Danio rerio) for accelerating our understanding of human skeletal genomics and outlining the remaining gaps in knowledge. We provide an overview of zebrafish skeletal morphophysiology and gene homology, shedding light on the advantages of human skeletal genomic exploration and validation. Knowledge of the biology underlying osteoporosis through animal models will lead to the translation into new, better and more effective therapeutic approaches.The advancement of human genomics has revolutionized our understanding of the genetic architecture of many skeletal diseases, including osteoporosis. However, interpreting results from human association studies remains a challenge, since index variants often reside in non-coding regions of the genome and do not possess an obvious regulatory function. To bridge the gap between genetic association and causality, a systematic functional investigation is necessary, such as the one offered by animal models. These models enable us to identify causal mechanisms, clarify the underlying biology, and apply interventions. Over the past several decades, small teleost fishes, mostly zebrafish and medaka, have emerged as powerful systems for modeling the genetics of human diseases. Due to their amenability to genetic intervention and the highly conserved genetic and physiological features, fish have become indispensable for skeletal genomic studies. The goal of this review is to summarize the evidence supporting the utility of Zebrafish ( Osteoporosis is the most prevalent bone condition in the ageing population. It is a disease that weakens the bones, making them highly susceptible to sudden and unexpected fractures . It is eGenome-wide association study (GWAS) and whole genome sequencing (WGS) analyses have transformed the field of genetics of complex diseases in general, and for osteoporosis (OP) in particular. Although a range of modifiable factors contribute to age-related bone loss, including diet, exercise, medications, and comorbidities, primary OP is largely mediated by genetic factors, making it a promising field for exploration by GWAS and WGS .Bone mineral density (BMD) remains the strongest predictor of fracture risk and is highly heritable . Over thHeritability of OP-associated traits may have quite a range—from 10 to 80%—but is always significantly different from zero. Despite the strong heritability associated with osteoporosis, the identification of causal genes remains complex. Historically, studies in mice have added functional evidence to accompany GWAS. More recently, zebrafish have been used as alternative models to explore variants harbored in protein-coding regions. In this review, we will address current challenges faced by researchers to bridge the wide gap between association and causality in osteoporosis. In addition, we will demonstrate the power of functional studies using small teleost zebrafish to underpin the genetics of osteoporosis and the biology behind this condition that currently affects over 200 million people worldwide.In 2007, the first GWAS of the then commonly measured osteoporosis-related phenotypes was published . Since tStudies conducted on fracture risk accumulated large sample sizes, including data from the GEFOS consortium and UK Biobank . An imponew loci  was released to be used by the wider scientific community [MEPE associated with heel bone density. To date, exome data from 200,643 UKBB enrollees are now available, which include ~10 million exonic variants. Interpreting results from human association studies requires bridging the gap between genetic association and molecular function. A systematic functional investigation is necessary to interpret significant variants/genes they regulate, to decipher the exact disease-causing genes, and the cells in which they act [The UK BioBank (UKBB) has recently sequenced whole exomes of >200 thousand participants, which were made available to the Exome Sequencing consortium. A subset of that enormous sample —rare subtrochanteric or diaphyseal fractures—are regarded as side effects of bisphosphonates (BPs). Zhou et al. summarized the most recent knowledge about the genetics of AFFs . AFFs hareatment . WES wasreatment . WES anaFF cases ,33. BispFF cases . RecentlFF cases .The genes regulated by SNPs can be located tens or hundreds of kilobase-pairs away and mingled among other genes, making the discovery of the actual regulated gene a tremendous challenge . IntuitiIt was shown that the distance between the lead SNP and the neighbor gene is a strong predictor of causality, yet there are examples of causal genes at GWAS loci that lie hundreds of kilobases away from the lead SNP ,38. The Since the majority of GWAS hits cannot be easily linked to a candidate causal gene, multiple methods and software are dedicated to the purpose of variant annotation, as depicted in recent reviews ,41. Of nWith WES being increasingly applied to large population-based settings, its annotation seems more straightforward (since these SNPs are coding). The American College of Medical Genetics and Genomics and the Association for Molecular Pathology have released standards and guidelines for the interpretation of sequence variants . AccordiFTO locus, which has been strongly associated with the risk of obesity [IRX3 and IRX5 but not those of IRX6 or FTO [Irx3 and Irx5 mice, the group showed the presence of an anti-obesity phenotype in Irx3 knockout and Irx5 heterozygous mice. Their studies confirm that variants in multiple enhancers within FTO obesity-associated regions regulate the expression of multiple genes (IRX3 and IRX5) in at least two obesity-relevant tissues (adipose and brain). In another study, Chesi et al. efficiently combined open chromatin landscape  with chromatin interactions data (Capture C) and BMD GWAS loci to map informative SNPs [CPED1, WNT16, and SFRP4, using cell cultures. They showed that knockdown of two novel genes (ING3 and EPDR1), not previously associated with BMD but highlighted through their chromatin analysis, affected osteoblast and adipogenic differentiation [The high complexity of the gene regulatory landscape also adds to the challenge in interpreting GWAS findings. Recent works have demonstrated that the genetic architecture of disease-associated loci may involve extensive pleiotropy . GWAS va obesity . Sobreir6 or FTO . By geneive SNPs . SNP prontiation . TogetheGiven the recent expansion of sequenced genomes, it became possible to intersect datasets for evolutionarily conserved genes, regulatory elements, or entire pathways with the evolution of homologous traits in a relatively unbiased fashion ,56. WhilIt has been postulated that cis-regulatory sequences and other non-coding elements may be a primary substrate for evolutionary divergence . IndeedAncient CNEs that arose in the vertebrate ancestor usually have only a small core of sequence conservation in fish species, while mammals often exhibit much broader conserved flanks. This observation inspired Madelaine et al. to look for GWAS-originated SNPs that fall in deeply conserved CNEs, from humans down to zebrafish, that also preserve gene synteny . SyntenyIRF6 enhancer-binding site in cleft lip and palate [RET enhancer in Hirschsprung disease [Phenotypic screening of genetically diverse species can reveal CNEs with specific trait associations. Such associations allow us to identify CNEs altered in human diseases, for example, the disruption of an d palate  and a mu disease . Non-codLBX1, previously identified as responsible for scoliosis [microRNA-9, rather than MEF2C as predicted by the original GWAS. Under miR-9 depletion, the zebrafish retinal vasculature formation was compromised [GWAS-derived SNPs embedded specifically in gene regulatory regions conserved to zebrafish are further expected to lie next to the orthologous gene(s) in both human and zebrafish, based on synteny. To exemplify the relevance of syntenic regions, Madelaine et al. identified SNPs associated with human diseases, such as rs11190870, mapped in a CNE close to coliosis . Madelaipromised . This woTaking advantage of synteny to predict causality, Clément et al. extensively mapped CNEs on the entire genome-scale and predicted enhancer-gene interactions using a method previously applied to only the human chromosome X, called PEGASUS . PEGASUSHDAC9) protein-coding sequence are associated with disruption of TWIST1 regulatory elements that reside within the HDAC9 sequence. Based on SVs within the HDAC9-TWIST1 locus, they defined the 3′ HDAC9 sequence (~500 Kb) as a critical TWIST1 regulatory region, encompassing craniofacial TWIST1 enhancers and CCCTC-binding factor (CTCF) sites. Deletions of either Twist1 enhancers (eTw5–7Δ/Δ) or CTCF site (CtcfΔ/Δ) within the Hdac9 protein-coding sequence in mice led to decreased Twist1 expression and altered anterior/posterior limb expression patterns of Shh pathway genes. The authors found that Twist1 frequently interacts with several regions encompassing enhancer candidates. Then, they tested these candidates for functional activity using zebrafish enhancer transgenic assay, in the craniofacial tissues of zebrafish embryos. The zebrafish enhancer assay showed that some candidate enhancers drove specific GFP expression in branchial arches and other facial bones. By this, Hirsch et al. provided an insight into the spatiotemporal regulatory network that controls Twist1 expression in the developing craniofacial tissues [A relevant recent work by Hirsch et al. from Birnbaum’s lab showed that structural variants (SVs) disrupting protein-coding sequences can also function as cis-regulatory elements . They sh tissues . These sOne of the goals of in silico and in vitro methods is to narrow down candidates and translate findings to in vivo models. Animal models have contributed to our understanding of mechanisms of human diseases, such as how the genetic analysis of diversity in outbred mice facilitates the identification of novel loci in humans . HoweverMost recently, Swan et al. explored data from 3823 mutant mouse strains for BMD . A totalglo1-/-) fish. Thus, validated diabetic induction methods are suggested to help researchers confirm their proposed models [Hyperglycemic zebrafish models are used as well in diabetes-related studies . Hypergld models .To date, even with the advanced Mouse KO and phenotyping collaborations, such as the International Mouse Phenotyping Consortium  and the To complement the usability of fish to model skeletal diseases, a recent review summarized the rapid emergence of zebrafish models of rare skeletal diseases during the last 10 years . Many avZebrafish have emerged as model organisms in bone research within recent decades, being choice models to confirm gene discovery and to perform functional analysis of human variants, often providing viable alternatives to mouse lethal alleles. One of the most fascinating advantages of zebrafish is their transparency A. Zebrafsp7. Remarkably, these findings in zebrafish precisely recapitulated those observed in a reported patient affected by osteogenesis imperfecta recessive that carried a homozygous loss-of-function mutation in SP7 [zic1, atp6v1c1a, atp6v1c1b, prkar1a, and prkar1b in zebrafish, unprecedently showing that loss-of-function of each of these genes could lead to craniofacial malformation and abnormal BMD, thus, exemplifying the use of zebrafish to elucidate genes playing a role also in developmental craniofacial conditions.In 2016, Kague et al. took advantage of the transparency offered by zebrafish to show the complete development of the cranial sutures in vivo for the first time . The samn in SP7 . TherefoWith the transparency gradually lost during development, the adult zebrafish endoskeleton becomes covered by musculature and mineralized scales. While in vivo imaging can still be used to study bony elements located superficially and permanently accessible in fish  A, to anaZebrafish passed through an additional whole genome duplication. Zebrafish gene duplicates (orthologs to mouse/human genes) may functionally balance each other, so single knockouts might be viable at least during embryonic and early larval periods, allowing basic analysis of skeletal development. Zebrafish orthologs sometimes manifest sub-functionalization, so that viable loss of function alleles of a specific paralog can be obtained and studied ,81. EachAlthough the evolutionary distance between zebrafish and humans date back to 450 million years, about 71% of zebrafish genes are conserved with humans. Moreover, when considering only genes involved in diseases, zebrafish have ~80% of disease-causing genes conserved with humans. For this reason, zebrafish have been an attractive model in forward genetic screening using Ethyl-N-nitrosourea (ENU)-driven chemical mutagenesis. In addition, in reverse genetics by targeting specific genes using gene-editing techniques such as zinc-finger nucleases (ZFINs) ,139,140,PLOD2) and osteoporosis (LRP5), and were able to reproduce similar phenotypic characteristics, such as low BMD, as those of mutants [We and others demonstrated that G0 knockouts reliably recapitulate complex mutant phenotypes, such as osteopenia and osteogenesis imperfecta ,144. Mos mutants ,144. ZebThe identification of genes involved in skeletal diseases can result in novel treatments for osteoporosis, as was the case for denosumab, an anti-RANKL monoclonal antibody ,147 and alk8-/-) [clemizole to treat patients with Dravet syndrome. Dravet syndrome is a catastrophic childhood epilepsy with early onset of seizures, caused primarily by mutations in SCN1A. Zebrafish scn1 mutants recapitulated Dravet syndrome and were thus used in a phenotypic screening resulting in the identification of Clemizole. Clemizole binds to serotonin receptors; its antiepileptic activity can be mimicked by other drugs acting on the serotonin signaling pathway . Griffin et al. tested lorcaserin in Dravet patients and showed reductions in seizure frequency and/or severity, similar to Clemizole in the fish [Interestingly, the first small-molecule inhibitor of BMP signaling, dorsomorphin, was one of the first compounds identified from a zebrafish chemical screening aiming to identify compounds that phenotypically reproduce loss of BMP signaling pathway  . Currentthe fish . These tthe fish ). Besidethe fish ,152. Likthe fish .Interestingly, for some drugs, zebrafish are able to recapitulate the effects observed in humans better than mouse models do. This is the case for thalidomide, mentioned above, which safety was originally tested in mice, but when administered to pregnant mice, the drug does not reach teratogenic levels in embryos, thus not causing birth defects as in human . It was rankl-induced OP (medaka) to validate their anti-resorptive and anabolic activities [Glycyrrhiza glabra roots) has a positive effect on osteoblast differentiation, as well as halts osteoclast activity in vitro. Carnovali et al. tested liquiritigenin in zebrafish, revealing increased bone formation rates in a dose-dependent manner and reduced TRAP staining in zebrafish scales of glucocorticoid-induced OP [The zebrafish models of damaging environmental exposures exist for tens of years, most prominently for toxicology research. Specifically for osteoporosis, several non-genetic models were established by the iron-stress , by predtivities . For exaduced OP . A similduced OP . Zebrafiduced OP , which aAlthough the zebrafish skeleton has a reduced requirement for resisting mechanical load due to residing within an aquatic environment, several studies have demonstrated that swim training can influence the timing of skeletogenesis in zebrafish larvae , as wellAlso, an important work by Witten et al. reminds us about the commonalities and specifics of small teleost biology in response to their environments . ZebrafiOsteoporosis is characterized by an imbalance between bone formation and bone resorption, where osteoclast activity exceeds that of osteoblasts. The behavior and interaction of bone cells that are commonly studied using cell cultures, can be easily studied in fish because they are see-through during a relatively long period of their development. Larvae zebrafish are often used to analyze osteoblast behavior, bone matrix deposition and mineralization . In mammHere it should be noted about the zebrafish exoskeleton  for the needs of comparative anatomical understanding. As part of the dermal skeleton, these structures harbor a mineralized matrix and serve as sources for rapid evaluation of bone formation and mineral deposits ,170. In sp7-/- and lrp5-/- [Adult zebrafish models to study osteoporosis have only been developed recently, alongside the study of the ageing zebrafish spine ,173,174. lrp5-/- ,93, etc. lrp5-/- ,108. Tabwnt16 or bmp1a1 [bmp1a fractures are prone to non-union [The endpoint of osteoporosis is the occurrence of a fracture. While the prediction of fractures in zebrafish is not comparable to that of humans, where FRAX (fracture assessment tool) is used; genetically modified zebrafish offer alternative ways to study fracture occurrence, prediction and fracture healing . The zebr bmp1a1 ,176. Moron-union ,107,108.WNT16 locus has been explored using zebrafish by several groups, serving as a good example of GWAS findings followed by functional validation in fish. Since the GWAS signal on 7q31 was discovered [WNT16, FAM3C, or CPED1 [WNT16 in the regulation of cortical bone thickness through increased resorption and reduced periosteal bone formation [wnt16 loss-of-function, incrementing our current knowledge about the gene in bone and its pleiotropic effects. Firstly, McGowan et al. showed that caudal fins of wnt16 zebrafish mutants were highly susceptible to fractures, with a 10 fold increase in numbers of calluses in mutants when compared to WT of a similar age [wnt16 mutant, reporting reduced bone density, curved spines and abnormal jaw [wnt16 in dermomyotome and sclerotome. By performing cell tracing experiments, they demonstrated that somatic wnt16+ cells are muscle precursors that contribute to muscle fibers. Lastly, they performed an analysis of lean mass in wnt16 mutants, which exhibited an altered distribution of lean mass and altered myomere morphology. This study suggests that wnt16 exerts a pleiotropic effect on bone and lean mass. Together, all three wnt16 zebrafish studies are complementary in concluding that wnt16 is necessary for bone mass and/or morphology, serving as a showcase for zebrafish functional studies to interpret findings from GWAS.The scovered ,177,178,or CPED1 . The orior CPED1 ,180. Theormation . In 2021ilar age . The autilar age . While Mrmal jaw . The samrmal jaw . Finallyrmal jaw . The autWhen it comes to the functional validation of bone-disease-related candidate genes highlighted through different venues, including WGS and GWAS, small teleost fish provide an unprecedented speed and precision not achievable with mammalian in vivo systems. Zebrafish are able to recapitulate human bone diseases and offer advantages for functional validation and deep phenotypic studies of osteoporosis-related genomic findings to an extent which they are preferable models, in many of the cases. It is expected that studies incorporating the fresh-water teleost model will continue increasing. We highlight key areas where we foresee the use of zebrafish in the osteoporosis research field.The in vivo aspect of how cells behave under normal conditions, or in diseases and after pharmacological interventions is an important area of research that will optimize future osteoporosis treatments . This haIt is worth mentioning the use of zebrafish exoskeleton and fins for supplementary skeletal studies. With the amenability of scales to be cultured in vitro and the regenerative capacity of fins, these dermal bones have been of interest to test osteoblast anabolic factors and are capable of relatively high-throughput experiments . Togetheklotho zebrafish mutants [Despite a few studies performed in the ageing zebrafish skeleton ,173,174, mutants , telomer mutants  and prog mutants  however  mutants , also reGiven the high number of loci identified to play a role in osteoporosis, we consider this specific gap in knowledge one of the top beneficiaries of what zebrafish can currently offer. The high efficiency of genomic editing in zebrafish using the CRISPR/Cas9 system, as mentioned above, allows us to accelerate our genetic validations using the first zebrafish generation (crispants) that are able to phenotypically recapitulate knockouts. This would allow us to implement the closest to high-throughput genetic screenings that a living vertebrate can achieve . With thFinally, non-coding variants regardless of their conservation within fish clades can be tested using zebrafish ,192. It We have mentioned a few areas where zebrafish are being implemented to add power and speed to the functional evaluation of osteoporosis-associated genes reinforcing them as a choice model organism to support bone-GWAS and help to bridge the current gap between association and causality. Having said this, it is notable that the legislators and the anti-animal-research activists are frustrated that, despite a legal requirement to use methods that do not involve animals, their development and uptake remains slow. Recently, the EU Parliament urged its constituents to accelerate the transition to a research system that does not use animals, pushing for alternative testing methods and phasing out the use of animals in research and testing. This is in line with the previous decade’s conventions and efforts focused on reducing, refining and replacing (3R) procedures on live animals for scientific purposes, as soon as it is scientifically justifiable and “without lowering the level of protection for human health and the environment”. It is advised that the scientists must be trained in using advanced non-animal models and in sharing best practices regarding the 3Rs. Thus, for example, both positive and negative indicators of animal welfare must be reported. As such, there is a pressing need for studies of welfare to more fully assess negative and positive factors to truly capture an animal’s experience of change in their health environment. Both the future of small-fish modeling in general and osteoporosis genetic research would benefit from this knowledge.


Danio rerio) is an alternative vertebrate model as a useful tool for the mechanism elucidation and drug discovery of various eye disorders, such as cataracts, glaucoma, diabetic retinopathy, age-related macular degeneration, photoreceptor degeneration, etc. The genetic and embryonic accessibility of zebrafish in combination with a behavioral assessment of visual function has made it a very popular model in ophthalmology. Zebrafish has also been widely used in ocular drug discovery, such as the screening of new anti-angiogenic compounds or neuroprotective drugs, and the oculotoxicity test. In this review, we summarized the applications of zebrafish as the models of eye disorders to study disease mechanism and investigate novel drug treatments.Visual impairment and blindness are common and seriously affect people’s work and quality of life in the world. Therefore, the effective therapies for eye diseases are of high priority. Zebrafish ( Until 2020, an estimated 295 million people suffer from the moderate and severe visual impairment worldwide, and among them, about 43.3 million people are even blind . The lea(Danio rerio) is a kind of common aquarium fish originating from India and has become a prominent vertebrate model for studying diseases [Zebrafish diseases ,5. Zebradiseases . ImportaIn this review, we highlighted the use of zebrafish in modeling eye diseases by (i) introducing the characteristic anatomy and development of zebrafish eye, (ii) summarizing zebrafish models of eye diseases, such as cornea dystrophy, cataract, glaucoma, ocular vascular diseases, and photoreceptor degeneration, and (iii) presenting contributions of these models in the investigation of new drug candidates for eye diseases.Although zebrafish eyes are very small compared with those of humans, they contain almost all the basic structures of human eyes. Firstly, we focused on the anatomy and development of the zebrafish eye to explain why zebrafish is a promising model for human eye diseases.Both of the zebrafish and human cornea contain five major layers: the epithelium, Bowman’s layer, stroma, Descemet’s membrane, and endothelium. In its mature state, the zebrafish corneal epithelium is 12.5 μm thick with four to six cell layers. The stroma is approximately 6 μm thick with 34 to 40 layers . The endIridocorneal angle, the region where the cornea meets the iris, hosts cells specialized in maintaining intraocular pressure (IOP) . IOP is Almost all the morphological features of human lens can be observed in the zebrafish eye . The fissws2), ultraviolet (sws1), green (rh2), and red (lws), among which the green and red cones exist as a physically fused double cones [Zebrafish is visually responsive at 72 h post fertilization (hpf), when the retina mirrors adult human retinal morphology and function ,13. Furtle cones . Visual Zebrafish visual acuity is typically measured using the behavioral tests, including optokinetic response and optomotor response. The optokinetic response is a robust behavior in which moving objects evoke the tracking eye movements . It is o(fli1: EGFP) line, which expresses EGFP under the control of fli1 regulatory sequences [The basic vascular biology of the developing zebrafish embryo is analogous to that of other vertebrates, and angiogenesis also plays a vital role in the zebrafish hyaloid vessel, which is similar to the development of retinal vasculature in mammalian embryos ,18. The equences ,23,24.The development of zebrafish eye is strongly similar with that of humans and other vertebrates ,26. TheyThe development of zebrafish eye is fairly rapid. Neurogenesis begins at 28 hpf, and zebrafish embryos possess visual function as early as 72 hpf ,28. The With genetic accessibility, similar characteristics of human ocular development and easy controllability of living environment zebrafish has been used as a popular model to study eye disorders. Over the past decades, many human ocular diseases, such as cataract, glaucoma, DR, and AMD, have already been modeled in zebrafish. Here, we briefly introduced some important zebrafish models of eye diseases from anterior segments to posterior segments.pip5k3, col17a1, and keratocan, also express in the zebrafish cornea. pip5k3 and col17a1 are quite conservative without ocular alteration, while keratocane is significant for corneal transparency and structure [lama1, a gene encoding an important basal membrane protein, leads to focal corneal dysplasia in zebrafish [Corneal dystrophies have a variable age of onset, variable inheritance, and progressive effects on corneal transparency and vision . Due to tructure ,36,37. Lebrafish . Overallebrafish . TherefoCataract, which is characterized by cloudy vision due to lens opacity, mainly includes congenital cataract and age-related cataract (ARC). Genetic studies have identified over 30 causative mutation genes for congenital or other early-onset forms of cataract and only few ARC-associated gene variants . NeverthCRYAB gene, a member of α-crystalline, results in congenital cataract by activating glucocorticoid receptor signaling [cloche mutant in zebrafish displays cataract related to the insolubility of γ-crystalline and the faulty differentiation of lens fiber cells [αA-crystalline in the cloche mutant. Therefore, the cloche mutation can be used to investigate the aggregation of lens crystallin and prevent cataract. In addition, the overexpression of Pax6, which is a paired box and homeobox domain protein expressing in the developing nervous system and eye, causes defects in lens fiber cells and human congenital cataract. The Pax6 mutant in zebrafish shows the alterations in the eye size and the abnormalities in lens differentiation [Pitx3 and Foxe3 genes can cause the mesenchymal dysgenesis of anterior segment and cataracts in humans, and the knockdown of Pitx3 and Foxe3 in zebrafish via antisense morpholino results in the lens dysmorphogenesis [Hsf4, a member of the heat-shock transcription factor family, lead to isolated cataracts in humans and an early onset cataract with multiple developmental defects in zebrafish lens by interrupting the terminal differentiation of a lens fiber cell [The use of zebrafish cataract model mainly focuses on the congenital cataract. Among the known gene mutations caused cataracts, mutations in lens crystallins account for the majority, followed by mutations in various growth or transcription factors, connexins, membrane proteins, and lipid metabolism . Hence, ignaling . Similarer cells . Meanwhintiation ,43,44. Togenesis ,47,48,49ber cell ,50. α-crystallins is considered to be titrated out by the binding of the damaged lens proteins as well as the truncation and insolubilization of the small heat shock proteins; so zebrafish is used to establish a link between in vitro mechanistic models of α-crystallin chaperone and their roles in lens aging [CRYGC gene  causes a remarkable reduction in the thermal stability of γC-crystalline and raises the risk of lens opacity when exposed to heat and UV-irradiation stresses, finally resulting in cataract [ARC also has a genetic component, which makes individuals with the variation more vulnerable to environmental insults and aging . Since tns aging ,54. Addicataract . Glaucoma is a kind of optic neuropathy characterized by the progressive and irreversible visual field loss and visual impairment secondary to RGC loss . PrimarySIX6 variants interrupt the development of the neural retina and result in a decreased number of RGC and an increased risk of glaucoma-associated visual impairment [FOXC1, which is one of the few well-established genes related to POAG [FOXC1 has been found as a vital mediator that reacts to oxidative pressure and suppresses apoptosis in cells associated with aqueous humor dynamics [Bugeye mutant, which develops high IOP, enlarged eye globes, morphological abnormalities, and functional deficits in the retina, is identified as the model for myopia and glaucoma [Zebrafish offer great chances to test specific hypotheses associated with glaucoma . For inspairment ,71,72. A to POAG . The tradynamics ,75. Furtglaucoma ,77. ManyNeurodegeneration in the form of RGC death is well documented in glaucoma. The chemical or oxidative stress-induced retinal damage is related to RGC injury and used in zebrafish research . For exaPathological retinal angiogenesis makes a great contribution to irreversible causes of visual impairment at all ages, such as retinopathy of prematurity (ROP), DR, and AMD. Due to the significant similarities of vasculature between zebrafish and human, zebrafish embryos have been used for the identification of genes and mechanisms involved in pathological retinal angiogenesis.The crude prevalence of blindness caused by DR shows a global increase in age-standardized prevalence in 2020 .pdx1 mutants in zebrafish provide the only known model in which hyperglycemia-induced retinal angiogenesis can be studied [Retinal abnormalities of hyperglycemic zebrafish are consistent with those of diabetic patients. After being immersed alternately in glucose solution and water for 28 days, zebrafish has a remarkably thinner IPL and INL . Moreove studied . Therefo studied ,100.(fli1:EGFP) zebrafish with a hypoxia-inducing agent, followed by GS4012 (a VEFG inducer) at 24 hpf; then, the number of sprouts and vascular branches dramatically grow in the central retinal vascular trunks [(fli1:EGFP) zebrafish can also develop severe retinal vascular proliferation [ROP is a kind of retinal vasoproliferative disease in premature infants and one of the leading causes of childhood blindness . As ROP r trunks . In addiferation .von Hippel-Lindau (VHL) gene promotes hypoxia-inducible factor signaling and consequent VEGF expression [VHL knockout zebrafish embryos [VHL mutant zebrafish can be a model for neovascular AMD.AMD, which blur the central vision, is a disorder with multifactorial pathogenesis, including angiogenesis, dysregulation in the complement, lipid, inflammatory, and extracellular matrix pathways ,104. Neopression . Accordi embryos . Hence, gnn mutant displays the AMD-related degeneration of red cones at around 5 dpf [HTRA1, a protein involved in the pathophysiology of AMD, can induce an accumulation of lipofuscin and melanolipofuscin between the photoreceptor and RPE layers in zebrafish [HTRA1 in zebrafish displays certain morphologic changes of the RPE, photoreceptor cell death, and lipofuscin accumulation, which are the features of early AMD [RP1L1 mutant zebrafish using CRISPR/Cas9 genome editing is the first zebrafish model of photoreceptor degeneration with subretinal drusen deposits, which is a hallmark of AMD [Dry AMD, the subtype characterized by RPE disorder, can result in the loss of photoreceptor cells. Interestingly, the zebrafish with the nd 5 dpf . Additioebrafish . The traarly AMD . Recentlk of AMD .Photoreceptor degeneration diseases are exceedingly various, creating the challenges of preventing or reversing vision loss. Due to the similarities in retinal anatomy and function between zebrafish and humans, the zebrafish model has become a predominant model for studying the photoreceptor development and disease. Here, we focused on retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA), which are two major kinds of retinal degeneration diseases .rhodopsin (RHO). Recently, various RHO mutant zebrafish models associated with dominant or recessive RP have been established with progressive rod degeneration [RHO mutants, which is consistent with the features of human RP caused by the RHO mutation [RP is a disease characterized by decreased night vision and loss of peripheral vision due to the progressive photoreceptor cell death and dysfunction of the photoreceptors. The most common cause of human autosomal RP is the mutation in the rod-specific opsin gene, neration ,111,112.mutation ,111. retinitis pigmentosa 2 (RP2), is characterized by the early onset and rapidly progressive vision loss before 40 years old in humans [RP2 in zebrafish results in a small eye phenotype, gradual loss of the photoreceptors’ outer segments (OSs), and defective photoreceptor function, mimicking human X-linked RP [RP2 in the pathogenesis of X-linked RP [X-linked RP, whose major cause is the mutation in n humans . Knockdoinked RP ,115. Furinked RP . AdditioCEP290, RPE65, CRB1, KCNJ13, GUCY2D, AIPL1, CRX, IMPDH1, LCA5, LRAT, RPGRIP1, SPATA7, RD3, RDH12, and TULP1. CEP290 mutant zebrafish displays an intracellular transport delay and a decreased visual perception, which is analogous to human LCA patients [LCA5 in zebrafish using CRISPR/Cas9 technology causes the impaired OS protein trafficking and then cone–rod dystrophy, which mimics the phenotype of cone–rod dystrophy in humans [LCA is a kind of inherited retinal dystrophy disease responsible for early-onset childhood blindness with immense genetic heterogeneity . Presentpatients . Similarn humans .ift28, ift88, and ift172 mutants of zebrafish have the rapidly degenerated photoreceptors and without the developed photoreceptor OS [kif3a (kinesin family 3a) mutant in zebrafish causes photoreceptors to dramatically degenerate and fail to develop OSs, resulting in the extinguished ERG in zebrafish larvae [Mutation genes involved in ciliogenesis initiation and the transport of cilium components can result in LCA or an LCA-like phenotype in mouse models . Intrafleptor OS ,135,136.h larvae ,137,138.Since the drug candidates can be added to the water culture medium rather than injected into the fish, zebrafish has become a promising model for the various successful phenotype-based drug discovery ,139. HerThe chemical testing in zebrafish can screen for new anti-angiogenic drugs for the eye diseases, which is analogous to the in vitro/ex vivo platforms. Therefore, zebrafish has been emerging as an exciting new model organism to discover anti-angiogenic drugs for ocular diseases. For instance, the screening of approximately 2000 compounds reveals that four small molecules affect retinal vessel morphology but do not produce obvious changes in the zebrafish trunk vessels and the retinal neuronal architecture . Similarvhl zebrafish [In a small chemical screen using zebrafish, LY294002, the PI3K inhibitor, is identified as an effective and selective inhibitor of ocular angiogenesis without systemic side effects and diminishing visual function . Additioebrafish ,143. A rebrafish .pde6c zebrafish model of retinal degeneration [Zebrafish models of the photoreceptor disease provide a platform for discovering novel neuroprotective drugs. Zebrafish can be utilized as phenotypes in screening neuroactive compounds for photoreceptor degeneration ,146,147.neration .atp6v0e mutant zebrafish model, a cone photoreceptor degeneration disease, HDAC6 inhibitors successfully reduce the number of apoptotic cells and improve the photoreceptor OS area and visual function [The overactivation of histone deacetylases (HDACs) has been detected in models of photoreceptor degeneration, and HDAC6 inhibition may prevent neurodegeneration . Moreovefunction ,153,154.It is conceivable that many drugs possess oculotoxicity. The prolonged or high-dose exposure to a certain drug may cause eye damage and vision loss. Given that the vertebrate eye is highly conserved, zebrafish can be a useful model for studying the ocular toxicity of drugs . ZebrafiZebrafish provides a convenient animal model for mechanism investigation and drug discovery in ophthalmology due to their similar eye structure with human and accessibility to genetic manipulation. In the last few years, genome editing technologies, particularly based on Crispr/Cas9, have made it fairly easy to generate lines of zebrafish with mutations in targeted genes . Hence, Zebrafish models might be more predominant, powerful, and promising tools for investigating the mechanisms of various human eye diseases and discovering the novel drug therapy in the future.


To determine the prevalence of asymptomatic cardiac autonomic neuropathy and its association with risk factors among patients with Type-2 diabetes mellitus (T2DM)The present case-control study was conducted at Department of Medicine, Civil Hospital, Dow University of Health Sciences (DUHS), Karachi, Pakistan during the period September` 2016 to May` 2017. After taking informed consent, subjects from both genders, 72 healthy controls and 72 clinically diagnosed T2DM diabetic patients, age between 30-65 years were selected by non-probability sampling technique. After taking medical history and demographics, Cardiac Autonomic Neuropathy (CAN) was identified by using Ewing`s cardiac autonomic reflex tests (CARTs) and association of risk factors was also investigated.Severe CAN was identified in 13.9% of T2DM patients while in none of the healthy controls. HR response to deep breathing test was most sensitive (sensitivity= 90%) among all tests. The most common symptoms were Numbness (75.9%) and constipation (69%), resting heart rate and diabetes duration was significantly associated with DCAN.CAN was highly prevalent in diabetic population that may lead to nephropathy and retinopathy in future. It is highly recommended to use sensitive and simple CARTs in clinics for early detection and early treatment of CAN. Diabetes mellitus (DM) is characterized by a high blood sugar level over a prolonged period and its mystifying nature led to pathophysiological alteration in almost all body systems, that causes economic, social and healthcare burden. Diabetes mellitus is a global epidemic that has affected 9.2% of adults globally in 2019.3Diabetes bring a lot of micro and macrovascular complications after its first onset.DCAN is an independent predictor of heart associated mortality and nephropathy, hence it is recommended to perform Cardiac autonomic reflex tests (CARTs) for assessment of subclinical DCAN at first time diagnosis of diabetes and every five years thereafter.There is no case-control study available from our population, only a few cross-sectional studies are available without utilization of five standard CARTs as recommended by American Diabetic Association. We designed this case-control study to identify and compare the frequency of asymptomatic CAN in Type-II diabetics and healthy controls, by utilizing full set of Ewing`s Gold standard CARTs in Type-II diabetics with no other comorbidities from Karachi, Pakistan.The present case-control study was carried out at Department of Medicine, Civil Hospital, Dow University of Health Sciences, Karachi, Pakistan from September` 2016 to May 2017. After taking ethical approval from DUHS IRB and Ethics Committee (IRB-508/DUHS/-14 Dated 9-10-2014). Total 144 study participants were included, 72 were T2DM clinically diagnosed cases while 72 were healthy controls, recruited through non-probability purposive sampling technique. Subjects were well informed for study procedure and informed consent was taken from each participant, detailed medical and family history of diabetes and demographics were measured carefully. T2DM patients who were otherwise healthy and with no history of previous or recent heart surgery, cardiac dysfunction, hypertension, apparent neuropathy/ nephropathy/ retinopathy and definite coronary artery dysfunction, were included in the study and vice versa were excluded. Those who were selected for study underwent Cardiovascular Reflex Tests (CARTs) for evaluation of CAN. Tests were performed by same examiner and on same device to avoid biasness in data collection.After initial rest of five minutes, blood pressure was recorded by using Mercury Sphygmomanometer  and standard 12 lead ECG was recorded by using Power Lab device, Lab Chart Pro-7 software and HRV analysis software module , and resting heart rate was automatically computed from lead II ECG recordings. All five Ewing`s cardiac reflex tests designed for the assessment of cardiac autonomic neuropathy were performed according to the procedure previously described in detail . Heart rHeart rate response to valsalva maneuver: HR change was expressed as the Valsalva ratio , (2) Heart rate response to deep breathing: The mean value of maximum minus minimum heart rates (beats per minute) for six breathing cycles was considered. , (3) Heart rate change on immediate standing: R-R intervals were measured at the 15th and at the 30th beat following beginning to stand. The HR response then expressed as 30:15 ratio , (4) Blood pressure response from lying to immediate standing: The SBP change after two minutes of standing up was measured as the change in response  and (5) Blood pressure response to sustained handgrip exercise: The mean difference highest DBP-value during and before exercise was considered as DPB response to exercise .Ewing`s CARTs consist of (1) Final diagnosis was based on combination of different test results: No CAN; when all five tests were normal or borderline), Early CAN; when only single Heart rate test was abnormal or two border-line, Definite CAN; when any two heart rate tests abnormal, Severe CAN; when any two heart rate tests abnormal plus either of the two Blood pressure tests abnormal.SPSS-20.0 was used for statistical data analysis. Quantitative data were presented as mean± SD and qualitative data were presented as frequency and percentage. ANOVA and t-tests were performed for quantitative and Chi square tests were performed to compare the categorical variables. Association of CAN with risk factors was identify by Logistic regression analysis. P-value less than 0.05 was considered statistically significant.2) were normal, yet significantly higher (P<0.05) in cases, with respective values in controls and cases were 22.01±4.3 and 24.78±3.9. Resting HR and resting SBP were significantly while DBP was insignificantly high in cases than controls , from both genders , respective mean age of controls and cases was 49.69±9.1 and 49.72±8.8 years, and this was not a significant difference (P>0.05). In both groups, mean values of BMI  in cases than controls . The oveDiabetes mellitus and its complications contribute to personal misery as well as constitute an economic burden on the resources of the society. The risk of developing cardiac autonomic neuropathy (CAN) among diabetics is associated with duration and magnitude of hyperglycemia. Usually, CAN showed a diverse spectrum of signs and symptoms, however, in case of diabetes, these manifestations are not apparent because autonomic nerve fibers become damaged and less sensitive to autonomic changes, unfortunately, it keeps silent for several years.Although, male participants were more in our study but, frequency of CAN was significantly higher (P<0.05%) in Type-2 diabetic females (44.7%) than males (35.3%). The present study results showed that females are more prone to develop CAN as compared to males. Most recent study from China, also depicted quite high frequency of DCAN, that is 80 out of 386 (20.72%) had DCAN in menopausal T2DM patients.case-control study to identify and compare the frequency of DCAN by utilizing the full set of five CARTs according to the guideline of American Diabetes Association, however, a few cross-sectional studies are available who did not utilize complete set of Ewing’s CARTs. Only one previously published study from Faisalabad, Pakistan, who performed five CARTs in Diabetics to find out the frequency of silent myocardial ischemia in diabetic patients, and it was depicted that even in such a small city of Faisalabad, the prevalence of DCAN was 53.8% with at least two CARTs positive in all patients.16Our study is first attempt from Pakistan to perform Another study from Hyderabad, PakistanThe present study will contribute considerable insight and data regarding DCAN from population of Karachi, Pakistan. The use of CARTs is not yet implemented in our society, we, appreciate the use of these simple and highly sensitive tests at clinics, at first time diagnosis of Type-2 diabetes and every five years thereafter, as recommended by American and Canadian diabetic associations.The strength of our study is that this is a case-control study and results can be compared easily in cases and controls, while in previous cross-sectional studies data from healthy controls was missing. Secondly, we have utilized complete set of Gold standard Ewing`s CARTs recommended by American Diabetes Association, so we are assertive for true results. Though study does not represent whole nation, yet Karachi being a metropolitan city we have data from people of different ethnicities of Pakistan and represented a broader view of this devastating complication of Diabetes.It is single centered study where most of the patients belong to low- or middle-class socioeconomic status, data from upper class is missing. Multicenter study may represent the actual burden of this disease in Karachi, Pakistan.Based on the present study findings, it is concluded that to prevent and reverse DCAN, it is important to use CARTs for early and cost-effective diagnosis, to incorporate lifestyle modifications and available therapeutic approaches. We recommend a multi-centered study at provincial level to find actual status of CAN in Pakistan among diabetic population.TN: Conception, research design, data collection, responsible and accountable for the integrity of the work.NNM: Manuscript preparation, Editing and proofreading, Review and final approval.KA: Research protocol, final drafting and review the manuscript.AS: Updated literature search and Statistical analysis, results computations.


Complex operations will be undertaken by a set of self-learning collaborating robots.• Knowledge and self-learning algorithms will become an important asset on the meat-packers balance sheet. Existing technology will be disrupted, and first movers will get ahead of their competition: The moment for decision is coming close.The wonderful story about Mr. Henry Ford visiting a Chicago slaughterhouse almost a hundred years ago is truly enjoyable. A meat-packers disassembly line inspired Ford Motor Company to organize its production in continuous assembly lines and sparked the industrial revolution further into higher efficiencies and fewer production flaws. The story makes people in the meat industry proud, and a visit to a modern slaughterhouse clearly demonstrates how far efficiency and productivity can be driven with sophisticated management systems, skilled employees, and highly specialized automation technology.Of course, there are big differences among the various species of animals that are being processed. In general, the level of automation is higher, the smaller the carcasses are. Poultry processors are usually highly automated, whereas beef processors are much less automated. The same observation goes for the line speed, where poultry processors can handle 20,000 carcasses per hour, pig processors 750 per hour, and beef processors 300 per hour.But the classical line production see  that we Another reason is that it is becoming increasingly difficult to attract workers to the meat industry. The work environment is strenuous and often the salary is low. Other sectors offer more attractive jobs, leaving the meat industry with a big recruitment problem.The supporting automation technology is yet another reason why we may see the end of line production in the meat industry . BecauseOn a more theoretical note, it can also be observed that the utilization of the automation technology is low and may be only 30% of the full capacity. This is the nature of line production due to the design. The automation technology is fitted to the production line and is awaiting the carcass to approach before the automation technology can perform the processing. Often the automation technology is standing idle a lot more than the processing time, and from an engineering point of view, this is highly inefficient and adds to production costs.When a production line is running at full speed, it has a high productivity, but experience shows that it is not uncommon that a single incident along the line causes line stops frequently. An uptime less than 80% is not uncommon and sometimes even as low as 50%. This clearly demonstrates the vulnerability of classical line production and the extreme demand for uptime of the automation technology fitted to the line. Keep in mind that any modern slaughterhouse receives animals on an ongoing basis and that breakdown can be detrimental to the inflow of animals and the preceding logistics. Uptime is king.So instead of designing the automation technology to fit the production line, why not design the production setup to fit the automation technology? We need to rethink the production design and it may well mean that we will reinstall the old cutting table where many processes were done by one operator in parallel instead of lines. In fact, this is exactly the development that the Computer Numerical Control (CNC) industry went through in the 1990s and that the automotive industry is going through more recently —migratinIdeally, a production cell is a delimited area where an item is being processed by numerous operations. It can be done by people, but in this context, it is the application of robots that makes it relevant. A robotic production cell can consist of one or more robots that process the carcass with many operations see .The robots will work simultaneously or even collaborate and ideally process an entire carcass including cutting and deboning. A robotic production cell is particularly relevant for larger carcasses due to the labor intensity and at this point lack of cost-efficient available automation technologies on the market.Why are robotic production cells interesting? Part of the answer lies in the fact that it enables much more powerful innovation. Until now, the meat industry and their technology providers have developed costly specialized automation technology, but the application of standardized industrial robots opens the door into the huge innovation storm that takes place in assembling industries . The autIn the pig industry, kill lines are already automated, and it is likely that robotic production cells will be a next-generation choice for technology providers. But a little further downstream, it has been almost impossible to automate the cutting and deboning areas. The product mix is high, production series may be short, and cutting operations are complex. In this situation, the robotic production cell is highly relevant and probably a feasible way to improve efficiency in this area.Robotic production cells will be organized in parallel to match the needed capacity of the slaughterhouse; basically, redundant robotic production cells that can perform the exact same operations. This redundancy implies that the risk of total production stops is much lower compared with the classical line production. If one production cell breaks down, the remaining production cells can still function, and production will continue although with a lower capacity. This is a huge advantage compared with the present situation.Establishing a robotic production cell is a big investment to any meat processor or technology provider. But the explosive development of technology creates a lot of tailwind. Sensors are key to the operation of the robots, and obviously, machine vision is an integral part of the function. The development is rapid, and cameras are becoming cheaper and more powerful year by year. Especially, three-dimensional-,Time-of-Flight-, and multispectral cameras are useful to give input to the robot control system in combination with tactile feedback systems .However, clever design of the tools mounted at the end-effector of the robots will make the entire operation much simpler. The correct choice of materials, design, and operation of the tools is the key to get optimal yields and correct product quality. Although tools are being designed as generic as possible to make sure that they can be used for several operations, they are still specialized to some extent. Therefore, more robots carrying different tools are needed. However, more robots are eating square meters, and there are never sufficient square meters available at the slaughterhouse. Automatic shift of tools is much preferred and will be a way to keep the footprint down of the robotic production cell.In the end, vast amounts of data are being created, and the control algorithms must be able to handle them sufficiently fast to be able to control the robot. Developing algorithms will be the true shift of paradigm, because the algorithms will not only be hard coded for a number of operations, but it will also be self-learning and adaptive. Once in operation, the algorithm will be improved based on the ongoing production. It can learn gradually about how to cut to other specifications, and it can accommodate the biological variation among each carcass, meat cut, or in longer terms, species change over time.The implications of this are huge because this is exactly what is needed to handle small production series and a complex product mix. Ideally, the robotic production cell can operate with an individual cutting pattern optimized for each individual item—a true hyperflexible production.As algorithms are self-learning, they will eventually become adapted to the products and procedures of the slaughterhouse. They will become part of the critical knowledge base that any company tries to protect and that is often part of the company’s competitive edge. Moreover, the algorithms represent a powerful way to transform tacit knowledge into solid documentation. The algorithms can be duplicated and proliferated, and in an international production setup, this is a powerful way to create an aligned and high-quality production, where trained algorithms can be introduced into new robotic production cells anywhere in the world. Furthermore, the algorithms can be interconnected across robotic production cells, across production plants, and across borders—what a powerful learning system!. Just like the roots of a tree. In a future not so far away, the algorithms may be the most important asset on the balance sheet.The concept of robotic production cells may hold the key to a new cell-based production paradigm at the slaughterhouse. However, to turn the idea into reality requires acting. To this end, the development of the world’s first robotic cell for pig production see  at a DanAs cell-based production completely disrupts the traditional line production, it is very challenging to integrate the robotic production cell into existing facilities. If it was possible to introduce cell-based production across the entire slaughterhouse at the same time, these challenges would of course not exist. However, the exploration of robotic production cells has only just begun, and a factory-wide installation is still very far away. A realistic path toward cell-based production will identify and replace parts of the traditional production line, and, therefore, solving problems related to integration is crucial. For this reason, the layout of the robotic production cell as well as the choice of products to be processed and how these will flow in and out have been considered. Six operations have been identified, all of which are carried out at the same location after the cold carcasses leave the chilling area and enter the primal cutting. The six processes are toe cutting, tenderloin extraction, ear cutting, stab wound removal, head cutting, and trisection. These choices make it feasible to install the robotic production cell in the existing production flow at the slaughterhouse.For the tests carried out, the carcasses are brought directly from the production and arrive in the test facilities hanging on rails from the ceiling. The carcasses are taken down onto a conveyor that carries the carcasses into the robotic production cell. After the carcass arrives inside the robotic production cell, it is analyzed with sensors and cameras to extract relevant information. The six operations are then executed by several robotic arms in parallel using dedicated tools developed for each individual task. Everything is orchestrated by a software control system running on a powerful PC next to the robotic production cell. The software is completely modular with key components running on separate threads in parallel to take full advantage of the available computing power. The software structure provides maximal flexibility and makes it easy to be extended with new modules, for instance for additional algorithms, sensors, cameras, tools, or robots.The core idea is to transfer the complexity from dedicated mechanical design to an intelligent software control system. This strategy keeps the cost down on custom machinery and adds the flexibility to reconfigure the system on the fly. It also drastically reduces the development time and facilitates the exploration of more innovative solutions for highly complex manual operations. The ongoing development at the test facilities is focused on intelligent control systems and smart tooling, including a generic fast tool change.One of the main challenges is designing the intelligent part of the control system. The question boils down to how the relevant information is extracted from various sensor and camera inputs to guide the robots. The progress in research and development in artificial intelligence, in particular deep neural networks , has madDesigning robust deep learning algorithms has always been difficult regardless of the application domain. However, the slaughterhouse takes the usual challenges to a new level due to the large variations in the input and the strict requirements on precision and capacity. Experienced butchers are both skilled and fast, and the individual processes are already highly optimized in the existing line production setup. Consequently, the algorithms must be very fast and extremely precise to make the robotic production cell a feasible replacement. The large biological variation and variations introduced from upstream processing by human operators or machines make this task extremely challenging.In the robotic production cell, the algorithms are provided with images of the carcass recorded by several three-dimensional cameras located inside the cell. During initial tests, it was quickly realized that common off-the-shelf deep learning algorithms, for instance, based on semantic segmentation  or objecAlthough several milestones have already been reached, many challenges still lie ahead. The robotic production cell test facility is a first attempt to bring the abstract concepts of multifunctional cell-based production into practice for the meat industry. The task is immense and, even when broken down into parts and solved one at the time, uncharted territory is explored for every step taken.So, what is next? Sometimes it is forgotten that intelligent control systems only provide intelligent solutions at the moment of creation. Automation solutions degrade over time because developers cannot predict what will happen in the future. Will the carcasses increase in size? Or maybe new machinery upstream introduces new physical features on the carcasses? Preparing for the next step, the potential application of a range of online learning algorithms is currently under investigation, for instance, reinforcement learning , which eThe digital development is so fast that even just understanding the new possibilities is a challenge. Everything becomes cheaper and Moore’s law  is also But there is an even more important aspect especially when it comes to capital expenditures and hardware. Hardware updates, new tools, new functionalities, new sensors, and so forth can be retrofitted in the cells. With the natural redundancy in a setup with robotic production cells, the actual retrofitting can be done simultaneously with production, and no stops are needed. A robotic production cell should not be looked upon as a complete machine but rather a versatile platform that continuously can be improved and adapted to new conditions.Most slaughterhouses are sorting carcasses based on value, size, and other parameters. There are millions of dollars hidden in correct sorting of the carcasses, which is basically to match carcass composition with customer specifications and expectations. Modern slaughterhouses have big cooling facilities to handle carcass variability. The reason is that the workers manually must cut to a certain specification based on the type of carcass that is being presented to them, and the only way to do that is to sort the carcasses in a cooling facility before fabrication.But that complexity disappears with the introduction of robotic production cells. In the ideal world, sorting is no longer needed because the production cell can cut the carcass optimally based on the biological variation. It assumes that there are sufficient appropriate customer orders received, but overall, it is a big simplification of the slaughterhouse logistics. A much simpler design is needed and energy for cooling can even be saved.As a bonus, it will be possible to introduce complete traceability down to each cut leaving the robotic production cell; a challenge that remains unsolved today and is currently handled with batch traceability in most cases.It has been demonstrated that it is possible to make a robotic production cell for a pig slaughterhouse. Technologies are available and the business case is very attractive. But of course, there is still a lot of work ahead.Technically there are three main areas that must be solved. First of all, it is necessary to develop a very fast shift of tools may be even on the fly. Robotic production cells will at least in the beginning need to be fitted into existing facilities, so a small footprint is essential. Shift of tools is common in other industries that use robots, but the challenge is the speed.Secondly, a sanitation system must be developed. Probably the most important thing with robotic production cells is that they enable production 24/7. The factory can increase its capacity maybe by 30% without adding any cost of production, and this is where the real business case for this production setup is hidden. This will require that the cells can be cleaned in place (CIP). Multiple robotic production cells create a high redundancy in the production system and, one cell can be cleaned, while the remaining cells are producing. There already exist CIP systems for robot solutions, but they have never been tested in slaughterhouses or in this kind of robotic production cells. Thirdly, logistics around the robotic production cells must be in place. Depending on how many operations the cell will be able to provide, the logistics around the cell will be complex. It is necessary with a simple conveyor design around the cell to make logistics as smooth as possible preferably without any transport boxes. It is easy to underestimate the risk of complex logistics, and in this case, it is not different.In the early days of automation, it was popular to state, that we want so much automation, that we can turn off the light in the factory, meaning that no people were necessary for the production. That statement is not relevant anymore, because robotic production cells still need skilled workers around them. Actually, the role of the workers will radically change. Today most of the work is standardized repetitive operations, where each operator is trained in a particular set of operations. With robotic production cells, the role of the operators is not only to oversee a set of cells but also to be the product quality expert. The skilled butcher will become very important, as their skills will be part of the learning input to the algorithms. If the cell meets a situation, where it does not know what to do, the skilled operator will teach the machinery, and the cell will have achieved a new learning input. The job will change from a blue-collar worker to a skilled technician. Jobs will be much fewer, but they will be better paid and less strenuous.How can the slaughterhouses get access to this kind of technology? As in all aspects of technology development, someone must be the first mover and probably that is the companies with the most urgent need. But beware that there is a dramatic disruptive potential in this technology. As a robotic production cell is basically a standard industrial platform, it opens for many more technology providers than the industry has today. Previous solutions were highly mechanized and integrated tying the slaughterhouse to the particular technology provider, but with this new production paradigm, the field is completely open, and any robot integrator would potentially be able to enter the arena. Moreover, the slaughterhouses will claim their rights to the algorithms, which will lower the bargaining power of the technology providers. Good news for the slaughterhouses and good news for new to the business technology providers, who wants to enter the arena. New technology also means new ways of working. Many slaughterhouses have agreements based on time studies or volumes, and these kinds of agreements will not make any sense with the new technology. As work moves from blue collar to technician type of work, the management approach must change accordingly.So, the first-mover will not only take the risk but also get ahead of their competition if it is a success and the moment for decision making is coming close.Self-learning robotic production cells, which are hyperflexible and which can be added with new features, both physically and digitally, represent a disruptive shift in the production paradigm in the meat industry. The circle is closed, and we are back to the cutting table. Maybe, the automotive industry will be inspired again a hundred years after the visit to Swift and Company’s slaughterhouse in Chicago.


Setting. Ophthalmology Division of San Rossore Medical Center, Pisa, Italy.  To evaluate clinical outcome during 24 months follow-up between small incision lenticule extraction combined with cross-linking (SMILE Xtra) and small incision lenticule extraction (SMILE) only.  Retrospective comparative case series.  The study comprised 70 eyes (35 patients); 40 eyes were corrected using SMILE and 30 eyes were corrected using SMILE Xtra using a low energy protocol. The outcomes were compared at 1, 6, 12, and 24 months postoperatively. p < 0.05). At 24 months the mean SEQs were −0.01 ± 0.24 D for SMILE and −0.15 ± 0.33 D for SMILE Xtra (p > 0.05). At 1, 6, 12, and 24 months, there were no statistically significant differences between the SMILE and SMILE Xtra groups in logarithm of the minimum angle of resolution (logMAR) uncorrected distance visual acuity (UDVA), safety, and efficacy index (p > 0.05). The mean average keratometry (K-avg) at 1, 6, 12, and 24 months after surgery did not shown any statistically significant difference between SMILE and SMILE Xtra group (p > 0.05). The mean maximum keratometry (K-max) readings at 1, 6, 12, and 24 months were not statistically significant between SMILE and SMILE Xtra group (p > 0.05). The preoperative mean thinnest point pachymetry (TTP) was 543.90 ± 22.85 μm in the SMILE group and 523.40 ± 37.01 μm in the SMILE Xtra group (p < 0.05). At 1, 6, 12, and 24 months the mean TTP was not statistically significant between the SMILE and SMILE Xtra groups (p > 0.05). At 24 months, the TTP was 408.29 ± 38.75 μm for the SMILE group and 402.22 ± 37 μm for the SMILE Xtra group (p > 0.05). In the preoperative period, the mean maximum posterior elevation (MPE) was 8.63 ± 4.35 μm for SMILE and 8.13 ± 2.54 μm for SMILE Xtra (p > 0.05). After the surgical procedure, both groups showed a statistically significant increase of the MPE (p < 0.05). At 24 months, the MPE was 11.00 ± 4.72 μm for SMILE Xtra and 10.14 ± 3.85 μm for the SMILE group (p > 0.05). In the preoperative period, the means of the root mean square (RMS) of high-order aberration (HOA) were 0.08 ± 0.03 μm for the SMILE group and 0.08 ± 0.03 μm for the SMILE Xtra group (p > 0.05). At 24 months, the RMS of HOA was 0.13 ± 0.07 μm for the SMILE group and 0.14 ± 0.07 μm for the SMILE Xtra group (p > 0.05). In the preoperative period, the root mean square of coma aberration (RMS-Coma) aberration was 0.06 ± 0.09 μm for the SMILE group and 0.04 ± 0.03 μm for the SMILE Xtra group (p > 0.05). At 24 months, the coma aberration of SMILE group was 0.12 ± 0.21 μm and 0.16 ± 0.25 μm for SMILE Xtra group (p > 0.05).  The mean spherical equivalent (SEQ) reduced from −7.18 ± 1.21 D to −0.01 ± 0.09 D in the SMILE group and from −6.20 ± 2.99 D to −0.04 ± 0.1 D postoperatively in SMILE Xtra ( SMILE Xtra procedure is a safe and simple procedure that can be offered to patients with high corneal ectasia risk because there were no differences in the indices of ectasia compared to the group treated only with SMILE which has a low corneal ectatic risk. The decision for refractive surgery in patients with high myopia, borderline topography, and thinner corneas is challenging. One of the most feared complications is postoperative ectasia, a progressive steepening, and thinning of the cornea –4.Collagen cross-linking (CXL) has been proven to be an effective modality to strengthen and stabilize the cornea in keratoconus and ectasia after corneal refractive surgery –8. CXL hThe small incision lenticule extraction (SMILE) technique provides a biomechanically stronger cornea since it preserves the integrity of the anterior cornea. Although a large case series has demonstrated an excellent safety profile for SMILE , cornealThe purpose of this study is to assess the 2-year clinical outcome of a series of small incision lenticule extraction combined with cross-linking (SMILE Xtra) cases using a low-energy protocol compared to SMILE alone.This study was a retrospective interventional comparative study. The patients of the current study signed an informed consent before the intervention. The study was approved by the Institutional Ethics Committee and adhered to the tenets of the Declaration of Helsinki. The data were anonymized or maintained with confidentiality.The first group included 30 eyes of 15 patients who underwent SMILE Xtra procedure. The second control group included 40 eyes of 20 patients, who were treated with the SMILE procedure only. Inclusion criteria of the study included moderate to high myopia with baseline spherical equivalent (SEQ) higher than 4 diopters, and all eyes had a emmetropic target refraction.μm, established keratoconus, family history of keratoconus or eye rubbing [Exclusion criteria included subjects with corneal thickness <450  rubbing , hyperopAll included patients had preoperative complete ophthalmic clinical examination including slit-lamp examination, intraocular pressure measurement, fundus examination, dry eye assessment, cycloplegic refraction, uncorrected distance visual acuity (UDVA), and corrected distance visual acuity (CDVA) measured with Snellen chart at 6 m, which was converted to minimum angle of resolution (logMAR) value. According to the Randleman Scoring for ectasia risk, eyes were classified into low (score ≤2), and moderate to high risk (score ≥3) . The SMIμm; cap diameter 7.0–7.5 mm; lenticule diameter 6.0–6.5 mm with a transition zone of 0.1 mm; cut energy 1.4 J; spot and tracking distance 2.0–3.0 μm. A 2 mm incision located at 10 o'clock position for both eyes was performed. A blunt spatula was used to separate the lenticule, which was then removed by forceps through the incision. Finally, the corneal interface was flushed with balanced salt solution. In SMILE Xtra cases, after lenticule removal, 0.22% riboflavin with saline  was injected through the small incision into the interface and left to soak for 90 seconds, followed by UV-A irradiation at 30 mW/cm2 for 90 seconds  using the Avedro KXL system.A single surgeon performed all the surgeries (M.F.) using an established technique under topical anesthesia. The SMILE procedure was performed using the 500 kHz VisuMax femtosecond laser (Carl Zeiss Meditec). The following parameters were used: cap thickness 130–140 Postoperative medications included ophthalmic topical tobramycin 0.3% and dexamethasone 0.1% suspension four times a day for 1 week and then steroids eye drops were tapered over 1 month. Finally preservative-free artificial teardrops were given for 3 months postoperatively. All patients were examined preoperatively and postoperatively at day 1, 1 week, 1, 6, 12, and 24 months.K-avg), maximum keratometry (K-max), corneal astigmatism, thinnest point pachymetry (TTP), mean maximum posterior elevation (MPE), means of the root mean square of high-order aberration (RMS-HOA), and root mean square of coma aberration (RMS-Coma). The efficacy index was calculated as the ratio of postoperative UDVA to preoperative CDVA, and the safety index was determined as the ratio of postoperative CDVA to preoperative CDVA.The visual acuity (Snellen chart at 6 m) was converted to logMAR value, and refraction was recorded at 1, 6, 12, and 24 months. The corneal tomography , corneal topography  and aberrometry  were performed. The following data were recorded: average keratometry . The parameters between SMILE Xtra and control group were compared with MannWhitney p > 0.05). According to the Randleman Scoring, 30 SMILE Xtra eyes (100%) had an ectasia risk factor score of 3 or higher (moderate/high risk). In the control group, 40 eyes (100%) had a score of 2 or lower (low risk). No intraoperative or postoperative complications occurred in either group. Postoperatively, there was no clinically detectable corneal haze in all cases.A total of 40 eyes for the SMILE group and 30 eyes for the SMILE Xtra group was included for analysis. The baseline demographic and preoperative data are summarized in p < 0.05). At 12 months, the mean errors in the correction in the SEQ were −0.01 ± 0.21 D for SMILE and −0.09 ± 0.18 D for SMILE Xtra (p > 0.05). The mean errors in the correction in the SEQ at 24 months were −0.01 ± 0.24 D for SMILE and −0.15 ± 0.33 D for SMILE Xtra (p > 0.05)  achieved UDVA 20/20 and only 2 eyes had UDVA 20/25. In the SMILE Xtra group, 29 eyes (96.66%) achieved UDVA 20/20 and only 1 eye had UDVA 20/25. At 24 months, in the SMILE group, 39 eyes (97.5%) achieved UDVA 20/20 and only 1 eye had UDVA 20/25. In the SMILE Xtra group, 29 eyes (96.66%) achieved UDVA 20/20 and only 1 eye had UDVA 20/25 .There was no statistically significant difference in logMAR UDVA at 1, 6, 12, and 24 months after surgery between the SMILE and SMILE Xtra groups (p > 0.05).The safety index and efficacy index of both groups at 1, 6, 12, and 24 months are summarized in K-avg values among SMILE and SMILE Xtra group  . At month 24 after surgery, no statistically significant difference in K values between the two groups  was observed.Preoperatively, there was no significant difference in  > 0.05) . The K-aK-avg at month 1, 6, 12, and 24 months after surgery, did not show any statistically significant difference between the SMILE and SMILE Xtra groups (p > 0.05).As shown in K-max values difference was not statistically significant in preoperative time between the SMILE and SMILE Xtra groups. After the surgical procedure, both groups showed a statistically significative increase of K-max (p < 0.05). The K-max readings at 1, 6, 12, and 24 months were not statistically significant between the SMILE and SMILE Xtra groups (p > 0.05) (The  > 0.05) .μm in the SMILE group and 523.40 ± 37.01 μm in the SMILE Xtra group (p < 0.05) (p < 0.05). At 1 month, the TPP means were 403.83 ± 35.51 μm for the SMILE group and 399.40 ± 40.82 μm for the SMILE Xtra group (p > 0.05). At 6 months, the TPP means were 407.94 ± 37.05 μm for the SMILE group and 394.45 ± 38.00 μm for the SMILE Xtra group (p > 0.05). At 12 months, the TPP means were 414.03 ± 36.28 μm for the SMILE group and 402.16 ± 39.52 μm for the SMILE Xtra group (p > 0.05). At 24 months, the TPP means were 408.29 ± 38.75 μm for the SMILE group and 402.22 ± 37 μm for SMILE Xtra (p > 0.05) (The means of the postoperative TPP were 543.90 ± 22.85  < 0.05) . After t > 0.05) .μm for SMILE and 8.13 ± 2.54 μm for SMILE Xtra (p > 0.05) (p < 0.05). At 1 month, the MPE means were 13.22 ± 5.86 μm for the SMILE Xtra group and 12.65 ± 5.85 μm for the SMILE group (p > 0.05). At 6 months, the MPE means were 14.81 ± 7.02 μm for the SMILE Xtra group and 12.47 ± 7.33 μm for the SMILE group (p > 0.05). At 12 months, the MPE means were 11.54 ± 5.15 μm for the SMILE Xtra group and 11.13 ± 4.39 μm for the SMILE group (p > 0.05). At 24 months, the MPE means were 11.00 ± 4.72 μm for the SMILE Xtra group and 10.14 ± 3.85 μm for the SMILE group (p > 0.05)  . After t > 0.05) .μm for the SMILE group and 0.08 ± 0.03 μm for the SMILE Xtra group (p > 0.05) (p < 0.05). At 1 month, there was no statistically significant difference between the SMILE (0.17 ± 0.10 μm) and SMILE Xtra groups (0.17 ± 0.09 μm) (p > 0.05). At 6 months, the mean RMS-HOA was 0.20 ± 0.20 μm for the SMILE group and 0.19 ± 0.14 μm for the SMILE Xtra group (p > 0.05). At the 12-month follow-up, the mean RMS-HOA was 14 ± 0.07 μm for the SMILE group and 0.12 ± 0.06 μm for the SMILE Xtra group (p > 0.05). At 24 months, the mean RMS-HOA was 0.13 ± 0.07 μm for the SMILE group and 0.14 ± 0.07 μm for the SMILE Xtra group (p > 0.05)  . After t > 0.05) .μm for SMILE and 0.04 ± 0.03 μm for SMILE Xtra (p > 0.05) (p > 0.05). At 1 month, the mean RMS-Coma aberration was 0.12 ± 0.15 μm for SMILE and 0.16 ± 0.18 μm for SMILE Xtra (p > 0.05). At 6 months, the mean RMS-Coma aberration was 0.14 ± 0.34 μm for the SMILE group and 0.08 ± 0.10 μm for the SMILE Xtra group (p > 0.05). At 12 months, the mean RMS-Coma aberration was 0.06 ± 0.07 μm for the SMILE group and 0.06 ± 0.05 μm for the SMILE Xtra group (p > 0.05). At 24 months, the mean RMS-Coma aberration of SMILE was 0.12 ± 0.21 μm and 0.16 ± 0.25 μm for the SMILE Xtra group (p > 0.05)  . After t > 0.05) .forme-fruste keratoconus [SMILE is a flapless procedure with the theoretical advantage of producing less weakening of the cornea, since the cap thickness contributes to the residual stromal bed. For this reason, SMILE is better option in treating higher myopic errors, thinner corneas, and cases with abnormal topography or atoconus , 18. Desatoconus , 19–21.Any corneal laser refractive procedure would certainly decrease the biomechanical stability of the cornea. Combining corneal collagen cross-linking with PRK or LASIK showed good results and has come into practice , 22. In 2 for different durations, with a total energy of 1.8 to 5.4 J/cm2, and all those different regimens proved to be safe and effective [The aim of SMILE Xtra is to deliver the least amount of energy that can stabilize the cornea. Excess energy may cause haze while too little energy may be insufficient to ensure corneal strength. Whereas established CXL protocols for treating keratoconus with long-term follow-up have been shown to be safe and effective , there affective , 18, 22.2 (30 mW/cm2 for 90 seconds). This amount of energy proved to be safe and well tolerated [2 of energy delivered for 75 seconds  [2 for 45 seconds  [2 total energy [In the preoperative time, the SMILE Xtra eyes had a significantly thinner TPP than the control and topographic alteration with an increased risk of ectasia. Our CXL protocol for the SMILE Xtra procedure involves the application of riboflavin directly to the stromal pocket after lenticule extraction followed by UV-A irradiation with a total energy of 2.7 J/cmolerated , as none4 J/cm2) . Ng et a8 J/cm2) . Graue-Hl energy .In our study, both SMILE and SMILE Xtra results showed excellent refractive outcomes. The UDVA were comparable between two groups, with refractive predictability reported in the literature , 29, 30.K-avg and K-max values, with no statistically significant difference from the SMILE group. Before the surgical procedure the TPP between the SMILE and SMILE Xtra showed a statistically significant difference. The SMILE Xtra group showed stable TPP from the 6th to 24th month of follow-up. The difference between the study and control group is not statistically significative at 24 months. Also, the MPE showed stable results during the 24 months of follow-up, with no statistically significant difference with SMILE group. The SMILE Xtra aberrometric data demonstrate no statistically significant differences with SMILE group for both RMS-HOA and RMS-Coma aberration.Regarding keratometry, the SMILE Xtra group showed stable The advantages of the current study are the comparative nature with a control group of SMILE cases and a follow-up period of 24 months. The limitations of our study are the retrospective nature of the study, the requirement of more cases, and need for a longer duration of follow-up to record the long-term effects. Moreover, it was not possible, until now, to evaluate the surgical techniques SMILE vs SMILE Xtra composed of only high-risk subjects in both groups, in order to reduce confounding variables.In conclusion, SMILE Xtra procedure is a safe and effective procedure that can be offered to patients undergoing SMILE with corneal ectasia risk.


The construction of a harmonious society requires college students to coordinate their ideological, political, and moral qualities with social development and the needs of the times. Through the investigation and analysis of the ideological, political, and moral qualities of college students, on the one hand, we can see that the ideological, political, and moral qualities of college students are generally positive and healthy. On the other hand, it also exposes the outstanding problems in the ideological and political aspects of college students and the shortcomings of the ideological and political work in colleges and universities. This paper analyzes the dynamic changes of college students' ideological and political changes and further studies the relationship between various indicators and students' ideological and moral qualities through multiple linear regression analysis. Colleges and universities are an important stage for ideological and political education for young students, and the ideological and political quality of college students is also a major criterion for evaluating the effectiveness of college education. With the continuous improvement of the socialist market economic system, the rapid development of the economy, society and science, and culture, and the integration of Chinese and foreign cultures, many new changes have taken place in the ideological values of current members of society, and some even have contradictions. As the successors and builders of the cause of socialism with Chinese characteristics, the ideological and moral conditions of contemporary college students have also appeared some new changes, new characteristics, and new conditions. In some college students, there are situations such as loss of ideals and beliefs, lack of social responsibility, a weakened spirit of hard work, and a weak concept of teamwork. At the same time, due to the continuous expansion of colleges and universities in my country in recent years and the influence of the global economic recession, new requirements have also been put forward for the ideological and political education work in colleges and universities. In this environment, it is very important and urgent to further strengthen the ideological and political education work of college students. For any society, college students are the most valuable human resources and the hope and future of a country and nation. Do a good job in the ideological and political education of college students, improve their ideological and political level, and train them to be builders and successors of the socialist cause with firm political beliefs and lofty political ideals. This will ensure the healthy and sustainable development of the socialist cause with Chinese characteristics. It has long-term and important strategic significance , 2. The In recent years, with the continuous development of my country's reform and opening up and the gradual improvement of the market economy system, many new situations, new characteristics, and new changes have emerged in the ideological and political quality of contemporary college students , 6. On tAll in all, the ideological and political quality of college students is related to the future and destiny of the country and the nation. Whether they can cultivate qualified and excellent builders and successors who meet the requirements of the cause of socialism with Chinese characteristics, it can be said that the ideological and political work of colleges and universities plays a vital role in it. . Under tStepwise regression: the basic idea of the stepwise regression analysis method is to automatically select the most important variables from a large number of available variables and establish a prediction or interpretation model for regression analysis. The basic idea is that the independent variables are introduced one by one, and the condition of the introduction is that the partial regression sum of squares is significant after testing. At the same time, each time a new independent variable is introduced, the old independent variables should be tested one by one, and the independent variables with insignificant partial regression sum of squares should be eliminated. In this way, it has been introduced and eliminated until neither new variables are introduced nor old variables are deleted. Its essence is to establish the “optimal” multiple linear regression equation. According to the above idea, stepwise regression can be used to screen and eliminate variables that cause multicollinearity. The specific steps are as follows: first is to perform a simple regression on each explanatory variable considered with the explanatory variable and then use the explanation that contributes the most to the explanatory variable. Based on the regression equation corresponding to the variable, the remaining explanatory variables are gradually introduced. After a stepwise regression, the explanatory variables that remained in the model were both significant and did not have severe multicollinearity.MATLAB is commercial mathematical software produced by MathWorks in the United States. It is used in data analysis, wireless communication, deep learning, image processing and computer vision, signal processing, quantitative finance and risk management, robotics, control systems, and other fields. MATLAB is a combination of the words matrix and laboratory, which means matrix factory (matrix laboratory). The software mainly faces the high-tech computing environment of scientific computing, visualization, and interactive programming. It integrates many powerful functions such as numerical analysis, matrix calculation, scientific data visualization, and modeling and simulation of nonlinear dynamic systems in an easy-to-use window environment for scientific research, engineering design, and many sciences that must perform the effective numerical calculation. Realm provides a comprehensive solution and is largely free from the editing mode of traditional noninteractive programming languages , 12  and part-time work (29.7%) are their main social practices. It can be seen from this that contemporary college students have few opportunities for social practice in ideological and political education, and their social practice ability has not been effectively improved, which leads them to place great expectations on social practice. At the same time, most colleges and universities believe that there are problems in the base construction, time arrangement, funding guarantee, and system establishment of social practice. Therefore, it is necessary to pay more attention to and strengthen the social practice work of college students, strive for local support, strengthen the construction of social practice bases, and guide students' social practice activities to develop in a long-term, positional, project-based, and hierarchical direction. Efforts should be made to explore the daily form of social practice activities and use weekends or other spare time to choose the community near the school as a fixed social practice base to carry out social practice activities.The peer groups of college students mainly include classmates, roommates, and members of clubs. Because college students get along with their peers day and night, have the same hobbies, similar life experiences, and have the same troubles and needs, they influence each other infrequent interactions, and especially in specific behaviors, they play a dominant role. The survey data in The influence of peer groups is mainly through good friends. The survey shows that middle school classmates (85.1%), college classmates (76.0%), and roommates (73.5%) are the main objects within the scope of college students' good friends. At the same time, the good friends of college students have also included some new objects, such as fellow villagers (32.7%), members of group organizations or student unions (17.6%), members of clubs (15.0%), netizens (11.7%), class teachers (9.8%), classroom teachers (9.8%), and counselors (9.1%). Once you understand the main scope of good friends for college students, you can start with these objects in a targeted manner and achieve the goal of ideological and political education through the familiarity and example of good friends. At the same time, the dormitory atmosphere is also an important factor affecting the ideological and political education of college students. According to the survey, “study” (51.3%) is the eternal theme discussed by college students in the dormitory. “Daily trifles” (32.3%), “employment prospects” (31.7%), “current affairs news” (31.3%), and “things happening in the class and school” (29.3%) were also discussed in the “squatting meeting” main content see . Therefox1, x2, ..., xm on y, the factors are introduced into the regression equation one by one from large to small. For the factors that have been introduced into the equation, after the introduction of new factors, they may be eliminated from the equation at any time because they have no significant effect on y. After the variable is introduced, it can also be put back in order to obtain a regression equation with some optimal properties [Stepwise regression is a common mathematical method for selecting regressors in multiple linear regression models , 10. Theoperties  and studoperties . It shouoperties . Many vaoperties . The foloperties  in the MF of the regression model, and the significant probability P associated with the analysis.The parameters of the regression equation are shown in x1), handling affairs (x2), morality and ethics (x3), participation in public welfare social practice (x4), laws and regulations (x5), love marriage (x6), successful employment (x7), and ideal beliefs (x8), were selected into the regression equation, while other variables were eliminated from the original regression equation. Using y to represent the event duration, the established multiple linear regression model isThe 16 variables in Figures It can be seen from the above formula that among the eight independent variables of the equation, ideal beliefs have the greatest impact on ideological and political changes. In addition, two variables, dealing with affairs and love and marriage, also have a large effect on the duration.The constant term in the regression equation is large, which makes the equation predict ideological and political changes, even if the values of all variables are 1, the minimum predicted value is 28.9. That is to say, for small events with small changes, the prediction of the equation will generally be too large.P  = 0).As can be seen from In order to examine the validity of the regression model, 170 groups of actual event data are used to test the prediction effect of the regression equation. The results are shown in As can be seen from α=0.0 and performed a nonparametric one-way ANOVA. The results show that  P=0.0058 < α, which shows that the multiple linear regression equation has significant statistical significance, and the prediction can basically obtain a satisfactory prediction effect. Finally, we use the above data to prove the feasibility of our model.In order to verify the significance of the prediction of the developed multiple regression model, this study took the significance level This paper conducts a step-by-step regression analysis of the ideological and political change group data of 660 students in a university and establishes the ideological and political dynamics with 8 variables of handling affairs, morality, participation in public welfare social practice, laws and regulations, love and marriage, successful employment, and ideals and beliefs. The multiple linear regression model of change prediction was used, and the prediction accuracy of the prediction model was tested with another 170 sets of data. The correlation coefficient between the predicted value and the actual value was as high as 0.8573. This shows that the multiple linear regression model proposed in this paper can more realistically reflect the duration characteristics of events and can basically obtain satisfactory prediction results. If more and more detailed data can be obtained for the establishment of multiple regression prediction models, it is believed that the prediction accuracy will be further improved. However, due to the extensiveness, randomness, and complexity of the factors that affect the duration of events, the author believes that even the best algorithms cannot predict the duration of events very accurately. It is hoped that the research in this paper can provide some guidance and reference for the development of college students' ideological and political development.