I claim that objective consequentialism (OC) faces a problem stemming from the existence in some situations of a plurality of chances relevant to the outcomes of an agent’s acts. I suggest that this phenomenon bears structural resemblance to the well-known Reference Class problem. I outline a few ways in which one could attempt to deal with the issue, suggesting that it is the higher-level chance that should be employed by OC. Perhaps the best point of departure is Lenman , the approach to ethics according to which ’the primary notion for moral theory is given by what is best (or (...) has greatest objective value) regardless of how things seem to the agent’  is the probability of X given Y (see below), the Any probabilistic consequentialism claims that agents have an obligation to maximise expected moral utility, that is, to maximise the value of what we will call the ’consequentialist formula’ (CF for short):I would like to stress that I am not suggesting objective consequentialism to be a sort of decision procedure; we should take it to be a criterion of rightness . He then offers detailed arguments that in a fundamentally deterministic world the chance functions can obtain only the values 0 and 1; in a deterministic world there are no non-trivial objective chances.One of the topics in philosophy of science which seems to have gained prominence since the later aughts is that of objective chance and, in particular, whether it makes sense to speak of non-trivial objective chances in deterministic worlds. One of the most cited papers on the topic is Schaffer . The autA number of authors, including for example Glynn , Frigg aThe Reader may be familiar with a popular outlook (probably inspired by Laplace) combining a fundamental determinism with the belief that any non-trivial probability assignments stem from our lack of knowledge about the inner workings of the world. Even disregarding doubts regarding this germinated by post-Newtonian physics, one could think that due to our cognitive imperfections it is impossible for us to know the whole state of the universe, but it is that whole state which uniquely determines the universe’s temporal evolution. Any non-trivial probability assignments are then, supposedly, epistemic in nature, corresponding to this lack of our knowledge. It needs to be stressed that a sizable part of the modern literature on objective chance in philosophy of science from which I have cited a few examples above consciously—and, in my opinion, correctly—negates this outlook: there are objective probabilities, in-the-world chances, at all levels under discussion.Diffusion: a rectangular container is filled with water. A portion of a dye is introduced to the container in one of its corners. We are interested in the chance that after 10 s more than 1 ml of the dye will be present in the liquid in the part of the container defined as being closer than 1 cm to the corner opposite to the one at which the dye was introduced. The deterministic laws of classical mechanics will give us one value of that chance, and the statistical laws regarding diffusion will give us another.Dice: a pair of dice is to be thrown on a gambling table. Suppose that some ’randomising’ apparatus is to be used—for example, the gambler is supposed to push a button turning on on a machine which will rotate a special tube containing the dice .Genetics: consider two binary plant traits. Suppose two plants are to be crossed which are heterozygous for each of the two traits. Consider a plant which is the product of this crossing. What is the chance that this particular plant will be homozygous for both traits? The laws of Mendelian genetics dictate the answer of 0.25; if the fundamental laws of our world are deterministic, they either dictate the chance being equal to 1 or dictate it being equal to 0.Meteorology: suppose the atmosphere of our planet admits a description at the microphysical level which is fully deterministic. However, the description of future weather events meteorologists—and we—are interested in belongs to a higher-level language, in which predictions are formulated which typically follow from statistical laws. A proposition concerning such an event, say, that at least one drop of rain falls tomorrow in Munich, is assigned an objective chance of 0 or 1 by the microphysical laws and a non-trivial objective chance by the statistical meteorological laws.A somewhat natural reaction to some of these examples may be to say that it would be beneficial to apply the crucial distinction between a concrete physical system in a particular microstate s and a type of systems classified as being in a macrostate S which can be realised by a multitude of microstates, including s. One could attempt to claim that the two chance functions corresponding to the two levels of descriptions have distinct domains: propositions about individual systems and propositions about system types. I would like to stress here that this would be a mistaken route: in the examples given we are talking about two different chances for the same proposition. Consider a proposition p regarding a future possible observable phenomenon, a trait a particular system can possess, described in a macro-level language. Then, it is perfectly possible that, for distinct values of x and y, that same physical system is at the same moment both (1) in a microstate governed by low-level laws which dictate a chance x of temporal evolution of that system which makes p true, and (2) in a macro state governed by higher-level laws which dictate a chance y of temporal evolution of that system which makes p true. That is, there are two distinct chances that p. If this is true for a system and some proposition p, I propose we say that the system exhibits chance plurality. We can sum this up in an informal definition, availing ourselves of the notions of 1) a physical system, 2) a proposition which is about a given physical system, and 3) level-relative chances:Chance plurality. A physical system exhibits chance plurality if and only if there is a proposition p about it and distinct level-relative chance functions In such cases it is meaningless to speak of the objective chance that p. Just like in the case of the reference class problem discussed above, fixing of an additional parameter is needed before ’the probability that p’ is defined. In the original problem the parameter was, perhaps obviously, the reference class. Here the parameter is the level of description . In science the issue is not likely to be of pragmatic relevance since the scientists working in the particular field will be interested in the higher-level laws, the low-level laws not being practically applicable: the geneticist will use the statistical laws of Mendelian genetics, the synoptic analyst will use the statistical laws of meteorology, and so on. Still, the issue is there: in situations of chance plurality, the question ’what is the objective chance that p?’ does not have an answer.Another of the principles Schaffer took to be constitutive of the role of chance took it to be codified by natural laws. Most of the examples familiar from the literature of objective chance which feature different chances at different levels of description either originally explicitly feature laws or can be, I think, naturally rephrased so that laws are mentioned. As illustrations of multiple level-relative chances consider the following examples  an argument that on both levels the six principles proposed by Schaffer are satisfied, which is bound to be a nontrivial task. I would not like for such examples to play the biggest role in my argument against the OC, since I would risk that even those otherwise sympathetic to the chance plurality idea would find them wanting. Still, not to give an impression that chance plurality as posing difficulties for the OC requires fundamental determinism,The Reader will have noticed that all examples of chance-plurality mentioned so far involved fundamental determinism; this is also the case with the example about John.not predetermined on it, but subscribe to some chancy laws. Suppose that, on some day, in view of the recent crime-rate increase in the railway station area the officer in charge of patrol assignment can choose to allocate more officers to that region—or to send additional officers to a hitherto peaceful residential block. Suppose the neighbourhood-level objective chance List and Pivato write about indeed assigns a higher chance of crime-related incidents to the railway station area. On the other hand, the particular configuration of the city’s residents’ locations and their conditions combined with their chancy laws of individual crime-related behavior leads, on that particular day, the lower-level chance of criminal incidents to be higher in the residential block in question. It is easy to see how this leads to a case similar to the one above, involving John, the gambler.The first case starts with the following example from List and Pivato , p. 141:The second idea follows a suggestion of one Reviewer who in the context of the plurality of chances mentioned currency exchange rates. My example will involve covered interest arbitrage Levinson , p. 25. due to the Market Forces in operation  the macro-chance of the British bonds ending up as the most profitable option in a week is higher than the chance that one of the two other options ends up as the most profitable;however, due to the particular configuration of individual buyers and sellers, it is the micro-chance of the French bonds ending up as the most profitable which is the highest among the three options.It is hopefully easy to see how one can on that basis construct an example similar to the one from the last section.The financial situation on the day Steven is supposed to make his announcement is as follows: the interest rates in the three countries together with the spot and future exchange rates dictate that investing in American bonds is clearly the least profitable option, while British bonds are slightly preferable profit-wise to the French ones. However, since people will be selling dollars for pounds and Euros, the spot dollar/pound and dollar/Euro rates will decrease, while the 1-year forward rate rate will increase. We can consider the micro-level of description of the financial market, involving individual buyers and sellers, and the macro-level, involving larger groups and bodies, on which the Market Forces operate. On the assumption that both of these levels involve chances, we can consider the situation in which:As already mentioned, I would not like these examples to be the main illustration of my argument against the OC. My objective in this paper is not to push forward the research on chance plurality; establishing whether the two examples from this subsection really ‘work’ would require e.g. a careful examination of whether we can legitimately speak about probabilistic laws in the context of economics and neuropsychological basis of human behavior—tasks which are clearly outside the scope of the current paper. I suggest, therefore, that the Reader keep in his or her mind the example of John the gambler as the main illustration of my point.No answer. We could decide that the question whether an agent ought to perform that act or not has no answer at all.Dideontism’.‘determinately true that the agent should perform It needs to be noticed that in all situations in which the CF is usually invoked, if an act does not maximise it, another act does. And so dideontism will make the above claim about at least two acts: that is, for two acts Williams .One privileged level. We could decide that from the levels of description to which the objective chance functions are assigned one is singled out as the one which determines the normative issues. Still, it is conceivable a priori that different levels could be normatively relevant in different situations: sometimes the microphysical one, and sometimes a higher one. Therefore, the options are: 3.1.(micro) In any situation featuring chance plurality, OC should employ the lower-level chance.3.2.(macro) In any situation featuring chance plurality, OC should employ the higher-level chance.3.3.(mixed) Which of the chance levels should be used by the OC depends on the details of the given situation.Option 1 seems wrong, since it is at least a priori natural to suppose that it will usually be possible to provide, for a given system, two levels of description giving rise to differing chance functions, making the situation in which an agent ought to act in a specific way too rare a phenomenon. Among many obvious disadvantages of option 2, apart from seemingly bringing us closer to the outlandish proposal from the current paper’s motto, one in particular comes to mind: already before indeterminacy is invoked, we seem to face an outright contradiction with ’Ought implies Can’. This is because for at least two conflicting acts A and B it is true that the agent should perform A and it is true that the agent should perform B, but it is impossible to perform both of these acts. If we claim, in response to this, that for any act it is not determinately true that the agent should perform it, and if we transfer this indeterminacy to the level of obligation, we can say that in the cases featuring chance plurality the agent does not have a determinate obligation to perform any of the given acts. This, however, does not alleviate the previous issue: while we avoid the contradiction with ’Determinately Ought implies Can’ (since there is nothing the agent determinately ought to do in such cases), the contradiction mentioned previously remains. This leaves us with option 3. As already mentioned, I believe it gives those who adhere to OC a way of dealing with the problem; still, perhaps a slight deviation from purity of its consequentialist aspect is required to hold that what I propose is indeed a solution.To repeat, we are considering situations in which the CF employed by the objective consequentialism awards some act two different values depending on which objective chance function is used. The issue is especially pressing if the act maximises the CF according to one of the functions  but does not according to the other . Assume there are only two relevant levels to be discussed. We seem to have three families of choices: Note first that neither option 3.1 nor 3.2 should be argued for using the Principal Principle (PP), even if we accept that by resorting to it we are, as just pointed out, abandoning the consequentialist purity of the position under discussion. We have already mentioned that according to one of Schaffer’s chance-related principles, chances guide rational credences. Writers are divided concerning various details concerning the PP , if there are two possible chances for X: .4 and .3, and if that agent’s credences in that each of these is the actual chance of X are respectively X. Namely, by the law of total probability, X is coordinated with that agent’s credences in what the chances of X are. PP may do its work even if the information about chance is fundamentally unobtainable, and can never be learned by anyone: it requires that, say, For example, if mentclasspt{minimaX conditional on what the chance of X is. Many formulations also include other, ‘admissible’X is specified. Usually the formulation one ends up with uses formulas of the sort ‘E is some admissible proposition. Now, for some arbitrarily chosen values of the micro-level chance function E’s) It might seem that we could contemplate the move which would have us employ in the CF that chance function which is used in the PP. This, however, will not help the cause of the OC, because, due to chance plurality, there is no single function doing the job. Most formulations of the PP will inform us about conditional credences of rational agents: credences in a proposition I do not see an argument for 3.1 or 3.3 which would be worth mentioning. However, in my opinion there is a route to option 3.2 which is available to the objective consequentialist—however, it will require abandoning the consequentialist purity of the position, that is, it will require one to care about more than just maximizing a value function. The route involves the notion of blame. Let me say at the outset that it will probably be of little interest to those who subscribe to ’quality of the will’ accounts of blame , and the other, which hangs on the behavior of a system whose not only macro- but also micro-physical state is fixed—the agent’s choice is not compatible with many physical possibilities corresponding to various possible states of the dice-rolling tube, but requires the tube to be used in the state in which it had been set up.It seems to me, then, that there are two general, hand-wavy approaches one can take. The first and preferable one would be to simply say that in general blame-talk is cause-talk, and since causation involves higher-level propositions, the chance level to be used in the CF should be the higher one.The second avenue can be opened by pointing to the fact that knowledge about the micro-level chances relevant to the given situation is typically unobtainable, while in principle it should be possible to attain information about the macro-level ones.The first approach seems to me, then, to be the more promising of the two. At this moment it seems to me that no other solutions present themselves, and even those considered here require the proponent of OC to abandon the consequentialist purity of that position, by bringing blame into the equation. If one is unhappy with both proposals, then I suggest that in view of recent developments in philosophy of science objective consequentialism should be abandoned.In this paper I identified a problem for objective consequentialism generated by chance plurality—on some occasions there is more than one chance function which could be employed in the consequentialist formula used to calculate the expected moral utility. I have suggested that if we take into account how the notion of blame is used we can reach the conclusion that in such cases it is the the higher level chance that should be called upon—this, however, is not an option available to a pure consequentialist. The general validity of this approach remains to be seen.


Investigate and analyze the current operation status of the community-based rehabilitation station in a district of Chongqing to provide some reference schemes for improving the construction of the community-based rehabilitation system for Chongqing.  Self-designed questionnaires were issued to 36 community-based rehabilitation stations in a district of Chongqing to investigate the human resources status, service projects, service methods, and other aspects of the community-based rehabilitation stations.  The community-based rehabilitation station lacks the participation of medical rehabilitation personnel, and only 33.3% of the community-based rehabilitation stations are composed of multidisciplinary human resources of medical and community staff. Community-based rehabilitation services focus on supply education and publicity (86.11%), and rehabilitation treatment services are not fully involved in the community-based rehabilitation service (44.44%). The methods of community-based rehabilitation services are mainly posters and other publicity activities (94.44%), and the community-based rehabilitation service methods are not highly goal-oriented.  The survey found some problems to be improved in the construction and operation of grass-roots community-based rehabilitation stations in Chongqing. Community-based rehabilitation stations should enrich the human resources and technology of medical rehabilitation, become an extension of the restoration of community health institutions, and promote the high-quality development of community-based rehabilitation. As an important platform for the rehabilitating of the disabled in China, the community-based rehabilitation station is the extension of the restoration of medical and health institutions outside the hospital. It plays an essential role in community-based rehabilitation with its nearby and local advantages. Since 2004, Chongqing Disabled Persons' Federation has built thousands of community-based rehabilitation stations and introduced relevant measures and policies to ensure the operation of community-based rehabilitation stations. However, in the further work of the Chongqing Disabled Persons' Federation, there is still a lack of the actual process of the data of the community-based rehabilitation station. The purpose of this study is to investigate the progress of community-based rehabilitation stations for the disabled in a district of Chongqing, discuss the construction and service of community-based rehabilitation stations, and provide a basis for the improvement and improvement of community-based rehabilitation services in Chongqing.In December 2020, the institutional establishment, operation, and business development of 36 community-based rehabilitation stations in Chongqing were investigated.A self-designed community-based rehabilitation station operation questionnaire and face-to-face survey method were adopted. Fill in and report by the person in charge of each community-based rehabilitation station in a district of Chongqing.First, the questionnaire and the instructions for filling the form were carefully formulated. Second, concentrate on training the investigators and explain the questionnaire in detail to reach the consensus on the key issues that need to be paid attention to in the survey. Investigators shall be appointed after passing the simulation survey and test. Third, carry out investigation, on-site guidance, spot check, and verify data.36 questionnaires were sent out, and 36 were effectively received with an effective recovery rate of 100%. All the questionnaires fill in independently and recover on the spot after the questionnaire is completed.Excel software was used to input and handle the data, and two investigators were in charge of inputting and proofreading data. Frequency and percentage were mainly used to describe the data.There are 11 (30.56%) community-based rehabilitation stations that have been operating for over ten years, 1 (2.78%) community-based rehabilitation station that has been working for five years (inclusive) to 9 years, 1 (2.78%) community-based rehabilitation station that has been working for four years, 5 (13.89%) community-based rehabilitation stations that have been working for three years, 15 (41.67%) community-based rehabilitation stations that have been working for two years, and 3 (8.33%) other that have been working for one year. Overall, a large proportion of the community-based rehabilitation stations in a district of Chongqing have been working for three years or less (63.89%), and their operating time is relatively short .Among the human resources composition structures of the community-based rehabilitation stations, 5 (13.89%) were composed solely of medical staff. 12 (33.33%) community-based rehabilitation stations were composed of medical and community staff, and 19 (52.78%) others were composed solely of community staff. Professional medical and health human resources are less involved in community-based rehabilitation stations .Among the service items of community-based rehabilitation stations, education and publicity services (86.11%) were the most, followed by auxiliary equipment fitting (69.44%), rehabilitation treatment (44.44%), referral (38.89%), public social affairs (25.00%), and vocational rehabilitation services not carried out. Rehabilitation treatment and referral services accounted for relatively few. High-level and targeted rehabilitation services in community-based rehabilitation stations are rather inadequate .Among the service modes of community-based rehabilitation stations, the focus was on posters (94.44%) and collective activities (61.11%), followed by in-station face-to-face service (50.00%) and door-to-door service (41.67%), while online interactive rehabilitation services were not carried out .Among the factors restricting the operation of community-based rehabilitation stations, small site area (41.67%) is considered the main factor limiting the procedure, in turn, understaffed (25.00%), others (22.22%), insufficient funding (19.44%), poor awareness of disabled rehabilitation (13.89%), lack of equipment (11.11%), lack of relevant knowledge or skills (8.33%), and lack of assessment mechanism (5.56%) .Rehabilitation is the most immediate, urgent, and realistic need of the disabled, patients with chronic diseases, and the elderly. It plays a vital role in dealing with the aging of the population and ensuring the health of the whole people. To achieve the sustainable development goal in 2030, rehabilitation services need to be strengthened to expand rehabilitation as a health strategy related to all humankinds in the whole life cycle and national health cover and meet the growing demand for rehabilitation .Rehabilitation services run throughout the process of healthcare services, and efforts should be made to improve its quality, accessibility, and affordability . CommuniTo meet to address the growing demand for rehabilitation, the plan for a Healthy China 2030 proposes that it is necessary to improve the medical and health service system and promote the extension of medical and health services to communities and families. The World Health Organization (WHO) also pointed out that rehabilitation should be included in the health service system, and hospitals and districts should provide rehabilitation services and reasonably allocate health service resources .Feng bo Liu proposed that different categories of disabled people are different in the rehabilitation needs, and the particularity of the needs of the different types disabled should be considered when providing rehabilitation services . The rehCommunity-based rehabilitation station is the central position and window of the disabled community-based rehabilitation and window. According to this survey, the community-based rehabilitation station has certain hardware facilities (such as site and rehabilitation equipment) and has achieved inevitable development, but there are some problems.According to this survey, the construction of the community-based rehabilitation station has been equipped with particular hardware facilities (such as site and rehabilitation equipment) and achieved certain development, but there are some problems. First, the structure of human rehabilitation resources is unreasonable. The operation of the community-based rehabilitation station mainly depends on the community staff, and the intervention of medical rehabilitation services is insufficient. Second, the supply of rehabilitation services focuses on posting posters and other areas of education or publicity activities. Finally, without the support of rehabilitation professionals and technical personnel, rehabilitation services are not strongly targeted. It is challenging to ensure high-quality community-based rehabilitation services, the stability of the work, and the sustainability of the service. Nonprofessional rehabilitation services cannot effectively solve the rehabilitation problem of the disabled.In the document on accelerating the development of the work of rehabilitation medicine, it is proposed to actively develop community-based and home-based rehabilitation medical care and support grass-roots medical institutions to enrich and innovate rehabilitation medical service models. Community-based rehabilitation stations, which are an essential carrier of rehabilitation into communities and services to families, should be integrated with grass-roots health institutions and become the “rehabilitation outpatient service” of grass-roots health institutions or the extension of medical services. Although the technical level of healthcare workers in grass-roots community health service centers (station) and rural towns generally remains to be improved, grass-roots medical staff have apparent advantages in ensuring residents' elderly care and rehabilitation. Through technical training and service model innovation, they can become the backbone of the combination of medical care and long-term care services, which is not only possible but also necessary .The development goal of community health service in China is the family doctor system . The eldTo comprehensively promote the construction of healthy China and actively respond to the aging population and other national strategies, the construction of community-based rehabilitation urgently needs health management department to include community-based rehabilitation medical facilities and talents such as community-based rehabilitation stations into the construction planning of the medical and health service system, improve the functions of primary health service institutions integrating prevention, medical treatment, rehabilitation and healthcare, integrate existing resources, and enhance the rehabilitation capacity of community health institutions based on community-based rehabilitation stations.Community-based rehabilitation stations are the main position and link for the elderly, chronic disease patients, the disabled, and other vulnerable groups to obtain community-based rehabilitation services. At present, the human resources and technology of medical rehabilitation of community-based rehabilitation stations should be enriched, so that the community-based rehabilitation stations can become the carrier of grass-roots health institutions to the community and families and open up the last “kilometer” of community-based rehabilitation, so as to achieve the accessible and high-quality development of community-based rehabilitation services.


The aim of this study was to translate and cross-culturally adapt the Rehabilitation Complexity Scale-Extended version 13 (RCS-E v13) to develop the Korean version of the Rehabilitation Complexity Scale (KRCS), and to explore its reliability, and concurrent and construct validity.This research was an observational study of a series of consecutive rehabilitation inpatients who were previously assessed with KRCS and grouped with the Korean rehabilitation patient group version 1.1 (KRPG v1.1). Translation and cross-cultural adaptation of the RCS-E v13 were implemented according to internationally recognized standards. Four hundred thirty inpatients diagnosed with complex neurological or musculoskeletal disabilities were enrolled. Physiatrists were asked to finish the KRCS at admission and to complete a second time with an interval of a minimum of 3 weeks to a maximum of 4 weeks for reliability evaluation. At discharge, the KRCS was completed a third time to explore constructive validity.P < .01). The scale was repeatable (Spearman rho 0.69–0.86) and correlated strongly with disability measures (Spearman rho 0.37–0.50). Exploratory factor analysis revealed 2 clear factors . The goodness-of-fit index in the confirmatory factor analysis was 0.87. The KRCS was associated with a higher explanatory power for rehabilitation resources and length of stay than the KRPG v1.1.The Cronbach-α was 0.63. The intraclass correlation coefficient values of the total score, Medical, Nursing, Care, Therapy Disciplines, Therapy Intensity, and Especial Needs domains were 0.86, 0.69, 0.84, 0.83, 0.74, 0.74, and 0.79, respectively (Our data suggest that the KRCS is a feasible, reliable, and valid tool that is appropriate for the measurement of clinical complexity in Korean intensive rehabilitation units. Further, it may provide case-mix adjustment to improve the rehabilitation delivery system in Korea. The rehabilitation institution makes a voluntary decision on the length of hospitalization and the number of rehabilitation services. Thus, a rehabilitation medical institution system was recently established in Korea to guarantee hospitalization period and rehabilitation services for subacute patients who need intensive rehabilitation services according to the timing and circumstances of the onset of a condition.In Korea, a 3-stage rehabilitation care delivery system is being considered. Acute rehabilitation is provided at general and tertiary hospitals, subacute rehabilitation is provided at inpatient rehabilitation institutions, and chronic rehabilitation is provided by outpatient or long-term rehabilitation services. However, there is no criteria or regulation for inpatient rehabilitation across the delivery system.The Korean rehabilitation patient group version 1.1 (KRPG v1.1) is currently utilized to reflect the characteristics of rehabilitation inpatients as the case-mix and payment tool. The etiologic disease, functional status , and the patient's age are the variables in the patients with brain or spinal cord injury. Patients with musculoskeletal problems or amputation are classified only by age.Previous study elucidated that the first version of the Korean rehabilitation patient group explained just 11.8% of the variance in charge for rehabilitation inpatients. In the most recent study, KRPG v1.1 explained 8.6% of the variance in charge for rehabilitation inpatients with acquired brain injury. Lack of accuracy and comprehensiveness of the KRPG v1.1 as the case-mix and payment tool for rehabilitation inpatients have been problematic issues.,9 The RCS-Extended version 13 (RCS-E v13) is currently utilized to measure the rehabilitation needs of patients in the UK Rehabilitation Outcome Collaborative Database. Recent studies demonstrated positive cross-cultural validation of the Danish and the Italian RCS-E v13.–13The Rehabilitation Complexity Scale (RCS) was introduced in 2007 to evaluate the complexity of rehabilitation needs. The RCS incorporates patient's real rehabilitation needs and it is practical and feasible for implementation in clinical practice.To establish a rehabilitation medical delivery system under the Korean circumstances, the current KRPG v1.1 alone is insufficient to address the complex rehabilitation needs because it solely depends on diagnostic, age-related, and disability measures. Therefore, it is necessary to complement the KRPG v1.1 and develop a more accurate, comprehensive, and feasible evaluation system based on the complexity of the needs as well as diagnostic and disability measures.The aim of this study was to translate and cross-culturally adapt the RCS-E v13 to generate the Korean version of the RCS (KRCS), to explore its reliability, and concurrent and construct validity, and to demonstrate its complementary value of KRCS by comparing KRPG v1.1 with the KRCS and the KRPG combined in identifying the rehabilitation needs and resources for patients hospitalized in rehabilitation institutions.22.1This research is a retrospective observational study and included data from a total of 430 inpatients  with neurological injury occurring within 3 months of onset or surgery, hip replacement after femur or hip fracture within 1 month of onset or surgery, or lower extremity amputation performed within 2 months of onset or surgery who admitted to 6 rehabilitation medical institutions and agreed on the subacute intensive rehabilitation program from January to August 2018. A sub-sample of 199 patients was also collected at discharge for the confirmatory factor analysis (CFA). A 24-hour medical care is provided in the rehabilitation medical institution for patients who cannot be treated as outpatients.2.2The KRPG v1.1 consists of different variables according to the disease group. The variables in the acquired brain injury group include age, Korean Version of Mini-Mental Status Examination, the Korean version of the Modified Barthel Index, Manual Muscle Testing, and Modified Ashworth Scale. Variables of spinal cord injury group include age, Manual Muscle Testing, Spinal Cord Independence Measure, the combination of the neurological level of injury and American Spinal Injury Association Impairment Scale, and Modified Ashworth Scale. Variables in the musculoskeletal injury group include age, the Korean version of the Modified Barthel Index, and Manual Muscle Testing.2.3,15 A medical doctor fluent in English and an interpreter who had lived in an English-speaking country independently translated the RCS-E v13 into the Korean language. After the reconciliation of these 2 forward translations into a single forward translation, 2 distinct interpreters whose first language is English and who are neither aware nor informed of the scale translated the last forward translation back into the original language (English). The final consensus exercise was done according to the medical conditions in Korea by adapting the modified Delphi survey method to achieve a consensus with 16 experts in rehabilitation.With the permission of the developer of RCS-E v13, translation and cross-cultural adaptation of the RCS-E v13 were implemented according to internationally accepted and recommended guidelines to develop the KRCS.2.4Two Delphi surveys were conducted through email from March to April 2018 to confirm the content validity of the initial KRCS. The panel of 16 experts in this research consisted of executives of the Korean Academy of Rehabilitation Medicine, the Korean Medical Association, and the Korean Physiatrists Association Korean Academy of Rehabilitation Medicine and physiatrists who provide rehabilitation services at the general and tertiary hospitals and inpatient rehabilitation institutions who are able to present professional opinions regarding the rehabilitation patient grouping system and the rehabilitation medical delivery system, and executives of the Korean Academic Society of Rehabilitation Nursing who were also experts with a position above a nursing director at the general and tertiary hospitals, or a position above that of academic staff at a nursing college.The first Delphi survey was based on the initial KRCS items to address appropriateness in terms of cross-cultural adaptation. Each domain and item was evaluated by a 4-point Likert scale . “Appropriateness” referred to the level of significance of the items in measuring the complexity of needs and suggesting a direction of the rehabilitation services.The second Delphi survey was conducted based on the results of the first Delphi survey to inform the panel of the indicators adopted, revised/supplemented, and deleted for their reference in reevaluation. The participants were asked to describe freely their opinions on each item. As with the first Delphi survey, the “appropriateness” of each item was evaluated on a 4-point Likert scale.–18 Those with 0.5 to less than 0.8 were discussed (mediated differences of opinions), and those with less than 0.5 were dropped. The final version was established after implementing all the necessary adjustments.The Content Validity Index (CVI) was calculated for each survey stage to verify the content validity of each item. A CVI value of 0.8 or greater was considered appropriate.2.5Internal consistency of the KRCS was examined using Cronbach alpha with 95% confidence intervals. Values of 0.6–0.7 were considered acceptable and value ≥0.7 were regarded as satisfactory.Reproducibility of test–retest repeatability was evaluated for individual items and total scores using the intra-class correlation coefficient (ICC). The interval between the test and the retest was limited from a minimum of 3 weeks to a maximum of 4 weeks to preclude the possibility of carry-over effects between the tests.2.6Spearman rho correlations were used to test criterion validity between the KRCS and other standards .2.7Construct validity was assessed using both exploratory and CFA. First, the Kaiser–Mayer–Olkin (KMO) measure and Bartlett test of sphericity were assessed to confirm the validity of factor analysis. The inter-factor correlation was studied. CFA was conducted using the data collected from 199 patients at discharge, where scores were distinct from data used for exploratory factor analysis, to use a cross-validation design.Exploratory factor analyses involving principal component analysis with orthogonal (Varimax) rotation were conducted to evaluate the dimensionality of the scale.2.8We investigated the coefficient of determination or the reduction of variance or R-squared of the KRCS with respect to the total cost, rehabilitation cost, medical cost, and length of stay and compared it with the KRPG version 1.1. R-squared explains how much variance of the data is “explained” by the model. “To explain” means to reduce the residual variance. Thus, the coefficient of determination is the ratio of explained variance to the total variance that tells about the strength of association between the variables.yi: medical expenses for the ith patientA: Overall average value of medical expensesAg: Average value of medical expenses in the g group2.9This study was approved by the Institutional Review Board of National Traffic Injury Rehabilitation Hospital (No. NTRH-18003). It was conducted in accordance with the Declaration of Helsinki.2.10P < .05 was used. The analysis was performed using SAS version 9.4  and R software , using traditional methods within the outline recommended by the COSMIN taxonomy.For all tests, a level of significance of 33.1In Korea, all of the services within the scope of hospitalization and rehabilitation are based on the doctor's prescription, hence, costs of medical care and rehabilitation services are subject to the doctor's prescription. Consequently, the prescription for patient assessment, medical care, and rehabilitation services is entirely a doctor's action. For example, in Korea, evaluation of the medical, nursing, and therapy needs are done by physiatrists whereas each need in original RCS-E v13 are evaluated by each discipline . Therefore, a cross-cultural adaptation of RCS-E v13 was needed to be carried out.The KRCS is a 26-point measure comprising 5 domains: Medical (0–5 points); Nursing (0–5 points); Care (0–4 points); Therapy (including the Therapy Disciplines and the Therapy Intensity. Therapy Disciplines + Therapy Intensity: 0–9 points); and Especial Needs (0–3 points), whereas the RCS-E v13 includes 5 domains: Care or Risk (0–4 points), Nursing (0–4 points), Therapy (0–8 points), Medical (0–4 points), and Equipment Needs (0–2points) and the total score is set at a maximum of 22 points. The higher the score, the more complex the needs are. Since the risk domain of RCS-E v13 concerns intellectual or behavioral disability, this domain was uninvolved in the KRCS according to the conditions and inpatient composition of the rehabilitation medical institutions in Korea.“Medical” refers to the medical needs of rehabilitation patients and consists of 6 items. It mainly represents the degree of medical care needed by the patients. It may distinguish patients who need medical care at tertiary hospitals, general hospitals , rehabilitation medical institutions, or outpatient clinics. “Nursing” denotes nursing needs including 6 items. In case of no need for skilled nursing, it is classified as Nursing 0, whereas the need for qualified nursing during hospitalization is indicated as Nursing 1–3, and the need for highly special nursing as Nursing 4 and Nursing 5. “Care” corresponds to “delegable nursing or caring needs.” In Korea, classifying the needs for care depending on the amount of time or number of caregivers may cause conceptual misunderstanding between care and compensation. Therefore, the “Care” domain in the KRCS refers to the requisite level of partial or continuous care. “Therapy” denotes rehabilitation therapy needs and is most similar to the RCS-E v13 in the United Kingdom. Items in “Therapy Disciplines” were modified to reflect the rehabilitation therapy in Korea. In terms of “Therapy Intensity,” 4 and 5 correspond to intensive rehabilitation during acute and subacute phases, whereas 0, 1, 2, and 3 correspond to rehabilitation in the chronic phase. “Especial Needs” refers to “other professional rehabilitation medical needs.” It is the most modified content in the RCS-E v13 because it reflects the clinical scenario and delivery system of rehabilitation medicine in Korea. It refers to the need for professional elements of rehabilitative medicine, which may be provided at a limited number of rehabilitation institutions or tertiary hospitals. No need for professional rehabilitation is classified as 0, the need for the referral at the regional level for specialized examination or therapy is classified as 1, and the referral need across the regional level is classified as 2.3.2Participant characteristics are presented in Table Total scores on the KRCS ranged from 0 to 26. The median values for the total score, Medical, Nursing, Care, Therapy Disciplines, Therapy Intensity, and Especial Needs domains were 16, 2, 2, 3, 3, 5, and 1, respectively.3.3The CVI values of items in the KRCS were 0.86–1.0 and S-CVI/Ave was 0.93, respectively. Therefore, none of the items was excluded during psychometric evaluation.3.4P < .01).The Cronbach alpha of the KRCS was 0.63 and there was no single item that if deleted would improve the overall Cronbach alpha value in the scale. The test–retest reliability was examined using the ICC. The ICC values of the total score, Medical, Nursing, Care, Therapy Disciplines, Therapy Intensity, and Especial Needs domains were 0.86, 0.69, 0.84, 0.83, 0.74, 0.74, and 0.79 (3.5ρ = 0.37–0.50) while Therapy Disciplines, Therapy Intensity, and Especial Needs domains showed a weak correlation.The results of the validity and relationship of the KRCS with the other measures are presented in Table 3.6P < .001).Before the exploratory factor analyses, KMO test and Bartlett test of sphericity were conducted to evaluate the factorability. The KMO value was 0.64, and the value of Bartlett test of sphericity was 340.96, with statistical significance  can easily understand and utilize the tool. Thirdly, this study was conducted at only a single level of the delivery system of rehabilitation medicine in Korea, that is, the intensive rehabilitation hospitals in the subacute phase. Larger and longitudinal studies are necessary for the precise evaluation of reliability and validity. Moreover, measurement of patients’ rehabilitation needs using the KRCS in the whole spectrum of rehabilitation medical service delivery system is required to investigate the gaps between needs and services and to establish the appropriate service delivery model in Korea.Some limitations of the present study need to be taken into account during the interpretation of results. First, the initial scores of patients who were already hospitalized at the start of the study might not be completely consistent with their actual rehabilitation needs at admission. Second, the sample size was not inadequate since KMO was 0.64, but a larger sample size might strengthen data integrity.Taken together, we conclude that the KRCS is a feasible, reliable, and valid tool that is appropriate for the measurement of clinical complexity in Korean intensive rehabilitation units. Further, it provides a measure based on case-mix adjustment to determine the rehabilitation setting and resources allocated to an individual patient within the rehabilitation process as a gatekeeping tool in the rehabilitation delivery system of Korea.This study was supported by the R&D grant (No. 5-2018-A0024-00001) for rehabilitation by Korea National Rehabilitation Center Research Institute, Ministry of Health & Welfare. Special thanks are due to Professor Lynne Turner-Stokes, the author of the scale, who provided the RCS-E v13, as used today in the United Kingdom, and assisted us with valuable comments on the development of the KRCS. Further thanks are due to Hyung-Ik Shin, Seong Hoon Lim, Jeehyun Yoo, Sun Im, Myung Eun Chung, Soon Yong Kwon, Hyun-Mi Oh, and Jihye Park who provided expert opinion on the development of the KRCS and further utilization of the scale for the establishment of rehabilitation medicine delivery system of South Korea. Moreover, the Medical Research Collaborating Center, Seoul National University Hospital, Seoul University College of Medicine, Seoul, South Korea provided statistical assistance.Conceptualization: Hoo Young Lee, Tae-Woo Kim.Data curation: Hoo Young Lee.Formal analysis: Hoo Young Lee.Funding acquisition: Tae-Woo Kim.Investigation: Hoo Young Lee, Jung Hyun Park.Methodology: Hoo Young Lee, Jung Hyun Park, Tae-Woo Kim.Project administration: Tae-Woo Kim.Resources: Hoo Young Lee.Software: Hoo Young Lee.Supervision: Jung Hyun Park, Tae-Woo Kim.Validation: Hoo Young Lee, Tae-Woo Kim.Visualization: Hoo Young Lee.Writing – original draft: Hoo Young Lee, Jung Hyun Park.Writing – review & editing: Hoo Young Lee, Tae-Woo Kim.


H. pylori, and the cytotoxic activity against human gastric adenocarcinoma (AGS) cells of a new series of ether compounds based on the structure of thymol. Structural analysis comprehended elemental analysis and 1H/13C/19F NMR spectra. The analysis of structure–activity relationships within this molecular library of 38 structurally-related compounds reported that some chemical modifications of the OH group of thymol led to broad-spectrum growth inhibition on all isolates. Preferred substitutions were benzyl groups compared to alkyl chains, and the specific presence of functional groups at para position of the benzyl moiety such as 4-CN and 4-Ph endowed the most anti-H. pylori activity toward all the strains with minimum inhibitory concentration (MIC) values up to 4 µg/mL. Poly-substitution on the benzyl ring was not essential. Moreover, several compounds characterized by the lowest minimum inhibitory concentration/minimum bactericidal concentration (MIC/MBC) values against H. pylori were also tested in order to verify a cytotoxic effect against AGS cells with respect to 5-fluorouracil and carvacrol. Three derivatives can be considered as new lead compounds alternative to current therapy to manage H. pylori infection, preventing the occurrence of severe gastric diseases. The present work confirms the possibility to use natural compounds as templates for the medicinal semi-synthesis.Following a similar approach on carvacrol-based derivatives, we investigated the synthesis and the microbiological screening against eight strains of  H. pylori [H. pylori causes no symptoms [H. pylori aptitude to adapt itself to the host and to develop resistance towards the antimicrobials commonly used in therapy [H. pylori antibiotic resistance. In this context, novel compounds such as components of essential oils endowed with alternative mechanisms of action and the ability to disaggregate lipidic multilayer structures are strongly suggested [Helicobacter pylori [Helicobacter pylori activity and limited cytotoxicity on normal cell lines [Thymol, a major natural monoterpene phenol in the essential oils of Lamiaceae and Apiaceae families, has been approved by European Union and Food and Drug Administration as a safe food additive as well as in cosmetics and agriculture industry. Among the terpenes, it has been demonstrated to be clinically relevant as an antimicrobial, antioxidant, and anti-inflammatory agent . As well. pylori ,3, prefesymptoms . The sur therapy . The res therapy , which luggested . More inr pylori  and, recll lines .H. pylori is considered as a class I carcinogen by the World Health Organization and can secrete virulence factors, which not only affect host signalling pathways but can also induce a sustained gastric inflammatory process ultimately leading to the development of cancerous conditions in the stomach and duodenum [50 of 400 µM after 24 h of treatment [50 of 75.63 µM [In addition, duodenum . In the duodenum , ascribireatment , whereas75.63 µM . Despite75.63 µM .H. pylori-induced gastric cancer and provide a better resistance to the acidic gastric environment.Starting from these important premises, we aimed at modifying the structure of this well-known natural product in order to achieve a small library of novel dual-action ether compounds, which can address multifaceted pathological conditions such as 2–39, we employed the synthetic approach reported in 2–7 and 9–39 (1) was reacted with the proper bromide in dry N,N’-dimethylformamide (DMF), in the presence of anhydrous potassium carbonate (K2CO3) and under nitrogen (N2) atmosphere. These reactions were performed at room temperature (RT) in order to avoid the reagent degradation. For the synthesis of compound 8 (13 that underwent the hydrolysis of the ethyl ester group to afford the carboxylic acid moiety. The hydrolysis was performed in mild conditions using lithium hydroxide (LiOH) monohydrate, in a mixture of water and methanol  at room temperature.For the synthesis of compounds and 9–39 a have bempound 8 b we star1H, 13C, and 19F NMR), whereas the purity of these compounds was confirmed by combustion analysis, Thin Layer Chromatography (TLC) parameters and, for solid compounds, melting point.The choice of such substituent was driven by the observation of a greater inhibition of microbial growth after the introduction of bulkier alkyl/benzyl groups on the hydroxyl moiety. The obtained compounds were stable at room temperature. The structures were confirmed by spectral studies (1–39) were tested in vitro against H. pylori growth and the 12 most promising ones also against AGS cells to suggest dual-action agents useful for the treatment of H. pylori-related gastric cancer development.After the procedures of purification and characterization and the in silico analysis of drug-likeness, all the compounds . All the strains were classified according to their antimicrobial susceptibility to metronidazole, clarithromycin, and amoxicillin following the international EUCAST  breakpoints. Thymol, with respect to carvacrol, displayed a weaker inhibitory activity against all the strains used with MIC and MBC values ranging from 64–128 µg/mL. These results are in accordance with those reported in the literature [The phenolic terpene thymol and its 38 semi-synthetic derivatives were firstly assayed against eight strains of terature ,17,18.1) (MIC/MBC of 64 µg/mL), slightly better than the values reported for other clinical isolates [H. pylori activity. Other ether groups can be tolerated suggesting a specific mechanism of action with respect to the direct alteration of the bacterial membrane.Four clinical isolates, namely F1, F40/499, F4, and F34/497, were the most sensitive to the treatment with thymol (isolates . Similar2–14), the MIC results demonstrated no or weak efficacy against all the strains as well as their parent compound, despite the presence of branched alkyl chains, unsaturations or specific functional groups . Only three derivatives  with linear and increasing alkyl chains  presented improved MIC values with respect to thymol against some clinical isolates (MIC/MBC = 16 µg/mL). Similar results were obtained for the aliphatic derivatives of carvacrol in our previous paper [Among the first cluster of alkyloxy derivatives (us paper .15–39), the simplest and unsubstituted compound (15) was slightly more potent than thymol, but the introduction of electron-withdrawing or electron-donating substituents at different positions induced an opposite trend on the inhibitory activity. Substitutions at the ortho position of the benzyl group were usually detrimental  except for the potent activity of compound 34 (o-NO2) on specific strains . Methoxy (19), chloro (28), and nitro (35) at meta position did not alter the anti-Helicobacter pylori activity, whereas m-CF3 (21) dramatically reduced it and m-F (25) elicited it. As reported for carvacrol-based compounds, derivatives with para substitution were generally more potent , except for 33 and 36. Two derivatives (24 and 38), with 4-CN and 4-Ph respectively, were endowed with the most anti-H. pylori activity toward all the considered strains with MIC values up to 4 µg/mL. Poly-substitution on the benzyl ring was not important (18 and 23), albeit three compounds  slightly improved the antimicrobial activity with respect to thymol. Finally, the insertion on the OH group of thymol of a naphthalene ring (37) was detrimental, whereas the presence of a phthalimide nucleus (39) enhanced the activity. Collectively, these data suggested for all the derivatives a bactericidal mechanism of action, considering the MBC/MIC ratio to be between 1–2. This biological activity did not seem to be strictly correlated to the presence of a slightly acidic and polar phenolic OH.Among the second cluster of benzyloxy and heteroarylmethyloxy derivatives (Helicobacter pylori activity (1) showed discrete cytotoxic effects by reducing cell viability of AGS cells (IC50 = 200 ± 6.5 μM) in a dose-dependent manner, which is in accordance with literature data [50 = 300 ± 6.4 μM). Out of 11 thymol derivatives, only three  presented a dose-dependent inhibitory effect on cell viability inferior to thymol. All of them possessed an IC50 value higher than the reference drug 5-fluorouracil .To better assess the dual-action behaviour of these compounds, the selection of the candidates for biological assays was guided by the anti-activity . Thymol ure data . It disp15) or a linear alkyloxy chain (9) was preferred in eliciting the inhibitory activity below 100 μM. The substitution of the benzyl ring with NO2, F, and CN led to a reduction of the biological effect as well as the poly-substitution (26 and 30). The change of the benzyl group with a phthalimide (39) was detrimental. Interestingly, compound 38 with a 4-Ph on the benzyl ring exerted a comparable activity with respect to the parent compound.Collectively, the functionalization of the OH moiety with an unsubstituted benzyloxy group  for a broader analysis (SwissADME) of their chemical-physical characteristics and Medicinal Chemistry properties . Log P, calculated by Moriguchi-based computer program (MLOGP), is one of the parameters that can estimate the proper absorption or permeation of a drug candidate [38 has also a low gastro-intestinal absorption owing to its very high MLOGP value. These features, if focused on drugs acting after oral administration specifically on the H. pylori-colonized gastric mucosa, should not be considered negatively. Interestingly, as proposed by the SwissADME tool, these compounds do not display any kind of interaction with permeability glycoprotein (P-gp) that promotes the efflux of cytotoxic drugs out of the cells. This characteristic is suitable to enhance the efficacy of anti-proliferative agents, due to the involvement of this protein in the multi-drug resistance [9 and 15 are able to be easily absorbed by the GI and provide the possibility to cross the BBB. Finally, the information obtained from the bioavailability radar graphical output suggests the drug-likeness depiction of the selected compounds including the optimal range of each physical-chemical property  essential to provide oral bioavailability. Collectively, these computed data are of interest for the clinical development of compounds acting as antibacterial or anti-cancer.All designed inhibitors have been analyzed by means of theoretical tools regarding the possibility to act as interfering/covalent compounds in different in vitro assays. Indeed, the analysis of substructures to elicit promiscuous pharmacological behaviour, commonly named PAINS, should be mandatory in Medicinal Chemistry for a further and proper development of such compounds in the clinical settings. Our top-rated thymol derivatives were devoid of this property. Moreover, their drug-likeness was evaluated based on the Lipinski’s rule of five, largely met by all the derivatives (for compounds andidate . In factsistance . The oth® melting point apparatus SMP1 and are uncorrected (temperatures are reported in °C). Structural analysis consisted of elemental analysis and 1H/13C/19F NMR spectra. 1H and 13C-NMR spectra were recorded both at 300 MHz and 75 MHz , while other compounds were analysed at 400 MHz and 101 MHz on a Bruker spectrometer , using CDCl3 and DMSO-6d, as the solvents at room temperature. Conversely, 19F spectra were recorded on a Bruker AVANCE 600 spectrometer at 564.7 MHz, using CDCl3 as the solvent. All the compounds were studied at the final concentration of ~25 mg/mL. 1H and 13C chemical shifts are expressed as δ units (parts per millions) and referenced to the residual solvent signal , whereas 19F chemical shifts are expressed as δ units relative to an external standard . 1H spectra are described as follows: δH : chemical shift/ppm  in Hertz (Hz), number of protons, assignment). 13C spectra are described as follows: δC : chemical shift/ppm (assignment) and are fully proton decoupled. 19F spectra are described as follows: δF : chemical shift/ppm  in Hertz, number of fluorine, assignment) and are reported as All reactions were carried out under a positive pressure of nitrogen in washed and oven-dried glassware. All the solvents and high-purity reagents were directly used as supplied by Sigma-Aldrich  without further purification. Where mixtures of solvents are specified, the stated ratios are volume:volume. All melting points were measured on a Stuart1, 1.0 equiv.) in dry DMF (10 mL) was added freshly ground and anhydrous potassium carbonate  under N2 atmosphere. The suspension was stirred for 15 min at room temperature; then, the proper (un)substituted benzyl or alkyl bromide (1.5 equiv.) was added and the reaction stirred until disappearance of the starting reagents, as detected by TLC (24–72 h). Once the reaction was completed, the mixture was poured into ice-cold water (100 mL) and extracted with dichloromethane . The organics were collected, dried over sodium sulphate (Na2SO4), and evaporated in vacuo to afford the crude mixture that was purified through silica gel column chromatography, using proper mixtures of n-hexane/ethyl acetate as mobile phase.To a stirring solution of thymol  in 10 mL of methanol was added dropwise a solution of lithium hydroxide (1.2 equiv.) in 10 mL of water. The reaction was stirred at room temperature for 24 h; then, the mixture was concentrated in vacuo to remove methanol and quenched with 3N HCl (15 mL). The precipitate was collected by filtration and washed with n-hexane to give the title compound 8, without further purification requirements.To a stirring solution of ethyl 2-(2-isopropyl-5-methylphenoxy)acetate (2-ethoxy-1-isopropyl-4-methylbenzene (2): colourless oil, 75% yield. 1H-NMR : δ 1.26–1.28 , 1.46–1.50 , 2.38 , 3.31–3.41 , 4.06–4.11 , 6.72 , 6.79 , 7.15 . 13C-NMR : δ 15.0 (CH3), 15.9 (ArCH3), 24.1 (2 × CH3), 34.2 (CH), 63.5 (OCH2), 109.6 (Ar), 117.9 (Ar), 124.1 (Ar), 130.4 (Ar), 147.8 (Ar), 157.1 (Ar). Anal. Calcd for C12H18O: C, 80.85; H, 10.18. Found: C, 80.79; H, 10.13.1-isopropyl-4-methyl-2-propoxybenzene (3): colourless oil, 72% yield. 1H-NMR : δ 1.38–1.43 , 1.58 , 2.10–2.19 , 2.66 , 3.64–3.71 , 4.21–4.25 , 6.99 , 7.06 , 7.43 . 13C-NMR : δ 11.1 (CH3), 21.6 (ArCH3), 23.1 (CH2), 23.2 (2 × CH3), 27.0 (CH), 69.6 (OCH2), 112.3 (Ar), 121.2 (Ar), 126.1 (Ar), 134.3 (Ar), 136.4 (Ar), 156.5 (Ar). Anal. Calcd for C13H20O: C, 81.20; H, 10.48. Found: C, 81.20; H, 10.45.2--1-isopropyl-4-methylbenzene (4): colourless oil, 64% yield. 1H-NMR : δ 1.54 , 2.61 , 3.62–3.72 , 4.77–4.80 , 5.52–5.56 , 5.70–5.77 , 6.30–6.41 , 6.94 , 7.04 , 7.40 . 13C-NMR : δ 21.6 (ArCH3), 23.0 (2 × CH3), 26.9 (CH), 68.9 (OCH2), 112.8 (Ar), 116.8 (=CH2), 121.6 (Ar), 126.8 (Ar), 134.0 (=CH), 134.5 (Ar), 136.4 (Ar), 156.0 (Ar). Anal. Calcd for C13H18O: C, 82.06; H, 9.54. Found: C, 82.03; H, 9.55.1-isopropyl-4-methyl-2-(prop-2-yn-1-yloxy)benzene (5): colourless oil, 82% yield. 1H-NMR : δ 1.57–1.60 , 2.67 , 2.74 , 3.67–3.70 , 4.93–4.95 , 7.09 , 7.13 , 7.44–7.48 . 13C-NMR : δ 21.6 (ArCH3), 23.2 (2 × CH3), 26.8 (CH), 56.2 (OCH2), 75.5 (≡CH), 79.5 (C≡), 113.3 (Ar), 122.6 (Ar), 126.4 (Ar), 134.9 (Ar), 136.4 (Ar), 155.1 (Ar). Anal. Calcd for C13H16O: C, 82.94; H, 8.57. Found: C, 82.97; H, 8.60.2-(2-isopropyl-5-methylphenoxy)acetonitrile (6): white sticky solid, 72% yield. 1H-NMR : δ 1.23–1.25 , 2.38 , 3.28–3.30 , 4.77–4.78 , 6.75 , 6.91 , 7.19 . 13C-NMR : δ 21.3 (ArCH3), 22.9 (2 × CH3), 26.5 (CH), 53.9 (OCH2), 112.9 (Ar), 115.5 (CN), 123.8 (Ar), 126.7 (Ar), 135.0 (Ar), 136.8 (Ar), 153.8 (Ar). Anal. Calcd for C12H15NO: C, 76.16; H, 7.99; N, 7.40. Found: C, 76.20; H, 8.03; N, 7.37.1-(2-isopropyl-5-methylphenoxy)propan-2-one (7): amber-yellow oil, 90% yield. 1H-NMR : δ 1.30 , 2.35–2.36 , 3.29–3.43 , 4.54 , 6.55 , 6.84 , 7.18 . 13C-NMR : δ 21.3 (ArCH3), 22.8 (2 × CH3), 26.7 (CH3), 26.8 (CH), 73.2 (OCH2), 112.0 (Ar), 122.3 (Ar), 126.3 (Ar), 134.1 (Ar), 136.5 (Ar), 154.8(Ar), 206.6 (C=O). Anal. Calcd for C13H18O2: C, 75.69; H, 8.80. Found: C, 75.72; H, 8.77.2-(2-isopropyl-5-methylphenoxy)acetic acid(8): white solid, 87% yield, mp = 143–145 °C. 1H-NMR : δ 1.23 , 2.32 , 3.32–3.37 , 4.69 , 6.57 , 6.82 , 7.14 , 8.40 . 13C-NMR : δ 21.3 (ArCH3), 22.8 (2 × CH3), 26.6 (CH), 65.2 (OCH2), 112.4 (Ar), 122.7 (Ar), 126.4 (Ar), 134.5 (Ar), 136.5 (Ar), 154.5 (Ar), 174.9 (CO). Anal. Calcd for C12H16O3: C, 69.21; H, 7.74. Found: C, 69.27; H, 7.77.2-butoxy-1-isopropyl-4-methylbenzene (9): colourless oil, 75% yield. 1H-NMR  δ 1.27–1.32 , 1.53 , 1.77–1.90 , 2.04–2.13 , 2.62 , 3.59–3.68 , 4.21–4.25 , 6.96 , 7.02 , 7.39 . 13C-NMR : δ 14.1 (CH3), 19.8 (CH2), 21.6 (ArCH3), 23.0 (2 × CH3), 26.9 (CH), 31.9 (CH2), 67.6 (OCH2), 112.3 (Ar), 121.1 (Ar), 126.0 (Ar), 134.2 (Ar), 136.4 (Ar), 156.5 (Ar). Anal. Calcd for C14H22O: C, 81.50; H, 10.75. Found: C, 81.55; H, 10.83.2-(but-2-en-1-yloxy)-1-isopropyl-4-methylbenzene (10): pale yellow oil, 81% yield. 1H-NMR : δ 1.47 , 1.98–2.00 , 2.56 , 3.57–3.61 , 4.66–4.69 , 5.95–6.06 , 6.90 , 6.98 , 7.34 . 13C-NMR : δ 18.1 (CH3), 21.5 (ArCH3), 23.0 (2 × CH3), 26.8 (CH), 68.9 (OCH2), 112.9 (Ar), 121.4 (Ar), 126.1 (=CH), 127.0 (Ar), 129.1 (=CH), 134.5 (Ar), 136.3 (Ar), 156.1 (Ar). Mixture of E/Z isomers with ratio of 5.2/1. For sake of clarity, we have reported only the signals related to the major isomer. Anal. Calcd for C14H20O: C, 82.30; H, 9.87. Found: C, 82.33; H, 9.84.1-isopropyl-4-methyl-2-((3-methylbut-2-en-1-yl)oxy)benzene (11): pale yellow oil, 78% yield. 1H-NMR : δ 1.38 , 1.90–1.96 , 2.49 , 3.45–3.54 , 4.68 , 5.66–5.71 , 6.85 , 6.91 , 7.26 . 13C-NMR : δ 18.3 (CH3), 21.5 (ArCH3), 23.0 (2 × CH3), 25.9 (CH3), 26.6 (CH), 65.2 (OCH2), 112.8 (Ar), 120.7 (-CH=), 121.2 (Ar), 126.0 (Ar), 134.5 (Ar), 136.2 (Ar), 137.0 (=C), 156.1 (Ar). Anal. Calcd for C15H22O: C, 82.52; H, 10.16. Found: C, 82.56; H, 10.12.1-isopropyl-4-methyl-2-(pentyloxy)benzene (12): colourless oil, 88% yield. 1H-NMR : δ 1.30 , 1.58 , 1.71–1.85 , 2.09–2.19 , 2.66 , 3.63–3.72 , 4.23–4.28 , 6.99 , 7.06 , 7.43 . 13C-NMR : δ 14.4 (CH3), 21.6 (ArCH3), 22.8 (CH2), 23.1 (2 × CH3), 27.0 (CH), 28.8 (CH2), 29.5 (CH2), 68.0 (OCH2), 112.3 (Ar), 121.2 (Ar), 126.0 (Ar), 134.3 (Ar), 136.4 (Ar), 156.5 (Ar). Anal. Calcd for C15H24O: C, 81.76; H, 10.98. Found: C, 81.80; H, 11.02.ethyl 2-(2-isopropyl-5-methylphenoxy)acetate (13): pale yellow oil, 69% yield. 1H-NMR : δ 1.36–1.40 , 2.41 , 3.52–3.55 , 4.30–4.38 , 4.70 , 6.66 , 6.89 , 7.23 . 13C-NMR  δ 14.2 (CH3), 21.3 (ArCH3), 22.8 (2 × CH3), 26.8 (CH), 61.1 (O2CHCH3), 65.6 (OCH2), 112.3 (Ar), 122.3 (Ar), 126.3 (Ar), 134.5 (Ar), 136.2 (Ar), 155.2 (Ar), 169.1 (C=O). Anal. Calcd for C14H20O3: C, 71.16; H, 8.53. Found: C, 71.20; H, 8.49.(E)-2-oxy)-1-isopropyl-4-methylbenzene (14): colourless oil, 82% yield. 1H-NMR : δ 1.33 , 1.74 , 1.81 , 1.85 , 2.19–2.27 , 2.44 , 3.42–3.44 , 4.65 , 5.20–5.23 , 5.61–5.64 , 6.8 , 6.85 , 7.21 . 13C-NMR : δ 16.7 (CH3), 17.8 (CH3), 21.5 (ArCH3), 22.9 (2 × CH3), 25.8 (CH3), 26.5 (CH2), 26.6 (CH), 39.6 (CH2), 65.1 (OCH2), 112.8 (Ar), 120.5 (=CH), 121.1 (Ar), 124.0 (=CH), 125.9 (Ar), 131.7 (=C), 134.4 (Ar), 136.2 (Ar), 140.1 (=C), 156.1 (Ar). Mixture of E/Z isomers with ratio of 9.3/1. For sake of clarity, we have reported only the signals related to the major isomer. Calcd for C20H30O: C, 83.86; H, 10.56. Found: C, 83.80; H, 10.51.2-(benzyloxy)-1-isopropyl-4-methylbenzene (15): pale yellow oil, 88% yield. 1H-NMR : δ 1.30 , 2.40 , 3.41–3.51 , 5.13 , 6.83 , 6.85 , 7.21 , 7.37–7.55 . 13C-NMR : δ 21.4 (ArCH3), 22.9 (2 × CH3), 26.6 (CH), 70.0 (OCH2), 112.7 (Ar), 121.5 (Ar), 126.0 (Ar), 127.2 (2 × Ar), 127.7 (Ar), 128.6 (2 × Ar), 134.4 (Ar), 136.4 (Ar), 137.7 (Ar), 155.9 (Ar). Anal. Calcd for C17H20O: C, 84.96; H, 8.39. Found: C, 84.90; H, 8.33.1-isopropyl-4-methyl-2-((2-methylbenzyl)oxy)benzene (16): pale yellow oil, 88% yield. 1H-NMR : δ 1.58 , 2.70 , 3.72-3.83 , 5.32 , 7.13–7.15 , 7.48–7.58 , 7.81–7.83 . 13C-NMR : δ 19.2 (ArCH3), 21.8 (ArCH3), 23.3 (2 × CH3), 26.8 (CH), 68.7 (OCH2), 112.7 (Ar), 121.8 (Ar), 126.3 (Ar), 126.4 (Ar), 128.3 (Ar), 128.5 (Ar), 135.0 (Ar), 134.6 (Ar), 135.8 (Ar), 136.6 (Ar), 136.6 (Ar), 156.2 (Ar). Anal. Calcd for C18H22O: C, 84.99; H, 8.72. Found: C, 84.95; H, 8.77.1-isopropyl-4-methyl-2-((4-methylbenzyl)oxy)benzene (17): pale yellow oil, 77% yield. 1H-NMR : δ 1.68 , 2.75 , 3.82–3.87 , 5.38 , 7.16 , 7.19 , 7.54–7.59 , 7.75 . 13C-NMR : δ 21.6 (ArCH3), 21.8 (ArCH3), 23.3 (2 × CH3), 27.1 (CH), 70.2 (OCH2), 113.0 (Ar), 121.8 (Ar), 126.3 (Ar), 127.7 (2 × Ar), 129.6 (2 × Ar), 128.6 (Ar), 135.0 (Ar), 136.6 (Ar), 137.7 (Ar), 156.3 (Ar). Anal. Calcd for C18H22O: C, 84.99; H, 8.72. Found: C, 84.93; H, 8.70.2-oxy)-1-isopropyl-4-methylbenzene (18): colourless oil, 67% yield. 1H-NMR : δ 1.28 , 2.38 , 2.40 , 3.40–3.47 , 5.04 , 6.80 , 6.82 , 7.02 , 7.12 , 7.18 . 13C-NMR : δ 21.3 (2 × ArCH3), 21.4 (ArCH3), 22.9 (2 × CH3), 26.6 (CH), 70.2 (OCH2), 112.8 (Ar), 121.4 (Ar), 125.0 (2 × Ar), 125.9 (Ar), 129.4 (Ar), 134.4 (Ar), 136.4 (Ar), 137.6 (Ar), 138.1 (2 × Ar), 156.0 (Ar). Anal. Calcd for C19H24O3: C, 85.03; H, 9.01. Found: C, 85.08; H, 9.00.1-isopropyl-2-((3-methoxybenzyl)oxy)-4-methylbenzene (19): colourless oil, 82% yield. 1H-NMR : δ 1.28 , 2.37 , 3.38–3.48 , 3.87 , 5.09 , 6.79 , 6.82 , 6.90–6.92 , 7.07–7.08 , 7.17 , 7.35 . 13C-NMR : δ 21.4 (ArCH3), 22.8 (2 × CH3), 26.7 (CH), 55.5 (OCH3), 69.8 (OCH2), 112.5 (Ar), 112.7 (Ar), 113.2 (Ar), 119.3 (Ar), 121.5 (Ar), 126.0 (Ar), 129.6 (Ar), 134.4 (Ar), 136.4 (Ar), 139.3 (Ar), 155.8 (Ar). Anal. Calcd for C18H22O2: C, 79.96; H, 8.20. Found: C, 79.90; H, 8.25.1-isopropyl-4-methyl-2-((2-(trifluoromethyl)benzyl)oxy)benzene (20): colourless oil, 77% yield. 1H-NMR : δ 1.39–1.42 , 2.46 , 3.55–3.57 , 5.42 , 6.85 , 6.94 , 7.30 , 7.51–7.54 , 7.68–7.71 , 7.82 , 7.96 . 13C-NMR : δ 21.4 (ArCH3), 22.9 (2 × CH3), 26.7 (CH), 66.3 , 112.7 (Ar), 121.9 (Ar), 124.6 , 125.9 , 126.2 (Ar) 127.2 , 127.6 (Ar), 128.4 (Ar), 132.3 (Ar), 134.4 (Ar), 136.5 (Ar), 136.6 (Ar), 155.5 (Ar). 19F NMR  δ−58.69 . Anal. Calcd for C18H19F3O: C, 70.12; H, 6.21. Found: C, 70.08; H, 6.23. 1-isopropyl-4-methyl-2-((3-(trifluoromethyl)benzyl)oxy)benzene (21): colourless oil, 69% yield. 1H-NMR : δ 1.59–1.63 , 2.65–2.66 , 3.74–3.77 , 5.35 , 7.06 , 7.13 , 7.48–7.51 , 7.75–7.78 , 7.87 , 7.93 , 8.08 . 13C-NMR : δ 21.5 (ArCH3), 23.0 (2 × CH3), 27.0 (CH), 69.3 (OCH2), 112.9 (Ar), 121.0 , 122.2 (Ar), 124.0 , 124.7 , 126.4 (Ar), 129.3 (Ar), 130.5 (Ar), 131.2 , 134.6 (Ar), 136.7 (Ar), 139.1 (Ar), 155.8 (Ar). 19F NMR  δ−60.98 . Anal. Calcd for C18H19F3O: C, 70.12; H, 6.21. Found: C, 70.10; H, 6.20. 1-isopropyl-4-methyl-2-((4-(trifluoromethyl)benzyl)oxy)benzene (22): colourless oil, 87% yield. 1H-NMR : δ 1.46 , 2.51 , 3.52–3.61 , 5.27 , 6.900 , 6.99 , 7.35 , 7.73 , 7.83 . 13C-NMR : δ 21.4 (ArCH3), 22.9 (2 × CH3), 26.8 (CH), 69.1 (OCH2), 112.7 (Ar), 120.8 , 122.0 (Ar), 125.6 , 126.3 (Ar) 127.2 (2 × Ar), 129.8 , 134.4 (Ar), 136.6 (Ar), 141.9 (Ar), 155.6 (Ar). 19F NMR  δ−60.80 . Anal. Calcd for C18H19F3O: C, 70.12; H, 6.21. Found: C, 70.16; H, 6.22. 2-benzyl)oxy)-1-isopropyl-4-methylbenzene (23): colourless oil, 80% yield. 1H-NMR : δ 1.27 , 2.37 , 3.33–3.43 , 5.20 , 6.75 , 6.86 , 7.19 , 7.89 , 7.96 . 13C-NMR : δ 21.3 (ArCH3), 22.8 (2 × CH3), 26.7 (CH), 68.6 (OCH2), 112.7 (Ar), 119.2 (Ar), 121.6–121.8 , 122.3 (Ar), 123.3 , 126.3 (Ar), 126.9 (Ar), 127.0 (Ar), 127.4 (Ar), 131.9 , 134.4 (Ar), 136.6 (Ar), 140.3 (Ar), 155.1 (Ar). 19F NMR  δ−66.85 . Anal. Calcd for C19H18F6O: C, 60.64; H, 4.82. Found: C, 60.60; H, 4.77.4-((2-isopropyl-5-methylphenoxy)methyl)benzonitrile (24): pale yellow solid, 71% yield, mp = 76–78 °C. 1H-NMR : δ 1.34–1.36 , 2.41 , 3.46–3.50 , 5.19 , 6.79 , 6.89 , 7.24 , 7.63 , 7.72 . 13C-NMR : δ 21.4 (ArCH3), 22.9 (2 × CH3), 26.7 (CH), 68.9 (OCH2), 111.5 (Ar), 112.6 (Ar), 118.9 (CN), 122.1 (Ar), 126.2 (Ar), 127.4 (2 × Ar), 132.4 (2 × Ar), 134.3 (Ar), 136.5 (Ar), 143.2 (Ar), 155.3 (Ar). Anal. Calcd for C18H19NO: C, 81.47; H, 7.22; N, 5.28. Found: C, 81.50; H, 7.20; N, 5.31.2-((3-fluorobenzyl)oxy)-1-isopropyl-4-methylbenzene (25): colourless oil, 82% yield. 1H-NMR : δ 1.59–1.61 , 2.65 , 3.71–3.81 , 5.30 , 7.03 , 7.12 , 7.25–7.31 , 7.47–7.52 , 7.57–7.64 . 13C-NMR : δ 21.6 (ArCH3), 23.1 (2 × CH3), 27.0 (CH), 69.3 (OCH2), 112.8 (Ar), 114.2 , 114.8 , 122.1 (Ar), 122.7 , 126.4 (Ar), 130.3 , 134.6 (Ar), 136.6 (Ar), 140.6 , 155.9 (Ar), 163.3 . 19F NMR  δ−111.18 , 6.2 Hz (meta), CF). Anal. Calcd for C17H19FO: C, 79.04; H, 7.41. Found: C, 79.10; H, 7.50.1,3-difluoro-2-((2-isopropyl-5-methylphenoxy)methyl)benzene (26): white solid, 83% yield, mp = 91–92 °C. 1H-NMR : δ 1.22 , 2.42 , 3.26–3.35 , 5.17 , 6.86 , 6.93–7.03 , 7.18 , 7.31–7.41 . 13C-NMR : δ 21.4 (ArCH3), 22.8 (2 × CH3), 26.5 (CH), 58.2 (OCH2), 111.3 (2 × Ar), 111.6 (Ar), 113.0 (Ar), 121.9 (Ar), 126.1 (Ar), 130.5 , 134.7 (Ar), 136.4 (Ar), 155.7 (Ar), 162.0 , 162.1 . 19F NMR  δ−112.97 . Anal. Calcd for C17H18F2O: C, 73.89; H, 6.57. Found: C, 73.93; H, 6.52.2-oxy)-1-isopropyl-4-methylbenzene (27): white solid, 90% yield, mp = 35–36 °C. 1H-NMR : δ 1.27 , 2.35 , 3.35–3.45 , 5.08 , 6.70 , 6.76–6.84 , 6.99–7.03 , 7.18 . 13C-NMR : δ 21.3 (ArCH3), 22.8 (2 × CH3), 26.6 (CH), 68.7 (OCH2), 103.0 , 109.5 , 112.6 (Ar), 121.9 (Ar), 126.2 (Ar), 134.4 (Ar), 136.5 (Ar), 141.8 , 155.2 (Ar), 163.1 , 163.2 . 19F NMR  δ−113.39 . Anal. Calcd for C17H18F2O: C, 73.89; H, 6.57. Found: C, 73.93; H, 6.61.2-((3-chlorobenzyl)oxy)-1-isopropyl-4-methylbenzene (28): yellow sticky oil, 91% yield. 1H-NMR : δ 1.28 , 2.37 , 3.40–3.44 , 5.08 , 6.76 , 6.84 , 7.19 , 7.35–7.38 , 7.49 . 13C-NMR : δ 21.4 (ArCH3), 22.9 (2 × CH3), 26.6 (CH), 69.2 (OCH2), 112.7 (Ar), 121.8 (Ar), 125.1 (Ar), 126.1 (Ar), 127.1 (Ar), 127.9 (Ar), 129.8 (Ar), 134.4 (Ar), 136.4 (Ar), 139.8 (Ar), 155.6 (Ar). Anal. Calcd for C17H19ClO: C, 74.31; H, 6.97. Found: C, 74.27; H, 6.90.2-((4-chlorobenzyl)oxy)-1-isopropyl-4-methylbenzene (29): colourless oil, 74% yield. 1H-NMR : δ 1.43–1.46 , 2.52 , 3.55–3.58 , 5.17 , 6.90 , 6.98 , 7.33 , 7.50–7.53 . 13C-NMR  δ 21.6 (ArCH3), 23.0 (2 × CH3), 26.9 (CH), 69.3 (OCH2), 112.8 (Ar), 121.9 (Ar), 126.2 (Ar), 128.6 (2 × Ar), 128.9 (2 × Ar), 133.6 (Ar), 134.4 (Ar), 136.3 (Ar), 136.5 (Ar), 155.8 (Ar). Anal. Calcd for C17H19ClO: C, 74.31; H, 6.97. Found: C, 74.37; H, 7.01.2-chloro-1-((2-isopropyl-5-methylphenoxy)methyl)-4-methoxybenzene (30): white solid, 71% yield, mp = 84–86 °C. 1H-NMR : δ 1.25 , 2.36 , 3.34–3.44 , 3.85 , 5.11 , 6.79 , 6.81 , 6.89 , 7.00 , 7.16 , 7.51 . 13C-NMR : δ 21.4 (ArCH3), 22.8 (2 × CH3), 26.6 (CH), 55.6 (OCH3), 67.1 (OCH2), 112.7 (Ar), 112.9 (Ar), 114.9 (Ar), 121.6 (Ar), 126.0 (Ar), 127.3 (Ar), 129.8 (Ar), 133.5 (Ar), 134.4 (Ar), 136.4 (Ar), 155.5 (Ar), 159.7 (Ar). Anal. Calcd for C18H21ClO2: C, 70.93; H, 6.94. Found: C, 70.88; H, 6.96.2-((2-bromobenzyl)oxy)-1-isopropyl-4-methylbenzene (31): white sticky solid, 71% yield. 1H-NMR : δ 1.47 , 2.52 , 3.59–3.66 , 5.29 , 6.94 , 6.98 , 7.30–7.35 , 7.49–7.54 , 7.73–7.76 , 7.80 . 13C-NMR : δ 21.4 (ArCH3), 22.9 (2 × CH3), 26.6 (CH), 70.0 (OCH2), 112.7 (Ar), 121.5 (Ar), 126.0 (Ar), 127.2 (Ar), 127.7 (Ar), 128.6 (Ar), 134.4 (Ar), 136.4 (Ar), 137.7 (Ar), 155.9 (Ar). Anal. Calcd for C17H19BrO: C, 63.69; H, 6.00. Found: C, 63.71; H, 5.57.2-((4-bromobenzyl)oxy)-1-isopropyl-4-methylbenzene (32): colourless oil, 71% yield. 1H-NMR : δ 1.52 , 2.58 , 3.61–3.70 , 5.20 , 6.96 , 7.05 , 7.40 , 7.52–7.54 , 7.70–7.74 . 13C-NMR : δ 21.7 (ArCH3), 23.1 (2 × CH3), 27.0 (CH), 69.4 (OCH2), 112.8 (Ar), 121.8 (Ar), 122.0 (Ar), 126.3 (Ar), 129.0 (2 × Ar), 131.9 (2 × Ar), 134.5 (Ar), 136.5 (Ar), 136.9 (Ar), 155.8 (Ar). Anal. Calcd for C17H19BrO: C, 63.69; H, 6.00. Found: C, 63.65; H, 6.07.2-((4-iodobenzyl)oxy)-1-isopropyl-4-methylbenzene (33): yellowish sticky oil, 83% yield. 1H-NMR : δ 1.26 , 2.36 , 3.33–3.43 , 5.04 , 6.74 , 6.82 , 7.17 , 7.23 , 7.76 . 13C-NMR : δ 21.4 (ArCH3), 22.8 (2 × CH3), 26.6 (CH), 69.3 (OCH2), 93.1 (Ar), 112.6 (Ar), 121.7 (Ar), 126.1 (Ar), 129.0 (2 × Ar), 134.3 (Ar), 136.4 (Ar), 137.4 (Ar), 137.6 (2 × Ar), 155.6 (Ar). Anal. Calcd for C17H19IO: C, 55.75; H, 5.23. Found: C, 55.80; H, 5.30.1-isopropyl-4-methyl-2-((2-nitrobenzyl)oxy)benzene (34): brown solid, 77% yield, mp = 77–79 °C. 1H-NMR : δ 1.26 , 2.32 , 3.38–3.43 , 5.48 , 6.73 , 6.81 , 7.16 , 7.50–7.53 , 7.69–7.75 , 7.96 , 8.20 . Anal. Calcd for C17H19NO3: C, 71.56; H, 6.71; N, 4.91. Found: C, 71.60; H, 6.75; N, 4.88.1-isopropyl-4-methyl-2-((3-nitrobenzyl)oxy)benzene (35): amber-yellow oil, 81% yield. 1H-NMR : δ 1.48–1.52 , 2.53 , 3.62–3.67 , 5.27 , 6.95 , 7.00 , 7.33–7.37 , 7.65–7.71 , 7.97 , 8.26–8.29 , 8.51 . 13C-NMR : δ 21.5 (ArCH3), 23.0 (2 × CH3), 27.0 (CH), 68.6 (OCH2), 112.7 (Ar), 121.8 (Ar), 122.3 (Ar), 122.7 (Ar), 126.3 (Ar), 129.7 (Ar), 133.0 (Ar), 134.3 (Ar), 136.6 (Ar), 140.1 (Ar), 148.5 (Ar), 155.5 (Ar). Anal. Calcd for C17H19NO3: C, 71.56; H, 6.71; N, 4.91. Found: C, 71.55; H, 6.73; N, 4.91.1-isopropyl-4-methyl-2-((4-nitrobenzyl)oxy)benzene (36): white solid, 81% yield, mp = 81–83 °C. 1H-NMR : δ 1.24–1.26 , 2.33 , 3.36–3.40 , 5.18 , 6.70 , 6.82 , 7.16 , 7.63 , 8.26–8.28 . 13C-NMR : δ 21.4 (ArCH3), 22.8 (2 × CH3), 26.7 (CH), 68.7 (OCH2), 112.5 (Ar), 122.0 (Ar), 123.9 (2 × Ar), 126.2 (Ar), 127.3 (2 × Ar), 134.3 (Ar), 136.5 (Ar), 145.1 (Ar), 147.4 (Ar), 155.1 (Ar). Anal. Calcd for C17H19NO3: C, 71.56; H, 6.71; N, 4.91. Found: C, 71.51; H, 6.67; N, 4.96.1-((2-isopropyl-5-methylphenoxy)methyl)naphthalene (37): pale yellow oil, 76% yield. 1H-NMR : δ 1.21 , 2.41 , 3.31–3.42 , 5.53 , 6.86 , 6.95 , 7.20 , 7.51–7.58 , 7.68 , 7.90 , 7.93–7.96 , 8.09–8.11 . 13C-NMR : δ 21.5 (ArCH3), 23.0 (2 × CH3), 26.4 (CH), 68.6 (OCH2), 112.6 (Ar), 121.6 (Ar), 123.8 (Ar), 125.4 (Ar), 125.9 (Ar), 126.0 (Ar), 126.1 (Ar), 126.3 (Ar), 128.7 (Ar), 128.8 (Ar), 131.5 (Ar), 133.0 (Ar), 133.7 (Ar), 134.5 (Ar), 136.4 (Ar), 155.9 (Ar). Anal. Calcd for C21H22O: C, 86.85; H, 7.64. Found: C, 86.84; H, 7.70.4-((2-isopropyl-5-methylphenoxy)methyl)-1,1′-biphenyl (38): white solid, 78% yield, mp = 91–92 °C. 1H-NMR : δ 1.29 , 2.38 , 3.40–3.50 , 5.16 , 6.83–6.84 , 7.19 , 7.38–7.42 , 7.47–7.52 , 7.57 , 7.64–7.68 . 13C-NMR : δ 21.4 (ArCH3), 22.9 (2 × CH3), 26.6 (CH), 69.7 (OCH2), 112.7 (Ar), 121.5 (Ar), 127.1 (2 × Ar), 127.3 (2 × Ar), 127.4 (Ar), 127.6 (2 × Ar), 128.8 (2 × Ar), 134.4 (Ar), 136.4 (Ar), 137.4 (Ar), 136.7 (Ar), 140.7 (Ar), 140.9 (Ar), 155.8 (Ar). Anal. Calcd for C23H24O: C, 87.30; H, 7.64. Found: C, 87.35; H, 7.67.2-((2-isopropyl-5-methylphenoxy)methyl)isoindoline-1,3-dione (39): white solid, 79% yield, mp = 121–122 °C. 1H-NMR : δ 1.18 , 2.36 ; 3.24–3.33 , 5.67 , 6.84 , 7.02 , 7.12 , 7.73–7.78 , 7.88–7.92 . 13C-NMR : δ 21.3 (ArCH3), 23.0 (2 × CH3), 26.5 (CH), 65.7 (OCH2), 115.0 (Ar), 123.2 (2 × Ar), 123.8 (2 × Ar), 126.3 (Ar), 131.8 (Ar), 134.5 (2 × Ar), 135.4 (Ar), 136.5 (Ar), 153.4 (Ar), 167.2 (2 × C=O). Anal. Calcd for C19H19NO3: C, 73.77; H, 6.19; N, 4.53. Found: C, 73.71; H, 6.24; N, 4.50.The MIC determination was performed by modified broth microdilution assay as previously described . For MBC1) and its derivatives  (600 mM) were freshly prepared in dimethyl sulfoxide (DMSO) and DMEM according to the experimental design by serial dilutions in complete culture medium. The final concentration of DMSO in experiments was 0.14%. No toxicity on AGS cells was observed (data not shown). 5-Fluorouracil and carvacrol  were used as positive controls.The human adenocarcinoma gastric cell line (AGS) was derived from an untreated human adenocarcinoma of the stomach and retained the same cytological characteristics of the malignant cells obtained from Caucasian patients . The AGSH-tetrazolium)) assay . The concentration ranges of thymol and its derivatives for the treatment was extrapolated from concentration-response curves built in preliminary experiments. Briefly, AGS cells were seeded in 96-well plates (6 × 103 cells/well) and treated for 24 h at 37 °C in a humidified atmosphere with 5% CO2 with several concentrations (50–800 μM) of each compound (5 replica wells for each treatment condition). Cells were incubated with the MTS solution for at least 1 h and cell viability was tested colorimetrically by measuring the absorbance at 490 nm using GloMax-Multi Detection System . Cell viability was reported as the percentage as compared with the untreated cells recognized as 100%. The IC50 value was determined from the concentration-response curves by nonlinear regression analysis [Cell viability was evaluated by MTS -5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2analysis .p value of 0.05 was assessed as statistically significant. IC50 values were obtained using the GraphPad Prism 7 software .A H. pylori and to show toxicity for AGS cells. This approach allowed us to demonstrate, as also reported for carvacrol analogues, that the antibacterial activity of these phenolic terpenes is not limited to the presence of the free OH group in the natural parent compounds and that their antimicrobial potential could be enlarged by chemical modifications. Indeed, the proper functionalization could improve the anti-Helicobacter pylori activity especially against strains endowed with a different susceptibility pattern to antibiotics currently used in therapy. Moreover, some derivatives could display an antiproliferative effect useful to assess them as dual-acting agents for contrasting the development of gastric cancer. Further studies will address the potential of these compounds to treat biofilm-associated H. pylori infections in vitro and in vivo due to the disaggregating ability of their parent compound [H. pylori [We have explored a thymol-based molecular library with large structural diversity to discover new dual-action agents characterized by the ability to reduce the growth of several strains of compound  and the compound . Future . pylori .


Metastatic prostate cancer (PC) is the second leading cause of cancer deaths in males. The lack of preclinical models and molecular characterization for advanced stage PC is a key barrier in understanding the aggressive subsets androgen receptor (AR) pathway active or AR-null castration-resistant prostate cancers (CRPC). Our study aimed to assess the potential of patient-derived xenograft (PDX) models and an approach integrating proteomic and transcriptomic techniques to explore the underlying drivers of metastatic PC. Transcriptomic and proteomic profiling of 42 PDX prostate tumors uncovered both previously established and unexpected molecular features of aggressive PC subsets. Of these, we confirmed the functional role of mitochondrial metabolism in AR-positive CRPC.Metastatic prostate cancer (PC) is the second leading cause of cancer deaths in males and has limited therapeutic options. The lack of preclinical models for advanced stage PC represents one of the primary barriers in understanding the key genetic drivers of aggressive subsets, including androgen receptor (AR) pathway active and AR-null castration-resistant prostate cancers (CRPC). In our studies, we described a series of LuCaP patient-derived xenograft (PDX) models representing the major genomic and phenotypic features of human disease. To fully exploit the potential of these preclinical models, we carried out a comprehensive transcriptomic and proteomic profiling of 42 LuCaP PDX prostate tumors. The collected proteomic data (~6000 data points) based on 71 antibodies revealed many of the previously known molecular markers associated with AR-positive and AR-null CRPC. Genomic analysis indicated subtype-specific activation of pathways such as Wnt/beta-catenin signaling, mTOR, and oxidative phosphorylation for AR-positive CRPC and upregulation of carbohydrate metabolism and glucose metabolism for AR-null CRPC. Of these, we functionally confirmed the role of mitochondrial metabolism in AR-positive CRPC cell lines. Our data highlight how the integration of transcriptomic and proteomic approaches and PDX systems as preclinical models can potentially map the connectivity of poorly understood signaling pathways in metastatic prostate cancer. Prostate cancer (PC) is the second leading cause of cancer-related death among men in Western countries . AlthougTP53 and PTEN, and showing heterogeneity in responses to treatment of advanced PC .Enrichr and Pathwaynet analyses were performed using the list of differently expressed genes identified by RPPA result with a cutoff of 1.5-fold between AR-null and AR-positive to identify five genes in AR-null and 11 genes in AR-positive CRPC ,11.v/v) ITS, 20 ng/mL EGF, 40 IU/mL penicillin and 40 µg/mL streptomycin. After 48 h, slices were treated with drugs at varying concentrations. Overall tumor tissue viability was measured using RealTime Glo (Promega) reagent according to the manufacturer’s instructions. IVIS images were taken before (day 0) and after drug treatment (day 6) using an IVIS Spectrum instrument .LuCaP tumor slices were prepared as described previously . BrieflyLuCaP PDX tumors developed from a series of prostate cancer metastases are well-established model systems representing several phenotypic characteristics of clinical PC, including differential androgen receptor activity ,13,14. TWe sought to elucidate critical features of the oncogenic state at the level of protein activities in 42 PDX models established from metastatic PC patient tumors using RPPA . RPPA isGenomic, epigenetic, transcriptomic, and signal transduction alteration, or clonal evolution can give rise to intra-tumoral heterogeneity . Since wp > 0.74) among the AR-positive and AR-null PC subtypes of LuCaP PDX tumors, respectively (p > 0.7) within each subtype of PC and showed moderate-to-high correlation across different subtypes between AR-positive and AR-null (p > 0.4). In general, the correlation among AR-positive tumor samples was lower than in AR-null tumors, indicating the heterogeneous nature of the AR-positive population, similarly as observed in a recent study using AR-positive biopsies [Intertumoral heterogeneity refers to the combination of intrinsic and extrinsic heterogeneity between patients with tumors of the same histopathological subtype. Of 35 LuCaP PDX samples analyzed in this study, 11 tumors represented AR-null, and 21 represented the adenocarcinoma AR-positive CRPC subtype. Similar to the results from intra-heterogeneity data, we observed a high correlation  and significantly higher levels of phospho-S6 ribosomal protein, β-catenin, E-cadherin, and phospho-HSP27 in AR-positive  LuCaP PDX tumors (p = 0.0650) and PKM1/2  in AR-null LuCaP PDX tumors , glycolysis and gluconeogenesis (5.0 × 10−7), pyruvate metabolism (6.6 × 10−5), and HIF-1 transcriptional activity in hypoxia (1.1 × 10−4) in AR-null (p = 9.9 × 10−6), androgen receptor signaling and proteolysis (1.3 × 10−5), the interleukin-2/PI3K pathway (p = 1.6 × 10−5), and the p38/beta MAPK downstream pathway (1.9 × 10−4)  a (Tables × 10−4) . OverallTo explore the potential interactions between the enriched genes that underlie the tumorigenesis and progression of AR-null and AR-positive and substantiate our Enrichr results, we performed PathwayNet analysis to predict the interactions of the enriched genes discovered through RPPA . Figure To further substantiate our proteomic data-driven discovery of subtype-specific signaling pathways, we sought to identify a set of genes that are differentially expressed between the subtypes of PC. We performed gene set enrichment analysis (GSEA) using previously determined array CGH data . GSEA reGSEA analysis of AR-null LuCaP PDX tumors revealed enrichment of E2F targets , epithelial–mesenchymal transition (EMT) , G2M  and histone methylation  gene sets d. All of50 < 100 nM) relative to the NCI-H660 cell line (EC50 > 100 µM) (50 160–760 nM) while it had no effect on the growth of NCI-H660 cells (EC50 > 1000 nM), suggesting that the mitochondrial metabolism pathway is critical for AR-positive CRPC growth. Conversely, we found that NCI-H660 were more susceptible to inhibition of histone demethylase (EC50 < 200 nM) relative to all AR-positive cell lines tested (EC50 550–3500 nM), supporting epigenetic modulators as potential targets for the treatment of the CRPC subtype. Overall, these perturbation studies confirmed the functional importance of distinct pathways identified in AR-positive and AR-null prostate cancers.Next, we asked whether the pathways identified by our integrated approach are functionally essential for the growth and survival of PC. We measured cell growth and viability of a panel of AR-positive  and AR-null (NCI-H660) cell lines treated with small molecule inhibitors targeting mTOR (Torin2), oxidative phosphorylation (antimycin), and histone demethylation (GSK-J4) pathways. Torin2 is a potent inhibitor of mTOR, ATM, and ATR and has been previously shown to inhibit the growth of several different cancers . Antimyc 100 µM) . Furtherp < 0.005, and 3-fold in LuCaP 147 CR, p < 0.005) (Having discovered an enrichment of genes involved in oxidative phosphorylation in AR-positive CRPC c and hav< 0.005) c. Inhibi< 0.005) d. Howeve< 0.005) d. Finall< 0.005) e. TogethDue to the highly unstable and evolving nature of prostate cancer, most patients ultimately become unresponsive even to ‘next-generation’ inhibitors of AR signaling . In partIn this study, we utilized LuCaP PDX tumor models, which represent physiologically relevant environments (in contrast to cell lines) to carry out proteomic profiling to identify subtype-specific pathways that are functionally important for advanced stages of PC. Our proteomic data were concordant with results of previously identified molecular markers and networks associated with AR-positive and AR-null subtypes . ConsistEnrichr identified many known signaling nodes and pathways involved in AR-positive and AR-null subtypes. These include pyruvate metabolism, HIF-1 transcription factor network, glycolysis in AR-null, and Wnt/beta-catenin signaling and AR signaling in AR-positive a. ElevatRecently, metabolic analysis of docetaxel-resistant prostate cancer cells showed a heightened respiratory phenotype and a shift from “Warburg” to oxidative phosphorylation, in agreement with our data . ConsistLuCaP PDX series represent histopathological, genomic, and proteomic features of clinical prostate cancers, making them suitable tools for biological discovery in the context of prostate cancer progression and drug resistance. However, a major challenge of working with LuCaP PDX models is that the expansion of human tumors under mouse physiological conditions can take months or years, which limits their potential for diagnostic and therapeutic applications. We have shown that organotypic tumor slices can be generated from LuCaP PDX tumors which maintain the characteristic of the native tumor tissue . Tumor sOverall, our comprehensive profiling of signaling pathways in metastatic LuCaP PDX models provides a valuable resource for the prostate cancer community interested in using these preclinical models for their studies. Our results also provide an impetus to other investigators and drug companies to utilize phosphorylation-rich RPPA data for predicting drug responses. Moreover, the integration of transcriptomic and proteomic approaches has the potential to map the connectivity of poorly understood signaling pathways of metastatic prostate cancer.