Aim: Our aim was to evaluate the effect of a 1-deamino-8-D-arginine vasopressin (DDAVP)-induced rise in VWF concentration on the pharmacokinetics of infused FVIII in hemophilia A patients. The half-life and mean residence time (MRT) of infused recombinant factor VIII (FVIII) concentrate are associated with pre-infusion levels of von Willebrand factor (VWF) in severely affected hemophilia A patients. It is currently unknown if individual FVIII concentrate half-life and MRT can be extended by increasing endogenous VWF levels. Four adult hemophilia A patients participated in this cross-over, placebo-controlled study. Each patient received either intravenous DDAVP or placebo, one hour prior to administration of 50 IU/kg plasma-derived immune-affinity purified FVIII concentrate. The combined administration of DDAVP and FVIII concentrate was well tolerated. The levels of VWF Antigen (Ag) doubled after DDAVP, whereas they remained stable after placebo infusion. This rise in VWF Ag resulted in a slight modification of the pharmacokinetic parameters of FVIII concentrate. The MRT of FVIII concentrate increased in all patients . However, in vivo recoveries tended to decrease following DDAVP administration. Collectively, these data show that administration of DDAVP did not improve the pharmacokinetics of FVIII concentrate in a clinically significant manner.Our results indicate that no clinical benefit is to be expected from the modification in FVIII pharmacokinetics resulting from DDAVP-administration prior to infusion of FVIII concentrate in hemophilia A patients. The treVWF is a multimeric glycoprotein synthesized by vascular endothelial cells and megakaryocytes . After sIn general, the survival of FVIII following intravenous administration is dependent on circulating VWF. The importance of VWF for sustained levels of circulating FVIII is clearly demonstrated in patients with the severe type of von Willebrand disease (vWD), in whom no circulating VWF is detectable. Morfini et al. showed that the half-life of a plasma- derived FVIII concentrate is strongly reduced in 11 vWD patients (mean 2.8 h) in comparison to hemophilia A patients mean 10.5 h), who have normal levels of VWF . The binding of FVIII is not influenced by the degree of multimerization of VWF, as is evident from the in vitro VWF binding experiments in this study (not shown) and data reported before ,31. WhenSecond, the FVIII concentrate used in this study contains residual amounts of VWF which might partially obscure the effect of the DDAVP induced rise of VWF. It is difficult to estimate the effect of the residual amount of VWF in the product on our outcomes, as knowledge is scant on the exact interaction between VWF and FVIII. An early study on the binding of FVIII to VWF provided evidence for multiple classes of FVIII-binding sites on VWF . HoweverThe differences observed between the two studies show that the stoichiometry of binding may depend on the technology used to assess binding. We suspect (but we cannot prove) that the differences observed are due the presence of multiple classes of binding sites for FVIII on VWF. Low affinity binding of FVIII may occur to all VWF subunits yielding a stoichiometry of 1:1 whereas high affinity binding of FVIII may occur to a subset of VWF subunits  with a stoichiometry of binding of 1:50. Competition studies with monoclonal antibodies with known epitopes demonstrated that the FVIII sequence Lys1673-Arg1689 is involved in the high- affinity interaction with VWF . FurtherIn light of the ambiguity regarding the VWF present in the FVIII product which may obscure the DDAVP induced effect, we looked into patient one (No. 1). For this patient we had data available from a DDAVP administration without placebo or FVIII concentrate. The VWF Ag peak following DDAVP only was 2.6 IU/ml, which was almost as high as the VWF Ag peak following FVIII concentrate after DDAVP administration . This indicates that the amount of VWF in the exogenous product is probably relatively small.Third, patients with lower baseline VWF levels may have an increased clearance of VWF. The increased clearance may also be present after a DDAVP induced rise in these patients .Although the MRT of FVIII concentrate was slightly prolonged, this did not result in a clinical benefit in FVIII concentrate survival curves. This apparent contradiction may be explained by the lower recovery of FVIII concentrate observed in three of the four patients after DDAVP administration. Expansion of the plasma volume as a result of the antidiuretic effect of DDAVP may partly account for this reduced recovery. The reduced recovery limits the beneficial effect of an increase in MRT for clinical purposes.Unfortunately, we have no data on the genotype of the four hemophilia A patients. This information might have been helpful to explain our observations, as for example mutations that cause a VWF binding defect may impair the prolongation of FVIII concentrate half-life. Moreover, this information may also have helped us to explain the differences in FVIII Act and FVIII Ag in our patients.In conclusion, our results indicate that no clinical benefit is to be expected from the modification in FVIII concentrate pharmacokinetics by DDAVP-administration prior to infusion of FVIII concentrate.


The Community Pharmacy Foundation is a non-profit organization dedicated to the advancement of community pharmacy practice and patient care delivery through grant funding and resource sharing. Since 2002, CPF has awarded 191 grants and over $9,200,000 (US dollars) in research and project grants. The purpose of this manuscript is to highlight the evolution of pharmacy practice and pharmacy education in the United States through the presentation of exemplary cases of Community Pharmacy Foundation funding that is aligned with new care delivery models and approaches to the advancement of patient-centered pharmacy care. Pharmacy began in colonial America as the United States of America was just beginning to form with apothecary shops and druggists. Over time, the pharmacy industry would be revolutionized as America became urbanized, and drug products became commercially produced. The role of the pharmacist and their education evolved as direct patient care became a clear expectation of the general public. By the 1990s, the pharmacy profession had carved out a new path that focused on pharmacist-led, patient-centered pharmaceutical care and medication therapy management services. The Community Pharmacy Foundation grant funding has aligned with this evolution since its founding in 2000, and multiple exemplary grants are presented as support. As the role of pharmacists again transitions from a fee-for-service model to a value-based model, the Community Pharmacy Foundation continues to provide grant funding for research and projects that support the advancement of community pharmacy practice, education, and expanded training of pharmacists. The Community Pharmacy Foundation (CPF) is a non-profit organization founded in 2000 that is dedicated to the advancement of community pharmacy practice and patient care delivery through grant funding and resource sharing . CPF wasThe development, processing, and use of findings that affirm the value of community pharmacy practice in the healthcare delivery system.The measurement, publication, and dissemination of findings documenting the value of professional services delivered to patients by community pharmacists.Efforts that measure the impact of pharmacist interventions in achieving the targeted therapeutic goals set collaboratively by the patient, the pharmacist, and other members of the healthcare team.Efforts that evaluate patient-specific outcomes with regard to the quality of care delivered by community pharmacists.The primary goals of CPF grant funding are:In January of 2002, CPF received its first grant submissions, and awarded its first two grants in May, 2002. Since 2002, CPF has awarded 191 grants and over $9,200,000 (US dollars) in research and project grants for the advancement of community pharmacy practice and patient care delivery improvement. The extent to which CPF grants have aligned with the primary goals of CPF has been reviewed in detail elsewhere . In geneThe purpose of this manuscript is to highlight the evolution of pharmacy practice and pharmacy education in the United States through the presentation of exemplary cases of the Community Pharmacy Foundation funding that is aligned with new care delivery models and approaches to the advancement of patient-centered pharmacy care.In Colonial America, there were very few standalone pharmacies. The first documented “pharmacist” was Bartholomew Browne of Salem in 1698 ,5. He opCombined physician medical practice and apothecary shops had been widely debated in England and were considered a conflict of interest . HoweverPharmacy education was also evolving as American apothecary shops began to pop up across the country. For example, the first diploma for apothecary practices was awarded in 1808 by the Legislature of the territory of Orleans, and in 1818, South Carolina was the first state to require a pharmaceutical examination before obtaining a pharmaceutical license . In DeceIn the 1840s, inferior drug products were being shipped from Europe that led to the Drug Importation Act of 1848 . This acBy the end of the 19th century, the practice of pharmacy was significantly changing. Parke, Davis, & Company created the first standardized pharmaceutical extract (Liquor Erogtae Purificatus) in 1879 that revolutionized the business of pharmacy [As these changes were occurring, so too was the education of pharmacists within the United States. In the 1950s, the entry-level degree for pharmacists transitioned to a professional degree, which has been the standard since 2000 . FurtherThe term “pharmaceutical care” was first used in 1975, referring to the care a given patient requires and receives which assures safe and rational drug use ,12. The p = 0.03) and could serve as a strategy for future patients with hypertension [Therefore, initial demonstration projects and pilot programs were conducted to help add to the knowledge base of pharmacists as healthcare providers. For example, CPF awarded its very first grant in May of 2002 for a program that sought to evaluate the effectiveness of a community pharmacist-based home blood pressure monitoring program . The sturtension .Another early study funded by CPF in 2002 examined pharmacy participation in the Wisconsin Medicaid Pharmaceutical Care Program (WMPCP) . PharmacAs more evidence became available about the value of pharmacists in helping improve patient outcomes expanded care delivery models began to be created. For example, CPF funded a study grant that was completed in 2006 and evaluated the effects of an extended diabetes care program compared to regular care on primary clinical outcomes such as hemoglobin A1c, low-density lipoprotein (LDL) cholesterol, and blood pressure . The extAt the same time, pharmacy education was also evolving to keep up with the changes in pharmacy practice. In 1997, APhA updated their post-graduate year-one (PGY1) community pharmacy residency program guidelines to reflect the new focus on pharmaceutical patient care . These r®) Editorial Panel in preparation of a proposal establishing reporting and billing codes for pharmacists’ clinical services. In official health reporting nomenclature of CPT®, Medication Therapy Management Services (MTMS) is described as face-to-face assessment and intervention as appropriate, by a pharmacist, to optimize the response to medications or to manage treatment-related medication interactions or complications [Medication therapy management (MTM) was the next development in the evolution of pharmacy practice. Origins of the term Medication Therapy Management can be traced to legislation proposed in the mid-1990s intended to reimburse pharmacists for pharmaceutical care services . Then inications . Furtherications ,25. CPF ications .MTM service has also been characterized by the Centers for Disease Control and Prevention (CDC) as “a distinct service or group of services provided by healthcare providers, including pharmacists, to ensure the best therapeutic outcomes for patients. MTM includes five core elements: medication therapy review, a personal medication record, a medication-related action plan, intervention or referral, and documentation and follow-up” . In addiCPF’s grant funding during this time also went through an evolution process by moving towards the funding of projects that were more outcomes based. A study by Isetts et al. compared the impact of CPF funding between the initial years and recent years of the foundation utilizing the AHRQ Impact Factor Framework . Their sCPF grants during the early years of MTM also helped to contribute to a professional consensus about the viability of MTM. For example, CPF funded a grant that was completed in 2008 that evaluated the effect of implementing MTM services  conducted by community pharmacists for a private health plan . The PCMThe objectives of the PCM pilot program were to evaluate the effect of PCM on medication appropriateness, characterize drug-therapy problems identified by PCM pharmacists, compare healthcare utilization among patients eligible for PCM services, assess the impact of PCM on patient’s self-reported health, and assess pharmacist barriers to providing PCM services . The pilAnother CPF grant awardee showed it was possible to set up a network of 135 pharmacists across seven states of the upper Midwest to provide MTM services to older adults . As a reThe funding of expanded MTM services with greater disease state complexity became commonplace after the viability of pharmacist-led MTM programs was established based upon CPF grant funding. For example, a grant completed in 2009 implemented a pharmacist-led rapid strep test service in the community pharmacy setting . FurtherSimilarly, a 2014 pilot project evaluated whether or not community pharmacists could identify patients at risk of worsening heart failure through the use of a clinical decision tool called the One Minute Clinic for Heart Failure (TOM-C HF) . TOM-C Hhttps://www.aphafoundation.org/incentive-grants) [The establishment of community pharmacy residency programs also began to grow rapidly during this time, with the number of programs almost tripling between 1999 and 2001 . This gr-grants) .In 2010, CPF funded a grant that surveyed the perceived value of providing community pharmacy residency training from the perspective of the colleges of pharmacy and pharmacy provider organizations . Survey Pharmacists are considered the most accessible healthcare provider, and are uniquely qualified to provide patient-centered care that engages patients in proper medication use and chronic disease state management . The proApproximately 60% of the grants awarded by CPF are direct-patient care focused. For example, a CPF grant completed in 2017 evaluated the effects of individualized patient care services by pharmacists on total costs of care, an adherence measure, and the use of high-risk medications by older patients . To accoAnother CPF grant completed in 2017 utilized targeted medication reviews by pharmacists to deliver pre-conception care as a public health demonstration project . CommuniValue-based services will require the collaboration of multiple healthcare providers including pharmacists to help patients achieve the best health outcomes. To better understand this requirement, a CPF grant completed in 2017 was conducted to increase knowledge about collaborative working relationships between pharmacists and other healthcare providers throughout multiple practice settings . The stuCPF grants supporting pharmacists in patient-centered medical homes (PCMH) are important for the understanding of community pharmacist roles and responsibilities in alternate payment models ,47,48,49CPF grant funding has also been awarded to projects that seek to evaluate and establish the role of community pharmacists in an ACO. For example, a grant completed in 2016 assessed the feasibility of integrating MTM services provided by community pharmacists into the clinical care teams and the health information technology (HIT) infrastructure for a Minnesota Medicaid ACO . The stuPharmacy education has also continued to evolve as pharmacists take on more advanced patient care roles. Since June of 2013, 34,824 pharmacists have graduated from ASHP accredited residency programs . Also, BIn summary, the Community Pharmacy Foundation is a non-profit organization whose mission is to support the advancement of community pharmacy practice and patient care delivery through grant funding and resource sharing. The history of pharmacy within the United States dates back to the beginning of the colonies, when physicians, druggists, and apothecaries were essential to providing health care in the new world. As America became urbanized and continued to grow in population, the necessity for domestic sources of drugs and pre-manufactured medications drastically changed the business of pharmacy, placing the pharmacist in a dispensing role. However, the pharmacist’s extensive drug therapy knowledge would create an environment to shift the focus back onto the patient and create new pharmacy care service models that have been the backbone of modern pharmacy practice in the United States. Since its founding, CPF has actively supported grants that are aligned with the evolution of pharmacy practice and CPFs mission. In the early years of the foundation, the majority of grants focused on building the pharmacy knowledge base, but have since shifted towards impacting the health outcomes of patients. In addition, the CPF grants awarded have also helped contribute to establishing reimbursement models for pharmacies and pharmacists who participate in advanced patient care and the advancement of the profession through education and training.


Renal papillary necrosis is a clinicopathological entity where any or all of the papillae undergo selective necrosis, which can be demonstrated either radiologically or histologically. The most important causes are diabetes, pyelonephritis, obstructive uropathy, tuberculosis, analgesic abuse or overuse, sickle cell disease and renal vein thrombosis. Although this condition was first described in the 19th century the clinical diagnosis of this condition remains a problem to this day. Uncomplicated papillary necrosis may initially remain occult to imaging by ultrasound and non-contrast CT, but may later be complicated by obstructive uropathy. A few studies have described renal papillary necrosis on CT urogram. In this case series, the authors describe the finding of calyceal filling defect with diffusion restriction in the calyx and the tip of the renal pyramid on MR urogram, along with other findings that are classically seen on intravenous urogram or CT urogram. To the best of our knowledge, the finding of diffusion restriction at the tip of the renal pyramid has not been described before. Further, literature review showed only a single study describing the classical findings of papillary necrosis on an MR urogram. The early diagnosis of papillary necrosis on MR imaging equips the radiologist to suggest short-term clinical and radiological follow-up to check for the development of hydronephrosis. Additionally, such risk stratification may enable early ureteric stenting to prevent the development of obstructive uropathy. The other causes of papillary necrosis are pyelonephritis, obstructive uropathy, tuberculosis, analgesic abuse or overuse, sickle cell disease and renal vein thrombosis. A few studies describing the findings of papillary necrosis on MR urogram exist. Along with the description of findings of papillary necrosis seen on intravenous urogram and CT urogram, in this case series the authors report the finding of diffusion restriction at the tip of the renal pyramid in renal papillary necrosis. The early diagnosis of this condition has the potential to alter management by either starting early treatment or withdrawing the inciting stimulus.4 The patients may be offered early stenting or percutaneous nephrostomy if the diagnosis of papillary necrosis can be established.Renal papillary necrosis is a clinicopathological entity where any or all of the papillae undergo selective necrosis that can be demonstrated either radiologically or histologically.Case1: Reported here is a 41-year-old male patient who had previously undergone pyeloplasty for right pelviureteric junction obstruction. The patient was diabetic since 10 years and had developed chronic kidney disease 5 years ago. The patient presented with fever with chills, burning micturition and right flank pain.–1, which prevented the administration of contrast.On examination the patient was febrile. Urine examination done just before the MR urogram showed 32 white blood cells/hpf and 1 bacteria/hpf. The creatinine level of the patient was 3.9 mg dlCT imaging was performed, which showed perinephric fat stranding and hydronephrosis with sudden tapering of the right ureter at the pelviureteric junction .MRI was performed to image the ureter and to diagnose the cause of obstruction. Clinical suspicion was of a post-pyeloplasty stricture. The patient’s high creatinine level prevented the administration of iodinated contrast.MRI showed hydronephrosis of the right kidney with sudden tapering at the level of the pelviureteric junction with diffusion restriction at the tip of the renal pyramid, with widening of the fornices, clubbing of the calyces and filling defects in the lower pole and interpolar calyx. Additionally, cleft was noted at the lower pole. These imaging findings were suggestive of a right pelviureteric junction stricture with papillary necrosis .Candida albicans on fungal culture. Nevertheless, the patient was started on broad-spectrum antibiotics with systemic antifungals with resultant resolution of fever and flank pain with the urinary white blood cell count returning to normal. Post treatment urine culture was normal.However,there was no growth of bacteria on urine culture for this patient. There was growth of Candida species other than –1.Case 2: Reported here is a 48-year-old female patient who is a known case of diabetes with chronic kidney disease. She previously had bilateral emphysematous pyelonephritis, which resolved with treatment. Stenting was done for the patient at that time, which was removed with resolution of patient symptoms and normalization of routine urine analysis and culture. In the current episode the patient presented with right flank pain and fever. Serum creatinine level of the patient was 6.1 mg dlMRI was requested in view of bilateral hydronephrosis on ultrasound imaging with the clinical differential diagnosis of pyelonephritis and ureteric calculus.MRI showed mild bilateral hydronepehrosis and bilateral perinephric fat stranding, which was more on the right side. Multiple filling defects were noted within the pelvicalyceal system on both sides, with diffusion restriction noted at the tips of two of the renal pyramids on the right side. A ring sign was seen in the calyces on the right side . ComplimUrine examination of the patient showed 10 white blood cells/hpf and culture showed growth of Klebsiella. Right-sided ureteric stenting was performed. The patient was treated with antibiotics following which her symptoms reduced and urine routine and culture returned to normal.–1.Case 3: Reported here is a 66-year-old non-hypertensive, non-diabetic female patient, known to have chronic renal failure who presented with progressively increasing flank pain. Initial evaluation by ultrasound imaging showed left-sided hydronephrosis . The creMRI was requested to rule out pyelonephritis. MRI showed filling defect in the proximal ureter causing hydroureteronephrosis. Further, coronal slice of the 3D MR cholangiopancreatography image showed filling defect in the upper polar calyx and diffusion-weighted images showed diffusion restriction in the calyx and renal pyramid .The patient underwent ureteric stenting under antibiotic coverage, where a brownish black irregular slough was removed. This was followed by relief of symptoms. The stent was removed after 3 months and the patient had an uneventful course at 6 month follow-up.–1. Laboratory evaluation showed increased white blood cell count and the presence of bacteria in urine routine examination. MRI was requested to establish the diagnosis of pyelonephritis and to rule out the recurrence of bladder carcinoma.Case 4: Reported here is a 47-year-old male who underwent radical cystoprostatectomy with bilateral ureteric reimplantation into the ileum for bladder carcinoma. The patient subsequently developed increased creatinine and acute renal failure with a creatinine level of 6.6 mg dlEvaluation by MRI showed a medially deviated left ureter with a filling defect in the left lower pole calyx. Further, a bulky right kidney with areas of parenchymal diffusion restriction surrounded by free fluid with filling defects in the right ureter, calyces and the renal pelvis suggested a diagnosis of right-sided pyelonephritis with bilateral papillary necrosis . FurtherThe medially deviated left ureter probably represents its post surgical course, ultimately terminating in its ureteric implantation. The filling defect in the left lower pole represents old papillary necrosis, either secondary to obstruction or due to an older event of pyelonephritis. This slough poses a risk of causing obstructive uropathy and hence left-sided percutaneous nephrostomy was done as a preventive measure.In view of ureteric reimplantation into the ileum, a right percutaneous nephrostomy was done with removal of slough. After the procedure, a nephrostogram showed free flow of contrast through the right pelvicalyceal system into the ileum .Proteus vulgaris. The patient improved with antibiotics and was put on twice weekly follow-up. This was followed up by a percutaneous nephrostomy on the left side.The urine culture of the patient showed growth of –1 and presented with back pain and fever raising a suspicion of pyelonephritis. Ultrasound imaging showed bilateral hydroureteronephrosis. Laboratory investigation revealed increased white blood cell count.Case 5: Reported here is a 64-year-old male patient, a known case of diabetes since 18 years, who presented with fever and burning micturition. The patient had an elevated creatinine level of 3.5 mg dlEscherichia coli  or contrast-enhanced CT or MR urography. MRI can provide valuable information by imaging the urine-filled ureter. Thus, at our institution, in this subset of patients, imaging with MRI is preferred. Further, in contrast to CT, MRI does not deliver any radiation dose to the patient. This becomes important since many patients with diabetes and patients with renal failure undergo multiple imaging examinations.5In this case review the authors discuss the findings of papillary necrosis on MR urogram. The patients showed calyceal filling defects with or without diffusion restriction, filling defects with clubbing of calyx, ring shadow, blunt tipped calyx, phantom calyx and clefts extending from the calyces to the pyramids. These findings of papillary necrosis have classically been described on intravenous urography and later on CT urography.Jung DC et al described the findings of papillary necrosis on CT urogram where they divided the disease process of papillary necrosis into four phases:5a) Early ischaemic changes in the medullary pyramid; b) clefts from the calyceal fornices to the medullary pyramid; c) sloughing of the papilla and d) the healing phase. Renal papillary necrosis is the consequence of an ischaemia in the renal papillae. Infections such as pyelonephritis causing inflammation of the interstitium may lead to compression of the medullary vasculature and predispose the renal papillae to ischaemic change. Perfusion compromise as a consequence of vasculitis in diabetes mellitus, tuberculosis, or the reduction of flow observed in the various causes of papillary necrosis sets the stage for ischaemic changes in the medullary pyramid.6 using the enhancement characteristics on the arterial corticomedullary phase, showed that in renal papillary necrosis the degree of enhancement was significantly lower than that of normal kidneys. In those patients who instituted therapy to relieve the underlying cause of papillary necrosis, at 3 months 57% of patients showed (20 out of 35) interval resolution of lesions.6 In this study, the stage of papillary necrosis is not evident, especially since CT cannot detect the ischaemic phase of papillary necrosis. Jung DC et al5 on CT urography described the CT findings in the early ischaemic phase of papillary necrosis as normal.Lang EK et al,7 Diffusion restriction can occur in the brain because the white matter tracts introduce anisotropy. Studies by Fukuda M et al and Wu Y et al9 showed the anisotropic nature of diffusion in the kidney due to the radially oriented vessels and tubules.Thus, diffusion restriction, which occurs by virtue of ischaemia and cytotoxic oedema, when occurring at the tip of the medullary pyramid and calyx, is likely to represent the early ischaemic phase of papillary necrosis. This is similar to the pathophysiology of acute ischaemia and stroke causing diffusion restriction due to cytotoxic oedema in the brain.However, based on the diffusion restriction at the calyx and the tip of the medullary pyramid, we propose that early medullary ischaemia can be detected, and thus treatment instituted, to reverse the inciting inflammation, vasospasm, vasculitis or compromise in microvascular perfusion, thereby preventing the progression of ischaemia beyond this stage.10Literature review showed only a case report by Schroeder J et al describing the features of renal papillary necrosis. In this case report they described features of papillary necrosis such as sloughed papilla in the calyx, clubbing of the calyx, a golf ball on a tee appearance and filling defects in the major calyx giving rise to a lobster claw appearance.11 In 1995, Hattery and King brought into question the efficacy of MR urography in making a diagnosis, given the resolution requirements needed to achieve good visualization of the calyceal and collecting system anatomy.12 Since then, until the case report published by Schroeder et al, to the best of our knowledge no study or case report has been published describing the findings of papillary necrosis on MR urography. Since then there has been tremendous progress in image acquisition techniques and hardware, enabling higher resolution of images.In 1995, Rothpearl et al described MR urography for the purpose of imaging the renal system. They proposed that in obstructed systems the anatomy of the calyces and collecting system can be easily demonstrated. One of the patients in this case series had papillary necrosis. However, the findings of papillary necrosis seen in that patient were not described in the case series.In the index study, papillary necrosis has been diagnosed and findings described on MR urogram, performed on a 1.5 T MR scanner. Thus we propose that static MR urography is sufficient to establish a diagnosis of papillary necrosis.Papillary necrosis can cause complications such as obstruction secondary to sloughing of papillae. The diffusion restriction at the calyces probably represents the finding of papillitis, that is, early ischaemic change at the tip of the medullary pyramid, which may later result in injury to the papilla, cause sloughing and later progress to intraluminal obstruction. Thus we propose that patients who have the finding of calyceal diffusion restriction, that is, ischaemia at the tip of the medullary pyramid, must be followed up more stringently so as to enable early intervention in the form of stenting or percutaneous nephrostomy if the patient develops features of obstruction. Further, in high-risk groups of patients prophylactic stenting may be advocated.Thus, in view of the potential to change the course of management and prevent significant renal morbidity the finding of diffusion restriction in the tip of the medullary pyramid is a very important new finding. Further, this case series reiterates the fact that contrast administration may not be necessary for the diagnosis of papillary necrosis.Diffusion restriction in the calyx and the tip of the renal pyramid is likely to be due to the ischaemic phase of papillary necrosis.Findings of papillary necrosis seen on CT urogram and intravenous urogram  can also be seen on MR urogram without the administration of contrast.With CT urogram and intravenous urogram the early diagnosis of papillary necrosis is difficult. However, with the use of MR urogram and diffusion-weighted imaging, early diagnosis of papillary necrosis is possible. This can permit risk stratification of patients, where high-risk patients may be offered early ureteric stenting to prevent the development of obstructive uropathy.The consent of the patients to publish the data and images was taken and is held on record.


The main step in a successful drug discovery pipeline is the identification of small potent compounds that selectively bind to the target of interest with high affinity. However, there is still a shortage of efficient and accurate computational methods with powerful capability to study and hence predict compound selectivity properties. In this work, we propose an affordable machine learning method to perform compound selectivity classification and prediction. For this purpose, we have collected compounds with reported activity and built a selectivity database formed of 153 cathepsin K and S inhibitors that are considered of medicinal interest. This database has three compound sets, two K/S and S/K selective ones and one non-selective KS one. We have subjected this database to the selectivity classification tool ‘Emergent Self-Organizing Maps’ for exploring its capability to differentiate selective cathepsin inhibitors for one target over the other. The method exhibited good clustering performance for selective ligands with high accuracy (up to 100 %). Among the possibilites, BAPs and MACCS molecular structural fingerprints were used for such a classification. The results exhibited the ability of the method for structure-selectivity relationship interpretation and selectivity markers were identified for the design of further novel inhibitors with high activity and target selectivity. Selectitivities . Classiftivities . In additivities  and HMG-tivities . In thisi.e., selectivity ratio SR 50) for one target (K or S) over another (S or K), whereas the remaining compound set  only contains compounds with less than a 10-fold potency difference (SR < 10) for the two targets that are thus considered non-selective. These molecules cover a broad range of binding activities  and represent different chemical scaffolds. The compound data sets were collected from reported sources to evaluate the compound selectivity using a SOM classification approach.Standard MACCS and BAPs fingerprints were used as efficient computational tools in SOM-based techniques to distinguish between compounds having different selectivity profiles. For this purpose, two previously assembled  data setThe self-organizing map (SOM) principle introduced by Kohonen  is used In accordance, the performance of BAPS in discrimination of different selectivity sets is better than that of MACCS and the combination form . The tabThe occurrence of each fingerprint bit was analyzed and computed for all clusters. A feature is defined as a selectivity marker that only occurs in at least 50% of the ligands in each cluster . The finThe structural features corresponding to preferentially set MACCS and BAPS keys obtained from frequency analysis of selective clusters were mapped onto the original ligands of these corresponding clusters. The results of this analysis are shown in Based on the SOM results, the structure-selectivity relationships (SSRs) of the selectivity sets of cathepsin inhibitors, are summarized in To validate the accuracy and robustness of the stability prediction of the SOM model, a different external subset of the ZINC database (1000 compound)  was usedInterestingly, the reported activity/selectivity profiles of these novel hits confirmed our method for addressing ligand selectivity and the success of using two structural fingerprints in defining and distinguishing cathepsin inhibitors of different selectivity profiles.A dataset of 153 selective cathepsin inhibitors exhibiting different selectivity profiles was collected from the literature and databases . On the The molecular structures of the current database were built and cross-checked using the builder in the MOE software . Each mohttp://databionic esom.sourceforge.net/. The original paper by Ultsch describes the general ESOM training procedure in details. The advantage of SOM/ESOM is that it is able to provide an intuitive visualization of the similarity of input data [SOM has attracted the attention of researchers because of its ability to analyze complex multidimensional data in an intuitively comprehensible visual manner. The SOM technique can be used well in compound pattern recognition, combinatorial library comparison, and combinatorial library design, splitting a dataset into the proper training and test sets before constructing a  model and other studies which require the analysis of distributions of compounds in some chemical space . The ESOput data ,47.Fingerprint bits of MACCS and BAPS types were analyzed by calculation of the frequency of occurrence in each cluster. The feature of at least 50% occurrence was selected and identified as selectivity markers. This analysis was carried out with an in-house generated perl script.The SOM models was experimentally validated using a 1000 compound subset of the ZINC database randomly selected, but having more structural similarity to the selectivity database. The compounds in ZINC was extracted and merged with the selective compounds and utilized for SOM clustering. The given clusters were analyzed and only mixed clusters formed of ligands of specific annotation  with ZINC compounds were taken. Five compounds were selected as nearest neighbors for selectivity database compounds from different clusters and were searched for their activity profile in web databases supporting biological activity.Cathepsin enzyme targets are of increasing interest due to their involvement in extracellular proteolytic activities and regulation of intermediates in certain diseases. A special selectivity database for two cathepsins was built and fully characterized. In this work, emergent SOMs were calculated using an ESOM algorithm with multiple neurons for selectivity set clustering. Two structural molecular descriptors, BAPs and MACCS fingerprints, were selected to be utilized in selectivity prediction of cathepsin K and S inhibitors by the self-organizing map technique. The resulting maps and clusters have extensively been analyzed. Investigation of the performances of fingerprints and extensive structure-selectivity relationship analysis of compound clusters led to the extraction of several selective substructures that are important in interpretation of inhibitor selectivity. These selectivity markers provided by fingerprint analysis could be very helpful in the lead optimization or the design of new hits with better activity and selectivity towards cathepsin targets. Finally, successful SOM-based selectivity clustering was applied and potential cathepsin K and S inhibitors were predicted.


The most frequent diseases of the urinary bladder are bacterial infections and bladder cancers. For both diseases, very high recurrence rates are characteristic: 50–80% for bladder cancer and more than 50% for bladder infections, causing loss of millions of dollars per year for medical treatment and sick leave. Despite years of searching for better treatment, the prevalence of bladder infections and bladder cancer remains unchanged and is even increasing in recent years. Very encouraging results in treatment of both diseases recently culminated from studies combining biopolymer chitosan with immunotherapy, and chitosan with antibiotics for treatment of bladder cancer and cystitis, respectably. In both pathways of research, the discoveries involving chitosan reached a successful long-lasting cure. The property of chitosan that boosted the effectivity of illness-specific drugs is its ability to enhance the accessibility of these drugs to the very sources of both pathologies that individual treatments without chitosan failed to achieve. Chitosan can thus be recognised as a very promising co-player in treatment of bladder cancer and bacterial cystitis. The main function of the urinary bladder is to enable controlled micturition by retaining the urine at constant pressure between periodic micturition. To prevent the permeation of potentially toxic and hypertonic urine back into underlying tissues and bloodstream during the retention, the luminal side of the urinary bladder is covered by a three-layered epithelium called the urothelium . The supTo maintain the barrier function in spite of constant changes of urine volume in the bladder, the umbrella cells have to adjust to extreme changes of the surface between filled and empty bladder ,9 by revSuch a stable epithelium is well adapted for maintaining the barrier function. However, this characteristic of the urothelium is largely responsible also for the limited success in treatment of the most frequent pathologies of the urinary bladder, bladder cancer and bacterial cystitis, because the blood-urine barrier prevents medications from reaching cancer cells in deeper layers of the urothelium and the bacteria hidden inside urothelial cells. To improve the penetration of drugs into urothelial tissue, several inducers of urothelial cell desquamation could be applied. Among them, mainly cyclophosphamide ,17, 12-oN-acetyl glucosamine, is obtained by partial deacetylation of chitin. In general, chitosan is regarded as a biodegradable, biocompatible nontoxic polymer [Mn = 108,700) increases the permeability of the epithelia is by its interactions with cell membranes. The high density of positive charges is responsible for chitosan to interact strongly with negatively charged [Ka value of the d-glucosamine residue of chitosan is about 6.2–7.0 [Chitosan, a cationic polysaccharide composed of glucosamine and  polymer . Chitosa polymer . Surpris polymer  and in v polymer . However polymer . Another charged  and neut charged ,28 in th charged , and whe charged . Protona charged . A highe 6.2–7.0 . The chaIntravesical application of chitosan  to experimental animals resulted in induction of urothelial cell desquamation  Figure A. HoweveIt has been well documented that by choosing the appropriate chitosan concentration and the duration of intravesical application, chitosan can induce a controlled desquamation of urothelial cells in experimental animals. Intravesical application of 0.005% chitosan dispersion  caused complete removal of exclusively superficial cells after 20 min of treatment. A complete regeneration of this mild injury was completed within 60 min after an application of chitosan, and no inflammatory cell response was determined in such a short period of time. In addition to the morphological characteristics of the regeneration process after the chitosan-induced disruption of the urothelium, functional regeneration was also shown as a rapid restoration of the transepithelial resistance of urothelial tissue. By in vivo and ex vivo experiments, such intravesical chitosan application was proven to be safe in experimental animals because only weak inflammatory response and no persistent urothelial damage were detected .co-glycolic acid) (PLGA) nanoparticles [Bladder cancer is the fourth most common cancer in males. Worldwide annual incidence of bladder cancer is estimated to be 14.1 million cancer cases around the world in 2012 ,35. The articles . ChitosaIn spite of encouraging results of using nanoparticles covered with chitosan, the penetration in deeper layers of the urothelium is still questionable, especially in the case of individual cancer cells migrating from the primary tumours below normal umbrella cells . The mosA very promising model of treatment of bladder cancer using chitosan as a temporary destructor of the barrier function in the urothelium was developed by D.A. Zaharoff’s group combining immune stimulant interleukin 12 (IL-12) with chitosan  that allows the penetration of the drug into the urothelium. The four-times-repeated treatments with a combination of IL-12 and chitosan eliminated 90% of bladder tumours in experimental animals and provoked a memory response protecting the animals from bladder tumours for the rest of their life  Figure . FurtherUrinary tract infections (UTI) include infections of the urethra (urethritis), bladder (cystitis), ureters (ureteritis), and kidney (pyelonephritis) . UropathChitosan offers versatile biomedical applications in urinary bladder epithelial cells due to the capability of this polymer to transitorily abolish the barrier function of urothelium and consequently to enable better penetration of specific drugs to the deeper cell layers. Chitosan has a great potential for clinical application in treatment of bladder tumours as a supplementary system in combination with cytostatic and immunotherapy, and also as an auxiliary antimicrobial drug in treatment of uroinfections. Common in both treatments of bladder cancer and bacterial infection of the urinary bladder is the benefit of local topical application, where higher dosages can be applied and the systemic side effects of the drugs otherwise used by oral administration is omitted.


African swine fever (ASF) has one of the highest case-fatality rates among pig diseases. Europe was considered ASF-free for about two decades until 2007, when the virus was introduced into Georgia. Since then, it has been identified throughout Eastern Europe, and reached Belgium in late 2018, increasing the risk of ASF being introduced into neighboring countries—namely Germany, Luxembourg, the Netherlands, and France. French authorities have therefore reinforced surveillance measures to improve the probability of detecting ASF rapidly if it emerges in France. Predictive modeling may help to anticipate the extent of virus spread and evaluate the efficiency of these surveillance measures. A previously published and well-documented model that simulates ASF virus spread was therefore tailored to realistically represent the French situation in terms of the geographic distribution of swine production sites and the commercial trade between them on the one hand, and the implementation of surveillance protocols on the other. The outcomes confirmed the moderate spread of ASF through the swine trade network, a situation that had been previously highlighted for the case of Denmark. However, the diversity of the French pig production landscape has revealed a huge potential for the geographic dispersal of the virus, especially should the index case occur in a low-density area, with a median source-to-case distance reaching 300 km. Free-range herds, which are more likely to have interactions with wild boars, were also identified as potential entrance gate for the virus. Transmissions from conventional herds were quasi-exclusively due to swine movement on the commercial network, representing 99% of transmission events. In contrast, 81% of transmission events occurred in the neighborhood of the index herd when the virus was introduced in free-range herds. The current surveillance measures were found relatively efficient for detecting the virus in large herds, leading to detection rates of 94%. However, infections on smaller production sites—which often have free-range herds—were more difficult to detect and would require screening protocols specifically targeting these smaller herds. African swine fever virus is a DNA virus belonging to the Asfarviridae family . With a To date, sub-Saharan Africa is seriously affected by ASF, the virus being endemic in several countries . DespiteASF is a notifiable disease according to European legislation, and strict containment and eradication policies are implemented in the European Union in the event of its suspicion. However, such policies require substantial human and financial resources, which drive the ability to detect the emergence of the virus in free countries and to control its spread in the meantime (hot period). Predictive modeling may therefore help to anticipate the extent of the virus's spread and to evaluate potential surveillance and control measures tailored to specific incursion scenarios. Halasa et al. recently developed such a model to analyze the epidemiological and economic consequences of ASF introduction on the swine production network in Denmark , 17. TheThe modeling work consisted in tailoring the DTU-DADS-ASF model fully described in the literature by Halasa et al. . Only a S), exposed but not infectious , not clinically affected but infectious , clinically affected , and not playing a role in transmission . Transmission is assumed to be either through direct contact between susceptible and infectious animals, or through environmental contamination due to infected leftovers. The environmental reservoir (E) is proportional to the number of ASF-related dead animals, and balanced by an exponential decay representing the virus's capacity for survival in the environment. Using the transmission rate (β) estimate of Guinat et al. (t (days) is expressed byThe herd is considered as a homogenous, randomly-mixed population, independent of its physiological status. The pigs evolve through five health statuses: susceptible . The duration of the latent, subclinical and clinical stages of newly-infected animals are randomly drawn from probability distributions derived from Halasa et al. . For direct contact modeling, the number of animals involved in the movement is next evaluated depending on the herd size and type of production site. The destination herd is then randomly selected based on (i) the distance between the seeder and receiving herd, (ii) the type of production site, and (iii) the herd size, which has to be large enough to receive the incoming animals. Finally, the probability of transmission is evaluated based on both the prevalence of infectious individuals on the seeder farm and the size of the incoming batch.For medium- and low-risk contact, the number of outgoing animals is again evaluated using a Poisson distribution with respective frequencies of contact derived from the literature , 21, 22.Transmission caused by indirect contact through travel to the slaughterhouse is represented in the same way with the exception of the number of potential contacts, which follows an exponential distribution where the average path length (mean number of herds en route to the slaughterhouse) is used as the distribution mean .Finally, to represent local spread due to shared material or fomites, all herds within a 2-km radius of an infected herd are subjected to a distance-based probability of infection related to the within–herd force of infection (Equation 1).Different introduction scenarios were evaluated depending on the density zone and herd type of the initial case (nucleus/multiplier or randomly-selected herds). For each scenario in this study, 2,000 simulations were run to achieve convergence of the outputs with a stable mean behavior and variability. Equations and epidemiological parameters are detailed in the supplementary material of the original paper describing the modeling framework .In the context of the imminent threat of AFS being introduced into France, the surveillance measures described by Halasa et al. have been reinforced . MortaliAll animal movements from and to these zones are prohibited for 45 (SZ) or 50 days (PZ), and all the herds in these two zones have to be monitored during that period. Clinical surveillance as described above is applied to both zones except for the second point: mortality notification is compulsory and systematically induces clinical inspection leading to further laboratory analyses (virology and serology). All herds in PZ are subject to mandatory serological surveillance visits, for which the sample size depends on the herd size and type . BreedinThe National Swine Identification Database (BDporc) has been registering all swine movements in France since 2010. Salines et al.  performeBased on pig trade network analysis, different scenarios regarding the type of herd in which ASF could be introduced were evaluated. We first considered introduction into breeding herds  having large outdegrees and movements mainly toward production herds . Seeder 2 in the four zones. The highest densities were observed in the western and south-western parts of France . When transmission occurred, the number of infected herds could reach 15, but 95% of these simulations resulted in the infection of eight herds or less. Sixty per cent of transmission occurrences involved small production herds with fewer than 80 pigs, and 37% concerned free-range herds. In contrast with previous results, local transmission was clearly identified as the major transmission route, accounting for 81% of events, whereas animal movements only represented 11% of transmissions . Taking The previous results clearly evidence the failure to detect infections occurring in small herds. We therefore assessed the impact of additional screening measures focusing specifically on these herds. We assumed that these herds were systematically subjected to clinical inspection as soon as they declared more than 15 dead or clinically-infected animals within two successive weeks , or when the whole population was affected during the same period. This latter assumption factored in the inspection of very small herds, which could have been easily omitted when considering only the previous surveillance measures.The results obtained with this additional screening procedure are provided in African swine fever has been spreading throughout Eastern Europe since 2007 and recently emerged in Western Europe . AlthougThe first scenario considered an introduction into herds at the top of the pyramidal structure of the French swine production system: nucleus, multiplier and farrowing herds. Although these kinds of herds are expected to have the highest biosecurity measures, hence the lowest probability of virus introduction, the structural analysis of the pig trade network highlighted these herds as having the highest outdegrees and outgoing contact chains , so theyThe second scenario considered free-range pig herds as index cases, assuming this type of production site to be more susceptible to viral exposure through potential contact with wild boars. Keeping the same model structure and assumptions, the results obtained here were quite different from those obtained with the previous scenario. Indeed, the infection was contained within seeder herds in 87.5% of simulations. When transmission did occur, however, up to 15 herds could be infected, clearly identifying a real risk of transmission even from herds with little network connectivity. Furthermore, local transmission was clearly the main transmission route in this case, corresponding to transmission via material shared between neighboring herds, whereas pig movements played a major role in the previous scenario. Although the tracing of pig movements is well-documented  and may Based on these results, we decided to evaluate the impact of additional screening focusing on small herds with <300 animals. We therefore assumed a systematic clinical inspection of these small herds when either the number of clinically infected or dead animals exceeded the threshold value of 15 pigs over a 14-day period (on average more than one affected or dead pig per day), or the whole population was affected during the same period. With this additional surveillance measure, the detection rate exceeded 95% for all scenarios with the same number of visits. Although the hot periods were similar when the index case involved a free-range herd, the higher detection rate allowed a faster reaction time, thus avoiding further secondary cases (only 4% of simulations in this case were affected by secondary infections). Furthermore, in this specific case, shortening the infection process through enhanced screening of small herds also enabled the number of herd visits to be made during the epidemic to be reduced. These results clearly show the beneficial impact of targeted surveillance on small herds in addition to the emergency surveillance protocol already in place.Although specific surveillance and control measures were integrated to represent the current situation in France, the model's outcomes were in close agreement with the results of Halasa et al. , 27. AfrThe raw data supporting the conclusions of this manuscript will be made available by the authors, without undue reservation, to any qualified researcher.TH developed the model. MA and NR designed the study and analyzed the results. MA performed data analysis, implemented the study, and wrote the manuscript. All the co-authors revised and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Within the past year, several studies have reported a positive role for the gut microbiome on the maintenance of skeletal muscle mass, evidence that contrasts previous reports of a negative role for the gut microbiome on the maintenance of whole body lean mass. The purpose of this mini-review is to clarify these seemingly discordant findings, and to review recently published studies that further elucidate the gut-muscle axis. A role for the gut microbiome on the maintenance of whole body lean mass, skeletal muscle mass, and physical functioning (defined as the gut-muscle axis) has been proposed by several independent research groups . A negatLactobacillus casei or Bifidobacterium longum increased the muscle mass/body weight ratio without affecting body weight , when compared with older adults that had reduced muscle strength   . Moreovebutyrate . HoweverPrevotellaceae, Prevotella, and fecal SCFAs (Bacteroides were increased in older adults in response to 12 weeks of endurance exercise training (which improved cardiorespiratory fitness)  , but fecIn sum, with the goal of further elucidating the gut-muscle axis in older adult humans, future studies aimed at increasing fecal SCFA production  and evaluating the impact on muscle mass and physical function are of interest.The author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Understanding the interaction between nanoparticles and the matrix and the properties of interphase is crucial to predict the macroscopic properties of a nanocomposite system. Here, we investigate the interaction between boehmite nanoparticles (BNPs) and epoxy using different atomic force microscopy (AFM) approaches. We demonstrate benefits of using multifrequency intermodulation AFM (ImAFM) to obtain information about conservative, dissipative and van der Waals tip-surface forces and probing local properties of nanoparticles, matrix and the interphase. We utilize scanning kelvin probe microscopy (SKPM) to probe surface potential as a tool to visualize material contrast with a physical parameter, which is independent from the mechanics of the surface. Combining the information from ImAFM stiffness and SKPM surface potential results in a precise characterization of interfacial region, demonstrating that the interphase is softer than epoxy and boehmite nanoparticles. Further, we investigated the effect of boehmite nanoparticles on the bulk properties of epoxy matrix. ImAFM stiffness maps revealed the significant stiffening effect of boehmite nanoparticles on anhydride-cured epoxy matrix. The energy dissipation of epoxy matrix locally measured by ImAFM shows a considerable increase compared to that of neat epoxy. These measurements suggest a substantial alteration of epoxy structure induced by the presence of boehmite. Epoxy materials are used as a matrix in carbon-fiber reinforced polymers to produce light-weight constructions for applications in such industries as automotive, aerospace and construction. Despite excellent properties such as high strength, high modulus, good adhesion, high chemical and heat resistance , the maiThe interfacial region between a filler and bulk matrix, which exhibits different chemical, physical and mechanical properties compared to bulk, is referred as interphase. It is widely accepted that the mechanical properties of composites are strongly influenced by the properties of their interphase . The natDetermination of interphase properties using experimental approaches is challenging due to resolution limitations in conventional mechanical characterization methods. Formation of interphases has been investigated widely in different studies using numerical methods ,15,16,17In the present work, we aim to study the effect of BNPs on anhydride-cured epoxy resin. First, we focus on visualizing and mechanical characterization of interphase by combining different information channels of ImAFM together with SKPM. Second, we investigate the effect of BNPs on bulk matrix (away from particles) including stiffness, and dissipating energy. Finally, we compare the results with macroscopic mechanical analysis of these nanocomposites reported in other works and propose a describing model.® LY 556, Huntsman, Inc.) cured with an anhydride curing agent methyl tetrahydrophtalic acid anhydride  and accelerated by an amine, 1-methyl-imidazole . The mixture of epoxy, hardener and accelerator is 100:90:1 parts per weight, respectively. BNPs used in this study are commercially available spray-dried nanoparticles with orthorhombic shape and primary particle size of approx.14 nm based on the manufacturer’s datasheet . First, suspensions of 30 wt % boehmite were provided and blended with DGEBA and further the hardener and accelerator are added to the blend. The concentrations used in this study is 0, 5 and 15 wt % BNP in 100:90:1 ratio of DGEBA, MTHPA and DY070, respectively. The epoxy mixture ratio used is the standard stoichiometric ratio (suggested by the manufacturer). The mixture is cured for 4 h at 80 °C to reach gelation and 4 h at 120 °C for post-curing. Dispersion and curing process was performed by Jux and coworker and described in details elsewhere [The epoxy system used in this study is bisphenol-A-diglycidyl ether . In ImAFM the cantilever is excited with not only one frequency such as in tapping mode but with two frequencies close to a resonance of the cantilever. Here, we choose frequencies 0.5 kHz above and below the frequency of the first flexural eigenmode of the cantilever. Away from the surface, the cantilever performs a beating motion. Engaged to the surface, the cantilever motion is distorted by the nonlinear tip-sample interaction which creates additional frequency components in the cantilever motion spectrum as shown in FI corresponds to the conservative part of the force describing the elastic behavior of the surface. The out-of-phase quadrature FQ measures the dissipated energy during a single oscillation cycle. Examples of FI and FQ curves are presented in FI(A) looks similar to those conventional force–distance curves: it consists of an attractive and repulsive regime. The amplitude in the beginning of the measuring cycle is low therefore there is no tip-surface interaction. By increasing the amplitude, tip and sample spends more time closer and the tip gets into attractive regime  which is due to van der Waals forces. With further increase of the amplitude, the tip makes contact with the surface and penetrates into it. In this region the tip experiences a net repulsive force . However, at this stage FI(A) cannot be treated directly as FDC curves since the force is plotted as a function of oscillation amplitude rather than tip position. Amplitude-dependence force spectroscopy (ADFS) uses the inverse Abel transform to converts FI(A) to a traditional force-tip position curves [The IMPs are directly correlated to the tip-surface force. For a single pixel, we can visualize this correlation with force quadrature curves which show the in-phase and out-of-phase component of the force with respect to the tip motion for each oscillation cycle . The in-n curves ,28. The FQ(A) describes the dissipative part of tip-surface interaction, which originates from viscous nature of the material [The material .For the analysis of spatially varying features, we create surface maps of the ADFS stiffness, the attractive force and the total energy dissipated during in a single pixel. It is noteworthy that the force quadrature curves shown in ImAFM measurements were carried out using MFP3D microscope . A multi-frequency lock-in amplifier  is used to generate the drive signals and measure the intermodulation spectra. The probes are HQ:NSC35  with resonance frequency of 190 kHz  is used. In this method, an AC signal excites the cantilever electrostatically at its resonance frequency. The potential difference between probe and the surface results in the mechanical oscillation of cantilever. The feedback loop nulls the oscillation by applying a bias voltage to the cantilever. This bias voltage is then collected as a contact potential difference (CPD). The corresponding equations and technical considerations are described in detail elsewhere [The vibrating capacitor or kelvin probe is a method to measure the contact potential difference (CPD) between a sample and tip also called surface potential Vsp . The samlsewhere . SKPM isIn this work we used MFP3D microscope  in SKPM mode. The gold-coated silicon probes with resonance frequency of 190.130 kHz, radius lower than 20 nm provided by Mikromasch  was used. During all SKPM measurements nap height is chosen to be 50 nm as the suitable height according to topographic features of the surface. The resulted scans shown in this article are corrected by offset plane with the purpose of enhancing the visibility of the contrast. Therefore, the scale shown in SKPM images are different than the actual values. The measurements were carried out in air, at room temperature, using the first eigenmode frequency. Therefore no major subsurface sensitivity is expected, since this would mainly be the case when using the second eigenmode .In In Wattr and stiffness maps, respectively, generated from ADFS curves. In a single ADFS curve obtained for each pixel, Wattr is calculated from the net attractive regime and the slope of the curve is proportional to stiffness. The Wattr map shows a clear contrast between the protrusions and the surrounding with a well-defined border. The area with sudden decrease in Wattr is located where the potential maps shows the presence of boehmite. Considering the van der Waals forces as the main driving force for net attractive regime, the low values of Wattr is an indication for a weaker van der Waals forces between the tip (gold) and BNPs than the epoxy. Van der Waals forces which are mainly originated from dipole–dipole and dipole-induced dipole interactions between tip and the surface, can be used as an additional information channel about the surface composition independent from its mechanics. Thus, when measuring the mechanical response with ImAFM, Wattr signal can also be used to visualize material contrast.Wattr maps. Therefore, the soft area relates to the particle-polymer interphase.Despite the existence of two distinguishable phases in It is noteworthy that the bulk matrix shows variations in stiffness in the scanned area. Blocks with high (yellow) and low (red) stiffnesses in bulk epoxy indicate the inhomogeneous nature of the matrix.Since sudden height changes affect the force measurements, it is crucial to investigate the roll of topography artifacts. Detailed analysis of topography-stiffness relation for the scanned surface is presented in To precisely distinguish the stiffness of particles, interphase and polymer, several areas with the presence of nanoparticles are selected and analyzed separately . One of (1)Dark blue points are related to pure BNP particles as they exhibit negative surface potential values (from −0.3 V to −0.5 V). They have large distributions of stiffness varying from 5 up to 22. The variation of stiffness values in the area related to pure BNPs can be due to following reasons: (i) Due to anisotropic nature of boehmite crystals, force curves obtained from different orientations show different stiffness values. (ii) Particles which are present in the nanocomposites are in fact secondary particles which are formed by aggregation of several primary particles with the size of 14 nms. Therefore, while in contact with the tip, several intra and inter-slippage between layers can occur which helps the deformation and results in apparent stiffness values which may be lower than the actual values.(2)Green points are related to the pure matrix, far from the particle, according to their surface potential values. In this area, potential values are mostly positive and have a narrower distribution (between −0.05 and 0.2 V) compared to that of BNPs. The stiffness variation in epoxy matrix is high the values are distributed between 5 to 50. The broad distribution of stiffness in epoxy phase is due to following reasons: i) Inhomogeneous phases in epoxy-anhydride cured systems which has been already reported in several studies ,36. ii) (3)The light blue cloud is related to the matrix in the immediate proximity of particles. This interfacial region has a gradient potential, but no gradient in stiffness is observed. The potential values start from low values in vicinity of particles (−0.3 V) increasing up to 0.05 V when getting close to the pure matrix. In all distances from the particle, the interphase shows stiffness values between 1 to 5. The homogenous interphase is unlike commonly reported interphase formation in which there was a gradient in property changes were observed . The sofIn the 2D histogram, the stiffness values are sorted based on the corresponding surface potential values and three distinguishable regions  was used as a tool to measure forces together with scanning kelvin probe macroscopy (SKPM) as an additional information channel to show material contrast independent from the mechanics of the surface. ImAFM maps demonstrated stiffness contrast between polymer, particle and the interphase. SKPM shows potential contrast between boehmite nanoparticles and epoxy matrix. Combination of mechanical and surface potential values led to a more precise determination of the location and stiffness of interphase. The results demonstrated the presence of a soft block of polymer near the interfacial region with no visible stiffness gradient. The stiffness of this region is considerably lower than both particles and polymer phase.Moreover, the effect of boehmite on the matrix properties was investigated by focusing on stiffness and energy dissipation during the tip-surface interaction obtained from ImAFM force curves. A significant stiffening effect of boehmite nanoparticles on anhydride-cured DGEBA was demonstrated. Meanwhile, the presence of boehmite resulted in increase of energy dissipation. We suggest that boehmite cause structural alteration of matrix by inducing local changes in stoichiometric ratio of the epoxy and hardener due to preferential surface absorption, covalent or non-covalent bonding between boehmite particles and mixture components.


Background: Wide-necked cerebral aneurysms at a bifurcation can be difficult to treat with endovascular techniques despite recent advancements.Objective: We describe a new technique of micro-scaffold remodeling of the aneurysm neck of wide-necked bifurcation aneurysms by placing one or more microcatheters and/or wires in the efferent vessels. We hypothesize that this technique would be a better choice to change the branch angulation, allowing for an improved configuration to stably deploy coils. We present a retrospective case series to illustrate this technique.Methods: 17 wide-necked bifurcation aneurysms in 17 patients were coil embolized using this technique during a 3 year study period. Branch-vessel microcatheters and/or microwires were used to remodel the aneurysm neck and support the coil mass. Statistical analysis of the branch angulation and neck-width changes were performed during treatment. Long-term clinical outcome and follow-up angiography was obtained in 8 patients.Results: Eleven patients had complete occlusion of their aneurysm (Raymond-Roy Class I), and 6 patients had Raymond-Roy Class 2 immediately after treatment. Efferent vessels demonstrated a statistically significant change in angulation with insertion of microcatheters or microwires, while neck width did not change significantly. There were four intraoperative complications and no neurological morbidity in the immediate post-operative period. Complete occlusion was documented for all 10 subjects with long-term follow-up.Conclusions: The micro-scaffold endosurgical remodeling technique is a useful adjunct in treating wide-necked bifurcation aneurysms. By elevating branch vessels away from the aneurysm neck, this technique allows for dense coil packing while decreasing the need for balloon or stent assistance. The success of coil-embolization in the treatment of intracranial aneurysms is dependent on its morphology, and is challenging in the case of wide-necked aneurysms that are located at a vessel bifurcation –3. This In an era when dedicated bifurcation aneurysm devices were not available, we devised a technique to address the challenges of treating wide-necked, bifurcation aneurysms for which available reported techniques were deemed to be either unfeasible or insufficient. Multiple microcatheters and/or microwires were used to temporarily change the configuration of the aneurysm neck and the bifurcation branches. We hypothesized that using these adjunctive devices to change the angle of the branches would provide a micro-scaffold with which to introduce and safely deploy coils. After the deployment of coils and removal of microcatheters and/or wires, the angle of the scaffolded branches reverts to its pre-procedural configuration, allowing the coils to remain in place thus obliterating the aneurysm.t-test. This was done with the assistance of statistical software Statistica (V.7). The number of coils and the degree of occlusion (Raymond-Roy Class) were analyzed. Follow-up catheter-based angiography was available in 10 patients over a 6–28 month period. Follow-up magnetic resonance angiography (MRA) was available in an additional 4 patients over a 2–24 month period  angiograms prior to procedure. All patients were coil-embolized under general anesthesia using a bi-plane Siemens Neurostar . Systemic heparin anticoagulation was used and monitored appropriately in all cases. In order to change the configuration of the bifurcation and the aneurysm ostium, a combination of up to 3 microcatheters  and/or microwires  were placed in the bifurcating vasculature at the aneurysm. Change in the bifurcation configuration was confirmed by roadmap fluoroscopy. All catheters were set up with continuous heparinized saline flush .When it was anticipated that coil loops in the aneurysm might obstruct the origin of a perforatoring vessel, a microcatheter was placed in the vessel with or without a microwire. The radiopaque wire provided a marker to select a working view during aneurysm coiling that demonstrated separation of the coil mass above from the radiopaque wire below. Because the wire tended to bow toward the aneurysm neck, the space below the wire relative to the aneurysm neck could be assured to be a patent branch. This was confirmed by periodic angiography; even when a large coil mass would have otherwise obscured the branch origin.All patients required only a single femoral artery access. In most the cases, a 6 Fr × 90 cm sheath  was used to accommodate all microwires and microcatheters. In the remainder of cases, a 6 Fr guide catheter  was used. The microcatheters and microwires were inserted at the sheath or guide catheter hub via stacked rotating hemostatic valves. By using an exchange microwire, a microcatheter which had been used to selectively catheterize a branch vessel could be removed and reused to selectively catheterize the aneurysm leaving only the exchange microwire in place in the branch. In other cases, microcatheteters with or without contained standard length microwires were left in branches and the microcatheters were continuously flushed. The presence of a microwire in a microcatheter tended to produce a greater change in branch vessel angulation than a microcatheter alone. Only the stented patients received adjunctive dual agent antiplatelet therapy. After temporarily reconfiguration of the bifurcation had been achieved using adjunctive microcatheters and/or microwires, up to 2 microcatheters were placed in the target aneurysm. Detachable coils  were subsequently used to embolize the aneurysm.During the course of target bifurcation aneurysm treatment in 3 patients, adjunctive placement of a stent  was necessary. In 2 of these cases, stent implantation in the dominant bifurcation branch having a lumen diameter ≥ 2 mm was anticipated to leave a portion of the aneurysm neck uncovered. Because the remaining < 2 mm diameter branch arising from the uncovered portion of the aneurysm neck supplied eloquent territory, symptomatic branch occlusion as a result of coiling was anticipated unless a method to preserve branch patency was applied. In each case, the nondominant branch and its eloquent territory was satisfactorily protected by temporary placement of a microcatheter containing a microwire. The microcatheter containing the microwire in the branch was jailed by the stent, and the microcatheter was easily removed after completion of coiling. In the last of these cases, a 4.5 mm diameter stent was used as a waffle cone to protect the central neck of an MCA bifurcation aneurysm with a neck that was wider than the expanded dimension of the stent and from which small diameter bifurcation branches arising at the lateral neck margins could not be covered by the stent in the central neck. In that case, microwire containing microcatheters were placed in each of the MCA bifurcation branches prior to placing the stent in order to provide coil support in the portions of the aneurysm neck that could not be covered by the stent. This was also done to mark the positions of the branch origins with the radiopaque microwires, and to preserve branch patency during the coiling procedure. As in the first two cases, the microcatheters were easily retrieved from the branch vessels without displacement of the stent or occlusion of the branch vessels.This study includes 17 aneurysms with findings as reported in Representative vessel angle before and during the procedure, as well as its normalization afterwards, are shown in The mean angle change before and during the procedure was 37.5° with a standard deviation (±) of 2.5. This represents the degree of conformational change of the aneurysm neck. Branch angles before and after embolization stayed the same. Long-term follow-up angiograms on 10 aneurysms showed no long-term changes in branch angulation. Mean + SE angle changes of all patients are shown in There were no vessel occlusions and no neurological deficits in the immediate post-operative period. Complications included 2 cases of asymptomatic localized subarachnoid hemorrhage and a thromboembolic event that caused temporary mild hand weakness and mild expressive aphasia. No evidence of frank wire perforation was seen in either case. The localized hemorrhage may have been due to stretching of very small perforators when the angulation of the branch vessels was changed by the neck remodeling wires contained in these branches. An asymptomatic branch vessel stenosis and a symptomatic MCA bifurcation occlusion occurred in late follow-up. The latter event occurred in a patient who received a Neuroform stent  and self-discontinued antiplatelet medication within 3 months of the procedure (subject 8). There was a 10% incidence of thromboembolic events, and a 5% incidence of SAH in the periprocedural period (up to 2 weeks postop). The rate of permanent neurologic deficits in the periprocedural period was 0%. We recognize that the incidence of complications is not zero in our patient group, but is an improvement from conventional endovascular methods and also similar to recent devices reported in literature –19.We describe a micro-scaffold technique to assist coil embolization of wide-necked bifurcation aneurysms using microcatheters and/or microwires placed across the aneurysm neck. This induces a conformational change in the bifurcation branch vessels. This temporary mechanical alteration of the vascular geometry often proves sufficient to protect vessel patency during coil embolization, particularly when parent vessel and/or branch vessel lumen diameter is not optimal for stent placement. This method also obviates repeated cycles of balloon inflation and deflation that may compromise vessel wall integrity and protects distal perfused parenchyma at risk of ischemic complications. The presence of these temporary devices, which tend to straighten the branch vessel vasculature and bow toward the aneurysm neck, provides buttressing of the coil mass when it is most needed during formation of a stable coil mass with the initial framing coils. We noted that the use of the devices changed the anatomic conformation of the bifurcation by altering the angle of incidence of the branch vessels relative to the course of the parent vessel. This narrows the angle between the branch vessels, and modifies the geometrical configuration of the aneurysm neck . In someWe found that the efferent vessel angle changed while the neck width of aneurysm remained the same. The subsequent removal of the microcatheters allowed for reversion of the branches to the initial configuration, allowing for coil retention within the aneurysmal fundus without herniation into parent vessels . This teOne of the limitations of this study is that multiple measurements from different trajectories could affect consistent measurements. This was one of the areas we spent a significant amount of time measuring and calculating. The angles would indeed change slightly when the trajectories were different; the final angle was an average of different measurements.Treatment of wide-necked bifurcation aneurysms with coils alone results in recanalization rates of 50–60% and recurrence rates of 30–40% . The intUse of the micro-scaffolding technique substituted for an infeasible Y stenting technique in the first 2 of our stented cases, and allowed endovascular treatment of a bifurcation aneurysm having an exceptionally wide neck and small diameter branches while avoiding use of infeasible double Y or X techniques in the last case. Although a stent was implanted in each of these 3 cases, a stent alone was not anticipated to preserve both bifurcation branches, and successful endovascular occlusion of the aneurysm with preservation of branch vessel patency was made possible by concomitant use of aneurysm neck micro-scaffolding technique we have described.In contradistinction to balloon remodeling techniques, during each of our micro-scaffolding assisted coil embolization procedures parent and branch vessel patency as confirmed by periodic angiography was maintained at all times, neither parent nor branch vessels were subjected to potential trauma caused by repeated cycles of micro-balloon inflation and deflation, and ischemia in downstream parenchyma was avoided.More recently, devices such as PulseRider Aneurysm Neck Reconstruction Device  and the Woven EndoBridge (WEB) device  have been proposed for use in the treatment of bifurcation aneurysms. The PulseRider is a self-expanding implant that is fully retrievable, adaptable stent with an open leaflet structure that uses less metal than a conventional stent, allowing the majority of the device's surface area to cover the neck of the aneurysm . The WEBAlthough these results seem promising, additional experience is needed to confirm the outcomes suggested by our experience using the micro-scaffolding assisted embolization technique in a small number of patients. Our study is also limited the lack of a concurrent control group with which to compare our results. However, we feel that our results compare favorably to published occlusion rates for stent-assisted coiling of wide-necked aneurysms. Notably, some newer devices discussed above received marketing approval on the basis of a small single arm trial . AnotherWe admit that our study is also limited by lack of follow-up in all patients. Further long-term anatomic and clinical follow-up will be needed to identify the subset of aneurysms that will most benefit from use of the micro-scaffolding assisted coil embolization technique and to fully assess the stability of bifurcation aneurysm occlusion achieved by the micro-scaffolding technique we have described.Wide-necked, bifurcation aneurysms encompassing branch vessels remain a challenge in endovascular neurosurgery due in part to the risk of compromise of nearby vasculature during coil embolization. Microwires and microcatheters may be used to remodel and reconstruct the local vascular anatomy and enable endosurgical repair. These temporary devices modify the conformation of the bifurcation vessels as evidenced by our pre- and post-embolization angle of incidence measurements as well as the change in the configuration of the aneurysm ostium. Additionally, they permit satisfactory coil embolization while concomitantly protecting parent and branch vessel lumens during exclusion of the aneurysm from the intracranial circulation. By using these simple, relatively inexpensive, and readily available adjunctive devices, the operator may fortify the aneurysm neck, induce local vascular conformational change, and provide a stable micro-scaffold to form an intra-aneurysmal coil mass. Technical challenges associated with balloon-assisted coiling and complex stent-assisted coiling, such as Y-stenting, are avoided; while satisfactory aneurysm occlusion, preserved vessel patency, decreased use of dual-antiplatelet therapy, and a low rate of recanalization requiring retreatment are achieved. The micro-scaffold technique provides a promising adjunctive treatment modality in selected cases.The views expressed are those of the author (PN) and do not necessarily reflect the official policy or position of the Food and Drug Administration, the Department of Health and Human Services, or the United States Government.Institutional Review Board approval and patient consents were obtained before data was retrospectively collected.All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. All devices utilized in the embolization procedures had PMA, 510(k), or HDE approvals and were on the shelf.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.