Eps) genes are reported to be important in fine-tuning flowering time in wheat independently of photoperiod (Ppd) and vernalisation (Vrn). Unlike Ppd and Vrn genes, Eps have relatively small effects and their physiological effect along with chromosomal position are not well defined. We evaluated eight lines derived from crossing two vernalisation insensitive lines, Paragon and Baj (late and early flowering respectively), to study the detailed effects of two newly identified QTLs, Eps-7D and Eps-2B and their interactions under field conditions. The effect of both QTLs was minor and was affected by the allelic status of the other. While the magnitude of effect of these QTLs on anthesis was similar, they are associated with very different profiles of pre-anthesis development which also depends on their interaction. Eps-7D affected both duration before and after terminal spikelet while not affecting final leaf number (FLN) so Eps-7D-early had a faster rate of leaf appearance. Eps-2B acted more specifically in the early reproductive phase and slightly altered FLN without affecting the leaf appearance rate. Both QTLs affected the spike fertility by altering the rate of floret development and mortality. The effect of Eps-2B was very small but consistent in that -late allele tended to produce more fertile florets.Earliness per se ( Moreover, fine tuning time to anthesis is relevant to improve adaptation and performance within a specific environment5. The possibility of coarse and fine tuning of time to anthesis in wheat  has helped to maximise yield because of optimised anthesis time7; and will be instrumental in adapting better to climate change9.Wheat adaptation has been possible by coarse tuning time to anthesis10. The duration of each of these phases plays a key role in determining the generation and degeneration of various organs  that define components of yield12. It has been hypothesised that developmental phases prior to anthesis can be adjusted with little or no changes in time to anthesis to keep improving adaptation along with stable or improved yield14.Wheat development from sowing to anthesis encompasses various stages that make up two major component phases: time from sowing to terminal spikelet (TS), combining the vegetative and early reproductive phases of leaf and spikelet initiation, and time from TS to anthesis, i.e. the late reproductive phase (LRP) of floret initiation and survivalVrn and Ppd genes, respectively1. Responses to photoperiod and vernalisation sensitivities can be found in all the three  phases of wheat development16. The effects of different Ppd and Vrn genes on wheat development have been well studied. There have been detailed studies on the possibilities of various combinations of these genes under different environments to develop a tailored cultivar to achieve desired time to anthesis with different combinations of pre-anthesis phases . In addition, cultivars carry residual differences in phenology after the photoperiod and vernalisation requirements have been completely satisfied, ascribed as earliness per se (Eps). In the past, the process of selecting for Ppd and Vrn genes has fixed whole breeding pools for a particular combination of photoperiod sensitivity and growth habit but Eps genes continue to segregate26. Having much smaller effect than Ppd and Vrn, Eps genes are ideal for fine-tuning wheat development21. The direct effect of Eps is known to be on heading or anthesis time, although few studies27 (Eps-Am 1-l of T. monococcum) have shown effects of Eps on the development of spikelets. Therefore, it can be speculated that the indirect effect of Eps on yield could be the reason for their indirect selection in the present cultivars25. Current cultivars may have a reasonable variation of Eps alleles, providing opportunities to study these alleles in order to improve our understanding on their effects on phenology as well as on yield.Wheat responds to various environmental stimuli like vernalisation and photoperiod and genetic factors responsible for these sensitivities are mainly Eps genes on time to anthesis, and even less on whether and how the rate of organ initiation is affected. These are areas that demand attention as Eps genes are quite numerous , and each potentially having a different mode of action . Dissecting the effects of Eps into vegetative or/and reproductive phases could be crucial when considering likely effects on yield30, more so on how development of organs are altered. The reports on effects of Eps have been inconsistent so far as some studies have reported effects limited to earlier phases32 and others to that of LRP34. These studies have shown context dependent expression of traits to the extent that the same allele has differential responses based on the background it is introgressed into35 and epistatic interaction with respect to Ppd and Vrn genetic factors25 along with a different magnitude of interaction with the growing temperature33. Furthermore, as different Eps genes may affect development differently, it may also be possible that they might interact in determining the effects on developmental traits. To the best of our knowledge there have been studies comparing in the same experiments different Eps genes36, but the interaction between different Eps genes has never been analysed (i.e. whether the effect of a particular Eps gene is affected by presence of another Eps), which is important as many Eps genes are acting simultaneously in any genotype.There have been fewer studies on effects of Eps QTLs on chromosomes 7D and 2B and also their interactions . For that purpose, we evaluated the effect of Eps-7D on contrasting Eps-2B backgrounds and vice–versa on (1) phenology, not only determining time to anthesis but also quantifying whether they mainly affect development before or after TS; (2) rate of leaf appearance; (3) dynamics of leaf, spikelet and floret primordia development; and (4) spike fertility.In the present study we aimed to analyse for the first time different developmental traits as affected by two newly identified 2B, 2D and 7D . Although specific tests of the genotypic differences in time to heading under saturating long days were not made, we assumed in principle that these genetic factors identified in chromosomes 2B and 7D are “earliness per se” (Eps) QTLs, simply based on the fact that they are definitively not Ppd genes and still produced significant differences in time to heading in a spring wheat background. With the aim to analyse the effect and possible interaction of the two Eps QTLs in detail, eight RILs were selected from the population, carrying all four possible combinations of alleles of the two genes , the magnitude of effect was different depending on the Eps-2B allele in the background  the results again provided evidence for an interaction with the allelic form of Eps-2B gene in the background  and only marginally affected the LRP in the second season when the Eps-2B gene in the background was the late allele , lines with the Eps-7D-late and -early alleles produced 9.55 and 9.57 leaves , respectively  when the background was the Eps-7D-late  and in line with the effects of this gene on time to anthesis the effect was smaller and less clear in the second growing season ; i.e. up to the fifth floret from the rachis. Outside of this range seeds were hardly ever produced. At the other end of the floret survival scale the two florets most proximal to the rachis (F1 and F2) were very similar and the likelihood of survival was always 100% for these florets, hence we focused here on the developmental progress of the F2, F3, F4 and F5 florets to reflect any effects of Eps genes on floret fertility.Detailed study of developmental dynamics of each individual floret initiated in 3 spikelet positions of the spike  was carried out to understand the basis of Eps-7D on development of florets showed evidence of its interaction with Eps-2B, and this interaction effect was also seen when comparing the differences between lines with Eps-7D-early and late which depended on the early or late allellic backgrounds of Eps-2B. When the background had the Eps-2B-late development of individual floret primordia was in general faster in lines with the Eps-7D-early allele and this resulted in a different likelihood of some labile florets to become fertile at anthesis  lines with the Eps-2B-late allele had maintained a faster rate of development than in lines with the Eps-2B-early allele, allowing these labile florets reaching the W10 stage in the former,  and increased the rate of floret survival, both contributing to an improved number of fertile florets compared with line carrying the Eps-7D-late  was similar . The patterns of floret initiation and mortality for each genotype were relatively similar for the three different spikelet positions considered  but effect of Eps-2B was relatively very small again such smaller effects were also noted for other Eps35. Therefore, either of them, but particularly the Eps-7D due to its more consistent effect, might be exploited to fine-tune time to anthesis in elite germplasm.The two newly identified 39. Eps-7D affected both time to TS and LRP while the subtle effect of Eps-2B on whole phase was only evident in time to TS27. Our study provides the first time proof for the interaction between two Eps in particular which was only speculated before38. Our observations in addition to that of other researcher35 suggest that different Eps genes may differ in their effects on individual developmental phases, even if their effect on the overall time to anthesis were similar.It is true that the changes in the whole phase from sowing to anthesis can be brought about by various combination of changes in its component pre-anthesis phases (with more or less independency) and its importance lies in the fact that each of these phases determine initiation and survival of various organs that may end up affecting yield componentslate allele of one Eps was enhanced in presence of the late allele of the other Eps , pointing towards probable additive effects for the duration of developmental phases. And discrepancies about the effect of same Eps in the literature (under different temperatures or background) also suggests the epistatic interaction of Eps with other unknown flowering genes and interaction with temperature. Therefore, it cannot be overemphasized how important it is to study individual Eps from a particular genetic background with the known flowering gene complex (other major and minor flowering genes involved) acting in the background in order to decode the functions of Eps (certainly beyond time to anthesis) for exploiting them in breeding. As Eps, unlike Ppd and Vrn, are present in almost all of the chromosomes, their abundancy provide an enormous opportunity to work with, although as most are likely to be minor genes with a probable additive effect, their abundance also poses difficulty in clear understanding of their function (and pathway).It was important to note that the delay due to Eps-7D did not alter the FLN Eps-2B-early had significantly  lower FLN than the respective late allele when the background was Eps-7D-late. Effect of Eps-2B on FLN support the study conducted by Hoogendoorn (1985)40 observing variations in FLN in their vernalized photoperiod insensitive lines. This differential effect of Eps-7D and Eps-2B on FLN when having similar effects on the duration of early phases of development shows another differential mechanisms of action of these genes in early developmental traits when seen in more detail. While both affected similarly the rate of development of the early phases (and might be presumed acted in that phase similarly), it seemed that the Eps-7D affected the rate of leaf initiation in parallel. Consequently, the lines with the Eps-7D-early allele had the same FLN as the lines with Eps-7D-late did; while Eps-2B seemed to have not affected the rate of leaf initiation and therefore the effects on duration of an early developmental phase is reflected on FLN. Furthermore, the Eps-7D gene affected the rate of leaf appearance as the main mechanism for changing time to anthesis, as also found by Ochagavía et al.35 for another Eps gene. These opposite effects on phyllochron, are commensurate with the fact that Eps-7D did also affect the duration of the LRP while Eps-2B restricted its effect to the earlier phases.The QTLs also differed in their effect on FLN, while Eps-7D and 2B affected the number of primordia initiated and the differences in the primordia was mainly contributed from spikelet primordia as the differences in FLN between late and early alleles of both the QTLs were rather small. And the differences in the primordia were mainly due to the differences in the duration of primordia initiation as there was no alteration in the plastochron. Such marginal effect of Eps on spikelet number per spike mainly due to the Eps effect on phenophases without affecting the rate of primordia initiated have been observed in other studies involving ¨major¨27 and ¨minor¨40Eps genes. Among the few studies reporting Eps effects beyond time to anthesis the studies by Lewis et al. (2008)27 in diploid wheat (under field condition) and Alvarez et al. (2016)25 in tetraploid wheat (under controlled conditions) were exceptions showing the effect of Eps-Am 1 bringing about larger changes in spikelet number per spike. This exception was justified by the unusual larger effect of that Eps on time to anthesis. Like other studies in the literature have reported, Eps QTLs bringing about significant (moderate to major) variation in developmental patterns have only brought about subtle variations in the components related to yield . Further, our results indicate that both the Eps QTLs alter developmental phase resulting in modification of anthesis time have contrasting pattern of their function on the dynamics of organs initiated.Further, both Eps-7D and Eps-2B had a contrasting effect on spike fertility presented as floret development and fertile floret per spike at anthesis, again the effect of both Eps on spike fertility was influenced by the presence of the early or late allele of the other Eps in the background. Unexpectedly, lines with the Eps-7D-early allele had a higher spike fertility compared to late allele despite the shorter LRP, at least when the background allele for Eps-2B was late. A general hypothesis is having a longer LRP would improve spike fertility which has a straight-forward explanation that longer duration allows distal florets to become fertile along with positive effect from improved spike dry weight (SDW)13. However, this is true only when the genetics involved in altering the duration do not affect the rate of development and the differences in the duration were big enough to cause variations in SDW. In this particular case, the situation was different as the period of floret development was similar between lines with contrasting alleles of Eps-7D, despite their differences in the LRP. The Eps-7D-early had faster rate of development of each individual floret and similar duration of floral development (due to an early onset of floret development) and that determined the improved rate of survival of distal florets to become fertile. On the other hand, the Eps-7D-late delayed the initiation of distal florets which then developed at a slower rate, consequently diminishing the likelihood of survival of many of the labile florets primordia, reaching anthesis with less fertile florets, overriding the effect of bearing slightly higher spikelet number per spike on the overall number of fertile florets per spike. The effect of Eps-2B on spike fertility was in alignment with the general hypothesis mentioned above in that the Eps-2B-late allele improved spike fertility  due to a slightly longer duration of floret development resulting in lower floret mortality as evidenced with other Eps genes36; and through extending the LRP manipulating the photoperiod42. Our results (when spike fertility was higher) further provide proof to the concept that variations in the floret fertility are mainly due to differences in the survivability  of produced florets  rather than improved maximum number of florets initiated43.TaFT-D1  is just 10 Mb distal to this marker at 68,416,466 and is an excellent candidate gene. In the spring wheat background described here, with saturating vernalisation, Vrn-D3 would exhibit the eps profile described here and elsewhere44. The 2B QTL peak marker, AX-94940971, is at 33,839,683 bp which is close to the predicted position of Ppd-B1 although this gene is not contained within the current 2B assembly of Chinese Spring. However, there is some evidence that this QTL is not a photoperiod insensitive allele of Ppd-B1. No QTL was identified at 2B when the same population was grown in Mexico (data not shown) although the 2D and 7D effects were just as strong. If the earliness effect described here was due to photoperiod insensitivity the additive effect and significance associated with this QTL would increase. It is also noticeable that the QTL effect is weaker than would be expected of Ppd-B1a and that there are two LOD peaks for this QTL leading us to suspect that the actual location is more proximal than Ppd-B1.As for the possible identity of genes underlying the two QTL described we are constrained by the genetic resolution offered by a population of 169 RILs. However, the QTL peak marker of the 7D effect is located at 58,868,234 bp (IWGSC RefSeq v1.0).46. The population was grown in unreplicated 1 m2 plots in Norwich, UK  in the 2015–2016 season (sowing date: 26 October 2015) under standard growing conditions and phenotyped for time of heading. Further, two more field experiments were carried out with eight RILs selected from the population .A population of 169 recombinant inbred lines was developed to generation F4 from a cross of variety ‘Paragon’ and ‘Baj’ following usual proceduresWeather data were collected daily from Meteocat  from a station located near the experimental site. The average temperatures from sowing to maturity (growing period) were 12.6 and 11.8 °C  while having similar genetic composition (mixture of Paragon and Baj) for the other major genes influencing anthesis time. The heading date QTL identified in Paragon × Baj are shown in Table Ppd-D1 and Rht-B1, which are both segregating in this population. Combining the different lines for their alleles of these two Eps genes, we end up with four contrasts to test the direct effects of these alleles as well as the interactions between them .Treatments consisted of eight lines Table  derived Genotypes were arranged in a randomized complete block design with three blocks. Plot size was six rows (0.20 m apart) wide and 4 m long. Three plants in each plot (9 plants per treatment) were marked after the seedling emergence stage. These marked plants were visually representative of the whole plot as well as had uniform plant density around them and were randomly chosen from any of the 4 central rows. In addition, we marked 1 linear meter in each experimental unit which showed uniform emergence of seedlings and optimum plant-to-plant density to be sampled for measurements at anthesis.46) and a genetic map was constructed using MSTmap online (http://mstmap.org/) with default setting and a grouping threshold of LOD = 10. Linkage groups were separated into different chromosomes manually and, as the length of linkage groups were inflated, the total length of the map was adjusted to 2100 cM. Full genotype files and genetic maps are given as supplementary material can be found at. Employing the genetic map, QTL detection was performed on heading date measurements from the UK trial, using package “qtl” (vs. 1.44–947) in two steps, the first scan determining co-factors and the second scan identifying robust QTL, taking the co-factors into account45.The Paragon × Baj RILs were genotyped using the 35 k Axiom Wheat Breeders’ array  from sowing. Despite the fact that the linear regressions in all cases were highly significant, the distribution of residuals indicated that a bi-linear trend was required . Therefore, we fitted a segmented linear regression forcing a breakpoint in rate of leaf appearance at leaf 7, because it has been shown that (1) this change in phyllochron coincides with Haun stages between 6 and 851 and (2) using that threshold for the change in slope of the bi-linear regression produces excellent outputs in a wide range of environmental (e.g. Ref.14) and genotypic contexts (e.g. Refs.53). Phyllochron is the time between the appearance of two successive leaves. It was calculated as the reciprocal of the rate of leaf appearance. In each case two values are generated, corresponding to the early  and late appearing leaves .The number of leaves emerging from the main shoot was recorded in the three marked plants once or twice a week depending on temperature. Measurements began from 1 leaf stage and continued until the flag leaf was fully emerged, using the scale described by Haun (1973)54. Time taken to reach apical stages including double ridge and terminal spikelet (TS) were recorded for all the lines in each block. Along with the apical stages, the number of leaf and spikelet primordia initiated at each sampling were counted.To determine the apical stage and number of primordia in the main shoot apex, one representative plant per experimental unit (three plants per treatment) was sampled randomly from the central rows. This was performed once or twice a week, depending on temperature, from the 2-leaf stage to terminal spikelet stage. The plants were taken to the laboratory for dissection under a binocular microscope . Apical stages were determined using the scale described by Kirby and Appleyard55. Wheat exhibits asynchronous development and growth of spikelets within the spike and florets within the spikelets is different. For that reason, we dissected 3 spikelets per spike, one from apical (3rd or 4th from the top) and one from central and one from the basal (3rd or 4th from the bottom) position of the spike. The florets within each spikelet position were numbered from F1 to Fn according to their position with respect to rachis, where F1 being the floret that was most proximal to the rachis and Fn the most distal floret. Floret development was observed from an early floret primordia stage (< W3.5) to until W10 stage  or highest stage attained by florets that was aborted. The time taken for the F1 to reach W10 stage from sowing was considered as the anthesis time and late reproductive phase (LRP) was calculated as period between TS and anthesis time.After TS stage, one plant from each experimental unit was sampled two or three times a week, again depending on temperature, until anthesis. This was to count the number of florets initiated and determine the stage of development for each floret primordium following the scale developed by Waddington et al. (1983)The number of living floret primordia was derived from the individual floret (F1 to Fn) development curve. The sum of all the florets that continued to develop was calculated for each sampling date, and then plotted against thermal time. This shows the maximum number of florets initiated and final number of fertile florets at anthesis. Only florets that reached W4.5  were considered for calculating living floret primordia. While F1 and F2 florets invariably  reached W10, fate of F3 to F6 florets was depended on genotype, spikelet position and field conditions but these florets at least reached W4.5 in all cases. Florets F7–F10 were initiated in most cases, but did not reach the threshold of W4.5 stage in most spikelets.Three plants were randomly selected from the marked 1 m of uniform plants in each experimental unit (9 plants per treatment) to “map” the number of fertile florets per spike, through counting them at each spikelet in the main-shoot spike . Florets were considered fertile if they were at least at the green anther stage (> W8.5), considering the florets within and across spikelets have asynchronous development and that floret death is highly unlikely when florets have progressed in development to very close to the stage of fertile floret.The data of the variables studied here was subjected to analysis of variance using the statistical software JMP Pro Version 14.0 . The significance level for the differences between Eps allele were calculated using LSmMean contrast. The two-way interaction between two Eps QTLs and three-way interaction between Eps QTLs and season were analyzed using full factorial model in JMP Pro version 14.0.Supplementary Information 1.Supplementary Information 2.


Peripheral ulcerative keratitis (PUK) is a severe inflammatory ocular disease that can affect patients with a long history of rheumatoid arthritis (RA). The use of biotherapy has revolutionized the treatment of the RA and has provided encouraging outcomes especially in the treatment of PUK reported in few cases. In this article, we describe the case of two patients with the history of perforated corneal ulcer complicating RA treated successfully by biologic agents.Case 1: A 45-year-old woman was diagnosed for over 17 years with sero-positive RA refractory to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). She had received one cycle of Rituximab with clinical and biological failure. In July 2017, she presented an active RA flare with a painful left eye and a decreased visual acuity. Ocular examination revealed a corneal perforation in the left eye and a pre-perforation in the right eye. She received an emergency bolus of methylprednisolone 1 g/day during three consecutive days and was followed by Infliximab. After thirteen months, Infliximab was effective on the rheumatic disease and on the corneal involvement as it stopped its gradual perforation in the right eye, and stabilized corneal ulcer in the left eye.Case 2: A 68-year-old man had been diagnosed since 2010 with sero-positive RA refractory to csDMARDs complicated in July 2017 by corneal perforation in the right eye. He was hospitalized for his ocular involvement and his active RA. He received an emergency bolus of methylprednisolone 500 mg/day during three consecutive days and was followed by Rituximab. After six months, we observed the stabilization of the right eye corneal damage and the resolution of articular symptoms.Our cases suggest the efficacy of Infliximab (case 1) and Rituximab (case 2) as a treatment of this severe and destructive keratolysis of the cornea complicating an active RA allowing to plan corneal graft. This positive therapeutic response will contribute to increase literature reports of this therapy success. Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease involving primarily the synovium of joints but can affect other organs including the eye. The ocular manifestations that can occur during the course of RA or that can be the initial sign of the disease are multiple and can include dry-eye syndrome, episcleritis, scleritis, sclero-uveitis, retinal vasculitis and peripheral ulcerative keratitis , 2. PhysA 45-year-old Moroccan woman, with the history of thyroidectomy for 18 years ago receiving the thyroid hormone replacement therapy. She had been diagnosed over the previous 17 years with sero-positive erosive and deforming RA, initially treated by Methotrexate given by intramuscular injection at the dose of 20 mg/week (the dose was adjusted to her weight) and 5 mg/day of oral Prednisone. The Methotrexate was stopped for therapeutic inefficacy after one year and substituted by Sulfasalazine at the dose of 2 g/day associated to 10 mg/day of oral Prednisone. The Salazopyrine was also discontinued for inefficacy after two years. In February 2017, the patient was hospitalized for active RA flare with a DAS28 (Disease Activity Score28) at 6.8 when the decision of biotherapy as a treatment was made. She received the first cycle of Rituximab made of two intravenous infusions at 2-week intervals (1 g/infusion) but five months later, she presented another severe RA flare (DAS28 = 6.2) concluding to the clinical and biological failure of Rituximab. The patient remained on oral corticosteroids at 10 mg/day. In July 2017, due to the occurrence of the redness and pain of the left eye with a decrease in the visual acuity, she consulted an ophthalmologist who objectified a perforated corneal ulcer in the left eye and pre-perforated corneal ulcer in the right eye. Concerning her rheumatic disease, she had a RA flare with DAS28 at 5.85. She received in emergency an intravenous high dose of methylprednisolone at the dose of 1 g/day during three consecutive days followed by Infliximab as biologic DMARDs, according to the RA protocol. Infliximab was administrated at 3 mg/kg in first infusion, followed 2 and 6 weeks later by other infusions, then an infusion every 8 weeks. The therapeutic decision was adopted conjointly with her ophthalmologist. Three months after the initiation of the therapy, the RA flare relieved with DAS28 at 3.8 and her eyes improved greatly with complete resolution of the inflammation. This treatment enabled to stabilize the perforated corneal ulcer in the left eye and to stop the progression of pre-perforated corneal ulcer to a veritable perforation. Thirteen months later, the positive ocular and articular therapeutic response was maintained with Infliximab on the follow-up visit with reduced DAS28 at 3.6 leading the ophthalmologist to plan corneal graft.A 68-year-old Moroccan man with a positive history of smoking habit had been diagnosed with sero-positive erosive and destructive RA and dry-eye syndrome since April 2010. He was treated by Methotrexate given by intramuscular injection at the dose of 20 mg/week (the dose was adjusted to his weight) and 5 mg/day of oral Prednisone. In July 2017, the patient was referred to our hospital by his ophthalmologist for severe RA flare complicated by perforated corneal ulcer of the right eye. The DAS28 was at 6.8. Due to his serious ocular condition complicating an active RA and taking into consideration the successful results of Rituximab as a treatment of ocular manifestations of RA especially PUK described in some articles, we decided, in collaboration with his ophthalmologist, to indicate the Rituximab. The patient received firstly a bolus of methylprednisolone at 500 mg a day during three consecutive days followed by two intravenous infusions of Rituximab at 2-week intervals (1 g/infusion).Six months later, we observed an interesting improvement with the stabilization of the right eye corneal damage and the resolution of articular symptoms with DAS28 at 3.2. Rituximab therapy was indicated systematically every year with the aim to control the underlying disease and to prepare the eye to corneal graft. Two years after the initiation of the therapy, we noted successful ocular and rheumatic outcomes.In rheumatoid arthritis, ocular involvement is common with an estimated incidence at 25% according to Messmer EM et al. , 7. AmonThe pathophysiology of PUK is not fully understood , 15. ManMedical management of this destructive ocular inflammation secondary to RA involves corticosteroids and immunosuppressants. The treatment strategy is based on a therapeutic escalation depending on the severity of the corneal ulcer and the underlying disease . InitialThe surgical treatment of PUK is indicated in cases of corneal perforation to preserve globe integrity. Different techniques can be carried out depending on the size of ulceration including tissue adhesives, bandage contact lens, lamellar graft, tectonic corneal grafting and amniotic membrane transplantation , 11. TheAccording to these outcomes, our patients received initially systemic CS to control this serious ocular complication and certainly the severe flare-up of the articular refractory disease. The CS were followed by biological therapy with the aim to obtain quick and effective results in such urgent cases especially after the inefficiency of csDMARDs in the management of the RA. In collaboration with their ophthalmologist and based on prior studies’ findings, we opted for Infliximab in case 1 after the failure of Rituximab as the first proposed biologic agent and Rituximab for case 2. The two biological therapies gave positive results during the follow-up visits after thirteen months (for case 1) and two years (for case 2) from the therapy initiation. They have led to stabilize the perforated corneal ulcers, to arrest progression of pre-perforated corneal ulcer to a veritable perforation and to control the RA as underling systemic vasculitis disease, which will allow their ophthalmologist to schedule keratoplasty.There is a lack of knowledge concerning the long-term efficacy and safety of the biologic agents for use in ocular inflammation related to systemic disease. Thus, further clinical studies are needed to help guide the treatment of this refractory ocular complication.


WHO endorsed the use of epilation as an alternative treatment to surgery for the management of both minor unoperated TT (UTT) and postoperative TT (PTT). However, some trachoma control programmes hesitated to implement epilation citing concerns that it would hamper TT surgical acceptance and result in larger numbers of and stiffer trichiatic eyelashes than the original TT lashes. We investigated the burden and phenotypes of post-epilation trichiatic eyelashes, and willingness to accept surgical management separately in unoperated and postoperative TT cases.rd of the upper eyelid) UTT (170) and PTT (169) from community-based screenings in Amhara Region, Ethiopia. Participants eyes were examined and data on present and future willingness to accept surgical management collected at baseline and every month for 6-months. Eyelashes touching the eye were counted and their phenotypes documented. Participants were trained on how to epilate. Epilation was done by the participants at home and by the examiner during follow-ups when requested by the participant. Follow-up rates were ≥97%. There was evidence of a significant reduction in the burden of trichiatic eyelashes in unoperated , and postoperative  cases 6-month after frequent epilation. Post-epilation trichiatic eyelashes at 6-months had higher odds of being thin , weak , and half-length  than the pre-epilation trichiatic eyelashes in unoperated cases. There was a significant increase in the proportion of weak trichiatic eyelashes  in postoperative cases. In all 6 follow-up time points, 120/164 (73.2%) of unoperated and 134/163 (82.2%) of postoperative cases indicated that they would accept surgery if their trichiasis progressed.We recruited cases with minor  unoperated (170) and postoperative TT (169) cases. We found, in the contrary to these concerns, the post-epilation eyelashes touching the eye were less damaging being fewer in number, thinner, weaker and shorter than the pre-epilation eyelashes. In addition, the majority of both unoperated and postoperative cases indicated that they are willing to accept surgery if their trichiasis progressed.Trachomatous Trichiasis (TT), the blinding stage of trachoma, ranges from few peripheral eyelashes touching the eye to all eyelashes scratching the cornea. TT is mainly treated with corrective eyelid surgery. However, not all TT cases require surgical correction, and some, particularly, those with few eyelashes decline surgery. Epilation, the repeated removal of eyelashes, is a very common clinical and traditional practice in many trachoma endemic settings. The World Health Organisation recommends that epilation can be offered as an alternative management strategy to surgery for patients with few eyelashes touching the eye or refusing surgery. However, some trachoma control programmes hesitated to implement epilation with the concern that it would hamper surgical acceptance and results in larger numbers of and stiffer eyelashes touching the eye than the original TT eyelashes. In this study, we explored if these concerns are true in epilating minor (≤5 eyelashes from the upper eyelid touching the eye or evidence of epilation in <1/3 Trachomatous trichiasis (TT), the blinding stage of trachoma, has variable phenotypes ranging from a single aberrant eyelash touching the eye without entropion (the inward rotation of the eyelid margin) to complete entropion with all eyelashes in-turned towards the eye and scratching the cornea. The WHO nd Global Scientific Meeting on TT indicates that repeat surgery leads to more unfavourable outcomes than the initial surgery.: 1.4[0.9] vs 1.9 [1.1]), and 6-month follow-up (mean lash burden [SD]: 0.2 [0.4] vs 1.1 [1.3]). On the other hand, the 4 postoperative cases who wanted to undergo repeat surgery tended to have higher burden of trichiatic eyelashes than those who didn’t want both at baseline (mean lash burden [SD]: 2.5 [1.9] vs 1.7 [1.2]), and 6 month (mean lash burden [SD]: 1.0 [0] vs 0.6 [0.9]). There were no differences in other trichiasis phonotypes between those who wanted to have surgery and those who didn’t.The majority of the unoperated (120/164 [73.2%]) and postoperative  were aware and 57/75 (44.2%) were unaware that they had trichiasis (p = 0.97). In addition, there was no difference in willingness to accept surgical management at baseline between prior-epilators and non-prior-epilators in both the unoperated  and postoperative  TT groups.CO and vision change results between baseline and follow-ups are presented in During the six-month period, 2,391 trichiatic eyelashes were removed by the examiner: 1,291 (54.0%) in the unoperated group and 1,100 (46.0%) in the postoperative group. Among these, 2,186 (91.4%) were completely epilated and 205 (8.6%) were incompletely epilated. More eyelashes in the postoperative (119 [58.0%]) than the unoperated group (86 [41.9%) were incompletely epilated . Mild pain was felt by 18/168 (10.7%) unoperated, and 3/169 (1.78%) postoperative cases (p = 0.001) during examiner epilation. Among those epilating at home using traditional forceps, 7/20 (35.0%) unoperated and 7/29 (24.1%) postoperative TT cases (p = 0.41) reported pain (any severity).After adjusting for the number of eyelashes touching the eye, the overall number of cases who epilated at home during the six follow-up timepoints was significantly lower than the number epilating at home at baseline in both the unoperated group  and postoperative group   and the number of people managed for TT globally has been reported. Among mard of the upper eyelid) is less likely to be painful and visually troubling than major trichiasis (>5 eyelashes touching the eye or evidence of epilation of ≥1/3rd of the upper eyelid). More than half of the cases had only a single lash touching the eye, which are likely to be missed during screening and impact and surveillance surveys. These data suggest that, firstly, there are still a significant proportion of people with minor TT who are unknown to the health system, a situation likely to persist well beyond 2020. Secondly, surgery is probably a less appealing option for such cases, who do not have both awareness of the trichiasis and a ‘felt need’ for intervention. This is possibly why half of the unoperated and postoperative TT cases in this study considered the less invasive epilation to be an adequate treatment alternative for their trichiasis. Other studies also reported that not having symptom from the trichiasis and symptoms being not bad enough are among barriers for surgical uptake.[Despite a strong trachoma control programme with robust community-based screening and surgical services, nearly half of the unoperated and about a third of the postoperative TT cases enrolled into this study were unaware that they had trichiasis. Minor trichiasis  of a new eyelash would take about 1–2 months , while iDirect comparison of photographs indicated that there is no change in CO grading between baseline and at the 6-month follow-up in both the unoperated and postoperative TT groups, while the field grading in the unoperated group showed mostly a peripheral progression . This is in line with the finding that post-epilation trichiatic eyelashes were more likely to be shorter than the pre-epilation trichiatic eyelashes, and hence be less likely to grow sufficiently long to reach the centre of the cornea. This is similar to the result of a clinical trial we conducted a few years ago in which photographic CO grading showed no change in minor unoperated cases recruited in the same study setting and randomised to the epilation arm while the field grading indicated a moderate variation. We have Epilation significantly improved VRQoL regardless of vision change for both unoperated and postoperative TT cases. The largest improvements were seen in the visual symptom subscale in both groups indicating that epilation is capable of relieving pain and discomfort from the trichiasis. Although, the effect was smaller, the VRQoL finding in this study is similar to what has been reported for TT surgery in earlier studies.,29,30 ThThis is the first longitudinal study with detailed phenotyping of post-epilation trichiatic eyelashes and measuring the effect of epilation in managing postoperative TT cases and its impact on quality of life. We employed logistically intensive frequent follow-ups with high follow-up rates to capture fast growing post-epilation trichiatic eyelashes. The interviews and examinations were conducted by the same persons at each visit, increasing the reliability of the data presented. However, the study has a number of limitations. The frequent follow-up and case management employed in this study may not reflect the realities in programmatic settings. There are no comparison participants that could have helped to explain what would have happened to people without trichiasis, and to people with trichiasis but who refused both epilation and surgery to support the trichiatic eyelash burden and phenotype, corneal opacity, vision, and quality of life change results. Post-epilation eyelash phenotype was studied only for the eyelashes touching the eye. It is possible that the characteristics of some post-epilation eyelashes pointing towards the eye but yet to touch it would be different. However, our purpose was to study post-epilation “trichiatic eyelashes”, and an eyelash not touching the eye is not a trichiatic eyelash. Importantly eyelashes not touching the eye were not epilated at any follow-up time point, therefore would not be captured in any of the next follow-up when they touch the eye given that not many patients were frequently epilating at home. The gradings have been conducted by a single examiner and quality assurance performed within the study team. Although we used a clear grading system eyelash strength and thickness are not always independent of each other. We recognise photo grading on the eyelashes phenotypes by an independent expert would have strengthened the results. The participants were advised to epilate at home after a training on how to epilate but only some practiced home epilation during the follow-up period. However, they were not provided epilation forceps as this was not permitted by the Ministry of Health of Ethiopia. Thus, most cases might have preferred to wait until the next follow-up for their eyes to be epilated by the study team with machine made forceps than by a community member with traditional forceps. This is evident from the fact that the proportion of cases epilating at home have significantly reduced during the follow-up period compared to the baseline. The small frequencies of homebased-epilation could not allow detailed analysis and limited the ability of the study in measuring its impact versus health facility-based epilation. However, in a previous trial that provided training to a friend or relative to do the epilation and two pairs of epilation forceps, we found results comparable with those in the present study mainly on trichiatic eyelash burden reduction and CO changes.,14 SurgiOverall, we found evidence that frequent epilation neither increases the burden of trichiasis nor results in more damaging stiff and thick post-epilation trichiatic eyelashes. In this study setting, cases with minor TT reported a willingness to accept corrective surgery if their trichiasis progressed, potentially contradicting the assumption that the programmatic implementation of epilation would affect surgical uptake. WHO in its Second Global Scientific Meeting on TT, recommended that “It is ethically important to inform the patient with minor trichiasis about both surgery and epilation, and to discuss the benefits and risks of each procedure so that an informed decision can be made”. PatientsS1 Table(PDF)Click here for additional data file.S1 Fig(TIFF)Click here for additional data file.


The aim of this study was to determine if qPET could be applied as an alternative response method in adults in the RAPID trial.PET-CT scans performed after 3 cycles of ABVD in RAPID were re-evaluated by an independent reader, blinded to PET results and outcome in RAPID. All initially involved regions were assessed visually and by qPET. The distribution of qPET measurements was compared for RAPID and C1 patients. Previously published qPET thresholds corresponding to visual DS (vDS) of 1–5 in C1 were used to derive quantitative DS (qDS) for RAPID patients.PET-CT scans were available for 450 patients from RAPID. vDS were 1 (171 scans), 2 (153 scans), 3 (72 scans), 4 (31 scans) and 5 (23 scans) respectively. The distribution of qPET values was similar to C1 patients, with a unimodal ‘normal’ distribution and a long tail to the right, suggestive of favorable response in the majority and less favorable response in the minority with outlying values. qPET thresholds from C1 applied in RAPID patients gave 86% concordance for vDS and qDS. There was 97% concordance for complete metabolic response  vs. no-CMR using the Lugano classification.qPET which was developed in pediatric patients receiving more intensive OEPA chemotherapy, was a suitable quantitative method for assessing response in adult patients treated with ABVD in a response-adapted setting in the RAPID trial. Achieving a balance between sufficient treatment to enable a high chance of cure whilst minimising toxicity to avoid late effects is a major concern in the treatment of Hodgkin lymphoma (HL) ,2, especA purely visual iPET assessment using the DS may be prone to inaccuracies, with substantial inter reader variability –20. BesiThe quantitative ‘qPET’ method was developed by members of our group to try and address some of these issues by introducing semi-automatic quantitative measurements. The method was derived from measurements made on iPET scans from 898 paediatric HL patients enrolled in the EuroNet-PHL-C1 (C1) trial ,23 and iThe histogram of qPET values obtained from analysing scans from pediatric patients in the C1 trial showed a mixed distribution. The majority of qPET values had a normal distribution located to the left of the graph with the mode  at 0.95 with a long tail to the right which included the minority of outlying qPET values. This distribution is suggestive of a favorable metabolic response in the majority of patients with values in the normally distributed part of the histogram and a less favorable response in the minority with outlying values. Based on this assumption, qPET cut-off points of 1.30 and 2.00 would discriminate favorable from unfavorable response with high sensitivity or high specificity, respectively.In order to translate qPET measurements into ‘quantitative’ Deauville scores (qDS), thresholds corresponding to visual Deauville scores (vDS) were also derived for the C1 patients. The lower qPET threshold values that corresponded to vDS of 3, 4 and 5 were 0.95, 1.30 and 2.00, respectively. It is noteworthy that the two thresholds in the histogram that distinguished patients with unfavorable response from those with favorable response with high sensitivity or high specificity respectively corresponded exactly to the qPET thresholds linking the visually and quantitatively assessed DS of 4 (above liver) and 5 (markedly above liver) ,15. ThisThe iPET assessment in the ongoing C2 trial is performed using qPET. Scans from patients with a qPET value < 1.30 (i.e. qDS 1–3) are considered to represent iPET ‘negative’ results. Radiotherapy is omitted for these patients after chemotherapy. Up until now, the qPET method has only been evaluated in pediatric patients with HL after receiving two cycles of Vincristine, Etoposide, Prednisone and Adriamycin (OEPA) ,26. We h602 patients were enrolled in the RAPID trial in the United Kingdom (UK) between 2003 and 2010 . The RAPThis subsidiary analysis was not subject to a formal amendment. A subset of data was shared with care taken to render it practically anonymized to the recipient. Review of PET data was included in the original protocol that was approved as part of the ethics application. Personal details were removed from the scans prior to transfer to the central reviewers at the imaging core lab and labelled with a trial specific ID number and patient initials. All patients enrolled in the RAPID study gave written informed consent. Ethical approval was granted by the North West Multicentre Research Ethics Committee (MREC 03/8/056).For the purpose of this analysis, the trial number and patient initials were removed and replaced by a new ID (from 1–602) which was a unique identifier not associated with the original study. The key to de-identify the patients is held by a separate organisation from the imaging core lab at University College London CRUK Cancer trials unit. Hence it was not possible for investigators in this analysis to identify patients.All available iPET-CT scans from enrolled patients were re- evaluated by an independent reader . PatientThe iPET re-evaluation was performed by a nuclear medicine physician experienced in reading PET-CT scans from patients with HL, blinded to the original scan results from the RAPID trial and from patient outcomes. The reader was from a different institution to the RAPID study investigators who had centrally reviewed scans for the trial.Baseline PET scans were not performed in the RAPID trial, however the reader was supplied with the site(s) of disease given on case record forms, taken from the baseline CT scan reports for patients as part of the trial. Sites of initial involvement on CT were recorded by anatomical region as cervical, supraclavicular, axillary, mediastinal and hilar (right and/or left) and other regions . The lesion with the highest residual uptake was used for the vDS as established in international guidelines .In addition to the visual re-evaluation, all lesions were assessed quantitatively using the qPET method . The qPEThe qPET thresholds derived from the C1 study were used to assign a qDS .450/571 RAPID patients had iPET-CT scans that were available for visual re-evaluation. 445 scans were analysed using the qPET method. For two patients, quantification was not feasible due to prominent brown fat activity at sites where initial disease was reported on CT. In three patients, quantification was not possible because the data from an older Philips PET scanner was not stored in units of activity concentration and the Hybrid3D program was not able to convert the data to SUV values.The assessment showed vDS of 1 (171 scans), 2 (153 scans), 3 (72 scans), 4 (31 scans) and 5 (23 scans) .The qPET values showed a unimodal distribution , with a Concordance between vDS and qDS was high at 86% (383/445) . For theIn the RAPID trial, the binary decision between iPET ‘negative’ and iPET ‘positive’ used to decide whether patients were eligible for randomisation was made between score 2 and score 3 ; scores 1 and 2 were regarded as CMR. With reference to this cut-off applied in RAPID, the concordance rate between vDS and qDS in this re-analysis of RAPID scan data was 90% (401/445). The specific agreement for a positive rating, which is the likelihood that one method (qDS or vDS) rated the response as score 3–5 when the other method was rated also as score 3–5 was 93%, while the specific agreement for a negative rating, which is the likelihood that one method rated the response as CMR when the other method was also CMR was 84%. In 44 patients, the qDS obtained using the qPET method would have changed the vDS result, from ‘negative’ to ‘positive’ in 33 patients and conversely from ‘positive’ to ‘negative’ in 11 patients.The Lugano classification recommends to use DS of 1–3 to define CMR with standard therapy. With reference to the Lugano cut-off, the concordance rate between vDS and qDS for CMR versus no-CMR was 97% (433/445). The specific agreement for a positive rating was 98%, while the specific agreement for a negative rating was 89%. In 12 patients the qDS obtained using the qPET method would have changed the vDS result, from CMR to no-CMR in 7 patients and from no-CMR to CMR in 11 patients.The qPET method was developed in pediatric patients enrolled in the C1 trial for whom treatment was adapted according to the result of an iPET scan, with radiotherapy omitted in good risk patients with a favorable metabolic response. These patients in the C1 trial received more intensive chemotherapy (OEPA) than is typically used in the treatment of adults with early-stage lymphoma, who usually receive ABVD chemotherapy . The keyPotential advantages of this approach are that it may improve interobserver agreement, especially among less experienced PET readers, and provide a continuous scale. Specifically qPET, which is not influenced by simultaneous contrast illusion  nor invoThe qPET distribution from patient scans in the C1 and the RAPID trials was very similar, with a pronounced peak around a qPET value of 0.95, suggesting these are the cases with favorable metabolic response with a tail of outlying values of cases with less favorable responses. The similarity in distribution suggests that the qPET distribution in HL may be independent of chemotherapy type, at least with respect to OEPA and ABVD. So far, the qPET method has not been evaluated in iPET scans from HL patients treated with other chemotherapy regimens such as Bleomycin, Etoposide, Adriamycin, Cyclophosphamide, Vincristine, Prednisone and Procarbazine (BEACOPP). Furthermore, it suggests that the qPET method may be applicable in adults with early stage disease as well as children undergoing PET response evaluation.In the RAPID trial there was a higher proportion of patients with qDS of 1–3 than in the C1 trial. The RAPID trial included only patients with Ann Arbor stages IA and IIA without mediastinal bulk, with more patients experiencing a favorable metabolic response compared to the C1 trial.The high concordance rate between vDS and qDS in RAPID using previously published qPET thresholds from C1  to transWe hypothesize that these thresholds may be transferable to some other lymphoma settings, since they likely depend more on the approximation of the visual impression of the degree of FDG uptake than on the tumour biology. The current clinically accepted definition of CMR ,17,33 naThe qPET measurement could be considered to be analogous to a laboratory parameter with a clearly defined normal range, as most HL patients have an excellent prognosis with a minority of cases with clearly abnormal results. This distribution depends on a large majority of patients showing a CMR and probably applies to HL but may be different for non-HL subtypes with poorer patient outcomes.A limitation of both the qPET method and the DS is their sensitivity to differences in scan reconstructions and voxel sizes . EffortsIn conclusion, this re-analysis of scans from patients in the RAPID trial suggests that qPET which was developed in paediatric patients receiving more intensive OEPA chemotherapy, is a suitable alternative method for assessing response in adult patients treated with ABVD in a response-adapted setting.S1 Raw Data(XLSX)Click here for additional data file.


Previous studies have shown that women tend to have a poorer postanesthesia recovery than men. Our research group has developed a mobile phone app called Recovery Assessment by Phone Points (RAPP) that includes the Swedish Web version of the Quality of Recovery (SwQoR) questionnaire to monitor and assess postoperative recovery.The aim of this study was to investigate sex differences in postoperative recovery and the number of health care contacts within 14 postoperative days in a cohort of day-surgery patients using RAPP.This study was a secondary analysis from a single-blind randomized controlled trial. Therefore, we did not calculate an a priori sample size regarding sex differences. We conducted the study at 4 day-surgery settings in Sweden from October 2015 to July 2016. Included were 494 patients  undergoing day surgery. The patients self-assessed their postoperative recovery for 14 postoperative days using the RAPP.P=.001 to P=.008). Men younger than 45 years reported significantly higher global scores on postoperative days 2 to 6 than did men 45 years of age or older (P=.001 to P=.006). Sex differences in postoperative recovery were not significant between the age groups.There were no significant sex differences in postoperative recovery or the number of health care contacts. Subgroup analysis showed that women younger than 45 years reported significantly higher global scores in the SwQoR questionnaire (hence a poorer recovery) on postoperative days 1 to 10 than did women who were 45 years of age or older  Previous research has shown that women seem to have a poorer quality of postanesthesia recovery than men ,2. Even Evidence is lacking with respect to daily potential sex differences in postoperative recovery and the number of health care contacts. Therefore, the aim of this study was to investigate, through use of an mHealth solution, whether there were any sex differences in postoperative recovery within 14 postoperative days in a cohort of day-surgery patients in Sweden.This was a secondary analysis of data from a prospective, single-blind, multicenter, randomized controlled trial performed at 4 different day-surgery settings in Sweden. We carried out this study in accordance with the study protocol  and obtaParticipants received written information about the study before the planned surgery. Oral information was provided by the research nurse, who also was responsible for participant inclusion on the same day as surgery, and for collecting oral and written consent from all participants. Inclusion criteria were undergoing day surgery, being able to understand the spoken and written Swedish language, having access to a mobile phone, and being 18 years of age or older. Exclusion criteria were having memory impairment, visual impairment, or alcohol or drug abuse, or undergoing a surgical abortion.The secondary aim of the randomized controlled trial was to investigate postoperative recovery. This paper presents only the participants who were randomly allocated to the intervention group . In the The primary end point for this study was postoperative recovery assessed by the SwQoR questionnaire. Reliability and validity tests have provided sufficient evidence that the SwQoR questionnaire is appropriate to use for day-surgery patients ,14,18,19On postoperative day 14, the participants answered a study-specific, paper-based questionnaire including yes/no questions (n=5) and the number of and reasons for all surgery-related health care contacts with primary care, an emergency department, Sweden’s 24-hour helpline (1177), an outpatient hospital, and contact via RAPP. We chose a 14-day follow-up because most care contacts are reported to be made in the first 2 weeks after day surgery .We also recorded the following data: sex, American Society of Anesthesiologists (ASA) classification, type of surgery, type of anesthesia, duration of surgery, and time spent in the PACU.t test, and Mann-Whitney U test, as appropriate. We analyzed various subgroups to determine differences between types of surgery  and age groups . To determine differences between age groups, we used the mean value as the cutoff. To assess clinical significance, we analyzed the Cohen d effect size  [We have presented the sample size calculation elsewhere; we did not calculate an a priori sample size regarding sex differences . Descript: >0.8) .P value <.01 was considered statistically significant in all analyses.For statistical analyses, we used IBM SPSS Statistics version 24 for Windows (IBM Corporation). A We enrolled patients between October 2015 and July 2016 and assessed 1796 patients for eligibility. In all, we excluded 770 patients before randomization for various reasons, as described elsewhere [P<.001; There were no significant differences between men and women in terms of age, ASA classification, duration of surgery, or time spent in the day-surgery unit. There were significant differences in type of anesthesia, type of airway management, and type of surgery between men and women P<.001; .dizziness , and on postoperative day 4, in which women scored higher on more sleeping difficulties . On postoperative day 12, men scored higher than women on reddened surgical wound .There were no significant differences between men and women in their replies to items of the SwQoR questionnaire except on postoperative day 1, in which women scored higher than men in The response rate decreased over time in both men and women .The SwQoR global score decreased over time. The mean score for men was 46 (SD 34) on postoperative day 1 and 17 (SD 21) on postoperative day 14. Corresponding numbers for women were 53 (SD 36) on postoperative day 1 and 22 (SD 28) on postoperative day 14. There were no significant differences in the global score between the sexes in postoperative recovery at any time point. Men had a global score below 30 at postoperative day 5, and women had a global score below 30 at postoperative day 8 .nausea or vomiting on postoperative day 1  and postoperative days 3 and 4 ; anxiety on postoperative day 1 ; dizziness on postoperative day 1  and postoperative days 3 to 5 ; sleeping difficulties on postoperative day 4  and postoperative day 8 ; and headache on postoperative day 9  and postoperative day 13 . Women 45 years and older of age scored higher on the items having difficulty returning to work or usual home activities on postoperative day 1  and having difficulty taking care of my personal hygiene on postoperative day 2 .When analyzing differences in items in the SwQoR questionnaire between the sexes in the 2 age groups, we found that women (<45 years) scored significantly higher  than men on the following items: having trouble breathing , sore throat , and fever  on postoperative day 10. Also, men scored higher than women on reddened surgical wound  on postoperative day 12 .Men scored significantly higher  on the items P range .001 to .006) than did men 45 years of age or older , we found that men and women had somewhat similar recovery profiles. Younger men (<45 years) reported significantly higher global scores  on postoperative days 2 to 6 , we found no significant differences between the sexes at any time during postoperative days 1 to 14.There were no statistical differences between sexes in health care contacts (planned or unplanned). Both men and women had most of their health care contacts via RAPP  questionnaire, investigating 427 men and women undergoing day surgery . Their rIt may be that using mHealth is more beneficial for women. If so, this is consistent with a study investigating a telehealth intervention, showing that women in the intervention group had lower incidences of depression, fatigue, sleeping difficulties, and pain after coronary artery bypass surgery . The posWe assessed postoperative recovery in this study using the patients’ own mobile phones. The benefit of using e-assessment with a mobile phone is familiarity with the technology, which makes it easy to use . PreviouPostoperative pain has been reported to be a common symptom during recovery at home . SwQoR mOur study showed that women 45 years and older reported significantly better postoperative recovery . The effect of the menstrual cycle phase on overall postoperative recovery have been investigated, showing that premenopausal women reported higher pain scores and had poorer recovery according to their scores . This stA total of 158 (57.6%) of the women and 104 (47.2 %) of the men were 45 years of age or older. As a result of these differences, we analyzed the type of surgery, in case the younger population was confounded by the distribution of type of surgery. The analysis showed significant differences between the groups. Hence, there is a possibility that surgery and type of anesthesia can also be confounders related to the nonsignificant findings between the sexes.The absence of significant differences between the sexes could have been due to the small sample size, and there might be a type II error. We calculated the sample size for the primary outcome, the cost effectiveness of RAPP ,16. HoweThis study indicated to that there are similarities in postoperative recovery and health care contacts between men and women. However, subgroup analysis showed that age may be an independent factor for poorer recovery in women and men. This knowledge can be used when informing female patients what to expect after discharge.


This post hoc analysis of clinical trial data evaluated long-term, self-reported mental and physical health-related quality of life (HRQoL) scores in schizophrenia patients receiving aripiprazole lauroxil (AL), an atypical long-acting injectable (LAI) antipsychotic approved for the treatment of schizophrenia in adults.The study population included 291 stable schizophrenia outpatients enrolled in 2 consecutive long-term safety studies of AL given every 4 weeks for up to 124 weeks. HRQoL was measured using the SF-36v2® Health Survey (SF-36v2) over the course of the follow-up. The primary outcome was change in SF-36v2 mental component summary (MCS) and physical component summary (PCS) scores from baseline to 124 weeks. To contextualize these scores, descriptive analyses were conducted to compare the scores with available scores for the general population as well as for other populations with chronic medical  or psychiatric  conditions.P < .05, all timepoints), while mean PCS score showed little change over 124 weeks. At baseline, patients had lower (worse) MCS scores than the normed general population, but by week 124, patients had MCS scores comparable to those in the general population. This pattern of change was not observed with PCS scores. Comparison of study MCS scores with those associated with other diseases showed that this schizophrenia cohort had lower scores than those with chronic medical conditions but higher scores than those with depression. PCS scores were higher in the study population than published scores for all reference populations at baseline and week 124.Results from this post hoc analysis indicated that the mean MCS score for patients continuing AL improved significantly from baseline over 124 weeks . The inclusion of the patient voice in clinical research is of growing interest in the field of psychiatry as well as to regulatory agencies such as the US Food and Drug Administration , 2. AtteAlthough some studies have evaluated the effect of antipsychotic medication on patient-rated HRQoL, most followed patients for 1 year or less , 6–10. FLong-term safety studies were conducted in a cohort of outpatients with schizophrenia who were followed for up to 3.5 years while receiving monthly AL treatment , 18. As ClinicalTrials.gov identifiers: NCT01626456 and NCT01895452) [This post hoc analysis included data from patients participating in 2 consecutive phase 3, multicenter, open-label safety studies of AL for a total duration of follow-up of 124 weeks (1895452) . Study dPatient HRQoL was measured using the SF-36v2, a well-studied, widely used general instrument for collecting information from patients on their mental and physical HRQoL . This inThe items of the SF-36v2 assess 8 domains of functional health and well-being: physical functioning, role limitations due to physical health, bodily pain, general health, vitality, social functioning, role limitations due to emotional health, and mental health. Weighted aggregates of these 8 domain scores are used to calculate 2 summary scores: the mental component summary (MCS) score and the physical component summary (PCS) score . The SF-Patients in the AL trials completed the SF-36v2 at baseline, 6 times during the first safety study  and 6 times during the second safety study (every 12 weeks and at the end of the study). For the post hoc primary study outcome, we evaluated the change in mental and physical HRQoL as measured by the SF-36v2 MCS and PCS scores from baseline to week 124 using least squares estimates. To contextualize the baseline and endpoint scores for our outpatient schizophrenia cohort, we descriptively compared baseline and week 124 SF-36v2 MCS and PCS scores for patients in the AL trials with those published for the general population and for 3 chronic conditions: the medical conditions of hypertension and type 2 diabetes and the mental health condition of depression (defined as major depression and/or dysthymia) . These cDiagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision) [Eligible patients were aged 18 to 70 years at study entry and were clinically stable, with a primary diagnosis of schizophrenia (evision) . Furtherevision) .Patients received 1 of 2 fixed-dose regimens of AL: 441 mg or 882 mg every 4 weeks. AL dose assignment has been described previously . No doseThe primary outcome of this post hoc analysis was the change in patients’ self-reported HRQoL (as measured by SF-36v2 MCS and PCS scores) from baseline to 124 weeks (least squares estimates). The post hoc analysis population included all patients in the first safety study full analysis set who completed the study and then entered and completed at least 1 HRQoL assessment in the second study.Descriptive statistics are reported, including frequencies and percentages for categorical variables and means (SDs) for continuous variables. For the SF-36v2 measures, mixed models for the change from baseline for MCS and PCS were fit with observed data after controlling for baseline score and geographic region. The least squares estimates for change score from baseline were obtained for mixed models. All analyses were performed using SAS 9.4 .Minimal important differences (MIDs) can be useful in interpreting SF-36v2 summary scores, as they provide a context for understanding score differences that extend beyond the evaluation of statistical significance. An MID is the smallest score difference between 2 independent groups that is perceived as clinically important or meaningful . ThreshoAs a secondary outcome in this post hoc analysis, baseline and week 124 SF-36v2 MCS and PCS scores for the AL population were descriptively compared with those for the general population and individuals with hypertension, type 2 diabetes, and clinical depression obtained from Maruish et al. .Figure P < .05 at all timepoints vs baseline; Fig. P < .05)  was lower than the scores for patients with hypertension (49.93) or type 2 diabetes (48.42); differences between these MCS scores for the study population and the 2 conditions exceeded the 3-point MID threshold  was higher than that of the patients with clinical depression (39.37) and exceeded the 3-point MID, indicating better mental HRQoL in the study population compared with the reference clinical depression population .This post hoc study examined the trajectory of change in self-reported HRQoL in stable patients with schizophrenia maintained on therapy with AL over 124 weeks measured by the SF-36v2, a commonly used instrument for measuring function and well-being. In addition, we descriptively compared clinical trial results with publicly available normed values from the general population as well as patients with 3 chronic conditions . To provide further context to the interpretation of differences between the schizophrenia clinical trial population and the external populations, we used threshold values representing MIDs.Our main finding is that mental HRQoL improved and was maintained over the course of 2 years compared with baseline scores in this population of patients with schizophrenia. This change does not seem to be an artifact of acute symptoms at baseline, given that the mean baseline PANSS score indicated that overall severity of illness was mild. Based on the MID for MCS, the baseline mean MCS score in the study population was lower than that in the general population, but by the end of the follow-up period over 2 years later, scores from the patients with schizophrenia did not differ from the normative general population scores. Some variability between post-baseline timepoints was noted in mean MCS and PCS scores; however, the magnitude of that variation was less than the MID of 3 points for the MCS and 2 points for the PCS and, therefore, is likely not clinically meaningful. In contrast, baseline PCS scores in the study population already resembled those in the general population at baseline and did not substantially change over time. Further, at week 124, mental health scores (MCS scores) in the study population were comparable to those among patients with hypertension or type 2 diabetes and were well above those among patients with depression (based on the MID). This finding is in line with findings from studies showing that major depressive disorder, as well as symptoms of depression in patients with schizophrenia, are associated with poor quality of life and that patients with depression have significantly poorer quality of life than either healthy populations or patients with other chronic diseases including hypertension –27.Our results suggest that continuing to treat stable patients with schizophrenia with the LAI antipsychotic AL is associated with improvements in self-reported HRQoL. Previously published studies of data from our cohort demonstrated the durability of remission with AL therapy  as well Our study findings for SF-36 MCS scores for a schizophrenia cohort are generally consistent with those of other studies. A recent analysis of data from an international observational study aimed to provide a better understanding of the use of SF-36 and a second HRQoL scale, the EuroQol-5 Dimension questionnaire, in patients with schizophrenia by analyzing the correlation between these general scales and disease-specific instruments and disease characteristics, as well as the correlations among the instruments themselves . SociodeSeveral studies in the literature have examined the effects of new treatments on HRQoL in schizophrenia but over considerably shorter durations than in the current study. Our study has several strengths relative to the existing literature, the latter of which predominantly report HRQoL results associated with oral or LAI antipsychotics for up to 1 year , 31, 32.The current analysis has several limitations. The inclusion of a subgroup of patients who successfully completed the 12-week pivotal efficacy and safety study may limit the generalizability of the results to a broader population of patients with schizophrenia, as it applies to a more stable cohort of patients. The attrition of patients who had poor tolerability or lack of clinical efficacy during the 124 weeks, as summarized in a safety analysis that included this patient population , may alsThe study may also have been limited by the use of a generic  measure rather than one that specifically addresses quality-of-life issues facing persons with schizophrenia. The SF-36v2, unlike tools designed for populations with serious mental illness, will not detect certain issues, such as stigma, affecting quality of life for these patients. These disadvantages are offset by the notable advantages shown here; specifically, the SF-36v2 is normed to the general population, and SF-36v2 HRQoL data are available for patients with other diseases, a feature that allows the comparisons presented in this paper. Because the SF-36v2 is a self-reported measure, its validity in patients with an illness like schizophrenia, which can affect insight, may be questioned. However, at least 2 previous studies have demonstrated that self-reported HRQoL in patients with schizophrenia is consistent over time and correlates well with clinician ratings for patients with schizophrenia who are not severely ill , 12.Additional limitations of the current analysis include the open-label and post hoc design, as well as the absence of a placebo control group. Comparing SF-36v2 scores from our study patients with normative data from other populations provides points of reference for a qualitative picture of HRQoL with AL; however, without a placebo control, possible effects on HRQoL of factors related to study procedures other than AL treatment cannot be discounted. Further, normative data were based on US population data; therefore, variability may exist between characteristics in the general population and those in the study population, as the latter was internationally based. Another limitation in the descriptive cross-disease comparisons is related to generalizability of data from a cohort from a single clinical trial to the broader disease population of schizophrenia (the same can be said for the data used for the other chronic conditions as well). Therefore, these data should not be used as a definitive comparison. To our knowledge, this is the first study of the SF-36v2 scale in a long-term clinical trial in which HRQoL of patients with schizophrenia was compared with that of patients with other diseases, and the purpose of these comparisons was to offer readers more qualitative perspectives.Our major finding was that ongoing treatment with the atypical LAI antipsychotic AL was associated with significant improvements in self-reported mental health quality of life that were sustained over a follow-up period lasting over 2 years. The pattern of MCS score improvement occurred in large part within the first 4 weeks of treatment and was maintained during the observation period. By week 20, mean patient scores were similar to normative scores of the general population. Physical HRQoL was reported to be within the range of the general population norms and was sustained without much change — either improving or worsening — throughout the same follow-up period. In sum, results of this study indicate that the LAI antipsychotic AL improves (and maintains) mental HRQoL in stable patients with schizophrenia.In the first study of its kind, we compared SF-36v2 MCS and PCS scores in this population of patients with schizophrenia to those in patients with 2 medical conditions (hypertension and diabetes) and another mental health condition (depression). The mental health scores of the schizophrenia population started lower (worse) than the scores of the population with other medical conditions but better than the scores of the population with depression. These comparisons help to anchor the baseline data to other conditions, something that has not frequently been done in quality-of-life literature in schizophrenia cohorts.


Small supernumerary marker chromosomes (sSMC) are a heterogeneous group of structurally abnormal chromosomes, with an incidence of 0,044% in newborns that increases up to almost 7 times in developmentally retarded patients. sSMC from all 24 chromosome have been described, most of them originate from the group of the acrocentric, with around half deriving from the chromosome 15. Non-acrocentric sSMC are less common and, in the 30 percent of the cases, are associated with phenotypic effect. Complex sSMC consist of chromosomal material derived from more than one chromosome. Genotype–phenotype correlations in patients with sSMC are difficult to assess. Clinical features depend on factors such as its size, genetic content, the involvement of imprinted genes which may be influenced by uniparental disomy and the level of mosaicism. Trisomy of the short arm of chromosome 18 (18p) is an infrequent finding and does not appear to be associated with a specific syndrome. However, mild intellectual disability with or without other anomalies is reported in almost one-third of the patients.Here we present clinical and molecular characterization of a new case of de novo complex sSMC consisting of the entire short arm of chromosome 18p associated with a centromere of either chromosome 13 or 21, evidenced in a 5-year-old boy during diagnostic workup for moderate intellectual disability and dysmorphisms. To date, only seven cases of isolated trisomy 18p due to a sSMC have been reported, three of which have been characterized by array CGH. In two of them the breakpoints and the size of the duplication have been described. In the manuscript we also reviewed cases reported in the DECIPHER database carrying similar duplication and also considered smaller duplications within the region of interest, in order to evaluate the presence of critical regions implicated in the pathological phenotype.Our case provides additional information about phenotypic effects of pure trisomy 18p, confirms chromosomal microarray analysis as gold standard to characterize complex sSMC, and supplies additional elements for genetic counselling. Small supernumerary marker chromosomes (sSMC) are a heterogeneous group of structurally abnormal chromosomes, with an incidence of 0.044% in newborns that increases up to almost 7 times in developmentally retarded patients . sSMC deGenotype–phenotype correlation for sSMCs is a challenging because clinical features depend on their size, the genetic content, the involvement of imprinted genes which may be influenced by uniparental disomy (UPD) and the level of mosaicism .Trisomy of the short arm of chromosome 18 (18p) is an infrequent finding and does not appear to be associated with a specific syndrome. However, mild intellectual disability with or without other anomalies is reported in almost one-third of the patients .Here we present clinical and molecular characterization of a new case of de novo complex small supernumerary marker chromosome (sSMC) consisting of the entire short arm of chromosome 18p associated with a centromere of either chromosome 13 or 21, evidenced in a 5-year-old boy during work up for moderate intellectual disability and dysmorphisms.To the best of our knowledge, the scientific literature reports about 35 cases of pure trisomy 18p, which may be originated by different chromosomal mechanisms: unbalanced translocations, duplications, deletion of 18p with an isochromosome 18p and supernumerary marker chromosomes, reviewed by Yu et al. 18p11.32 p11.21(14257_14122546)x3Trisomy 18p is a rare chromosomal aberration usually not associated to a characteristic facial appearance with a cognitive spectrum ranging from normal intelligence to moderated intellectual disability. To the best of our knowledge there are six cases with pure 18 trisomy associated to sSMC.  [Analyzing the DECIPHER database (r.ac.uk)  we foundZNF519 gene  showing in addition to intellectual disability hypotonia and/or ataxia. These duplications encompass from a minimum of 14 to maximum of 20 of additional genes located on the centromeric side of the ectively , 17. FurDECIPHER data seem to provide evidence about the role of small 18p duplications in worse clinical effects than the whole duplication. Beside intellectual disability, patients show other severe clinical features such as autism, abnormality of cardiovascular system morphology.Deletions usually have serious effects while the interpretation of duplications is often a challenge and their role on the phenotype remain largely unresolved. If a gene at the ends of the duplication is broken, the phenotype of the subject could be comparable to haploinsufficiency. Moreover, a duplicated region could be inserted into another gene, but this does not happen in our subject.ARHGAP28, LINC00668 and LAMA1) in 10 years old boy with moderate psychomotor delay and other physical anomalies: cerebellar vermis hypoplasia, coloboma, deafness and GH deficiency.In the literature there are some reports of interstitial microduplication that partially overlap each other with some genes in common. Giordano et al.  describeLAMA1, a gene mutated in Poretti-Boltshauser syndrome, a neurodevelopmental disorder presenting congenital cerebellar anomalies and characterized by delayed motor development with cognitive function ranging from normal to intellectually disabled [LAMA1 may be a dosage-sensitive gene, considering that both loss of function mutations and duplications result in cerebellar alterations.DECIPHER patient ID 25404 carry a duplication of 1,11 Mb at 18p11.31-p11.23 showing clinical features similar to those described by Giordano et al. [disabled . It is tBalasubramanian et al.  report aKashevarova et al.  report oWhy some subjects with specific genomic imbalance present intellectual disabilities and other abnormalities while in others the same imbalance is without clinical effect is not clear. Further study will be needed to understand also the role of environmental factors on phenotype.The case here presented together with those previously reported supports the mild phenotype effect associated to the duplication of entire 18p. Extensive follow-up is essential to provide adequate genetic counseling when the same chromosomal anomaly is found in prenatal diagnosis.