The association of periodontal disease in people diagnosed with RA is emerging as an important driver of the RA autoimmune response. Screening for and treating periodontal disease might benefit people with RA. We performed a systematic literature review to investigate the effect of periodontal treatment on RA disease activity.Medline/PubMed, Embase and Cochrane databases were searched. Studies investigating the effect of periodontal treatment on various RA disease activity measures were included. The quality of included studies was assessed. Data were grouped and analysed according to RA disease outcome measures, and a narrative synthesis was performed.We identified a total of 21 studies, of which 11 were of non-randomized experimental design trials and 10 were randomized controlled trials. The quality of the studies ranged from low to serious/critical levels of bias. RA DAS-28 was the primary outcome for most studies. A total of 9 out of 17 studies reported a significant intra-group change in DAS-28. Three studies demonstrated a significant intra-group improvement in ACPA level after non-surgical periodontal treatment. Other RA biomarkers showed high levels of variability at baseline and after periodontal treatment.There is some evidence to suggest that periodontal treatment improves RA disease activity in the short term, as measured by DAS-28. Further high-quality studies with longer durations of follow-up are needed. The selection of the study population, periodontal interventions, biomarkers and outcome measures should all be considered when designing future studies. There is a need for well-balanced subject groups with prespecified disease characteristics. Key messagesA short course of periodontal treatment can significantly improve RA disease activity.Periodontal treatment might influence serum ACPA levels in people with RA and co-existent periodontitis.Further high-quality intervention studies with longer study durations are needed.RA is an autoimmune inflammatory condition that primarily affects the joints. RA autoimmunity is thought to be initiated at mucosal sites, such as the oral cavity, lung and gastrointestinal tract. At these sites, local inflammation [e.g. periodontitis (PD)] can be driven by genetic or environmental risk factors (e.g. cigarette smoke). The combination of mucosal inflammation and local bacterial dysbiosis might be responsible for triggering the RA autoimmune response, in particular ACPA, the serological hallmark of RA . Of the Periodontitis is an inflammatory condition of the tooth supporting structures initiated by microbial biofilms on the tooth surface  and exacerbated by a dysregulated host response. There is also a similar dysregulation of the pro-inflammatory cytokines to that seen in RA . The res+ at-risk individuals without arthritis [Porphyromonas gingivalis, has a peptidylarginine deiminase enzyme that can citrullinate cytoskeletal filaments, which might promote the production of ACPAs. It is therefore hypothesized that changes in the oral microbiome in PD could be a trigger for RA-related autoimmunity. A study investigating microbial composition of subgingival plaque in CCP+ subjects at risk of RA found dysbiotic subgingival microbiome composition in addition to an increased prevalence of P. gingivalis compared with healthy controls [There is mounting evidence to support a relationship between RA and PD. It has been found that periodontal disease is more prevalent in people with RA . PD is arthritis . A key pcontrols .Building on the putative association between PD and RA, a logical question is: can periodontal therapy influence disease activity and disease progression in RA? Recent reviews have found improved DASs after non-surgical periodontal treatment . We aim Rheumatology Advances in Practice online. A systematic literature search was designed with input from an expert librarian and informatician at Leeds Teaching Hospitals NHS Trust using a combination of key words and MESH terms. The search was conducted according to a prespecified protocol and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines . SearcheScreening of search results was undertaken independently by two authors (Z.M. and J.T.). Any disagreement was resolved through discussion and, where necessary, arbitration by a third author (K.M.).For each article, the effect of NSPT on RA disease activity was analysed, and the following themes emerged from the data: the effect of treatment on DAS-28, ACPA, ESR and CRP, RF, swollen and tender joints, morning stiffness, HAQ and other ancillary RA biomarkers.s.e.m. was provided. Data were tabulated for a narrative synthesis and grouped by RA disease outcome measure.Effect measures of NSPT on outcome measure were calculated as the mean difference between baseline and follow-up (intra-group comparison) and/or the mean difference between groups (inter-group comparison). Where possible, the Included articles were quality appraised using the Risk Of Bias In Non-randomized Studies—of Interventions (ROBINS-I)  and the The systematic review was not registered. There was no deviation from the protocol throughout the review.Rheumatology Advances in Practice online, details the excluded studies. A total of 21 articles were included in the analysis; 10 were of randomized controlled trial design and 11 of non-randomized intervention design. The study characteristics are detailed in The screening results are summarized in the PRISMA flow diagram . SupplemDAS-28 was reported in a total of 17 studies. DAS-28 was calculated using ESR in eight studies, in two studies using CRP and one study reported both formats. Whether CRP or ESR was used was not reported in seven studies. Of the 17 studies, 9 demonstrated a statistically significant improvement in the DAS-28 after NSPT, compared with baseline. Of the 10 studies that reported on inter-group analysis, 6 studies demonstrated a statistically significant difference between the experimental and control arms.et al. [P = 0.013). This represents the longest study duration to show improved DAS-28.A recent paper by Nguyen et al. , compariet al. [+PD+ and 30 RA+PD− subjects. At 45 days after NSPT, the RA+PD+ group had a reduction of DAS-28 from 4.34 to 3.12, . However, this study has a high risk of bias owing to the randomization process.Moura et al.  conducteet al. [P = 0.04) and a decrease of DAS-28 CRP from a median of 3.26 to 2.76 (P = 0.002).In an analysis of a subgroup of 22 participants who had RA, Białowas et al.  showed tet al. [P < 0.01). However, at the 3- and 6-month re-evaluation there was no significant further change.Bıyıkoğlu et al. , in theiet al. [P. gingivalis counts at both baseline and the 3-month re-evaluation .Cosgarea et al.  failed tet al. [Monsarrat et al.  failed tet al. [P = 0.002). The mean DAS-28 reduction was 1.05 , whereas in the control group there was no mean reduction.Khare et al.  comparedRheumatology Advances in Practice online.The full results are summarized in Rheumatology Advances in Practice online, summarizes the change in serum CRP and ESR values after NSPT.A total of 7 studies evaluated the effect of periodontal intervention on CRP , 32, 33,Rheumatology Advances in Practice online, summarizes the changes in RF after NSPT.Seven studies evaluated RF levels before and after NSPT. Five studies , 32, 33 A total of six studies evaluated serum ACPA. Three studies reported a significant reduction in serum ACPA levels after NSPT.et al. [r = 0.939, P < 0.001).Zhao et al.  found a et al. [P < 0.001). Likewise, Nguyen et al. [P < 0.001).Anusha et al.  found a n et al.  found a et al. [et al. [P. gingivalis abundance from periodontal pocket samples. Rheumatology Advances in Practice online, summarizes the change in serum ACPA values after NSPT.Ding et al.  failed t [et al.  found noRheumatology Advances in Practice online, summarizes the effect of NSPT on ancillary biomarkers.A total of 9 out of 21 studies investigated the effect of NSPT on ancillary biomarkers. Four studies investigated the effect of NSPT on serum TNF-α. Two of the studies , 31 founA total of four studies included data on the effect of NSPT on swollen and tender joint counts. Two of these four studies reported that there was a statistically significant improvement in swollen and tender joint counts after treatment.et al. [P < 0.01 in both cases). They also found a statistically significant reduction in tender joint count in group C (P < 0.05) but not in group A.Ortiz et al.  found a et al. [P = 0.01) and tender joint count (P = 0.04) 6 weeks after NSPT. Neither Al-Katma et al. [et al. [Białowas et al.  found a a et al.  nor Okad [et al.  found a Two studies evaluated the duration of early morning stiffness , 27. Neiet al. [There were no adverse events reported in any of the included studies from NSPT in the study populations. Of interest, however, in the study by Monsarrat et al. , two parThis systematic review has identified and included new data providing an important update on this topic. The relationship between periodontal disease and RA, and the potential impact of NSPT on RA continue to be research areas of great interest. This is reflected in the markedly increased frequency of studies exploring these links in the last 5 years . We founStudy design was highly variable, with a moderate to critical risk of bias in most studies. The most common risks for biases were in measurements of outcomes and selection of the reported result for non-randomized study designs assessed using the ROBINS-I tool. For randomized controlled trials, the reporting/design of the randomization process and measurement of outcomes were most frequently areas of concern. Several trials were multiple-arm studies with a range of interventions, disease status , making meaningful inter-group comparisons difficult. Such designs also meant that there was no true control group in many cases .Although systematic reviews with meta-analyses have been published examining the impact of periodontal therapy on RA , we feltCase definitions for both periodontal disease and RA varied significantly between studies. This is important because the severity of periodontal disease and subsequent levels of oral mucosal inflammation might be an important prognostic factors. Levels of baseline RA-related systemic inflammation might have similar importance regarding RA-related outcome measures. Future studies should follow the 2017 World Workshop on the Classification of Periodontal and Peri-Implant Diseases and Conditions  to charaDescription of the periodontal interventions frequently lacked sufficient detail, with the experience of the operator , instruments/equipment used, thresholds for plaque control before treatment and any time limits rarely reported. In the five studies that followed subjects up to 6 months, only a single course of NSPT was provided, whereas the accepted standard of care is for ∼3-monthly supportive therapy . This miMost of the included studies (16 of 21) had a primary endpoint of 3 months or less. Although this may be adequate to demonstrate proof of concept, because both RA and periodontal disease are chronic conditions, the clinical significance of acute changes after a single course of treatment is questionable. Whether the improvements seen in most studies would be sustained with continued treatment or supportive therapy remains to be investigated.Most studies measured several RA-specific and ancillary pro-inflammatory biomarkers . Although identification of candidate biomarkers is an important objective, these markers were highly variable both at baseline and after treatment and did not appear to be suitable as independent measures of disease activity. Although levels of inflammatory markers offer one explanation for a common mechanism of action for the impact of periodontal therapy on both periodontal disease and RA activity, most of these biomarkers do not appear to be useful proxies for more robust clinical measures, such as DAS-28 for RA or bleeding on probing/probing pocket depth for periodontal disease. One promising biomarker as an outcome measure for assessing the impact of NSPT on RA disease activity is ACPA, for which three studies found there to be a significant reduction after treatment , 26, 32.Regarding interpretation of DAS-28 reduction, future studies should take care to report consistent DAS-28 formats. This review found inconsistency in the use of either DAS-28-ESR or DAS-28-CRP, and occasionally, the format was not reported. This is particularly important because CRP has been shown to be elevated in individuals with periodontal disease and no systemic disease . TherefoReporting of additional outcomes was limited for most studies. Adverse events were rarely reported, although in the studies that did report them these were rare, predictable and known consequences of periodontal therapy (e.g. dentine hypersensitivity). Only two studies , 27 repoBox 1. We make these recommendations for future researchWhen reported, the duration of RA in the study populations was at least several years. The participants also had persistent active disease, despite pharmacotherapy. Despite such recalcitrant disease characteristics, most studies demonstrated a clinically meaningful reduction in disease activity, underscoring the potential for management of periodontal disease as a potential adjunctive measure. One study that recruited refractory RA participants but did not meet the inclusion criteria was the study by Möller et al. [This systematic review had several strengths. New data have been captured by our search, thus providing an important update on this topic. We specified open inclusion criteria to include all potentially relevant studies, including subgroups of individual study arms where relevant. We used a comprehensive risk of bias/quality assessment for all study designs. We elected to avoid meta-analyses owing to the heterogeneity of study design, high risk of bias present in most studies and clinical variability between study samples. Based on the limitations of currently available studies, we have suggested considerations for the design of future research to evaluate the impact of NSPT on RA . A qualir et al. . They co+ individuals who have not yet progressed to RA compared with controls [Although more research is needed, we found clear support for the use of NSPT in people who have both PD and RA. Recent studies have shown that there is a higher incidence of periodontal disease in ACPAcontrols . We recoIt has been suggested that periodontal inflammation might precede joint inflammation and therefore that the periodontium could be the site of RA disease initiation in some individuals. Early detection/treatment of PD in the pre-RA phase could therefore delay/prevent RA . Recent Funding: There was no funding associated with this research.Disclosure statement: The authors have declared no conflicts of interest.Registration: The systematic review was not registered. There was no deviation from the protocol throughout the review.rkac061_Supplementary_DataClick here for additional data file.


Sir,We thank Kessler et al. for their comments on our study.We carried out a population study with the aim to evaluate the impact of introduction of STAN in Norway on the following outcome measures: occurrence of fetal and neonatal deaths, Apgar scores <7, intrapartum cesarean sections and instrumental vaginal deliveries.Kessler et al.Kessler et al.According to the authors, “the number of theoretically preventable neonatal deaths is substantially lower than its total count”.It is difficult to estimate exactly how many intrapartum stillbirths could have been prevented. A reasonable estimate is that three to four intrapartum stillbirths could have been prevented yearly by STAN. This is a low number, in particular since there are about 55 000 deliveries each year in Norway. Also note that the regression coefficient is small Table . During Kessler et al.Note that the starting point for our graph in Figure Kessler et al.Kessler et al.Kessler et al.In their Letter to the Editor, Kessler et al. conclude that “the data presented in the study do not support its key message”. The authors put forward several arguments to justify their conclusion. Below, we present their arguments, and give our response.Figure S1Click here for additional data file.


Philosophical Transactions published G. I. Taylor’s seminal paper on the stability of what we now call Taylor–Couette flow. In the century since the paper was published, Taylor’s ground-breaking linear stability analysis of fluid flow between two rotating cylinders has had an enormous impact on the field of fluid mechanics. The paper’s influence has extended to general rotating flows, geophysical flows and astrophysical flows, not to mention its significance in firmly establishing several foundational concepts in fluid mechanics that are now broadly accepted. This two-part issue includes review articles and research articles spanning a broad range of contemporary research areas, all rooted in Taylor’s landmark paper.In 1923, the Philosophical Transactions paper (part 1)’.This article is part of the theme issue ‘Taylor–Couette and related flows on the centennial of Taylor’s seminal  All the solutions are for the same equations, only with different values of . We have no reason to think that there are any terms missing from these equationsrprise.’  .. 2Philosophical Transactions.Part 1 of this theme issue is a combination of review articles and research articles having a root in Taylor’s 1923 paper and often connecting directly to Taylor’s vision of future work on the problem. The authors who have contributed to this theme issue are leading researchers in the field of Taylor–Couette and related flows. They represent an international community of scientists and engineers with research interests that span a broad range of flow physics and applications, all of which can trace their heritage back to Taylor’s 1923 paper in the et al. investigate ‘a dynamical skeleton of turbulence’ experimentally and numerically. Wiswell et al. conduct experiments on end-effects in low aspect ratio Taylor–Couette flow. Jeganathan et al. present numerical results on the origin of turbulent Taylor rolls. Oishi & Baxter use a generalized quasi-linear approximation to study non-normality in spiral turbulence.For the classical Taylor–Couette problem with a Newtonian fluid, the focus of modern research has largely moved beyond the linear onset of instability studied by Taylor to consider instead the highly supercritical, turbulent regime. Crowley et al. and Meyer et al. each present numerical results obtained by imposing radial temperature gradients in the underlying cylindrical geometry. Further extensions of Taylor–Couette flow include multi-phase flows, where Baroudi et al. review Taylor–Couette flow of suspensions, followed by experimental studies by Alam & Ghosh, Yi et al. on emulsions, and Blaauw et al. on bubbly drag reduction by switching from fresh to salt water.Fundamentally new areas of research are opened up by combining Taylor–Couette flows with convection. Kang et al. review experiments involving elasto-inertial transitions, and Song et al. review turbulent flows of dilute polymeric solutions.Three further extensions of the classical Taylor–Couette problem are magnetohydrodynamic, ferrofluidic and viscoelastic flows. At first glance, these might seem very different, but they modify the original problem in somewhat similar ways, by providing new ways of coupling fluid parcels via magnetic tension in magnetohydrodynamics, magnetic forces in ferrofluids, or polymeric elasticity in viscoelastic flows. Guseva & Tobias present numerical studies and theoretical analysis of transition to chaos and modal structure in magnetohydrodynamic flows. Altmeyer numerically explores ferrofluidic wavy Taylor vortices under alternating magnetic fields. For the viscoelastic problem, Boulafentis et al. review routes to turbulence in rotating disc boundary layers and cavities, demonstrating that ideas and methods similar to those used in the Taylor–Couette geometry can often be applied in other flow systems as well.Finally, there are a variety of systems and geometries that are not strictly Taylor–Couette flows as such, but are nevertheless closely related. Martinand . 3Philosophical Transactions builds on the ongoing interest in Taylor–Couette flow and its many important derivatives in terms of current research, perspectives on the influence of Taylor’s seminal paper, and its future impact on many related fields.Although Taylor–Couette flow has been studied for a century , it continues to provide a basis for a broad range of research. This two-part issue of the


Appropriate prenatal care (PNC) is essential for improving maternal and infant health; nevertheless, millions of women in low- and middle-income countries (LMICs) do not receive it properly. The objective of this review is to identify and summarize the qualitative studies that report on health system-related barriers in PNC management in LMICs.This systematic review was conducted in 2022. A range of electronic databases including PubMed, Web of Knowledge, CINHAL, SCOPUS, Embase, and Science Direct were searched for qualitative studies conducted in LMICs. The reference lists of eligible studies also were hand searched. The studies that reported health system-related barrier of PNC management from the perspectives of PNC stakeholders were considered for inclusion. Study quality assessment was performed applying the Critical Appraisal Skills Programme (CASP) checklist, and thematic analyses performed.Of the 32 included studies, 25 (78%) were published either in or after 2013. The total population sample included 1677 participants including 629 pregnant women, 122 mothers, 240 healthcare providers, 54 key informed, 164 women of childbearing age, 380 community members, and 88 participants from other groups . Of 32 studies meeting inclusion criteria, four major themes emerged: (1) healthcare provider-related issues; (2) service delivery issues; (3) inaccessible PNC; and (4) poor PNC infrastructure.This systematic review provided essential findings regarding PNC barriers in LMICs to help inform the development of effective PNC strategies and public policy programs. Qualityet al., et al., As a qualitative evidence synthesis method, we applied thematic synthesis  were published either in or after 2013. The studies took place in 21 countries across four continents. Of the included studies, 59% discussed countries or regions in Africa, with Tanzania and Malawi being the most common of these; 25% discussed Asian countries or regions and only one study (3.1%); and discussed barriers in the South America and one in Papua New Guinea from Oceania (3.1%).Numbers of participants varied from five to 295, with most between 20 and 80 participants. The total population sample included 1677 participants including 629 pregnant women, 122 mothers, 240 healthcare providers, 54 key informed, 164 women of child bearing age, 380 community members, and 88 participants from other groups .The overall quality assessment of the studies was conducted by rating CASP items Table . All of We categorized the review findings into four main themes: healthcare provider-related issues, service delivery issues, inaccessible PNC, and poor PNC infrastructure. There are one to five subthemes under each theme that are presented in Figure Concerns about the negative impact of healthcare providers’ issues on the PNC emerged as a prominent theme with five subthemes: (1) human resource shortage; (2) lack of female PNC providers; (3) insufficient PNC providers’ knowledge; (4) poor relationship with PNC clients; and (5) lack of motivation.et al., et al., et al., Baffour-Awuah et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Participants in many of included studies expressed concerns over insufficient human resources  long distance; (2) unaffordable PNC; and (3) long waiting times.et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Many of participants believed that pregnant women cannot afford the cost of PNC. They reported high cost of care, laboratory tests, and medications (Mathole et al., et al., et al., et al., et al., et al., et al., et al., et al., Waiting time was another important accessibility area in which frustration was expressed. The participants believed that long waiting times would be the factor which would discourage pregnant women from seeking PNC services (Larsen et al., et al., et al., et al., et al., et al., et al., et al., et al., According to participants’ perspectives, geographical access to PNC appears inadequate. They mentioned that PNC seekers’ access to care is restricted by long distance (Larsen et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., We found that many of participants complained that poor PNC clinic facilities hindered PNC provision or utilization (Larsen PNC is an essential component of improving maternal and infant health during pregnancy and birth, by treating and monitoring potential complications. This review set out to summarize the qualitative literature concerning the healthcare system-related barriers in PNC management in LMICs. Included studies came from a variety of countries and help understand the range of different potential difficulties in PNC management from several continents. Findings of this systematic review suggest that PNC in LMICs can be challenged by a number of barriers at different levels of healthcare systems, including human resources aspects, service delivery issues, PNC accessibility, and PNC infrastructures.In addition to a wide range of countries with low- and middle-income settings, the included studies encompassed a wide range data from different types of PNC stakeholders such as healthcare providers, pregnant women, male partners, and community members. This indicates that PNC stakeholders, in any role, are aware that PNC is provided in a context lead by the healthcare system.et al., et al., It is notable that the majority of barriers identified within the evidence emerged within the human resources and service delivery themes. This stakeholder perception is supported by other systematic reviews investigating LMICs barriers in other maternal health contexts such as midwifery care (Filby et al., et al., et al., et al., Many of the emerged barriers in this review of qualitative studies also match those observed in earlier quantitative studies. For example, one of them highlighted insufficient geographical accessibility (Kuupiel This review provides a comprehensive approach to qualitative studies of healthcare system-related barriers to PNC in LMICs. Exploring pregnant women, PNC providers, and general population accounts also provided a rounded understanding of PNC barriers from multiple perspectives.There are several important limitations to note when interpreting the results of this review. One limitation is that it we only included articles published in English, which may suggest that the potentially relevant studies from cultural contexts where English is not the norm may be missed. In addition, limited time and resources prevented a more thorough and comprehensive search of the gray literature, a body of evidence that may have had more to offer PNC clients’ experiences and perspectives.Despite all of the works that has been conducted in the area of PNC barriers, the current review noted a significant gap in the evidence base related to PNC and healthcare systems. This important gap is the perspectives of women who are underrepresented in the data: pregnant women who did not make it to PNC. Because of health system-centric nature of the majority of related literature, there is much more information about pregnant women who stayed in care than about those who never attend PNC.This review contributes to the current debate on the knowledge of key barriers to PNC in LMICs contexts. Findings of this systematic review suggest that PNC in LMICs can be challenged by a number of barriers at different levels of healthcare systems, including human resources aspects, service delivery issues, PNC accessibility, and PNC infrastructures. Healthcare policymakers in LMICs, when planning and managing the PNC, should consider the lessons learnt from previous reports as synthesized in this review and should carefully develop strategies to prevent and mitigate common barriers to successful PNC.


S. Najm et al., RSC Adv., 2022, 12, 29613–29626, https://doi.org/10.1039/D2RA04790J.Correction for ‘Mechanism and principle of doping: realizing of silver incorporation in CdS thin film  The authors regret that the list of affiliations was incorrectly shown in the original manuscript. The corrected list of affiliations is as shown below.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers.


Micromixers are important components of lab-on-a-chip systems, and also have many biological and chemical applications . MicromiHejazian et al.  reviewedBanos et al.  examinedKoike and Takayama  introducOevreeide et al.  proposed2O3 nanoparticles affects the pressure drop and thermal mixing for a Re range from 0.1 to 25 was tested. The results revealed that higher nanofluid concentration and stronger chaotic advection improved the hydrodynamic and thermal performances over the whole Re range remarkably. Mahammedi et al. [Tayeb et al.  numericai et al.  also numi et al.  reportedI appreciate all the authors who contributed to this Special Issue. Additionally, thanks also go to the reviewers for the submitted papers and the editorial staff who conducted the review process. Further contribution to this topic can be made to the Topical Collection “Micromixers: Analysis, Design and Fabrication” of this journal.


Heliconius butterflies or heterostyly in Primula—have been studied since the Modern Synthesis, we still understand very little about how they evolve and persist in nature. The genetic architecture of supergenes is a critical factor affecting their evolutionary fate, as it can change key parameters such as recombination rate and effective population size, potentially redirecting molecular evolution of the supergene in addition to the surrounding genomic region. To understand supergene evolution, we must link genomic architecture with evolutionary patterns and processes. This is now becoming possible with recent advances in sequencing technology and powerful forward computer simulations. The present theme issue brings together theoretical and empirical papers, as well as opinion and synthesis papers, which showcase the architectural diversity of supergenes and connect this to critical processes in supergene evolution, such as polymorphism maintenance and mutation accumulation. Here, we summarize those insights to highlight new ideas and methods that illuminate the path forward for the study of supergenes in nature.Supergenes are tightly linked sets of loci that are inherited together and control complex phenotypes. While classical supergenes—governing traits such as wing patterns in This article is part of the theme issue ‘Genomic architecture of supergenes: causes and evolutionary consequences’. As a New genomic, theoretical and bioinformatic methods now allow us to begin to understand the complex evolutionary history and diversity of supergenes ,3,18,19.The present collection of papers integrates (i) theoretical (including simulation) studies that generate predictions about supergene evolution, (ii) empirical studies that dissect genomic variation associated with supergenes, and (iii) synthetic opinion and review papers that tie together these diverse aspects of supergene evolution. Papers in this theme issue showcase the stunning architectural and taxonomic diversity of supergenes and cover a broad range of subjects relevant to our understanding of supergenes including local adaptation versus gene flow; parallel evolution; mutation accumulation and balanced lethality; sexually antagonistic selection; sex chromosome evolution; speciation; chromatin architecture and gene expression; and selfish genetic elements. In this introduction, we review the advances made by these papers, summarize the genomic architecture they uncover (§2) and detail how it connects to three major questions in supergene research: the role of supergenes in adaptation (§3), maintenance of supergene polymorphism (§4), and mutation accumulation in supergenes (§5). We highlight methodologies that can move the field forward and focus on outstanding questions in supergene evolution.. 2Characterizing the genomic architecture of supergenes is the first step towards understanding their evolution. A major focal point is to comprehend the underlying genetic mechanisms of recombination suppression between supergene haplotypes. Certain genetic mechanisms can generate unbalanced gametes in supergene heterozygotes , which has the two-pronged effect of generating underdominance as well as reducing effective recombination. For example, improper segregation of chromosomes in translocation heterozygotes can lead to the creation of aneuploid gametes  at a rate of 18–80% ,25. The et al. [Danaus chrysippus. They find three alleles that differ dramatically in sequence, each containing multiple duplicated regions and inversions. Comparing BC supergene structure across the Danaus phylogeny, the authors reconstruct this supergene's evolutionary history and infer that it initially arose when a large genomic region was repeatedly duplicated approximately 7.5 Myr, with several inversions arising subsequently within this region of duplicated segments. Recombination suppression across the supergene probably spread through the fixation of these inversions, in addition to the genetic divergence of duplicated segments followed by differential loss of some of these duplicated regions. This second process of divergence and loss of duplicates may be a common contributor to supergene evolution.Kim et al.  use trioet al. [Papilio butterflies that controls female-limited mimicry [Papilio polytes, no inversion is present in H in Papilio memnon [et al. [P. memnon and P. polytes. Using knock-down and expression studies, the authors are able to directly link genes within the supergene to different aspects of the female wing colour patterns. The authors show that both systems exhibit strong linkage disequilibrium in the supergene region as well as accumulation of repetitive sequences, a hallmark of low recombination regions [P. polytes seems to have generated a new gene, U3X, that regulates the expression of other loci within the supergene. Overall, this suggests that selection for the inversion may be acting on the breakpoints (i.e. direct selection on the inversion itself), as opposed to other characteristics such as reduced recombination.Komata et al.  also use mimicry ,29. Two o memnon ,30,31. T [et al.  put toge regions –36. Surpet al. [et al. [et al. [Not all supergenes show suppressed recombination between haplotypes. Dufresnes et al.  investiget al. . In factet al. . Amphibi [et al.  review t [et al. . Dufresn [et al.  highlighDrosophila pseudoobscura to a map of topologically associated domains (TADs). TADs, which represent a form of higher order chromatin interactions, are self-interacting regions of the genome hypothesized to regulate gene expression [In addition to affecting linkage between loci, supergenes may also go beyond DNA changes to alter the epigenome, i.e. chromatin and methylation patterns. The ensuing consequences of supergenes on epigenomic modifications have been little explored up to now. In their paper, Wright & Schaeffer  explore pression –45. Wrigpression  examine t-haplotypes in mice [Sp haplotype in the Alpine silver ant, Formica selysi [Segregation distorter in Drosophila melanogaster [et al. [Mimulus guttatus is a supergene, segregating in multiple Mimulus populations in the Pacific northwest. They show that in several populations, D is a large (10–12 Mb) non-recombining region that leads to female meiotic drive and contributes to pollen inviability when homozygous . D shows evidence of prior selective sweeps (possibly separate sweeps in two populations), but appears to be maintained within populations as a balanced polymorphism. Transcriptomes of individuals with and without the D allele indicate that many genes located within the supergene show reduction of expression in developing and reproductive tissues, suggesting many of the effects of D are cis-acting, similar to findings for other non-driving supergenes [et al. [SIM3), further contributing to our knowledge of selfish supergenes.Supergenes may also be selfish genetic elements, containing alleles that are specialized in over-representing themselves in the next generation through segregation distortion ,47. Ther in mice , the Sp a selysi  and Segrnogaster . Finseth [et al.  provide pergenes –53. Fins [et al.  identify. 3et al. [et al. [Supergenes provide a mechanism that allows multiple favourable trait combinations to be maintained in the face of recombination. While the role of supergenes in adaptation has been well established ,18,19,54et al.  use simu [et al.  examine et al. [Schaal et al.  address et al. [et al. [Stenløkk et al.  use empi [et al. .et al. [et al. [A second critical question regarding the role of supergenes in adaptation is whether supergenes repeatedly arise. Observations of the same supergene are common in isolated populations of the same species or in closely related species and could result from several different evolutionary scenarios: multiple independent origins of the supergene, the presence of the supergene in a common ancestor or adaptive introgression of supergenes. Kay et al.  and West [et al.  use bothet al. [Kay et al.  examine et al. . Thus, bet al. [The mechanisms behind the role of supergenes in parallel adaptation with gene flow is reviewed and modelled by Westram et al. . The autet al. [Heliconius numata. Within the supergene, which is itself composed of three chromosomal inversions, the authors identify several independent, putatively adaptive loci that are associated with different aspects of wing patterning. The results of Jay et al. [et al. [A third challenge in studying how supergenes facilitate adaptation is identifying adaptive variants in large regions of linkage disequilibrium generated by recombination suppression. Jay et al.  use a muy et al.  are cons [et al. ).et al. [CRHR1, KANLS1 and MAPT) that might underlie these phenotypes. The second inversion studied, 8p23.1, is also associated with several related phenotypes and gene expression differences; however, the complex breakpoint structure, and the apparent lack of genetic divergence within the inverted region away from the breakpoints, renders understanding the effects of this inversion challenging. Studying the properties of supergenes in humans is fundamentally important, not only for gaining evolutionary insights, but also for an improved understanding of how supergenes such as inversions impact human health and disease.Campoy et al.  review a. 4et al. [et al. [et al. [Many known supergenes are over 1 Myr old , begginget al.  and Berd [et al. . Dagilis [et al.  take a met al. [F. selysi. This supergene has two haplotypes, Sm and Sp, that control colony structure in this haplodiploid species. In monogyne colonies, all queens and workers are Sm/Sm and males are Sm. In polygyne colonies queens and workers are Sm/Sp or Sp/Sp. However, the males produced in these colonies are only Sp, indicating the transmission ratio distortion caused by the Sp haplotype via a maternal killing effect [et al. [Multiple forms of balancing selection are probably needed to protect polymorphism over long time scales, but we understand little about which combinations of selective pressures can achieve this. Tafreshi et al.  examine g effect . Tafresh [et al.  find thaet al. [et al. [One of the major challenges of supergene polymorphism maintenance is that the allelic content of the supergene haplotypes can shift over time. In particular, supergenes may accumulate deleterious mutations that lessen the selective edge of certain haplotype combinations . Using set al.  examine et al. ). AOD deet al. ,72. Berd [et al.  find thaet al. [et al. [Gasterosteus nipponicus) [Another form of balancing selection that may maintain a supergene polymorphism within a population is sexually antagonistic selection, in which an allele that increases the fitness of males decreases the fitness of females, or vice versa. Dagilis et al.  investiget al. –75, but  [et al.  take advponicus) , which f. 5et al. [et al. [The reduction in effective recombination between supergene haplotypes can be viewed as a double-edged sword: it can facilitate adaptive processes when beneficial alleles are brought together, but might also speed up the accumulation of deleterious mutations . This iset al.  use simu [et al.  look foret al. use simulations in SLiM [Berdan  in SLiM ,78 to ex in SLiM . The aut in SLiM ,80.et al. [Stenløkk et al.  directly. 6By bringing together diverse empirical and theoretical studies of supergenes, this theme issue provides new insights into supergene evolution. While supergenes are a classical subject in evolutionary biology, investigating the evolution of supergenes has only really taken off within the twenty-first century ,18,19,54


That neOur efforts in publications –5 have b (i)a single, fixed material reference configuration from which to measure the deformation of a two-dimensional elastic body; (ii)a suitable class of competitors and related variations when formulating a solid mechanics problem within the calculus of variations. We sketch the basis for our line of argument here, relegating details and further clarifying discussion to subsequent §3a–3c. In §2, we briefly appraise the claims of van der Heijden & Starostin [et al. [The major issues with the strategy of Starostin & van der Heidjen , reprisetarostin  concerni [et al. .fixed pair Equation (2) from the comment , which dct, from , their ewhere in . Then, ilined in  is not bsame fixed rectangular reference configuration, say In formulating their variational problem, Starostin & van der Heijden  thus ovently, in  Starosti Heijden  is an isIn their variational problem, Starostin & van der Heidjen  envisionsible in  is to bem 1) of  will suf Heidjen  and furt of  willm (1) of . HoweverAn objective justification of the above comments is provided in §3. In the next §2, we briefly address the criticisms of our publications  that van. 2planar development connected to their complete class of rectifying developable parameterizations.Chen & Fried  do not eet al. [et al. [et al. [et al. [Chen et al.  focus onet al.  are alsoet al.  are cite [et al.  to the s [et al.  elaborat [et al. . The obs [et al.  have no  [et al. .et al. [Chen et al.  obtain aet al. [et al. [Chen et al.  focus onet al. , a work  [et al.  demonstret al. [shape of the rectangle is fixed but not the position of its internal material points, relative to which the deformation of a placement (1) is to be measured.The comments contained in van der Heijden & Starostin  do not pet al. –5. By inet al.  do exposet al.  and doestarostin  introduc. 3Here, we present the basis upon which we have earlier discussed the work of Starostin & van der Heijden . In §3a, (a)The fundamental problem of determining the equilibrium configuration of a free-standing Möbius band that is formed from the deformation of a flat unstretchable rectangular material strip by joining its two ends together after a Sadowsky ,8 and WuSadowsky ,10, and 1 with the aim of solving this problem, considered the variational problem of minimizing the Wunderlich [Most recently, Starostin & van der Heijden ,1 with tnderlich ,10 funct2 The isometric mapping Being developable, The Wunderlich ,10 functrization , then H=ius band , a midli (b)unstretchable Möbius band in the absence of tractions or couple tractions on its edge. Analogous to the various descriptors of Starostin & van der Heijden  apply a fined in , and repgiven in  with η in  to the m3isometric deformation of the fixed, undistorted material reference configuration deformation of the fixed, undistorted material reference configuration is not an isometric deformation. The consequence is that the set of rectifying developable Möbius bands as given in  in  and the n one material object, and that their intention was to study the material length-preserving deformation of a given undistorted rectangular material strip into a free-standing isometry relation between each Möbius band and a flat rectangle in fixed rectangular material reference configuration relative to which a deformation to each Möbius band is measured.Starostin & van der Heijden  set up tduced in . A fixedduced in  could befixed rectangular material reference configuration, Starostin & van der Heijden [By restricting the class of variational competitors to be the set of rectifying developable Möbius bands, and by neglecting to introduce a  Heijden , amended Heijden , did notrated in , their vion R of , relativ used in  to define aid of  and (3.9ly, from  and (3.9 through  and (3.8Granted, Starostin & van der Heijden , amendednderlich ,10 functThe Wunderlich ,10 functed as in , then it Heijden  but incl Heijden , and as  Heijden  recognizIn closing, we emphasize that any mechanics-based study of the isometric deformation a given fixed rectangular material reference strip into a rectifying developable surface is of distinctly limited applicability. For example, the only way to maintain the parameterization of a rectifying developable and to isometrically deform a flat rectangular shape onto the surface of a right circular cylinder is to wrap it so that two of its parallel edges are coincident with the generators of the cylinder—but there are other ways, helical in form, that do not involve maintaining the parameterization of a rectifying developable, to achieve an isometric wrapping. Moreover, as Chen, Fosdick & Fried , §4.3 shClick here for additional data file.


Despite reports of an elevated risk of breast cancer associated with antipsychotic use in women, existing evidence remains inconclusive. We aimed to examine existing observational data in the literature and determine this hypothesised association.We searched Embase, PubMed and Web of Science™ databases on 27 January 2022 for articles reporting relevant cohort or case-control studies published since inception, supplemented with hand searches of the reference lists of the included articles. Quality of studies was assessed using the Newcastle-Ottawa Scale. We generated the pooled odds ratio (OR) and pooled hazard ratio (HR) using a random-effects model to quantify the association. This study was registered with PROSPERO (CRD42022307913).N = 2 031 380) and seven for meta-analysis (N = 1 557 013). All included studies were rated as high-quality (seven to nine stars). Six studies reported a significant association of antipsychotic use with breast cancer, and a stronger association was reported when a greater extent of antipsychotic use, e.g. longer duration, was operationalised as the exposure. Pooled estimates of HRs extracted from cohort studies and ORs from case-control studies were 1.39 [95% confidence interval (CI) 1.11–1.73] and 1.37 (95% CI 0.90–2.09), suggesting a moderate association of antipsychotic use with breast cancer.Nine observational studies, including five cohort and four case-control studies, were eventually included for review (Antipsychotic use is moderately associated with breast cancer, possibly mediated by prolactin-elevating properties of certain medications. This risk should be weighed against the potential treatment effects for a balanced prescription decision. Studies were excluded if they were not published in English, had a study design that was neither cohort nor case-control, included participants who developed breast cancer prior to antipsychotic exposure or did not compare antipsychotic use to non-use, such as comparing between different classes of antipsychotics.All published cohort and case-control observational studies that investigated and quantified the association of antipsychotic use .The methodological quality of each included study was assessed using the Newcastle-Ottawa Scale (NOS). Like the data extraction procedure, the quality assessment was conducted independently by JCNL and DWYN. Study quality was indicated by numbers of stars, with nine representing the highest possible methodological rigour. See online Supplementary eTable 3 for details of the quality assessment procedures. Cohen's kappa was not calculated for the quality assessment decisions, as nine studies were included and there were only a few discrepancies, which were resolved through in-depth discussions.I2 statistic was used to examine the heterogeneity of the estimates across studies. Upon a sufficient number of included studies, the Egger's regression test was conducted to detect any publication bias in the pooled estimates. The pooled estimates and test for heterogeneity were implemented using Cochrane Collaboration Review Manager (Version 5.4.1).Upon satisfactory assessment result with regards to multivariable adjustment according to the NOS, meta-analyses of the estimates of the association, i.e. odds ratios (ORs) and hazard ratios (HRs), were conducted. Stratified by study design, i.e. cohort and case-control studies, the estimates of the association of antipsychotic use and breast cancer were pooled using a random effects model. The exposure was binarily operationalised as any antipsychotic use compared with non-use. In cases where this operationalisation was not possible, the longest-term exposure category, or the category representing the farthest extent of antipsychotic use, were used in comparison with non-use in the pooled estimates. The inverse variance weighting method was used to determine the relative importance between studies while the N =  2 031 380) were included for a qualitative synthesis and quality assessment. Cohen's kappa for title and abstract screening  and full-text selection  suggest moderate and substantial agreement respectively. Two studies were excluded from the meta-analysis  provided adequate data for a pooled estimate of the hypothesised association. Study characteristics and results, as well as quality assessment scores are tabulated in As shown in et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., The included studies have been conducted in five countries/jurisdictions: three studies in the United States   and substance misuse. Five of the nine studies had made such adjustments  for 1–4 years of antipsychotic use and 1.74 (95% CI 1.38–2.21) for at least 5 years of antipsychotic use , whereas breast cancer risk amongst antipsychotic users of less than 6 years were reported to be non-significant. In contrast, the dose–response relationship was not observed in the atypical antipsychotic subgroup of Chou et al., where an apparent association was observed with lower exposure instead of increased exposure. They reported HRs 2.49 (95% CI 1.69–3.66) and 1.05 (95% CI 0.58–1.87) for mean antipsychotic exposure of less than 28 and greater than 245 g/year, respectively.Despite a null association with the exposure defined as any antipsychotic use, long-term use  was found to have a small association with breast cancer development in Pottegård et al. . An incret al., et al., et al., et al., et al.   with breast cancer with a >30% increased risk observed, although the pooled OR did not reach statistical significance . As only three and four studies were included in the pooled estimates of the OR and HR, we did not conduct the Egger's regression test for publication bias.Using a random effects model, we pooled the HRs and ORs of breast cancer between antipsychotic users and non-users from four cohort studies , this action increases prolactin secretion (Besnard et al., et al., et al., et al., et al., With an increasingly prevalent use of antipsychotic medications worldwide, the risk of adverse events associated with it should be investigated in more breadth and depth to inform clinical practice. This study on the potentially elevated risk of breast cancer adds to the current knowledge of adverse events associated with antipsychotic use, such as stroke and myocardial infarction were investigated previously (Douglas and Smeeth, et al., The increased use of routine electronic health records in pharmacovigilance studies have contributed to the existing literature significantly, as shown in the included studies in this review. While providing a typically large sample size with realistic real-world clinical data, there are intrinsic limitations to these records. Specifically, the lack of lifestyle and other important factors might introduce bias to the estimated association. Primary data collection may provide much more detailed information but with a much-limited sample size. Therefore, both types of research are much warranted, and the evidence needs to be considered in the context of a variety of study designs with various strengths and weaknesses for a balanced overall assessment. With the benefits of record-linkage techniques with prescription registries, antipsychotic prescription practices such as antipsychotic polypharmacy in comparison with monotherapy can be addressed in future studies. One review suggested that aripiprazole use in combination with another antipsychotic was associated with better lipid profile outcomes than the use of other antipsychotic polypharmacy or monotherapy, although the quality of evidence was lacking (Ijaz et al. through the use of anticonvulsants and lithium as comparator drugs, which are also prescribed to patients with psychiatric disorders such as anxiety, depression and bipolar disorder, but with no known risk of hyperprolactinaemia (Ajmal et al., In spite of the important clinical implications, there are several limitations. First, the reviewed evidence is all generated from observational research without randomisation. There is likely unmeasured confounding effects and causal inferences need to be made with great caution. Specifically, the comparators selected for some included studies may not be entirely suitable and could be subject to potential selection bias. One example of mitigating this bias is demonstrated in Rahman et al., et al., There are also limitations specific to this review as well. First, although the meta-analysis generated consistent results across study designs, i.e. cohort and case-control, the association could not be appropriately pooled across designs to increase the precision of the estimate. Second, the number of studies is too small to provide a more precise estimate of the hypothesised association and the presence of publication bias could not be tested as a result. Third, significant heterogeneity was observed between studies even within the same design, probably due to different populations, research practice and availability of data, further studies with more accrued data should investigate factors that contribute to this heterogeneity. Recent studies reported higher basal epigenetic changes in African American women (Joshi In conclusion, we found a moderate association between the use of antipsychotics and breast cancer with a more evident association observed with prolactin-elevating medications and greater extent of antipsychotic exposure. This risk, together with other known associated adverse events, should be weighed against the anticipated treatment outcomes for a balanced clinical management decision.


Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age with a reported prevalence ranging from 6% to 20% . In 2004PCOS has long been accepted as the major cause of anovulatory infertility and hirsutism, with an increased risk of developing metabolic abnormalities, type 2 diabetes mellitus (T2DM), obstetrical complications, mood disorders, cardiovascular and cerebrovascular events, venous thromboembolism, and endometrial and ovarian cancer . The conWe asked the authors who participated in this Research Topic to consider the following questions: How to dive deep into the pathophysiology of PCOS? What are the new insights into metabolic dysfunctions, such as basal/glucose stimulated hyperinsulinemia and insulin resistance (IR), obesity, hyperandrogenism, and subfertility in PCOS? Among the repertoire of clinical management of PCOS, is there any exciting progress in pharmacological and lifestyle interventions? Is it possible to make a clinical diagnosis of PCOS through specific biomarkers? Can we effectively personalize assisted reproductive technology (ART) procedures for PCOS patients? How does PCOS influence maternal and offspring health? Why is it always associated with obstetrical complications including preeclampsia, very preterm birth (defined as <32 weeks of gestation), and gestational diabetes mellitus (GDM)? For the offspring of patients with PCOS, what symptoms are they inclined to display? What is the mechanistic role of the microbiome in PCOS? The result of this call is a relatively comprehensive collection of 33 articles regarding such aspects.Ding et al. give a comprehensive review of the mutual role of IR and HA on PCOS development. Song et al. provide an experimental study in a rat model which demonstrates that androgen excess could damage mitochondrial ultrastructure by depressing the expression of NDUFB8 and ATP5j and thereby influence the function of granulosa cells (GCs) in PCOS. Furthermore, the risk of epilepsy and antiseizure medications on PCOS through the HPO axis is reviewed by Li et al.In reports of pioneering studies, the most consistent feature of PCOS is an elevated level of testosterone and/or androstenedione in serum . Ding etJiang et al. reveal that a higher expression of ANGPTL4 in GCs might be associated with glucose and lipid metabolic disorders in PCOS. Differently expressed elements of store-operated Ca2+ entry (SOCE) are analyzed in the work by Song et al. and are proved to contribute to the dysfunction of ovarian GCs and hormonal changes. Deng et al. conduct a whole genome transcriptomic sequencing and find DLGAP5 as a candidate gene for PCOS.Liu et al. show that IL-15 affects the inflammation state, steroidogenesis, and survival of GCs. Ding et al. indicate that adipose tissue-derived extracellular vesicles-miR-26b promote GCs apoptosis. To supplement, Zhou et al. review the seminal features and therapeutic potential of extracellular vesicles in PCOS. Finally, Gu et al. have an extensive discussion on the relationship between the microbiome and sexual hormones, immune homeostasis as well as insulin resistance.Immune balance and immune microenvironment may play a significant role in the infertility of PCOS patients. He et al. provide an update that increased apolipoprotein B/A1 ratio is associated with worse metabolic syndrome components, hyperandrogenemia, IR, and elevated liver enzymes. The new aspect of excessive visceral adipose tissue mass is analyzed in the contribution by Zhang et al., demonstrating it is this characteristic but not other fat compartments that can exacerbate the risk of hyperuricemia in PCOS. Yang et al. describe the positive correlation between neck circumference and serum uric acid levels. The increased risk factor of PCOS is examined in the contribution of Chen et al., who defined IL-17, SDF1a, SCGFb, and IL-4 as potential biomarkers for PCOS. With the rapid development of artificial intelligence, Lv et al. propose an automated deep learning algorithm for exploring the potential of scleral changes in PCOS detection.Since the expense of the diagnostic evaluation accounted for only a minor part of the total costs, more liberal screening for PCOS appears to be a cost-effective strategy. Given the probable multifactorial cause of PCOS, a specific plan for early risk prediction of diagnosis is not yet possible. Hence, further studies of the early biomarkers of PCOS and early intervention of at-risk adolescents are sorely needed. Patients with PCOS are at risk of experiencing obstetrical complications including preeclampsia, very preterm birth, and GDM . Their oMai et al. demonstrate that PCOS exhibited higher CLBR and better ovarian reserve and response. When it comes to the independent variables for determining CLBR of aged patients with PCOS, this view is counter-argued by Guan et al., with a retrospective cohort study presenting significantly decreased CLBR for females of advanced reproductive age up to 37. Compared to regular menstruation or oligomenorrhea, a higher overall incidence of adverse pregnancy outcomes in PCOS patients with amenorrhea is presented by Yu et al. In addition, Du et al. point out that preterm birth in PCOS is associated with a BMI≥24 kg/m2 plus serum AMH>6.45 ng/ml. According to Jiang et al., advanced age, obesity, total cholesterol, triglycerides, and insulin resistance (IR) are all independent risk factors for a lower chance of achieving a live birth.The issue of cumulative live birth rate (CLBR) in PCOS is dealt with by two articles. Zhang et al. and Jiang et al. respectively, focus on the health of PCOS offspring and broaden our understanding of PCOS offsprings’ cardiometabolic status and autistic traits. Xie et al. have generated letrozole-induced PCOS-IR rat models and treated them with metformin. In this article, they interpret that metformin might improve obesity, hyperinsulinemia, and IR in female offspring.Two articles, by Gu et al. review the current evidence of the role of lifestyle modifications in PCOS, including diet modifications, exercise modifications, sleep modifications, mood modifications, and weight modifications. A meta-analysis by Shang et al., involving 20 RCTs with 1113 participants, depicts that diet intervention significantly improves fertility outcomes, reproductive endocrine, and clinical hyperandrogenism. Shen et al. submit another meta-analysis, which regards tea supplements as adjuvant therapy for improvement in body weight, fasting blood glucose, and insulin. Through remodeling gut microbiota, Wang et al. show that a high-fiber diet could alleviate chronic metabolic inflammation, reproductive function, and brain-gut peptides secretion in their study.As the primary treatment of metabolic dysfunction in PCOS, lifestyle interventions prevent progression to T2DM and lower cardiovascular risk as well as improve ovulation in 40–50% of patients with PCOS , 9. Gu eYao et al., which underscores the role of metabolome changes for BAT transplantation in improving reproductive and metabolic phenotypes in PCOS. Furthermore, Ye et al. pinpoint that cold treatment could also improve ovulation and hormone disorders via activating endogenous BAT.Functional abnormalities of adipose tissue do exist in PCOS patients, mainly manifesting as IR and inflammation . As antiLin et al. provide a novel perspective on the regulation of microbial taxa and SCFA content after SG, which might explain the mechanism of the amelioration of PCOS-related reproductive and metabolic disorders.Sleeve gastrectomy (SG) is a popular bariatric surgical procedure. However, its suitability and potential mechanisms in PCOS remain ambiguous. Chen et al. compare the implantation rate, clinical pregnancy rate, and live birth rate between progestin-primed ovarian stimulation and the short protocol. The former shows significantly more positive results.Due to the poor quality of oocytes retrieved from patients with PCOS, IVF treatment is always accompanied by lower-quality embryos with a low implantation rate . Chen etAlthough a substantial fraction of information has been added to the existing pool of knowledge of PCOS in the past decades, much remains to be elucidated. We sincerely thank all contributors and reviewers for their support in putting this timely collection of articles together and hope that the readers will find useful answers to their questions.YiW drafted this editorial. PL, RL, YaW and HH revised and approved the final submitted version.This work is supported by the National Key Research and Development Program of China (2021YFC2700701), the National Natural Science Foundation of China (82088102), CAMS Innovation Fund for Medical Sciences (2019-I2M-5-064), Collaborative Innovation Program of Shanghai Municipal Health Commission (2020CXJQ01), Clinical Research Plan of SHDC (SHDC2020CR1008A) and Shanghai Frontiers Science Research Base of Reproduction and Development.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


This paper reviews the flow behavior and mathematical modeling of various metals and alloys at a wide range of temperatures and strain rates. Furthermore, it discusses the effects of strain rate and temperature on flow behavior. Johnson–Cook is a strong phenomenological model that has been used extensively for predictions of the flow behaviors of metals and alloys. It has been implemented in finite element software packages to optimize strain, strain rate, and temperature as well as to simulate real behaviors in severe conditions. Thus, this work will discuss and critically review the well-proven Johnson–Cook and modified Johnson–Cook-based models. The latest model modifications, along with their strengths and limitations, are introduced and compared. The coupling effect between flow parameters is also presented and discussed. The various methods and techniques used for the determination of model constants are highlighted and discussed. Finally, future research directions for the mathematical modeling of flow behavior are provided. Hot deformation is one of the most well-known ways to enhance the mechanical properties of metals and alloys ,3,4,5,6 The constitutive models for the prediction of flow stress behavior at different strain rates and temperatures can be categorized as physical-based models ,34,35,36The high complexity of the non-linear behavior of flow stress at elevated temperatures and different strain rates for some alloys causes the JC model to fail to reach precise predictions from time to time ,62,63. TIn this article, the effect of strain rate and temperature on the flow stress behavior of metals and alloys is outlined. Subsequently, the constitutive modeling and accuracy of predictions at a wide range of temperatures and strain rates using original JC and over thirty modified JC-based models are critically reviewed and presented. Furthermore, the implemented methods and approaches that are used to determine the constants that constitute the models are explained. Finally, a summary based on the three terms of the original JC and modified JC-based models is presented. The future potential of this research area is also considered.A common flow stress curve under hot deformation is shown in −1 are shown in The flow behaviors of the B07  and GH51As a result of DRX, dislocation is formed due to the release of stored elastic energy in the hardening region, which results in homogeneous sub-grains. As the strain increases, the misorientations between sub-grains increase, and the sub-grains are turned into fine grains ,121,122.−1), fine grains due to full DRX are developed. It also shows the formation of a few column grains in addition to the equiaxed grains as the strain rate increases (0.1 s−1 and 5 s−1). The effect of strain rate on the hot deformation of other alloys has been reported with the same findings, such as magnesium [Shi et al.  studied agnesium , CoCrFeMagnesium , nickel agnesium ,140, aluagnesium , iron [1agnesium , and titagnesium  alloys.−1 and 0.1 s−1, respectively. As can be seen, the peak stress decreases as the temperature increases. Similar findings can be found in [found in ,147,148.found in ,150, in found in ,152.Song et al.  studied In this section, the well-known JC and modified JC-based models are presented and carefully reviewed. In addition, the associated methods to determine the models’ constants are also considered.Johnson and Cook  introducTo determine the JC constants, reference values for both the strain rate and temperature must be chosen at the beginning. In both reference values, Equation (1) reduces toTaking the logarithm after performing some rearrangements, Equation (2) can be linearly expressed asThe value of constant After performing some rearrangements, Equation (4) can be linearly expressed asConstant than 0.1 , since tBy taking the logarithm after performing some rearrangements, at reference strain rate, Equation (1) can be written asConstant Li et al.  determin2742 cf. a. Consta0.08 cf. b, while 5847 cf. c. The ab5847 cf. d.−1 and 875 °C. The FES was also helpful in checking the behavior of the superplastic-forming of the tested alloy . This modified JC model was applied to OFHC copper, 7075-T6 aluminum, wrought iron, and high-strength steel. The modified JC model that was introduced by Rule and Jones [Rule and Jones  presentend Jones  can be end Jones  modifiedThe predicted stresses obtained using the modified JC model that was presented by Rule and Jones  are compKang et al.  modifiedodel see . At the −1 [Couque et al.  presente.001 s−1 . Constanodel see . At the Constants e et al.  for the A similar modification for the strain rate term is presented by Johnson et al. , in whicLin et al.  introducAt the reference strain rate and reference temperature, Equation (14) reduces torain cf. a. At theAfter performing some rearrangements, Equation (16) can be written asStrain rate constant nε·* cf. b.To obtain the value of the two constants, By taking the logarithm of both sides, Equation (18) can be written asBy plotting he slope d.Experimental stresses are compared to predicted stresses that were obtained by the modified JC model that was introduced by Lin et al.  for typiHou Q. Y. et al.  modifiedodel see . At diffBy plotting A good agreement between experimental stresses and predicted stresses obtained by the modified JC that was presented by Hou Q. Y. et al.  for Mg–1Perez et al.  used theg et al.  modifiedg et al. .Shin and Kim  modified and Kim  can be eIn another published article, Shin and Kim  studied Maheshwari et al.  modifiedodel see . Taking By plotting By plotting Compared with the original JC model, the modified JC that was introduced by Maheshwari et al.  gave accThe predictability of the flow behavior using the modified JC that is presented by Maheshwari et al. , along wWang et al.  modifiedBy plotting ined cf. a. Hence,lope cf. b.At different strain rate values, after performing some rearrangements, Equation (26) can be written asTaking the logarithm of both sides and introducing a new parameter, A comparison between experimental stresses and predicted stresses obtained using the modified JC model that was presented by Wang et al.  for 30CrLin et al.  modified−1·K−1. In this modification, and in order to overcome the difficulty of finding yield stress, the yield stress is replaced by beak stress and defined using an Arrhenius-type equation as per :(30)σ0=1ned; see  for moreBy plotting At different values for both the temperature and strain rate, different values of  pε· see .Lin et al.  fitted BA comparison between experimental stresses and predicted stresses obtained using the modified JC model that was introduced by Lin et al.  for the Lin et al.  presenteLin et al.  determinA comparison between the experimental stresses and predicted stresses obtained using the modified JC model that was presented by Lin et al.  for the Li et al.  introducTaking logarithms for both sides after performing some rearrangements, Equation (35) can be written asThe slope of the equation is By taking logarithms for both sides, Equation (37) can be introduced asDifferent values for the slope, i et al.  determinGood predictability for the prediction of the flow stress of T24 steel using the modified JC model that was presented by Li et al.  is obtaiSong et al.  modifiedTaking logarithms for both sides, after performing some rearrangements, Equation (40) can be introduced asBy plotting the left side vs. ined cf. .The modified JC model that was introduced by Song et al.  providedWang et al.  modifiedodel see . Constantion cf. a asCε·,Good agreement between experimental stresses and predicted stresses using the modified model for the flow behavior of Inconel 718 is thus obtained. However, this method does not provide accurate or precise predictions b.Another sine wave approximation of constant u et al.  to prediTan et al.  modifiedodel see . The cond ε· cf.  in the oConstant n et al.  as:(44)CCompared to the predictions of the original JC model cf. a, the moChen et al.  modifiedMaterial constants n et al.  to minimThe predicted stresses obtained using the modified JC model that was presented by Chen et al.  were fouWang et al.  modifiedMaterial constants nd Jones .The modified JC model that was introduced by Wang et al.  providedShokry  introducions see . Shokry stresses .3Fe3Cr2Ti2 alloy at high temperatures and different strain rates [A comparison between experimental stresses and predicted stresses obtained by the original JC and the modified JC that was presented by Shokry  is shownin rates  when comZhao et al.  used theσ=A+B1ε+BGood agreement between experimental stresses and predicted stresses is obtained using the modified JC model that was introduced by Zhao et al. , with R:Iturbe et al.  introducth T cf. a, and exrate cf. b.The modified JC model that was presented by Iturbe et al.  providedTao et al.  presenteo et al.  can be eture cf. a. Thus, n T* cf. b, and, fn T* cf. c.Good agreement can be seen between the experimental stresses and predicted stresses for the prediction of the flow behavior of the Ti-6Al-4V alloy obtained using the modified JC model that was introduced by Tao et al.  cf. Figa. The moHe et al.  introducTo obtain constants lues cf. a. Finalld b3 cf. b. ConstaComparisons between the experimental stresses and predicted stresses for the 10%Cr steel alloy obtained using both the JC model and the modified JC model that was introduced by He et al.  are showHou X. et al.  modifiedAfter performing some rearrangements, Equation (54) can be written asTaking logarithms for both sides and plotting odel see .A comparison between the experimental stresses and predicted stresses for the Ti-6Al-4V alloy under hot deformation using both the original JC model cf. a and thePromoppatum et al.  studied Zhang et al.  modifiedBy taking logarithms for both sides, lues cf. a.A comparison between experimental stresses and predicted stresses obtained using the modified JC model that was introduced by Zhang et al.  for the Niu et al.  introducAt the reference strain rate and reference temperature, Equation (58) lowers toBy plotting Consequently, constants Accordingly, constants Very accurate predictions of the flow stress for the tested alloy are obtained when comparing predicted stresses obtained using the modified JC model that was introduced by Niu et al. , with exChakrabarty et al.  presenteodel see . At the Chakrabarty et al.  determinthod cf. a. The mothod cf. b.Li et al.  modifiedBy plotting TLAB cf. a. At theThe modified JC model that was introduced by Li et al.  succeedeQian et al.  presenten et al.  implemeny et al.  in theirConstants odel see . At the Constants Constant The modified JC model that was introduced by Qian et al.  improvedLiu et al.  modifiedAt the reference strain rate and reference temperature, Equation (73) lowers toBy plotting The modified JC model that was presented by Liu et al.  showed gYu et al.  proposedBy introducing a new parameter, ting cf. a.Compared with the original JC model, the modified JC model that was presented by Yu et al.  predictiWang et al.  modifiedg et al.  presenteComparisons between the experimental stresses and predicted stresses obtained by the modified JC model that was introduced by Wang et al.  for the Shokry et al.  introducThe four constants of After expansion, Equation (81) extends to four terms with four constants that are constituted with strain and are determined by utilizing regression analysis. At the reference temperature, after performing some rearrangements, Equation (80) is simplified toNine constants are constituted with the strain and strain rate and are determined utilizing regression analysis. At different strain rate values, after performing some rearrangements, Equation (80) is expressed asThe right term provides 27 constants of Precise predictions of the flow behavior of nickel-based (U720LI) and aluminum-based (AA7020) alloys using the improved generic modification of the original JC that was presented by Shokry et al.  are achiPriest et al.  introducodel see . At the Using linear regression, at different temperature and strain rate values, different values for the slope of Equation (85), d cc cf. a. At theAt different temperatures, different values for the slope of Equation (86), d cm cf. b.A comparison between the experimental stresses and predicted stresses for the flow behavior of C45 steel alloy under hot deformations obtained using both the original JC model and the modified JC model that was introduced by Priest et al.  is shownThe flow behavior of metals and alloys is highly affected by hot working conditions, strain, strain rate, and temperature. As temperature decreases and strain rate increases, strain hardening increases. This is due to the emergence of crystal defects, mainly dislocations, strain-induced stages, or twin boundaries through plastic deformation ,191,192.Modeling the flow behavior of metals and alloys at a wide range of temperatures and strain rates is essential to optimize hot working conditions as well as predict the mechanical behavior of metals and alloys with applications under severe conditions such as dynamic loadings and elevated temperatures. The Johnson–Cook model  is one oThe JC model starts by predicting flow stress using the strain-hardening term, followed by multiplying strain rate and softening terms. The JC model employs the Ludwik equation  to repres nickel , iron [3s nickel , aluminus nickel ,52, and s nickel  alloys. s nickel , replaces nickel  equationg et al.  for 30Cred as in ,81 for Ted as in ,85,96 foThe strain rate term has received a lot of modifications in the original JC model, which can be implemented when studying hot deformation as well as dynamic loadings. Rule and Jones  modifiedg et al. , in whic4V tubes  and ball4V tubes . Anothertionship ,84 for ttionship  to preditionship ,93,94,96tionship  obtainedmodel in ,85,88 foThe thermal-softening term in the original JC model has also received a lot of modifications. The early modified softening term was introduced by Meyers et al. , in whicn et al.  introducoV steel , HastelloV steel , 40CrNi oV steel , and 229oV steel . It is aoV steel , with 30oV steel  10%Cr stlized in . Anotherlized in  to overcz et al.  so that n et al.  replacedloy 800H  and CuCrloy 800H , providio et al.  for the g et al.  for the duced in , is replduced in  for the duced in  for the In this review article, the flow behavior of metals and alloys at a wide range of strain rates and different temperatures is studied. Thus, the constitutive model of the original JC model, as well as more than thirty modified JC-based models, are critically reviewed and commented on. In addition, the methods and techniques that are used to determine model constants are presented and explained. Finally, a summary of modifications based on the three terms of the original JC model is presented.The Johnson–Cook model has been widely used to predict the flow behavior of metals and alloys at a wide range of temperatures and strain rates. In this regard, modified JC-based models were introduced for accurate predictions of the flow behavior for metals and alloys with complex non-linear behavior in which the JC model fails to precisely predict the flow behavior.Lin et al.  providedThe improved generic modification for the JC model that was introduced by Shokry et al.  can be cComparing predicted stresses using the original JC model and the modified JC-based models for the same types of alloys might be a future direction to precisely assess and evaluate the predictability of the JC model and modified JC-based models.Another future direction is considering the inverse analysis methods and the techniques that are based on non-linear least squares methods to minimize the mean square error between experimental and predicted values for the accurate determination of model constants.Coupling the original JC model and the modified JC-based models with other models such as the Zerilli–Armstrong and Arrhenius models might be another future direction.The combination of multiple factors and their interactions, which may affect the flow stress response, is a much more efficient research methodology for empirical modeling. The Johnson–Cook model is a strong phenomenological model that has been extensively used for predictions of the flow behavior of metals and alloys. It has been implemented in finite element software packages, which enhances its importance in performing simulation analysis of hot working processes; optimizing strain, strain rate, and temperature; and simulating real applications in severe conditions. The findings of this review can be summarized as follows:


Plant roots perform multiple essential functions defining plant ecological success and ecosystem functioning. For instance, roots are vital for plant nutrient and water uptake, thus regulating net primary production and nutrient cycling . In the Yang et al. put forward that plant characteristics such as plant transpiration and root length were the main determinants of HR magnitude whereas soil factors such as water table depth or soil texture were also important yet indirect drivers.Water relations are key to understanding the ecology of terrestrial plant communities, and one determining component of water balance is the process of hydraulic redistribution HR; . The terAn et al. and de la Riva et al. demonstrate that there is a main trend of variation in the multidimensional root space in line with expectations of the root economics spectrum in over 300 species in China and Spain, whereas Jiang et al. found weak or no correlation between fine-root traits in 48 species from a single semiarid ecosystem. Further, Wang et al. provide insights into the existence of a trade-off between the number and the size of fine roots of temperate tree species. Collectively these results suggest belowground trait covariation and trade-offs are strongly driven by environmental gradients . The majority of research on phenotypic variation to date has focused aboveground , March-Salas et al. proved that precipitation predictability promotes intra- and trans-generational plasticity in root traits, observing differential root trait responses between ancestors and descendants. Moreover, Xu et al. found that, for lianas and vines in tropical ecosystems, phenotypic variation in root diameter in root tips is strongly linked to changes in cortex thickness and cortex cell size rather than on stele diameter variation. These studies widen the characterisation of trait phenotypic variability and decipher the complex and context dependent interactions between root traits and the environment.Phenotypic variation is an important driver of plant performance under different environmental conditions , and longer root hair length in Norway spruce; and contrasting distributions with distance from rhizoplane suggesting differential contributions of root vs. microbial enzymatic activity. In a field study, Borden et al. found specific root respiration covaried with morphological and chemical root traits, and while microbial abundance in the rhizosphere coordinated with root trait variation, this was not the case in bulk soil.Root-soil interactions occur at multiple spatial and temporal scales and are driven by complex processes occurring between roots, microbes, and the soil environment. Discerning relationships between root traits and root-soil interactions can improve our understanding of plant responses to, and their effects on, the environment . Song etWang et al. stated in this special issue: “the importance of root traits in ecosystem-level functioning, is increasingly recognized but still not well-understood”. This special issue showcases studies observing the role of root traits as key drivers of ecosystem services, such as phytoremediation, crop productivity and carbon cycle. Fratte et al. demonstrate that mulching application increases below-ground biomass, which may favour the proliferation of microbes devoted to soil organic contaminants’ degradation. In another study with cropped lentil plants in arid nutrient-poor environments, El-hady et al. showed that the application of root activator and phosphorus enhanced plant growth and productivity by invigorating root traits. While Borden et al. identify connections between root trait variation with carbon dioxide emissions from soil. These studies improve our understanding of the direct benefits of plant root systems in delivery of ecosystem services via root trait-function relationships.Theoretical and empirical evidence predicts that root traits are directly linked with soil structure, nutrient cycling, production and, consequently, ecosystem functioning . Thus, rThis special issue brings together research from multiple fields of root ecology that are unified in their trait based approach. Taken together, this special issue gives a complex but realistic picture of the multidimensional and dynamic roles roots play belowground, defining plant resource uptake strategies and performance, and driving ecosystem functioning and services. However, the ability to scale up fine root trait variation to community and ecosystem functioning level requires more critical investigations that make empirical connections between anatomical, morphological, and physiological characteristics of plant roots with ecosystem scale processes.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.


Two types of sonoelastography (SE) are commonly explored: strain and shear wave. Sonoelastography can be used in multiple medical subspecialties to assess pathological tissular changes by obtaining mechanical properties, shear wave speed, and strain ratio data. Although there are various radiological imaging methods, such as MRI or CT scan, to assess musculoskeletal structures , SE is more accessible since this approach is of low cost and does not involve radiation. As of 2018, SE has garnered promising data in multiple studies. Preliminary clinico-radiological correlations have been established to bridge tissue biomechanical findings with their respective clinical pathologies. Specifically, concerning the shoulder complex, recent findings have described mechanical tissue changes in shoulder capsulitis. The long head of the biceps and supraspinatus SE were among the recently studied structures with conditions regarding impingement, tendinosis, and tears. Since ultrasonography has established itself as an important tool in shoulder evaluation, it completes the history and physical examination skills of the clinicians. This study will provide an update on the most recent findings on SE of shoulder structures.Sonoelastography is a relatively new non-invasive imaging tool to assess the  Sonoelastography is a relatively new and non-invasive ultrasound (US) technique that provides information about mechanical properties of tissues, such as stiffness, based on the palpation method . There aA thorough search of the most recent literature was conducted. A systematic search of MEDLINE (PubMed), EMBASE (Ovid), and Web of Science was performed to identify relevant publications from January 2018 to May 2021. The following text words, Medical Subject Headings (MeSH) terms, and Boolean operators were used: “elastography or sonoelastography or elastosonography” and “shoulder,” “shoulder joint,” “shoulder pain” “biceps,” “capsulitis,” “labrum,” “deltoid,” “infraspinatus,” “supraspinatus,” “rotator cuff,” “teres major or minor,” “acromioclavicular joint,” “scapula,” “coracohumeral,” “coracoacromial,” “coracoclavicular,” “quadrangular space,” “triangular space or interval,” and “spinoglenoid.” We excluded all articles not related to shoulder region or elastography or SE. The search was conducted with English and French language restriction. A further triage was performed using the COVIDENCE sorting platform to retain the final articles reviewed in this article.In recent years, several articles were published for sonoelastographic evaluation of different shoulder pathologies. A systematic review by Chiu et al. analyzed 11 studies covering the use of SE in pathologies such as adhesive capsulitis, rotator cuff tendinopathy, and tear (targeting mainly the supraspinatus tendon as well as the infraspinatus tendon and deltoid muscle) . They foDemirel et al. explored the diagnostic value of supraspinatus muscle SE in supraspinatus impingement syndrome in a cross-sectional study . MeasureMackintosh et al. used 2D shear wave SE to predict fatty infiltration of the supraspinatus muscle as a prognostic factor in determining supraspinatus tendon repair failure . They evBrage et al. explored the discriminative validity of ultrasound SE for patients with painful supraspinatus tendinopathy . They coBrage et al. assessed the intra-rater and inter-rater reliability of SE in the supraspinatus tendon evaluation . They inItoigawa et al. investigated changes in the supraspinatus muscle and tendon stiffness after arthroscopic rotator cuff (RC) repair . They coLin et al. aimed to determine whether SWE can detect biomechanical changes in the supraspinatus muscle concerning supraspinatus tendon abnormality before US grayscale changes . They evVasishta et al. assessed the relationship between tendon stiffness on SE and supraspinatus tendinopathy grading on MRI  in 25 patients . They reYoo et al. investigated the value of SWE for the estimation of the supraspinatus tendon tear chronicity . They evFontenelle et al. compared the mechanical properties of the supraspinatus tendon in two different age groups using SWE . They evHackett et al. evaluated the reliability of SWE to evaluate the stiffness of normal and tendinopathic supraspinatus tendons . They asZhou et al. explored the value of SWE in the treatment efficacy and prognostic evaluation of supraspinatus tendinopathy . SupraspNocera et al. determined the healing response after RC repairs using a multimodality imaging approach with MRI, power Doppler and SWE . They evItoigawa et al. determined the feasibility of SWE to evaluate the RC muscle stiffness before arthroscopic RC repair with the intention to explore the surgical procedure's difficulty and compare SWE with the Goutallier stage on MRI . They inKim et al. evaluated the activity of the deltoid, supraspinatus, and infraspinatus muscles using SWE compared with the isokinetic dynamometry and surface electromyography methods on 12 volunteers . They foYun et al. compared the elasticity of the supraspinatus and infraspinatus tendon in idiopathic adhesive capsulitis patients with a control group to evaluate the tendon elasticity relationship . They obSahan et al. investigated SE and SWE characteristics of the long head of the biceps tendon (LHBT) tendinosis compared with MRI findings . They evWada et al. used SWE to evaluate the stiffness of the capsule, RC tendons and muscles, the coracohumeral ligament (CHL), and LHBT in patients with frozen shoulder . They coHsu et al. used SE to investigate whether corticosteroid injections influenced the elasticity of tendons . ConsidePossible barriers to the SE technique include operator dependency and limitations such as artifacts and reliability. During SE evaluation, it is important to mention the age, gender, muscle segment, shoulder position, and tension applied to the tendon or muscle of subject. In both SE and SWE methods, the biggest shortcoming seems to be choosing the region of interest (ROI) to be calculated with US machines by the Young modulus. For shear wave SE evaluation, there is controversy in previously published articles with regard to terminology. The shear wave SE does not directly measure stiffness, which is the resistance of a material to elastic deformity . It measConcerning recently published shoulder SE articles, shoulder capsulitis showed increased stiffness in supraspinatus and infraspinatus tendons and CHL on SWE evaluation . For fatAB-Gh, AB-Gr, and C-EM wrote the manuscript. DL, AB-G, and SS amended and finalized the final proof of the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.