Interrater reliability, aka intercoder reliability, is defined as true agreement between raters, aka coders, without chance agreement. It is used across many disciplines including medical and health research to measure the quality of ratings, coding, diagnoses, or other observations and judgements. While numerous indices of interrater reliability are available, experts disagree on which ones are legitimate or more appropriate.o), the oldest and the simplest index, is also the most flawed because it fails to estimate and remove chance agreement, which is produced by raters’ random rating. The experts, however, disagree on which chance estimators are legitimate or better. The experts also disagree on which of the three factors, rating category, distribution skew, or task difficulty, an index should rely on to estimate chance agreement, or which factors the known indices in fact rely on.Almost all agree that percent agreement , showed as the most accurate predictor of reliability, reporting directional r2 = .84. It was also the third best approximator, overestimating observed reliability by 13 percentage points on average. The three most acclaimed and most popular indices, Scott’s π, Cohen’s κ and Krippendorff’s α, underperformed all other indices, reporting directional r2 = .312 and underestimated reliability by 31.4 ~ 31.8 points. The newest index, Gwet’s AC1, emerged as the second-best predictor and the most accurate approximator. Bennett et al’s S ranked behind AC1, and Perreault and Leigh’s Ir ranked the fourth both for prediction and approximation. The reliance on category and skew and failure to rely on difficulty explain why the six chance-adjusted indices often underperformed ao, which they were created to outperform. The evidence corroborated the notion that the chance-adjusted indices assume intentional and maximum random rating while the raters instead exhibited involuntary and reluctant random rating.The most criticized index, percent agreement (aThe authors call for more empirical studies and especially more controlled experiments to falsify or qualify this study. If the main findings are replicated and the underlying theories supported, new thinking and new indices may be needed. Index designers may need to refrain from assuming intentional and maximum random rating, and instead assume involuntary and reluctant random rating. Accordingly, the new indices may need to rely on task difficulty, rather than distribution skew or rating category, to estimate chance agreement.The online version contains supplementary material available at 10.1186/s12874-022-01707-5. Bennett and colleagues’ S and Perreault and Leigh’s Ir estimate ac as functions of category (C) [c as functions of distribution skew (sk) [1 makes ac a function of both category and skew. Although many other indices are available and new indices continue to emerge, only these seven are in regular use and continue to be recommended or advocated, according to comprehensive reviews [Intercoder or interrater reliability is used to measure measurement quality in many disciplines, including health and medical research –10. A senoted ao , 11. Alment (ac) –5, 12–14gory (C) , 15. Scokew (sk) –19. Gwet reviews –26.o) ignores chance agreement (ac), therefore is inflated.Percent agreement  inflates S, Ik) deflates π, κ & α by inflating the indices’ ac estimates.Distribution skew  Which indices are valid or more accurate when estimating reliability or chance agreement? 2) What factors affect the indices? 3) What factors should affect the indices? Answers to Questions 2 and 3 explain the answers to Question 1 , 27. UndThe intentional-random assumption, aka maximum-random assumption, is said to be a root cause of many known paradoxes, abnormalities, and other misbehaviors of the indices, because raters are believed to be have honestly and truthfully. Random ratings, if any, should be involuntary rather than intentional, task-dependent rather than invariably maximized , 28–30.Chance agreement is a product of rater behavior, and the debates are ultimately about rater behavior , 31: Whao, six equivalents of S, two equivalents of π, and one equivalent of κ, covering 18 indices in total, all of which had been analyzed mathematically by Zhao, Liu and Deng [This paper reports a controlled experiment that manipulated category, skew, and difficulty, and observed raters’ behavioral responses. The seven indices were tested against the observed behavior. The findings also apply to the two equivalents of aand Deng .f ranges 0 ~ 1, 0 for the least and 1 for the most difficult), and three levels of skew , as summarized in Table We conducted a 4 × 8 × 3 between-subject controlled experiment with 4 subjects per cell. Here the term “subject” refers to the unit of analysis of a study, such as a participating patient in an experiment on the effectiveness of a new drug. A “subject” in this study, however, was a rating session with 100 pairs of rating by two raters. As 4 × 8 × 3 × 4 = 384, this study was based on 384 rating sessions, i.e., subjects. The three manipulated factors included four levels of category , eight levels of difficulty . The Additional file ac) was twice the wrong agreement  was observed agreement ao minus oac  and difficulty (df) and 16 main dependent variables, which are the seven indices’ reliability and chance estimations plus the observed true reliability (ori) and true chance agreement (oca). As the two main estimands, ori and oca sometimes also serve as independent variables when assessing their impacts on the indices’ estimations. Tables Thus, this REORD experiment features three manipulated independent variables, category I, skew (s2 = r•|r|) to gauge the predictive accuracy of the seven indices and their chance estimators  in Table e to assess and compare the chance estimators of the indices, denoted me(ac) in Table The second function of the indices is to evaluate measurement instruments against fixed benchmarks, such as 0.67 and 0.80, that some reliability authorities recommend , 44, 45.2 > .8 as the primary benchmark and me < .02 as the secondary benchmark when evaluating the seven indices. Section V of the Additional file We adopted drp < α, where α = .05, .01, or .001. We however also take a functionalist view of p values, striving to follow the best statistical practice [p < α;avoiding the terms containing “significance," e.g., “statistical significance,” for p < α as a prescreen threshold, passing which allows us to assess, interpret, and compare effect size indicators on percentage scales, such as r2, dr2 and me, with some confidence;considering using terms such as “statistical pretest” and “statistically acknowledged” where we would have traditionally used “significance test” and “statistically significant;”reserving the terms containing “significant” and “significance” for effect sizes of substantive importance.This study observes the tradition of reporting practice –50:avoidp values may be found in our prior work [More of our views and practices regarding the functions of ior work –53.Findings are summarized in Tables Overall, 2.86% of the raters’ decisions fell on the short bars . As expected, there were fewer agreements on short bars, averaging 0.45% . These agreements showed no detectable effects on the main relations under investigation. The correlations between the manipulated variables were practically zero, confirming orthogonality, which indicates minimal confounding or multicollinearity.o, the oldest and the most criticized index of interrater reliability, did well predicting true reliability, showing dr2 = .841 , outperforming the second best, AC1 (dr2 = .721), and the third best, S (dr2 = .691) by more than 10 points, although the latter two met the tentative benchmark dr2 > .67.Percent agreement, a841 Line , Table 32 = .312, failing the tentative benchmark by margins. They also underperformed the next worst, Ir, by 28.7 points (dr2 = .599).The most respected three, π, κ and α, tied as the least accurate predictor, reporting dro. The low r2 means large predictive errors, suggesting that the three indices too often assign lower scores to more reliable instruments, and attach higher scores to less reliable ratings. They failed to differentiate reliable instruments from unreliable ones accurately and consistently.The underperformances of the chance-adjusted indices, especially the popular π, κ and α, were disappointing, considering that the whole mission of the indices was to outperform a2 scores. It is noticed, again, that κ and α ranked among the lowest while percent agreement (ao) ranked the highest. Figure 2 = .9768, p < .001), supporting a design feature of this study, which is to analyze the indices’ chance estimates for the purpose of understanding the indices.Figure ri) was observed , indicating large approximation errors. As the experts would have predicted, percent agreement (ao) overestimated reliability, reporting em = .13  and S (me = .096). also outperformed ao . Ir overestimated reliability across the board like ao did  of em much smaller than that of me. Of the other five indices, em and me are about equal in size , much smaller than any of the other five indices did. By contrast, κ, π and α again produced the largest errors, reporting em ranging from −.318 ~ −.314, much worse than the next worst, Ir  and a 55.5% reliability (ori) were observed, while percent agreement (ao) assumed 0% chance agreement and reported a 68.5% reliability, which means a 13-point overestimation  of ao to stay above the .8 threshold. As ao outperformed all six indices on the primary benchmark (r2) and outperformed four out of the six on the secondary benchmark (me), an argument could be made that overestimating and misestimating chance agreement can be as counterproductive as overlooking chance agreement.In this experiment, the chance agreement of ar and AC1 would have predicted, category (C) had large and negative effects on chance estimations Sac, Irac and ACac, with dr2 ranging −.863 ~ −.661,  and − .019 (p < .01)  on π, κ and α, as their authors intended . A change from extremely easy to extremely difficult decreased ori by over 68 percentage points and increased oac by nearly 36 points . Each difference between the difficulty effect on reliability estimation and the difficulty effect on observed reliability was statistically acknowledged at p < .001.Difficulty showed weaker effects on the six chance-adjusted indices , suggesting the negative correlations between the chance-adjusted indices and difficulty (dr2 = −.566 ~ −.389) are likely due to ao embedded in the indices.By contrast, a1 had not handled difficulty properly, and AC1 handled it better, at least than κ [ac and difficulty  explained less than 8% of the variance in each of the category-based indices’ chance estimates, Sac (2.1%), Irac (2.1%), and ACac (7.5%). Although the correlations were stronger for the skew-based indices’ chance estimates, πac (− 15.1%), κac (− 15.2%), and αac (− 15.1%), the dr2 coefficients were all negative, suggesting that the three indices tended to give higher estimates when the true chance agreements were lower, and give lower estimates when the true chance agreements were higher. Clearly, the index-estimated random rating and the observed raters’ random rating were completely different entities. This finding supports the argument that the chance-adjusted indices assume intentional and maximum random rating while typical raters conduct involuntary and task-dependent random rating. The mismatches between the assumptions and the observations explain the negligible or negative correlations between the estimates and the estimands.This study provided corroborating empirical evidence. The indices’ chance estimates were poorly correlated with their estimands, the observed chance agreements Table , Line 8.More corroborating evidence for the maximum-random assumption came from the large overestimation of chance agreement by the six chance-adjusted indices, as shown in Line 12 of Table The more detailed and situational evidence of the behavioral assumptions come from the influences of the four factors and the indices' offset and aggravation behaviors, which are discussed below.o Overlooked chance agreement. S, Ir and AC1 inappropriately relied on category. π, κ And α inappropriately relied on skew. While difficulty had a strong and positive effect on chance agreement, all chance adjusted indices failed to rely on difficulty. π, κ and α even relied on its opposite, easiness. The misassumptions, including missed, mistaken, and contra assumptions, impeded estimation. π, κ And α fared worse in part because they entailed more and more devastating misassumptions, some of which had been mistaken as evidence of sophistications.Each index of interrater reliability implied one or more misassumptions about chance agreement. aRecall that the main mission of the chance adjusted indices is to remove chance agreement in order to improve on percent agreement. When they mishandled the factors affecting chance agreement, they misestimated chance agreement, thereby misestimated reliability. Misassumptions about the four factors are keys to understanding the indices’ underperformance.For more detailed understandings, we discuss below the offsetting mechanism, which interacts with the assumptions and misassumptions of the indices to define the indices’ behavior.Puzzles may arise if one peruses Tables Each chance-adjusted index relied on a wrong factor, skew or category, to estimate chance agreement; none of them relied on the right factor, difficulty. How come some approximated chance agreement far better than the others , thereby it offset the overestimation even more than the other two category-based indices.To explain Puzzle 1, we note that the category-based indices assumed that larger number of categories decreased chance agreement  condition did not reach that theoretical maximum, reporting an oac = .38 .In actual rating, however, aac, Irac and ACac decreased quickly under the category assumption , the decrease partially offset the 37-point overestimation, making Sac, Irac and ACac less inaccurate. By contrast, κac, πac & αac rejected the category assumption to remain unchanged (Columns N ~ P), hence did not benefit from the partial offset. Thus, Sac, Irac & ACac became less inaccurate than κac, πac & αac.When category increased from ground zero, Sac, πac & αac increased with skew , the increase further aggravated the 37-point overestimation, making κac, πac & αac even more inaccurate. By contrast, Sac and Irac rejected the skew assumption to remain unchanged , hence did not suffer from the aggravation. Thus, κac, πac & αac became even more inaccurate than Sac & Irac.Now return to ground zero, then increase skew. Under the skew assumption, κac reversed it, by assuming that skew reduced ac (M8 ~ M10). While the assumption also mismatched the observed skew effects (I8 ~ I10), the decrease further reduced the once 37-point overestimation. Here two unjustified assumptions, category and reversed skew, joined hands to partially offset another unjustified assumption, intentional and maximum random. Thus, ACac became even less inaccurate than Sac & Irac, hence the least inaccurate of the six. As the effect of intentional-and-maximum-random assumption was stronger than the other two effects combined, a net effect was that even ACac still overestimated chance agreement.Rather than accepting or rejecting the skew assumption, ACThere were other under-offsets, over-offsets, and counter-offsets, i.e., aggravations, some of which discussed below. Behind multifarious offsets were multifarious assumptions about rater behaviors, which fought or allied with each other or stayed neutral to produce the multifarious outcomes. Two wrongs sometimes made one right, sometimes half right, and often three, four, or more wrongs.c not only from percent agreement (ao), but also from the realm of consideration [c is subtracted twice in Eq. o in the numerator, and second from 1 in the denominator, which represents 100% of the realm of consideration. Two offsets occurred as a result. First, ac offsets ao in the numerator. Second, ac in the denominator offsets its own impact in the numerator. As the self-offsets weaken ac’s effects, ao dominates Eq. c–oac correlations exerted weaker effects than the strong and positive ao-ori correlation.To understand Puzzle 2, recall that, assuming intentional and maximum random rating, index designers wanted to remove the maximum amount of chance agreement from all considerations, which requires to remove aderation , 44, 45.o) that worked inside the indices to keep them from performing and looking even worse  for ac, which is Eq. By setting estimated reliability  and ori (.555) into Eq. c > .292 (Line 9) also underestimated reliability (Line 6), and the three  reporting ac < .292 also overestimated reliability. At the same time, all six overestimated chance agreement (Line 12). Due to the chance-removal offset, it is possible and possibly common for some category-based indices to overestimate both chance agreement and reliability.For any rating session, an index accurately estimated reliability when aand ori .55 into Ei = ori) only when it overestimates chance agreement (ac > oac), an index that estimates chance agreement accurately (ac = oac) inevitably underestimates reliability (ri < ori), except in the extreme and impractical situation when ri = ori = 0. The paradox, applicable for all known chance-adjusted indices, is rooted in the chance-removal offset imposed by Eq. A previously undocumented paradox emerges from this analysis Eqs.  and 2. Ar adopts the chance estimator of S, Irac = Sac, and takes the square root of S as the reliability estimation [r, as Ir = S½ for 1 ≥ S ≥ 0 and Ir = 0 for − 1 ≥ S < 0. When chance agreement is overestimated, the square root operation constitutes an additional offset [r overestimates chance agreement more than AC1; at the meantime, due to the square root over-offset of Ir, Ir overestimates reliability more than AC1. The two offsets explain Puzzle 5.To understand Puzzle 5, recall that Perreault and Leigh’s Itimation . S ≤ Ir,l offset . Due to m or overlook the sizable individual errors by S shown in me.A rating session in this experiment simulates a study. In practice, errors do not offset across studies, e.g., one study’s overestimation of Disease A does not offset another study’s underestimation of Disease B. We should not overemphasize the near-zero aggregated error by S shown in eo) stood out as the most accurate predictor of reliability  and the best approximator (me = .093). S ranked behind AC1 for both functions .Of the seven indices, percent agreement .The most respected, the most often required, and the most often applied indices, π, κ and α, ranked the last for both functions . Failing to rely on difficulty further explains the three indices’ underperformances in prediction. Moreover, π, κ & α relied on the opposite difficulty, easiness, to estimate chance agreement , which further explains π, κ & α’s worse performances than S, Ir, and AC1.Difficulty exhibited a substantial and positive effects on chance agreement (drAn index indicates a certain concept. What did the seven indices indicate? Did they indicate what they purport to indicate?o was the only index meeting the primary benchmark (dr2 > .8), thereby also meeting the competitive benchmark. By overlooking chance agreements, ao overestimated reliability by 13 percentage points . The overestimation appeared across the board, as shown in Columns A and B (Lines 4 through 18) of Table o’s deficiency by discounting a certain amount, such as 15 points, treating ao-0.15 as a crude estimation of reliability. Overall, in this experiment percent agreement behaved as a good predictor and a 13-point over-approximator of interrater reliability.Percent agreement ao by removing estimated chance agreement ac. Unfortunately, their ac estimations failed to accurately estimate true chance agreement oac. Sac, Irac, and ACac were slightly influenced by oac , suggesting they indicated fewness of category more than they indicated chance agreement. The other three chance estimators, πac, κac & αac, predicted far less accurately. They indicated mostly skew (dr2 = .434 ~ .437),the opposite of observed chance agreement oac, and easiness  and S (me = .096), did outperform ao (me = .13) for approximation, which was due more to opportune offsets between misassumptions, and less to removing chance agreements  and S (.691), passed the threshold dr2 > 0.67 for tentative acceptance (Table 1 (me = .093) was the one meeting the competitive benchmark. AC1 and S were also two of the four indices meeting the secondary benchmark, me < .2  and S (dr2 = .175). Fortunately for the two indices, the category effects were much smaller than the estimand effects of ori (dr2 = .721 & .691). The two indices underestimated reliability when C = 2, and overestimated when C ≥ 4  failed the tentative benchmark for prediction but satisfied the secondary benchmark for proximity. It overestimated reliability across the board. Overall, Ir was a poor predictor and an 18-point over-approximator of interrater reliability. Ir’s overestimation was worse when the number of categories was increased.I2 = .312) were far below the primary benchmark of dr2 > .8 or the tentative benchmark of dr2 > .67; and their approximation errors (me = .323 ~ .327) were far above the secondary benchmark me < .2. Furthermore, evenness (1-skew) exerted nearly as large effects on the trio  as their estimand ori did (dr2 = .312), suggesting that the trio indicated distribution evenness nearly as much as they indicated interrater reliability. More even distributions raised π, κ and α nearly as effectively as higher reliability did, even though skew or evenness showed no effect on observed reliability or chance agreement.The performances of π, κ and α belong to another class. The trio’s estimation-estimand correlations (dr2 = .312) or evenness (dr2 = .292 ~ .293).Overall, π, κ & α were crude predictors of reliability and evenness, and 31-point under-approximators of reliability. They were crude because they showed large errors when predicting reliability (dr2 (.292 ~ .293) were too low to make π, κ & α precise indicators of evenness or skew, they were too high to make the trio pure indicators of reliability. The correlation can be even more disconcerting if one considers its impact on the creation and diffusion of knowledge. Reviewers and researchers use the trio to screen measurements and manuscripts, while the trio systematically favor more even distributions, making the world appear flatter. It would be a collective version of the conservative bias, or evenness bias, except this one permeates scientific knowledge [o showed none of this disparaging deficiency (dr2 = .000).While drnowledge , 65. By Like most controlled experiments, this study had limited external validity. The raters made visual judgments, which did not represent all tasks. The categories stopped at eight. The short-bar categories were largely empty by design. Each session had only two raters. The list could go on. To avoid unwarranted generalization, we used past tense to describe the indices’ behaviors and their impact.Our findings, however, have been speculated or predicted by the theoretical analyses, mathematical derivations and Monte Carlo simulations , 66–70. The indices were advertised to be “standard” and “global” for “general purpose” , 42, 71.o and AC1 may deserve more credence.Despite the lack of empirical evidence in support of the reigning indices, the spiral of inertia in their defense likely will continue for a while , 58. In More controlled experiments are called for to falsify or qualify the findings of and the theories behind this experiment, and to test the other reliability indices against their estimands –73.New indices may be needed. Index designers may be more cautious about the assumptions that raters conduct intentional and maximum chance rating, or their chance rating is determined by skew or category. More thoughts may be given to the possibility that raters conduct instead involuntary and task-dependent random rating, and more weights given to task difficulty. The index designers are encouraged to assess and adjust their ideas and indices against behavioral data, including the data from this experiment, which will be made public upon publication of this manuscript.Mathematical statistics use a system of axioms and theorems to build tools for analyzing behavioral data. The REORD  methodology reverses the logic, using observed behavior to inform statistical methods. The application might not be limited to interrater reliability. REORD, for example, may open a new front for the studies of sensitivity and specificity measures, two practical tools often used in medical and health research. REORD may also help to investigate the empirical relationship between reliability and validity, two of the most fundamental concepts of scientific enquiry.The researchers in this REORD experiment told the raters nothing about the prevalence or the skew of the long and short bars. As prevalence and skew were programmed to vary randomly between trials and between rating sessions, the researchers themselves did not know about the prevalence or skew until data analysis, and the raters could not have guessed accurately. This design feature was chosen because it resembled one type of research condition, under which raters don’t know what to expect, therefore they don’t expect.For some tasks, however, raters do expect about prevalence and skew, due to their prior experience with the same tasks or their prior exposure to second-hand information. A follow-up study may investigate the impact of such expectations on raters’ rating or the indices of reliability, sensitivity, and specificity.Expectations about distribution, prevalence, and skew can be programmed into artificial intelligence (AI) to aid automated diagnoses, judgements, scorings, evaluations, ratings, and other decisions by machines. Unlike human decisions and human expectations that are often vague and varying, machine decisions and machine expectations can be programmed to be super clear and super consistent , 75. TopAdditional file 1.


Rhizopus oryzae; compounds with an imidazole moiety, such as the compound 7, were documented to have energetic antibacterial, antifungal properties. As a result of these findings, this research suggests that the synthesized compounds could be an excellent choice for controlling black fungus diseases. Furthermore, a molecular docking study was achieved on the synthesized compounds, of which compounds 2, 6, and 7 showed the best interactions with the selected protein targets.Novel 1,3,4-thiadiazole derivatives were synthesized through the reaction of methyl 2-(4-hydroxy-3-methoxybenzylidene) hydrazine-1-carbodithioate and the appropriate hydrazonoyl halides in the presence of a few drops of diisopropylethylamine. The chemical structure of the newly fabricated compounds was inferred from their microanalytical and spectral data. With the increase in microbial diseases, fungi remain a devastating threat to human health because of the resistance of microorganisms to antifungal drugs. COVID-19-associated pulmonary aspergillosis (CAPA) and COVID-19-associated mucormycosis (CAM) have higher mortality rates in many populations. The present study aimed to find new antifungal agents using the disc diffusion method, and minimal inhibitory concentration (MIC) values were estimated by the microdilution assay. An in vitro experiment of six synthesized chemical compounds exhibited antifungal activity against  Aspergillus, Candida, mucoromycetes, and others were also identified in COVID-19 sufferers thiadiazole derivatives displayed significantly forceful antibacterial activities with MIC values of 0.03, 0.03, and 0.5 μg/mL against S aureus, B. subtilis, and E. coli, respectively.Serbanl et al.  examinedr et al.  who estaK. pneumoniae, P. aeruginosa, S. aureus, B. subtilis, and R. oryzae approximately logged 6 RLU/mL. The total ATP levels decreased rapidly in Gram-negative bacteria and then slowly fell in fungal species throughout the experiment, while for the control vials, the total ATP levels remained relatively constant. The results exhibit that the effective dose of the compound 7 showed higher biocidal effects for all tested microbes, where the ATP level disappeared after 10 h for K. pneumoniae, after 12 h for P. aeruginosa, after 16 h for B. subtilis, and after 18 h for S. aureus and R. oryzae  level were registered at three time intervals . The results displayed that all tested compounds were secure, lacking toxic effects, and safe for living organisms. All the recorded EC50% readings after 5, 10, and 15 min were less than 100, indicating that these studied compounds were biocompatible and non-toxic  as in 7 showed the highest inhibition compared to the others. It did the same in silico by forming the highest number of interactions (four H-bonds and other pi interactions) that qualified it to serve as a potential good inhibitor.Phenylalanyl (Phe)-tRNA synthetase (PheRS) is an essential enzyme that catalyzes the transfer of phenylalanine to the Phe-specific transfer RNA (tRNA(Phe)), an important step in protein biosynthesis . This en2, 4, 5, 6, 7 showed good inhibitory effects on Gram-positive bacteria. Similar to the co-crystalized inhibitor, they could interact with residues such as ile175, ile86, and pro87, including the H-bonds, forming resides, ser55 and asp81. Compounds 2 and 7 formed a higher number of H-bonds (3). The compounds showed better binding compared to the co-crystalized inhibitor of GyrB in terms of binding energy, nature, number, and types of the formed bonds/ interactions.Bacterial DNA gyrase B (GyrB), an enzyme that negatively double-stranded DNA, became an attractive target for the examination of new antibacterial agents. Thiazoles were identified as having an inhibitory effect on the GyrB, with its ATP-binding site . As repr2, 4, 5, 6, and 7 exhibited a promising antifungal activity on the tested fungal strain at roughly close strengths with better advantage for compound 7 over the others. This could be interpreted in the light of the docking results where compounds could form interactions within the pocket of CYP51 as with those developed by the standard inhibitor posaconazole (residues leu376 and tyr118) as shown in Sterol 14α-demethylase (CYP51) is an essential cytochrome P450 enzyme for sterols biosynthesis in fungi and is a key target of clinical drugs for controlling fungal diseases . In the 2, 6, and 7 for further steps of drug development as antimicrobial agents.In the light of in vitro and silico results, one could recommend compounds 1H- and 13C-NMR spectra were recorded in (CD3)2SO solutions on a BRUKER 500 FT-NMR system spectrometer, and chemical shifts are expressed in ppm units using TMS as an internal reference. Mass spectra were recorded on a GC-MS QP1000 EX Shimadzu. Elemental analyses were carried out at the Microanalytical Center of Cairo University, Cairo, Egypt.All melting points were determined on an electrothermal apparatus and are uncorrected. IR spectra were recorded (KBr discs) on a Shimadzu FT-IR 8201 PC spectrophotometer. 1) acted as key molecule to produce new 1,3,4-thiadiazole derivatives by its reaction with the appropriate hydrazonoyl halides utilizing the grindstone chemistry; in detail, a mixture of 1.28 mg (5 mmol) of compound 1 and the appropriate hydrazonoyl halides (5 mmol) were ground with a pestle in an open mortar at RT with the addition of few drops (2–3) of DIPEA (diisopropyl ethyl amine) as catalytic amount, for 3–5 min till the mixture turned into the melt. The initial syrup grinding continued for 5–15 min, and the reaction was monitored by TLC (Thin Layer Chromatography) using ethyl acetate/petroleum ether  as eluent. The solid was collected, washed with water, and then ethanol and recrystallized from the proper solvent to afford the desired molecules 2–7.Methyl-2-(4-hydroxy-3-methoxybenzylidene)hydrazine-1-carbodithioate (−1): v 3481 (OH), 1725 (C=O), 1599 (C=N), 1554 (C=C); 1H-NMR (DMSO-d6): δ 1.27 , 3.72 , 4.12 , 7.33–7.45 , 8.29 , 9.65 ;13C-NMR : δ 13.57 (CH3), 55.52 (OCH3), 63.72 (CH2), 111.18 (Ar), 117.60 (Ar), 122.51 (Ar), 123.55 (Ar), 124.50 (Ar), 127.31(Ar), 128.90 (Ar), 129.28 (Ar), 137.62 (Ar), 142.27(Ar), 146.92 (Ar), 149.52 (CH), 156.12 (Ar), 157.06 (C=N), 161.72(C=O); MS m/z (%): 434 , 432 . Anal. Calcd. for C19H17ClN4O4S (432): C, 52.72; H, 3.96; N, 12.94. Found: C, 52.65; H, 3.92; N, 12.89%.Yellow solid (75%); m.p. 161–163 °C, FT-IR , 1715 , 16,050 (C=N), 1565 (C=N); 1H-NMR: δ 1.22 , 3.85 , 4.42 , 7.31–7.33 , 8.22 , 9.75 ; 13C-NMR: δ 13.97 (CH3), 54.53 (OCH3), 62.71 (CH2), 111.19 (Ar), 115.58 (Ar), 121.37 (Ar), 123.52 (Ar), 126.51 (Ar), 128.47 (Ar), 135.19 (Ar), 136.90 (Ar), 142.90 (Ar), 147.93 (Ar), 149.55 (CH), 151.93 (Ar), 157.07 (C=N), 162.62 (C=O); MS m/z (%): 443 . Anal. Calcd. for C19H17N5O6S (443): C, 51.46; H, 3.86; N, 15.79. Found: C, 51.42; H, 3.92; N, 15.85%.Yellow solid (82%); m.p. 182–184 °C, FT-IR: v 3495 (OH), 1678 (C=O), 1600 (C=N), 1557 (C=C); 1H-NMR: δ 2.47 , 3.65 , 7.54–7.85 , 8.22 , 9.55 ; 13C-NMR: δ 25.13 (CH3), 55.53 (OCH3), 111.02 (Ar), 115.60 (Ar), 122.60 (Ar), 124.49 (Ar), 125.12 (Ar), 127.14 (Ar), 137.53 (Ar), 145.19 (Ar), 149.55 (CH), 151.16 (Ar), 155.37 (C=N), 165.03 (C=O); MS m/z (%): 404 , 402 ; Anal. Calcd. for C18H15ClN4O3S (402): C, 53.67; H, 3.75; N, 13.91. Found: C, 53.62; H, 3.71; N, 13.89%.Orange crystals from acetic acid (72%); m.p. 214–216 °C, FT-IR: v 3502 (OH), 1681 (C=O), 1600 (C=N); 1H-NMR: δ 2.51 , 3.79 , 7.30–7.32 , 8.27 , 9.54 ; 13C-NMR: δ 20.65 (CH3), 57.51 (OCH3), 110.92 (Ar), 111.52 (Ar), 123.56 (Ar), 125.51 (Ar), 127.50 (Ar), 136.27 (Ar), 137.57 (Ar), 145.82 (Ar), 147.53 (Ar), 149.12 (CH), 156.28 (C=N), 164.12 (C=O); MS m/z (%): 413 %. Anal. Calcd. for C18H15N5O5S (413): C, 52.30; H, 3.66; N, 16.94. Found: C, 52.28; H, 3.57; N, 16.98%.Orange crystals from acetic acid (61%); m.p. 191–193 °C, FT-IR: v 3451 (OH), 3387, 1681 (C=O), 1578 (C=C); 1H-NMR: δ 2.57 , 3.73 , 6.86–7.72 , 8.38 , 9.85 , 10.72 ; 13C-NMR: δ 20.21(CH3), 56.07 (OCH3), 112.05 (Ar), 115.61 (Ar), 122.06 (Ar), 123.14 (Ar), 124.20 (Ar), 125.50 (Ar), 127.14 (Ar), 128.15 (Ar), 134.54 (Ar), 135.12 (Ar), 148.13 (CH), 151.04 (Ar), 154.89 (C=N), 164.16 (C=O); MS m/z [%]: 445 (M+), 459 (75); Anal. Calcd. for C24H21N5O3S (459): C, 62.73; H, 4.61; N, 15.24%. Found: C, 62.78; H, 4.58; N, 15.21%.Yellow crystals from ethanol, m.p. 222–224 °C; yield (85%); FT-IR: v 3447 , 1661 (C=O), 1600 (C=N), 1539 (C=C); 1H-NMR: δ 3.52 , 7.22–7.95 , 8.36 , 9.65 , 10.58 ; 13C-NMR: δ 52.5 (OCH3), 110.15 (Ar), 118.81 (Ar), 122.76 (Ar), 122.43 (Ar), 123.77 (Ar), 124.58 (Ar), 127.94 (Ar), 128.22 (Ar), 135.14 (Ar), 136.24 (Ar), 145.33 (Ar), 149.15 (CH), 155.89 (Ar), 156.26 (C=N), 162.16 (C=O); MS m/z [%]: 491 , 444 (75), 370 (32), 281 (18), 225 (81), 155 (12), 127(18), 66 (25); Anal. Calcd. for C23H18N6O5S (490): C, 56.32; H, 3.70; N, 17.13%. Found: C, 56.27; H, 3.65; N, 17.09%.Yellow crystals from ethanol, m.p. 182–184 °C; yield (75%); FT-IR: Two strategies were employed in the antibacterial and antifungal assessment. The first was the Kirby–Bauer disc diffusion method, which was utilized to determine the width of the zone of inhibition (ZOI) for each bacterial and fungal strain. The second strategy, microbial growth inhibition, was utilized to define the minimum inhibitory concentration (MICs) values of synthesized compounds on bacterial and fungal strain proliferation.A standard stock solution of each compound was assembled by dissolving 10 mg of each compound in 1 mL of 10% dimethyl sulfoxide (DMSO) as a solvent .Rhizopus oryzae was applied as a model for fungal strain. Likewise, four bacterial species were used, namely Pseudomonas aeruginosa and Klebsiella pneumoniae as a model for Gram-negative species, and Staphylococcus aureus and Bacillus subtilis as a model for Gram-positive strains. The conserved bacterial and fungal cultures were re-cultivated by transferring a single colony of each organism into tubes containing 10 mL of nutrient broth for bacteria and Sabouraud Dextrose broth for fungi, and all inculcated tubes were incubated for 18–24 h at 37 °C for bacteria and 3–4 days at 28 °C for fungi -2-[(4-methylphenoxy) methyl]-1,3-thiazole-4-carboxamide), DNA Gyrase B (GyrB) complexed with its co-crystallized inhibitor (4-methyl-5-[3-(methylsulfanyl)-1H-pyrazol-5-yl]-2-thiophen-2-yl-1,3-thiazole) and the fungal sterol 14α-demethylase (CYP51) with its co-crystallized inhibitor (posconazol) were obtained from protein databank using http://www.rcsb.org, accessed on 8 May 2022  to be docked against the tested compounds. The protein structure was prepared for docking by eliminating water molecules and the co-crystalized ligand (androstenedione). Hydrogens were added then protein structure was saved as PDB file by Biovia Discovery studio 2021. The compounds from 2 to 7 were docked against “4P74, 3G75 and 5FSA” proteins, with cavity space dimensions , , and , respectively. Docking was performed using Autodock Vina’s scoring function of the graphic user interface software PyRx 0.8.The X-ray crystal structure of bacterial phenylalanyl-tRNA synthetase (PheRS) complex with its co-crystallized inhibitor (7 has remarkable antimicrobial features and potential for pharmaceutical use as a new medication candidate against bacterial and fungal infections. Some of the studied compounds, including compounds 6 and 7, have been ascertained to be promising nominees for additional effectiveness evaluation based on the attained results. Moreover, the computational study revealed that compounds 2, 6, and 7 showed the best interactions with the selected protein targets.The current investigation has potential biomedical implications as the antibacterial and antifungal properties of specific synthetic compounds were successfully evaluated. This serves as a foundation for ongoing studies into alternative antibiotics which are hoped to develop more promising therapies against potential pathogens, especially black fungus and pathogenic bacteria. The results show that compound


The current important limitations to the implementation of Evidence-Based Practice (EBP) in the rehabilitation field are related to the validation process of interventions. Indeed, most of the strict guidelines that have been developed for the validation of new drugs  cannot—or can only partially—be applied in rehabilitation. Well-powered, high-quality randomized controlled trials are more difficult to organize in rehabilitation , which reduces the possibility of conducting systematic reviews and meta-analyses, as currently high levels of evidence are sparse. The current limitations of EBP in rehabilitation are presented in this narrative review, and innovative solutions are suggested, such as technology-supported rehabilitation systems, continuous assessment, pragmatic trials, rehabilitation treatment specification systems, and advanced statistical methods, to tackle the current limitations. The development and implementation of new technologies can increase the quality of research and the level of evidence supporting rehabilitation, provided some adaptations are made to our research methodology. For centuries the practice of medicine was based on clinical judgment and doctors’ intuition, rather than on scientific evidence. At this time, medicine was referred to as an art—“the art of Medicine”—rather than a science. In the 1960s, thanks to the development of modern research, the amount of data was growing, and some researchers, led by Alvan Feinstein, started to challenge the way medicine was performed, bringing the risk of bias into attention that could affect clinical judgment . He callThe cornerstones of EBM are still—currently—randomized controlled trials (RCT), which are studies with the highest level of evidence . HoweverOn the other hand, over the last few years, there have been significant advances and developments in modern epidemiology, both in medicine  and in rehabilitation, with the growing development of new technologies , allowing for objective measurements and technology-supported rehabilitation .RCTs are currently not fully adapted to the development of precision therapy , or are difficult to put in place quickly in the context of emerging infectious diseases  . EBM hasTherefore, the aim of this narrative review is to summarize the different study designs currently available in rehabilitation research and discuss their limitations. Then, the current limitations and future perspectives of EBP are discussed in the context of current rehabilitation interventions.The traditional flow of development and the different validation steps of a new treatment are presented in Concerning drug validation, RCTs are requested by the authorities before starting discussions on the marketing of a new molecule. In the past, a new treatment had to be more efficient  than a placebo . However, when treatment is already available (gold-standard), it is unethical to deprive half of the participants of a study of this treatment . TherefoThe complexity and challenges related to the validation of a new intervention can be summarized in two constraints—time and cost, which will lead to various challenges, such as small sample sizes and low statistical power, bias, and low external validity in the studies.Most of the time and financial resources are deployed during Phase 3 of clinical development .Combining the results of different studies in a meta-analysis helps to address, partially, the external validity issues , but above all it increases the statistical power by increasing the number of participants . It is wIn the first part, we inventoried the challenges inherent in RCTs and meta-analyses. In this section, we aim to discuss new developments and techniques that can be used to speed up research by decreasing the number of participants required, reduce the time of studies if necessary, and allow the better allocation of human and financial resources , while aThe development, implementation and use of technology in rehabilitation is not new. We might mention here the development of the passive system of pulley therapy to assist physiotherapists, and of course the development of continuous passive motion devices, which have revolutionized the care of patients after total knee prostheses . HoweverRehabilitation may be aided by one or more existing technologies, such as robotics, muscle and brain stimulation, sensors-based exergames, or virtual reality ,47.Recent years have seen an increase in the use of robot-mediated treatment in rehabilitation to enable highly adaptable, repetitive, rigorous, and quantified physical exercise . TherefoTechnology-supported rehabilitation has gained appeal due to its ability to give an objective and, if necessary, blinded assessment, which can be automated (time saver) and allows for the measurable evaluation of motor function by taking into account the characteristics of the patients   that measure mobility in unsupervised, everyday living situations are indeed gaining traction as forms of adjunctive clinical evaluations. Because the data collected in these ecologically valid and patient-relevant environments can capture varied and unexpected events, they may be able to overcome the limitations of routine clinical tests . Remote Interestingly, this monitoring can be coupled with direct feedback and better communication with the care team, which may result in better goal setting. Studies show that continuous follow-up is not only useful for monitoring the evolution of patients and gathering data, but also has a direct effect on the progress of the patients, and leads to a significant reduction in rehospitalizations among those receiving the continuous monitoring . Remote health assessments that collect real-world data outside of clinic settings necessitate a thorough understanding of appropriate data collection, quality evaluation, analysis, and interpretation techniques. Therefore, future development must focus on the integration of information from the rehabilitation and unsupervised assessments to better evaluate the efficacy of rehabilitation interventions.In the past, patient allocation in RCTs was done equally between the different groups, and the study went on until the end . This poses two major threats: it does not allow one to stop the study in the event of a higher occurrence of side effects in the treated group, or in the event of a more favorable evolution in the treated group, in which case it is unethical to continue giving non-effective treatment to half of the subjects included in the study. Adaptive trial designs permit planned data-driven modifications during the trial program, which may reduce costs, accelerate study timelines, address challenges with recruitment and heterogeneity, and mitigate inefficiencies associated with non-responders. The use of existing information to model estimated outcomes, explore statistical methods, and model the effects of adaptations to the operational elements of the trial without compromising the trial’s integrity and validity, is essential to such designs ,74. InteIn rehabilitation, to the authors’ best knowledge, this type of study design is not yet being implemented, but it would be particularly well adapted to studies on rare pathologies  and/or on expensive and long treatments . Some of the many factors implicated in the failure of conventional RCTs may be mitigated through the use of more adaptable, flexible methods to make trials “smarter”. For rehabilitation, given the limited research resources in some facilities and the relatively small population, it may be impossible to conduct additional studies concurrently. Therefore, reducing the length of time required to complete a study could encourage more research and the expedited development of novel methods .Adaptative trials rely on the development of robust intermediate or continuous statistical analyses. New methods, such as Bayesian adaptative designs  and deepIndeed, changes in the design of the studies are made after analyses are carried out by the statisticians . The development of data sciences and the implementation of new techniques in the field of rehabilitation also open up new perspectives for the agile adaptation of the treatment, ultimately leading to precision treatment . HoweverWe have previously seen that personalized treatment conflicts with the strict protocols for RCTs ,84,85. IConcerning the meta-analysis, the two main biases were the selection bias and the publication bias. As regards the selection bias, researchers are working on automated methods  that could improve and speed up the selection of studies, but this method is still under development . On the The goal of clinical research is to improve the health and quality of life of the patients. For this, EBP has been developed to guide practitioners in their daily practice and to ensure that they integrate the latest research optimally into their treatments. In this last part, we are going to discuss how to ease and increase the translation between research and clinical practice, focusing on pragmatic trials and the development of the rehabilitation treatment specification system.As stated above, one of the most significant limitations of RCTs is the weak translation between research results and clinical reality . The twoImproving treatment adherence may have a more significant influence on the health of our population than the discovery of any new therapy . AlthougThanks to the development of technologies, home-based assessment and monitoring are becoming popular in research and practice , and smaThe second limitation, the lack of representativeness of the patients included in the studies, is trickier to handle. Most of the research is performed in university hospitals, representing only a specific part of the population . The proAlthough significant advances have been made in measuring the outcomes of rehabilitation interventions, comparably less progress has been made in measuring the treatment processes that lead to improved outcomes . The fieAlthough EBP is the current trend in healthcare practice, some clinicians and physicians are above all focused on the limitations of this approach . According to them, EBP does not represent a scientific approach to health and care—it is only a restrictive interpretation of the scientific approach to clinical practice . AnotherCurrently, most physiotherapists perceive EBP as useful and necessary, but it is important to note that there is a gap between perceived and actual knowledge of EBP . We thinAlthough RCTs have been, and still are, considered the most robust form of clinical studies, we have seen that they present a risk of bias, similar to meta-analysis, and are sometimes difficult to apply in the rehabilitation field. To resolve some of the weakness of RCTs, mainly the length of study and the number of patients needed, adaptative trials have been developed and are increasingly used in medical research, but this is not yet being applied (or is to a very limited extent) in the field of rehabilitation. The development of technology-supported rehabilitation offers unique perspectives to monitor the progress of patients during the rehabilitation process. The data collected should be used to increase the quality of the trial by allowing the blinding of assessors and automated standardized data collection.


Hyperreflective foci (HRF) features in macular edema associated with different etiologies may indicate the disease pathogenesis and help to choose proper treatment. The goal of this study is to investigate the retinal microstructural features of macular edema (ME) secondary to multiple etiologies with spectral-domain optical coherence tomography (SD-OCT) and analyze the origin of HRF in ME.This was a retrospective study. SD-OCT images were reviewed to investigate macular microstructural features such as the number and distribution of HRF and hard exudates and the internal reflectivity of the cysts. The differences in microstructural features between groups and the correlations between the number of HRF and other parameters were analyzed.P < 0.05). The frequency of hard exudates and enhanced internal reflectivity of the cysts in the DME group were significantly higher than ME secondary to other etiologies . Within the DME group, the number of HRF in the patients with hard exudates was significantly higher than that in the patients without hard exudates (P < 0.001).A total of 101 eyes with ME from 86 diabetic  patients, 51 eyes from 51 patients with ME secondary to branch retinal vein occlusion , 59 eyes from 58 central retinal vein occlusion  patients, and 26 eyes from 22 uveitis  patients were included in this study. The number of HRF, the frequency of hard exudates and the enhanced internal reflectivity of the cysts were significantly different among the groups. The number of HRF in the DME group was significantly higher than that in the other groups (all HRF detected with SD-OCT were more frequent in DME patients than in BRVO-ME, CRVO-ME, or UME patients. The occurrence of HRF was correlated with the frequency of hard exudates. HRF may result from the deposition of macromolecular exudates in the retina, which is speculated to be a precursor of hard exudates. Macular edema (ME) is a major cause of visual impairment in a variety of diseases including metabolic, vascular, and inflammatory retinal diseases –3. As reSpectral-domain optical coherence tomography (SD-OCT) is a noninvasive retinal imaging technique, which is currently widely used in retinal diseases, including macular edema. SD-OCT provides high-resolution retinal microstructure images, which greatly facilitate the diagnosis and follow-up of macular edema . TypicalClinically, another newly described SD-OCT feature is believed to be correlated with HRF, which is enhanced internal reflectivity of the edema cyst , 28. TheIn this study, we compared the HRF characteristics among several leading etiologies of macular edema, including diabetic retinopathy (DR), branch retinal vein occlusion (BRVO), central retinal vein occlusion (CRVO), and uveitis, analyzed the correlation between the number of HRF and hard exudates. Along with HRF, the enhanced internal reflectivity of the cyst was also investigated. Additionally, the correlations between HRF and the features of hard exudates in DME patients was studied to analyze the properties and origin of HRF.This study was approved by the Institutional Review Board of Peking University First Hospital. Medical records of diabetic macular edema (DME), macular edema secondary to branch retinal vein occlusion , macular edema secondary to central retinal vein occlusion , and noninfectious uveitic macular edema (UME) patients diagnosed at the Department of Ophthalmology, Peking University First Hospital between January 2015 and October 2019 were reviewed retrospectively. The SD-OCT images of each patient were reviewed. Both eyes of the same patient were included if the ME was bilateral and shared the same etiology.1) Low SD-OCT image quality due to unclear refracting media.2) Intravitreal anti-vascular endothelial growth factor injection within 3 months prior to the SD-OCT image.3) Cataract surgery or refractive surgery within 3 months prior to the SD-OCT image.4) Dexamethasone intravitreal implant or fluocinolone acetonide intravitreal implant within 6 months prior to the SD-OCT image; Systemic or periocular corticoid treatment within 6 months prior to the SD-OCT image.5) Comorbidity with other fundus diseases, glaucoma, vitreous macular traction, pathologic myopia, or a history of vitrectomy or fundus laser treatment.6) Presence of proliferative diabetic retinopathy.7) UME due to Vogt-Koyanagi-Harada disease.The exclusion criteria were as follows:The SD-OCT images  from all study groups were obtained with a horizontal scan centered on the fovea using an enhanced depth imaging (EDI) protocol and 50 automated real-time repetitions. The retinal layers were termed the inner retinal layer  and the inner nuclear layer (INL)), middle retinal layer  and the outer nuclear layer (ONL)), and outer retinal layer  and the retinal pigment epithelium (RPE)).1) Hard exudates .2) Enhanced internal reflectivity of the cyst .SD-OCT images were analyzed by two experienced ophthalmologists (RZ and SX). They were masked to all clinical information including diagnosis, and consistency between the two researchers was tested. A third experienced ophthalmologist was invited to make decisions in case of disagreement to reduce relevant errors (WZ). The following morphological characteristics were recorded:Based on previous reports , 30, HRFM . P < 0.05 was considered to indicate a statistically significant difference, and the corresponding Bonferroni correction was performed for statistical significance values during intragroup paired comparisons after multigroup comparisons.1) The overall differences in sex, hard exudate frequency, and enhanced internal reflectivity of the cysts among groups were statistically analyzed with the chi-square test or Fisher's exact test. The DME group was compared with the other groups using Kruskal–Wallis test, and the corresponding Bonferroni correction was performed for the statistical significance value.2) After the normality and homogeneity of variance tests were conducted on the numbers of HRF among the groups, the differences in the numbers of HRF between the overall groups were statistically analyzed by independent-sample Kruskal–Wallis test, and then pairwise comparisons were made between the DME group and the other groups. The corresponding Bonferroni correction was performed for the statistical significance value.3) The DME group was divided into two subgroups according to the frequency of hard exudates and the enhanced internal reflectivity of the cyst. The number of HRF in each retinal layer in the DME group was compared between the two subgroups. Two independent-sample Mann–Whitney U tests were used for statistical analysis.The statistical software SPSS 24.0  was used for data analysis. Classified variables were expressed as frequencies (n) and percentages (%); non-normally distributed continuous variables were expressed as quaternary P < 0.001and P = 0.009, respectively.Two hundred thirty-seven eyes from 217 patients were included in this study; 101 eyes were from 86 DME patients, 51 from 51 BRVO-ME patients, 59 from 58 CRVO-ME patients, and 26 from 22 UME patients. The demographic characteristics of each group are shown in Table P < 0.001). The occurrence rates of the enhanced internal reflectivity of the cyst in the four groups were 36.6%, 5.9%, 5.1% and 0, respectively. In DME group, the enhanced internal reflectivity of the cysts presented more frequently than in other groups and the difference was significant (P < 0.001). The frequency of hard exudates and enhanced internal reflectivity of the cysts in macular edema of different etiologies are shown in Figs. Hard exudates and enhanced internal reflectivity of the cysts were more frequently seen in the DME patients. The frequency of hard exudates in the DME, BRVO-ME, CRVO-ME and UME patients were 42.6%, 7.8%, 5.1% and 0, respectively. The result was significantly different among the groups (P < 0.001).The number of HRF in different retinal layers were analyzed. Representative images of HRF were shown in Fig. P < 0.01). In ILM-INL layer, HRF in the DME group was significantly more frequent than that in the UME group (P = 0.009). No significant difference was found between the DME group and the BRVO-ME (P = 0.606), nor between the DME and CRVO-ME group (P = 1.00) in this layer. In the ELM-RPE layer, HRF amount in the DME group was significantly higher than that in the CRVO-ME group (P < 0.001), but when compared the DME group with BRVO-ME and UME group, there was no significant difference . No significant difference in HRF numbers was found between males and females or among the age groups .The number of HRF in the DME group in ILM-ONL, ILM-INL, OPL-ONL and ELM-RPE layer were shown in Table P < 0.05). The results were shown in Fig. The DME patients were divided into two subgroups according to the presence of hard exudates in the retina. The correlation of HRF and hard exudates were analyzed. The number of HRF in each retinal layer was significantly greater in the hard exudate ( +) subgroup  breakdown caused by tissue ischemia and hypoxia ; while iThe origin of HRF has drawn the interests of numerous teams around the world. Some studies , 17, 18 Noticeably, in studies with positive associations between HRF and inflammatory conditions, the hyperreflective dots observed on SD-OCT images were smaller in size and lower in reflective strength . The sigIn this research, we analyzed the features of HRF in different retinal layers. Previous studies indicated the HRF in different retinal layers correlated with different prognosis and therapeutic effect , 38. In In addition, we observed enhanced signal inside the cysts. Hard exudates are usually considered to be the deposition of macromolecular exudates such as lipids and lipoproteins in retinal tissues after BRB destruction. The enhanced signal in the edema cyst is speculated to be the fibrinogen exudates due to BRB destruction or inflammatory products . In our Although the conclusion of this study is that HRF in DME were precursors to hard exudates, we cannot rule out that HRF in other groups of macular edema may represent inflammatory reaction products such as microglia. Some investigators found the number of HRF decrease after anti-inflammatory therapy . We specThe sample size and retrospective nature limited the current study to further analyze the relationship between HRF and more detailed clinical manifestations including the retinal ischemic degree. In the future, prospective studies with large samples representing different causes of macular edema are needed to dynamically observe the changes in HRF to further determine the formation mechanism of HRF.In conclusion, we demonstrated that HRF in DME patients are closely related to hard exudates. We speculated the HRF in DME patients represent the deposition of large molecular exudates such as proteins and lipids in retinal tissue, which may be the precursor to hard exudates. HRF in DME patients may be an important sign of BRB destruction.


Background: Current rehabilitation care paradigms are not well aligned with the needs of frail older adults, but the resultant impact on rehabilitation outcomes is unclear. Understanding how frailty may impact rehabilitation outcomes, and understanding some of the underlying mechanisms, may help inform payment policy changes. Design: This study was a cross-sectional analysis of data from Round 5 of the National Health and Aging and Trends Study (NHATS). We identified older adults who had completed one or more episodes of rehabilitation care and used a validated 5-item NHATS Fried Frailty scale to categorize patients as frail (3/5 or more) or non-frail (≤2/5). We then evaluated the association between frailty status and three key patient outcomes: (1) achievement of rehabilitation goals, (2) functional improvement during rehabilitation episodes, and (3) discontinuation of therapy after exhausting insurance benefits. Lastly, we used multivariable, survey-weighted logistic regression models to estimate adjusted relationships between frailty and rehabilitation outcomes. Results: An estimated 5.6 million survey-weighted older adults in the United States (95% CI 5.1 to 6.0 million) completed an episode of rehabilitation in the past year, an estimated 1,271,290  of whom were frail. Frail rehabilitation recipients were generally older, had a greater comorbidity burden, and had a higher prevalence of dementia. In adjusted models, frailty was associated with poorer functional outcomes, a lower probability of meeting rehabilitation goals and a greater likelihood of exhausting rehabilitation insurance benefits. Conclusions: Exercise is a well-supported intervention for the management of frailty, but our results suggest that frail older adults are not getting the volume or intensity of rehabilitation treatment needed to maximally improve outcomes—in part due to limited payer coverage of rehabilitation services in the United States. An estimated 15% of all older adults in the United States are frail ,3. AmongAmong the potential mechanisms for poor translation of exercise research into clinical rehabilitation settings, is the poor alignment of insurance payment paradigms in the United States with care needs for frail older adults. Rehabilitation in a hospital, skilled nursing facility, or inpatient rehabilitation facility is often delivered over a short length of time , which might not be enough to address the long-standing deficits related to frailty . SimilarThus, the purpose of this study is to evaluate the impact of frailty on patient-reported rehabilitation outcomes among older adults, and secondarily assess whether frail older adults are more likely to exhaust their insurance rehabilitation benefits during an episode of care. To answer these important questions, we leveraged the National Health and Aging Trends Study (NHATS), a nationally representative sample of Medicare beneficiaries aged 65 and older in the United States. Our hypothesis was that frail older adults would be more likely to report poor rehabilitation outcomes and have a greater likelihood of exhausting insurance benefits. This cohort study used data from the 5th wave (Round 5) of the NHATS survey. The details of this complex, nationally representative survey of older adults in the United States have been published elsewhere . BrieflyDuring the Round 5 annual interview, participants were asked: “In the last year, have you received any rehabilitation services?” Participants who responded affirmatively were coded as rehabilitation participants for our analysis. We additionally identified the setting in which rehabilitation was received , whether rehabilitation was being received after surgery, what was the main medical condition for which rehabilitation was received, and what patient-identified concerns were they hoping to address. Frailty among rehabilitation participants was identified using a modified Fried frailty score  developed in NHATS data by Bandeen-Roche and colleagues . Particin = 3; functioning: n = 4, and insurance n = 158). The text of the questions is provided in the Using self-reported data from the rehabilitation module of the NHATS survey, we captured whether the patients met all or most of their goals when rehabilitation services ended (yes/no), whether their functioning or ability improved while receiving rehabilitation as compared to worsened function or unchanged (categorized as improved/not improved), and whether they had met the limits of their insurance coverage when rehabilitation services ended (yes/no). Participants who refused to answer or responded that they did not know the answer to the questions were categorized as missing , chronic health conditions, dementia status (possible or probable as defined by prior NHATS work), history of falls, hospitalizations in the last year, and whether the participant was in a marriage or partnership. We also included an assessment of food insecurity using a previously validated measure to assess the difference in nutritional status among frail and non-frail rehabilitation users . n = 7070), excluding those living in nursing homes or other institutional settings. We then excluded a small number (n = 236) of participants with missing frailty data that precluded accurate classification . Our final analytic sample consisted of the 1003 older adults who had completed an episode of rehabilitation care in the year prior to the NHATS interview  using multivariable logistic regression. Multivariable models were adjusted for age, sex, surgical history, dementia classification, a count of activities of daily living for which a person need help from another person, and the presence of any of the following chronic health conditions: prior myocardial infarction, heart disease, hypertension, arthritis, osteoporosis, diabetes mellitus, and lung disease. The resultant adjusted odds ratios (aOR) and 95% confidence intervals (CI) represent the relative odds of frail rehabilitation participants experiencing the outcome as compared to a non-frail participant. p-value < 0.05; because this study was exploratory, we did not adjust for multiple tests. Data analysis was conducted from November 2021 through April 2022. All analyses were performed in SAS 9.4 .To account for the complex survey design, all multivariable models included analytic weights, strata, and clustering parameters specific to the 2015 NHATS cohort. In all cases, statistical significance was defined as a two-sided The primary analysis included 1003 rehabilitation episodes, representing an estimated 5,577,972 survey-weighted older adults in the United States . Of those, 292 were classified as frail . n = 47/289, 16.3%) as compared to non-frail . Lastly, frail patients more commonly received rehabilitation in inpatient settings or home settings versus outpatient settings as compared to non-frail rehabilitation participants  and instrumental ADLs (IADLs) ,11. A coExercise is considered a first-line treatment for the management of frailty, and at least one study has shown multicomponent exercise programs undertaken over a period of 24 weeks have generally shown to be most effective at addressing functional impairments . Yet, tyRehabilitation services could play a vital role in promoting high-quality aging in place among frail older adults. Unfortunately, our findings suggest current payer policies related to rehabilitation may be inadequate for the frail population. First, several Medicare policies cap receipt of outpatient rehabilitation services through the use of somewhat arbitrary cost thresholds—thresholds that Medicare explicitly indicates should be exceeded sparingly in billing guidance . AnotherOur study has several key strengths and some limitations that need to be acknowledged. Major strengths include the use of a large nationally representative dataset capturing both a well-validated frailty phenotype and several important domains of rehabilitation use and outcomes for community-dwelling older adults. Our study was limited by an inability to determine which rehabilitation service was predominantly provided —it is unclear whether frail older adults are receiving services from those disciplines in different ways. We also did not know the specific diagnoses for which PT was sought. Our study was also cross-sectional, which did not allow us to evaluate causal or temporal relationships between frailty and the observed vulnerabilities—later studies may help better untangle the mechanisms contributing to frailty among this population to better guide rehabilitation interventions. Rehabilitation therapy is a critical service for older adults in the United States and may be particularly important for those with frailty—who are more likely to be over 80 years of age, socioeconomically disadvantaged, and experiencing food insecurity as compared to their peers. Frail older adults have poorer outcomes when receiving rehabilitation care and are more likely to report stopping therapy after exhausting insurance benefits. Exercise is a well-supported intervention for the management of frailty, but our results suggest that frail older adults may not be getting the volume or intensity of rehabilitation treatment needed to maximally improve outcomes—in part due to limited payer coverage of rehabilitation services in the United States. Both changes in clinical processes and payer policies are likely needed to mitigate frailty-related outcome disparities for older rehabilitation users.


ObjectiveWe aim to assess the awareness and evaluation pattern among physiatrists regarding cancer rehabilitation and associated barriers to access.DesignThe present study is a cross-sectional study in the Physical Medicine and Rehabilitation (PMR) Association Annual Meeting in Puerto Rico that used a 10-item questionnaire to summarize physiatrists’ clinical patterns with their persons diagnosed with cancer (PDWCs).ResultsThirty-eight (66.7%) participants answered they received minimal to no education about cancer rehabilitation benefits. Cancer patients represented 10% or less of the weekly patient load for 47 (82.5%) physiatrists surveyed. The most common type of cancer encountered was breast cancer for the management of adverse effects. Twenty-nine (50.9%) physiatrists answered that a multifactorial barrier was the cause for limited services within this population group. All participants agreed that rehabilitation is at least sometimes beneficial for cancer patients, and 54 (94.7%) believed these services are needed.ConclusionAlthough rehabilitation specialists learn about the benefits of rehabilitation for PDWCs, there continues to be a limited number of PDWCs evaluated, mainly due to poor access, lack of information about cancer rehabilitation, and economic difficulties. Further efforts should be made to emphasize the importance of integrating rehabilitation techniques in the care of PDWCs. Few diagnoses in medicine impose a larger physical, emotional, and economic burden than cancer . OverallCancer rehabilitation entails an impairment-driven multidisciplinary approach aimed at improving the QOL of PDWCs by minimizing the functional and psychological effects of cancer and its treatments. To this end, the role of the physiatrist has been increasingly recognized as essential for the holistic management of PDWCs . PhysiatAlthough the benefits of prehabilitation and rehabilitation have been extensively documented, these services continue to be underpromoted and underutilized by this population ,8. Lack SurveyA group consisting of one oncologist and three Physical Medicine and Rehabilitation (PMR) physicians discussed relevant aspects of cancer rehabilitation to develop a questionnaire that allows the identification of important aspects within cancer rehabilitation education and practice. A questionnaire was developed based on previously published instruments with permission from their authors ,12. The ParticipantsThe study took place at the Regional Annual Meeting of the Association of Physical Medicine and Rehabilitation of Puerto Rico in 2017. Physiatrists encountered during the meeting were invited to participate in our study. An informative sheet about the study was delivered to the participants willing to answer the survey where we emphasized to subjects that participation was voluntary and confidential. After the participants verbally agreed to participate, the survey was shared for completion.Data collectionQuestionnaires were collected by the investigators after completion and separated to avoid identification. An identification number was assigned to each participant, and all collected data were kept secure and private using a locked computer at the PMR department at the university where only the investigators were able to access the data. Data was recorded using Microsoft Office Excel 2016 .Statistical analysisQuestionnaire data were analyzed using IBM SPSS for Windows version 25 . Characterization of the study group was completed by descriptive analysis. Means and standard deviations (SDs) within the groups were determined for each variable. When survey items allowed participants to provide more than one response, all responses were included for analysis.Fifty-seven physiatrists agreed to complete our 10-item survey. Participant demographics are presented in Table In terms of their training, 18 (31.6%) physiatrists subjectively said they had received moderate education about cancer rehabilitation and its benefits, whereas 38 (66.7%) had received minimal to no education. Forty-two (73.7%) participants answered that the patient’s prognosis did not affect their referral for physical or occupational therapy.Breast cancer was the most commonly evaluated cancer, followed by brain and spine cancer Table . ThirteeLack of knowledge about the benefits of rehabilitation was identified as the most common barrier to starting a rehabilitation program in this population; however, 29 (50.9%) participants considered this to be a multifactorial problem. All participants agreed that rehabilitation is at least sometimes beneficial for cancer patients, and 54 (94.7%) believed these services are needed. All subjects agreed that, if available, they would refer their patients to a comprehensive cancer rehabilitation program.To our knowledge, this is the first study describing the knowledge and attitudes toward cancer rehabilitation among general physiatrists in Puerto Rico. Our cohort consisted of 57 physiatrists with a mean age of 49 years, similar to recent national age average estimates . PhysiatFatigue, pain, and impaired mobility are common adverse effects experienced by cancer patients, which could benefit from an evaluation from a physiatrist. Additionally, recent studies have shown that chemotherapy-induced peripheral neuropathy persists in approximately 40% of cancer survivors . DespiteDespite an overlap between the cancer population and other groups within the scope of a general physiatrist, holistic rehabilitation care of cancer patients requires discrete clinical experiences to the breadth of the cancer population and their unique needs. To this end, most of the surveyed physiatrists (66.7%) reported receiving minimal to no formal training during residency about cancer rehabilitation. Considering that a similar percentage (64.9%) of our participants reported having practiced for more than 10 years, future studies evaluating the relationship between years removed from residency and the recent Accreditation Council for Graduate Medical Education (ACGME) requirement that physiatrists demonstrate competence in the rehabilitation and psychosocial care of patients with cancer could provide valuable insight on recent trends and progress .Further, a focused training curriculum in oncology rehabilitation is not standard in most PMR residencies . A studyMost of the surveyed physiatrists identified a lack of knowledge about its benefits and poor understanding of the referral process as the main barriers to oncology rehabilitation care. To this end, physiatrists must lead the education efforts to address these issues, both among other healthcare providers and in the community. Participating in national oncology forums, offering conferences at local oncology meetings, and participating in routine multidisciplinary meetings are all initiatives that could increase the overall awareness of the physical and psychosocial benefits of cancer rehabilitation.Most rehabilitation programs establish goals based on functional status prior to diagnosis, stage of disease, and prognosis. In our study, all of the surveyed physiatrists consider cancer rehabilitation beneficial, regardless of the patient’s disease stage or prognosis. Other studies have shown that only 35% of physiatrists accepted cancer patients regardless of their prognosis . EvidencOur study represents a small cohort limited to the physiatrists community in Puerto Rico, which limits the generalizability of our results. Future studies aimed at identifying barriers in specific geographic areas and socioeconomic circumstances may allow for a targeted local and national response. Recall bias is another possible limitation given the design of our study.Rehabilitation care is needed but currently is suboptimal to meet the growing demand of PDWCs. Unfortunately, most patients are not routinely referred to physiatrists for evaluation of musculoskeletal and neurologic adverse effects. Although most physiatrists acknowledge the value of rehabilitation care for this population, multiple barriers that affect its delivery exist. Some of these barriers include limited exposure to the cancer population during residency, lack of knowledge of its benefits, limited access to rehabilitation services, and the need for improvement in referral mechanisms.


Blumeria graminis f. sp. tritici, Bgt, recently clarified as B. graminis s. str.), is one of the most destructive diseases of wheat. Pm60 is a nucleotide-binding leucine-rich repeat (NLR) gene that confers race-specific resistance to Bgt. Allelic variants  were found in Triticum urartu and T. dicoccoides, the wild progenitors of wheat. In the present study, we studied the diversity of the Pm60 locus in a large set of wheat germplasm and found 20 tetraploid wheats harboring the Pm60 alleles, which correspond to three novel haplotypes (HapI–HapIII). HapI  and HapII  were present in domesticated tetraploid wheats, whereas HapIII  was identified in wild tetraploid T. araraticum. A sequence comparison of HapII and HapIII revealed that they differed by three SNPs and a GCC deletion. Results of the phylogenetic analysis revealed that HapII was more closely related to the functional haplotype MlIW172. Infection tests showed that HapII-carrying lines display a partial resistance response to Bgt#GH, while HapI was susceptible. Our results provide insights into the genetic evolution of the Pm60 locus and potential valuable alleles for powdery mildew resistance breeding.Wheat powdery mildew ( Blumeria graminis f. sp. tritici, Bgt), recently clarified as B. graminis s. str. [Bgt-resistant cultivars is the most effective and environmentally safe strategy to control this disease [Bgt isolates [Pm1–Pm69) have been formally documented and genetically mapped on different chromosomes in wheat [Pm genes were identified from wheat wild relatives, such as Triticum urartu [T. dicoccoides [Aegilops biuncialis [Wheat powdery mildew  protein [T. urartu populations and designated as Pm60, Pm60a, and Pm60b. The coding region of Pm60a has a 240-nucleotide deletion, whereas Pm60b contains a 240-nucleotide insertion, as compared with the Pm60 sequence in PI428309, which resulted in the loss or addition of two of the leucine-rich repeat (LRR) motifs of Pm60. Although the deletion or insertion did not affect the resistance to Bgt isolate E09 [Pm60a substantially narrowed the resistance spectrum [Pm60 was highly resistant to 43 out of 54 Bgt isolates tested, whereas Pm60a was only resistant to 5 of them [Pm60a, designated as Pm60a’, was presented in multiple susceptible T. urartu accessions. The Pm60a’ sequence was 98.52% identical to Pm60a, with 58 single nucleotide polymorphisms (SNPs) and a 3-nucleotide deletion [Powdery mildew resistance gene  protein . Three alate E09 , the delspectrum . For exa of them . A nonfudeletion .T. dicoccoides) harbors the Pm60 allele (TdPm60), which is an ortholog of Pm60 from T. urartu. TdPm60 was found to be present in the wild emmer donor lines of resistance genes PmG16 [MlWE18 [MlIW72 [MlIW172 [MlWE18 and MlIW172 were confirmed to be the functional alleles of Pm60 by using ethyl methanesulfonate (EMS) mutagenesis and genetic transformation [TdPm60 constitutes a strong candidate for PmG16 mildew resistance [Pm60 alleles revealed diversifications in sequence variation in the locus and presence/absence polymorphisms in wild emmer wheat populations [MlWE18 and MlIW172, together with additional eight haplotypes (Hap1–Hp8) of TdPm60, were defined in wild emmer [Pm60 alleles from T. dicoccoides and T. urartu. A different resistance spectrum of functional Pm60 alleles was observed when inoculated with 20 Bgt isolates sampled from different locations of China [Pm60 alleles and haplotypes are promising for breeding powdery mildew resistance wheat cultivars.The wild emmer wheat  (PI and CItr numbers) and Triticeae Research Institute, Sichuan Agricultural University, Chengdu, China (AS numbers). Two hundred thirty-eight genotypes of different wheat species  were usePm60 (M-Pm60-S1) [Pm60 region. Touchdown PCR amplification was carried out as described by Huang et al. [Wheat seeds were wrapped in a moist filter paper and put in a chamber at a temperature of 4 °C for 3 days and transferred into a growth chamber at a temperature of 10 °C during the dark period (8 h) and 20 °C during the light period 16h) for 10 days. Total genomic DNA was prepared from seedling leaves using the cetyltrimethylammonium bromide (CTAB) method as described by Zhang et al. . The DNAPm60-S1)  was progh for 10 Pm60 alleles were previously isolated from T. urartu and T. dicoccoides accessions. To characterize whether Pm60 alleles are present in other wheat species, we screened a collection of 238 wheat germplasm using the PCR-based molecular marker M-Pm60-S1, which covers the LRR regions and can differentiate the Pm60, Pm60a, and Pm60b alleles by the size of amplified products (M-Pm60-S1 were selected to obtain the entire Pm60 sequences (from start to stop codons) using four primer pairs amplifying overlapping fragments . Sequences were assembled and subjected to multiple alignments using DNAMAN software version 6.0 . The final sequences were manually corrected, and SNPs were visually checked on a chromatogram to ensure their quality. products A. The acragments , which w. urartu . The fouPm60 alleles and homologous sequences from cereals were selected for phylogenetic analyses. The Pm60 homologs in the phylogeny tree were identified from the National Centre for Biotechnology Information (NCBI) database and the Ensembl Plants website. Multiple sequence alignments were performed with BioEdit [The published  BioEdit , and a nBgt isolates including Bgt#1-25, Bgt#15-9-4, Bgt#WJ, Bgt#SZS, and Bgt#GH were used to test the response of wheat accessions harboring different Pm60 haplotypes in the present study. Isolates Bgt#1-25 and Bgt#15-9-4 were kindly provided by Wenqi Shi from the Institute of Plant Protection and Soil Fertility, Hubei Academy of Agricultural Sciences. The isolates Bgt#WJ and Bgt#SZS were newly purified from bread wheat in the experimental fields of Sichuan Agricultural University and Sichuan Academy of Agricultural Sciences, respectively. The isolate Bgt#GH was purified from bread wheat in the greenhouse of Sichuan Agricultural University. Wheat accessions PI352335, PI355465, PI415152, and CItr7685 carrying HapI and accessions PI190949, PI113392, PI124494, and AS285 carrying HapII of Pm60 were randomly selected for the powdery mildew resistance test. Wild emmer wheat accession G18-16  [Five sistant) . The IT Pm60 functional marker M-Pm60-S1 could amplify 591 bp for Pm60a, 831 bp for Pm60, or 1071 bp for Pm60b, whereas there was no amplification product for the absence of Pm60 alleles [M-Pm60-S1 marker, whereas 218 showed no amplification  haplotypes (T. dicoccon (n = 6) and T. turanicum (n = 1) accessions; HapII was identified in T. carthlicum (n = 2), T. durum (n = 4), and T. turanicum (n = 4) accessions; HapIII was only found in T. armeniacum accession PI361859  and their wild relatives   were clustered very close to this reported Pm60. TRIUR3_00771 and TRIUR3_00770 from T. urartu acc. G1812, Ae.speltoides.TS01.7B01G0976700.1 from Ae. speltoides, TRIDC7AG077150.1 from T. dicoccoides acc. Zavitan, and TraesCS7D01G542200.1 from T. aestivum cv. Chinese Spring (CS) were classified on a cluster with longer branches than the Pm60 proteins. TRITD7Av1G277190.1 and TRITD7Bv1G230590.1 from T. durum acc. Svevo, and BRADI_1g29658v3 and BRADI_2g38192v3 from Brachypodium distachyon, were located as an outgroup in the phylogenetic tree.To determine the phylogenetic relationship between Pm60 proteins and homologs in the annotated genome assemblies of domesticated wheat (ccoides) , an unroccoides) . The resPm60 haplotypes confers resistance to powdery mildew, a leaf infection test at the seedling stage was initially performed in eight randomly selected wheat accessions carrying either HapI or HapII of Pm60 using different Bgt isolates. HapIII was not involved in the inoculation test due to the unavailable seeds of T. armeniacum accession PI 361859. All accessions were susceptible (IT = 3–4) to Bgt isolates Bgt #1-25, Bgt#15-9-4, Bgt#WJ, and Bgt#SZS, whereas PI190949, PI113392, PI124494, and AS285 carrying HapII of Pm60 showed partial resistance to Bgt#GH . HapI was similar to Pm60. HapII and HapIII had a 240 nt deletion, which was the same as the previously reported Pm60a. Among them, HapI was present only in domesticated tetraploid wheats T. dicoccom and T. turanicum; HapII was found in tetraploid wheats T. durum, T. turanicum, and T. carthlicum; whereas HapIII was only identified in wild tetraploid T. araraticum accession PI361859. morphism ,11,14. Tm60 form ,14. The nly once ,14. In tPm60 gene were clustered into one clade, suggesting the evolutionary conservation of the Pm60 locus in Triticum species. T. dicoccun  is the domesticated form of T. dicoccoides and is believed to have been domesticated probably in southeast Turkey. Cultivated emmer was later evolved into the free-threshing ears of durum wheat [T. dicoccoides [TdPm60 form. HapII in cultivated T. durum was likely derived from emmer wheat. HapIII in T. araraticum (AuAuGG) might be independently inherited from T. urartu by the polyploidization event. Further studies are still needed to test these hypotheses. Phylogenetic analyses indicated that all proteins encoded by the um wheat ,19. Theroccoides  with an Pm60a’ with 58 SNPs and a 3-nucleotide deletion was detected in several susceptible T. urartu accessions, implying that these SNPs and deletion could be important for the resistance function [Pm60 haplotypes (HapI–HapIII) and functional TuPm60a. Besides, HapI and HapIII sequences had 3 nt deletion in the interdomain region between the CC and NB-ARC domains of Pm60 as compared with HapII and TuPm60. HapII and HapIII sequences had a 240 nt deletion, which was the same as the previously reported TuPm60a [Bgt isolates, whereas HapII  carrying lines showed partial resistance (IT=2) to Bgt#GH, suggesting that HapII may be functional. HapII differed from HapI by 10 SNPs and a 3 bp InDel as well as 240 nt deletion, which resulted in the loss of the two leucine-rich repeat motifs  and in T. urartu  when inoculated with 20 Bgt isolates [Pm60 cannot provide durable protection against wheat powdery mildew. Therefore, allele pyramiding of Pm60 or pyramiding of Pm60 with other disease resistance genes/alleles is valuable for breeding disease resistance wheat cultivars.Pyramiding of several resistance genes or resistance alleles has the potential to improve resistance in terms of durability and spectrum ,22. TdPm‘bridge’ ,8. The disolates . It seem


The Italian law 81/2014 has given a strong push to the design of therapeutic-rehabilitative paths for psychiatric patients who are offenders. This innovation requires a constant organizational effort on the part of mental health services to enforce the law. The rehabilitation team is represented by different professionals like psychiatrists, psychologists, nurses, psychiatric rehabilitation technicians, educators, social workers and others. They must be able to work in an integrated way among them and with private social sector.It is in our interest to reach an agreement between different professionals working in the rehabilitation-forensic field about good practices.We have prepared a survey to identify good practices in the field of psychosocial rehabilitation of the offender psychiatric patient, involving different professionals who have expertise.This audit revealed, in everybody’s opinion, that these offending citizens have received a security measure capable of having greater control over their actions in a therapeutic-rehabilitative perspective but it is fundamental to educate them also to exercise their own safety for a social shared culture. Ensuring the safety of the offender during the therapeutic-rehabilitative path is as important as responding to a society’s need for social security.Satisfying a society’s need for security, established by the Judge and the Law, all this cannot separated from the active exercise of security of the offending psychiatric patient towards himself, through psychoeducation. The safety towards others and towards oneself can constitute a good practice in the field of psychosocial rehabilitation.No significant relationships.


To develop therapy resistance to androgen receptor (AR) pathway inhibitors such enzalutamide (ENZ), prostate cancer (PCa) cells commonly adopt two surviving strategies. One is to strengthen the AR signaling to overcome the inhibitory effects of ENZ. It is frequently observed that AR gene amplification, overexpression, and generation of AR splicing variants occur in ~70–80% of castrate-resistant prostate cancers (CRPC) . The othRecently, Gao et al.,  reportedKinesins  are a suThe question remains as to whether enhanced KIF15 expression is responsible for ENZ-resistance of PCa or it is a consequence of ENZ-resistance. The authors provided convincing evidence that the gain-of-function of KIF15 conferred PCa cells growth advantage under ENZ treatment. However, they also showed that agonist-activated AR was recruited to the KIF15 promoter to upregulate its transcription. Prolonged ENZ treatment also induced KIF15 expression. These results suggest that re-activated AR signaling in ENZ-R cancer cells is responsible for KIF15 upregulation. However, increased KIF15 expression may also reflect the proliferative status of ENZ-R cells since these cells were selected by ENZ treatment with gained proliferative phenotypes, and KIF15 is known for its essential role during mitosis. KIF15 maybe be a multifunctional protein that may be a part of the complicated mechanisms contributing to ENZ-R and is also needed for mitosis of ENZ-R cells driven by AR and AR splice variants.It would be interesting to study the temporal and spatial relationship between KIF15 and AR. The AR protein is shuffling between the cytoplasm and nucleus during interphase, while liganded-AR is closely bound to the mitotic chromatin during all the stages . This exThe molecular mechanism by which co-targeting KIF15 and AR to achieve stronger tumor suppression needs further investigation. Kif15-IN-1 is an inhibitor of KIF15  and its In summary, this study provides a novel mechanism by which the mitotic kinesin KIF15 increases AR protein stability and propose a combination therapy of co-targeting KIF15 and AR to improve PCa patient outcome.