Breast cancer screening in women taking hormone replacement therapy needs updating.

Breast cancer screening by mammography is widely used. The diagnostic accuracy is limited, with a positive predictive value of 16%. Therefore, a stepwise investigation, with repeat mammography and confirmation by pathology, is usually proposed. Although this stepwise investigation intends to avoid overtreatment, the many false positives result in unnecessary fear and diagnostic surgery in many women. The false negatives are not known since these women have not been investigated. Given the estimated low risk of missing breast cancer and the slow growth, repeating a screening mammography every two years is sufficient. The false positive screening results, increase with breast density, and breast density increases when hormone replacement therapy (HRT) is given. It, therefore, is suggested to use clinical judgment and stop HRT for 3 to 6 months before repeating the mammography instead of starting immediately a stepwise investigation in all women.

Sex and gender differences in healthcare utilisation trajectories: a cohort study among Quebec workers living with chronic pain.

OBJECTIVES: Chronic pain (CP) is a poorly recognised and frequently inadequately treated condition affecting one in five adults. Reflecting on sociodemographic disparities as barriers to CP care in Canada was recently established as a federal priority. The objective of this study was to assess sex and gender differences in healthcare utilisation trajectories among workers living with CP. DESIGN: Retrospective cohort study. PARTICIPANTS: This study was conducted using the TorSaDE Cohort which links the 2007-2016 Canadian Community Health Surveys and Quebec administrative databases (longitudinal claims). Among 2955 workers living with CP, the annual number of healthcare contacts was computed during the 3 years after survey completion. OUTCOME: Group-based trajectory modelling was used to identify subgroups of individuals with similar patterns of healthcare utilisation over time (healthcare utilisation trajectories). RESULTS: Across the study population, three distinct 3-year healthcare utilisation trajectories were found: (1) low healthcare users (59.9%), (2) moderate healthcare users (33.6%) and (3) heavy healthcare users (6.4%). Sex and gender differences were found in the number of distinct trajectories and the stability of the number of healthcare contacts over time. Multivariable analysis revealed that independent of other sociodemographic characteristics and severity of health condition, sex-but not gender-was associated with the heavy healthcare utilisation longitudinal trajectory (with females showing a greater likelihood; OR 2.6, 95% CI 1.6 to 4.1). CONCLUSIONS: Our results underline the importance of assessing sex-based disparities in help-seeking behaviours, access to healthcare and resource utilisation among persons living with CP.

Review: Targeted nutrition in gestating sows: opportunities to enhance sow performance and piglet vitality.

Birth weight is a key factor for piglet survival, and therefore, there is ongoing interest in how nutrition during gestation can influence birth weight. Interestingly, sows are generally fed one single diet throughout gestation. This paper reviews past attempts to increase foetal growth to term and discusses opportunities to target nutritional manipulations at specific windows of gestation where key developmental events occur. Birth weight limits chances to survive mainly in piglets with birth weight below 1 kg. These piglets represent around 16% of the population. Given the normal distribution of birth weight, the mean birth weight needs to be increased by at least 50-100 g to have a meaningful impact on this proportion of the population and on perinatal survival. Based on existing variation in reported mean birth weight across a number of studies, it is argued that it is unrealistic to expect an increase in mean birth weight of more than 100 g. Attempts in the past to increase birth weight have focussed on the last trimester of gestation, when foetal growth is accelerated. Increase in feed allowance or nutritional concepts that target placenta vascularisation have not been successful. It is argued that nutritional manipulations should rather focus on the middle of gestation, since in that period, placenta growth occurs and since placenta size limits the foetal size. Alternatively, nutritional manipulations can target placentation during the embryonic phase.

Effect of low colostrum intake on gastrointestinal development and uterine and cervical morphometrical architecture in the neonatal gilt.

To assess the importance of natural variation in colostrum intake on piglet gastrointestinal and reproductive development, two equally sized female piglets from each of 27 litters were selected, one with low (average 226 g) and one with high (average 401 g) colostrum intake. At weaning (23 d of age), piglets were euthanised to perform macromorphological measurements on ileum, colon, cervix and uterus tissues, and to obtain tissue samples from the cervix and uterus for histology. Sections of uterine and cervical preparations were analysed using digital image analysis. Despite being selected for the same birth weight (average 1.1 kg, standard deviation 0.18 kg), piglets with low colostrum intake weighed 5.91 ± 0.17 kg and piglets with high colostrum intake weighed 6.96 ± 0.19 kg at weaning (P < 0.05). Most of the micro- and macroscopic measures such as length and weight of ileum and colon, cervix and uterus, luminal size of cervix and uterus, number of cervical crypts and uterine glands, were greater in gilts with high colostrum intake. The histological architecture of the uterus and cervix in gilts with high colostrum intake showed more complexity, reflecting more advanced development in these piglets. In conclusion, these data demonstrate that independent of birth weight, natural variation in colostrum intake is related to the overall development of neonatal piglets, affecting body growth, as well as growth and development of the gut and reproductive tract.

Strategies aimed at preventing long-term opioid use in trauma and orthopaedic surgery: a scoping review.

BACKGROUND: Long-term opioid use, which may have significant individual and societal impacts, has been documented in up to 20% of patients after trauma or orthopaedic surgery. The objectives of this scoping review were to systematically map the research on strategies aiming to prevent chronic opioid use in these populations and to identify knowledge gaps in this area. METHODS: This scoping review is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) Checklist. We searched seven databases and websites of relevant organizations. Selected studies and guidelines were published between January 2008 and September 2021. Preventive strategies were categorized as: system-based, pharmacological, educational, multimodal, and others. We summarized findings using measures of central tendency and frequency along with p-values. We also reported the level of evidence and the strength of recommendations presented in clinical guidelines. RESULTS: A total of 391 studies met the inclusion criteria after initial screening from which 66 studies and 20 guidelines were selected. Studies mainly focused on orthopaedic surgery (62,1%), trauma (30.3%) and spine surgery (7.6%). Among system-based strategies, hospital-based individualized opioid tapering protocols, and regulation initiatives limiting the prescription of opioids were associated with statistically significant decreases in morphine equivalent doses (MEDs) at 1 to 3 months following trauma and orthopaedic surgery. Among pharmacological strategies, only the use of non-steroidal anti-inflammatory drugs and beta blockers led to a significant reduction in MEDs up to 12 months after orthopaedic surgery. Most studies on educational strategies, multimodal strategies and psychological strategies were associated with significant reductions in MEDs beyond 1 month. The majority of recommendations from clinical practice guidelines were of low level of evidence. CONCLUSIONS: This scoping review advances knowledge on existing strategies to prevent long-term opioid use in trauma and orthopaedic surgery patients. We observed that system-based, educational, multimodal and psychological strategies are the most promising. Future research should focus on determining which strategies should be implemented particularly in trauma patients at high risk for long-term use, testing those that can promote a judicious prescription of opioids while preventing an illicit use, and evaluating their effects on relevant patient-reported and social outcomes.

Implication of imposing fertilizer limitations on energy, agriculture, and land systems.

Since the 1950's, global fertilizer usage has increased by more than 800% resulting in detrimental impacts to the environment. The projected increase in crop production due to increasing demands for food, feed, biofuel, and other uses, may further increase fertilizer usage. Studies have examined achieving agricultural intensification in environmentally sustainable ways, however, they have not focused on the whole-system economic aspects of changes in fertilizer usage over the long term. We utilize the Global Change Analysis Model (GCAM) to explore the impact of reducing global fertilizer usage on land use change, agricultural commodity price and production, energy production, and greenhouse gas emissions. We find that constrained fertilizer availability results in reduced global cropland area, particularly land used for bioenergy production, and expanded forested area. These results are driven by price impacts which lead to shifts in agricultural production between commodity types, regions, and technologies, and which lead to decreased agricultural commodity demands.

Exploiting digital droplet PCR and Next Generation Sequencing technologies to determine the relative abundance of individual Eimeria species in a DNA sample.

DNA-based diagnostic assays for detecting infections with Eimeria species have been limited to providing identification and presence/absence data for samples containing oocysts. Modern technologies that generate quantitative data, such as droplet digital PCR (ddPCR) and Next Generation Sequencing (NGS), utilize a relatively short amplicon size containing sufficient species-specific variation for reliable species level identification. Targeting the cytochrome c oxidase subunit III gene in the mitochondrial genome, we established protocols using these technologies to determine the relative abundance of the number of copies/µL of Eimeria species in a sample. Samples from chickens of known and unknown Eimeria species composition were analyzed to determine the suitability of these technologies as diagnostic assays. All technologies demonstrated robust capability of identifying and quantifying the Eimeria species in samples. The new quantitative assays described herein will produce invaluable detail of Eimeria species infections for an array of situations in commercial chicken production systems, enabling further characterization of the disease profile and allowing for the development or enhancement of new intervention strategies.

NFL strongly correlates with TNF-R1 in the plasma of AD patients, but not with cognitive decline.

Peripheral inflammation mechanisms involved in Alzheimer's disease (AD) have yet to be accurately characterized and the identification of blood biomarker profiles could help predict cognitive decline and optimize patient care. Blood biomarkers described to date have failed to provide a consensus signature, which is mainly due to the heterogeneity of the methods used or the cohort. The present work aims to describe the potential informativity of peripheral inflammation in AD, focusing in particular on the potential association between the level of plasma neurofilament light (NFL), peripheral inflammation (by quantifying IL-1ß, IL-6, TNFα, CCL5, TNF-R1, sIL-6R, TIMP-1, IL-8 in blood) and cognitive decline (assessed by the MMSE and ADAScog scales) through a 2-year follow-up of 40 AD patients from the Cytocogma cohort (CHU Poitiers, Pr M. Paccalin). Our results show for the first time a strong correlation between plasma NFL and TNF-R1 at each time of follow-up (baseline, 12 and 24 months), thus opening an interesting perspective for the prognosis of AD patients.

Restoration of anticoccidial sensitivity to a commercial broiler chicken facility in Canada.

Increasing resistance of Eimeria species to anticoccidial medications is an issue in the broiler chicken industry. Using drug-sensitive strains in live-coccidiosis vaccines has been shown to improve anticoccidial effectiveness in US-based broiler production. In Canada, litter is removed between flocks, which differ from the US industry practice. Thus, we investigated the use of drug-sensitive vaccine strains in a Canadian broiler production facility with suspected anticoccidial resistance. Weekly fecal samples were collected from flocks before, during, and after vaccine seeding to determine oocyst shedding patterns; following the vaccine seeding, OPG counts from similar aged birds were lower than flocks before live-coccidiosis vaccine use. Eimeria species isolates, collected before and after vaccine seeding, were used in 2 anticoccidial sensitivity tests to evaluate their susceptibility to commercially available anticoccidial medications; a low-dose challenge to define parasite replication, and a high-dose challenge to monitor broiler performance. In both experiments, isolates collected after seeding were more susceptible to almost every anticoccidial medication evaluated compared with the isolates collected before seeding. These results demonstrate an improvement in sensitivity to many anticoccidials after the use of live-coccidiosis vaccines at this facility. However, the regulated removal of litter at the end of each flock required under Canadian broiler chicken production management rules could limit the establishment of vaccine-strain Eimeria species in broiler facilities and could shorten the longevity of improved drug sensitivity observed in this study.

A method for experimental warming of developing tree seeds with a common garden demonstration of seedling responses.

BACKGROUND: Forest dieback driven by rapid climate warming threatens ecosystems worldwide. The health of forested ecosystems depends on how tree species respond to warming during all life history stages. While it is known that seed development is temperature-sensitive, little is known about possible effects of climate warming on seed development and subsequent seedling performance. Exposure of seeds to high air temperatures may influence subsequent seedling performance negatively, though conversely, warming during seed development may aid acclimation of seedlings to subsequent thermal stress. Technical challenges associated with in-situ warming of developing tree seeds limit understanding of how tree species may respond to seed development in a warmer climate. RESULTS: We developed and validated a simple method for passively warming seeds as they develop in tree canopies to enable controlled study of climate warming on seedling performance. We quantified thermal effects of the cone-warming method across individual pine trees and stands by measuring the air temperature surrounding seed cones using thermal loggers and the temperature of seed cone tissue using thermocouples. We then investigated seedling phenotypes in relation to the warming method through a common garden study. We assessed seedling morphology, physiology, and mycorrhizal nodulation in response to experimental cone-warming in 20 seed-source-tree canopies on the San Francisco Peaks in northern Arizona, USA. The warming method increased air temperature surrounding developing seed cones by 2.1 °C, a plausible increase in mean air temperature by 2050 under current climate projections. Notable effect sizes of cone-warming were detected for seedling root length, shoot length, and diameter at root collar using Cohen's Local f2. Root length was affected most by cone-warming, but effect sizes of cone-warming on root length and diameter at root collar became negligible after the first year of growth. Cone-warming had small but significant effects on mycorrhizal fungal richness and seedling multispectral near-infrared indices indicative of plant health. CONCLUSIONS: The method was shown to reliably elevate the temperature surrounding seed cones and thereby facilitate experimental in-situ climate warming research on forest trees. The method was furthermore shown to influence plant traits that may affect seedling performance under climate warming.

Monitoring coccidia in commercial broiler chicken flocks in Ontario: comparing oocyst cycling patterns in flocks using anticoccidial medications or live vaccination.

Coccidiosis, the parasitic disease caused by Eimeria spp., is controlled during broiler chicken production through the inclusion of in-feed anticoccidial medications. Live-coccidiosis vaccination has become an increasingly common alternative to these medications. Monitoring infections with Eimeria spp. in flocks can be accomplished through determining the concentration of oocysts excreted in the fecal material (i.e., oocysts per gram; OPG). The purpose of our study was to sample commercial Ontario broiler chicken flocks at various times of the year to determine weekly OPG counts for flocks that use either an in-feed anticoccidial medication or a live-coccidiosis vaccine. Weekly sampling of 95 flocks from placement to market permitted documentation of oocyst cycling patterns typical of conventional and antibiotic-free flocks, and variation of these patterns in summer and winter. Medicated flocks had higher and later peak oocyst shedding compared with vaccinated flocks. Flocks reared in the summer peaked in oocyst shedding earlier than flocks reared in the winter. Despite what appears to be poorer coccidiosis control in the medicated flocks, the performance data were similar for these flocks compared with vaccinated flocks. This is the first study describing typical patterns of parasite shedding in Ontarian commercial broiler chicken flocks; these data will provide a baseline of expected Eimeria spp. infections in Canadian broiler chicken flocks to ensure optimal coccidiosis prevention.

The effect of added oat hulls or sugar beet pulp to diets containing rapidly or slowly digestible protein sources on broiler growth performance from 0 to 36 days of age.

The effects of formulating broiler diets that contain sources of either rapidly or slowly digestible protein and 2 different dietary fiber sources on growth performance were studied in broilers chickens from 0 to 36 d of age. A total of 1,920 one-day-old, male Ross 708 broiler chickens were randomly allocated and housed in 48 floor pens (40 birds/pen) to one of 4 dietary treatments. Birds were allotted according to a completely randomized block design using a factorial arrangement of treatments with 2 protein digestion rates (rapidly or slowly) and 2 dietary fiber sources [3% oat hulls (OH) or 3% sugar beet pulp (SBP)] from 0 to 36 d of age. All diets were formulated to be isocaloric and isonitrogenous. The pen was the experimental unit for all variables studied (12 replicates/treatment). Data were analyzed using the MIXED procedure of SAS, and the model included the main effects of the protein digestion rate, dietary fiber source, and their interaction. There were 3 experimental feeding phases; starter (from day 0-14), grower (from day 14-28), and finisher (from day 28-36). Results indicated that broilers fed diets containing sources that supplied more rapidly digestible protein had 4% greater (P < 0.01) ADG and improved (P < 0.01) the feed conversion ratio (FCR) by 5% throughout the experiment, most notably after the starter phase. Diets containing 3% OH increased (P < 0.05) the ADFI and ADG (P < 0.05) in the starter phase compared with broilers fed diets containing 3% SBP, without affecting the FCR. The ADG and FCR of broilers fed diets containing sources of slowly digestible protein were improved (P < 0.05) to the level of broilers fed rapidly digestible protein containing diets with the addition of 3% OH. It is concluded that broiler diets should be formulated to contain a high concentration of ingredients that supply rapidly digestible protein, but if this is cost-prohibitive, then 3% OH could be used to increase the ADFI and ADG and potentially protein digestion rates to reduce the FCR.

Early-life conditioning strategies to reduce dietary phosphorus in broilers: underlying mechanisms.

Chickens adapt to P and Ca restriction during the very first days of life by improving P utilisation efficiency. The present study was built to identify the mechanisms underlying this adaptive capacity, and to identify the optimal window of application of the restriction (depletion). A total of 1600 Cobb 500TM male broilers were used. During each phase (from age 0 to 4 d, 5 to 8 d, 9 to 18 d and 19 to 33 d), the animals received either a control diet (H) or a restricted diet (L) with reduced levels of non-phytate P (nPP) and Ca (between -14 and -25 % for both) with four dietary sequences: HHHH, HLHL, LHHL and LLHL. None of the feeding strategies affected growth. Tibia ash content at day 4 and 8 was impaired when the L diet was fed from 0 to 4 and 5 to 8 d, respectively (P = 0⋅038 and P = 0⋅005). Whatever the early restriction period or length between 0 and 8 d of age, the mineralisation delay was compensated by day 18. This was accompanied by an increased mRNA expression of the Ca transporter, CALB1, and an increased apparent ileal digestibility of Ca at day 8 (P < 0⋅001). This adaptation was limited to the starter phase in restricted birds. No effect was seen on P transporters mRNA or protein expression. In conclusion, birds adapted to mineral restriction by increasing Ca and nPP utilisation efficiencies. Depletion-repletion strategies are promising in improving the sustainability of broiler production but need to be validated in phytase-supplemented diets.

Foetal scalp blood sampling and ST-analysis of the foetal ECG for intrapartum foetal monitoring: a restricted systematic review.

BACKGROUND: To investigate if foetal scalp blood sampling (FBS) is useful in preventing foetal metabolic acidosis in labour when ST-analysis of the foetal ECG (STAN ® ) is already being used as a second line technique for intrapartum foetal monitoring with cardiotocography (CTG). DESIGN: Restricted systematic review. METHODS: Based on a literature search in July 2019, a restricted systematic review was performed. Studies comparing CTG+STAN ® +FBS with CTG+STAN ® , CTG+FBS or CTG only were included. Observational studies allowing FBS in addition to STAN ® reporting the indications, results and neonatal outcomes were included as well. RESULTS: Five randomised controlled trials (RCT) and seven observational trials were analysed. Based on the analysis of data coming from one RCT, FBS identifies foetal acidosis in 9.9% when performed in specific situations. Similarly, in observational trials it was found that in up to 10% of cases where STAN ® registration was less reliable, FBS suggested foetal acidosis. However, there is no evidence that FBS in these cases was capable of preventing metabolic acidosis or its neurological consequences. CONCLUSION: Based on the available literature, no recommendations in favour of combining FBS with STAN ® monitoring can be made.

Current and emerging avenues for Alzheimer's disease drug targets.

Alzheimer's disease (AD), the most frequent cause of dementia, is escalating as a global epidemic, and so far, there is neither cure nor treatment to alter its progression. The most important feature of the disease is neuronal death and loss of cognitive functions, caused probably from several pathological processes in the brain. The main neuropathological features of AD are widely described as amyloid beta (Aß) plaques and neurofibrillary tangles of the aggregated protein tau, which contribute to the disease. Nevertheless, AD brains suffer from a variety of alterations in function, such as energy metabolism, inflammation and synaptic activity. The latest decades have seen an explosion of genes and molecules that can be employed as targets aiming to improve brain physiology, which can result in preventive strategies for AD. Moreover, therapeutics using these targets can help AD brains to sustain function during the development of AD pathology. Here, we review broadly recent information for potential targets that can modify AD through diverse pharmacological and nonpharmacological approaches including gene therapy. We propose that AD could be tackled not only using combination therapies including Aß and tau, but also considering insulin and cholesterol metabolism, vascular function, synaptic plasticity, epigenetics, neurovascular junction and blood-brain barrier targets that have been studied recently. We also make a case for the role of gut microbiota in AD. Our hope is to promote the continuing research of diverse targets affecting AD and promote diverse targeting as a near-future strategy.

Contribution of flow MRI in the therapeutic management of middle face high flow arteriovenous malformation: A case report.

BACKROUND: The radiosurgical management of high flow arteriovenous malformations (HFAVM) in the "destructive" stage requires a precise hemodynamic and anatomical assessment. PATIENT AND METHODS/CASE REPORT: We report the case of a 32 years-old patient with a large ulcerated face HFAVM, on which Doppler ultrasound was impossible to perform. We show that, by combining 3D PCA and 2D CINE PC-MRI sequences, magnetic resonance imaging is capable to provide a complete morphometric and velocimetric mapping of the nidus and feeding arteries of the HFAVM. CONCLUSION: Although Doppler ultrasound is the reference examination in the HFAVM, Flow MRI without contrast agent provides an advantageous alternative to assess vascular pathologies and choose the therapeutic strategy.

Does Phase-Contrast Imaging through the Cerebral Aqueduct Predict the Outcome of Lumbar CSF Drainage or Shunt Surgery in Patients with Suspected Adult Hydrocephalus?

BACKGROUND AND PURPOSE: Radiologic imaging plays a key role in diagnosing chronic adult hydrocephalus, but its role in predicting prognosis is still controversial. We sought to evaluate the effectiveness of cardiac-gated phase-contrast MR imaging through the cerebral aqueduct in predicting the clinical response to diagnostic lumbar puncture/lumbar drainage and shunt surgery in suspected adult hydrocephalus. MATERIALS AND METHODS: In this retrospective study, the phase-contrast MR imaging of 185 patients with suspected chronic adult hydrocephalus was evaluated using the CSF Flow software package. Decision-making for shunt placement was performed in this cohort on the basis of clinical assessment alone without the availability of quantitative phase-contrast MR imaging results. We recorded the response to lumbar puncture or lumbar drainage and shunt surgery using quantitative tests such as the Tinetti Test, the Timed Up and Go, and the Mini-Mental State Examination and qualitative measures of gait, urinary, and cognitive symptom improvement before and after lumbar puncture/lumbar drainage and shunt surgery. Quantitative analysis of phase-contrast MR imaging was compared with clinical outcome measures. RESULTS: Both CSF stroke volume and flow rate overlapped between lumbar puncture/lumbar drainage responders and nonresponders. There was also a significant overlap between shunt responders and nonresponders. Aqueductal stroke volume or flow rate alone was a poor predictor of lumbar puncture/lumbar drainage and shunt surgery response. Quantitative clinical measures after lumbar puncture/lumbar drainage were better predictors of shunt response. CONCLUSIONS: This study suggests that the results of phase-contrast MR imaging through the cerebral aqueduct alone should not be used to select patients for diagnostic or therapeutic CSF diversion.

Longitudinal chemokine profile expression in a blood-brain barrier model from Alzheimer transgenic versus wild-type mice.

BACKGROUND: Alzheimer's disease is widely described since the discovery of histopathological lesions in Mrs. Auguste Deter in 1906. However to date, there is no effective treatment to deal with the many cellular and molecular alterations. The complexity is even higher with the growing evidence of involvement of the peripheral blood mononuclear cells (PBMCs). Indeed, monocytes and T cells are shown in the cerebral parenchyma of AD patients, and these cells grafted to the periphery are able to go through the blood-brain barrier (BBB) in transgenic mouse models. It is known that BBB is disrupted at a late stage of AD. Chemokines represent major regulators of the transmigration of PBMCs, but many data were obtained on AD animal models. No data are available on the role of AD BBB in a healthy brain parenchyma. Therefore, the purpose of this study was to analyze the longitudinal chemokine profile expression in a BBB model from AD transgenic mice versus wild-type (WT) mice. METHODS: A primary mouse BBB model was used with a luminal compartment either AD or WT and an abluminal compartment WT consisting of astrocytes and microglia. PBMCs were extracted by a ficoll gradient and incubated in the transwell with a direct contact with the luminal side, including the endothelial cells and pericytes. Then, the complete BBB model was incubated during 48 h, before supernatants and cell lysates were collected. Chemokines were quantified by X-MAP® luminex technology. RESULTS: Abluminal CX3CL1 production increased in 12-month-old AD BBB while CX3CL1 levels decreased in luminal lysates. CCL3 in luminal compartment increased with aging and was significantly different compared to AD BBB at 12 months. In addition, abluminal CCL2 in 12-month-old AD BBB greatly decreased compared to levels in WT BBB. On the contrary, no modification was observed for CCL4, CCL5, and CXCL10. CONCLUSION: These first findings highlighted the impact of AD luminal compartment on chemokine signature in a healthy brain parenchyma, suggesting new therapeutic or diagnostic approaches.