Monomorium pharaonis) and honey bees (Apis mellifera), representing two independent origins of eusociality. We identify a substantial shared core of genes upregulated in the abdomens of queen ants and honey bees that also tends to be upregulated in mated female flies, suggesting that these genes are part of a conserved insect reproductive groundplan. Outside of this shared groundplan, few genes are differentially expressed in common. Instead, the majority of the thousands of caste-associated genes are plastically expressed, rapidly evolving, and relatively evolutionarily young. These results emphasize that the recruitment of both highly conserved and lineage-specific genes underlie the convergent evolution of novel traits such as eusociality.Eusociality has convergently evolved multiple times, but the genomic basis of caste-based division of labor and degree to which independent origins of eusociality have utilized common genes remain largely unknown. Here we characterize caste-specific transcriptomic profiles across development and adult body segments from pharaoh ants ( Eusocial caste systems have evolved independently multiple times. Here, Warner et al. investigate the amount of shared vs. lineage-specific genes involved in the evolution of caste in pharaoh ants and honey bees by comparing transcriptomes across tissues, developmental stages, and castes. Comparative genomic studies indicate that parallel adaptive changes in the protein-coding sequences of the same genes are frequently associated with the evolution of convergent phenotypes in closely related populations and species3. Decades of research in evolutionary developmental biology also emphasize that changes in the expression of a relatively small toolkit of deeply conserved genes are often associated with convergently evolved phenotypes in distantly related species4. Alternatively, convergent phenotypic evolution between lineages could involve distinct subsets of genes in each lineage, including taxonomically restricted genes, genes which have no detectable orthology outside of a given lineage5. Taxonomically restricted genes have been shown to be important for lineage-specific evolutionary novelties6, but their relative contribution to the evolution of convergent phenotypes is unknown.The degree to which convergent phenotypic evolution involves the same sets of genes or pathways is a major unanswered question7. Eusocial insect societies are founded upon a novel caste polyphenism, in which reproductive queen and non-reproductive worker female castes develop from the same genome, depending mainly on socially regulated nutritional inputs9. Within the worker caste, further specialization often occurs as individuals age and progress through a series of tasks, including nursing and foraging7.The evolution of eusociality in several insect lineages  provides a striking example of convergent phenotypic innovation10. Leading hypotheses for the evolution of caste-based division of labor in social insects also stress the use and modification of highly conserved developmental and physiological mechanisms15. For example, the reproductive and non-reproductive phases of ancestral solitary insects are thought to have been decoupled to produce reproductive and non-reproductive castes16, and worker division of labor is similarly thought to be derived from the decoupling of the ancestral reproductive cycle17. Along the same lines, it has been suggested that the convergent evolution of novel social behavior involves changes to the regulation of a core toolkit of genes underlying highly conserved physiological processes, such as metabolism15.Polyphenic traits are often thought to evolve from pre-existing developmental plasticity18. Similar pathways also play key roles in regulating division of labor between queen and worker castes in both ants and honey bees, though the mechanistic details vary22. While comparative genomic and transcriptomic studies have often similarly emphasized common general functions, such as metabolism, such studies have thus far only identified very small sets of specific genes associated with the convergent evolution of caste, worker behavior, or eusociality in independent lineages27. Alternatively, many transcriptomic studies have argued for the importance of taxonomically restricted genes for the evolution of caste-based division of labor34. It is unclear if the lack of common specific genes is due to biological differences between the species or methodological details, because studies in each species were not designed, conducted, or analyzed in parallel.Studies focused on candidate genes underlying the genetic basis of caste-based division of labor within individual eusocial species have often found support for the importance of highly conserved genes and pathways associated with reproduction and metabolism. For example, worker division of labor in honey bees is regulated by interactions between juvenile hormone, vitellogenin, and insulin/TOR signaling pathways27, but there has been little effort to quantify the relative importance of shared versus unshared genes to the convergent evolution of caste-based division of labor. Most of these studies have either focused on the brain or whole-body samples37, although expression bias between queens and workers has been shown to be dependent upon developmental stage and tissue type40. Finally, the transcriptomic signatures of reproductive physiology are strongest in the abdomen41, the location of reproductive organs, but no past study has explicitly compared caste bias in abdominal tissues in species from lineages representing independent origins of eusociality.Previous work has mainly focused on identifying whether there is significant overlap of genes or gene pathways associated with caste-based division of labor between independent lineagesMonomorium pharaonis) and the honey bee (Apis mellifera). We focus on these two study species because they represent two independent origins of eusociality in the ant and corbiculate bee lineages42 as well as two independent elaborations of eusociality, each characterized by strong queen-worker dimorphism and age-based worker division of labor43. We perform all sampling, sequencing, and analysis for the two species in parallel to maximize compatibility between the data sets. We leverage this extensive data set to quantify in an unbiased manner the relative contribution of differential expression of shared versus distinct genes at each life stage and tissue to the convergent evolution of caste-based division of labor. We identify a large group of genes which are associated with queen abdomens in both eusocial species and tend to be female biased in Drosophila melanogaster. Outside of this shared core, few genes are differentially expressed in both species in the same tissue or developmental stage, and genes with high degrees of caste-biased expression tend to be weakly constrained in terms of expression profile and sequence evolution.Here, we present a comprehensive developmental transcriptomic data set investigating gene expression associated with reproductive caste and age-based worker division of labor in the pharaoh ant , behavior (nurse workers versus forager workers), and sex . In total, we constructed 177 mRNA-sequencing libraries across 28 distinct sample types for each species (Supplementary Table 2 fold change between queen and worker samples) was weakly positively correlated between ant and honey bee orthologs in all three adult tissues, with the strongest correlation in the abdomen, but uncorrelated or negatively correlated in all larval and pupal stages . The top enriched Gene Ontology (GO) terms for caste-associated DEGs in each species were dominated by metabolism, signaling, and developmental processes  between queens and workers increased throughout development, peaking in the adult abdomen Fig. . In all 43 and pharaoh ants33 exhibit age-based worker division of labor, in which younger individuals tend to specialize on nursing and other within-nest activities and older individuals specialize on foraging. To identify genes associated with age-based worker division of labor, we performed differential expression analysis between nurses and foragers in each adult tissue, separately for each species. In general, there were very few behavioral DEGs shared between the two species . The top enriched GO terms for behavioral DEGs in each species were dominated by metabolism and developmental processes . Furthermore, abdominal DEGs with shared queen bias were more likely to be identified as ancient than DEGs with shared worker bias . In general, the evolutionary age of genes was associated with expression bias between castes, though the direction of the effect was not consistent across all tissues and stages  and 41% (2544/6255) of the total developmental DEGs in each species  into context. We compared the proportion of genes that were differentially expressed across embryonic and larval development in both species, given that the molecular mechanisms of development are thought to be highly conservedN = 1006 genes in the module for ants, N = 1174 genes for honey bees). We identified hub genes in each module , genes which are centrally connected in networks and strongly associated with queen abdominal expression45. Many annotated hub genes are inferred to have functions associated with reproduction and maternal effects (Supplementary Tables Vg receptor was identified in each species)20 and vasa46, while others are important maternal proteins, such as Smaug47 and ovo48. Furthermore, genes for which Drosophila melanogaster orthologs are known to function in oogenesis (based on FlyBase Gene Ontology49) were more highly connected within the queen abdominal modules than genes not associated with oogenesis , though not for ants . Finally, we identified 181 genes which were present in the queen abdominal module of both species. These genes tended to be queen biased (78.5% [142/181] upregulated in queens of both species) and were more centrally located within modules than genes found in only one species-specific module , we performed gene co-expression analysis, separately for each species. We focused on modules specifically associated with queens because the majority of shared DEGs were queen upregulated. We identified a module of genes, specifically associated with queen abdominal expression in each species . Indeed, there was a positive correlation between gene-wise lognts Fig.  a, b. Innts Fig. . The cornts Fig. .Fig. 3CaD. melanogaster using available data from male and mated female whole bodies44. Shared queen-biased abdominal DEGs tended to be upregulated in females in D. melanogaster , while shared worker-biased abdominal DEGs tended to be upregulated in males , indicative of shared queen  and female (fly) downregulation. Though we detected few shared caste-associated DEGs in the head and thorax , these DEGs showed the same pattern, where orthologs of queen-biased DEGs were significantly more female biased in D. melanogaster than orthologs of worker-biased DEGs , and overall behavior bias was similarly correlated between species . Within species, overall caste and behavior bias were also correlated to each other . This indicates that plasticity in gene expression is correlated across contexts (caste versus behavior) and species. GO terms associated with high overall caste bias were largely linked to metabolism, while those associated with high overall behavior bias were largely linked to developmental processes . Genes that were loosely connected  in co-expression networks constructed across all samples tended to exhibit more caste and behavior bias in comparison with highly connected genes  tended to exhibit higher levels of caste and behavior bias  or behavior (nursing versus foraging). Genes with younger estimated evolutionary ages tended to exhibit higher overall caste bias Fig.  and behanes Fig. . Similarnes Fig. , where tias Fig. . Importa17. In this study, we identified a large set (~1500) of genes with shared caste-biased abdominal expression in pharaoh ants and honey bees  change over the course of the worker’s adult lifetiments Fig. , and the37. This lineage-specific architecture comprises large groups of both orthologous genes with different expression patterns and taxonomically restricted genes  we found. It is likely that a relatively small number of core conserved genes exist as upstream hubs in regulatory networks, and layered downstream of this core is a myriad of taxonomically restricted genes as well as conserved genes with lineage-specific expression patterns60. This is consistent with models for the evolution of hierarchical developmental gene-regulatory networks, whereby a relatively small number of highly conserved genes act upstream to initiate gene cascades , while batteries of downstream genes are evolutionarily labile and largely responsible for lineage-specific features61. Recent studies have made progress elucidating the function of several core genes and pathways for caste62. Large-scale transcriptomic studies such as ours serve a complimentary, indispensable role of identifying the full suite of genes underlying caste-based division of labor in multiple independent lineages.Our study shows that the recruitment of a large core of conserved reproductive-associated genes, which can be described as a reproductive groundplan, is fundamental to the convergent evolution of caste-based division of labor in ants and honey bees. However, our study also reveals that the bulk of the full genetic architecture underlying the expression of social insect caste-based division of labor varies between lineages. This is reflected by the general biology of social insects, in that independently evolved societies share reproductive division of labor, the main defining feature of eusociality, but also display a wide diversity of lineage-specific adaptationsMonomorium pharaonis and the honey bee Apis mellifera, including seven developmental stages  plus each of three adult body segments  in both species  from the same colony, such that each biological replicate corresponds to a colony. The only exception to this was mature honey bee queens, which were sampled from separate unrelated colonies. In collecting these samples, we complied with all relevant ethical regulations for animal testing and research.We collected parallel time series RNA-seq data of caste development in the pharaoh ant M. pharaonis across development, we created 27 replicate colonies of ~400 workers and ~400 total larvae from a large mixed genetic source. We removed queens from each colony, which stimulates the production of new queens and males from existing eggs and L1 larvae in M. pharaonis64. We pre-assigned each colony to one of nine sample types, ordered by developmental timing . We allowed the 27 colonies to grow for 4 weeks, and collected samples progressively when the youngest individuals left in the colonies represented the assigned developmental stage .To collect samples of 66. To synchronize pupal developmental collection, we exclusively sampled pupae whose eyes had darkened. We sampled males as soon as they had eclosed as adults from the pupal stage. While M. pharaonis does exhibit age polyethism with respect to nursing and foraging67, the precise dynamics with regard to age are not well studied in comparison with honey bees. Therefore, we distinguished between nurses and foragers based on behavioral observation. Specifically, we observed nurses feeding larvae and we observed foragers collecting food. We sampled egg-laying mature queens (3–4 months old) from the group of queens we initially removed to stimulate reproduction to ensure that queens and workers came from the same genetic background.We identified larval stage and caste as previously described, by hair and morphologyA. mellifera across development, we established experimental colonies, in which queens were allowed to lay directly onto empty comb for 24 h to ensure control of larval age and that larvae of a given replicate were from the same queen. We collected eggs after this period directly from the comb. After 3 days, we grafted a subset of hatched larvae into artificial queen cells in queenless portions of the hive. Starting at that day, we sampled the five stages of larvae (L1–L5) on each consecutive day. We sampled pupae once their eyes had darkened to synchronize developmental timing. We sampled males by placing hair-roller cages on top of cells during pupation and waiting for individuals to emerge from pupation. We sampled egg-laying mature queens from separate, unrelated colonies and pooled them into replicate samples. We paint-marked worker individuals upon emergence from the pupal stage and sampled nurses that were less than 7 days old and foragers that were greater than 21 days old.To collect samples of 68, with the only alteration being that the input RNA was 50 ng and the cycle number of cDNA amplification was increased to 16. To compare sample quality across the experiment and test our ability to detect lowly expressed genes, we added ERCC92 (Thermo Fisher Scientific Inc.) spike-in mixes to the total RNA prior to amplification. We pooled libraries with an equal amount of cDNA and sequenced single-end for 50 cycles in Illumina Hiseq 2500. We aligned reads to reference genomes using Bowtie269. All reads were aligned to NCBI gene models . We estimated read count and transcripts per million (TPM) using RSEM70.We isolated RNA using Trizol reagents. We performed cDNA synthesis and library preparation using a previously described protocol71. Similarly, to identify behavioral DEGs, we performed differential expression analyses between nurses and foragers for each tissue. To identify developmental DEGs in each species, we constructed models with all larval and egg samples and identified genes differentially expressed between any developmental stage, controlling for overall caste differences. To estimate gene-wise sex bias of D. melanogaster orthologs, we downloaded available whole-body RNA-seq data44, consisting of one 5-day-old and one 30-day-old fly of each sex, and performed differential expression analysis as above.To identify caste-associated differentially expressed genes (DEGs), we performed differential expression analysis between queens and workers at each developmental stage and tissue, separately for each species. We removed lowly expressed genes that did not meet one of two criteria: (1) counts per million (CPM) greater than one in at least half the samples, or (2) CPM > 1 in all samples of a given tissue/stage/caste combination (to ensure tissue-specific genes were retained). We removed 2350 lowly expressed genes in ants, leaving 10,804 genes for further analysis, and we removed 2036 genes in bees, leaving 11,775 genes for further analysis. We constructed GLM-like models, including replicate and caste, and identified genes associated with caste at each stage or tissue using EdgeRA. mellifera and M. pharaonis, we started with a curated orthology map of aculeata species from OrthoDB972. We downloaded amino acid sequences for each species from RefSeq73. We associated transcripts with OrthoDB9 protein names using BLASTp  and identified the aculeata ortholog group matched by each gene based on the identified BLASTp hits. In this way, we identified 1:1, one-to-many, and many-to-many orthologous groups between A. mellifera and M. pharaonis. For direct comparison of the species, we restricted our analysis to 1:1 orthologs . We identified three-way 1:1:1 orthologs between A. mellifera, M. pharaonis, and Drosophila melanogaster using a similar procedure based on endopterygota orthology groups from OrthoDB9.To identify orthologs between 74. Given that our data contained a large number of sample types, we reasoned that we could employ biclustering to identify groups of genes particularly associated with a given sample type. While our level of biological replication (N = 3 for each tissue/caste/stage combination) is low, including all samples in our biclustering analysis allows high resolution of gene–gene co-expression relationships, and biclustering allows for specificity of gene–sample relationships. We performed plaid clustering, one of the top performing biclustering algorithms in a recent survey75, using the R package biclust76. Plaid clustering models expression level for each gene as a function of bicluster weights, where only biclusters containing the gene contribute to predicted expression level77. The algorithm iteratively constructs layers containing samples and genes and retains layers that improve the model fit, where layers represent biclusters.In contrast to many network methods which assess gene–gene relationships across all samples, biclustering seeks to identify a group of genes which are coexpressed  across a subset of sample types78. While a large number of interesting bicluster definitions are possible, we decided to identify biclusters that consistently contained all queen-abdomen samples to focus our investigation on the tissue that exhibited the strongest signature of caste bias. Specifically, we extracted biclusters containing all three mature queen-abdomen samples and no more than three other samples total. Honey bee queen-abdomen samples clustered with egg samples, while pharaoh ant queen samples did not cluster with egg samples. It is possible that this difference is a result of a difference of age of the eggs at time of collection: honey bee eggs were 24 h old and likely still contained maternal RNA, while pharaoh ant eggs were 7 days old.Plaid clustering is non-deterministic, and individual biclusters are not found in every iteration of clustering. To define a reasonable ensemble of biclusters, we performed clustering 1000 times separately for each species, using inverse hyperbolic sine transformed TPM (transcripts per million)N = 1006 genes; Supplementary Fig. N = 1174 genes).Because the same genes were not always present in such a bicluster, we tabulated the number of queen-abdomen biclusters each gene was found in and retained genes present in a higher proportion of biclusters than a given cutoff, determined by inspection of frequency distributions of bicluster presence. In pharaoh ants, we found a large set of genes present in greater than 90% of queen-abdomen biclusters, and we retained these genes for further analysis .We proceeded with our analysis using these identified sets of genes, which we term modules associated with queen abdominal expression. We calculated connectivity in the module  as the sum of pairwise Pearson correlations, where correlation values are raised to the sixth power, the standard value for unsigned weighted gene co-expression networks81. For example, genes found in ants and honey bees but not in non-aculeate hymenopterans would be labeled “aculeata” genes, while genes shared between vertebrates and insects would be labeled “bilateria”. For our purposes, we decided to focus on the difference between “ancient” genes, which we defined as displaying orthology with non-insect animals, and a number of hierarchical younger categories: insect, hymenopteran, aculeate, ant, bee, and novel .We estimated the evolutionary age of each gene using phylostratigraphy. Phylostratigraphy groups genes into hierarchical age categories based on identifiable orthology (using BLASTp)81. Because we largely planned to focus on younger age categories, we constructed a protein database containing all annotated hymenopteran genomes . We added to this group ten non-hymenopteran insect genomes and ten non-arthropod genomes 81 and accurately place them along the hymenopteran phylogeny.A key component of phylostratigraphy is the creation of a BLAST database in which to identify orthologsA. mellifera worker nurses and foragers32. To classify genes by their tissue specificity, we calculated τ, a commonly used metric of expression specificity82. τ ranges from 0 to 1, where 0 indicates that genes are ubiquitously expressed and 1 indicates that genes are exclusively expressed in one tissue.We downloaded available RNA-sequencing data on 12 tissues in A. mellifera:A. cerana; M. pharaonis:S. invicta). For each 1:1 ortholog pair, we selected the longest transcript associated with the gene for each pair of species. We aligned orthologous protein sequences using ClustalW83, derived nucleotide alignments from protein alignments using pal2nal84, and estimated pairwise dN/dS of nucleotide alignments using PAML, package codeml85.We estimated evolutionary rate using dN/dS, the ratio of non-synonymous to synonymous nucleotide changes. We estimated pairwise dN/dS between each focal species and a second closely related species with an available genome  terms to A. mellifera and M. pharaonis orthologs. We identified GO terms associated with caste- or behavior biased differentially expressed genes using the P-value of differential expression between queens and workers or nurses and foragers. We identified GO terms associated with overall caste or behavior bias using the Euclidean distance of log2 fold change between queens and workers or nurses and foragers at each stage. We identified enriched terms with P-value < 0.05.We performed Gene Set Enrichment Analysis (GSEA) using the R package topGOFurther information on research design is available in the Supplementary InformationPeer Review FileReporting SummarySource Data


Isolated posterior inferior cerebellar artery dissections can cause subarachnoid hemorrhages or infarctions. Surgical and endovascular treatments for hemorrhagic stroke cases and medical treatments using antithrombotic agents for ischemic stroke cases have been performed, but there are very few reports on nonstroke isolated posterior inferior cerebellar artery dissections, and the treatment strategy for nonstroke cases has not been established.A 48-year-old healthy male felt a severe, throbbing headache on the right side and came to our clinic on the fourth day following onset. MRI examinations revealed a right posterior inferior cerebellar artery dissection and showed no infarctions or hemorrhages. He was observed carefully with continuous monitoring of blood pressure, hydrated sufficiently, and given analgesic anti-inflammatory agents. Two weeks later, the dissected vessel’s diameter grew to the maximum size, though the patient’s headache rapidly improved around that day. Surgical or endovascular treatments for prevention of subarachnoid hemorrhage were recommended, but careful conservative therapy was continued in accordance with the patient’s wishes. Gradually, the dissection finding improved. Four months later, MRI examinations showed his right posterior inferior cerebellar artery was almost normal in size and shape.This is the first detailed report on a nonstroke isolated posterior inferior cerebellar artery dissection that spontaneously occurred and healed, observed by serial high-resolution MRI examinations.The online version of this article (10.1186/s12883-019-1352-0) contains supplementary material, which is available to authorized users. Isolated posterior inferior cerebellar artery dissections (iPICADs) can cause subarachnoid hemorrhages or infarctions . The incA 48-year-old male, who had no past medical or traumatic history and no family history of cerebral artery dissections, suddenly felt a severe, throbbing headache on the right side and came to our clinic on the fourth day following onset. MRI examinations showed a tiny dissection-like finding (pearl and string sign-like) on his right proximal segment (tonsillomedullar segment) of posterior inferior cerebellar artery (PICA) Fig. a. No intMRI examinations showed no apparent intramural hematoma, double lumen, or intimal flap indicating artery dissection. PICA is a tiny vessel and it is possible that these findings could not be detected even by high-resolution MRI techniques. Recently, the chronological changes in the size and shape of the affected vessels have been considered to be one of the criteria for diagnosing cervicocephalic artery dissections, including intracranial small vessels such as PICA. Table Conventional angiography may have provided useful information to confirm the patient’s PICA condition; however, for this patient, serial high-resolution MRI examinations, including HRVWI, were sufficient to confirm the condition of the vessel. T1-weighted HRVWI was used to confirm the intraluminal size change. The outer diameter was followed by basi-parallel anatomical scanning (BPAS), one type of T2-weighted HRVWI .Among cervicocephalic artery dissections, vertebral artery dissections (VADs) are common, and the therapeutic strategy for VAD has been established . The repIt is interesting that the severity of the patient’s headache might be related to the chronological changes of the MRI findings. The patient felt a severe, throbbing headache continuously while MRI findings of PICAD were worsening. After the occipital pain was relieved, his PICAD finding stopped worsening and gradually improved on MRI examinations.Conservative therapy is usually selected for nonstroke VAD, whereas the therapeutic strategy for nonstroke iPICAD is not yet determined. The other case of the reported two iPICAD without stroke was surgically treated to prevent subarachnoid hemorrhage because the dissection finding by radiological examination was progressive . It mighThis is the first detailed report on a nonstroke iPICAD that spontaneously occurred and healed, observed by MRI examinations. In this case, serial high-resolution MRI examinations clearly showed the spontaneous healing course of iPICAD without stroke.Additional file 1:Figure S4. The inner diameters and areas of the dissected PICA were measured using cross-sectional view of T1-weighted HRVWI. (TIF 744 kb)Additional file 2:Figure S5. The outer diameters of the dissected PICA were measured using original data of T2-weighted HRVWI (BPAS). The measured values are shown in Fig.


Primary malignant tumors of the spine are rare and mainly include chordoma, chondrosarcoma, Ewing sarcoma or primitive neuroectodermal tumor, and osteosarcoma. The final diagnosis is based on the combination of patient age, topographic and histologic features of the tumor, and lesion pattern on computed tomography (CT) and magnetic resonance (MR) imaging. Imaging evaluation includes radiography, CT, bone scintigraphy, and MR imaging. CT is more useful than radiography for evaluating location of the lesion and analyzing bone destruction and matrix, whereas MR has unmatched ability to assess soft tissue extension. This pictorial review provides an overview of the most prevalent primitive malignant tumors of spine. Primary malignant tumors of the spine are rare and mainly include chordoma, chondrosarcoma, Ewing sarcoma or primitive neuroectodermal tumor (PNET), and osteosarcoma . In patiOsteosarcoma is a primitive malignant bone tumor characterized by the production of osteoid or immature bone from neoplastic cells . Spinal 5MR of spinal osteosarcoma is usually nonspecific. Mineralized component of the tumor shows low signal on T1-weighted images (WI) and T2-WI, whereas the nonmineralized component displays a high signal on T2-WI. Fluid-fluid levels have been described in association with telangiectatic osteosarcoma . ExpansiLocal recurrence is estimated at 20% after en bloc excision and 60% after locoregional excision 8.Chondrosarcomas represent a heterogenous group of tumors characterized by their capacity of cartilage formation . ChondroMost lesions represent primary chondrosarcoma; however, secondary chondrosarcoma may also occur when osteochondroma (solitary or multiple with hereditary multiple exostoses) undergoes malignant transformation . RadiogrOn MR the tumor is of low signal on T1-WI Figure  and heteChordoma is a rare malignant neoplasm arising from the embryonic remnants of the primitive notochord and accounts for 2–4% of all primary malignant bone neoplasm, with an estimated prevalence of 0.51 per million. Chordomas generally occur in middle-aged patients, with a peak prevalence in the 5th–6th decades. Spinal chordomas have a 2:1 male–female ratio .Eighty-five per cent of chordomas occur in spheno-occipital skull base (35%), sacro-coccygeal area (50%) , and theRadiographs and CT scan usually show a lytic lesion of a vertebral body associated with a soft-tissue mass with a “mushroom” appearance, spanning several segments and sparing the disks. Areas of amorphous calcifications are noted in 40% of chordomas of the mobile spine and in up to 90% of sacrococcygeal lesions . Bone seChordomas show signal characteristics parallel to nucleus pulposus of the disk (notochord) on MR being low to intermediate signal on T1-WI Figure  and veryChordoma should be differentiated from giant embryonic remnants of the notochord . Unlike in chordoma, radiographs and CT fail to demonstrate a distinct lesion in giant notochordal rest, instead showing either normal bone or a variable degree of sclerosis . Bone scChordoma is a low-grade and slowly growing tumor but generally has a poor long-term prognosis. Metasases are rare, estimated between 4 to 43% of patients , but locEwing sarcoma and PNET are defined as round cell sarcomas that show varying degrees of neuroectodermal differentiation . Ewing sPain is the most common symptom of patients suffering from spinal Ewing’s sarcoma . NeuroloThe prognosis in Ewing sarcoma/PNET has improved in the modern era of treatment and current survival rate is estimated to be 41% . The besLymphoma is categorized as primary osseous lymphoma if bone is the only known site of disease for six months . It is aHistologically, most bony lymphomas show a mixed cell infiltrate in which the cellular size and shape differ considerably. The very characteristic infiltrative pattern should suggest the diagnosis of lymphoma. The medullary bony trabeculae may show reactive sclerosis .Radiologically, the lesions are lytic Figure , mixed, The treatment options of the primary bone lymphomas are surgical, chemotherapy, and radiotherapy . IsolatePlasmocytoma Figure  is a cliThe most common symptom is local pain in the region of the affected spine, radicular pain or neurological deficit.The spine is involved in 25–50% of the cases. Thoracic vertebrae are most commonly involved . The malThe treatment of choice is chemotherapy and/or radiation therapy at 40 Gy to 50 Gy . SolitarIn 2014, the International Myeloma Working Group (IMWG) revised diagnostic criteria for multiple myeloma (MM), allowing the use of specific biomarkers and modern imaging tools to define the disease in addition to the established CRAB features . MultiplSkeletal involvement occurs in 80–90% of patients with MM . VertebrTen to 20% of patients with multiple myeloma are normal on radiography 43. PathoAlthough new or enlarging lesions generally mean disease progression, lytic bone lesions rarely show evidence of healing on plain radiographs, and routine follow-up skeletal survey is of no benefit .Whole-body multidetector computerized tomography (WB-MDCT) is a preferable imaging tool over whole-body X-ray (WBXR) surveys for assessment of fracture risk and characterization of compression fractures . LimitatMR in patients with clinical and laboratory findings of symptomatic myeloma provides prognostic information and may detect unsuspected myeloma lesions . Five diAbnormal signal can also be observed after chemotherapy and the use of growth factors or in young individuals with hyperplasia of normal haematopoiesis. Thus, the clinical context should be taken into account when evaluating MR, and MR should not be performed close to chemotherapy. Diffuse marrow infiltration has a decreased signal on T1-WI and an increased signal on STIR. The overall performance of MR is enhanced by applying dynamic contrast-enhanced MR and diffusion-weighted imaging sequences, providing additional functional information on bone marrow vascularization and cellularity .Posttreatment MRI typically demonstrates a gradual replacement of marrow infiltration or focal lesions by marrow fat, but this may be delayed up to four or five years in some focal lesions .FDG PET/CT is particularly sensitive for the detection of extramedullary disease and can help detect the metabolically active lesions that often precede evidence of osseous destruction at conventional radiography . Both MR


Remarkable responses have been documented using CAR T cells against several malignancies, including leukemias and lymphomas. Based on these successes, the extension of CAR T cell therapy for pancreatic cancer holds great promise. However, there are a number of challenges that limit the full potential of CAR T cell therapies for pancreatic cancer, including the highly immunosuppressive tumor microenvironment (TME). In this article, we will review the recent progress in using CAR T cells in pancreatic cancer preclinical and clinical settings, discuss hurdles for utilizing the full potential of CAR T cell therapy and propose research strategies and future perspectives. Research into the use of CAR T cell therapy in pancreatic cancer setting is rapidly gaining momentum and understanding strategies to overcome the current challenges in the pancreatic cancer setting will allow the development of effective CAR T cell therapies, either alone or in combination with other treatments to benefit pancreatic cancer patients.Conventional treatments for pancreatic cancer are largely ineffective, and the prognosis for the vast majority of patients is poor. Clearly, new treatment options are desperately needed. Immunotherapy offers hope for the development of treatments for pancreatic cancer. A central requirement for the efficacy of this approach is the existence of cancer antigen-specific T cells, but these are often not present or difficult to isolate for most pancreatic tumors. Nevertheless, specific T cells can be generated using genetic modification to express chimeric antigen receptors (CAR), which can enable T cell responses against pancreatic tumor cells. CAR T cells can be produced  Pancreatic cancer presents a major challenge in the clinic and is one of the most aggressive tumor types. Pancreatic cancer is the fourth most common cause of cancer death , 2 and iThe most common clinical therapeutic approaches against pancreatic cancer include surgical resection, radiotherapy, chemotherapy, and combination of these treatments . SurgicaCurrently, immunotherapy has been offered as an important cancer treatment for a number of cancer types , 15 and Adoptive cellular therapies involving an infusion of effector immune cells into patients have generated remarkable responses in some cancers  and chimex vivo to express a CAR specific for a tumor antigen of choice and adoptively transferred into the patient to treat established cancers  is a glycoprotein present mainly in mesothelial cells and overexpressed in a variety of human cancers including malignant pleural mesothelioma, ovarian, lung and pancreatic cancers . MSLN haPreclinical studies have demonstrated that CAR T cells against MSLNs could potentially be effective against PDAC. When MSLN-CAR T cells were adoptively transferred intratumorally or intravenously (i.v.) into NSG mice bearing pre-established subcutaneous patient-derived mesothelioma, the tumor burden was greatly reduced in size and some tumors were completely eradicated, demonstrating the potential of targeting this antigen . Due to Prostate stem cell antigen (PSCA) is a glycosylphosphatidylinositol-anchored cell surface protein involved in intracellular signaling, although much of its function remains unclear. PSCA is expressed in the epithelial cells including that of prostate, kidney, skin, stomach, urinary bladder, esophagus and placenta, and also expressed in differentiating cells such as the ones of prostate and gastric epithelial cells. PSCA has also been detected in several cancer types including prostate, urinary bladder and pancreatic cancers . Aberran+ pancreatic cancer cell lines without lysing PSCA− target cell in vitro  is a cell surface glycoprotein belonging to the immunoglobulin (Ig) superfamily and plays a role in cell adhesion. CEA is one of the “oncofetal” antigens, typically produced in the gastrointestinal tissue during fetal development , 44. Altin vitro and demonstrated anti-tumor effect in vivo in a clinically relevant orthotopic CEA+ murine model. The recipient CEA transgenic mice express CEA in their intestinal and pulmonary tracts. Ten days post intrapancreatic injections of Panc02-CEA+ cells, the recipient mice received CEA-CAR T cells. Interestingly, the injection of the CAR T cells eradicated tumors without any damage to normal tissues that are CEAlow  is overexpressed in multiple epithelial adenocarcinomas, such as that of breast, colon, and pancreatic cancers. Importantly, under normal conditions, MUC1 is heavily glycosylated and expressed on the apical surface of epithelial cells, but in tumor cells MUC1 is aberrantly glycosylated. This modification of the MUC1 antigen reveals epitopes associated with the core protein, which is usually masked by oligosaccharides. Overexpression of aberrantly glycosylated MUC1 is associated with multiple metastatic cancers. In particular, MUC1 is aberrantly expressed in 60% of pancreatic cancers and is correlated with poor prognosis, enhanced metastasis, and chemoresistance  has been identified as the receptor to CD47. The binding of tumor-expressing CD47 to SIRPα on immune cells leads to the activation of the downstream signaling pathway in immune cells and inhibits the immune phagocyte-dependent clearance of tumors. CD47 has been identified in several types of hematological and solid cancers including pancreatic cancer , 53. In + cancer cells in vitro and it will be interesting to assess their efficacy in clinical trials  is a transmembrane glycoprotein belonging to the epidermal growth factor receptor (EGFR) family. The binding of HER2 to its ligand induces heterodimerization of the receptors, which mediates the activation of intracellular tyrosine kinase signaling cascades and leads to cell proliferation and differentiation. Overexpression of HER2 induces dimerization of HER2 and initiates signal transduction without ligand binding. Overexpression of HER2 has been reported in multiple cancer types making it an attractive target for CAR T cell treatment . Howeverd safety .HER2 expression is observed in 20–60% of pancreatic cancer cases and therefore, it is a potential target for CAR T cell treatment –61. ReceOther putative growth factor receptors that could be targeted against pancreatic cancer using CARs include insulin-like growth factor receptor-1 (IGF1R), EGFR, vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR) and platelet-derived growth factors (PDGFRs) that are expressed at elevated levels in pancreatic cancers and contribute the cancer's malignant phenotype . IGF1R iCD24 is a mucin-like protein. It was originally discovered as the ligand for P-selectin and involved in signal transduction mediated by the members of the protein tyrosine kinase family. CD24 expression is observed in over 70% of PDAC tumors and in putative PDAC cancer stem cells (CSC). CSC can also express CD44 and epithelial specific antigen (ESA) or CD133. Given the prevalence of early-disseminated metastases, CSCs are believed to play a key role in the pancreatic cancer development and progression. Among these PDAC CSC protein markers, CD24 has the lowest expression in normal tissue and thus is proposed as a suitable target antigen for immunotherapy . A studyFibroblast activation protein (FAP) is a type II integral membrane serine protease. Healthy adult tissues have no detectable FAP expression. However, under certain biological circumstances, such as remodeling, wound healing, and embryogenesis, FAP expression has been observed. FAP is also present in a large proportion of tumor stromal fibroblasts in the majority of epithelial carcinomas including pancreatic cancers  and its in vitro activity observed, the injection of the FAP-CAR T cells only elicited limited in vivo anti-tumor effect. Unexpected side effects such as cachexia and lethal bone toxicities were observed. The off-target effect was due to the expression of FAP on murine bone marrow stromal cells (BMSCs). In this study, human BMSCs were also identified in expressing FAP and could be recognized by FAP-CAR T cells  expressed on pancreatic cancer cells have been targeted in various clinical trials to redirect CAR T cells against pancreatic cancer including MSLN, CEA, PSCA, MUC1, and HER2 .7 to 3 × 108 per m2. Higher doses of RNA transfected T cells are used, since they present less of a risk due to their limited duration of CAR expression. The majority of studies involve a single dose of CAR T cells; some trials use multiple doses  is used. Rimiducid is administered with PSCA-specific CAR T cells that contain an inducible MyD88/CD40 (iMC) costimulatory domain. In another trial (NCT02416466), radiation is delivered using Yttrium-90 microspheres to maximize the tumoricidal effects of CAR T cells and minimize the effects on healthy liver parenchyma in patients with liver metastases.The majority of clinical trials of CAR T cells in pancreatic cancer are in early stages of recruitment, but some have been completed and initial reports are available. CAR T cells are generally well-tolerated in pancreatic cancer patients, although some toxicity was reported when targeting CEA . DespiteA major obstacle for immunotherapies, in particular CAR T cell therapies, in solid tumors is the immunosuppressive tumor microenvironment (TME) . The TMEA unique feature of the pancreatic TME is the desmoplastic stromal reaction, which promotes tumor growth and provides a physical barrier for therapeutic drugs and T cell infiltration. In fact, PDAC is one of the most stroma-rich cancers and in some cases, the stromal components precede pancreatic cancer cells. In normal pancreas, the pancreatic stellate cells (PSCs) are a rare population and function to store retinoids in a form of lipid droplets in the cytosol. During pancreatic cancer progression, the pancreatic stellate cells (PSCs) become activated by tumor-secreted cytokines, lose retinoid droplets and transform into a myofibroblast phenotype. The activated PSCs secrete extracellular matrix (ECM) proteins and deposit collagens to form a dense fibrotic cancer stroma . In addiin vitro (Approaches that enable CAR T cells to sustain and function in the TMEs have been investigated in a large number of preclinical and clinical studies in a range of malignancies, and the results have revealed various potential strategies against pancreatic cancers. For example, depleting immunosuppressive cell subsets such as Tregs, MDSCs and TAMs has demonstrated enhanced efficacy of CAR T cell therapies . These sin vitro . In our in vitro . In humain vitro , 99.Another strategy for enhancing CAR T cell efficacy in solid tumors is blocking the inhibitory signals received by the T cells from immunosuppressive populations in the TME. Checkpoint inhibitors, against molecules such as PD-1, CTLA4, TIM-3, and LAG-3 have shown promise as single agents in a number of cancer types  but unfoIn addition, a number of strategies have been tested to enhance CAR cells to sustain in a suppressive cytokine milieu. Methods such as introducing the CD137 signaling domain within the CAR intracellular domain to increase mitochondrial biogenesis , expressGiven the limited options for efficacious pancreatic cancer treatment and the success of CAR T cells in hematological malignancies, in which TME differs in its degree of immunosuppression, overcoming this obstacle in pancreatic cancer will be an important consideration for future research.Pancreatic cancer is the most lethal cancer and new therapies are urgently needed. CAR T cell therapy represents a revolutionary treatment for cancers and has generated remarkable responses in hematological malignancies. The extension of CAR T cell therapy into pancreatic cancer recently started and this field is moving forward rapidly. Due to its unique immunosuppressive TME and antigen complexity and heterogeneity , pancreaAA, MK, and CS: conception and design; AA, AO, TS, JC, MK, and CS: write, review, and revision of the manuscript; MK and CS: supervision.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.


Salvia miltiorrhiza. Salvianolic acid A & B have been reported to owe anti-cancer, anti-inflammatory and cardioprotective activities. Currently salvianolic acids have been emerged as potent anti-cancer molecules. Salvianolic acid A & B fight cancer progression by prompting apoptosis, halting cell cycle and adjourning metastasis by targeting multiple deregulated signaling networks of cancer. Moreover, salvianolic acid A & B display potency towards sensitizing cancer cells to chemo-drugs. The review purposes that salvianolic acid A & B supply a novel opportunity for drug discovery but further experimentation is mandatory to embellish the knowledge of their pharmacological usage and to access their toxicological limits in order to establish these compounds as potential multitarget future drugs.Nature has generously offered life-saving therapies to mankind by providing evolutionarily optimized drug-like entities in the form of natural products. These splendid gifts of nature have served as most suitable candidates for anti-cancer drug discovery due to their pleiotropic activity on target molecules. This review aims to provide an update on the natural sources and bioactivities of such gifts from nature, salvianolic acid A & B, which are major bioactive constituents of a traditional Chinses medicinal herb,  Medicinal plants and herbs have established their worth as a primary source of bioactive molecules having therapeutic potentiality since times Artemisia annuaMedicinal plants laid the foundation of first sophisticated medicinal system in Mesopotamia back in 2600 BC Various investigations have reported emerging role of natural products as anti-oxidant  Salvia miltiorrhiza. Salvianolic acid A and B have been known to possess various bioactivities such as anti-inflammatory Polyphenols are a broad family of natural products encompassing flavonoids Although several researchers have reviewed the role of salvianolic acids as cardio-protective and antioxidant agents but no one has still attempted to review the anti-cancer properties of salvianolic acid. Therefore, this review is an effort to update research community about the anti-cancer potential of salvianolic acids with specifically focusing on their action mechanism. Manual searches were checked by various sites as PubMed, Elsevier and Google. Following keywords were used for searching: Salvianolic acid, natural products, anticancer activity and salvianolic acid A, B and its biological activities.Salvia miltiorrhiza which is a Chinese herbal plant. The roots of Salvia miltiorrhiza are utilized in Chinese medicines which are extensively used for the cure of cancer. Salvianolic acid A and B  has been extracted from the roots of Salvia miltiorrhizaSalvia yunnanensis, two known polyphenols were isolated salvianolic acid A and lithospermic acid Salvia yunnanensis is also a traditional Chinese herb used as a substitute of Salvia miltiorrhizaSalvianolic acids are the most abundant compounds of in vitro/ in vivo studies have revealed the potential of salvianolic acids as potent anticancer agents.The nature-derived pharmacologically active polyphenolic compounds, salvianolic acids, have been declared to possess various bioactivities such as antiinflammatory, anticancer, antioxidant and cardio-protective. Multiple Cancer is a multifaceted disease characterized by unrestricted cellular proliferation caused due to functional dysregulation of various important genes encoding for key proteins such as tumor suppressers, anti-apoptotic proteins as well as growth factors Approximately 60% of anticancer agents have been emerged from nature including marine biota, microorganisms and plants Secondary metabolites isolated from plants as stilbenoids, flavonoids and phenolics have been reported for their potential anticancer activities Apoptosis is characterized as regulated and systematized mode of cellular death involving the genetically determined eradication of unwanted cells SAA and SAB have been emerged as novel anticancer paradigms for multitargeted prevention of cancer. Anticancer characteristics of SAA and SAB has been revealed to be associated with triggering apoptosis through activation of caspases, reducing anti-apoptotic proteins (Bcl-2), activation of proapoptotic proteins , modulating PI3K/ Akt/ MAPK pathways, NF-ĸB inhibition and ROS accumulation Table .Cells have evolved two main pathways for apoptosis; extrinsic or death receptor pathway and intrinsic pathway SAA treatment induced apoptosis in KG-1, THP-1 and Kasumi-1 cells via intrinsic apoptotic pathway by upregulating Bak, decreasing Bcl-xl, followed by cleavage of PARP and caspase-3 activation PTEN, a widely mutated tumor suppressor gene, modulates several intricate cellular networks such as MAPK and PI3K/ Akt pathways, thus, maintaining cellular homeostasis of growth and development in vitroSAA treatment to A549 cells up-regulated p-PTEN in a time-dependent mode. Increased phosphorylation of PTEN significantly suppressed PI3K/AKT signaling, thus, reducing invasive capabilities of cancerous cells NF-κB, a downstream target of STAT3, is a family of five transcriptional factors  which form specific protein complexes and via binding at the promoter region of DNA, this family regulates a number of essential cellular processes SAB lowered the levels of NF-κB and MDM-2 and caused dose-mediated blockage of LPS stimulated PGE2 and COX-2 in treated JHU-013 cells Metastasis remains the most complicated hurdle to overcome for cancer treatment that accounts for 90% of the cancer related deaths SAA blocked EMT via enhancing E-cadherin  while significantly lowering the levels of vimentin and N-cadherin, thus, inhibiting the migration and invasive capabilities of MCF-7 cells Emergence of resistance against chemo-drugs is a major challenge towards effective cancer treatment. Thus, therapies overcoming drug resistance are greatly needed 50 values of cisplatin towards resistant lung cancer cells Salvianolic acid A has potential to attenuate Akt/mTOR network via blocking c-MET expression which ultimately restores the sensitivity of A549/DDP cells towards cisplatin. Combined treatment of SAA and cisplatin significantly lowered the ICAdministration of 5 and 20 mg/ kg SAA to leukemia xenografted mouse model significantly inhibited growth of tumors. Treatment of SAA didn't induce any alterations in body weight and overall health of the treated animals suggesting that SAA might turn up as safer chemotherapeutic agent. Moreover, SAA treatment to primary leukemia cells obtained from acute myeloid leukemia patients induced apoptosis in 80-95% of the cells at the concentration of 50-100 μM 50 value was 1747 mg/kg, which is hundred times higher than its effective dose. Moreover, no toxicity to heart, brain, kidney, lung and liver structure was observed at any dose which clearly represent that SAB is a bio safe natural entity S. miltiorrhiza for the treatment of stroke, heart attack and several other pathological conditions in vivo, pharmacodynamic and pharmacokinetic studies along with preclinical trials are clearly needed to establish these compounds as potent natural cancer killers in future.To assess the biosafety profile and toxicity of SAB in rats, combinatorial treatment of SAB and ginsenoside Rg1 was given to mice. LDIn this article, we emphasized on the journey of salvianolic acid A and B as potent anticancer and anti-tumor agent. Organized data from multiple lines of evidences have provided a clearer image of the effective role of SAA and SAB against different cancer types. SAA and SAB have broad range of toxicity against numerous human cancerous cells. Salvianolic acids mechanistically proceed through modulation of various signaling networks such as MAPK, P13K/Akt, NF-κB and mTOR and pathways which are often deregulated in cancers and are also associated with drug resistance. In the light of these reports, it can be hypothesized that SAA and SAB may become potent lead compounds for anticancer drugs but additional experimentation, preclinical trials and medicinal chemistry studies are yet required to explore full spectrum of its pharmaceutic potential. Its effectiveness and safety could offer much more commercial value for medicinal purposes, thus, the next drug lead might be just around the corner and are we ready to pursue this opportunity.


Cataract surgery with pseudophakic mini-monovision has lower out-of-pocket patient expense than premium multifocal intraocular lenses (IOL). The purpose of this study was to evaluate patient-reported satisfaction and spectacle dependence for key activities of daily living after cataract surgery with pseudophakic mini-monovision. The study also examined statistical relationships between patient demographic variables, visual acuity and satisfaction.Prospective cohort study of 56 patients (112 eyes) who underwent bilateral cataract surgery with pseudophakic mini-monovision. Mini-monovision corrects one eye for distance vision and the other eye is focused at near with − 0.75 to − 1.75 D of myopia. All patients with 1 diopter or greater of corneal astigmatism had a monofocal toric IOLs implanted or limbal relaxing incision. The main study outcomes were assessed at the last follow-up appointment and included refraction, visual acuity, patient reported spectacle use, and patient satisfaction. Descriptive statistics, correlation matrixes and Pearson’s chi-square tests were examined.Uncorrected visual acuity was significantly better post-operatively. Most patients reported the surgery met their expectations for decreased dependence on spectacles (93%). Most patients report little or no use of spectacles post-operatively for computer use (93%), distance viewing (93%) and general use throughout the day (87%). A small number of patients report spectacle use for reading (9%) and night driving (18%). There were no relationships detected between demographic variables and visual acuity or patient satisfaction.Aging of the population presents one of the biggest challenges in the health sector, which includes a rising number of individuals with chronic vision impairment and increased demand for accessible treatment strategies. Cataract surgery with pseudophakic mini-monovision results in high patient satisfaction and considerable reduction in spectacle dependence. Pseudophakic mini-monovision technique is a low-cost, valuable option for patients who would like to reduce dependence on spectacles post-operatively and should be considered along with premium multifocal IOLs in options available for patients based on their needs, preferences and clinical indicators. Reducing spectacle dependence with the pseudophakic mini-monovision technique could improve the functionality, independence and quality of life for many patients who are unsuitable or are unable to pay additional fees associated with premium multifocal IOLs. Decreased spectacle dependence with a minimum of optical disturbances has become a major refractive goal of cataract surgery. However, patients with traditional cataract surgery are often dependent on spectacles post-operatively. Several surgical options exist for reducing spectacle dependence including bilateral diffractive multifocal intraocular lenses (IOLs) and traditional monofocal IOLs with pseudophakic mini-monovision. Multifocal IOLs are increasingly used to reduce spectacle dependence, although these IOLs may not be a feasible option for many patients due to additional out-of-pocket expense patients may incur for facility and physician charges attributable to multifocal IOLs .Monovision using traditional monofocal IOLs is a surgical option that corrects distance vision in the dominant eye; the non-dominant eye focuses intentionally for near to mid-range vision. This leads to the process of neuroadaptation where the brain can use the distance image from the dominant eye and the near image from the non-dominant eye to achieve a wider range of functional vision . In thisBoth multifocal IOLs and monofocal IOLs with mini-monovision technique have been found to significantly improve uncorrected visual acuity and spectacle independence –8. A fewIn the United States, there is economic incentive for surgeons to use multifocal IOLs in lieu of mini-monovision with monofocal IOLs because the physician can legally make a surcharge to the patient for the use of a premium multifocal IOL, which is typically an out-of-pocket expense for patients . High paThe National Academy of Medicine promotes research on approaches to reduce vision impairment that are focused on patient-centered care and low-cost treatment strategies . Mini-moThis prospective cohort study was a partnership between Eye Consultants of Northern Virginia (ECNV) and George Mason University, College of Health and Human Services. The ECNV and George Mason University Internal Review Board approved the study protocols. Study outcomes include clinical measures of uncorrected visual acuity and patient-reported data obtained through a questionnaire completed by patients at the 3-month post-operative follow up exam. The questionnaire consisted of 6 items measuring spectacle use for near, mid-range and distance functions such as driving at night, using the computer, and reading. The questionnaire also asked patients to rate their overall satisfaction with mini-monovision cataract surgery for reduction of spectacle dependence. Chart reviews were conducted by ECNV ophthalmologists and ophthalmic technicians to extract patient demographic data and measures of visual function.The sample was drawn from all patients at ECNV in need of bilateral cataract extraction who chose the mini-monovision cataract surgery option, which included 63 consecutive patients between 2012 and 2015. Patients who experienced major ocular pathology such as corneal dystrophy, degeneration or macular pathology were excluded from the study. There were 56 patients (112 eyes) who fully completed the questionnaire on spectacle use and satisfaction, resulting in an 89% response rate. All patients provided informed consent prior to surgery and before completion of the questionnaire.All patients had a complete preoperative ophthalmic examination including subjective and objective refraction, biomicroscopy of the anterior and posterior eye segments, intraocular pressure (IOP), macular optical coherence tomography (OCT), automated and manual keratometry, optical biometry, and immersion A-scan.Pseudophakic mini-monovision was chosen for this study because the gradual difference between the two eyes is more tolerable by patients than full monovision. For purposes of this study, the definition of mini-monovision is the near eye calculated between − 1.25 and − 1.50 diopters spherical equivalent. In all patients the dominant eye was corrected for distance vision. Toric IOLs or limbal relaxing incision were used on patients who had corneal astigmatism greater than 1 diopters. Two patients who previously wore monovision contact lenses, the refractive outcome was calculated for − 2.00 diopters. The same experienced surgeon (M.G.) performed all of the surgeries under topical anesthesia using a standard phacoemulsification procedure. All patients were treated with aspheric IOL implants (AcrySof®IQ IOL or the AcrySof® Toric/IQ IOL).Routine postoperative examinations were performed 1 day, 3 weeks and 3 months (up to 6 months) after surgery. The exam included testing for visual acuity, visual aberrations, IOP, subjective and objective refraction and biomicroscopy of the anterior segment. The main study outcomes were assessed at the last follow-up visit. Outcomes included visual acuity, visual aberrations, patient reported questionnaire data on spectacle usage for common Activities of Daily Living (ADLs), and patient satisfaction with reduction of spectacle dependence following the mini-monovision technique.P value of less than .05 was considered statistically significant for this study.Statistical analyses were performed using STATA 14 software. Measures of central tendency and dispersion are provided on patient demographic variables and responses to survey questions. Correlation matrixes and Pearson’s chi-square tests were examined to determine associations between patient demographic variables, visual acuity, and overall patient satisfaction with reduction of spectacle dependence following surgery. The paired-samples t-test was performed to compare pre- and postoperative visual acuity means (converted to logMAR units) to test for statistical significance. A This study included 112 eyes of 56 patients. Cataract surgery was uneventful in all cases and there were no intraoperative complications. All patients completed the questionnaire on spectacle dependence and attended the last follow-up visit. The sample comprised of 39 female and 17 male patients between the ages of 55 and 80.Patient demographic information and surgical procedures are presented in Table P < .001). The target refraction for the distance eye was plano and the near eye was − 1.25 to − 1.50. Fifty-one patients (91%) were within ±.50 diopters of the intended spherical equivalent for the distance eye. Fifty-two patients (93%) were within ±.50 diopters of the target range for the near eye. There were no patient reports of meaningful glare or halos for near or distance functions.The preoperative and postoperative visual acuity are reported in Table All patients completed a questionnaire on spectacle use and satisfaction, see Table Questions on spectacle use were based on a frequency scale from 0 to 10, with 0 representing never wearing spectacles and 10 representing always wearing spectacles. Overall, patients reported low use of spectacles for specific activities for distance, mid-range and near functions. Patient report of spectacle use was lowest for computer use, distance viewing, and for general use throughout the day. The majority of patients 51 (93%) reported low scores  for the amount of time they wear spectacles while working on a computer. Likewise, most patients, 51 (93%), also reported low scores  for the amount of time they wear spectacles for distance viewing. Slightly fewer patients, 48 (87%), reported low scores  for the amount of time they wear spectacles throughout the day.The highest reported use of spectacles was for reading and for driving at night. Most patients, 41 (73%), reported low scores  for wearing spectacles for reading, with 5 (9%) patients reported high scores . Similarly, 42 patients (76%) reported low scores  for wearing spectacles for night driving; however, 11 (18%) patients reported high scores  for wearing spectacles for driving at night. The study findings indicate that for most patients cataract surgery with the mini-monovision technique relieved their need for spectacles for distance, mid-range and near functions. Nevertheless, a small number of patients need vision correction with spectacles for reading and driving at night.P = .467) or near eye . No association was found between age and post-operative uncorrected visual acuity in the distance eye . However, a statistically significant positive association was found between age and post-operative uncorrected visual acuity in the near eye . No associations were found between patient age and patient satisfaction , nor were there associations between patient gender and satisfaction . A statistically significant positive association was found between post-surgery uncorrected visual acuity and patient satisfaction, indicating that patients with better vision were more satisfied with cataract surgery involving the mini-monovision technique .Correlation matrixes and Pearson’s chi-square tests were examined to determine associations between patient demographic variables, visual acuity and satisfaction. No associations were found between gender and post-operative uncorrected visual acuity in the distance eye (Pearson chi2 2.54, Results of this study found that cataract surgery with the mini-monovision technique significantly improved patients’ uncorrected visual acuity and reduced their spectacle dependence. Almost all patients in the study reported that cataract surgery with the mini-monovision technique met their expectations for decreasing dependence on spectacles, with most patients reporting little or no use of spectacles post-operatively. Patients reported low use of spectacles for computer work, distance viewing, and general activities throughout the day. The quality and levels of light and/or the distance from the object may be related to the need for a small number of patients to wear spectacles postoperatively for reading and driving at night. Previous research has found that patients who receive either monofocal or multifocal IOL for cataract surgery have issues with night driving . Other sStudy results also found a positive relationship between post-surgery uncorrected visual acuity and patient satisfaction, indicating that patients with better vision were more satisfied with cataract surgery involving the mini-monovision technique. While there was significant improvement in visual acuity postoperatively, patients with poorer outcomes were less satisfied with pseudophakic mini-monovision for spectacle dependence. It is also possible that postoperative astigmatism interferes with near, mid-range and distance visual acuity, and therefore with patient satisfaction and spectacle dependence.Results of this study, along with other research , indicatThe decision to opt for either cataract surgery with multifocal IOLs or cataract surgery with the mini-monovision technique should be based on consideration of patient motivation to achieve spectacle independence , patientResults of this study should be considered along with study limitations, which include a small sample size, limited number of ADLs assessed in the questionnaire, and the lack of comparison data on patient satisfaction outcomes with other options to reduce patient dependence on spectacles following cataract surgery. Future studies should focus on assessment of spectacle dependence when performing ADLs with technologies such as cellular messaging and cellular entry search . Future Aging of the population presents one of the biggest challenges in the health sector, which includes a rising number of individuals with chronic vision impairment and increased demand for accessible treatment strategies. Pseudophakic mini-monovision is a low-cost option for patients who would like to reduce dependence on spectacles post-operatively and should be considered along with multifocal IOLs in options available for patients based on their needs, preferences and clinical indicators. Reducing spectacle dependence with the mini-monovision technique could improve the functionality, independence and quality of life for many patients who are unsuitable for multifocal IOLs or are unable to pay additional fees associated with multifocal IOLs.


Selected clinically stable patients with heart failure (HF) who require prolongedintravenous inotropic therapy may benefit from its continuity out of theintensive care unit (ICU). We aimed to report on the initial experience andsafety of a structured protocol for inotropic therapy in non-intensive careunits in 28 consecutive patients hospitalized with HF that were discharged fromICU. The utilization of low to moderate inotropic doses oriented by asafety-focused process of care may reconfigure their role as a transitiontherapy while awaiting definitive advanced therapies and enable early ICUdischarge. Among patients admitted withdecompensated HF, around 12 to 14% receive inotropes.In the acute setting, continuous inotropic infusions are usually initiated inintensive care units (ICU), where doses may be titrated with careful monitoring ofpro-arrhythmogenic and vasodilatory effects until the patient is stabilized. Somepatients may require longer periods of inotropic support, and, depending on theirclinical status, may benefit from the continuity of inotropic therapy in a lessintensive care setting. Our aim is to report the initial experience of a structuredprotocol for intravenous inotropic therapy in non-intensive care units, focusing onsafety processes and end-points.st, 2017 wererecorded.We retrospectively reviewed all consecutive patients hospitalized with HF that weredischarged from ICU on an intravenous inotropic infusion in our tertiary, academichospital from July, 2015 to December, 2017. The strategy to promote discharge to theward on inotropic therapy was supported by an institutional protocol, which issummarized in the 3Categorical variables are presented as absolute numbers and percentages, andquantitative variables as mean ± standard deviation or median andinterquartile range, as appropriate. A Kaplan-Meier curve was plotted forsurvival free from heart transplant or LVAD implant during follow-up, andcumulative incidence curves were calculated for all-cause mortality and hearttransplant or LVAD using competing risk analysis with the R Software, version3.4.4 .We reviewed 28 patients with HF that were discharged from the ICU to the ward onintravenous inotropes after the protocol was created. The cohort was followed for a median of 154 days. Among those in whom inotropes werediscontinued and that had hospital discharge free of heart transplant or LVADimplant (n = 8), two were readmitted for HF within 30 days. Competing outcomes formortality during the follow-up period are demonstrated in During the period on inotropic support in the ward, nine patients returned to ICU dueto worsening HF - two of those for worsening pre-existing atrial fibrillation oratrial flutter. No episodes of new atrial fibrillation or atrial flutter wereobserved. Six patients developed recurrent non-sustained ventricular arrhythmia, andinotropic dose was reduced; of those, four were hypokalemic (≤ 3.5 mmol/L)when arrhythmias were observed. One patient had a central venous catheter exit-siteinfection, and one had a peripherally inserted central catheter-related bloodstreaminfection. Seven events of protocol violation were identified: use of peripheralvenous access for drug infusion (n = 2); and, increments in inotropic dose in theward (n = 5). None of them incurred in clinical adverse events.In the present report, we described our initial experience with a safety-focusedprotocol for the use of continuous intravenous inotropes in hospitalized patientswith advanced HF outside the ICU. We demonstrated that a subset of clinically stablepatients on inotropes may benefit from transition to a less intensive care settingfollowing careful standard operating procedures, without a significant burden ofadverse events. These safety measures are aligned with our institutional program forquality improvement.4 The use of intravenous inotropicagents remains controversial, as many reports have associated its utilization withunfavourable outcomes. A deleterious effect of its use on long-term mortality amongpatients discharged alive, however, has not been suggested by a recent Europeanregistry report.1Current guidelines indicate that inotropes can be used in specific clinical settings,especially cardiogenic shock or bridge therapy in patients with refractory HFawaiting heart transplant or LVAD. Also, those not candidates for definitivetherapies could be considered for long-term inotrope as palliation.5 Avoidanceof traditional high doses of inotropes, the administration under careful monitoringconditions and strict electrolyte correction strategies may allow broader use ofthese agents.In this study, we describe a selected population of patients with advanced HF thathas not been well-documented in most studies evaluating inotropes - mostlyclinically stable hospitalized patients intended for inotropic wean or bridge todefinite therapies. Concerning safety outcomes, most of the arrhythmogenic eventsoccurred in the context of electrolyte disturbances, which can be potentiallyavoided with careful monitoring. Considering the growing HF severity and theinotrope potential as a bridge therapy in hospitalized patients, a contemporaryapproach to their utilization has been to focus on the safety profile of its usewhile maintaining the traditional goals of therapy (the 'until' therapy), asdescribed by Stevenson.A contemporary, safety-focused approach to the use of low to moderate doses ofintravenous inotropic agents in less resource-intensive settings may be feasible,potentially reconfiguring the use of these agents in different scenarios, rangingfrom bridge therapy to end-of-life palliation.