Interventions for prudent antibiotic use in primary healthcare: an econometric analysis.

BACKGROUND: Rational antibiotic prescribing is crucial to combat antibiotic resistance. Optimal strategies to improve antibiotic use are not known. Strama, the Swedish strategic program against antibiotic resistance, has been successful in reducing antibiotic prescription rates. This study investigates whether two specific interventions directed toward healthcare centers, an informational visit and a self-evaluation meeting, played a role in observed reduction in rates of antibiotic prescriptions in primary healthcare. METHODS: The study was a retrospective, observational, empirical analysis exploiting the variation in the timing of the interventions and considering past prescriptions through use of estimations from dynamic panel data models. Primary healthcare data from 2011 to 2014 were examined. Data were from public and private primary healthcare centers in western Sweden. The key variables were prescription of antibiotics and indicator variables for the two interventions. RESULTS: The first intervention, an educational information intervention, decreased the number of prescriptions among public healthcare centers, but this effect was only temporary. We found no proof that the second intervention, a self-evaluation meeting at the healthcare center, had an impact on the reduction of prescriptions. CONCLUSIONS: Single educational interventions aimed at influencing rates of antibiotic prescriptions have limited impact. A multifaceted approach is needed in efforts to reduce the use of antibiotics in primary health care.

To what extent does surrounding landscape explain stand-level occurrence of conservation-relevant species in fragmented boreal and hemi-boreal forest? - a systematic review.

BACKGROUND: Forestry and land-use change are leading causes of habitat loss, degradation, and fragmentation worldwide. The boreal forest biome is no exception, and only a small proportion of this forest type remains intact. Since forestry will remain a major land-use in this region, measures must be taken to ensure forest dependent biodiversity. Stand level features and structures promoting conservation relevant species have received much attention, but the landscape level perspective is often missing. Hence, we review the literature that has related fragmentation in the surrounding landscape to occurrence of threatened, declining, red-listed, rare, or deadwood dependent species as well as those considered to be indicator, flagship, umbrella, and/or keystone species in a given boreal forest stand. METHODS: A comprehensive search string was developed, benchmarked, and adapted for four bibliographic databases, two search engines, and 37 specialist websites. The online evidence synthesis tool Cadima was used for screening of both abstracts and full texts. All articles meeting the inclusion criteria were subject to study validity assessment and included in a narrative table. Studies reporting means and variance were included in quantitative meta-analysis when more than 3 comparable studies were available. RESULTS: The searches resulted in 20 890 unique articles that were reduced to 172 studies from 153 articles. These studies related stand level presence, abundance, species richness, and/or composition of conservation relevant species to landscape factors such as: categorical fragmentation intensity (higher vs. lower), amount of habitat or non-habitat, distance to habitat, and/or habitat configuration, on scales ranging from tens to tens of thousands of ha. Forty-three studies were suitable for meta-analysis. These showed a significant negative effect of fragmentation on both presence and abundance of conservation relevant species, as well as a near significant trend for species richness. This was particularly clear when fragmentation was measured as distance to surrounding habitat for presence, and as habitat amount for abundance. The organism groups with the strongest support for a negative effect of fragmentation were wood fungi and birds. CONCLUSION: As hypothesised, there is strong support for negative effects of fragmentation in boreal forest. These results emphasize the negative consequences of the intensive forestry and associated landscape transformation that has been the norm for the last century. We argue that this should have direct implications for policy makers to shift towards including a landscape perspective in all planning of harvesting, preserving, and restoring forest. In addition, we found that research effort has been very uneven between organism groups, that studies on landscape change over time were rare, and that many studies have not quantified the difference in fragmentation intensity among landscapes making it difficult to quantify the extent of the negative effect. One way forward would be to revisit the studies included here in to incorporate change over time, as well as a true quantification of landscape fragmentation. By doing so, the scale of the negative effects would be much better analysed, which would greatly assist conservation practitioners all throughout the boreal forest biome.

Antibiotic prescription: Knowledge among physicians and nurses in western Sweden.

Misuse and overuse of antibiotics are common in primary care. Guidelines for prescribing of antibiotics are often not followed We conducted a survey of 120 health centers in western Sweden to investigate to what extent physicians and nurses think they know and comply with the guidelines for prescribing of antibiotics. A large majority of the respondents answered that they know the guidelines well. However, many also believed that physicians/nurses in general know less about and are worse at following the guidelines than themselves, indicating optimism bias. According to the respondents the main reason for non-compliance with guidelines was patient expectations. The survey also showed that both physicians' and nurses' actual knowledge of when it is effective to prescribe antibiotics is incomplete. Interventions to reduce unnecessary antibiotic therapy in primary care should target the failing congruence between the perceived knowledge of guidelines for antibiotic therapy and actual knowledge.

Heparin Conjugate Pretreatment of Kidneys From Deceased Donors Before Transplantation: Results From the First-in-human Randomized Phase I Trial.

Pretreating porcine kidneys with Corline Heparin Conjugate (CHC) during hypothermic machine perfusion (HMP) has been shown to reduce preservation injury and improve early kidney function. In this first-in-human phase I study, the safety and tolerability of transplanting CHC-pretreated kidneys were evaluated. Methods: CHC or placebo was added to the preservation solution during HMP of donated kidneys from deceased donors for at least 3 h before transplantation into adult patients. The primary safety endpoint was the number and severity of adverse events (AEs) and serious AEs (SAEs) during the first 30 d after transplantation. Results: In the first 30 d, 66 AEs were reported in 8 patients who received CHC-pretreated kidneys with 39 AEs in 8 patients who received placebo-pretreated kidneys (P = 0.1 in post hoc analysis). The most common AEs were hypertension (CHC, n = 5; placebo, n = 2) and anemia (CHC, n = 5; placebo, n = 2). Most AEs were assessed as mild (58%) or moderate (39%) and not related to treatment (95%). There were 2 SAEs reported in each group. One SAE, considered possibly related to CHC treatment, was a case of severe postprocedural hemorrhage that required reoperation. No patients needed dialysis. There were no observed rejections and no patient deaths. Conclusions: Pretreatment of kidneys with CHC before transplantation was considered safe and tolerable. Efficacy studies are now planned to investigate if CHC can reduce early ischemia-reperfusion injury in humans.

Are only-children different? Evidence from a lab-in-the-field experiment of the Chinese one-child policy.

In this paper, we present evidence from a lab-in-the-field experiment of the effects of the Chinese one-child policy on adults in China who were born just before and after the introduction of the policy. We measure risk, uncertainty, and time preferences, as well as subjects' preferences in the social domain, i.e., concerning competitiveness, cooperation, and bargaining. We sampled people from three Chinese provinces born both before and after the introduction of the policy in 1979. We utilize the fact that the one-child policy was introduced at different times and with different degrees of strictness in different provinces. Overall, we find a statistically significant effect only on risk and uncertainty aversion and not on any other preferences in the experiments: Those born after the introduction of the one-child policy are less risk and uncertainty averse. These results hold for various robustness checks and heterogeneity tests. Hence, our results do not confirm the general wisdom and stereotype of only-children in China being "little emperors."

To what extent does surrounding landscape explain stand-level occurrence of conservation-relevant species in fragmented boreal and hemi-boreal forest?-a systematic review protocol.

BACKGROUND: Silviculture and land-use change has reduced the amount of natural forest worldwide and left what remains confined to isolated fragments or stands. To understand processes governing species occurrence in such stands, much attention has been given to stand-level factors such as size, structure, and deadwood amount. However, the surrounding matrix will directly impact species dispersal and persistence, and the link between the surrounding landscape configuration, composition and history, and stand-level species occurrence has received insufficient attention. Thus, to facilitate optimisation of forest management and species conservation, we propose a review addressing 'To what extent does surrounding landscape explain stand-level occurrence of conservation-relevant species in fragmented boreal and hemi-boreal forest?'. METHODS: The proposed systematic review will identify and synthesise relevant articles following the CEE guidelines for evidence synthesis and the ROSES standards. A search for peer-reviewed and grey literature will be conducted using four databases, two online search engines, and 36 specialist websites. Identified articles will be screened for eligibility in a two-step process; first on title and abstract, and second on the full text. Screening will be based on predefined eligibility criteria related to a PECO-model; population being boreal and hemi-boreal forest, exposure being fragmentation, comparator being landscapes with alternative composition, configuration, or history, and outcome being occurrence (i.e., presence and/or abundance) of conservation-relevant species. All articles that pass the full-text screening will go through study validity assessment and data extraction, and be part of a narrative review. If enough studies prove comparable, quantitative meta-analyses will also be performed. The objective of the narrative review and the meta-analyses will be to address the primary question as well as six secondary questions, and to identify important knowledge gaps.

The Singleton Fallacy: Why Current Critiques of Language Models Miss the Point.

This paper discusses the current critique against neural network-based Natural Language Understanding solutions known as language models. We argue that much of the current debate revolves around an argumentation error that we refer to as the singleton fallacy: the assumption that a concept (in this case, language, meaning, and understanding) refers to a single and uniform phenomenon, which in the current debate is assumed to be unobtainable by (current) language models. By contrast, we argue that positing some form of (mental) "unobtanium" as definiens for understanding inevitably leads to a dualistic position, and that such a position is precisely the original motivation for developing distributional methods in computational linguistics. As such, we argue that language models present a theoretically (and practically) sound approach that is our current best bet for computers to achieve language understanding. This understanding must however be understood as a computational means to an end.

Quantifying turbulent wall shear stress in a stenosed pipe using large eddy simulation.

Large eddy simulation was applied for flow of Re=2000 in a stenosed pipe in order to undertake a thorough investigation of the wall shear stress (WSS) in turbulent flow. A decomposition of the WSS into time averaged and fluctuating components is proposed. It was concluded that a scale resolving technique is required to completely describe the WSS pattern in a subject specific vessel model, since the poststenotic region was dominated by large axial and circumferential fluctuations. Three poststenotic regions of different WSS characteristics were identified. The recirculation zone was subject to a time averaged WSS in the retrograde direction and large fluctuations. After reattachment there was an antegrade shear and smaller fluctuations than in the recirculation zone. At the reattachment the fluctuations were the largest, but no direction dominated over time. Due to symmetry the circumferential time average was always zero. Thus, in a blood vessel, the axial fluctuations would affect endothelial cells in a stretched state, whereas the circumferential fluctuations would act in a relaxed direction.

Value of statistical life and cause of accident: a choice experiment.

The purpose of this study is to compare the value of statistical life (VSL) estimates for traffic, drowning, and fire accidents. Using a choice experiment in a mail survey of 5,000 Swedish respondents we estimated the willingness to pay for risk reductions in the three accidents. In the experiment respondents were asked a series of questions, whether they would choose risk reducing investments where type of accident, cost of the investment, the risk reduction acquired, and the baseline risk varied between questions. The VSLs for fire and drowning accidents were found to be about 1/3 lower than that for traffic accidents. Although respondents worry more about traffic accidents, this alone cannot explain the difference in VSL estimates. The difference between fire and drowning accidents was not found to be statistically significant.

Who is willing to stay sick for the collective? - Individual characteristics, experience, and trust.

•We study attitudes towards antibiotics and antibiotic resistance.•We analyze results from a novel web-survey of Swedish citizens (n = 1906).•Acceptability of doctor's decision not to prescribe antibiotics was found to be large.•Trust in the healthcare sector is linked to acceptability of doctor's decision.•Concern about antibiotic resistance is linked to willingness to limit antibiotic use.

Perfusion of Porcine Kidneys With Macromolecular Heparin Reduces Early Ischemia Reperfusion Injury.

BACKGROUND: Previously, we have been able to demonstrate the possibility of coating the inner surface of the renal arteries in porcine kidneys with a heparin conjugate during hypothermic machine perfusion (HMP). The purpose of this study was to assess the efficacy of this treatment in reducing early ischemia-reperfusion injury. METHOD: Brain death was induced in male landrace pigs by stepwise volume expansion of an epidural balloon catheter until negative cerebral perfusion pressure (CPP) was obtained. Both kidneys (matched pairs; n = 6 + 6) were preserved for 20 hours by HMP during which 50 mg heparin conjugate was added to one of the HMP systems (treated group). A customized ex vivo normothermic oxygenated perfusion (NP) system with added exogenous creatinine was used to evaluate early kidney function. Blood, urine and histological samples were collected during the subsequent 3 hours of NP. RESULTS: Kidney weight was lower at the end of NP (P = 0.017) in the treated group compared with control kidneys. The rate of decline in creatinine level was faster (P = 0.024), total urinary volume was higher (P = 0.031), and the level of urine neutrophil gelatinase-associated lipocalin (NGAL) was lower (P = 0.031) in the treated group. Histologically, less tubular changes were seen (P = 0.046). During NP intrarenal resistance remained lower (P < 0.0001) in the treated group. CONCLUSIONS: Perfusion of porcine kidneys with heparin conjugate during HMP reduces preservation injury and improves organ function shortly after reperfusion. No increased risk of bleeding was seen in this setup. This protective strategy may potentially improve the quality of transplanted kidneys in the clinical setting.

Combining segment generation with direct step-and-shoot optimization in intensity-modulated radiation therapy.

A method for generating a sequence of intensity-modulated radiation therapy step-and-shoot plans with increasing number of segments is presented. The objectives are to generate high-quality plans with few, large and regular segments, and to make the planning process more intuitive. The proposed method combines segment generation with direct step-and-shoot optimization, where leaf positions and segment weights are optimized simultaneously. The segment generation is based on a column generation approach. The method is evaluated on a test suite consisting of five head-and-neck cases and five prostate cases, planned for delivery with an Elekta SLi accelerator. The adjustment of segment shapes by direct step-and-shoot optimization improves the plan quality compared to using fixed segment shapes. The improvement in plan quality when adding segments is larger for plans with few segments. Eventually, adding more segments contributes very little to the plan quality, but increases the plan complexity. Thus, the method provides a tool for controlling the number of segments and, indirectly, the delivery time. This can support the planner in finding a sound trade-off between plan quality and treatment complexity.

Escherichia coli Bacteria Develop Adaptive Resistance to Antibacterial ZnO Nanoparticles.

Antibacterial agents based on nanoparticles (NPs) have many important applications, e.g., for the textile industry, surface disinfection, wound dressing, water treatment, and food preservation. Because of their prevalent use it is important to understand whether bacteria could develop resistance to such antibacterial NPs similarly to the resistance that bacteria are known to develop to antibiotics. Here, it is reported that Escherichia coli (E. coli) develops adaptive resistance to antibacterial ZnO NPs after several days' exposure to the NPs. But, in contrast to antibiotics-resistance, the observed resistance to ZnO NPs is not stable-after several days without exposure to the NPs, the bacteria regain their sensitivity to the NPs' antibacterial properties. Based on the analyses it is suggested that the observed resistance is caused by changes in the shape of the bacteria and the expressions of membrane proteins. The findings provide insights into the response of bacteria to antibacterial NPs, which is important to elucidate for designing and evaluating the risk of applications based on antibacterial NPs.

Enhanced protection of the renal vascular endothelium improves early outcome in kidney transplantation: Preclinical investigations in pig and mouse.

Ischemia reperfusion injury is one of the major complications responsible for delayed graft function in kidney transplantation. Applications to reduce reperfusion injury are essential due to the widespread use of kidneys from deceased organ donors where the risk for delayed graft function is especially prominent. We have recently shown that coating of inflamed or damaged endothelial cells with a unique heparin conjugate reduces thrombosis and leukocyte recruitment. In this study we evaluated the binding capacity of the heparin conjugate to cultured human endothelial cells, to kidneys from brain-dead porcine donors, and to murine kidneys during static cold storage. The heparin conjugate was able to stably bind cultured endothelial cells with high avidity, and to the renal vasculature of explanted kidneys from pigs and mice. Treatment of murine kidneys prior to transplantation reduced platelet deposition and leukocyte infiltration 24 hours post-transplantation, and significantly improved graft function. The present study thus shows the benefits of enhanced protection of the renal vasculature during cold storage, whereby increasing the antithrombotic and anti-adhesive properties of the vascular endothelium yields improved renal function early after transplantation.

In vivo h-VEGF165 gene transfer improves early endothelialisation and patency in synthetic vascular grafts.

OBJECTIVES: Small-diameter synthetic vascular graft performance is inferior to autologous vein grafts. This study tested the hypotheses that local in vivo administration of plasmids encoding for human vascular endothelial growth factor (VEGF), or co-administration of plasmids encoding for human vascular endothelial growth factor/plasmids encoding for fibroblast growth factor-2 in the tissues surrounding a porous synthetic vascular graft would enhance graft endothelialisation and, consecutively, graft patency. METHODS: First, optimal gene for small-diameter synthetic graft endothelialisation was studied in rat abdominal aorta model (n=132): plasmids encoding for human vascular endothelial growth factor; co-administration of plasmids encoding for human vascular endothelial growth factor/plasmids encoding for fibroblast growth factor-2; or control plasmids were injected around 60 microm ePTFE graft. Second, optimal small-diameter synthetic graft design for endothelialisation was explored in rabbit abdominal aorta model (n=90). Various ePTFE grafts or pre-clotted polyester grafts were used with/without plasmids encoding for human vascular endothelial growth factor. Third, clinically used medium-size synthetic grafts were investigated with/without plasmids encoding for human vascular endothelial growth factor in dog carotid (n=20) and femoral arteries (n=15). Endothelialisation was assessed in midgraft area with scanning electron microscopy. RESULTS: In rats, plasmids encoding for human vascular endothelial growth factor enhanced endothelialisation; whereas co-administration of plasmids encoding for human vascular endothelial growth factor/plasmids encoding for fibroblast growth factor-2 had worst outcome at 1 week (NS), 2 weeks (P=0.01) and 4 weeks (P=0.02). In rabbits, pre-clotted polyester grafts had a trend for faster endothelialisation than ePTFE grafts (P=0.08); whereas plasmids encoding for human vascular endothelial growth factor enhanced endothelialisation compared to controls at 2 weeks (P=0.06), however, the effect reversed at 4 weeks (P=0.03). In dogs, synthetic graft patency was improved by plasmids encoding for human vascular endothelial growth factor in femoral position (P=0.103); whereas all carotid grafts were patent at 6 weeks. CONCLUSIONS: Thus, these data suggested that endothelialisation was fastest in pre-clotted polyester grafts; and that local application of plasmids encoding for human vascular endothelial growth factor had a potential to improve early endothelialisation and patency in synthetic vascular grafts.

Iterative regularization in intensity-modulated radiation therapy optimization.

A common way to solve intensity-modulated radiation therapy (IMRT) optimization problems is to use a beamlet-based approach. The approach is usually employed in a three-step manner: first a beamlet-weight optimization problem is solved, then the fluence profiles are converted into step-and-shoot segments, and finally postoptimization of the segment weights is performed. A drawback of beamlet-based approaches is that beamlet-weight optimization problems are ill-conditioned and have to be regularized in order to produce smooth fluence profiles that are suitable for conversion. The purpose of this paper is twofold: first, to explain the suitability of solving beamlet-based IMRT problems by a BFGS quasi-Newton sequential quadratic programming method with diagonal initial Hessian estimate, and second, to empirically show that beamlet-weight optimization problems should be solved in relatively few iterations when using this optimization method. The explanation of the suitability is based on viewing the optimization method as an iterative regularization method. In iterative regularization, the optimization problem is solved approximately by iterating long enough to obtain a solution close to the optimal one, but terminating before too much noise occurs. Iterative regularization requires an optimization method that initially proceeds in smooth directions and makes rapid initial progress. Solving ten beamlet-based IMRT problems with dose-volume objectives and bounds on the beamlet-weights, we find that the considered optimization method fulfills the requirements for performing iterative regularization. After segment-weight optimization, the treatments obtained using 35 beamlet-weight iterations outperform the treatments obtained using 100 beamlet-weight iterations, both in terms of objective value and of target uniformity. We conclude that iterating too long may in fact deteriorate the quality of the deliverable plan.

Consumer preferences for food product quality attributes from Swedish agriculture.

This paper employs a choice experiment to obtain consumer preferences and willingness to pay for food product quality attributes currently not available in Sweden. Data were obtained from a large mail survey and estimated with a random parameter logit model. We found evidence for intraproduct differences in consumer preferences for identical attributes, as well as interproduct discrepancies in ranking of attributes. Furthermore, we found evidence of a market failure relating to the potential use of genetically modified animal fodder. Finally, we found support for the idea that a cheap-talk script can alleviate problems of external validity of choice experiments. Our results are useful in forming product differentiation strategies within the food industry, as well as for the formation of food policy.

Attachment of flexible heparin chains to gelatin scaffolds improves endothelial cell infiltration.

Long-term survival of implanted cells requires oxygen and nutrients, the need for which is met by vascularization of the implant. The use of scaffolds with surface-attached heparin as anchoring points for angiogenic growth factors has been reported to improve this process. We examined the potential role of surface modification of gelatin scaffolds in promoting endothelial cell infiltration by using a unique macromolecular conjugate of heparin as a coating. Compared to other heparin coatings, this surface modification provides flexible heparin chains, representing a new concept in heparin conjugation. In vitro cell infiltration of scaffolds was assessed using a three-dimensional model in which the novel heparin surface, without growth factors, showed a 2.5-fold increase in the number of infiltrating endothelial cells when compared to control scaffolds. No additional improvement was achieved by adding growth factors (vascular endothelial growth factor and/or fibroblast growth factor-2) to the scaffold. In vivo experiments confirmed these results and also showed that the addition of angiogenic growth factors did not significantly increase the endothelial cell infiltration but increased the number of inflammatory cells in the implanted scaffolds. The endothelial cell-stimulating ability of the heparin surface alone, combined with its growth factor-binding capacity, renders it an interesting candidate surface treatment to create a prevascularized site prepared for implantation of cells and tissues, in particular those sensitive to inflammation but in need of supportive revascularization, such as pancreatic islets of Langerhans.

Preclinical evaluation of a 68Ga-labeled biotin analogue for applications in islet transplantation.

INTRODUCTION: Islet transplantation is a promising treatment for type 1 diabetes mellitus, but the fate of the cells after intraportal infusion is unclear. It is therefore imperative to develop novel techniques for noninvasive imaging and quantification of events following islet transplantation. METHODS: Small islet-like microbeads, avidin-covered agarose resins (AARs), were used as a model system for islet transplantation. Capability for specific [(68)Ga]Ga-DOTA-(PEG)(2)-biotin uptake and retention for either AARs or human islets conjugated with avidin by means of a heparin scaffold was studied in vitro. Biodistribution of the novel positron emission tomography (PET) tracer [(68)Ga]Ga-DOTA-(PEG)(2)-biotin was evaluated in mice treated by intraportal transplantation of AARs by µPET/computed tomography and ex vivo organ distribution and compared with control mice. RESULTS: AARs had high capability to bind [(68)Ga]Ga-DOTA-(PEG)(2)-biotin, close to 50% of administrated tracer/µl in vitro (>0.25 MBq/µl). Avidin-tagged human islets could bind on average 2.2% of administered tracer/µl. Specificity (>90%) and retention (>90% after 1 h) were high for both AARs and avidin-tagged islets. Hepatic tracer uptake and retention were increased in mice transplanted with AARs [standardized uptake value (SUV)=2.6] compared to the untreated group (SUV=1.4). In vivo uptake of tracer to AARs was blocked by preadministration of unlabeled biotin. CONCLUSIONS: Avidin-tagged islet-like objects can be tracked in hepatic volume after intraportal transplantation by using [(68)Ga]Ga-DOTA-(PEG)(2)-biotin and PET.

Increased heat resistance in mycelia from wood fungi prevalent in forests characterized by fire: a possible adaptation to forest fire.

Forest fires have been the major stand-replacing/modifying disturbance in boreal forests. To adapt to fire disturbance, different strategies have evolved. This study focuses on wood fungi, and a specific adaptation to forest fire: increased heat resistance in their mycelia. Fifteen species of wood fungi were selected and a priori sorted in two groups according to their prevalence in fire-affected environments. The fungi were cultivated on fresh wood and exposed to 100, 140, 180, 220 °C for 5, 10, 15, 20 and 25 min. under laboratory conditions. A clear difference was found among the two groups. Species prevalent in fire-affected habitats had a much higher survival rate over all combinations of time and temperature compared to species associated with other environments. Thus, the results indicate that fire adaptation in terms of increased heat resistance in mycelia occurs in some species of wood fungi. Such adaptation will influence the ecology and population dynamics of wood fungi, as well as having implications for best practices during restoration fires.