The alternative silica sources were RHA and residual diatomaceous earth (RDE) from the beer industry. The geopolymer mixture substituted the lime–pozzolan mixture for 30% replacement in weight. The hybrid systems showed better mechanical strengths for the short and medium curing ages in relation to the lime–pozzolan mixtures. Thermogravimetric analyses were performed to characterise the types of products formed in these mixtures. In the durability studies, hybrid systems better performed in freeze–thaw cycles and obtained lower capillarity water absorption values.This work studies the possibility of using geopolymer materials to enhance the mechanical and durability properties of hydrated lime–pozzolan mixtures, which gave rise to the so-called “hybrid systems”. Two different waste types were used as pozzolan in the lime–pozzolan system: rice husk ash (RHA) and spent fluid catalytic cracking (FCC). The geopolymer fabricated with FCC was activated with commercial reagents (NaOH and Na Both the restoration and conservation of cultural heritage must be carried out to ensure compatibility with the original materials, while also meeting certain durability and mechanical strength standards.The latter is important for those buildings constructed in seismic areas . The her2 and perlite to the mixture. These authors concluded that adding nano-TiO2 and perlite produced lower compressive strengths than mortars with only lime and pozzolans but, in turn, the behaviour related to resistance to salts attacks was better.In recent decades, many studies have focused on restoring ancient buildings employing mixtures of lime with natural and artificial pozzolans ,5,6,7. FDespite many publications having studied its properties, using lime–pozzolan mixtures is a less developed research line than the cement–pozzolan mixture. In the present work, two pozzolans for which studies endorse their use were tested: rice husk ash (RHA) and spent fluid catalytic cracking (FCC) residue.RHA employed as pozzolan in mixtures with lime has been previously studied under different conditions. Pavia et al.  studied Arizzi and Cultrone  comparedOther monuments that have remained in perfect condition throughout history, whose construction has aroused interest, are the pyramids of Egypt. Davidovits is the creator of the term “geopolymer”, and bases much of his research on the theory that the binder of these pyramids is mainly a mixture of natron, crushed limestone, clay, lime and water . By applUsing lime in alkaline activation mixtures has been explored in many research works. In the majority of them, the use of lime is limited to quantities between 1 and 20%, but normally at <10% ,17,18,19This study proposes employing alternative geopolymeric materials  t2SiO3  were utilised to prepare alkaline-activating solutions.Hydrated lime CL90-S (according to UNE-EN 459-1 ) was useThis study employed: spent FCC residue, supplied by BP Oil España S.A.U ; RHA from Dacsa S.A ; RDE, which came from Heineken España . The chemical compositions of these materials are shown in These materials’ particle size distributions, as determined by a laser dispersion analysis, are depicted in 2SiO3), and the second with alternative alkaline-activating solutions based on NaOH and alternative silica sources (RHA or RDE). All the activating solutions were prepared at a SiO2/Na2O molar ratio of 1.17, a water:binder ratio of 0.6 and 1.69 mol of Na2O per kg of precursor [The geopolymeric binder was produced using two different alkaline activating solutions: the first with commercial reagents , “RHA” for an alternative solution using RHA as the alternative silica source and “RDE” for an alternative solution employing RDE as an alternative silica source. For example, a mortar named H-FCC/RHA represents a hybrid mortar using 70 wt.% of lime–FCC  and 30 wt.% of FCC (a precursor of a geopolymeric binder) activated with an alternative alkaline-activating solution based on RHA.The nomenclature assigned to the traditional mixtures based on lime–pozzolan is “T-X”, where “T” indicates a traditional mixture and “X” is related to the used pozzolan: “FCC” or “RHA”. For hybrid systems, the adopted nomenclature is H-X/Y, where “H” indicates hybrid systems, “X” is related to the pozzolan used in the previously explained traditional mixture (lime–pozzolan) and “Y” denotes the type of alkaline-activating solution: “C“ stands for commercial solution , and cured under the same conditions, were prepared according to the microstructural analysis.3) for 3, 7, 28 and 90 curing days. The TGA in pastes was carried out for 3, 28 and 90 curing days by TGA 850 Mettler-Toledo equipment. Experiments were performed at a heating rate of 10°C min−1 from 50 °C to 600 °C in a nitrogen atmosphere using pin-holed aluminium-sealed crucibles. The microstructure of the selected pastes was assessed by field emission electron microscopy (FESEM). Images were taken at 2kV and samples were previously carbon coated.A universal test machine was used for the compressive strength tests of the cubic specimens  were used for the durability tests. The capillarity water absorption coefficient (CWAC) was determined following the procedure described in UNE-EN 1015-18 [Prismatic specimens  after 90 curing days regardless of the employed pozzolan type.2SiO3 reagent production [Properties were enhanced for the hybrid binders containing lime–FCC. After comparing the effect of the alkaline-activating solution on the compressive strength of the H-FCC/Y systems, the RHA employed as an alternative silica source gave better results than RDE and the commercial reagents. Moreover, the hybrid mortars prepared using RDE as an alternative silica source yielded a similar compressive strength to the hybrid systems using commercial reagents for 3–28 curing days. These results are very interesting from an environmental point of view because of the high carbon footprint associated with Naoduction . The effoduction .2O3 employed in mixtures to form C-(N)-A-S-H gels.For the H-RHA/Y systems, a similar trend was observed independently of the type of alkaline-activating solution: commercial reagents, RHA and RDE as alternative silica sources. The maximum compressive strength (about 20 MPa) was achieved after 90 curing days for H-RHA/C. The fact that the results were similar was probably due to the smaller amount of amorphous AlThe geopolymeric binder generally improved the compressive strength for the proposed hybrid systems, which obtained good values at 3–7 curing days. This fact could contribute to the large-scale application of these new hybrid binders to the conservation and restoration of cultural heritage.In view of the results obtained, we can assume that another possible application of these mortars could be in the manufacture of simple prefabricated elements such as curbs, tiles, pavers, etc.All the specimens were water saturated for 24 h and then weighed under dry-surface-saturated (SSD) conditions before the freeze–thaw cycles. Specimens were measured after the 6th and 30th freeze–thaw cycles to make comparisons to the initial values (0 cycles). All the assessed systems presented incremented mass for the 6th freeze–thaw cycle vs. the initial mass to yield up to 12%. This was probably due to the entrained water in cracks/microcracks caused by water volume variation ,29. AfteThe values of the flexural and compressive strengths of the mortars after the cycles are represented in Compressive strength was less affected, and all the loss percentages were below 50%. Once again, hybrid systems achieved similar losses to traditional lime–pozzolan systems. No significant differences were found for using RHA or FCC. For comparison purposes, T-FCC yielded 10.22 MPa in compressive strength after 30 cycles, whereas H-FCC/RHA and H-FCC/RDE yielded 16.43 and 16.46 MPa, respectively. This finding means that the mechanical properties for the hybrid systems after the freeze–thaw cycles were significantly better than for the traditional hydrated lime–based system. Similarly to RHA, T-RHA had 6.92 MPa compressive strength after 30 cycles, whereas the corresponding hybrid systems with RHA and RDE obtained 12.04 MPa and 11.95 MPa.The good behaviour found indicates that these mixtures would be suitable for applications in aggressive freeze–thaw environments.Capillary water absorption is directly related to pore structure characteristics: size, pore shape, connectivity, among other factors . An inveAs the results of the resistances revealed, the influence of using a setting accelerator had positive effects during the first 24 h of curing. At 28 curing days, both resistances came very close to the results of the mortars without the setting accelerator.2min0.5). For example, the value of the mortar with MK was 1.4 kg/(m2min0.5). These values are consistent with those obtained in the present work.Throughout the entire series, the lime–pozzolan mixture values were higher than those of their respective hybrid mortars containing geopolymer. Lime–RHA was the mortar with the highest CWAC value. The CWAC values in the lime and lime–pozzolan mortars obtained by Veiga et al.  were 1.12O3/SiO2 from FCC by alkaline activation [tivation . In a pativation .It seemed evident that the geopolymeric reaction predominated when the geopolymeric binder was added to the binary lime–FCC system, and the presence of an alkaline activator promoted the formation of new products. These data agree with those obtained by other authors who confirmed in MK/lime pastes with a higher concentration of hydroxides  that geopolymeric gel predominated over pozzolanic products, which became secondary products ,38. Rega-The hybrid binder improves compressive strength and yields good values at 3–7 curing days.-The systems with alternative silica sources obtain similar results to commercial reagents. This is a very important goal for achieving more environmentally friendly systems.-The CWAC values of the hybrid systems are lower than those of their respective traditional systems. This behaviour is positive in durability terms.-The mechanical properties after the freeze–thaw cycles for the hybrid systems are significantly better than for the traditional hydrated lime-based system.-The TGA performed with the cured pastes shows that the nature of cementing gels changes with the presence of geopolymeric binders, and the consumption of hydrated lime is completed at early curing ages because of C(N)-A-S-H gel formation.The present research work demonstrates the viability of using various waste types from different sources as construction material. Hybrid mortars can be employed as restoration materials with better mechanical performance than pozzolan–lime mortars. We conclude that:


Avian coronavirus (AvCoV) adapted to BHK-21 cells was passaged 15 times in VERO cells, the virus load and the variants at each passage being determined by RT-qPCR and genome-length deep sequencing. From BHK-21 P2 to VERO P3, a trend for the extinction of variants was followed by stability up to VERO P11 and both the emergence and the rise in frequency in some variants, while the virus loads were stable up to VERO P12. At the spillover from BHK-21 to VERO cells, variants that both emerged, showed a rise in frequency or were extinguished were detected on the spike, while variants at the M gene showed the same pattern only at VERO passage 13. Furthermore, nsps 3-5, 9 and 15 variants were detected at lower passages compared to the consensus sequences, with those at nsp3 being detected in the spectra also at higher passages. This suggests that quasispecies coronavirus evolution in spillovers follows the virus life cycle, starting with the evolution of the receptor binding proteins, followed by the replicase and then proteins involved in virion assembly, keeping the general fitness of the mutant spectrum stable.To understand the population genetics events during coronavirus host switches, the Beaudette strain of  Avian coronavirus (AvCoV) , for which chickens  are the natural hosts, can be isolated in chicken embryo eggs but is of a rather fastidious growth in cell cultures  at the 5’ and 3’ ends of approximately 500 nt each; all but the N gene are structurally poly but functionally monocistronic and include a leader sequence at the 5’ end with transcription regulating sequences (TRS) complementary to the leader upstream of each ORF .The 5’ two-thirds of the genome encode the replicase polyprotein that gives rise to 15 nonstructural proteins  via proteolytic cleavage by nsps 2 (picornavirus 3C-like protease) and 3 (papain-like protease). Those 15 proteins, including nsp12, the RNA-dependent RNA-polymerase, and nsp14, a 3’-5’ exonuclease, are involved in the replication and transcription steps .On the envelope, the spike protein, with 1,163 aa, is found in a trimeric form, with 20 nm projections above the surface of the envelope; each monomer is composed of the S1 amino-terminal external (with the receptor binding site) and the S2 carboxi-terminal internal (with the fusogenic motif) domains .Downstream of the S gene, one finds gene E (99 aa), which codes for the envelope protein, an essential protein for the assembly of virions, together with the M (membrane) protein (223 aa) that comes next on the genome order. The most 3’ gene codes for the nucleocapsid N protein (409 aa), an RNA-binding phosphoprotein that makes the coronavirus helical nucleocapsid . FurtherAvCoV readily replicates on the respiratory, reproductive and enteric tracts as well as in the kidneys of chickens but has also been found to have switched hosts to wild birds and other domestic species, such as turkeys and quail ,b. Host Due to its role in receptor binding, the spike protein is considered the main vector in coronavirus interspecies jumps, as it overcomes the receptor diversity barrier among different host species . NonetheTo overcome these limitations, this manuscript reports the complete genome quasispecies evolution of AvCoV after an artificial spillover from BHK-21 (baby hamster kidney) to VERO (African green monkey) cell lines as an experimental evolution model to help uncover coronavirus population genetic features that could be markers of interspecies jumps.Mesocricetus auratus, monlolayyer passage number=110) with a virus load of 9.50E+06 genome copies/µL was used as the ancestor virus. VERO cells  were purchased from the Adolfo Lutz Institute, Brazil and maintained in MEM with 10% fetal calf serum (FCS) at 37 ºC.The Beaudette strain of AvCoV lineage GI-1 at the second passage in BHK-21 cells  under 100x magnification in a light microscope. The monolayers were then frozen at -80 °C, and the same procedures were used for the following passages.3 to 109 copies per reaction  normalized to β-actin.Genome copy numbers in each passage, in the ancestor virus, and in the mock passages were determined by qPCR as described by Total RNA was extracted using TRIzol® LS (Ambion) and RNeasy® Mini kit (Qiagen) after supernatants from the ancestor virus and from the 15 passages in VERO cells were filtered through 0.45 µm filters and treated with Turbo™ DNase (Ambion) and RNase™ Cocktail Enzyme mix (Ambion) per the manufacturer’s instructions.. Reads were then obtained in a NextSeq500 MID Output 300 System (Illumina) (2 x 150 bp).Next, ds-cDNAs were prepared using random primers, SuperScript™ III Reverse Transcriptase (Invitrogen) and 3’-5’ exo - Klenow DNA Polymerase™ (Ambion) per the manufacturer’s instructions, and libraries were obtained using Nextera® Sample Preparation (Illumina). The ds-cDNAs were then purified with magnetic beads using AMPure® XP (Beckman Coulter Life Sciences) and quantified with qPCR using KAPA® Fast Universal (Sigma-Aldrich)The dominant consensus genome for the ancestral virus was obtained by the reference assembly in CLC Genomics Workbench 20 (Qiagen), and the complete genome of the Beaudette strain (NC_001451.1) was used as a reference. Then, the genome of each previous passage was used as a reference to assemble the genome of the next passage up to passage 15 in VERO cells.Variants were detected after reads were mapped again using the consensus obtained for each specific passage using the following parameters in CLC: low frequency variants detection, 100 coverage, 10 counts, 5% frequency, 1% significance and 20 central and neighborhood qualities.Mesocricetus auratus  and Chlorocebus sabaeus (the closest species for which codon usage data was available regarding the origin of the VERO lineage) codon usage tables available at the Kazusa Codon Usage Database (https://www.kazusa.or.jp/codon/) and calculated with CalCAlc2 (The codon adaptation index (CAI) was calculated for the consensus sequences of the ancestor virus and the 15 VERO passages based on Syncytial CPE in all passages was evident at 24 h postinoculation (hpi) and reached a maximum at 48 hpi, with no noticeable differences in CPE intensity among passages. All mock-infected monolayers showed no CPE.The viral load in the ancestor virus was 9.50E+06 copies/µL sample and 7.61E+06 copies/µL at VERO P1; the average viral load for the VERO passages was 4.49E+07 copies/µL sample, with maximum and minimum viral loads at VERO passages 12 (2.18E+08 copies/µL sample) and 13 (3.81E+06 copies/µL sample), respectively . All moc2=0.58) and the coverage and the number of variants (r2=0.03), including the data from the ancestor virus.Fifty-one variants were found in the ancestor virus; the minimum and maximum number of variants were reached at VERO passages 8 (n=10) and 13 (n=56), respectively (Table 1). A low correlation was found between the virus load and the number of variants  correlation coefficient with fluctuations in virus loads, while for all other proteins, this value ranged from 0 (S and E) to 0.63 (nsps13 and 16).2=1-0.71) on fluctuations in virus loads, with both an increase in loads and a recovery after the drop in load at VERO P13.Out of the 31 variants with fluctuations in the frequency of nonsynonymous variants that make up these classes, nsp9 K10R, nsp12 H138P, nsp5 A140S and M P14S showed a strong effect size (r2=0.52) was found for the variants S S469F, nsp5 L139F, nsp3 K892N and nsp3 V192A when the virus load rose from 6.8 to 7.1 log/µL sample from VERO P3 to P4. The remaining 23 variants showed weak or very weak effects on virus loads.A moderate effect size on virus load  deletion was found for VERO P6 to P15.At the 5’UTR, dominant consensus sequences showed a C2A mutation at P14 that reverted to C at P15, and a G11T mutation at P13 and P14 that reverted to G at P15. Also, a A501T mutation at VERO P13 and 14 reverted to A at P15, a A503T mutation at P13 reverted to A at P14, a G504C mutation at P13 and P14 mutated to A at P15 and a C505T mutation at P12, 13 and 14 mutated to A at P15.Mean CAI values were stable for the ancestor virus and all VERO passages: 0.61 for the hamster reference and 0.47 for the green monkey reference.i.e., host change) from BHK-21 to VERO cells, variants emerged (S25P and S53Y) and showed both a rise in frequency (V27G and S53F) or, on the other hand, quenching (T84M) or a decrease in frequency (K116R) in this region of the spike.The receptor-binding domain for the AvCoV M41 strain, which is homologous to the Beaudette strain, has been mapped to the 253 N-terminal amino acids of the spike protein, with residues 19-69 being the more critical ones . Herein,α2,3-linked sialic acid has been shown to be a receptor for AvCoV, but the ability of the Beaudette strain to replicate in cell cultures might be due to binding to heparan sulfate via spike amino acids SRRKRS (residues 686-691) , which wChlorocebus sp monkeys, the origin of VERO cells . M plays a major role in the late phase of the coronavirus cycle, interacting with the envelope E protein during the assembly of new virions .2 1-0.71) on virus load increase and may indicate a selective advantage for the mutant spectra at the passages in which they emerged and might have contributed to more efficient RNA synthesis in the case of nsps and more efficient virion assembly in the case of the M protein.Variants nsp9 K10R, nsp12 H138P, nsp5 A140S and M P14S showed a strong effect size   , althougThe Beaudette strain has also been used to assess the evolution of mutant spectra in serial (up to 65 passages) passages in VERO cells . PopulatNo codon usage adaptation was detected either at the spillover or during the VERO passages, an indication that selection based on amino acid changes was the unique vector of AvCoV evolution in VERO cells.From these results, a pattern can be drawn in regard to the order of emergence and extinction of variants and dominant genomes of AvCoV during adaptation to a new host following the virus life cycle. This starts with the evolution of the receptor binding proteins, followed by the replicase and then proteins involved in virion assembly, keeping the general fitness of the mutant spectrum stable.Nonetheless, experiments with higher passage numbers and a greater variety of cell lines must be performed to test the validity of this pattern in independent studies. In addition, other methods, such as plaque assays and AvCoV haplotype assembly, need to be used to assess virus fitness.


There is increasing evidence that arthropod-borne pathogens exploit saliva of their vectors during the transmission process to vertebrate hosts. Extensive research of the composition of tick saliva and its role in blood-feeding and transmission of pathogens started in the late 1980s and led to a number of discoveries on the composition and function of salivary molecules, some of which are associated with pathogen transmission. The study by Jones et al. published in 1989 can be ranked among the pioneer works in this field as it demonstrated for the first time the role of tick salivary glands in enhancement of transmission of a tick-borne virus. Thogoto virus was used in the model and subsequently similar results were obtained for tick-borne encephalitis virus. After a relatively silent period of almost 20 years, interest in tick–arbovirus–host interactions emerged again in the 2010s. However, no particular salivary molecule(s) enhancing virus transmission has (have) been identified to date. Intensive research in this field will certainly lead to new discoveries with future implications in the control of transmission of dangerous tick-borne viruses. The importance of salivary gland secretions in tick feeding was first outlined in detail by Kemp et al. . Saliva Lutzomyia longipalpis and the protozoan parasite Leishmania major that causes cutaneous leishmaniasis [Rhipicephalus appendiculatus ticks and Thogoto virus (THOV) (Orthomyxoviridae) that uninfected ticks acquired the virus when they co-fed on the same host with infected ticks, while no viraemia could be detected in the host blood. Based on these observations, a novel mode of arthropod-borne virus transmission, non-viraemic transmission (NVT) was proposed. This localized spread of virus without viraemia is of particular interest as it appears to be much more efficient than classical viraemic transmission. Investigations into the NVT dynamics showed an increase in the percentage of nymphs which acquired the virus with duration of co-feeding, whereas NVT occurred even after physical separation of the infected and uninfected ticks [R. appendiculatus SGE and suggested that the enhancement was not a result of a direct action of SGE on the virus, but was rather achieved by manipulation of the immune response of the host. This phenomenon was named “saliva-activated transmission” [Flaviviridae) transmitted by Ixodes ricinus and I. persulcatus [Enhancement of the infectivity of a pathogen by arthropod salivary gland extracts (SGE) was first demonstrated in the sandfly maniasis . In the maniasis  demonstred ticks . “What ied ticks  discovermission” ,12, latemission”  which mesulcatus ,17,18,19Borrelia burgdorferi s.l.), and an increasing number of saliva molecules that promote SAT, but also a few vector molecules that are exploited by the pathogens directly during transmission have been discovered; for reviews, see [Since the beginning of the 21th century, research has been focused on exploration of the transmission mechanisms of tick-borne bacteria  feeding simultaneously (co-feeding) on the same uninfected, non-viraemic guinea pigs. To further explore the mechanisms of NVT, Jones et al. [R. appendiculatus nymphs , extracts from R. appendiculatus ovaries, muscle, midgut, Malphigian tubules and whole ticks without salivary glands or mosquito SGE, or with THOV alone (control). The highest percentages of THOV-positive nymphs  were detected among those that had fed on animals inoculated with a mixture of the virus and SGE of R. appendiculatus and A. variegatum. Further experiments were conducted to determine whether the enhancing factor(s) were present in R. appendiculatus salivary glands during different stages of feeding. For this purpose, similar to the previous experiment, guinea pigs were infested with R. appendiculatus nymphs and inoculated with a mixture of THOV and SGE derived from uninfected R. appendiculatus females at 0, 1, 4, 6 or 8 days of feeding. The highest percentage of infected nymphs (78%) was detected on guinea pigs that were inoculated with SGE of 6-day fed R. appendiculatus females, while enhancement of virus transmission was not observed when SGE of unfed or 1-day fed ticks was used. Another group of tick-infested guinea pigs was inoculated either with a mixture of SGE of 5-day fed R. appendiculatus and virus, or separately with SGE and virus into different parts of the skin. The authors observed enhanced transmission only in animals inoculated with the mixture of SGE and virus. No viraemia was detected in any of the experimental guinea pigs.Jones et al.  demonstrs et al.  infesteds nymphs . After iThree main results were demonstrated by the experiments performed by Jones et al. : (1) spehttps://www.webofscience.com/wos/woscc/basic-search (accessed on 30 November 2022)), this scientific work was cited in 103 published scientific articles in different scientific fields, mainly in Parasitology and Immunology.The paper by Jones et al.  significhttps://pubmed.ncbi.nlm.nih.gov; accessed on 30 November 2022) using the terms “tick saliva” and “transmission”; “tick salivary gland” and “transmission”; “tick” and “SAT” (from 1989 till present) showed 179 scientific papers including 46 (25.7%) reviews (Ixodes spp. was the most studied (44%), followed by Dermacentor spp. (18%), Amblyomma spp., (17%), Rhipicephalus spp. (16%), Hyalomma spp. (3%) and Rhipicephalus (Boophilus) spp. (2%)  B.In the 1990s, follow-up studies to the work by Jones et al.  were carI. persulcatus and I. ricinus (Prostriata) [D. marginatus, D. reticulatus and R. appendiculatus (Metastriata) [D. reticulatus SGE and vesicular stomatitis virus [The THOV transmission model was adopted in subsequent studies and NVT and SAT were demonstrated for TBEV and its natural vectors striata) ,15,19,31striata) ,18,32. Tis virus ,34,35.I. ricinus, whereby significantly lower transmission rates were detected in ticks feeding on tick-resistant bank voles than on susceptible wild mice (Apodemus spp.) [I. ricinus to feeding sites of uninfected ticks was delayed in bank voles [Difference in the capacity to support co-feeding transmission of TBEV was observed between two natural hosts of immature us spp.) . This dink voles . Howevernk voles . In TBEVnk voles . HoweverFlaviviridae and Bunyavirales) transmitted by hard ticks [Asfaviridae), the only one DNA virus which is transmitted by soft ticks [In addition to THOV and TBEV, indirect evidence of SAT has been documented for a few other RNA viruses  in the mouse brain when the animals were infected with a low viral dose [Flaviviridae, no significant effects of H. marginatum SGE on response of dermal dendritic cells and Langerhans cells or on replication of Crimean-Congo haemorrhagic fever virus  were determined. SGE rather inhibited migration of antigen-presenting cells from the feeding site [During the last two decades, several in vitro as well as in vivo studies aimed at revealing the mechanisms of immunomodulation at the tick–virus–host interface have been carried out. In vitro studies have focused on interactions of tick–host innate immune responses and revealed inhibition of the antiviral function of interferon  and suppic cells  and induic cells . Suppresobserved . Thus, sral dose . All theing site .I. scapularis nymphs were characterized [I. ricinus salivary glands infected with TBEV, differential expression of uncategorized genes, genes encoding proteases, Kunitz-type serine protease inhibitors, cytotoxins, and lipocalins during early stages of feeding was observed which may play an important role in virus transmission [Application of modern high-throughput and systems biology approaches has greatly advanced the knowledge of tick sialotranscriptomes and proteomes. Different expression profiles for a number of genes in salivary glands, depending on the presence or absence of pathogenic microorganisms, have been revealed, and a few salivary molecules implicated in pathogen transmission have been identified . Differecterized . In the cterized . In I. rsmission .I. scapularis nymphs elicited innate inflammatory response in the host skin [I. ricinus females was characterized by an inflammatory environment and a neutrophil-dominated immune response, highlighting the modulation of inflammatory chemokine and cytokine pathways in virus transmission. Mononuclear phagocytes and fibroblasts were identified as the primary targets for TBEV infection [As indicated in earlier studies, SAT factors create immunologically favourable conditions in the tick attachment site that facilitate virus transmission and affect pathogenesis. In a series of in vivo studies, transcriptional analyses of early cutaneous responses of laboratory mice to tick attachment and transmission of flaviviruses were carried out. Attachment of uninfected ost skin ,58. In cost skin  and macrost skin . By usinost skin . Transcrnfection .I. scapularis ISE6 cell line for transmission of viral RNA and proteins to human keratinocytes and blood endothelial cells. The findings suggest that flaviviruses use arthropod-derived exosomes as a novel means for viral RNA and protein transmission from the vector to the host [A. maculatum and I. scapularis saliva and salivary glands were shown to delay wound healing by modulating the levels of the chemokine CXXL12 and interleukin-8 in human skin keratinocytes [Recently, it was discovered that tick-borne Langat virus (LGTV) utilizes extracellular vesicles (exosomes) derived from the host . In vivoinocytes . Thus, einocytes .To conclude, it is still not clear if tick-borne viruses exploit any specific salivary molecule(s) for transmission, or their transmission is promoted only indirectly by SAT factors, i.e., mainly by salivary molecules that modulate immune reactions in the host skin. In the second case, the SAT factors enhancing transmission of viruses may involve the same molecules as those which enhance transmission of tick-borne bacteria. However, there is a possibility that both mechanisms of transmission interact. Intensive research in this field will certainly lead to the discovery of new molecules with future implications in the control of transmission of dangerous tick-borne viruses.


Long-acting injectable (LAI) antipsychotics, along with community treatment orders (CTOs), are used to improve treatment effectiveness through adherence among individuals with schizophrenia. Understanding real-world medication adherence, and healthcare resource utilization (HRU) and costs in individuals with schizophrenia overall and by CTO status before and after second generation antipsychotic (SGA)-LAI initiation may guide strategies to optimize treatment among those with schizophrenia.This retrospective observational single-arm study utilized administrative health data from Alberta, Canada. Adults (≥ 18 years) with schizophrenia who initiated a SGA-LAI (no use in the previous 2-years) between April 1, 2014 and March 31, 2016, and had ≥ 1 additional dispensation of a SGA-LAI were included; index date was the date of SGA-LAI initiation. Medication possession ratio (MPR) was determined, and paired t-tests were used to examine mean differences in all-cause and mental health-related HRU and costs (Canadian dollars), comprised of hospitalizations, physician visits, emergency department visits, and total visits, over the 2-year post-index and 2-year pre-index periods. Analyses were stratified by presence or absence of an active CTO during the pre-index and/or post-index periods.p < 0.001) for hospitalizations, physician visits, emergency department visits, and total visits; mean total all-cause HRU costs were $33,788  lower post- versus pre-index , and total mental health-related HRU costs were $34,198  lower post- versus pre-index  per-patient. Forty-three percent had ≥ 1 active CTO during the study period; HRU and costs varied according to CTO status.Among 1,211 adults with schizophrenia who initiated SGA-LAIs, 64% were males with a mean age of 38 (standard deviation [SD] 14) years. The mean overall antipsychotic MPR was 0.39  greater during the 2-year post-index period (0.84 [SD 0.26]) compared with the 2-year pre-index period (0.45 [SD 0.40]). All-cause and mental health-related HRU and costs were lower post-index versus pre-index (SGA-LAIs are associated with greater medication adherence, and lower HRU and costs however the latter vary according to CTO status.The online version contains supplementary material available at 10.1186/s12888-022-04075-y. Schizophrenia is a serious chronic mental illness affecting approximately 0.3% to 1.0% of the global population . AlthougPharmacotherapy with antipsychotics is considered to be the cornerstone of symptom treatment and relapse prevention among individuals with schizophrenia –6. HowevWhile CTOs are a common component of clinical practice in the treatment of schizophrenia, few studies investigating the effects of LAI antipsychotics on healthcare resource utilization (HRU) and associated costs have incorporated CTO information . AdditioThis retrospective, non-interventional, single arm study is reported according to the STROBE guidelines . Ethics Administrative data from the Discharge Abstract Database (DAD), National Ambulatory Care Reporting System (NACRS), Practitioner Claims, and Pharmaceutical Information Network (PIN) were used. CTO data was obtained from Alberta Health Services. Data were linked to the Population Registry, which contains demographic information for all Albertans with Alberta Health Care Insurance Plan (AHCIP) coverage; all Alberta residents are eligible for AHCIP and over 99% participate . The DADThe population of interest were adults with schizophrenia who initiated SGA-LAIs in Alberta within the inclusion period from April 1, 2014 to March 31, 2016. Eligibility criteria included those who: 1) initiated a SGA-LAI (≥ 1 dispensation within no use in the previous 2-years) during the inclusion period , 2) had ≥ 1 additional SGA-LAI dispensation during the 2-year post-index period, 3) met the case definition for schizophrenia within 9 years prior to the index date , 4) wereCTO status was defined by the presence or absence of ≥ 1 active CTO during the 2-year pre-index and/or post-index periods. The resultant four CTO categories included individuals: 1) without any active CTOs in both the pre- and post-index periods (pre = no / post = no), 2) with ≥ 1 active CTO in both the pre- and post-index periods (pre = yes / post = yes), 3) with ≥ 1 active CTO during the pre-index, but not the post-index period (pre = yes / post = no), and 4) with no active CTO during the pre-index period, but ≥ 1 active CTO during the post-index period (pre = no / post = yes).Study measures were presented for the overall cohort and by CTO status. Baseline characteristics on the index date included age, sex, urban or rural residence , and the SGA-LAI that was initiated. A Charlson Comorbidity Index (CCI) score was determined during the 2-year period before the index date; the score was based on the presence or absence of 17 individual comorbid conditions that were weighted according to their potential for influencing mortality .Study outcomes included antipsychotic medication adherence, all-cause and mental health-related HRU, and associated healthcare costs that were measured and compared between the 2-year pre-index and post-index periods for all subjects within the overall cohort and the CTO subgroups. The number of individuals who received ≥ 1 dispensation for an antipsychotic medication was determined, and medication possession ratio (MPR) was calculated based on the number of antipsychotic medication days of supply during the 2-year pre- and post-index periods among all subjects , and presented overall; for completeness specific formulations  and generations (first or second) of antipsychotic medications were also presented  or counts and percentages, where appropriate. Paired t-tests were used to test for statistically significant differences between the pre- and post-index periods for HRU and associated costs; costs were also compared using Wilcoxon signed-rank tests and medians and interquartile ranges (IQR) were reported. A conventional alpha of 0.05 and a two-tailed level of significance were used; accompanying 95% confidence intervals (CI) are reported. Statistical analyses were performed using Python version 3.6.5 and STATA version 17.0.n = 689; 57%]; pre = yes / post = yes ), and 20% had a CTO status change .Of the 3,456 individuals who received a SGA-LAI dispensation during the inclusion period, 1,211 met eligibility criteria .Figure Among the CTO cohorts, all-cause and mental health-related total, hospital, physician, and ED visits were significantly lower in the post-index period compared with the pre-index period, with the exception of the pre = no / post = yes CTO cohort that displayed no significant differences in HRU visits between the pre- and post-index periods . Statistical results were the same when median costs were compared using the Wilcoxon signed-rank test , with the exception of the pre = no / post = yes CTO cohort that displayed no significant differences in HRU costs , and had similar decreases in HRU and costs as the overall cohort. Among those with a change in CTO status during the study period, the pre = yes / post = no CTO cohort consistently showed the largest differences in HRU and costs between the pre- (higher) and post- (lower) index periods; the pre = no / post = yes CTO cohort displayed no significant differences in HRU visits and costs between the pre- and post-index periods. Collectively, results of this study indicate that SGA-LAIs may be an effective strategy for assisting with long-term antipsychotic medication adherence, and while causality cannot be established, lower HRU and associated costs to the healthcare system occurred over a 2-year period after SGA-LAI initiation; however, these can vary depending on CTO status.Approaches to improve treatment adherence among individuals living with schizophrenia include LAI formulations of antipsychotics , 11. In . (2018) found that the number of hospitalizations and ED visits were lower in the 1-year period after initiation compared to the year prior, and that the observed 64% reduction in total HRU costs was primarily driven by the pre-post difference in hospitalization costs [. (2018) who also reported no significant pre-post differences in physician visits, we found that the number of physician visits were significantly lower in the post- versus pre-index period, which may be partially due to the longer observation period employed in the current study, as a 2-year observation period has been suggested to result in a higher likelihood of detecting a difference compared with 1-year periods [Results from the overall study cohort are consistent with recent observational studies, which have reported lower HRU and costs after initiation of LAI antipsychotic medication compared with before among individuals with schizophrenia , 28. Amoon costs , which hon costs . However periods . Collect periods .. (2009) found that in Ontario, Canada, patients who were placed on a CTO had severe and persistent mental illness [. (2017) conducted a mirror-image study investigating individuals living with schizophrenia or schizoaffective disorder who initiated a SGA-LAI while hospitalized in Quebec, Canada [Another unique aspect of this study was that analysis was also performed based on CTO status during the study period, of which 43% of individuals received at least one active CTO. The intention of a CTO is to assist with improving treatment adherence in patients with greater illness severity. To this end, O’Brien et al illness . Not sur illness ; however, Canada . The autThis study has several important strengths, including the large size, population-based design, incorporation of CTO status, and long observation periods. However, this study is also subject to a number of limitations that should be taken into consideration when interpreting results. 1) While individuals with schizophrenia were identified using a validated case definition, administrative health data was used as opposed to medical records, and therefore there is a potential for misclassification of the study groups or measures. 2) Pre-post study designs lack a control group, hence the outcome patterns in the counter-factual patients who are similar to our patient group in all aspects except SGA-LAI initiation are unknown; this is particularly important when interpreting outcomes in patients who had a change in CTO status, which may be an indicator of other factors including disease instability. 3) PIN data only captures dispensations of prescription medications, and therefore actual medication up-take by patients is unknown. However, since LAI antipsychotics are injected by healthcare professionals, the dispensation of SGA-LAIs in this study should be highly representative of the actual uptake. 4) Use of over-the-counter medications, prescription medications provided in a hospital or secondary care setting, and other non-pharmacotherapy treatments are not captured within provincial administrative data and therefore, not reported.Among adults with schizophrenia, antipsychotic medication adherence was higher, and HRU and associated costs primarily comprised of hospitalization costs, were lower during the 2-year period after SGA-LAI initiation as compared to before, extending findings of previous mirror-image and naturalistic studies. CTOs should be considered in research studies involving individuals with schizophrenia as they are commonly used in this population and our results show that HRU and associated costs can vary depending on CTO status.Additional file 1. Diagnostic codes used within the schizophrenia case finding algorithm. Additional file 2. Identification of oral and long-acting injectable antipsychotics based on anatomical therapeutic chemical classification and/or drug identification number.Additional file 3. Antipsychotic medication use and mean possession ratio among the CTO cohorts.Additional file 4. Healthcare resource utilization during the pre- and post-index periods among the CTO cohorts.Additional file 5. Median healthcare costs during the pre- and post-index periods among the overall and CTO cohorts.


This paper presents a numerical reduced-order modeling (ROM) approach for complex multi-layered arrays of piezoelectric micromachined ultrasonic transducers (PMUTs). The numerical modeling technique adopted to generate an array of PMUTs consisting of a considerable number of transducers allows for a large reduction in computational cost without reducing accuracy. The modeling idea is based on coupling shell elements applied to the PMUT structural layers with 3D-solid elements applied to the piezoelectric layer. A set of eigenfrequency and frequency domain analyses are presented considering a single ROM of a PMUT performing in different ambients and the performing central frequencies are obtained for every considered scenario. A unique arrangement of 228 PMUTs is presented and tested for its ability to transmit and receive acoustic waves. The operating frequency band of the array and the level of interference and cross-talk among different PMUTs in the near field are estimated. Finally, the results from a preliminary experimental test performed to analyze the acoustic abilities of an 8 × 8 array of PMUTs are presented. A corresponding numerical model is created and the obtained results matched the experimental data, leading to a validation of the modeling technique proposed in this work. Ultrasonic transducers are devices able to generate and detect ultrasonic waves propagating in air, liquid, or solid media. Particularly, piezoelectric micromachined ultrasonic transducers (PMUTs) are devices fabricated on silicon using micro-electro-mechanical systems (MEMS) technologies based on the piezoelectric effect. The applications of piezoelectric materials in smart micro-systems , such asThis work presents the numerical multiphysics modeling and simulation of an array of PMUTs. The main objective is to provide an innovative reduced-order model (ROM) of the array of PMUTs and to investigate its electro-mechanical-acoustic performances. The ROM of the PMUTs is defined by coupling shell and solid elements. The advantage of using shell elements for modeling vibrating plates over solid elements when it comes to meshing and time solutions is self-explanatory. Depending on the size of the model and the capabilities of the hardware, the run-time and the total number of degrees of freedom (DOF) are highly reduced when using shell elements instead of solid elements without compromising the accuracy of the results. Solid elements have no limitations in terms of generating and representing a geometry, while shells are mainly designed to represent structures whose thicknesses are much smaller with respect to the other two dimensions, which is the case in our multi-layered system ,17. The This paper is structured as follows. The This section presents the modeling techniques adopted for a single PMUT. The 3D finite element model is created using COMSOL Multiphysics V5.6. The circular diaphragm of the PMUT shown in l fields .The ROM technique used to create the PMUT is based on the coupling of 3D solid elements with thin shell structural elements. A linear stress–charge model is used to represent the behavior of the active piezoelectric material.The “radius-to-thickness” ratio of the multi-layered system is very high. Hence, shell elements are the best candidates to be used to model the different layers of the PMUT. As long as the thicknesses of the layers modeled using shell elements are thin enough, the model ensures highly accurate results.The multi-layered PMUT is modeled using shell elements apart from the active PZT layer as shown in The meshing adopted for the FOM, shown in A set of different models are created to assess the mechanical properties of the ROM for the single PMUT. First, eigenfrequency analysis is performed for the single PMUT in vacuum and in water. A frequency sweep analysis is carried out in the frequency domain and the results of the study are given in terms of the amplitude of the transversal component of the displacement field of the center of the plate.The analyses described in this section are performed on: (i) the ROM of a PMUT coupling shells and solid elements; and (ii) an FOM of a PMUT created entirely using solid elements. The results obtained from the ROM are compared with FOM to evaluate its accuracy, performance, and the level of computational time reduction in ROM. Great agreement in performance is obtained between the two models.A single PMUT in a vacuum is simulated using the mesh presented in the previous section. A total of 156363 DOF are used in the case of the FOM while only 2961 DOF are used for the ROM; hence, a reduction in DOF of almost two orders of magnitude is reported. This represents the simplest case in which the PMUT is not interacting with any other structural element that would affect its natural frequency. The results show very good agreement between the ROM and the FOM. A first mode shape with a central frequency of The analysis performed on the single PMUT is not computationally demanding and hence it does not show the potential advantages of using the proposed modeling technique, namely the ROM, over the FOM. To better show the advantages of the proposed ROM strategy, the same analysis is carried out on an array of 5 × 5 PMUTs. The mesh adopted to realize the array is built starting from the one used for the single PMUT case presented in 3) and a sound velocity c of 1481.4 (m/s). The water domain is modeled as a hemisphere with a radius of ≈2.5 mm, which is approximately three times the minimum wavelength  a standing alone cluster and (ii) an array made of the 12 electrically independent clusters all in receiving mode, as can be seen in Figures This section presents a preliminary experimental campaign carried out to test the acoustic capabilities of an array of PMUTs. The acoustic test is performed on a test object in immersion, a mobile phone battery with an aluminum case. The measurements were conducted using a setup shown in A 16 × 16 membrane fitted in a square configuration defines the transducer used in the acoustic test. Only an 8 × 8 square area is activated in this test. The transmission phase is activated by driving the PMUTs in the array using a single-cycle sinusoidal wave. The input signal is a single-cycle sinusoidal burst characterized by a 10 V peak-to-peak amplitude and a 2 (MHz) frequency. A 15 V DC bias was applied to the PMUT. The experimental setup is shown in A numerical FEM is generated to simulate the two testing cases. The array is created using the proposed ROM of PMUTs. Since the configuration of the array is square in shape, modeling the two cases is less computationally expensive if the symmetry property of the setup is utilized. Hence, only a 4 × 4 array of PMUTs is modeled to represent the experimental setups, as shown in This paper proposes a complete set of modeling techniques to create an ROM of large arrays of PMUTs with a high level of accuracy. The strategy adopted to create the ROM is based on coupling solid elements with shell elements to create the multi-layered system of PMUTs. The combination of them and the application to the modeling and simulation of the PMUTs large array outlines the novelty of this work. Thee validation of the functionality and accuracy of the ROM are investigated by considering PMUTs operating in different scenarios, in vacuum and in immersion.A set of eigenfrequency and frequency domain analyses are carried out on both the ROM and the FOM, referring only to a single PMUT, considering different scenarios. Results are obtained in terms of the operating central frequencies and the corresponding transversal displacement of the central point of PMUTs. The results show very good agreement between the two modeling techniques, hence confirming the validity of the ROM technique adopted. To compare the computational time reduction, an eigenfrequency analysis, solving for the first eigenvalue corresponding to the first mode shape of the PMUT, was carried out on a 5 × 5 array. The FOM array required 27 min and 26 s to run the simulation while the ROM took only 14 s. Hence, the ROM provides a great reduction in the DOF and the computational time needed for the analysis of the complex system of PMUTs without reducing the accuracy of the system.Once the ROM of a PMUT is validated, a large number of PMUTs are modeled in a special array configuration. The proposed array is tested for its abilities in both the transmission and reception phases. The proposed ROM of an array showed an FBW of 57.25% in transmission and an FBW of 151.96%. The advantages of using the proposed approach stand on the possibility of very fast and accurate evaluations of the PMUTs array performances including the effect of the multiple interactions among the transducers occurring in the near field. Therefore, extremely accurate and useful cross-talk estimations are possible. Hence, the adopted reduced approach represents an excellent alternative to the full-order model that would require an extremely large computational time.A preliminary experimental test was carried out to study the acoustic capabilities of an 8 × 8 PMUTs array. The setup was created for battery-monitoring applications. The test considered two cases of a pulse-echo scenario in immersion: (i) a mobile phone battery; and (ii) a stainless steel reflector. Results are collected from the array in terms of recorded voltage that represents the echo of the reflected waves. Numerical models using the ROM of PMUTs are developed for the two cases and the recorded voltage in the array showed high agreement in the magnitude of the recorded voltage and the time at which the echo is recorded. Future work will concern deeper analysis of the cross-talk among the transducers. The performance of the proposed ROM not only on fluid domains but also on solids like in the structural health monitoring applications will be also tested.


Endoscopic treatment of a pancreatic pseudocyst complicated by pancreaticojejunostomy (PJ) stricture is challenging.A 76-year-old woman presented with worsening abdominal pain and dyspepsia. She had been receiving adjuvant chemotherapy (capecitabine and cisplatin) for 4 months after pylorus-preserving pancreaticoduodenectomy (PPPD) for the treatment of extrahepatic cholangiocarcinoma.Laboratory findings included elevated serum amylase (145 U/L) and lipase (437 U/L) levels. Abdominal computed tomography (CT) showed a pancreatic pseudocyst of approximately 3 cm in size and pancreatic duct dilatation in the remnant pancreas. According to the Response Evaluation Criteria in Solid Tumors, cholangiocarcinoma is a stable disease.Endoscopic drainage of the pancreatic pseudocyst was planned. Single-balloon enteroscopy (SBE)-guided endoscopic retrograde pancreatography (ERP) with endoscopic ultrasonography (EUS) using a mini probe demonstrated a membranous PJ stricture and a pancreatic pseudocyst. Endoscopic pseudocyst drainage using a 7-Fr plastic stent was successfully performed after needle-knife incision of the PJ stricture. Follow-up abdominal CT after 3 weeks showed complete resolution of the pseudocyst. Chemotherapy was resumed.SBE-guided ERP with EUS using a mini probe may be an effective and safe treatment in a patient with a pancreatic pseudocyst complicated by membranous PJ stricture after PPPD. Delayed gastric emptying and pancreatic fistulas are the most common complications of PD and pancreaticojejunostomy (PJ) stricture. PJ stricture can cause abdominal pain, recurrent acute pancreatitis, and pseudocyst.,3 The main treatment of PJ stricture includes endoscopic drainage or surgical revision.,5 Surgical revision of PJ stricture is complex and is associated with high morbidity up to 26%; thus, surgeons may hesitate to perform additional surgery for this benign disease. In turn, endoscopic drainage is preferred in most cases. Traditionally, endoscopic drainage of PJ stricture is performed via endoscopic retrograde pancreatography (ERP). Because ERP after PD is challenging, low technical and clinical success rates have been reported. Herein, we report a case in which a pancreatic pseudocyst complicated by membranous PJ stricture was successfully treated via short-type single-balloon enteroscopy (SBE)-guided ERP and endoscopic ultrasonography (EUS) using a mini probe.Pancreaticoduodenectomy (PD) is the primary surgical treatment for cancers involving the pancreatic head, distal common bile duct, and duodenum.A 76-year-old woman from the oncology department was referred to the gastroenterology department with epigastric pain and dyspepsia that had started 1 month ago and had worsened over the last 2 weeks. Physical examination showed tenderness in the epigastric area. She denied having fever or chills. Nine months ago, she was diagnosed with extrahepatic cholangiocarcinoma with lymph node metastasis. After 3 months of neoadjuvant chemotherapy with gemcitabine, cisplatin, and albumin-bound paclitaxel, she underwent laparoscopic pylorus-preserving PD with R1 resection. After pylorus-preserving PD, she had been receiving capecitabine and cisplatin as adjuvant chemotherapy in the oncology department for 4 months. Three weeks ago, chemotherapy was stopped because of aggravated abdominal pain and poor oral intake.Laboratory findings were as follows: white blood cell count, 8000/µL (neutrophils 80.9%); hemoglobin, 8.8 g/dL; platelet, 160,000/µL; aspartic acid aminotransferase, 27 (10–37) IU/L; alanine aminotransferase, 46 (10–37) IU/L; alkaline phosphate, 548 (35–129) IU/L; total bilirubin, 0.77 (0.2–1.3) mg/dL; amylase, 145 (0–100) U/L; lipase, 437 (7–60) U/L; C-reactive protein, 13.47 (< 0.3) mg/dL; and carbohydrate antigen 19–9 31.2 (0–37) U/mL. Abdominal computed tomography (CT) revealed a mild dilatation of intrahepatic bile ducts, a newly appearing 3-cm-sized pancreatic pseudocyst, and pancreatic duct dilatation in the remnant pancreas . After cannulation of the pseudocyst with a 0.035-inch guidewire  and a catheter , the obtained pancreatogram confirmed the pseudocyst and dilated pancreatic duct  was used for intubation to the blind end of the jejunum Fig. . Two dayuct Fig. B and C. uct Fig. B and C.  Because the most common indications of PD were pancreatic head cancer or distal cholangiocarcinoma in the past, the overall survival time of the patients was not long enough to unveil PJ stricture as a complication after PD. However, nowadays, with the advancements in chemotherapy and surgical techniques and broader indications of PD such as chronic pancreatitis and pancreas cystic neoplasm, the average time to develop PJ stricture after PD is 12 to 46 months and the occurrence rate ranges from 2% to 11.3%.,8 PJ stricture has been recognized to cause persistent abdominal pain, recurrent acute pancreatitis, and pseudocysts.,4PJ stricture is a challenging late complication after PD.–11 Although DBE may provide much better outcomes, SBE enables less preparation time and better maneuverability than DBE. Additionally, short-type SBE with a shorter length and wider working channel allows the utilization of almost all conventional instruments for ERP. Therefore, we used short-type SBE in the present case, and intubation into the afferent limb and identification of HJ and PJ anastomosis sites were successful within a relatively short time (approximately 20 min).Endoscopic treatment of PJ stricture has been appealing to endoscopists. However, ERP after PD is challenging. First, it is difficult to access the afferent limb and identify PJ anastomosis with standard endoscopes because of the long length of the afferent limb, postoperative strictures, and acute angulation. Recently, SBE- or double-balloon enteroscopy (DBE)-guided ERP has increased successful intubation rates up to 71% to 97.5%.,14,15 Therefore, endoscopic ultrasound-guided pancreatic duct drainage (EUS-PDD) techniques have been developed. The three techniques of EUS-PDD include the rendezvous technique, transenteric antegrade stenting, and transmural stenting. Compared with the traditional ERP approach, EUS-PDD has the advantage of higher technical success rates ranging from 72% to 92.5%.,15 However, it is associated with higher complication rates than the traditional ERP approach. In a multicenter study comparing EUS-PDD with enteroscopy-guided ERP after Whipple surgery, adverse events were more common in the EUS-PDD group . A systematic review summarized more adverse events with EUS-PDD than with traditional ERP. A wide range of adverse events from EUS-PDD included abdominal pain, bleeding, pancreatitis, perforation, pancreatic abscess, guidewire shearing, fever, pneumoperitoneum, pseudocyst, and perigastric fluid collection. As such, the current guidelines recommend EUS-PDD as a salvage procedure after failed ERP or an alternative to enteroscopy-guided ERP in patients with surgically altered anatomy.Then, cannulation and treatment of the PJ stricture are other challenges in patients with PD. Even with the use of balloon enteroscopy including SBE or DBE, technical success ranges from 23.1% to 76%.,20 However, no consensus is established yet regarding the treatment of pseudocysts complicated by PJ strictures. A symptomatic pseudocyst complicated by PJ stricture might be treated with various nonsurgical methods including percutaneous catheter, EUS-, and enteroscopy-guided drainage. Abdominal CT of the current case showed that a pseudocyst was located at the PJ site, which was right below the left hepatic lobe and at least 4 cm off from the stomach (Fig.  Therefore, we performed enteroscopy-guided drainage. EUS with a mini probe was also planned to determine the exact location of the pseudocyst complicated by the PJ stricture.Finally, it is a real challenge to treat a symptomatic pseudocyst complicated by PJ stricture. Current guidelines recommend EUS-guided transmural drainage or transpapillary drainage for pseudocysts adjacent to the stomach or duodenum.ach Fig. . Althoug,15 Furthermore, both HJ and PJ anastomosis sites can be examined. By directly examining HJ and PJ anastomosis sites, biopsies can be performed, and the cause of HJ or PJ stricture – whether it is a benign or a recurred malignancy – can be evaluated. In the current case, a biopsy was taken at the HJ site and revealed well-differentiated adenocarcinoma. Precise diagnosis by histology may lead to a significant change in further treatment and may affect the patient’s survival.Enteroscopy-guided ERP for the treatment of complicated PJ stricture has several advantages. It is more physiological than EUS-guided interventions. No new pancreatoenteric fistulas have to be made. It also has lower complication rates than EUS-guided interventions.In summary, a symptomatic pancreatic pseudocyst complicated by PJ stricture was treated by SBE-guided ERP with EUS using a mini probe. EUS using a mini probe played the main role in delineating the needle-knife puncture site by viewing the underlying pseudocyst and PJ site anastomosis. Moreover, SBE helped in detecting cholangiocarcinoma at the HJ anastomosis site. The resolution of the pseudocyst by endoscopic drainage and early detection of cholangiocarcinoma made it possible to continue adjuvant chemotherapy. Short-type enteroscopy-guided ERP with EUS using a mini probe could be considered an effective and safe treatment modality in patients with a pancreatic pseudocyst complicated by PJ stricture.Conceptualization: Chang-Hwan ParkMethodology: Eunae ChoProject administration: Eunae Cho, Seo Yeon ChoResources: Eunae ChoWriting–original draft: Eunae ChoWriting–review & editing: Chang-Hwan Park


While most viral infections cause mild symptoms and a spontaneous favorable resolution, some can lead to severe or protracted manifestations, specifically in immunocompromised hosts. Kidney injuries related to viral infections may have multiple causes related to the infection severity, drug toxicity or direct or indirect viral-associated nephropathy. We review here the described virus-associated nephropathies in order to guide diagnosis strategies and treatments in cases of acute kidney injury (AKI) occurring concomitantly with a viral infection. The occurrence of virus-associated nephropathy depends on multiple factors: the local epidemiology of the virus, its ability to infect renal cells and the patient’s underlying immune response, which varies with the state of immunosuppression. Clear comprehension of pathophysiological mechanisms associated with a summary of described direct and indirect injuries should help physicians to diagnose and treat viral associated nephropathies. Viruses are among the most common pathogens involved in infectious diseases and have a global distribution . While mViral infections represent an important consideration for healthcare workers in charge of renal diseases. First, patients with kidney diseases are often immunocompromised  and may be confronted with opportunistic infections, including those caused by viruses ,5. SeconThe literature on kidney injuries related to viral infections is broad due to the multiplicity of potentially involved viruses and the numerous causes: hypovolemia secondary to infection severity, direct or indirect viral-associated nephropathy and drug toxicity being the major ones. The aim of this review is to provide physicians with broad but clear information about virus-associated nephropathies in order to guide diagnosis strategies and treatments in cases of acute kidney injury (AKI) occurring concomitantly with a viral infection.+ T-cell counts [+ T cells. Indeed, DC-SIGN (CD 209) was a preferential receptor for podocyte infection by HIV, and DEC-205 was the main one for tubular epithelial cells [APOL-1 at-risk alleles [APOL-1 genotype variations [The HIV/AIDS pandemic remains a worldwide health issue. There have been about 33 million deaths in the past 40 years, and there are 38 million people living with HIV . Numeroul counts . Its incl counts . Glomerul counts . The patl counts . In vitral cells . Additioal cells . Thus, Hal cells ; see Fig alleles . For thi-SIGN CD 9 was a pHIV immune-complex renal disease (HIVICD) is nowadays the leading glomerulopathy in the era of cART . Indeed,Diffuse infiltrative lymphocytosis syndrome (DILS) is another presentation of HIV-related nephropathies, represented by a tubulointerstitial infiltrate of polyclonal reactive cells . FinallyPicornaviridae family that approximately infects 1.5 million people each year [HAV is a nonenveloped single-stranded RNA virus belonging to the ach year . HAV-indach year . Acute Hach year ,30. AKI ach year ,31. Repoach year , but casach year  and glomach year ,34 have ach year ,36 ide analogues (NAs) with limited nephrotoxicity should be used in cases of renal disease . Adding Flaviviridae family with both hepatotropic and lymphotropic properties [HCV is an enveloped, single-stranded RNA virus belonging to the operties . Around operties . Acute ioperties  and is aoperties  in aboutoperties . HCV infoperties . Brieflyoperties . The glooperties ; see Figoperties , FSGS [6operties ,70, fibroperties ,72,73 haoperties . HCV infoperties  and is aoperties , post-troperties  and immuoperties . Howeveroperties , as theyoperties ,81. Immuoperties . Althougoperties .Hepeviridae family [HEV is a nonenveloped single-stranded RNA virus belonging to the e family . Four mae family ,84. Acute family . Extra-he family . HEV infe family  even in e family , and AKIe family . Renal de family . HEV gene family ,90. A ree family . The rece family . Many hoe family . To datee family .Glomerulonephritis is the most frequent described disease ,87 with Coronaviridae family. It recently emerged as a major threat to KTRs and hemodialysis patients, especially during the first waves of the Coronavirus disease 2019 (COVID-19) pandemic [SARS-CoV-2 is an enveloped, single-stranded RNA virus belonging to the pandemic . Moreovepandemic  and are pandemic .In the specific setting of renal injury related to SARS-CoV-2 infection, several presentations have been described. The frequency of acute kidney injury (AKI) varies among published series, ranging from 5% to 50%, depending primarily on the severity of infection ,103,104.APOL-1 genotype rather than disease severity, according to the “two-hits” theory [The other major cause of AKI is the development of collapsing FSGS in 25 to 40% of cases of so-called COVID-19 associated nephropathy (COVAN) ,119,120.” theory ,123,124;” theory  and thro” theory ,127 are ” theory ,128. How” theory .Orthomyxoviridae family. An impact of influenza infection on the kidneys, mostly studied during the H1N1 pandemic, is uncommon but can contribute to a deterioration in the patient’s condition. AKI was observed in approximately 50% of patients hospitalized in intensive care units and was associated with significantly worse outcomes [Influenza virus is an enveloped, single-stranded, fragmented RNA virus belonging to the outcomes . Howeveroutcomes ,132, wheoutcomes . The cauoutcomes . In mostoutcomes ,136. In outcomes ,138,139 outcomes  have beeoutcomes ,142.Eight members of the family Herpesviridae strictly infect humans. They are enveloped, double stranded DNA viruses and are characterized by their ability to persist lifelong in a latent state after primary infection. Mechanisms of herpesviruses’ entry into the cell share the use of a conserved core fusion complex (gH/gL and gB) and some specificities that depend on the herpesvirus involved .Primary HSV infection is very common and usually occurs during childhood; possible recurrences throughout life that may be triggered by several known factors . In immuVZV’s involvement in nephrology is quite similar to that of HSV: primary infection and recurrence can be more frequent and severe in immunocompromised patients, and specific treatment  is a source of nephrotoxicity. VZV infection involves the same complex of fusion proteins as other herpesviruses; however, it is more oriented toward cell-to-cell fusion than virus-to-cell fusion . As for EBV, also known as human herpesvirus 4 (HHV4), infects up to 90% of the population, primarily in childhood, and then establishes a lifelong latent infection in memory B cells . Ephrin Tubulointerstitial nephritis with polyclonal immune infiltrate has also been described repeatedly in the literature as a cause of AKI during EBV infection ,171. FewCMV’s seroprevalence among the adult population exceeds 80%, and it has a high geographic variability (>90% in low outcome countries and <50% in some other regions) . It ofteOne of the first suspected associations between CMV infection and kidney pathology was the controversial description of CMV-related IgA nephropathy . HoweverWhilst AKI may be frequently associated with CMV replication in KTRs, its causes may be multiple and often not related with a virus-associated nephropathy. Digestive symptoms can be severe in cases of CMV disease and lead to ATN, particularly in KTRs with frail allograft function. Foscarnet, an antiviral drug used in cases of resistance mutations to ganciclovir, is a major source of nephrotoxicity .Besides the virus’s tropism for epithelial cells of the kidney/urinary tract and the virus’s excretion in urine in large quantities for years upon CMV infection, kidney disease is not part of the clinical spectrum of CMV infection, and renal function impairment has only very rarely been reported in neonates and infants. The best-described specific lesion induced by CMV is tubulointerstitial nephritis ,189,190,On the contrary, acute glomerulonephritis following CMV infection has been reported, mainly in immunocompromised patients , and is + T cells are the main target of HHV6, a latent tropism toward kidney epithelial cells has been demonstrated [HHV6 primary infection usually occurs during the first two years of life, leading to non-specific symptoms such as fever and cutaneous rash . CD46 isnstrated . Reactivnstrated ,207. In nstrated , and posnstrated . To the As for EBV, with which it is closely related, HHV8 is a pro-oncogenic virus known for its involvement in Kaposi sarcoma’s occurrence in HIV patients . Its serPolyomaviridae family. The four classified BKPyV genotypes all lead to mostly asymptomatic infections during childhood. It has a seroprevalence of around 80–90% [BKPyV, similarly to JC virus, is a nonenveloped, double-stranded DNA virus belonging to the d 80–90% . BKPyV hd 80–90% . BKPyV id 80–90% ,221, eved 80–90% . Followid 80–90% , but whed 80–90% ,225. Thed 80–90% ; see Figd 80–90% . Reactiod 80–90% ,228,229.Finally, rare glomerular proliferative focal lesions have also been reported, but their significance and correlation with BKPyV are uncertain due to the absence of viral inclusions and their significant impact on allograft function .The JC virus was described the same year as BKPyV in an immunocompromised patient that presented with progressive multifocal leukoencephalopathy . SimilarHowever, contrary to BKPyV, JC virus reactivation usually does not coincide with viral nephropathy, and almost never affects kidney allograft function ,238. Of APOL-1 inhibition (opposite effect to the HIVAN mechanism), but these results may also simply reflect a lower global inflammatory state, which is well known to accelerate chronic kidney disease progression [Surprisingly, a nephroprotective effect of JC viraemia has recently been suggested . The progression ,244. FurFlaviviridae family with four known serotypes  [APOL-1 risk allele but with demonstrated infection in the kidney tissues. Finally, thrombotic microangiopathy has also been reported [DENV is an arthropod-borne, enveloped, single-stranded RNA virus (arbovirus) belonging to the  -3, -4) . DENV in -3, -4) ,247,248. -3, -4) ,250,251. -3, -4) . Direct  -3, -4) . However -3, -4) , and vir -3, -4) . Glomeru -3, -4)  and huma -3, -4) , notably -3, -4) ,258 and  -3, -4) , withoutreported ,261. No reported . Of notereported ,262,263.Hantaviridae family. Two distinct clinical syndromes are classically defined—although overlap may exist: hemorrhagic fever with renal syndrome (HFRS) caused by old-world (Europe and Asia) hantaviruses and the more severe hantavirus cardiopulmonary syndrome (HCPS)—with no specific renal disease—caused by new-world (North and South America) hantaviruses [+ lymphocyte infiltrate leads to hypovolemia and ATN [Hantaviruses are enveloped, tri-segmented, single-stranded RNA viruses belonging to the aviruses . Both diaviruses . Humans aviruses . HFRS caaviruses . A mildeaviruses . Shortlyaviruses . A constaviruses . Specifiaviruses . Endothe and ATN . These p and ATN . Less of and ATN ; and may and ATN , possibl and ATN . Rodent  and ATN .Parvoviridae family. B19V is a ubiquitous, strictly human pathogenic virus. Its transmission route relies on respiratory droplet projections. B19V is characterized by a tropism for erythroid progenitor cells, but it can persist in many non-erythroid tissues as well [B19V is a nonenveloped, single-stranded DNA virus belonging to the  as well ,275. Thr as well . Most sy as well , explain as well —with pro as well ,280. In  as well . There i as well , which i as well .HAdV are non-enveloped, double-stranded DNA viruses belonging to the Adenoviridae family. They are ubiquitous and easily transmitted through inhalation of aerosolized droplets or the fecal–oral route . More thMeV is an enveloped, single-stranded RNA virus belonging to the Paramyxoviridae family  that affThe occurrence of virus-associated nephropathy depends on multiple factors: the local epidemiology of the virus, and its ability to infect renal cells or to lead to immune-mediated renal damage influenced by the patient’s underlying immune response . Current


Mendel’s First Law requires explanation because of the possibility of ‘meiotic drivers’, genes that distort fair segregation for selfish gain. The suppression of drive, and the restoration of fair segregation, is often attributed to genes at loci unlinked to the drive locus—such genes cannot benefit from drive but do suffer its associated fitness costs. However, selection can also favour suppressors at loci linked to the drive locus, raising the question of whether suppression of drive usually comes from linked or unlinked loci. Here, I study linked and unlinked suppression in a two-locus model with initial stable polymorphism at the drive locus. I find that the invasion rate of suppressors is a decreasing function of the recombination fraction between the drive and suppressor loci. Surprisingly, the relative likelihood of unlinked vs. linked suppression increases with the strength of drive and is insensitive to the fitness costs of the driver allele. I find that the chromosomal position of the driver influences how rapidly it is suppressed, with a driver in the middle of a chromosome suppressed more rapidly than a driver near the tip. When drive is strong, only a small number of chromosomes are required for suppression usually to derive from unlinked loci. In contrast, when drive is weak, and especially when suppressor alleles are associated with fitness costs, suppression will usually come from linked loci unless the genome comprises many chromosomes. Mendel’s First Law, that of fair segregation, holds across most genomic loci in most of the sexual species in which segregation patterns have been characterized. This wide jurisdiction is in spite of genes, called meiotic drivers, that distort segregation in their own favour, gaining a selfish transmission advantage that allows them to spread through a population even when they reduce organismal fitness Prout .Compounding this threat to Mendel’s First Law, theory has shown that genes at other loci can be under selection to distort segregation at a linked polymorphic locus Liberman . It is tWith the aim of rescuing Mendel’s First Law from these theoretical attacks, Eshel  showed tHowever, modifiers at linked loci also can be selected to restore Mendelian segregation at a focal locus Liberman , and theThis question has gained fresh importance with the proposal and development of synthetic gene drives for the control of pest and pathogen populations Burt, . A key cHere, I study the prospects of linked and unlinked suppression in a simple, two-locus model with initial polymorphism at the drive locus owing to recessive fitness costs of the drive allele. This model is relevant to a number of well-known examples of meiotic drive /2 of the gametes of Dd heterozygotes, where δ > 0 is the ‘strength of drive’.The model species is a cosexual diploid, with random mating in a population of size D be costly and that DD homozygotes suffer disproportionately large fitness costs , the system evolves to a stable polymorphism at which D’s frequency is p = δ/s and mean fitness is 1 − p2s , as a function of r, δ, s, and the genotype in which M first appears . This quantity will mainly be contrasted across different recombination fractions r, so I will write it as E(r). I assume that suppressors appear by mutation sufficiently infrequently that the fate of M—establishment or loss—will almost certainly be resolved before the appearance of another suppressor. This assumption allows focus to be limited to the two-locus system.The quantity of primary interest is the probability δ, s, r, and M’s initial genotype, with a population size of N = 10,000. For each configuration, as many trials were run as could be completed within a set computational time window (24 h CPU time); the number of trials therefore varied across configurations, but was always large enough that standard errors were negligibly small.Wright–Fisher simulations of the above model were run for various configurations of M was lost, (ii) D was lost, or (iii) M attained a frequency greater than 99% . I scored events (ii) and (iii) as ‘establishment’ of M, ignoring the possibility of D being lost by drift . To ensure that d and D were seldom lost by drift, I focused on parameter regimes where 0.2 < p < 0.8.Each trial proceeded until (i) δ, s, and r, an average establishment probability of M, E, was calculated by weighting the estimates obtained for the four initial genotypes dM/dm, DM/dm, Dm/dM, and DM/Dm by (1−p)2, p(1 − p), p(1 − p), and p2 respectively.For each configuration of M in certain parameter cases, I calculate the proportionate rate of increase of M when rare, ε ≪ 1 is the frequency of M in one generation and M as E ≈ 2sM , or at a locus very tightly linked to the drive locus (r ≈ 0). If M initially appears alongside the drive allele D (with probability p), it forms a permanent (or nearly so), costly, non-driving haplotype that is almost certain to go extinct.First, consider the case where the suppressor allele M appears alongside d (with probability 1 − p), it forms a haplotype that is never driven against, and which always (or at least for very many generations) resides in individuals with fitness 1 relative to the population average 1 − p2s. In this case, M therefore has a selective advantagep2s.If, instead, M when r ≈ 0 is thereforeThe average establishment probability of mentclass2pt{minimμl per gamete, so that the population supply at the locus is 2Nμl per generation. Then the rate at which suppressors establish (their ‘invasion rate’) at the locus is approximatelySuppose that the mutation rate to suppressor alleles at the drive locus (or at a given tightly linked locus) is M appears at a locus unlinked to the drive locus (r = 1/2), it enjoys a selective advantage because, by reducing its co-transmission with the costly D allele from Dd heterozygotes, it is transmitted to fitter offspring on average , M’s reduction in co-transmission with D from Dd heterozygotes, δ/2, and the average fitness cost to D-inheriting offspring, ps. M’s suppression of drive in the parental generation therefore increases the average fitness of offspring to whom it is transmitted by an amount ~p2(1 − p)δs.If ge Eshel . QuantitM spreads because its suppression of drive generates negative linkage disequilibrium (LD) between itself and the costly D allele  is therefore approximatelyNμu per generation, the invasion rate of suppressor alleles at the locus isIn more precise terms, and Coop  and Muraand Coop ]. Therefδ. It is surprising that this ratio is independent of s and increasing in δ, since, by common interpretation, the ‘interests’ of unlinked suppressors are in restoring population mean fitness while the primary advantage to linked suppressors is the avoidance of drive. By this interpretation, we might expect the ratio of invasion rates of unlinked vs. linked suppressors to increase with s and decrease with δ ,,5), we fδ < 1/2. That is, the ‘partisan’ interests of a linked suppressor are effectively stronger than the ‘parliamentary’ interests of an unlinked suppressor only if drive is sufficiently weak. This threshold value of δ is especially relevant since, when drive is limited to the meiosis of one sex , the value of δ for the species, averaged across the two sexes, is necessarily ≤1/2.From the same comparison, we see that the establishment probability of a suppressor at a tightly linked locus is greater than at an unlinked locus if n chromosomes of equal physical length. Then the overall invasion rate of linked suppressors is proportional to 4Nμlp2(1 − p)s, while the overall invasion rate of unlinked suppressors is proportional to 8Nμu(n − 1)p2(1 − p)δs. Assuming the per-locus rate of appearance of suppressor alleles to be the same at linked and unlinked loci (μl = μu), unlinked suppression is seen to be more likely than linked suppression if 2(n − 1)δ > 1, i.e., if n > 1 + 1/(2δ). This calculation can be generalized to allow for unequal chromosome lengths (Appendix 3).Taking into account the relative numbers of linked and unlinked loci, Eqs.  and 6)  6) reveas = 0.1, δ = 0.05. Results for other parameter configurations are displayed in Fig. Figure M is a Mendelian allele with no direct effect on fitness, it can spread only via LD with d  which, since M’s dynamics below this copy number are dominated by drift, takes ~1/(2sM) generations on average. Therefore, if a copy of M is unlikely to recombine away from its associated d allele in 1/(2sM) generations (r ≪ 2sM), it behaves as if perfectly linked to d in its crucial establishment phase. The establishment probability of suppressors at these recombination distances is therefore similar to that of a perfectly linked suppressor given in Eq. (E(r) ≈ 2p2(1 − p)s  which confers on M a selective advantage sM ≈ p2(1 − p)sδ/r and therefore an establishment probabilityThe second regime is where the suppressor and drive loci are sufficiently loosely linked that, in sδ/r.Eq. S1.M was estimated for a necessarily sparse sample of recombination fractions r between the suppressor and drive loci. To estimate the establishment probability E(r) as a smooth function of r, I interpolated these simulation estimates using a cubic spline. This enables calculation, for arbitrary genetic maps and genomic positions of the drive locus, of the overall invasion rate of suppression and its likely genomic source.In the simulations, the establishment probability of L Morgans. Suppose further that there is no crossover interference, so that genetic distances l translate to recombination fractions via Haldane’s map function, x ϵ  along the normalized length of the chromosome, then the average establishment probability of a suppressor appearing by mutation somewhere along the chromosome—assuming each position to be equally likely—iss = 0.1 and δ = 0.05. The position of the drive locus is seen to affect the average establishment probability of linked suppressors: distorters in the middle of the chromosome are more readily suppressed than distorters at the end. The reason is that a central distorter has tightly linked loci on either side of it, and a maximum genetic distance to another locus on the chromosome of half the chromosome’s length; in contrast, a distal distorter has tightly linked loci to only one side, and the maximum distance to another locus is the chromosome’s full length. Therefore, the average recombination fraction with a randomly placed suppressor locus is smaller for central than for distal drive loci, and so the average establishment probability of suppressors is higher in the former case. Since recombination relations to unlinked loci do not depend on a locus’s chromosomal position, this argument extends to genomes with more than one chromosome: suppression of centrally located distorters should be more rapid than suppression of distally located distorters.I first address the importance of the chromosomal position of the drive locus. Consider a genome with a single chromosome and a uniform genetic map of length  Haldane . If the entclass1pt{minimaE(r) also enables calculation, for various linkage maps, of the relative likelihood of linked vs. unlinked suppression. Figure δ, and is insensitive to the fitness cost of the driver, s /2 to Second, I have assumed that the suppressor allele n et al. ]. SupposM’s only effect is on the segregation ratio at the drive locus. In particular, I have assumed that M does not directly affect the fitness of its bearers. However, fitness costs to suppressor alleles are known in a number of drive systems . This sUnder many other fitness schemes, however, the driver is expected to spread to fixation if unsuppressed Prout . PolymorThe comparisons in this paper assume that the rate of mutation to suppressor alleles is uniform across the genome—in particular, suppressors are equally likely to appear at a locus on the same chromosome as the drive locus and at a locus on a different chromosome. This assumption focuses attention on the selective forces promoting suppression in different regions of the genome; i.e., the relative strengths of the ‘partisan’ interests of linked suppressors and the ‘parliamentary’ interests of unlinked suppressors.However, the assumption is unlikely to hold in many empirical instances of meiotic drive. For example, a theme that has emerged from recent molecular characterization of suppressors in several drive systems is that suppression often occurs via RNA interference [e.g., Dawe et al. , SvedberOn the other hand, when suppression is constrained to certain sites in the genome but drive can occur on any chromosome, suppressors appearing at a given site will usually be unlinked to the driver they suppress. The centromere drive hypothesis (Henikoff et al. Finally, in assuming that the mutational appearance of suppressor alleles follows the establishment of stable polymorphism at the drive locus, I have implicitly assumed that the mechanism of suppression is tailored to the driver in question. However, the regular occurrence of meiotic drive at various locations in the genome can ultimately select for alterations of the genetic system that inhibit drive in general, such as to the recombination rate (Haig and Grafen Supplementary Figures S1 and S2