A Rare Cause of Breathlessness in a Patient on Hemodialysis.

Patients suffering from end stage renal disease (ESRD) often present to the emergency with breathlessness, mostly due to fluid overload. We report a rare case of recurrent unilateral massive pleural effusion in an ESRD patient on maintenance hemodialysis (MHD). The patient was on MHD thrice weekly for the last 2 years with right internal jugular vein (IJV) tunneled cuffed catheter (TCC). Chylothorax was identified as the cause of recurrent pleural effusion which was due to superior vena cava stenosis (SVCO). It was managed successfully by balloon venoplasty of SVC and anticoagulation. SVCO is a rare but a serious complication in patients on long term indwelling dialysis catheters. Physicians involved in the care of dialysis patients must be aware about complications of long term dialysis catheters like central vein stenosis. A strong suspicion of chylothorax should be reserved for a patient with recurrent unilateral pleural effusion and long term dialysis catheters.

Regulation of dendrite morphology and excitatory synapse formation by zDHHC15.

Protein palmitoylation is the most common post-translational lipid modification in the brain and is mediated by a family of 24 zDHHC enzymes. There has been growing interest in zDHHCs due to mounting evidence that these enzymes play key roles in the development and function of neuronal connections, and the fact that a number of zDHHCs have been associated with neurodevelopmental and neurodegenerative diseases. Loss-of-function variants in several zDHHCs, including zDHHC15, have been identified in patients with intellectual disabilities; however, the function of zDHHC15 in the brain has not been well studied. Here, we demonstrate that knocking down zDHHC15 in primary rat hippocampal cultures reduces dendritic outgrowth and arborization, as well as spine maturation. Moreover, knockdown of zDHHC15 reduces palmitoylation of PSD-95 and its trafficking into dendrites, resulting in an overall decrease in the density of excitatory synapses being formed onto mutant cells.

Rap1 GTPases Are Master Regulators of Neural Cell Polarity in the Developing Neocortex.

During the development of the mammalian neocortex, the generation of neurons by neural progenitors and their migration to the final position are closely coordinated. The highly polarized radial glial cells (RGCs) serve both as progenitor cells to generate neurons and as support for the migration of these neurons. After their generation, neurons transiently assume a multipolar morphology before they polarize and begin their migration along the RGCs. Here, we show that Rap1 GTPases perform essential functions for cortical organization as master regulators of cell polarity. Conditional deletion of Rap1 GTPases leads to a complete loss of cortical lamination. In RGCs, Rap1 GTPases are required to maintain their polarized organization. In newborn neurons, the loss of Rap1 GTPases prevents the formation of axons and leading processes and thereby interferes with radial migration. Taken together, the loss of RGC and neuronal polarity results in the disruption of cortical organization.

Synergistic activity of BET protein antagonist-based combinations in mantle cell lymphoma cells sensitive or resistant to ibrutinib.

Mantle cell lymphoma (MCL) cells exhibit increased B-cell receptor and nuclear factor (NF)-κB activities. The bromodomain and extra-terminal (BET) protein bromodomain 4 is essential for the transcriptional activity of NF-κB. Here, we demonstrate that treatment with the BET protein bromodomain antagonist (BA) JQ1 attenuates MYC and cyclin-dependent kinase (CDK)4/6, inhibits the nuclear RelA levels and the expression of NF-κB target genes, including Bruton tyrosine kinase (BTK) in MCL cells. Although lowering the levels of the antiapoptotic B-cell lymphoma (BCL)2 family proteins, BA treatment induces the proapoptotic protein BIM and exerts dose-dependent lethality against cultured and primary MCL cells. Cotreatment with BA and the BTK inhibitor ibrutinib synergistically induces apoptosis of MCL cells. Compared with each agent alone, cotreatment with BA and ibrutinib markedly improved the median survival of mice engrafted with the MCL cells. BA treatment also induced apoptosis of the in vitro isolated, ibrutinib-resistant MCL cells, which overexpress CDK6, BCL2, Bcl-xL, XIAP, and AKT, but lack ibrutinib resistance-conferring BTK mutation. Cotreatment with BA and panobinostat (pan-histone deacetylase inhibitor) or palbociclib (CDK4/6 inhibitor) or ABT-199 (BCL2 antagonist) synergistically induced apoptosis of the ibrutinib-resistant MCL cells. These findings highlight and support further in vivo evaluation of the efficacy of the BA-based combinations with these agents against MCL, including ibrutinib-resistant MCL.

Molecular antagonism and plasticity of regulatory and inflammatory T cell programs.

Regulatory T (Treg) and T helper 17 (Th17) cells were recently proposed to be reciprocally regulated during differentiation. To understand the underlying mechanisms, we utilized a Th17 reporter mouse with a red fluorescent protein (RFP) sequence inserted into the interleukin-17F (IL-17F) gene. Using IL-17F-RFP together with a Foxp3 reporter, we found that the development of Th17 and Foxp3(+) Treg cells was associated in immune responses. Although TGF-beta receptor I signaling was required for both Foxp3 and IL-17 induction, SMAD4 was only involved in Foxp3 upregulation. Foxp3 inhibited Th17 differentiation by antagonizing the function of the transcription factors RORgammat and ROR*. In contrast, IL-6 overcame this suppressive effect of Foxp3 and, together with IL-1, induced genetic reprogramming in Foxp3(+) Treg cells. STAT3 regulated Foxp3 downregulation, whereas STAT3, RORgamma, and ROR* were required for IL-17 expression in Treg cells. Our data demonstrate molecular antagonism and plasticity of Treg and Th17 cell programs.

Regulation of Rap GTPases in mammalian neurons.

Small GTPases are central regulators of many cellular processes. The highly conserved Rap GTPases perform essential functions in the mammalian nervous system during development and in mature neurons. During neocortical development, Rap1 is required to regulate cadherin- and integrin-mediated adhesion. In the adult nervous system Rap1 and Rap2 regulate the maturation and plasticity of dendritic spine and synapses. Although genetic studies have revealed important roles of Rap GTPases in neurons, their regulation by guanine nucleotide exchange factors (GEFs) that activate them and GTPase activating proteins (GAPs) that inactivate them by stimulating their intrinsic GTPase activity is just beginning to be explored in vivo. Here we review how GEFs and GAPs regulate Rap GTPases in the nervous system with a focus on their in vivo function.

Influence of Sterilization Technologies on Electrospun Poly(ester urea)s for Soft Tissue Repair.

Degradable poly(ester urea)s (PEU)s were electrospun into nanofiber sheets and assessed for their potential to be used in soft tissue repair. The level of residual solvent was measured and the effects of ethylene oxide and electron beam sterilization techniques on molecular mass, mass distribution, and morphology were quantified. Two PEU compositions that formed stable nanofiber sheets were advanced into a pilot study in vitro and in vivo as candidate materials for hernia repair. Cell viability, spreading, proliferation, and migration were examined in vitro. Nanofiber sheets were implanted subcutaneously into mice and analyzed via microangiography and histology for tissue incorporation. Nanofiber sheets performed similarly to decellularized extracellular matrix (ECM) in vitro, but the lack of sufficient pore structure inhibited cellular infiltration after 14 days of culture. The lack of microporous features in nanofiber sheets also contributed to low levels of cellular infiltration, angiogenesis, and matrix deposition in vivo. A preliminary study to increase pore size in nanofibers was performed using coaxial electrospinning resulting in significant improvement in tissue infiltration in vivo.

Patterns of uveitis at the Apex Institute for Eye Care in India: Results from a prospectively enrolled patient data base (2011-2013).

The purpose of the study was to identify the clinical and etiological profile of uveitis at the apex institute for eye care in India. This is a prospective, prevalence study. 980 consecutive patients with uveitis referred to uvea clinic, Dr. RP Centre for Ophthalmic Sciences (Ophthalmology division, All India Institute of Medical Sciences). Demographic data of each patient were noted and a thorough ocular examination including slit lamp examination and dilated fundus evaluation was carried out. OCT and fluorescein angiography were undertaken whenever indicated. Uveitis was classified based on the anatomic location of inflammation (IUSG classification). Relevant serological and radiological investigations were obtained based on systemic symptomatology, and if the uveitis was recurrent (even in the absence of systemic symptoms). The presence of a systemic disease was confirmed by obtaining an internist consultation. The main outcome measures include pattern of uveitis according to anatomical classification and the etiology. Out of 980 patients with uveitis, 413 (42.14 %) patients had anterior uveitis, 131 (13.36 %) had intermediate uveitis, 165 (16.83 %) had posterior uveitis, 91 (9.2 %) had panuveitis, 47 (4.7 %) had retinal vasculitis, 22 (2.24 %) had scleritis, 17 (1.7 %) had masquerade syndromes, 8 (0.8 %) had keratouveitis, 22 (2.24 %) had sclerokeratouveitis, 19 (1.9 %) had endophthalmitis and 45 (4.5 %) had other causes of inflammation including trauma and intraocular surgery. Out of all uveitic patients definite etiological correlation could be made out in 225 (23 %) patients; thus 77 % were categorised as idiopathic. Only 9 % of all patients were found to have uveitis with an infectious etiology. Amongst infectious causes of uveitis tuberculosis was the leading cause, accounting for sixty percent of all infectious uveitis (approximately 5 % of overall uveitis). Non-infectious uveitis etiology accounted for more than 90 % of all cases with ankylosing spondylitis being the most common followed by sarcoidosis and juvenile rheumatoid arthritis. Amongst known uveitic syndromes serpiginous like choroidopathy was the most common and was followed by acute posterior placoid pigmented epitheliopathy and Fuch's heterochromic iridocyclitis. Infection, including tuberculosis, is an infrequent cause of uveitis in the study population. Multicentric, collaborative efforts are required to improve levels of clinical evidence and evolve consensus in establishing stringent guidelines for labelling uveitis as being of infectious etiology.

In vivo functions of small GTPases in neocortical development.

The complex mammalian cortex develops from a simple neuroepithelium through the proliferation of neuronal progenitors, their asymmetric division and cell migration. Newly generated neurons transiently assume a multipolar morphology before they polarize to form a trailing axon and a leading process that is required for their radial migration. The polarization and migration events during cortical development are under the control of multiple signaling cascades that coordinate the different cellular processes involved in neuronal differentiation. GTPases perform essential functions at different stages of neuronal development as central components of these pathways. They have been widely studied using cell lines and primary neuronal cultures but their physiological function in vivo still remains to be explored in many cases. Here we review the function of GTPases that have been studied genetically by the analysis of the embryonic nervous system in knockout mice. The phenotype of these mutants has highlighted the importance of GTPases for different steps of development by orchestrating cytoskeletal rearrangements and neuronal polarization.

Entry of human papillomavirus type 16 by actin-dependent, clathrin- and lipid raft-independent endocytosis.

Infectious endocytosis of incoming human papillomavirus type 16 (HPV-16), the main etiological agent of cervical cancer, is poorly characterized in terms of cellular requirements and pathways. Conflicting reports attribute HPV-16 entry to clathrin-dependent and -independent mechanisms. To comprehensively describe the cell biological features of HPV-16 entry into human epithelial cells, we compared HPV-16 pseudovirion (PsV) infection in the context of cell perturbations (drug inhibition, siRNA silencing, overexpression of dominant mutants) to five other viruses (influenza A virus, Semliki Forest virus, simian virus 40, vesicular stomatitis virus, and vaccinia virus) with defined endocytic requirements. Our analysis included infection data, i.e. GFP expression after plasmid delivery by HPV-16 PsV, and endocytosis assays in combination with electron, immunofluorescence, and video microscopy. The results indicated that HPV-16 entry into HeLa and HaCaT cells was clathrin-, caveolin-, cholesterol- and dynamin-independent. The virus made use of a potentially novel ligand-induced endocytic pathway related to macropinocytosis. This pathway was distinct from classical macropinocytosis in regards to vesicle size, cholesterol-sensitivity, and GTPase requirements, but similar in respect to the need for tyrosine kinase signaling, actin dynamics, Na⁺/H⁺ exchangers, PAK-1 and PKC. After internalization the virus was transported to late endosomes and/or endolysosomes, and activated through exposure to low pH.

Pip5k1γ regulates axon formation by limiting Rap1 activity.

During their differentiation, neurons establish a highly polarized morphology by forming axons and dendrites. Cortical and hippocampal neurons initially extend several short neurites that all have the potential to become an axon. One of these neurites is then selected as the axon by a combination of positive and negative feedback signals that promote axon formation and prevent the remaining neurites from developing into axons. Here, we show that Pip5k1γ is required for the formation of a single axon as a negative feedback signal that regulates C3G and Rap1 through the generation of phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2). Impairing the function of Pip5k1γ results in a hyper-activation of the Fyn/C3G/Rap1 pathway, which induces the formation of supernumerary axons. Application of a hyper-osmotic shock to modulate membrane tension has a similar effect, increasing Rap1 activity and inducing the formation of supernumerary axons. In both cases, the induction of supernumerary axons can be reverted by expressing constitutively active Pip5k. Our results show that PI(4,5)P2-dependent membrane properties limit the activity of C3G and Rap1 to ensure the extension of a single axon.

UDP-glucose 4, 6-dehydratase activity plays an important role in maintaining cell wall integrity and virulence of Candida albicans.

Candida albicans, a human fungal pathogen, undergoes morphogenetic changes that are associated with virulence. We report here that GAL102 in C. albicans encodes a homolog of dTDP-glucose 4,6-dehydratase, an enzyme that affects cell wall properties as well as virulence of many pathogenic bacteria. We found that GAL102 deletion leads to greater sensitivity to antifungal drugs and cell wall destabilizing agents like Calcofluor white and Congo red. The mutant also formed biofilms consisting mainly of hyphal cells that show less turgor. The NMR analysis of cell wall mannans of gal102 deletion strain revealed that a major constituent of mannan is missing and the phosphomannan component known to affect virulence is greatly reduced. We also observed that there was a substantial reduction in the expression of genes involved in biofilm formation but increase in the expression of genes encoding glycosylphosphatidylinositol-anchored proteins in the mutant. These, along with altered mannosylation of cell wall proteins together might be responsible for multiple phenotypes displayed by the mutant. Finally, the mutant was unable to grow in the presence of resident peritoneal macrophages and elicited a weak pro-inflammatory cytokine response in vitro. Similarly, this mutant elicited a poor serum pro-inflammatory cytokine response as judged by IFNγ and TNFα levels and showed reduced virulence in a mouse model of systemic candidiasis. Importantly, an Ala substitution for a conserved Lys residue in the active site motif YXXXK, that abrogates the enzyme activity also showed reduced virulence and increased filamentation similar to the gal102 deletion strain. Since inactivating the enzyme encoded by GAL102 makes the cells sensitive to antifungal drugs and reduces its virulence, it can serve as a potential drug target in combination therapies for C. albicans and related pathogens.

Impact of advanced laparoscopy courses on present surgical practice.

BACKGROUND AND OBJECTIVES: The introduction of new surgical techniques has made training in laparoscopic procedures a necessity for the practicing surgeon, but acquisition of new surgical skills is a formidable task. This study was conducted to assess the impact of advanced laparoscopic workshops on caseload patterns of practicing surgeons. METHODS: After we obtained institutional review board approval, a survey of practicing surgeons who participated in advanced laparoscopic courses was distributed; the results were analyzed for statistical significance. The courses were held at the University of Nebraska Medical Center between January 2002 and December 2010. Questionnaires were mailed, faxed, and e-mailed to surgeons. RESULTS: Of the 109 surgeons who participated in the advanced laparoscopy courses, 79 received surveys and 30 were excluded from the survey because of their affiliation with the University of Nebraska Medical Center. A total of 47 responses (59%) were received from 41 male and 6 female surgeons. The median response time from completion of the course to completion of the survey was 13.2 months (range, 6.8-19.1 months). The mean age of participating surgeons was 39.2 years (range, 29-51 years). The mean time since residency was 8.4 years (range, 0.8-21 years). Eleven surgeons had completed a minimal number of laparoscopic cases in residency (<50), 17 surgeons had completed a moderate number of laparoscopic procedures in residency (50-200), and 21 surgeons had completed a significant number of cases during residency (>200). Of the surgeons who responded, 94% were in private practice. Fifty-seven percent of the participating surgeons who responded reported a change in laparoscopic practice patterns after the courses. Of these surgeons, 24% had a limited residency laparoscopy exposure of <50 cases. Surgeons who were exposed to ≥50 laparoscopic cases during their residency showed a statistically significant increase in the number of laparoscopic procedures performed after their class compared with surgeons who did not receive ≥50 laparoscopic cases in residency (P = .03). In addition, regardless of the procedures learned in a specific class, surgeons with ≥50 laparoscopic cases in residency had a statistically significant increase in their laparoscopic colectomy and laparoscopic hernia procedure caseload (P < .01). However, there was no statistically significant difference in laparoscopic caseload between surgeons who had completed 50 to 200 laparoscopic residency cases and those who had completed greater than 200 laparoscopic residency cases (P = .31). Furthermore, the participant's age (P = .23), practice type (P = .61), and years in practice (P = .22) had no statistical significance with regard to the adoption of laparoscopic procedures after courses taken. This finding is congruent with the findings of other researchers. Future interest in advanced laparoscopy courses was noted in 70% of surgeons and was more pronounced in surgeons with ≥50 cases in residency. CONCLUSION: Advanced laparoscopic workshops provide an efficacious instrument in educating surgeons on minimally invasive surgical techniques. Participating surgeons significantly increased the number of course-specific procedures that they performed but also increased the number of other laparoscopic surgeries, suggesting that a certain proficiency in laparoscopic skills is translated to multiple surgical procedures. Laparoscopy experience of ≥50 cases during residency is a strong predictor of an increase in the number of advanced laparoscopic cases after attending courses.

Discharge disposition after pancreatic resection for malignancy: analysis of national trends.

OBJECTIVES: The aim of this study is to analyse national trends in discharge disposition following pancreatic resection for malignancy in the USA. METHODS: The Nationwide Inpatient Sample database was queried for 1993-2005 to identify patients who underwent pancreatic resection for malignancy. The status of patients at discharge (to home, home with home health care or to another facility) was noted. RESULTS: A weighted total of 51 866 patients who underwent pancreatectomy for malignant neoplasm of the pancreas were identified. Patients who died in the postoperative period and patients without a specified discharge disposition were excluded, leaving 43 603 patients for inclusion in the study. Overall mortality improved over the period of the study from 7.1% in 1993 to 5.2% in 2005. The number of patients discharged to another facility increased significantly from 5.5% in 1993 to 13.3% in 2005. Similarly, the number of patients discharged to home with home health assistance increased from 20.0% in 1993 to 33.0% in 2005. This corresponded with a statistically significant decrease in the number of patients discharged to home without assistance, from 74.5% in 1993 to 53.7% in 2005 (P= 0.002). CONCLUSIONS: The results of our study demonstrate that following pancreatic resection for malignancy, nearly half the patients will require some assistance after discharge.

Acute Hepatitis C After Penile Stem Cell Injection.

Hepatitis C is a viral infection that is transmitted via blood or other bodily fluids and usually manifests as a chronic infection. We present a unique case of acute hepatitis C from a penile stem cell injection. Although previous cases have reported the reactivation of chronic hepatitis C after hematopoietic stem cell transplantation, it is uncommon for hepatitis C to present acutely, especially in an immunocompetent patient. To our knowledge, this is the first case of acute hepatitis C after a penile stem cell injection.

COVID-19 Vaccine Cardiac Complications: A Case Series on Implications of Marijuana in Adolescents With Myopericarditis.

We report on two critically ill pediatric patients, aged 16 and 18 years, presenting with acute myopericarditis at a tertiary-care center in New Jersey, United States. Both patients had their severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccinations, tested negative for SARS-CoV-2, and shared only significant history of asthma. Clinical presentations were similar to acute onset chest pain that worsened with deep inspiration. One patient reported a history of vaping and escalating marijuana use several hours preceding presentation. Both patients had elevated troponin on admission and had ST-segment elevation on electrocardiogram (EKG), thus prompting admission to the pediatric intensive care unit (PICU) for cardiac monitoring. Myopericarditis has multiple etiologies and is a newly described rare complication of the SARS-CoV-2 vaccine. It can also occur as a complication of vaping and frequent marijuana drug use. Our paper highlights the importance of a detailed social and drug history in adolescents presenting with chest pain. The clinical characterization is necessary to promote better case definitions and the design of targeted interventions for this vulnerable group.

Arterioureteral Fistula in the Setting of Radical Cystoprostatectomy and Ileal Conduit Creation.

Arterioureteral fistulas (AUF) following ileal conduit reconstruction are rare and not well-studied. We present a life-threatening bleed from an AUF due to an ileal conduit urinary diversion. In addition, we identify the challenges in the diagnostic process as well as management strategies. We present a 63-year-old male with ileal conduit reconstruction for bladder cancer with an AUF developing years after the reconstruction, which was ultimately managed with angioplasty.

Mask-Induced Partial Transection of the External Ear Requiring Complex Surgical Reconstruction.

During the COVID-19 pandemic, wearing masks to prevent the spread of infection has been imperative. Though many wear N-95 masks with circumferential head straps, the use of surgical ear loop-style masks has increased. Dermatologic complications, such as contact dermatitis, psoriasis, and local irritation, have been described in several reports. One such complication has been pressure injury to the external ear, secondary to friction from the ear loops. While external ear pressure ulcers caused by mask-wearing have already been observed, injuries extensive enough to require surgical reconstruction have yet to be described. Herein, we present a unique case of an elderly male with a severe external ear deformity caused by prolonged, uninterrupted mask-wearing that was treated with a complex ear reconstruction. The pressure caused a full-thickness erosion of the helical and conchal cartilage with partial auricle amputation from constant mask wear. We describe an unusual and interesting problem caused indirectly by the coronavirus pandemic and discuss potential methods to protect oneself against skin injury from mask usage while simultaneously preventing viral transmission.

Endothelial PlexinD1 signaling instructs spinal cord vascularization and motor neuron development.

How the vascular and neural compartment cooperate to achieve such a complex and highly specialized structure as the central nervous system is still unclear. Here, we reveal a crosstalk between motor neurons (MNs) and endothelial cells (ECs), necessary for the coordinated development of MNs. By analyzing cell-to-cell interaction profiles of the mouse developing spinal cord, we uncovered semaphorin 3C (Sema3C) and PlexinD1 as a communication axis between MNs and ECs. Using cell-specific knockout mice and in vitro assays, we demonstrate that removal of Sema3C in MNs, or its receptor PlexinD1 in ECs, results in premature and aberrant vascularization of MN columns. Those vascular defects impair MN axon exit from the spinal cord. Impaired PlexinD1 signaling in ECs also causes MN maturation defects at later stages. This study highlights the importance of a timely and spatially controlled communication between MNs and ECs for proper spinal cord development.

Role of intravitreal bevacizumab in Eales disease with dense vitreous hemorrhage: a prospective randomized control study.

PURPOSE: To investigate the role of intravitreal bevacizumab in Eales disease with dense vitreous hemorrhage. METHODS: This is a prospective randomized control trial. Twenty eyes of 20 patients with dense vitreous hemorrhage because of Eales disease were randomly distributed in Group 1 (n = 10) and Group 2 (n = 10). Group 1 eyes received intravitreal injection of bevacizumab (1.25 mg/0.05 mL) every 4 weeks, and Group 2 eyes were observed. Patients of both groups were followed-up every 2 weeks. Vitrectomy was performed in case of nonresolving vitreous hemorrhage Grade 2 or more after 3 months of enrollment or immediately if retinal detachment was detected. Intraoperative difficulties while performing surgery and excessive bleeding were noted. The primary outcome measures were reduction in the grade of vitreous hemorrhage and the need for vitrectomy. RESULTS: Only 1 eye from Group 1 and 2 eyes from Group 2 showed decrease in vitreous hemorrhage to Grade 2 (P = 0.531, 95% confidence interval). But all three eyes required vitrectomy because of persisting poor vision. Postoperative mean vision ± SD in Group 1 was 1.2 ± 0.57 in logarithm of the minimum angle of resolution units, and in Group 2, it was 0.78 ± 0.41 in logarithm of the minimum angle of resolution units (P = 0.086, 95% confidence interval). Three eyes (30%) in Group 1 had tractional retinal detachment after a single bevacizumab injection, while none of the Group 2 eyes had tractional retinal detachment (P = 0.060, 95% confidence interval). Vitrectomy was performed in all three eyes and had poor visual outcome after surgery. No intraoperative difficulties were noted in either group. CONCLUSION: Our study showed that repeated intravitreal bevacizumab in patients with Eales disease with dense vitreous hemorrhage may not hasten the resolution of vitreous hemorrhage or reduce the need for vitrectomy. Moreover, tractional retinal detachment may be a serious complication of therapy and hence should be closely monitored because it entails a poor visual prognosis.