with Fasciola hepatica (liver fluke) causes fasciolosis (or fascioliasis) and poses a considerable economic as well as welfare burden to both the agricultural and animal health sectors. Here, we explore the ex vivo anthelmintic potential of synthetic derivatives of hederagenin, isolated in bulk from Hedera helix. Thirty-six compounds were initially screened against F. hepatica newly excysted juveniles (NEJs) of the Italian strain. Eleven of these compounds were active against NEJs and were selected for further study, using adult F. hepatica derived from a local abattoir (provenance unknown). From these eleven compounds, six demonstrated activity and were further assessed against immature liver flukes of the Italian strain. Subsequently, the most active compounds (n = 5) were further evaluated in ex vivo dose response experiments against adult Italian strain liver flukes. Overall, MC042 was identified as the most active molecule and the EC50 obtained from immature and adult liver fluke assays (at 24 h post co-culture) are estimated as 1.07 μM and 13.02 μM, respectively. When compared to the in vitro cytotoxicity of MDBK bovine cell line, MC042 demonstrated the highest anthelmintic selectivity (44.37 for immature and 3.64 for adult flukes). These data indicate that modified hederagenins display properties suitable for further investigations as candidate flukicides.

The embedding of pre-Hispanic decorated carved stones into the facades of colonial Mexican churches has long been a well-known phenomenon. 1 The practice bears a family resemblance to the incorpora...

The World Health Organisation estimate there are about 1 billion migrants in the world today. The scale of population movement and a global refugee crisis presents an enormous challenge for healthcare provision, and too often the specific health needs of refugees and migrants are not met. This study assessed refugee, asylum seeker and vulnerable migrants’ (AMRs') experience of front line primary healthcare in a region of the United Kingdom designated as a ‘City of Sanctuary’. A questionnaire study explored the views of people seeking refuge and third sector workers supporting them. The majority of AMRs were registered with a GP and positive about their consultations. The views of third sector workers provided a less favourable window into their experience of primary care. In conclusion, the work highlighted patchy experience of primary care, even in a region of the UK designated as a ‘City of Sanctuary’ for people seeking refuge. There is a need for further education of rights to care in the UK, information for people on how to navigate local healthcare systems, consistent access to routine health checks and translation services.

α-galactosidase (α-GAL) and α-N-acetylgalactosaminidase (α-NAGAL) are two glycosyl hydrolases responsible for maintaining cellular homeostasis by regulating glycan substrates on proteins and lipids. Mutations in the human genes encoding either enzyme lead to neurological and neuromuscular impairments seen in both Fabry- and Schindler/Kanzaki- diseases. Here, we investigate whether the parasitic blood fluke Schistosoma mansoni, responsible for the neglected tropical disease schistosomiasis, also contains functionally important α-GAL and α-NAGAL proteins. As infection, parasite maturation and host interactions are all governed by carefully-regulated glycosylation processes, inhibiting S. mansoni’s α-GAL and α-NAGAL activities could lead to the development of novel chemotherapeutics. Sequence and phylogenetic analyses of putative α-GAL/α-NAGAL protein types showed Smp_089290 to be the only S. mansoni protein to contain the functional amino acid residues necessary for α-GAL/α-NAGAL substrate cleavage. Both α-GAL and α-NAGAL enzymatic activities were higher in females compared to males (p α-GAL), which was consistent with smp_089290’s female biased expression. Spatial localisation of smp_089290 revealed accumulation in parenchymal cells, neuronal cells, and the vitellaria and mature vitellocytes of the adult schistosome. siRNA-mediated knockdown (>90%) of smp_089290 in adult worms significantly inhibited α-NAGAL activity when compared to control worms (siLuc treated males, p, Author summary Schistosomiasis is a parasitic disease caused by infection with blood flukes, which leads to acute and chronic pathology in millions of infected individuals located in deprived tropical and subtropical regions. Elucidating the function of schistosome genes has provided a clearer view on their roles in various molecular pathways, which are critical to successful parasitism. This information is invaluable when progressing novel drug and vaccine candidates. Here, we add to the existing knowledge of the Schistosoma mansoni parasitic glycan processing and modification machinery by functionally characterising a glycosyl hydrolase (S. mansoni α-N-acetylgalactosaminidase, SmNAGAL). We demonstrate that this protein is enzymatically active and important in coordinating parasite movement in adult male and female schistosomes. Additionally, we provide evidence that this protein regulates pathways associated with egg production in female schistosomes, which is responsible for inducing pathological reactions. Developing drugs that inhibit SmNAGAL enzymatic activity could provide a novel approach for controlling schistosomiasis.

BACKGROUND The COVID-19 pandemic has led to the rapid implementation of remote care delivery in type 1 diabetes. We studied current modes of care delivery, healthcare professional experiences and impact on insulin pump training in type 1 diabetes care in the United Kingdom (UK). METHODS The UK Diabetes Technology Network designed a 48-question survey aimed at health care professionals providing care in type 1 diabetes. RESULTS One hundred and forty three health care professionals (48% diabetes physicians, 52% diabetes educators, 88% working in adult services) from approximately 75 UK centres (52% university hospitals, 46% general and community hospitals), responded to the survey. Telephone consultations were the main modality of care delivery. There was a higher reported time taken for video consultations versus telephone (p

Vaccination is considered the best strategy for limiting and eliminating the COVID-19 pandemic. The success of this strategy relies on the rate of vaccine deployment and acceptance across the globe. As these efforts are being conducted, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus is continuously mutating, which leads to the emergence of variants with increased transmissibility, virulence, and lower response the vaccines. One important question is whether surveillance testing is still needed in order to limit SARS-CoV-2 transmission in an increasingly vaccinated population. In this study, we developed a multi-scale mathematical model of SARS-CoV-2 transmission in a vaccinated population and used it to predict the role of testing in an outbreak with alpha and delta variants. We found that, when the alpha variant is dominant, testing is effective when vaccination levels are low to moderate and its impact is diminished when vaccination levels are high. When the delta variant is dominant, widespread vaccination is necessary in order to prevent significant outbreaks. When only moderate vaccination can be achieved, frequent testing can significantly reduce the cumulative size of delta variant outbreak, with the impact of testing having maximum effects when focused on the non-vaccinated population.

The COVID-19 pandemic has significantly impacted on doctors’ education and opportunities for professional development with almost all education now offered on virtual platforms. Houghton et al 1 have outlined how this poses a particular challenge for teaching the practical aspects of medicine compared with theoretical, declarative knowledge. However, in their article they encourage medical educators to embrace these changes and ‘make a virtue out of necessity ’ . We share an example where being forced to move to a virtual platform improved doctors’ training in the practical management of medical emergencies in the community, and has led to a permanent change in how we will deliver this training in future years. General practitioners (GPs) have a responsibility to provide prompt and effective care when attending to life threatening emergencies in their surgeries. These are relatively uncommon and previous research has shown this is an area where some doctors lack confidence and competence.2–4 In the current National Health Service crisis, with stretched resources, it is particularly important that GPs are equipped to manage time critical emergencies, because GP surgeries are deemed a place of safety and 999 ambulances can be redirected to other emergencies, thereby delaying transfer to secondary care for patients in GP settings. In previous years, the Dorset GP training scheme provided classroom based training in managing …

The covid-19 pandemic has led to rapid implementation of remote care delivery in type 1 diabetes (T1D). An understanding of current modes of care delivery and HCP experiences is required to improve care. The UK Diabetes Technology Network undertook an online survey aimed at members providing care in T1D. One hundred and forty three HCPs (47.6% diabetes physicians, 51.8% diabetes educators) from 105 UK NHS centers (51.7% university hospitals, 45.8% general/community hospitals), responded. Median (IQR) percentage of consultations and time taken via face-to-face, telephone and video were 20%(5-30), 30 minutes (20-34); 50% (30-80), 20 minutes (15-30) and 10% (0-35), 30 minutes (20-30), respectively. Sixty four percent responded that remote consultations offered an effective strategy for care delivery. Common barriers were patient familiarity with technology (72%) and access to patient device data (67.1%). Devices with smartphone based automated cloud uploads made consultations easier (73.4%), more effective (84.6%) and facilitated hospital discharges (60.9%). Median (IQR) responses on a 7-point scale for effectiveness of remote training, compared to face-to face, for new CSII starts, CSII renewals and CGM starts, were reported as 5 (4-6), 5.5 (5-6) and 6 (5-6), respectively. Common barriers included patient digital literacy (60.8%), limited HCP experience (46.2%) and time required per patient (43.6%). A reduction in new starts (72.8%) and renewals (60.9%) for CSII was highlighted by most. Variation was noted in proportion of new CSII starts being done virtually (53.9% respondents reporting 60%). Most (92.4%) responded that remote consultations and technology training are likely to continue post-Covid19. This survey highlights the impact of COVID-19 on access to diabetes technology and demonstrates how HCP’s have embraced remote care delivery, but digital literacy remains a barrier. Disclosure H. E. Forde: Consultant; Self; Dexcom, Inc. P. Choudhary: Advisory Panel; Self; Abbott Diabetes, Insulet Corporation, Lilly Diabetes, Medtronic, Sanofi-Aventis, Speaker’s Bureau; Self; Dexcom, Inc., Novo Nordisk. S. Hussain: Speaker’s Bureau; Self; Novo Nordisk.

Summary A 41-year-old male presented to the Emergency Department with a 6-month history of back and hip pain. Skeletal survey revealed bilateral pubic rami fractures and MRI of the spine demonstrated multiple thoracic and lumbar fractures. Secondary work up for osteoporosis was undertaken. There was no evidence of hyperparathyroidism and the patient was vitamin D replete. Testosterone (T) was low at 1.7 nmol/L (8.6–29.0) and gonadotrophins were undetectable. The patient failed a 1 mg dexamethasone suppression test (DST) with a morning cortisol of 570 nmol/L ( Learning points Unexplained osteoporosis requires thorough investigation and the workup for secondary causes is not complete without excluding glucocorticoid excess. MTC should be considered when searching for sources of ectopic ACTH secretion. Resistance to tyrosine kinase inhibitors is well described with MTC and clinicians should have a low threshold for screening for recurrent disease.

Control strategies that employ real time polymerase chain reaction (RT-PCR) tests for the diagnosis and surveillance of COVID-19 epidemic are inefficient in fighting the epidemic due to high cost, delays in obtaining results, and the need of specialized personnel and equipment for laboratory processing. Cheaper and faster alternatives, such as antigen and paper-strip tests, have been proposed. They return results rapidly, but have lower sensitivity thresholds for detecting virus. To quantify the effects of the tradeoffs between sensitivity, cost, testing frequency, and delay in test return on the overall course of an outbreak, we built a multi-scale immuno-epidemiological model that connects the virus profile of infected individuals with transmission and testing at the population level. We investigated various randomized testing strategies and found that, for fixed testing capacity, lower sensitivity tests with shorter return delays slightly flatten the daily incidence curve and delay the time to the peak daily incidence. However, compared with RT-PCR testing, they do not always reduce the cumulative case count at half a year into the outbreak. When testing frequency is increased to account for the lower cost of less sensitive tests, we observe a large reduction in cumulative case counts, from 55.4% to as low as 1.22% half a year into the outbreak. The improvement is preserved even when the testing budget is reduced by one half or one third. Our results predict that surveillance testing that employs low-sensitivity tests at high frequency is an effective tool for epidemic control.

Control strategies that employ real time polymerase chain reaction (RT-PCR) tests for the diagnosis and surveillance of COVID-19 epidemic are inefficient in fighting the epidemic due to high cost, delays in obtaining results, and the need of specialized personnel and equipment for laboratory processing. Cheaper and faster alternatives, such as antigen and paper-strip tests, have been proposed. They return results rapidly, but have lower sensitivity thresholds for detecting virus. To quantify the effects of the tradeoffs between sensitivity, cost, testing frequency, and delay in test return on the overall course of an outbreak, we built a multi-scale immuno-epidemiological model that connects the virus profile of infected individuals with transmission and testing at the population level. We investigated various randomized testing strategies and found that, for fixed testing capacity, lower sensitivity tests with shorter return delays slightly flatten the daily incidence curve and delay the time to the peak daily incidence. However, compared with RT-PCR testing, they do not always reduce the cumulative case count at half a year into the outbreak. When testing frequency is increased to account for the lower cost of less sensitive tests, we observe a large reduction in cumulative case counts, from 57% to as low as 1.5% half a year into the outbreak and to 3.2% three years into the outbreak. The improvement is preserved even when the testing budget is reduced by one half or one third. Our results predict that surveillance testing that employs low-sensitivity tests at high frequency is an effective tool for epidemic control.

Activated platelet-rich plasma (PRP) has been used in the clinical settings of wound healing and regenerative medicine, with activation typically induced by the addition of bovine thrombin. To eliminate issues with availability, cost and potential side effects associated with bovine thrombin, ex vivo PRP activation using pulse electric fields (PEF) has been proposed and demonstrated. The present study characterizes the effect of PEF voltage and pulse width, in combination with a range of calcium concentrations, on clot formation, growth factor release, and serotonin (5-HT) release from dense granules. The main findings are: 1) increasing calcium concentrations with most PEF conditions leads to increased levels of PDGF and 5-HT release; 2) whether EGF levels increase or decrease with increasing calcium concentration depends on the specific PEF parameters; 3) the pattern of PDGF and EGF levels in supernatants suggest that these molecules are localized differently within platelets; 4) significant levels of PDGF, EGF, and 5-HT can be released without inducing clot formation or hemoglobin release. In conclusion, voltage, pulse width and calcium concentration can be used to control and tune the release of growth factors, serotonin and hemoglobin from PEF-activated PRP. Because growth factor requirements vary for different types of wounds and for wounds at different stages of healing, the unique balance of factors in supernatants of PEF-activated PRP may provide more clinically advantageous than the current standard of bovine thrombin-activated PRP.

Peer-led teaching is well established within many undergraduate medical courses but relatively underutilised in postgraduate training, despite the fact it can be useful for both teachers and learners. A significant number of doctors training to be GPs bring expertise and experience from other specialities and in this paper we explore the potential of using 'expert trainees' to teach their peers on postgraduate GP training programmes. A GP trainee with expertise in Lifestyle Medicine taught alongside local and national experts and delivered workshops to her peers. Questionnaires were used to establish the acceptability and quality of 'expert trainee' peer-led education. This was a positive experience for the 'expert trainee' who felt valued both as a trainee and as someone with expert knowledge, and for her peers with excellent feedback on her workshop. The knowledge and skills of 'expert trainees' represent an untapped resource which could be more systematically and effectively used within GP education.

The value of arts based medical education is becoming increasingly well established in\ud undergraduate curricula. However, little is known about its value, and acceptability, to\ud qualified doctors undertaking postgraduate training. In this work we examined GP trainees’\ud views on whether arts based education was useful for their professional development and,\ud if so, what they perceived its value to be. All first and second year GP trainees on the Dorset\ud Vocational Training Scheme attended a one day course which showcased how the arts (film,\ud poetry, painting, photography, theatre) could enhance their professional development as\ud doctors. GP trainees rated the day as interesting, enjoyable and thought proving. The\ud majority felt that the arts could contribute to making them more competent and humane\ud doctors’. Following this, we ran a mandatory six months arts based course for six GP\ud trainees, and evaluated their feedback through qualitative analysis of a focus group\ud discussion. Overall, GP trainees found the course enjoyable and valuable to their learning. It\ud not only gave them a deeper appreciation of the patient’s perspective, but also encouraged\ud them to think about their own health and wellbeing

The capacity and the commitment to reflect are integral to the practice of medicine and are core components of most general practitioners (GP) training programmes. Teaching through the humanities is a growing area within medical education, but one which is often considered a voluntary ‘add-on’ for the interested doctor. This article describes an evaluation of a highly innovative pedagogical project which used photography as a means to enhance GP trainees’ reflective capacity, self-awareness and professional development. Photography was used as a tool to develop GP trainees’ skills in recognising and articulating the attitudes, feelings and values that might impact on their clinical work and to enhance their confidence in their ability to deal with these concerns/issues. We submit that photography is uniquely well suited for facilitating insight and self-reflection because it provides the ability to record ‘at the touch of a button’ those scenes and images to which our attention is intuitively drawn without the need for—or the interference of—conscious decisions. This allows us the opportunity to reflect later on the reasons for our intuitive attraction to these scenes. These photography workshops were a compulsory part of the GP training programme and, despite the participants’ traditional scientific backgrounds, the results clearly demonstrate the willingness of participants to accept—even embrace—the use of art as a tool for learning. The GP trainees who took part in this project acknowledged it to be beneficial for both their personal and professional development.

Background Treatment decisions for patients with immune thrombocytopenia (ITP) are difficult because patients with similarly low platelet counts differ in their bleeding tendency. We recently reported that platelet function tests, independent of platelet count, are associated with concurrent bleeding severity, suggesting that these tests may be useful indicators of future bleeding in ITP. Objectives To test this hypothesis, we evaluated the consistency of these platelet function tests over time and their association with subsequent bleeding severity. Methods Bleeding score and platelet biomarkers were evaluated in a cross-sectional study of children with ITP at two visits separated by a median of 10 months. Results and Conclusions Correlations between Visit 1 and Visit 2 results for immature platelet fraction, circulating and agonist-stimulated platelet surface P-selectin, and activated GPIIb–IIIa and GPIbα indicated consistency of the platelet phenotype over time. Consistent with our previous findings, platelet biomarkers at each visit were significantly associated with the concurrent bleeding score. Furthermore, increased P-selectin on circulating platelets and reduced agonist-stimulated P-selectin and activated GPIIb–IIIa-positive platelets at Visit 1 were significantly associated with bleeding scores at Visit 2 and remained significantly associated with bleeding severity after adjustment for platelet count. These results suggest a mechanistic link between desensitization of agonist receptors and increased bleeding severity. In summary, platelet function in ITP, independent of platelet count, is consistent over time and is associated with both concurrent and subsequent bleeding severity. These findings support further evaluation of platelet function testing to help guide patient management in ITP.

ObjectiveTo identify and understand the factors that contribute to medication errors associated with the use of computerized provider order entry (CPOE) in pediatrics and provide recommendations on how CPOE systems could be improved.Materials and MethodsWe conducted a systematic literature review across 3 large databases: the Cumulative Index to Nursing and Allied Health Literature, Embase, and Medline. Three independent reviewers screened the titles, and 2 authors then independently reviewed all abstracts and full texts, with 1 author acting as a constant across all publications. Data were extracted onto a customized data extraction sheet, and a narrative synthesis of all eligible studies was undertaken.ResultsA total of 47 articles were included in this review. We identified 5 factors that contributed to errors with the use of a CPOE system: (1) lack of drug dosing alerts, which failed to detect calculation errors; (2) generation of inappropriate dosing alerts, such as warnings based on incorrect drug indications; (3) inappropriate drug duplication alerts, as a result of the system failing to consider factors such as the route of administration; (4) dropdown menu selection errors; and (5) system design issues, such as a lack of suitable dosing options for a particular drug.Discussion and ConclusionsThis review highlights 5 key factors that contributed to the occurrence of CPOE-related medication errors in pediatrics. Dosing support is the most important. More advanced clinical decision support that can suggest doses based on the drug indication is needed.

Context: According to the World Health Organisation 'more people are on the move now than ever before with an estimated 1 billion migrants in the world today and 68 million forcibly displaced people'. GPs are on the frontline of healthcare in the UK and have a responsibility to provide free and equitable access for everyone. Aim: The main aim of our work was to assess GP trainees' current experience, knowledge and attitudes towards caring for refugees, asylum seekers and undocumented migrants. Description: 30 final year GP trainees on the Dorset Vocational Training Scheme (VTS) were asked to participate by completing a questionnaire. Outcomes: The results show that GP trainees lack knowledge regarding migrants health needs, rights to care, including whether there is a duty to disclose an illegal immigrant and what to do if a patient could not provide proof of identification. They lacked experience and confidence in caring for this group of patients, with the biggest perceived challenge being language barriers. Conclusions: Education in primary care needs to respond to meet the challenge of population movement (5), and this project highlighted a need to improve education on migrants' rights to care, local support groups, as well as common health problems. In response, we have reviewed our curriculum and introduced an education session on refugee health for all our GP trainees in Dorset.

General Practitioners (GPs) have a responsibility to provide prompt and effective care when attending to life threatening emergencies in their GP surgeries. Primary care staff undertake mandatory, annual basic life support training. However, most emergencies are peri-arrest situations, and this is an area where GPs lack confidence and competence [1, 2]. The importance of effective, early intervention in peri-arrest scenarios was highlighted by the NCEPOD report “Time to Intervene (2012)” [3]. This report suggested that better early assessment and intervention may have prevented progression to cardiorespiratory arrest. GPs need to be equipped to manage ‘time critical’ emergencies, particularly as GP surgeries are deemed a place of safety and 999 ambulances can be redirected to other emergencies, thereby delaying transfer to secondary care for patients in GP settings. In previous work, we demonstrated that GPs’ confidence in managing time critical emergencies was initially low, and significantly improved immediately after attending ‘real-world’, simulation based workshops [1]. The value of real-world, in-house simulation based training has also been shown to increase “practical preparedness” in the context of resuscitation training (4). However, there is relatively little data regarding the long term value of simulation based training in primary care (5). In the current paper, we assessed whether our workshops had any longer-term benefit on participants’ confidence in managing emergencies and if it led to any changes in clinical practice.

In this article, I present the results of an analysis of codex-style polychrome ceramics recovered from excavations of commoner households at the Late Postclassic center of Tututepec (Yucu Dzaa), Oaxaca, Mexico. In employing a basic semiotic approach, I examine the images depicted on these materials to draw inferences regarding salient themes they expressed, and how these themes related to broader social discourse and political ideology. In short, I argue that the data suggest an articulation between the popular ideologies of commoners and ideals that were promoted by the site's ruling elites, a concordance that likely arose through dialogic social processes, rather than coercion or false consciousness. This state of affairs may have contributed to the success of the polity, which was the center of a powerful territorial empire at the time of Spanish contact.

The development of cervical cells from normal cells infected by human papillomavirus into invasive cancer cells can be modeled using population dynamics of the cells and free virus. The cell populations are separated into four compartments: susceptible cells, infected cells, precancerous cells and cancer cells. The model system of differential equations also has a free virus compartment in the system, which infect normal cells. We analyze the local stability of the equilibrium points of the model and investigate the parameters, which play an important role in the progression toward invasive cancer. By simulation, we investigate the boundary between initial conditions of solutions, which tend to stable equilibrium point, representing controlled infection, and those which tend to unbounded growth of the cancer cell population. Parameters affected by drug treatment are varied, and their effect on the risk of cancer progression is explored.

Platelet-rich plasma (PRP) is an emerging autologous biologic method for wound healing. Clinicians apply PRP either topically (where it is activated ex-vivo before treatment by adding an external agent to trigger clotting and the release of growth factors that facilitate wound healing) or through injection (where it is activated in vivo at the injury site with no prior activation before injection). Because topical PRP activation typically utilizes bovine thrombin, which has significant potential side effects and high costs, recent studies have assessed the efficacy of combining extracellular calcium (EC) and electric pulses (EPs) to activate PRP. The potential to apply this novel technique to PRP both topically and internally via injection raises the question about the ability to tune the clotting time and growth factor release for a given application. While previous studies have assessed the impact of applying EPs of various durations either directly (conductive coupling) or indirectly (capacitive coupling) to PRP containing EC, no studies have assessed the tunability of this activation based on modifying EP parameters, EP delivery method (conductive or capacitive coupling), and the EC concentration. We hypothesize that tuning these parameters will modify intracellular calcium uptake to permit the control of growth factor release and clotting time, which are critical for optimizing PRP for either topical or internal clinical applications. A pilot study for a single donor demonstrates the potential for tunability as a function of the intensity of membrane manipulation and calcium concentration, which facilitate the increase of cytosolic calcium. This motivates future studies assessing EC and EP optimization and in vivo studies to determine the overall efficacy of this tunability for wound healing.

Essentials Thrombopoietin (TPO) lowers the threshold for platelet activation. TPO receptor agonists (RAs) may therefore also lead to platelet activation. Patients with chronic liver disease and thrombocytopenia participated in a randomized trial. The TPO-RA avatrombopag did not increase platelet activation in vivo or reactivity in vitro. Background The thrombopoietin (TPO) receptor agonist (TPO-RA) avatrombopag has recently been Food and Drug Administration-approved for the treatment of thrombocytopenia in patients with chronic liver disease (CLD) scheduled for a procedure. The TPO receptor c-mpl is expressed on the platelet surface, and TPO lowers the threshold for platelet activation. TPO-RAs may therefore also lead to platelet activation. Objectives To evaluate the effects of avatrombopag on platelet activation. Patients/methods CLD patients with thrombocytopenia participated in a randomized, double-blind, placebo-controlled, parallel-group study. No patient received a platelet transfusion within 10 days of study blood draws. Platelet activation was evaluated with whole blood flow cytometry (which, unlike other methods, is accurate in thrombocytopenic samples). Results Avatrombopag, but not placebo, increased platelet counts. As measured by platelet surface P-selectin and activated glycoprotein IIb-IIIa: (i) the numbers of circulating activated platelets were not increased in avatrombopag-treated patients as compared with placebo-treated patients; and (ii) platelet reactivity to low and high concentrations of ADP and thrombin receptor-activating peptide was not increased in avatrombopag-treated patients as compared with placebo-treated patients. Conclusions In this randomized, double-blind, placebo-controlled, parallel-group study of CLD patients with thrombocytopenia, avatrombopag increased platelet counts but did not increase platelet activation in vivo or platelet reactivity in vitro.

Experimental studies have shown that the size and infectious-stage of viral inoculum influence disease outcomes in rhesus macaques infected with simian immunodeficiency virus. The possible contribution to disease outcome of antibody developed after transmission and/or present in the inoculum in free or bound form is not understood. In this study, we develop a mathematical model of virus-antibody immune complex formation and use it to predict their role in transmission and protection. The model exhibits a bistable switch between clearance and persistence states. We fitted it to temporal virus data and estimated the parameter values for free virus infectivity rate and antibody carrying capacity for which the model transitions between virus clearance and persistence when the initial conditions (in particular the ratio of immune complexes to free virus) vary. We used these results to quantify the minimum virus amount in the inoculum needed to establish persistent infections in the presence and absence of protective antibodies.

Background It is well known that both mefloquine and doxycycline are commonly associated with adverse effects when taken for malaria chemoprophylaxis. However, the relative impact of these on travelers' ability to work is not so well understood. The aim of this study was to identify which drug has a lesser impact on the ability to work as measured by self-reported severity of adverse effects via a questionnaire. Methods This was a questionnaire-based two-arm cohort study. Participants were soldiers selected from 10 consecutive units training in Kenya during 2012 and 2013. The exposure was either doxycycline or mefloquine and the main outcome measure was impact upon ability to work. Each cohort was advised to take doxycycline or mefloquine with exceptions at the individual level where medically or occupationally advised. Results Significantly more ( p

Class II division 1 malocclusion is common and various methods have been suggested for successful treatment in the growing patient. A number of recent high-quality studies have been undertaken to assess the efficacy of these treatments. We aim to outline the existing best evidence that supports current practice, with a review of the effect of treatment timing on outcome. This will provide a sound evidence-base for General Dental Practitioners for assessing, advising and referring young patients for treatment. CPD/Clinical Relevance: General Dental Practitioners should understand the management options and optimal time for treating growing patients with a Class II division 1 malocclusion.

Tututepec was a regional capital that dominated much of southern Oaxaca, Mexico, during the Late Postclassic period (A.D. 1100-1522). This article synthesizes the results of compositional (neutron activation and petrography), stylistic, and iconographic analyses of pottery from commoner household excavations at Tututepec to address questions concerning ceramic production and distribution and also to shed light on aspects of political economy and domestic ritual at the capital. The study focuses primarily on Mixteca-Puebla polychromes, painted serving vessels bearing complex decorative motifs. Our compositional analyses, interpreted in light of the bedrock geology of the region, indicate that commoners obtained at least six to ten distinct varieties of pottery made from raw materials available locally within greater Tututepec. We argue that households probably acquired pottery through a central marketplace at the capital. In addition, our study demonstrates that commoners had regular access to polychromes from multiple producers, challenging the widespread notion that these vessels were restricted to elites who controlled their production. We argue that polychrome serving vessels played a prominent role in commonly occurring domestic rituals. Furthermore, commoners appear to have consciously selected vessels painted with imagery associated with warfare and sacrifice, suggesting that they actively supported the official imperial ideology of Tututepec.

Malnutrition means ‘poor nutrition’ when there is a deficiency of energy and nutrients in the diet that causes a measurable clinical outcome or impact on body composition or function.1 As such, malnutrition can refer to people who are overweight but the term is more often used to apply to people who are underweight. Malnutrition (as undernutrition) affects an estimated 3 million people in the UK (those either malnourished or at risk), the majority of whom are living in the community (93%).2 It can be a cause and consequence of illness, and is a common clinical and public health problem that has largely been ignored in primary care.3,4 This may be because the reverse problems of overeating, and obesity, have been the focus of attention in regard to weight management and nutritional status.\ud \ud Malnutrition can have a profound detrimental impact on disease risk, progression, and prognosis, as well as increasing complications after injury and delaying recovery from illness. It results in greater healthcare needs in the community, including more frequent access to GP services and increased needs at home. Recent estimates suggest that the health and social care cost of malnutrition in both adults and children in England alone exceeds £19 billion, and half of this expenditure is due to people >65 years.3 Overall, the cost of treating a malnourished patient is over three times more than treating a non-malnourished patient. It is only set to increase with an ageing population and the rising cost of health and social care services.

The hepatitis delta virus (HDV) is a rarest form of viral hepatitis, but has the worst outcomes for patients. It is a subviral satellite dependent on coinfection with hepatitis B (HBV) to replicate within the host liver. To date, there has been little to no modeling effort for HDV. Deriving and analyzing such a mathematical model poses difficulty as it requires the inclusion of (HBV). Here we begin with a well-studied HBV model from the literature and expand it to incorporate HDV. We investigate two models, one with and one without infected hepatocyte replication. Additionally, we consider treatment by the drug lamivudine. Comparison of model simulations with experimental results of lamivudine treatment indicate that infected cell proliferation may play a significant role in chronic HDV infection. Our results also shed light on several questions surrounding HDV and illustrate the need for more data.

Much has been written about the current crisis in UK general practice.1 GPs in the UK report finding their job more stressful than GPs in other countries2 and the reasons for the pressures in UK primary care have been well rehearsed in the literature and media, including management of patients with increasingly complex needs and expectations, increasing numbers of face-to-face consultations, work that is more intense, and longer working days.3 Compounding these pressures, GP practices are finding it difficult to recruit and retain GPs, resulting in a concurrent workforce crisis.1 This is all contributing to the destabilisation of the traditional structure of primary care based on the partnership model.1,4,5 The King’s Fund report on the state of English general practice1 found that GPs in training intended to work as locums (44%) or salaried doctors (48%) after qualification, with only 3% intending to work as partners. Another study reporting similar results4 found that less than a third of GP trainees hoped to work full time a year after qualification. Only 33% of GP trainees reported that they would become a doctor if they had the chance to go back and 34% stated they would consider specialties other than general practice. Fewer than half reported that they would recommend general practice to junior doctors. Reasons included workload, job-related stress, …