PWS) and Angelman (AS) syndromes are rare genetic disorders characterized by deletions, uniparental disomy, and imprinting defects at chromosome 15. The loss of function of specific genes caused by genetic alterations in paternal allele causes PWS while the absence in maternal allele results AS. The laboratory diagnosis of PWS and AS is complex and demands molecular biology and cytogenetics techniques to identify the genetic mechanism related to the development of the disease. The DNA methylation analysis in chromosome 15 at the SNURF‐SNRPN locus through MS‐PCR confirms the diagnosis and distinguishes between PWS and AS. Our study aimed to establish the MS‐PCR technique associated with High‐Resolution Melting (MS‐HRM) in PWS and AS diagnostic with a single pair of primers.Prader Willi  PWS, 3(7%) AS, and 21(49%) Normal. FISH analysis detected four cases of PWS caused by deletions in chromosome 15.MS‐HRM showed good performance with a unique pair of primers, dispensing electrophoresis gel analysis, offering a quick and reproducible diagnostic.The  In the presence of saturating concentrations of DNA‐binding dyes, the specific sequence of the amplicon determines the melting behavior as the solution temperature is increased. The intensity of fluorescence decreases as the double‐stranded DNA becomes single‐stranded and the dye is released. The melt temperature (Tm) in which 50% of the DNA is in the double‐stranded state can be approximated by taking the derivative of the melting curve. The characteristic melting curve can be used to detect variations in the DNA sequence in the amplicon without the need for any post‐PCR processing. The method is easy to use, highly sensitive, specific, low cost and produces rapid turnaround in the sample  with a previous DNA bisulfite treatment to diagnose PWS, and AS. MS‐HRM allows detection of differences up to 0.2°C showing the capacity to distinguishing both syndromes with a single pair of primers . As a control, blood samples from healthy individuals were collected. DNA extraction was performed using the DNAeasy Blood & Tissue Kit obtained from Qiagen  following instructions provided by the standard kit protocol. The DNA quality was assessed with NanoDrop Spectrophotometer. The DNA purity was also evaluated through the wavelength 260/280 and 260/230, avoiding contaminants.2.2The cytogenetic study was performed from peripheral blood sample stimulated by phytohemagglutinin according to standard protocol. The analysis was carried out by Karyotype G banding (GTG) (450/550 bands per haploid set) according to ISCN 2016. The FISH analysis was performed in nucleus and metaphases chromosomal preparations according to standard protocols using SNRPN/GABRB3 probe (Cytocell Inc).2.3™ methylation kit . The final protocol step was to elute in 10 μl of nuclease‐free water according to the manufacturer's instructions. The modified DNA was quantified and was assessed with NanoDrop Spectrophotometer.The genomic DNA input was 250 ng/μl to be modified with sodium bisulfite using the EZ DNA2.4® Hot Start PCR Master Mix  with Hot Start Taq DNA polymerase and nuclease‐free water. Primer‐Blast online tool  for methylated and nonmethylated alleles: 5′‐Ggatttttgtattgcggtaaataag ‐3′ (forward/PWS_F), 5′‐Caactaaccttacccactccatc‐3′ (reverse/PWS_R). As a control, the set of primers described by Kosaki et al. (The Methylation‐Specific PCR (MS‐PCR) was performed in 25 μl of a mixture containing 10 pmol of each primer , 12.5 μl Maximai et al.  methylat2.5Methylation‐Sensitive High‐Resolution Melting (MS‐HRM) was performed on the 7500 Fast Real‐Time PCR System Mix . Each sample was analyzed in triplicate for MS‐HRM. Primers were designed according to the principles outlined by Wojdacz and Hansen . The pri2.6NG_01295) using Blast tools to assess the sequence identity. The software M‐Coffee tool was used to confirm the methylated and unmethylated cytosines present in the bisulfite‐treated DNA sequence.The DNA amplified by MS‐HRM was submitted to a DNA purification methodology, following the protocol from PureLink Quick Gel Extraction kit and PCR Purification Combo Kit . The purified DNA amplificons were submitted to a Bisulfite Sequencing. BigDye V. 3.1 (ThermoScientific) was used for Bisulfite genomic Sanger sequencing procedure on an ABI 3730 capillary sequencer (ThermoScientific). Sequences were compared to the reference genome . The amplicons were differentiated by the temperature required for dissociation of the DNA double‐strand , identifying 21 (49%) patients from the 43 studied with normal methylation profile due to the presence of two peaks related to the maternal and paternal alleles. In the remaining patients, MS‐HRM detected 22 (51%) patients with alterations in the region of chromosome 15, 19 (44%) with the absence of the paternal dissociation peak characterizing PWS, and 3 (7%) with the absence of the maternal dissociation peak, confirming the diagnosis of AS  of the 43 suspected patients, identifying two (7%) patients with deletions bigger than 6 Mb of DNA in the chromosome 15 at the region associated with Prader‐Willi syndrome. The GTG technique also identified 28 (93%) individuals from the study with no deletions in the same region analyzed.The Bisulfite Sanger sequencing method confirmed that the amplicons were in the We also performed a cytogenetic study through a FISH technique using two region‐specific probes (SNRPN and 15qter). The technique was performed in 19 (44%) of the 43 suspected cases, detecting four (21%) cases of deletions at chromosome 15. Furthermore, FISH analysis has confirmed GTG results in 15 (79%) of the suspects with no deletions at chromosome 15 . All the listed techniques are laborious, expensive, and time‐consuming to obtain the final result/diagnosis.In newborns and young children, PWS is challenging to diagnose only by clinical examination. Molecular analysis is required for fast and precise diagnosis. Many molecular strategies evaluate the SNURF‐SNRPN locus will confirm the diagnosis; however, without specifying the etiology. For elucidating the genetic mechanism related to the development disease, complementary techniques such as Multiplex Ligation Probe dependent Amplification (MLPA), Fluorescence In Situ Hybridization (FISH), or Microsatellite Analysis may be used  PWS cases caused by deletions while 28 (93%) negative karyotypes were found. A cytogenetic study was also performed through FISH technique. The FISH analysis was performed in 19 patients identifying four (21%) cases with deletions in the PWS/AS region; the remaining 15 (79%) cases of the suspects had no deletions in the region. The resolution of the FISH technique is higher than GTG analysis due to the hybridization of fluorescently labeled specific DNA sequence probes identifying with greater precision deletions and others chromosomal abnormalities.The detection rate of deleterious changes between the FISH and GTG techniques indicated an agreement of 50%. The GTG identified two cases of deletions while the FISH technique confirmed the two cases and identified two further cases, totaling four patients. The use of probes to identify deletions proved to be efficient due to the specificity of the reaction, culminating in an increase in sensitivity and chromosomal abnormalities detection.The gender distribution in the group of patients with clinical suspicion of PWS was 23 (53%) male and 20 (47%) female. The prevalence of detection of methylation alterations among the 22 individuals with confirmed alteration was 13 (56%) in the male group and 9 (44%) in the female group. Although the syndromes affect both sexes equally, it was possible to notice a higher prevalence of genetic alterations in the male group.There are several methods developed for methylation analysis (Kurdyukov & Bullock, The amplicon size directly affects the sensitivity of genotyping. Shorter amplicon fragments generally allow better discrimination of small sequence differences. As the size of the amplicon decrease, the differences in melting temperature between the genotypes increase, allowing a better differentiation between normal and altered samples. Chou, Lyon, and Wittwer  describeMS‐HRM can provide the possibility to find changes in the genome by differences in the curvature of the dissociation curve, indicating changes in the gene sequence or the methylation pattern without the need for sequencing. It is essential for the differential diagnosis of patients presenting complex clinical phenotypes, including developmental delay and intellectual disability. MS‐HRM approaches can be used to accurately identify patients with these conditions, assisting in the interpretation of genetic variations of unknown significance in these conditions. Finally, it can be used as part of the molecular routine screening protocols in patients with a wide range of developmental delay and intellectual disability disorders, unsolved cases or those requiring differential diagnosis.Changes in the expression of imprinted genes have been associated with an increasing number of human diseases, including PWS and AS. Besides, the methylation profile may alter the development of different cell types through a pleiotropic effect on the genome. Witoelar et al.  observedThe MS‐HRM technique offers quick, high precision, and sufficient robustness for clinical use with the implementation of a multiplexed protocols for DNA methylation to improve efficiency. Due the analysis occurs without the need for additional techniques, the MS‐HRM methodology provides a reduced risk of cross‐contamination between samples which is a significant problem in both research and diagnostic laboratories.The method herein presented has significant advantages over conventional analysis using MS‐PCR followed by Electrophoresis gel. The MS‐HRM with a unique pair of primers does not need additional techniques such as agarose gel electrophoresis, reducing the time taken to obtain an accurate result and reducing the risks of cross‐contamination between samples. Due to the high capacity of parallel samples analyses, the method also shows to be robust and with a fast and straightforward interpretation of the results providing a quick test result. The sensitivity of MS‐HRM allows the detection of a tiny fraction of sample is important in the analysis of samples, which are difficult to obtain especially from newborn hypotonic infants. Besides, high reproducibility of HRM makes this method suitable for both research and diagnostic applications in the study of PWS and AS syndromes. A quick and accurate diagnosis of PWS or AS allows effective medicament intervention, avoiding several characteristics of these disorders, providing a better quality of life.All authors have no conflicts of interest to declare. Click here for additional data file. Click here for additional data file.


Expanded carrier screening (ECS) panels that use next‐generation sequencing aim to identify pathogenic variants in coding and clinically relevant non‐coding regions of hundreds of genes, each associated with a serious recessive condition. ECS has established analytical validity and clinical utility, meaning that variants are accurately identified and pathogenic variants tend to alter patients' clinical management, respectively. However, the clinical validity of ECS, that is, correct discernment of whether an identified variant is indeed pathogenic, has only been shown for single conditions, not for panels. Here, we evaluate the clinical validity of a >170‐condition ECS panel by assessing concordance between >12 000 variant interpretations classified with guideline‐based criteria to their corresponding per‐variant combined classifications in ClinVar. We observe 99% concordance at the level of unique variants. A more clinically relevant frequency‐weighted analysis reveals that fewer than 1 in 500 patients are expected to receive a report with a variant that has a discordant classification. Importantly, gene‐level concordance is not diminished for rare ECS conditions, suggesting that large panels do not balloon the panel‐wide false‐positive rate. Finally, because ECS is intended to serve all reproductive‐age couples, we show that classification of novel variants is feasible and scales predictably for a large population.  This requirement can be broken down into three steps to assess whether it is satisfied: (a) demonstration that the screened genes are associated with the conditions of interest, (b) evaluation of whether the test accurately discovers variants in those genes , and (c) correct discernment of which variants are pathogenic and which are benign. The first step has been satisfied for many of the most prevalent conditions screened by ECS  for the Foresight ECS, which uses NGS of full exons or specialized assays to detect SNVs, indels, and CNVs in genes that cause 176 different recessive conditions. These classifications were generated in a manner consistent with the ACMG/AMP variant interpretation guidelines either manually or using software‐assisted classification (for variants without literature references), and classifications are routinely re‐evaluated as new data are obtained.2.2FMR1, HBA1/2, SMN1/2) were excluded due to use of specialized assays that do not require interpretation of novel variants. Assertions with a “date last evaluated” before March 5th 2015 were ignored because they preceded publication of the ACMG/AMP variant interpretation guidelines. Additionally, assertions from before January 1st 2016 by one submitter were excluded after personal communication. Assertions by MWH were not included in the ClinVar dataset. Only rare variants  were included in the analysis, as those with higher frequency are expected to be benign according to ACMG guidelines  variant in GJB2cis with other variants were excluded. The ASL gene did not have any ClinVar submissions passing the above filters and was not included in further analyses.MWH classifications were compared against those from the April 2018 release of ClinVar, which underwent filtering to remove artifacts. Classifications from submitters with fewer than 100 submissions for genes implicated in any of the 176 conditions of interest were excluded. Three of the 176 conditions . ClinVar assertions were combined per variant using a majority rule. In the case of a tie, the variant was considered non‐reportable. The combined entry was used for concordance analysis. The latest MWH interpretations for variants for which either the combined ClinVar interpretation or the MWH interpretation at the time of this study was “reportable” have been submitted to ClinVar under the name Counsyl (https://www.ncbi.nlm.nih.gov/clinvar/submitters/320494/).We evaluated and categorized differences between MWH and ClinVar classifications for the 172 genes of interest, simplifying assertions to “reportable”  ClinVar entries were classified as either concordant with MWH interpretations, or falling into one of seven discordance categories: (a) homozygotes observed in population studies; (b) unclear submitter classification; (c) no published cases; (d) adult onset; (e) dependent variant (where the interpretation depends on the presence of other variants); (f) reduced penetrance; (g) variable expressivity. Any discordant variant not falling into one of the seven categories was considered an “uncategorized discordance” and was considered to count toward false positives or false negatives (see below). Each discordant variant was evaluated by an expert variant interpreter to categorize the discordance.Alleles were weighted by their population frequency (described below) to estimate the frequencies of different variant categories and to establish the respective rates at which a patient is expected to receive a report with concordant or discordant variants.2.4Variant observations in 265 189 patients with a “routine carrier screening” test indication sequenced between January 1st 2014 and April 18th 2018 at MWH were used for variant frequency analysis according to WIRB protocol #1‐1134598‐1. For genes on chromosome X, the variants were analyzed in the context of two chromosomes per individual .2.5The aggregate clinical sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were estimated at the level of variant classification. To model the minimum of these values for our laboratory, we assumed that the combined ClinVar interpretations were always correct. Specifically, true positives were concordant reportable variants ; true negatives were concordant non‐reportable variants ; false positives were variants that MWH considered reportable but combined ClinVar submissions considered non‐reportable, and false negatives were variants that MWH considered non‐reportable but combined ClinVar submissions considered reportable. When calculating sensitivity, specificity, PPV, and NPV, we used the aggregate probability of having a variant of each different type  rather than the number of such variants  to obtain clinically relevant performance values. The probabilities of individuals having variants in two or more categories were also evaluated and included in the performance calculations according to Table To establish the clinical performance of the combined ECS panel, the per‐gene performance metrics were combined in a weighted manner proportional to the gene's share of the panel. For example, the per‐gene sensitivity values were weighted by the approximate proportion of all carriers due to the given gene.2.6To assess the workload required to interpret novel variants, we estimated the rate of observing novel alleles in the patient population and measured the time needed to interpret new variants. First, we determined how many previously unobserved alleles were found in groups of 1000 consecutive patients and then calculated the rate of novel alleles per patient. For ease of representation of this fractional number, we multiplied the number by 100 to obtain the number of novel alleles per 100 patients. Second, we analyzed the self‐reported time expended on variant interpretation. Variant interpreters routinely provided the itemized time consumed for different parts of the variant interpretation process  using self‐reporting tools available in the variant‐interpretation interface. The self‐reported times were not inclusive of the whole variant‐interpretation process; for example, it did not include laboratory‐director review time.3Our approach to assessing the clinical validity of a >170‐condition ECS panel is best illustrated through an example  were concordant between the MWH interpretation and the combined ClinVar interpretation . After expert review, 44.7% of discordant variants had a clear explanation that warranted removal from further analyses in an ECS context: 25.7% of all discordances were because of variants with seemingly unreliable classifications based on sparse data and a hedged description . Eleven percent were variants with no published cases and no other lines of evidence to support pathogenic classification, 3.4% were variants with homozygotes observed in the population (suggesting that the variant is either benign or low penetrance), and 4.6% were due to categories where reporting of variants in a carrier‐screening setting might not be appropriate compared to a diagnostic setting . These variants with clearly explained discordances were not counted in the clinical performance analysis . The decreasing rate of novel alleles observed as more patients are screened can facilitate ECS laboratory workflow in two manners: (a) laboratories can pre‐interpret a set of the more common variants in order to obtain a reduced and predictable rate of novel alleles as patients undergo screening, and (b) laboratories can better predict the labor required for ongoing variant interpretation.NGS‐based ECS with interpretation of novel variants is only clinically viable for a laboratory if its classification workflow can handle a large volume of tests and has well‐understood behavior over time. Therefore, we next investigated the relationship between the number of patients tested and novel variants identified, as well as the drivers of time needed for classification. The number of observed novel variants exhibited a power‐law‐type behavior Figure A as evidThe time required to interpret variants was tracked as part of the classification‐software interface. Each operator followed a standardized operating procedure for the variant‐interpretation process, and each interpretation required approval by a certified clinical molecular geneticist. The mean time to interpret a variant was 1 hour and 13 minutes (median time 45 minutes) based on self‐reported timing by the operators. The largest contribution to this time was the identification and analysis of literature related to the variant in question. Generally, benign/likely benign variants tended to consume less time for interpretation than VUS or reportable variants did  by our laboratory, consistent with an adaptation of ACMG criteria that accounts for screening a large asymptomatic population.The transformation of ECS in recent years—expansion of panel size and transition from genotyping to NGS technologies—has engendered concern that ECS panels will yield an abundance of false positives that unnecessarily cause anxiety for patients, increase clinical burden for providers, and escalate testing costs for payers. This intuition fails to account for three mitigating factors specific to ECS: (a) each severe disease added to an ECS panel tends to have progressively lower carrier frequency, (b) a higher level of evidence for pathogenicity is required for interpretation in ECS than in other screening contexts, and (c) VUSs are not reported in ECS. Consequently, variants in low‐frequency diseases will likely not have spurious evidence sufficient to yield a pathogenic or likely pathogenic classification , and are more likely to fall into the non‐reportable VUS category. Indeed, the high frequency of a variant relative to the incidence of a disease may be used as evidence against pathogenicity in the ACMG variant‐interpretation framework, so misclassified variants in low‐prevalence diseases are not likely to significantly increase the number of incorrect reports. In Figure A limitation of the current work is that classification concordance with ClinVar is an imperfect proxy for correct variant interpretation. For instance, classifications for a variant could be 100% concordant but also clinically incorrect . Furthermore, it would be trivially possible for a laboratory that lacks a variant‐interpretation system altogether to achieve 100% concordance simply by duplicating the classifications in ClinVar. Ideally, pathogenicity is assessed through identification of enrichment of the variant in cases, depletion in controls, impact in animal models, supporting functional assays, and more. But, these are precisely the factors incorporated into the ACMG criteria; thus, the burden of clinical‐validity proof shifts to establishing that laboratories consistently applied these criteria, which—coming full circle, and as demonstrated here—can be evaluated by concordance among independently generated classifications.In this study, we differentiated between “raw discordances” and final discordances, and this analysis required the involvement of a variant‐interpretation expert. For instance, we observed 61 discordances involving unclear ClinVar submissions that would be hard to parse in an automated manner ; therefore, reconciliation by a trained expert was needed to generate a final accounting of concordant and discordant variants. Further, discordances were excluded when there was a clear difference in the level of evidence required to consider a variant reportable in ECS or in an affected population, with the latter commonly the case for the many diagnostic laboratories that submit to ClinVar. The differences in patient population for various laboratories are often challenging to programmatically identify , necessitating the involvement of an expert.Widespread clinical uptake of ECS panels that use NGS to interrogate many genes could oversubscribe variant‐interpretation resources if the determinants of the time required for classification are poorly understood. We showed that the demand for interpretation of novel variants can be anticipated from the size of the test's region of interest and/or the variant frequencies observed in a relatively small sample population. Many variants could be enumerated and interpreted in advance of clinical testing to buffer against fluctuations in the workload of expert interpreters. Automated tools, for example, for database and literature searches, further streamline variant interpretation such that most variants can be interpreted by an expert in less than an hour using an SOP. Additionally, many variants can be interpreted using the SOP through automated methods, for example, in the case of common intronic variants without literature references. Our results show that variant interpretation can be scaled to population‐screening levels without sacrificing clinical performance.Based on the variant‐interpretation concordance analyses presented here and in several previous studies describing the genes selected for inclusion on the panel,All authors are former employees of Counsyl, a company providing ECS. Since the acquisition of Counsyl by Myriad, the Counsyl ECS is offered by Myriad Women's Health, whose employees include the co‐authors Elizabeth Collins, Krista Moyer, Rebecca Mar‐Heyming, and Hyunseok P. Kang. Co‐authors Kristjan E. Kaseniit, Christine Lo, and Dale Muzzey are employed by Myriad.5TABLE S1 Details of sensitivity, specificity, positive predictive value, and negative predictive value calculationsClick here for additional data file.TABLE S2 Details of the 12 151 variants used in the clinical variant classification performance analysisClick here for additional data file.TABLE S3 Details of the 106 variants excluded from the clinical variant classification performance analysisClick here for additional data file.TABLE S4 Per‐gene clinical variant classification performanceClick here for additional data file.


Historical harvesting pushed many whale species to the brink of extinction. Although most Southern Hemisphere populations are slowly recovering, the influence of future climate change on their recovery remains unknown. We investigate the impacts of two anthropogenic pressures—historical commercial whaling and future climate change—on populations of baleen whales  and their prey (krill and copepods) in the Southern Ocean. We use a climate–biological coupled “Model of Intermediate Complexity for Ecosystem Assessments” (MICE) that links krill and whale population dynamics with climate change drivers, including changes in ocean temperature, primary productivity and sea ice. Models predict negative future impacts of climate change on krill and all whale species, although the magnitude of impacts on whales differs among populations. Despite initial recovery from historical whaling, models predict concerning declines under climate change, even local extinctions by 2100, for Pacific populations of blue, fin and southern right whales, and Atlantic/Indian fin and humpback whales. Predicted declines were a consequence of reduced prey (copepods/krill) from warming and increasing interspecific competition between whale species. We model whale population recovery under an alternative scenario whereby whales adapt their migratory patterns to accommodate changing sea ice in the Antarctic and a shifting prey base. Plasticity in range size and migration was predicted to improve recovery for ice‐associated blue and minke whales. Our study highlights the need for ongoing protection to help depleted whale populations recover, as well as local management to ensure the krill prey base remains viable, but this may have limited success without immediate action to reduce emissions. We predict impacts of historical commercial whaling , and future climate change, including changing sea‐surface temperature , primary productivity and sea‐ice extent, on populations of baleen whales and their prey (krill and copepods) across the Southern Hemisphere. Despite initial recovery from commercial harvesting, models predict concerning declines for whale populations due to climate change by 2,100 for populations of blue , fin , humpback  and Southern right whales  as a consequence of reduced krill prey (grey line) from warming. After tThe climate at some polar regions is changing faster than any other region in the world  and other zooplankton prey are found in high numbers. Their slow population growth rates, tight synchrony between life history and water temperatures, and dependency on lower trophic level prey, such as krill linked directly to primary productivity, may make baleen whales likely to be particularly sensitive to future climate change penguins versus increases in ice‐intolerant gentoo (Pygoscelis papua) and chinstrap (Pygoscelis antarctica) penguins in the West Antarctic Peninsula have been attributed by some to a climate shift, with increasing maritime influences from the north affecting ice availability and snow accumulation   forced by a General Circulation Model that includes ocean and atmosphere dynamics  for five baleen whale species , and their krill and copepod prey  from 40°S to 80°S.The MICE includes four spatial zones, delimited by splitting the Southern Hemisphere into two oceanic Areas corresponding to the Atlantic/Indian Oceans (and corresponding Southern Ocean region) (130°E–60°W) and the Pacific Ocean and Southern Ocean region (60°W–130°E). These zones followed standards used in previous Southern Ocean ecosystem models  for the top 50 m of the ocean, mean SST to a depth of 20 m  and relative concentration proportion (0–1) from the Australia Community Climate and Earths System Simulator . Phytoplankton was converted into annual average chlorophyll (mmol.m−3) per Latitude band assuming a Nitrogen‐to‐Carbon (16:106) and a Carbon‐to‐Chlorophyll (50:1) conversion ratio  and future (2000–2100) model projections for mean standing phytoplankton biomass  is the krill recruitment as a function of spawner biomass (note recruits are defined as 1 year old) in area A and Latitude Lper year y, M is the (time‐invariant) input natural mortality rate for krill  per individual whale per year from the literature, using estimates from Ratnarajah et al. (3tons/year) . Starting krill biomass for the entire region was set at 379 Mt , and relative proportional summer spatial distribution in each Latitude and Area for whale species j  and that at each time step (and hence is used to determine whether krill consumption is above or below the equilibrium level):We assumed whales feed on the larger‐sized krill (age 4 and older) as this was the best representation of likely ages or sizes eaten. Finally, we use this value to generate the consumption multiplier term νL,yj,A, or relative proportion of each whale population j distributed (on average) in each of the 10° Latitude bands in each Area during the summer feeding months, was first estimated and fixed based on the historical catch distribution   and krill whole wet mass w (grams) of animals of age a in latitude L of area A in year y was based on the following power relationship refined using Equation 3 from Hewitt, Watkins et al. wL,yl(mm) to age in years (t), based on Siegel (ℓ∞ was the maximum length of krill (mm), κ and t0 were krill growth rate parameters from Hill et al. , based on experimental and observational literature  to SST (°C), and food availability indicated by chlorophyll‐a concentration . Although there are a number of alternative models for evaluating Antarctic krill growth, few estimate growth as a function of temperature, which our literature review   at the start of the initial year of the NPZD model (1900). We calculated the spatial distribution of pre‐exploitation spawning biomass l et al. , which dh is the stock recruitment steepness parameter  and σR is the standard deviation of the log krill stock‐recruitment residuals , using the following equation:where y et al. ), RL,0A ls Table . We calcThe growth, abundance and spawning success of krill in Models 1 and 2 were thus influenced directly by both environmental variables , whale predation, as well as the availability of prey for the krill themselves over time  S1 and winter (tropics) S2, respectively, assumed to occur as a pulse at the start of the season during time step y, maximum annual number of offspring and fraction of female calves (input from catches), respectively, of whale species j in area A  of the relationship between predator–prey net interaction outcome  and their preferred diet (krill vs. copepods). Future whale numbers for Models 1 and 2 were thus driven indirectly by changes in prey availability due to warming . We held whale distributions prior to 2012 constant. Although the direction of change can be predicted with some certainty  to describe the relationship between whale distribution and sea‐ice extent and thickness. In the first instance, parameters of this relationship were estimated using We fitted whale trajectories to an index of abundance from available surveys for the five whale species adjusted to represent female numbers only. Parameter uncertainty was explored in a previous model version  of the total preharvesting numbers of blue, fin, southern right and humpback whales remained across the Southern Hemisphere by the early 1970s, due to unsustainable catches of these species totalling over 1.3 million whales between 1890 and 2012  estimated less than 3%  was shifted 5° south to where krill density is currently greater, and we assumed some prey switching occurred by halving the proportion of krill consumed by whales in latitudes 50–60°S and increasing the corresponding proportion of alternative prey sources consumed (our copepod group in the model). Few major changes were observed in recovery trajectories for Pacific populations, but faster recovery for fin and blue whales was predicted in the Atlantic/Indian region, although this tapered off for fins by the end of the 21st century Figure . AlternaWe ran an additional model investigating the adaptive capacity of whales to future sea‐ice change, based on whale energy expenditure and distribution. Concomitant with projected warming in Antarctic waters from the climate–NPZD model were projected changes in sea‐ice extent, with the greatest melting in our model predicted in the Atlantic/Indian sector Figure . Whale m4The recovery of baleen whales in the past few decades following the cessation of >200 years of intense whaling in the Southern Ocean exemplifies the benefits of modern conservation protection measures, such as the restrictions on commercial whaling implemented by the IWC, to reduce human pressures on species of conservation concern. Earlier research predicted that baleen whale populations previously depleted by historical whaling would continue to recover  under the RCP8.5 scenario, and hence the model predictions for whale populations start to diverge. Additionally, there are too few survey and other data available to reliably distinguish between alternative models attempting to explain recent changes in whale populations due to environmental changes over the past two–three decades (the period for which data are available from our model and which includes a slow rise in SST) Punt, . Our hisModel trajectories show substantially slower rates of increase in whale populations over the next 50 years, in some cases reduced by one third to those of the climate‐decoupled trajectories (Model 3), leading in some cases to population crashes not observed in models that ignore multiple climate impacts (e.g. Mori & Butterworth, This study fills an important knowledge gap concerning how baleen whales might respond to a changing climate, including examining how phenotypic plasticity may improve recovery for certain species. We highlight potential benefits for some whale populations, particularly those ice‐associated species distributed across high latitudes such as blue and minke whales, if they have the capacity to adapt and change their feeding patterns given changing sea ice in the Antarctic and a shifting prey base. This is because of projected increases in productivity and low trophic prey biomass around Antarctica, compared to large declines in their primary krill prey around the Antarctic circumpolar current further north. Such phenotypic plasticity has already been observed in the Northern Hemisphere, with changes in phenology in response to ocean warming demonstrated by fin and baleen whales in the Gulf of St Lawrence Canada (Ramp, Delarue, Palsbøll, Sears, & Hammond, The climate predictions used in this study are broadly consistent with other climate models and observations. The greatest future warming by the end of the 21st century was predicted in the Atlantic/Indian region, supporting recent findings of rapid climate change and sea‐ice melt already observed in the West Antarctic Peninsula (Mulvaney et al., 2 emissions are not reduced (Sanford et al., Our study has several inherent assumptions and uncertainties inherent in our approach. First, the global climate–NPZD model used in this study uses the highest greenhouse emission scenario (RCP8.5 (Peters et al., Second, outputs from the sea‐ice–linked model are only a first approximation to the types of direct impacts that habitat change and warming might have on whales. Other possible adaptive mechanisms warrant future investigation, including whether predicted warming in lower latitudes where migratory whales breed might increase the chance of juvenile survival due to range contractions, and decreased energy expenditure during migrations between feeding and breeding grounds (Cooke, Rowntree, & Payne, Third, given the complexities of modelling whale consumption over a large geographic area and based on limited information, we used the intermediate complexity approach to represent the overall net outcome of the predator–prey interactions. For simplicity we assumed predation by other species on krill remained constant, but these species may exert a strong influence on prey biomass in Southern Ocean ecosystems. The abundance of species such as seals that prey on krill has been posited to have increased in the wake of whale depletion during the mid 20th century (Mori & Butterworth, Finally, we used deterministic model projections and a range of sensitivity tests to provide a first approximation of the likely impact of climate on future population trends. We acknowledge that natural variability is important too in these systems, and that stochastic simulations would enable a more in‐depth analysis of extinction risk. However, considering the already large uncertainty associated with predicting the influence of climate change on whale dynamics we focused on a first‐order approximation. This is also because there is additional spatial variability in krill population dynamics that operates at a finer scale than the broad scale we used in our model. Furthermore, given the different historical recovery rates shown by subpopulations of some species such as southern right and humpback whales (Jackson et al., There are three potential options to lessen future risks to both vulnerable whale species and krill. First, greenhouse gas emissions could be reduced. With global emissions tracking the highest greenhouse gas emissions scenario (RCP8.5 (Peters et al.,  Click here for additional data file.


Ncc is knocked out, also have decreased serum magnesium concentrations with renal magnesium wasting and decreased expression of Trpm6 mRNA and Trpm6 protein , in which patients have hyperkalemia and hypertension as a result of NCC overactivation due to activation of the upstream With No Lysine (WNK)/Ste20p‐related proline‐ and alanine‐rich kinase (SPAK) kinase cascade  subunits and decreased natriuretic response to benzamil, and diminished ENaC‐dependent kaliuretic effect of short‐term thiazide treatment , unmasks a renal magnesium wasting phenotype that is greater than that seen in thiazide‐treated control mice, despite increased ARR is supported by the National Institutes of Health (DK106350 and DK110358) and the American Heart Association (16CSA28530002).The author declares no conflicts of interest.


Dispersal as well as population growth is a key demographic process that determines population dynamics. However, determining the effects of environmental covariates on dispersal from spatial‐temporal abundance proxy data is challenging owing to the complexity of model specification for directional dispersal permeability and the extremely high computational loads for numerical integration. In this paper, we present a case study estimating how environmental covariates affect the dispersal of Japanese sika deer by developing a spatially explicit state‐space matrix model coupled with an improved numerical integration technique (Markov chain Monte Carlo with particle filters). In particular, we explored the environmental drivers of inhomogeneous range expansion, characteristic of animals with short dispersal. Our model framework successfully reproduced the complex population dynamics of sika deer, including rapid changes in densely populated areas and distribution fronts within a decade. Furthermore, our results revealed that the inhomogeneous range expansion of sika deer seemed to be primarily caused by the dispersal process  rather than population growth. Our state‐space matrix model enables the inference of population dynamics for a broad range of organisms, even those with low dispersal ability, in heterogeneous landscapes, and could address many pressing issues in conservation biology and ecosystem management. These mIn wildlife populations, dispersal is a key demographic process especially when the target population forms a metapopulation structure or shows range expansion dynamics  originating from spatially variable environments. If environmental elements have negligible effects on advection, the dispersal probability between locations is approximately expressed by symmetric Gaussian or long‐tailed exponential kernels , which are widely used for animals with relatively high dispersal ability, such as birds and insects . We circumvent the above modeling issues by developing a state‐space matrix model and an improved method for the numerical integration of particle filters. Japanese sika deer are undergoing range expansion, and this is a major target for wildlife management in most parts of Japan. Their browsing and grazing behaviors are known to clear forest‐floor vegetation, harm the bark of timber trees, and cause agricultural crop damage  and the number of hunted sika deer in 2000–2009 . The grid size was determined from the daily deer movement capacity  and dispersal probability from grid cell i to j (ijM), process models were specified as follows:Our process models describe the population dynamics of sika deer considering demographic stochasticity. In the study area, sika deer dynamics are influenced by three main demographic processes: population growth , hunting mortality , and dispersal (in winter). Let (i) population growth process:(ii) hunting mortality process:i,tH is the number of hunted individuals at grid cell i in year t; andwhere (iii) dispersal process:Nj,i,tm is the number of dispersed individuals from grid cell j to i in year t. We incorporated dispersal‐related demographic stochasticity  into the process model because range expansion to new locations is strongly determined by chance, particularly for relatively small grid sizes. Note that Ni,th≥Hi,t is necessarily satisfied at each grid.where The deer distribution range in 2000 is considered to reflect earlier historical range expansion  area at grid cell i and in is the set of adjacent grid cells to grid cell i. Because damage of the preferred plant Aucuba japonica in 2001 is a reliable proxy of sika deer presence/absence  and standardized forest edge length (EDGEi):Our parameter models describe the relations between sika deer demographic parameters  and environmental covariates. First, we expressed population growth rates by standardized broad‐leaf forest area  by standardized total forest area and presence/absence of rivers. For this purpose, we define Mi,jΔ as the short‐term movement probability during a fraction of a year, ∆t. Considering the short‐term movement probability (with a sufficiently short ∆t), we can ignore the dispersal between distant grid cells, and readily specify this probability by the dispersal distance between adjacent grid cells  and environmental covariates :Second, we expressed the dispersal probability  in our analysis, which appeared to be a sufficiently short time period compared to the observed speed of sika deer range expansion. As most elements of the short‐term movement probability are zero, the annual dispersal probability can be efficiently calculated by sparse matrix implementation. We chose a reflective boundary condition for considering dispersal probability across the edge of our study area  and its proxies from the fecal pellet count survey  and block count survey . We modeled negative binomial or Poisson distributions as the detection uncertainty related to each survey. Using a proportionality constant between sika deer densities and fecal pellet counts (γ > 0) and the dispersion parameter of fecal pellet counts (θ > 0), data models of abundance proxies were obtained as follows:Our data models describe the relations between sika deer abundance before population growth (AiB is the unit area of block count survey (0.95–2.21 km2) and tf and tb are the sets of grid cells in which a fecal pellet count survey and block count survey were conducted in year t, respectively. Note that our notation for the negative binomial distribution uses shape and inverse‐scale parameters. The overdispersion of fecal pellet counts is considered to result from local microtopography and microclimate.where 2) by government officials . Assuming that the hunting rate was constant at each grid cell within a management unit , we expressed this data uncertainty with a multinomial distribution as follows:Records of hunted sika deer were summarized for 66 management units , measured by Freeman‐Tukey statistic . However, these assumptions can be readily modified and extended to fit available data and characteristics of focal species .All the data are available at Dryad digital repository ( Click here for additional data file.


The study presents the findings of a meta‐ethnographic study, developing a conceptual model for peer‐assisted learning for undergraduate nurses in clinical practice.Qualitative meta‐ethnography.Meta‐ethnography was used to synthesize the findings of two ethnographic studies and a qualitative review related to the influence of peer‐assisted learning on student nurses in clinical practice.Four key themes were identified underpinned by six sub‐themes: (a) “Social” whereby “connecting with peers” is an important part in peer‐assisted learning. (b) “Enabling” peers through “collaborative support for advice and guidance” and “reducing anxiety/increasing confidence.” (c) “Organizational” aspects in peer‐assisted learning in “establishing structure and navigating practice” and “establishing the role of the PAL.” (d) “Learning” as a product of developing knowledge and skills through “sharing of practice experience” and “enhancing knowledge of care.” The conceptual model presents a structure outlining elements required for developing effective knowledge and skills through peer‐assisted learning. The exp1.1In a recent systematic review, Carey, Kent, and Latour  exploredThe evidence indicates that models for supporting student learning through PAL are limited. Christiansen and Bell , in theiA more recent model in development is the Collaborative Learning in Practice (CLiP) model (Lobo, Arthur, & Laittimer, A definition of coaching in nursing is a collaborative relationship between a coach and willing individual using conversation to help the individual achieve their goal (Donner & Wheeler, In consideration of model for supporting learning, the UK Council of Deans of Health  acknowle22.1A synthesis of the best available evidence was undertaken using meta‐ethnography to formalize a conceptual model for PAL. The meta‐ethnography used the findings of two observational studies, of which one was published (Carey, Chick, et al., The synthesis of qualitative research is a concept that has been slowly gaining momentum in the area of health care (Dixon‐Woods, Agarwal, Jones, Young, & Sutton, The success of Noblit and Hare's synthesis was based on small groups, in two to six papers, of closely related studies, a similarity fitting in the context of the chosen larger project and its publications. However, the rationale for this choice of method compared with other examples of qualitative synthesis was the quality of the seven‐step process created for conducting meta‐ethnography (Noblit & Hare, Other considerations given to models for synthesizing qualitative research, included framework synthesis, derived from framework analysis (Ritchie & Spencer, 2.2The seven‐step process Table  was usedStage three encouraged reading and rereading the chosen studies ensuring that attention was paid to the details in the accounts (Noblit & Hare, As part of stage five, the presented key findings, which were made up of sub‐themes and key categories, were respectively chosen as second‐order constructs from the collective projects and translated according to interpretations by the primary researcher Table . A recenWhat follows next is stage six whereby the researcher uses interpretations of the secondary constructs to synthesize and make sense of the translation process. According to Noblit and Hare , what sh3The aggregated findings from secondary constructs were synthesized into four key themes; social, enabling, organizational and learning, underpinned by six sub‐themes that make up the conceptual model for PAL Figure .3.1[Systematic review]Peers naturally form the friendships needed and practice socialization to use each other as resources. Through these actions, they develop their own specific communities.’…“the students see each other as a discrete group which only fellow students can understand and so develop their own parallel community to help each other: being in the same boat.” The social theme is comprised of the sub‐theme: “connecting with peers,” where socialization forms an important part of PAL. Connecting with peers acknowledges how contributions towards PAL in practice are often underpinned by the communities formed by students who through shared status of equals develop friendships and practice socialization. The sub‐theme was aggregated from the secondary constructs; “connecting with peers to create bonding and mutual support” and “context for peer interaction and non‐interaction.” Connecting with peers to create bonding and mutual support takes into account how students converge together through their acknowledgement of their role, use each other as valuable sources of information and thus form their own community of support as captured in the systematic review:[Observational study nursing students: child health field]It was noted the context of how these interactions could be formed based on friendships and friendliness of other peers. The junior peer participants are all from the same year group and although they noted to have separate friendship groups, they gave a perceived impression of general acceptance and developing friendship towards one another. This sub‐theme also takes into consideration the context for peer interaction and non‐interaction, which further captures how peers interact with each other when engaging in PAL in clinical practice. Across both ethnographic studies exploring PAL amongst child health and adult student nurses, their interactions acknowledged socialization as a key part when engaging in PAL. This was particularly noted in the observational study with child health nursing students:3.2[Observational study nursing students: adult field]Questioning was highlighted as an approach to check understanding and seek clarification of a variety of clinical questions and tasks. Interestingly this offered reference towards perceived increased confidence through the availability of peers. The enabling theme is comprised of two sub‐themes: “collaborative support for advice and guidance” and “reducing anxiety/increasing confidence.” The first sub‐theme, “collaborative support for advice and guidance” was aggregated from five secondary constructs: “discussion concerning clinical and academic assessment,” “positive interaction for communication and questioning,” “collaborative advice, assurance and clarification,” “collaboration with nurse mentors” and “support and reassuring learning from mentors.” This sub‐theme captures the importance of seeking advice, assurance and clarification for confirming understanding amongst student nurses engaging in PAL. In these situations, students practice their ability to seek support in PAL that enables them to move forward in developing their knowledge and skills when in clinical practice:[Observational study nursing students: child health field]Collaboration between first year student nurses and one of the qualified nurse mentors to seek clarification on aspects of the observations they have taken. Mentor clarifies the accuracy of their query and encourages them to make this as a note on the observation chart. To ensure knowledge was correct, qualified nurse mentors were frequently called on as part of a process of clarification and confirmation of actions undertaken, generally when peer knowledge had reached its limit:[Systematic review]Findings reflect how peer learning and support have perceived positive benefits in decreasing stress and anxiety and improving self‐confidence. The second sub‐theme, reducing anxiety/increasing confidence was aggregated from two secondary constructs; “Increased confidence/reducing anxiety and stress” and “Supportive recognition of peers.” This sub‐theme captures how students across both fields of nursing when engaging in PAL have increased confidence and are able to reduce anxiety through the support of their peer colleagues. Furthermore, as seen in previous extracts, the process of seeking clarification and advice has increased perceived confidence of peers through these actions.3.3[Observational study nursing students: child health field]An opportunity to establish a better understanding of the working structure, but also where they fit into their role as student nurses. Interestingly some of the junior peers were located in different clinical areas, but the opportunity to support each other in navigation was not restricted to one particular clinical area. The organizational theme is comprised of two sub‐themes: “establishing structure and navigating practice” and “establishing the role of the PAL.” The first sub‐theme, “establishing structure and navigating practice” was aggregated from two secondary constructs: “peer support for infrastructure and environment” and “navigating the course in clinical practice.” Finding your way in practice was captured as a point of concern for student nurses, who often worked solo in their practice placement areas. Interestingly, students across the fields of child health and adult nursing found that engaging in PAL provided organizational benefits. Students were able to establish where they fit into the structure as student nurses and use each other for navigating clinical practice daily, using PAL as:[Systematic review]These arose occasionally in the area of accurately defining the roles of peers within the same pairs. This was evident in aspects of clinical task allocation. In these instances, it was noted by one peer that their partner was keen to take on the lion share of the clinical activity. The second sub‐theme, “establishing the role of the PAL” was aggregated from two secondary constructs; “complex choices when sharing learning opportunities” and “delegation and planning roles.” These constructs highlighted the importance of how student nurses establish their roles when engaging in PAL. The complex choices that students faced when engaging with PAL often came from challenges of negotiating tasks, personality clashes and more accurately student nurse peers lacking ability to clearly define their roles:[Observational study nursing students: adult field]The role of assigning a task or a role was presented as an open and fluid discussion between peers with an equal sharing of thoughts and ideas when engaging with PAL. Within these discussion peers were able to plan the task to be completed by defining the parameters and ensuring through effective communication that each person was clear on their role. Interestingly, the primary studies exploring the influence of PAL amongst groups of child health and adult student nurses found the reverse. In reports from these findings, it was noted how student nurses from both child health and adult fields took the time to establish their roles and responsibilities linked to task allocation:3.4[Systematic review]Together these findings reflect how peers work together to develop their clinical knowledge and skills, as well as their judgement to model effective care. The learning theme is comprised of the sub‐theme: “shared experience and learning.” This sub‐theme takes into the account the opportunities for developing knowledge and skills and how PAL contributes towards students’ learning. The sub‐theme was derived from seven secondary constructs; “sharing of practice experience,” “enhancing knowledge of care,” “complementary learning aids clinical skill development,” “positive support linked to clinical observation and clinical task,” “informal interaction for teaching, learning and discussion,” “discussion linked to best practice standards” and “working together to provide patient care.” Viewing the concept of learning as a whole, student nurses who engage in PAL are able to develop their knowledge through discussing standards of care and their actions when working together as PALS. In addition, they were able to develop their skills as student nurses, helping to better apply these to their role and those under their care:[Observational study nursing students: child health field]The context for sharing of experiences were used to reinforce learning around topics of clinical practice. Furthermore, learning was also obtained through student nurse peers who used shared experiences and previous knowledge to apply this in the opportunities presented when engaging in PAL:4This newly created conceptual model for PAL in clinical practice provides a structure where the overall goal is the development of knowledge and skills to help student nurses become more proficient in clinical practice. This follows a similar notion to the novice to expert model, whereby the acquisition of knowledge and skills is achieved through levels of proficiency, underpinned by experience and learning Benner, . Each ofSocialization practice appeared to be an important factor in peers connecting with each other to engage effectively in PAL when in clinical practice. The impact of socialization has been acknowledged as a key point of nurse education, whereby nurses need to be properly socialized in their profession to be effective in highly functioning teams (Levett‐Jones, Lathlean, Higgins, & McMillan, One of the components that makes up part of the model was PAL being used for enabling the students to move forward in developing their knowledge and skills. This arose from the need for peers to be able to seek support of their colleagues through advice and clarification. A recent study captured the same in the support provided by student nurse peers in clinical simulation, whereby the ability to seek clarification and receive guidance from peers enabled knowledge and skills acquisition (Li, Petrini, & Stone, The concept of organization and establishing structure for students engaging in PAL is one that is missing from the current literature. Students, as they engage in PAL, can be used as a means to determine where they fit into the structure of clinical practice as student nurses. Aside from the larger project, one study noted the challenges of student nurses working solo, without the input of peers, as a barrier to determining where they fit into the working structure (Christiansen & Bell, The learning that is achieved when engaging in PAL, as outlined in theme four, is largely influenced by shared experience. When relating this back to Benner's  Novice tPeers working together were able to develop their knowledge and skills and reinforce learning through their own‐shared experience. This was directly observed by Austria, Baraki, and Doig  who foun4.1We acknowledge that the model was developed predominantly from a larger project and that not all elements were from published material. However, the available evidence of qualitative studies was included in the systematic review, and we also acknowledged that the exploration of PAL in nursing clinical practice is limited.5The importance of developing knowledge and skills to facilitate student nurses becoming proficient in clinical practice is a current point of focus in a changing healthcare workforce. The emphasis of educating the future nurse leans towards models of peer coaching, but does not discount the need to look at options, such as PAL. The aim of this study was to create a conceptual model of PAL, informed by a secondary meta‐ethnography that synthesized the evidence in a large study that considered the influence of PAL on student nurses in clinical practice. The development of this conceptual model presents a bold structure to outline the elements required for effective engagement and achievement of knowledge and skills attainment. These components highlight the previous captured data in the translation process and determine how these fit together to offer a more defined model that can be used in clinical practice as a structure for future engagement in PAL.6The next phase in the research process is to evaluate the influence of the conceptual model when implemented in clinical practice. This will determine how the model contributes towards the development of students’ knowledge and skills when engaging in PAL from the perspective of educators and the students themselves. The benefits of meta‐ethnography for identifying gaps in the research for further exploration were highlighted in the methods section (Britten et al., The corresponding author and co‐authors confirm that there are no conflicts of interest.


To characterize patients with neurogenic bladder (NGB), their treatment patterns, healthcare resource utilization, and associated costs based on records from a primary care database in the United Kingdom.This was a retrospective, descriptive, observational study of anonymized data from the Clinical Practice Research Datalink and Hospital Episode Statistics databases . Adults with a definitive or probable diagnosis of NGB and ≥1 referral to a urologist were included.The study cohort included 3913 patients with definitive (n = 363) or probable (n = 3550) NGB. Patients had a mean of 8.6  comorbidities, and mean Anticholinergic Cognitive Burden Scale score of 6.6 . During 12 months’ follow‐up, urinary tract infection (UTI) and urinary incontinence were the most common complications. Most patients (92.2%) received ≥1 prescription for an antimuscarinic agent or mirabegron, and 53.9% of patients received prescriptions for UTI‐specific antibiotics. The mean number of visits to a general practitioner for any cause was 67.7  per individual. Almost half (46.7%) of the study cohort visited a specialist during the 12‐month follow‐up period, and 11.0% had ≥1 hospital admission. Total mean per patient costs for healthcare resource utilization was £2395.The burden of illness, healthcare resource needs, and associated costs among patients with NGB are considerable. Drug prescribing patterns are consistent with the symptoms and complications of NGB, although increased awareness of drugs with anticholinergic activity among prescribers may help to reduce the cumulative anticholinergic burden in this vulnerable population. CPRD is a longitudinal primary care research database that collates medical records from 674 general practices across the UK, and is representative of the national population in terms of age, sex, and ethnicity.The study was conducted in compliance with requirements for ensuring the rights of participants in noninterventional studies.2.2The study selection period was from 1 January 2004 to 31 December 2016. Adults aged ≥19 years with a definitive or probable diagnosis of NGB were included. A definitive diagnosis required ≥1 diagnosis of NGB or neuropathic bladder within the study selection period. A probable diagnosis required a diagnosis of Parkinson's disease, multiple sclerosis, spinal cord injury, or stroke within the study selection period; or a diagnosis of spina bifida within the entire CPRD database, in addition to a subsequent diagnosis of overactive bladder (OAB) and/or ≥1 prescription for an OAB medication. Patients were also required to have ≥12 months of continuous enrollment in the CPRD database before the index date , and 12 months continuous enrollment after diagnosis of OAB or OAB drug prescription . All patients were required to have ≥1 referral to a urologist within 12 months before or 12 months after the index date. Patients with idiopathic OAB, a diagnosis of dementia, or those missing data for age or sex were excluded. Only patients deemed acceptable for research by the CPRD, and for whom the study period occurred during an uninterrupted period where the practice was deemed “up to standard,”2.3Full details and definitions of study endpoints are provided in Table S1. For the primary objectives, comorbidities were assessed using a proxy measure, that is, the number of drug classes prescribed according to British National Formulary (BNF) headers.Secondary objectives were to describe healthcare resource utilization and related costs during the 12‐month follow‐up period. Resource use was defined as all‐cause general practitioner (GP) consultations, urological investigations , specialist visits (urologist and gynecologist), prescriptions for incontinence pads, procedures/surgical interventions (urology), and hospital visits (urology). Costs were estimated by multiplying each occurrence of resource use by unit costs derived from NHS tariffs or other UK‐specific sources2.4Statistical analyses were descriptive only. Analyses were performed in the overall study cohort and stratified by underlying neurological condition , age (19‐65 vs >65 years), and sex . A sensitivity analysis of the primary objective was performed using an alternative definition of patients with probable NGB, that is, the diagnosis of neurological condition and OAB diagnosis/OAB drug prescription could be in any order. Analyses were performed using SAS, version 9.4 .2.5Approval for the study protocol was obtained from the CPRD Independent Scientific Advisory Committee [protocol: 17_207RMn].33.1Between 1 January 2004 and 31 December 2016, 19 499 patients with definitive or probable NGB were identified  years, and 59.6% were men (Table 3.2Two‐thousand one‐hundred and thirty‐seven (54.6%) patients received ≥1 prescription for drugs with anticholinergic activity before the index period  patients were receiving an oral antimuscarinic agent or mirabegron. The most commonly prescribed agents were solifenacin , oxybutynin immediate‐release , tolterodine , and oxybutynin extended‐release  (Table 3.3Most of the study cohort 92.2%) received ≥ 1 prescription for an oral antimuscarinic agent or mirabegron over the 12‐month follow‐up period  patients had UTIs and 557 (14.2%) patients experienced urinary incontinence . The results were similar to those of the base‐case analysis (data not shown).4This study provides detailed descriptive information about patients with NGB and, to our knowledge, is the first study to characterize this patient population in the UK. Over the 13‐year study selection period, we identified 363 patients with a definitive diagnosis of NGB and a further 3550 patients with probable NGB based on proxy inclusion criteria. The high number of probable cases suggests that many patients with NGB may not be formally diagnosed in the UK, and is possibly indicative of low awareness of the condition among GPs and neurologists, or limitations in data coding practices. A notable feature of patient selection in our study was the requirement for at least one referral to a urologist, a criterion intended to reduce the risk of including non‐NGB patients. This requirement led to the exclusion of many patients (61%) from the original source cohort, suggesting that our final study cohort may be an underestimate of the true size of the NGB population. It also highlights that primary care providers may take responsibility for much of the care of patients with NGB. We recognize also that the requirement for a urologist referral may have removed some patients with a lower burden of illness from our study, and suggest that this should be considered when interpreting the data.Our findings suggest that patients with NGB have multiple comorbidities and complications. Urinary incontinence and UTIs were common, and more than half (54%) of our study population received prescriptions for UTI‐specific antibiotics. Serious complications  were rare and affected less than 1% of patients each, although observation of these events is likely limited by the short 12‐month follow‐up period. A similar spectrum of complications was documented in a large US claims database study of patients with NGB (n = 46 271),The drug utilization patterns documented in our study were consistent with current NGB treatment guidelines.Neurological patients may be particularly susceptible to the unwanted central actions of some drugs because the integrity of the blood‐brain barrier can be disrupted by the disease process.High levels of healthcare resource use were evident in our study population. On average, patients visited or made contact with their general practice 68 times over a 12‐month period. Patients also visited a specialist twice on average and had one urology‐related hospital admission and one surgical procedure over a 12‐month period. An unexpected finding was the very low rate of prescribing for incontinence pads (0.4%), which was at odds with the reporting rate for urinary incontinence (14%) in our study. It seems likely that patients purchased pads as an out‐of‐pocket expense rather than obtaining them by prescription. After applying unit costs from standard UK sources, the average costs for healthcare resource utilization (excluding drugs) across the overall study cohort was an estimated £2395 per individual over 12 months. To our knowledge, this is first study to provide a comprehensive evaluation of healthcare‐related costs in patients with NGB, as previous cost‐of‐illness studies have focused on emergency department admissions alone.The patient selection criteria adopted in our study  may introduce selection bias and limit the generalizability of our findings. However, when studying a condition such as NBG with proposed underdiagnoses and low awareness in some clinician groups, the selection process must adopt an appropriate level of specificity and sensitivity. Further, the drug choices reported are likely to have been influenced by NICE and may differ from other countries. The main limitations of our study were its retrospective design and the absence of a control cohort to compare outcomes against. Cost estimates are likely to be conservative as the unit costs and NHS tariffs used in our study did not capture all relevant direct medical costs , and drug acquisition costs were also not considered.We suggest that future studies should include a longer follow‐up period and include less common neurological conditions associated with NGB . Physician surveys, to better understand the rationale for prescribing decisions, as well as studies of cognitive function in patients receiving antimuscarinic agents would also be of interest.5Our findings suggest that NGB may be underrecognized among primary care providers in the UK. The burden of illness, healthcare needs and associated costs evident in our study population were considerable. Drug prescribing patterns were consistent with the symptoms and complications of NGB, although increased awareness and reduced prescribing of agents with anticholinergic effects may help to improve health outcomes in this vulnerable patient population.AJ and MA worked full time at Astellas Pharma under a Knowledge Transfer Partnership (KTP) scheme with Manchester Metropolitan University (MMU) when the research was conducted; JN was an employee of Astellas Pharma when the research was conducted; FF reports receiving grants from Astellas during the conduct of the study (project was funded as part of MMU/Astellas KTP), and grants from Astellas outside the submitted work; ES and NC are employees of Astellas Pharma; RA reports receiving grants from Astellas during the conduct of the study, and grants from Astellas outside the submitted work; DdR reports receiving grants from Astellas, Ferring and nonfinancial support from Pierre‐Fabre outside the submitted work; MJD reports nonfinancial support from Astellas during the conduct of the study, personal fees from Allergan, Astellas, and grants and personal fees from Ferring outside the submitted work.http://www.clinicalstudydatarequest.com under "Sponsor Specific Details for Astellas."Access to anonymized individual participant level data will not be provided for this trial as it meets one or more of the exceptions described on Supporting informationClick here for additional data file.


Acne‐like skin reactions frequently occur in patients undergoing treatment with drugs inhibiting the epidermal growth factor receptor. Recently, the effects of vitamin K1 containing cream  as prophylactic skin treatment in addition to doxycycline were explored in a double‐blind randomized phase II trial (EVITA) in patients with metastatic colorectal cancer receiving cetuximab. EVITA demonstrated a trend towards less severe skin rash in Reconval K1‐treated patients using the tripartite WoMo skin reaction grading score as a thorough tool for quantification of drug related skin reactions. This gender‐specific analysis of the EVITA trial evaluated the application of the WoMo score for assessment of epidermal growth factor receptor (EGFR)‐related skin toxicities according to treatment arm and gender. To show the robustness of results parametric and non‐parametric statistical analyses were conducted. All three parts of the WoMo score independently demonstrated the superiority of the treatment arm  regarding a significant reduction in acneiform skin reactions in women. Men did not benefit from Reconval K1 cream at any time point in none of the WoMo score analyses. The treatment effect in women was confirmed by the use of skin rash categories based on the final WoMo overall score and mixed effect longitudinal multiple linear regression analysis. The WoMo score represents a sensitive tool for studies exploiting treatments against EGFR mediated acne‐like skin rash. Part C of the WoMo score seems to be sufficient for quantification of drug related skin toxicities in further studies. Standard WoMo skin reaction score values for future studies are provided. Preliminary data of one segregated part of the statistical analysis  were recently reported indicating that women derived a benefit from the use of Reconval K1 cream in terms of the overall WoMo score while men did not.2An exploratory analysis of data from the EVITA study was conducted. EVITA was a randomized, double‐blind, vehicle‐controlled phase II investigator‐initiated clinical trial  in patients with metastatic (K)RAS wild type colorectal cancer treated with FOLFIRI plus cetuximab as first line treatment.The current exploratory analysis focused on the evolution of WoMo values  over time according to gender with a special focus on WoMo part C (ie on the severity of skin rash). To exclude gender‐specific compliance differences, we analyzed the adherence to study treatment by gender  as well as the use of anti‐cancer drugs .P‐values is discussed in the sense of exploratory data analysis. Moreover, an analysis of the application of the WoMo skin toxicity grading categories  into account, mixed effect longitudinal multiple linear regression was applied to model square root (Sqrt) (WoMo C) by gender as a function of week, drug, and week*drug interaction including patient as a random effect. Week as main effect was included as a continuous variable where a 4‐knot spline was found most appropriate to ensure sufficient flexibility for fitting the time course of WoMo C. Because of the skewness of the distribution of WoMo C and its truncation at 0, the Sqrt transformation was applied for statistical modeling. Mean time course of WoMo variables (not transformed) is presented by gender and treatment. In addition to these parametric analyses, simple non‐parametric analyses were conducted using the Wilcoxon Rank‐Sum test to compare the WoMo levels over the course of the observation period at each visit. The pattern of resulting Statistical analyses were performed using SAS JMP V13.2.1 .3A total of n = 126 patients were included in the primary analysis of the EVITA trial. Four of these patients could not be included in the current analysis due to missing post‐baseline WoMo values leaving a total of n = 122 patients for the analysis (n = 85 men and n = 37 women). The main characteristics are depicted in Table 3.1Gender‐specific analyses including treatment duration and cumulative doses of anti‐cancer drugs administered as well as adherence to the prophylactic skin treatment  during the 8‐week skin treatment period are provided in Supplementary Comparably, for both, men and women, the median and cumulative numbers of daily administrations of doxycycline and Reconval K1/vehicle creams were virtually identical.3.2P < 0.05) while no statistically significant difference between arms was found for the male patients on any time point . The treatment effect of Reconval K1 cream is visible at an early time point but clearly emerges over time .For the subgroup of male patients no treatment effect is seen during the 12‐week observation period . The results according to categories and gender are depicted in Figure 4The current exploratory gender‐specific analysis of the EVITA trial was done in order to evaluate the application of the tripartite WoMo score on the development of skin rash in patients receiving cetuximab‐based therapy as first line treatment for metastatic colorectal cancer. In the original EVITA trial the primary endpoint – incidence of grade ≥2 skin rash according to NCI CTC criteria – was not reached.The major results of the in‐depth gender‐specific evaluation of the WoMo score presented herein are the consistently decreased mean values for all WoMo parts  in women treated with Reconval K1 compared to the vehicle. The consistent impact of Reconval K1 cream on ameliorating the values of all 3 WoMo parts is striking, particularly because for men an effect of Reconval K1 cream was not seen on any of the 3 WoMo parts at any time point. The observed effect was verified by modeling these data for WoMo part C using mixed effect longitudinal multiple linear regression analysis. Thus, an overall treatment effect as reported for the WoMo final scoreThe breakdown of the WoMo categories demonstrated a comparable high number of women developing no rash at all when treated with both, doxycycline and Reconval K1 cream, while in contrast, only a minority of men presented without signs of skin rash from week 2 on.The restriction of positive effects of Reconval K1 cream on female skin only could have several reasons. An important factor could be a better compliance of females in terms of a correct use of the topical applicable Reconval K1 cream. For instance, it has been reported that men are less likely to use sunscreenThe positive effects of vitamin K containing cream on anti‐EGFR drug‐related acneiform skin rash are based on an EGFR (re)activation on keratinocytes counteracting the EGFR inhibitory effects caused by the systemic anti‐EGFR treatment.Moreover, gender‐specific dimorphisms regarding the hormonal modulation of EGFR could cause the better effect of Reconval K1 on females. It has been demonstrated that sexual hormones like estrogen and testosteron can influence pro‐EGF and EGF receptor mRNA levels, thus modulating EGFR concentration and EGFR binding.We acknowledge that a retrospective exploratory analysis has inherent shortcomings and the statistical methods for the current analysis were not pre‐specified in the study protocol. The subgroup of female patients analyzed herein may be regarded as rather small to draw firm conclusions and confirmatory studies might be considered. However, the statistical significances of the observed benefit of the study drug in all analyses of the different parts of the WoMo score justify the recommendation of an application of the WoMo score in further studies.5The WoMo score represents a sensitive tool for studies exploiting treatments against EGFR mediated acne‐like skin rash. Part C of the WoMo score seems to be sufficient for a valuable evaluation of skin toxicities.MRG has received honoraria from Roche, MSD, BMS, Merck KGaA, Novartis, Pierre Fabre. S‐E A‐B has an advisory role with Merck, Roche, Celgene, Lilly, Nordic Pharma, Bristol‐Myers Squibb, and MSD Sharp & Dohme; is a speaker for Roche, Celgene, Lilly, Nordic Pharma, AIO gGmbH, MCI, promedicis, and Forum für Medizinische Fortbildung; He is CEO/founder of IKF Klinische Krebsforschung GmbH and has received research grants from Sanofi, Merck, Roche, Celgene, Vifor, Medac, Hospira, Lilly, German Cancer Aid (Krebshilfe), German Research Foundation and the Federal Ministry of Education and Research. RDH has received honoraria from Merck KGaA, Amgen, Roche, MSD, BMS, medac, Lilly, Sanofi, Boehringer. He has served as an advisor for Amgen, Merck KGaA, Roche, MSD, BMS, medac, Lilly, Sanofi, Boehringer. His institution has received research funding from Amgen, Merck KGaA, Amgen, Sanofi. All remaining authors have declared no conflict of interest. Click here for additional data file. Click here for additional data file. Click here for additional data file. Click here for additional data file. Click here for additional data file.


Solitary fibrous tumor (SFT) of the pleura is a rare neoplasm which is challenging for clinicians to treat and radiologists to diagnose. Herein, we report a case of recurrence of SFT of the pleura in a 77‐year‐old patient which was diagnosed and surgically treated on the first occasion in 2005. The patient had a recurrence in 2016 which was treated and then six months later, he again experienced chest pain and a further local recurrence was found. Taking into consideration the age and comorbidities of the patient, CT‐guided percutaneous microwave‐thermal ablation was preferrable to surgery and a safe and highly effective local ablative technique with few side‐effects. Microwave thermoablation is an effective and safe technique for pleural solitary fibrous tumor.Microwave thermoablation helps reduce tumor‐related pain in patients affected by pleural solitary fibrous tumor.Solitary fibrous tumor (SFT) of the pleura represents less than 5% of all pleural neoplasms. Effusions are frequently large, occupying 50% or more of the hemithorax and obscuring the pleural tumor.In September 2005, a 65‐year‐old patient attended the clinic complaining of exertional dyspnea. His medical history was unremarkable and laboratory tests were normal. Chest X‐ray revealed an enormous space‐occupying lesion in the left hemithorax which was causing left lung collapse and right‐sided mediastinal shift. Multi‐detector computed tomography (MDCT) confirmed these features, but the relationship to the parietal pleura and mediastinal structures was unclear. Intravenous contrast administration with multiphase acquisition showed high vascularity of the tumor, with no lymphoadenopathy or compression of the left pulmonary artery. Surgical thoracotomy showed an encapsulated tumor, occupying the left pleural cavity and compressing the lung without invasion of mediastinal structures. The tumor was surgically removed en bloc and the left lung immediately re‐expanded. The tumor was enormous measuring 30 × 19 cm and weighed 4050 g.After a period of 11 years, in April 2016, the patient returned to the clinic for a routine chest X‐ray which showed a small rounded area of high attenuation, confirmed by multiphase MDCT, and the mass was surgically removed a few weeks later. In October 2016 a new mass of 40 x 36 mm was found in a different pleural location  is a widely used ablation technique based on inducing necrosis through high temperatures. MWA systems generate an ellipsoidal microwave field around a needle‐like applicator that is introduced into the tissue. Since water molecules have a positively and a negatively charged pole, they tend to align with the electromagnetic waves. The oscillation of the electromagnetic wave therefore causes a rapid flip motion of the water molecules which results in heating of the adjacent tissue through the mechanism of dielectric hysteresis. If the MW frequency perfectly matches the molecule‐specific resonance frequency of the water molecules, all the energy will be turned into heat, but the penetrability into the tissue will be low. The frequencies used by the current MW manufacturers (915 MHz and 2450 MHz) only partially match the resonance frequency of the water molecules, thus assuring efficient energy conversion into heat with satisfactory tissue penetrability.In conclusion, MW thermoablation is safe and highly effective for the local ablative treatment of lung lesions and particularly in cases of SFT of the pleura recurrence after surgery. Moreover, this technique avoids long‐term hospitalization and all the risks associated with surgery.The author declares there is no conflict of interest.


Triticeae tribe that provide essential grains for the human diet. Investigation of the genes and alleles that underpin domestication‐related traits has provided valuable insights into the molecular regulation of inflorescence development of the Triticeae, and further investigation of modified forms of architecture are proving to be equally fruitful. The identified genes are involved in diverse biological processes, including transcriptional regulation, hormone biosynthesis and metabolism, post‐transcriptional and post‐translational regulation, which alter inflorescence architecture by modifying the development and fertility of lateral organs, called spikelets and florets. Recent advances in sequencing capabilities and the generation of mutant populations are accelerating the identification of genes that influence inflorescence development, which is important given that genetic variation for this trait promises to be a valuable resource for optimizing grain production. This review assesses recent advances in our understanding of the genes controlling inflorescence development in wheat and barley, with the aim of highlighting the importance of improvements in developmental biology for optimizing the agronomic performance of staple crop plants.Modifications of inflorescence architecture have been crucial for the successful domestication of wheat and barley, which are central members of the  Triticeae tribe, including the staple crops of wheat and barley. We focus on the key domestication related traits, and recent studies that have used modified forms of inflorescence architecture to identify genes regulating spikelet and floret development.© 2018 Institute of Botany, Chinese Academy of SciencesThis review summarizes the recent advances on the genetic regulation of inflorescence architecture in the  Scott A. BodenEdited by: Thorsten Schnurbusch, Leibniz Institute of Plant Genetics and Crop Plant Research (IPK), GermanyTriticeae tribe, which includes the important cereals bread wheat (Triticum aestivum), durum wheat (T. turgidum), barley (Hordeum vulgare) and rye , provides a significant proportion of global nutrition. The grains of these important crops are produced on a structure called the inflorescence   leading to extreme suppression of lateral spikelet fertility caused by a missense mutation that is predicted to prolong VRS1 protein function through later stages of inflorescence development  domain transcription factor   with TB1 homologues in wheat, maize, rice, and Brachypodium distachyon shows that the Int‐c.a allele is less evolutionarily conserved than the int‐c.b allele, suggesting that six‐rowed barley contains a deleterious Vrs5/Int‐c allele with reduced function  biosynthesis genes, which is thought to contribute to the delay in inflorescence development observed in vrs2 mutants  from the grain, relative to the non‐free‐threshing ancestral wheat lines, including emmer (T. dicoccoides Körn.) and einkorn (T. boeoticum Boiss.) that carry the q allele. The Q allele also prevents grain loss that occurs in emmer and einkorn due to brittle inflorescences that shatter into spikelets at maturity  binding site. The effects of the Q gene are dosage dependent, with increased transcript levels being associated with corresponding levels of inflorescence compactness and reduced plant height , in combination with yeast two hybrid screen and a firefly luciferase complementation imaging assay, showed that Q protein is likely to function as a transcriptional co‐repressor in partnership with TaTPL  gene has demonstrated that its activity has a major impact on inflorescence density, with Zeo1.b plants having inflorescences twice as dense as wild‐type plants. The responsible genomic region was narrowed to a gene encoding a transcription factor with two AP2 DNA‐binding domains, in addition to a miR172‐binding site, and was therefore named as HvAP2. The mutation in HvAP2 that increased density of the inflorescence was concluded to be in the miR172 binding site, which reduced the cleavage efficiency of HvAP2. Interestingly, the authors showed that miR172 appears to function predominantly during the early stages of inflorescence development, but not in the later developmental stages, indicating a critical role during the transition from spikelet formation to awn initiation and internode elongation  transcription factor, which is homologous to the FRIZZY PANICLE (FZP) and BRANCED SILKLESS (Bd1) genes of rice and maize, respectively  and COMPOSITUM 2 (COM2) genes of tetraploid wheat and barley mutants, respectively, facilitate development of inflorescence‐like structures at rachis nodes where a spikelet typically forms, suggesting that BH1 and COM2 function is required for the axillary meristems to obtain a spikelet identity  , which is a pseudo‐response regulator that regulates photoperiod responsive flowering pathways in wheat and barley , which is a central integrator of flowering that promotes flowering under inductive photoperiods by activating expression of meristem identity genes within the shoot apical meristem  acts downstream of Ppd‐1 to influence spikelet number, with loss of FT‐B1 resulting in increased spikelet number, in a thermally‐responsive manner  function in wheat, which facilitates paired spikelet development, in a dosage dependent manner, by interacting with FT1 and reducing FT1‐dependent activation of spikelet meristem identity genes  extending the period between completion of floret primordia development and initiation of floret degeneration, and (ii) optimizing assimilate distribution to spikelets and florets, which is supported by floret fertility being associated with ovary size at anthesis  and VEGETATIVE TO REPRODUCTIVE TRNASITION2 (VRT2) that are repressed during the transition, and genes including SQUAMOSA PROMOTER BINDING‐LIKE PROTEIN4 (SPL4), KNOTTED1 (KN1) and SUPPRESSOR OF CONSTANS1 (SOC1) that were activated  were also upregulated during the floral transition; interestingly, these genes were among those mis‐expressed in vrs3 and vrs2 mutants , SEP3, PISTILLATA (PI) and APETALA3 (AP3), as well as MADS box transcription factors, including VERNALIZATION1 (VRN1), BM3 and BM8 , and were upregulated in SAMs of barley lines that contain null alleles for EARLY FLOWERING3 , WFZP, LAX PANICLE1 (LAX1) and TERMINAL FLOWER1 (TFL1) as genes whose expression was associated significantly with spikelet number , which encodes the barley DELLA protein that controls GA‐dependent growth responses (Chandler et al. Sln1 revealed amino acids that specifically control size of the shoot apical meristem and the number of florets that form on a barley inflorescence. This illustrates the possibility to improve yield‐related traits by an advanced understanding of gene function (Chandler and Harding Q gene in wheat and VRS1 protein in the deficiens mutant indicates that post‐transcriptional and post‐translational regulation of gene and protein activity plays an important role during inflorescence development, which could be an important area of future research (Debernardi et al. The opportunity to benefit from an improved understanding of protein function has been demonstrated through analysis of Vrs1‐5 genes in barley also presents an opportunity to investigate the broader role of row‐type genes during inflorescence and grain development by combining alleles to make double or triple mutant lines (Zwirek et al. vrs3 allele into the cultivar Morex, which contains the six‐rowed Vrs1 and Vrs5 alleles, improved uniformity of grain size by increasing the width and area of grains produced by the lateral spikelets (Bull et al. Vrs genes and their contribution to key agronomic traits. Similarly, comparative analysis of the transcriptome data from the vrs mutants may help identify downstream genes that are commonly affected by the six‐rowed alleles, which may help uncover more about the molecular regulation of spikelet architecture (Bull et al. Identification of the Vrs5/TB1 facilitates development of the lateral spikelets, whereas in wheat, increased dosage of TB1 promotes formation of secondary spikelets, which could be interpreted to mean that Vrs5/TB1 suppresses axillary spikelet development in barley but promotes more elaborate branching in wheat (Ramsay et al. Vrs5/TB1 promotes meristem dormancy, which influences the transition of meristem determinacy and outgrowth of lateral organs. In this scenario, an increased dosage of TB1 in wheat suppresses the transition of a lateral branch meristem into a spikelet meristem to facilitate development of a short branch composed of two spikelets, whereas in barley, reduced function of Vrs5/TB1 disrupts the dormancy of the lateral spikelet primordia to facilitate development and growth of fertile lateral spikelets.The genetic relatedness of wheat and barley, in combination with the altered inflorescence and spikelet meristem determinacy of these two species, provides a unique opportunity to determine the genes and biological processes that contribute to the diverse inflorescence architecture of cereals. For example, in barley, reduced function of Vrs1 and HOX2, will advance our understanding of the genetic regulation of inflorescence development within each species, while also contributing to our knowledge about the biological processes that contribute to the diverse architectures of wheat and barley (Komatsuda et al. Vrs4 as a homologue of RAMOSA2, which has a well‐characterized role in regulating inflorescence architecture in maize (Bortiri et al. Similar comparisons of reciprocal gene function in wheat and barley, such as Triticeae. This research is now being extended to investigate the genetic basis of modified inflorescence architectures, and further research that uses new genomic and mutant resources promises to provide valuable insights into the genes that control spikelet and floret development. Continued investigation of the genetic regulation of inflorescence architecture in the Triticeae promises to be a rich area of research to pursue fundamental knowledge about plant reproductive development, while also providing valuable insights that can be used by breeders to optimize key yield‐related traits for increased grain production in wheat and barley.In conclusion, analysis of the genes that underpin key domestication‐related traits of inflorescence architecture in barley and wheat has contributed significantly to our understanding of the molecular processes that regulate inflorescence development in the