Several studies have suggested that intestinal flora may play an important role in allergic diseases. The purpose of this study was to investigate the effect of probiotics of Bifidobacterium triplex on the symptoms of allergic rhinitis (AR). The effects of this probiotic on the immune system have been reported in some studies, but most previous studies have been in animals.60 infants and young children with AR were randomly divided into 2 groups: probiotics/placebo group. The main outcome was the use of a comprehensive symptom drug score to assess allergy symptoms. In addition, health-related quality of life was investigated . Secondary outcomes included a visual analog scale of allergy burden and a second quality of life questionnaire. This report describes the study design of a randomized controlled trial.The study design described a double-center, randomized, location at the Minda Hospital of Hubei Minzu University and West China Hospital of Sichuan University, which will be focused on the study about probiotics treatment and its effect on AR symptoms.http://www.chictr.org.cn/listbycreater.aspx (Identifier: ChiCTR2000031175), Registered March 22, 2020.It has been registered at  AR is life-threatening, however it can significantly affect the quality of life of infants and young children, leading to poor sleep quality and lack of concentration, which seriously affects the growth and development of infants and young children. In addition, AR is also closely related to asthma, nasal polyps, sinusitis, otitis media and other diseases. The prevalence of AR has been increasing year by year globally, ranging from 2.2% to 45.1%. With the rapid development of society and changes in living environment, the incidence of AR among infants and young children in China is also increasing, which seriously affects the physical and mental health of infants and young children.Allergic rhinitis (AR) is a non-infectious inflammatory disease of nasal mucosa mediated by specific IgE after exposure to allergens in susceptible infants and young children.1 / TH2 immune response imbalance of CD4 + T lymphocytes plays an important role in the pathogenesis of AR. This theory is to discuss the pathogenesis of AR from the perspective of immunology. The strong TH2 cell reaction plays an important role in the occurrence and development of AR.In recent years, Sakaguchi et al found that the TH2 cytokines to mediate the TH1/ TH2 balance, thus preventing the occurrence of food allergy. Animal experiments have found that lactic acid bacteria can promote TH1 immune response and inhibit TH2 immune response, so as to put the body's immune system in a dynamic balance and inhibit the occurrence of allergic reactions.Probiotics and breast milk are identified as two factors that can affect the course of allergic disease. The effect of probiotics on immune function has been a hot topic in allergic diseases in recent years. It has been reported that probiotics can improve the intestinal mucosal immune function of allergic rats and down-regulate the function of TH found that breastfeeding for more than 3 months can effectively reduce the probability of infants suffering from ectopic dermatitis and laryngeal wheezing, especially for those infants and young children with a family history of allergies. One of the reasons that breast-fed infants are less susceptible to allergic diseases than artificially fed infants is the presence of beneficial oligosaccharides in breast milk. Bifidobacteria dominated the intestinal flora of breast-fed infants at 6 to 7 days, while the number of bifidobacteria in the intestinal flora of artificially fed infants was small and the bacterial species was diverse. In present study, we aim to conduct a double-blind randomized controlled trial study to explore the effect of probiotics on AR in infants and young children.Prebiotics are defined by Gibson and Roberfroid, first proposed in 1995: Prebiotics are undigested or indigestible food ingredients that contribute to host health by selectively stimulating bacterial proliferation and/or activity in the colon. Some studies have found that breastfeeding within 6 months after birth is a protective factor for AR in infants and young children, and Odijk et al22.12.1.1 We aim to explore the role of probiotics in preventing allergic diseases in infants and young children.2.1.2 We aim to explore the effect of probiotics on AR in infants and young children.2.2A total of 60 patients with AR in Otorhinolaryngology-Head and Neck Surgery, Minda Hospital of Hubei Minzu University and West China Hospital of Sichuan University from May 2020 to April 2022 will be selected and randomly divided into probiotic/placebo group according to the numerical table. The study divided the patients into two groups. Patients will be divided into a double-blind probiotic/placebo study, we will assess allergy Symptoms using health-related quality of life by means of diaries, quality of life problems (RQLQ), and Combined Symptoms and Medication Score (CSMS). CSMS is a simple and standardized way to balance symptoms with the need for antidepressants. RQLQ is a disease-specific indicator used to assess health-related quality of life, including the patient's physical, social and emotional health.2.3Inclusion criteria include the following:(1)We will recruit and include 60 participants aged 0 to 6 with a history of AR.(2)The plan has an equal proportion of male and female, however this is not enforced.(3)AR must be diagnosed by a doctor .(4)Participants were required to present the results of tests sensitive to air allergen IgE  no more than 24 months prior to the trial.Exclusion criteria include the following:Patients with a history of diabetes, gastrointestinal disease, use of antibiotic drugs in the past 6 weeks, and any known psychiatric or neurological disorders.Anatomical changes such as septal rupture or perforation were also ruled out.2.4The study design will be described as a two-center, randomized, location study of probiotics in affiliated hospital of Hubei university for nationalities and its effect on AR symptoms. Probiotic treatment will be compared to the placebo application model, and we will provide probiotics to all patients for another 4 weeks after the trial phase.Probiotic treatment will be performed by Bifidobacterium triplex. Probiotics are provided in drops. The placebo treatment consisted of dropping carrier solutions containing probiotic treatments , but was no different in color, smell, or taste from probiotics.2.5Reservations will be made at the end of the first meeting for the following dates to facilitate participants’ reservations. Data from each measurement will be collected in writing at a face-to-face meeting and then recorded electronically at the Minda Hospital of Hubei Minzu University. Once recorded, the data is locked to prevent changes. Data lost because it did not appear will be encoded as incomplete. Then, SPSS vision. 25 will be used to analyze the result data. All data collected on the paper will be tagged with a research identification number to prevent identification of participants and stored in a locked cabinet. Only the author of the research report can access these identified data sets.2.6Tools to measure primary indicators include the following:(1)The health-related quality of life by means of diaries.(2)In this study, RQLQ will be used to evaluate the comfort level of the 2 groups of patients.(3)CSMS will be used to evaluate allergy symptoms.2.7After completing the first evaluation (the first interview), the research assistant opened an opaque envelope to determine that the participants were randomly assigned to two groups. Randomization is based on a computer-generated sequence of random Numbers built by an independent investigator. These researchers will be independent of the study members responsible for recruiting participants. All outcome measurements will be performed by blind experimenters.2.8t-test will be performed to compare the changes in measures within groups. Statistical significance will be considered at P < .05.Statistical analyses will be implemented by SPSS 17.0 and Microsoft Excel 2007 software. Data will be represented as mean ± standard deviation (SD). A 3,8 In recent years, it has been widely reported that probiotics can improve the intestinal mucosal immune function of allergic rats and down-regulate the function of TH2 cytokines to mediate the TH1/ TH2 balance, thus preventing the occurrence of food allergy. Animal experiments have revealed that lactic acid bacteria can promote TH1 immune response, inhibit TH2 immune response, make the body's immune system in a dynamic balance and inhibit the occurrence of allergic reactions. In addition, animal studies have demonstrated that lactic acid bacteria can induce the production of IL-12 and IFN-γ, reduce the production of IL -4, IL-5 and IL-3, promote the immune response of TH1 and inhibit the occurrence of allergic reactions. Therefore, prebiotics might have the preventing potential on AR.The effect of probiotics on immune function has been a hot topic in allergic diseases in recent years.,11 Probiotics can also secrete TGF-β and interleukin-10 through TH3 cells and Tr1 cells, inhibit the production of Ig E, thus inhibiting the TH2 immune response, so as to put the immune system in a dynamic equilibrium state. In recent years, studies have found that infants and young children born after six months of breast-feeding is the protective factors of AR infants and young children breastfed babies than formula-fed infants are less likely to suffer from allergic diseases, one of the reasons is beneficial in breast milk is born yuan oligosaccharides or low poly galactose, after the birth of the baby to play an important role in the development of the immune system.,15Prebiotics are a group of indigestible food ingredients that promote the colonization and growth of probiotics in the intestinal environment.The study design described a double-center, randomized, location at the Minda Hospital of Hubei Minzu University and West China Hospital of Sichuan University, which will be focused on the study about probiotics treatment and its effect on AR symptoms.Xueqiu Cao conceived the idea for this study; Ping Zhong and Jiao Zhu provided statistical plan; Xueqiu Cao and Gang Li drafted the protocol. Yun Zheng reviewed the protocol and provided critical feedback. All authors approved the article in its final form.


After the first emotional improvement, patients experienced six emotional deteriorations , while their function consistently increased . Clinicians should be aware of the relationship between emotional changes and functional progression as well as the occurrence of emotional fluctuations when supervising and consulting patients during postoperative rehabilitation. A larger study is warranted to generalize the results.An interrelationship between psychological and physical health is generally accepted in the field of sports medicine. This preliminary study explored the association between emotional changes and functional outcomes and aimed to describe how each aspect progresses during postoperative rehabilitation. Four collegiate student-athletes  who underwent supervised postoperative rehabilitation due to a lower-extremity injury volunteered for participation in the study. Emotion was quantified using a visual analogue scale prior to and after each session while self-reported function using the Lower-extremity Functional Scale was assessed every eight sessions throughout rehabilitation. There was a moderate correlation between emotional changes and functional outcomes ( Sports injuries often require surgical intervention. During postoperative rehabilitation, patients (athletes) experience negative psychological responses such as frustration and self-doubt ,2. The qThe interactive relationship between emotional status and functional outcomes is generally accepted in the field of sports medicine. For example, individuals with higher degrees of psychological well-being display a better immune function  or physiThe major components of postoperative rehabilitation generally consist of aerobic, flexibility, resistance, and balance exercises in conjunction with therapeutic modalities . The rehTherefore, in this preliminary study, we sought to describe the association between emotional changes and functional outcomes and to describe how each aspect progresses during the course of postoperative rehabilitation. Emotion was quantified using a 100 mm VAS  before aCollegiate student-athletes  who underwent an orthopedic surgery due to a lower-extremity injury were recruited through convenient sampling between February 2019 and January 2020. A lower-extremity injury was defined as a lower-extremity musculoskeletal condition that required surgery. Surgery was defined as a medical intervention performed by an orthopedic surgeon, aiming to fix or repair injured structures. Once a surgery date was scheduled after consulting with an orthopedic surgeon, patients were informed about the study. After a full understanding of the eligibility criteria and the testing procedures, patients gave written informed consent and determined to participate in the study. The informed consent form and the study procedures were approved by the Institutional Review Board of the Kyung Hee University (KHSIRB-19-001). Patients who had surgery in the preceding 48 h prior to obtaining the baseline data collection were excluded. Patients who had the following conditions (either pre-existing or current) for the last six months or who were taking medications due to these conditions were also excluded: (1) any medical conditions  that may influence emotional and functional status and (2) mental disturbance, defined as any health condition affecting emotional and/or behavioral change, other than one from the musculoskeletal condition that met the inclusion criteria.Eleven patients initially volunteered but seven were subsequently excluded—four were excluded because the baseline data were not obtained within 48 h from surgery, two were discontinued from rehabilitation because of facility shutdown due to the coronavirus disease 2019 pandemic and one transferred to another clinic due to the long distance between home and the rehabilitation clinic. Therefore, four patients were finally analyzed , who performed all dependent measurements. Each patient’s number of rehabilitation sessions (number of clinic visits) and time for each rehabilitation session (in minutes) were recorded. Specific therapeutic interventions as classified by six categories  were also obtained.Emotion was recorded using a modified VAS  before aDifferent numbers of clinic visits (number of rehabilitation sessions) for each patient yielded different amounts of data points. To conduct statistical analysis, data for emotion and function were session-normalized using a polynomial function . The mear) was calculated to determine the bivariate relationships (p < 0.05) among the datasets of the emotion  and that of function. To examine the presence of ups and downs in each dependent measurement throughout the rehabilitation period, two-way (time × session interaction: emotion) and one-way (session effect: emotion before and after each session and function) analyses of variance (p < 0.05) were performed. To determine ups and downs in reference to the values at the first session (and to reduce the type I error), Dunnett’s comparisons were performed as post-hoc tests (p < 0.10). To test differences in therapeutic interventions  across patients, a chi-square test using binary variables was conducted (p < 0.05). To determine practical significance, Cohen’s d effect sizes (ES) were calculated when statistical differences existed [Pearson correlation coefficient  and function. For overall emotion, the r value was 0.58 (p < 0.0001).All comparisons in the bivariate correlations were statistically significant . Regardless of session , however, overall emotion was improved by 6% after each session of rehabilitation . Meanwhile, regardless of time , patient emotions were altered over the rehabilitation period , patients experienced six emotional downs throughout rehabilitation . There was no statistically significant difference among emotions recorded after sessions  consistently progressed after the first improvement (33 points) at the 9th session  and there was no functional deterioration . Therapeutic modality (29%) and resistance exercise (28%) were the two most frequent treatments, followed by aerobic (16%), balance (11%), flexibility (11%), and plyometrics (5%) exercises. On average, our patients began rehabilitation 2.5 days after their surgery, visited the clinic 50 times (50 sessions of rehabilitation) during the rehabilitation period of 17.2 weeks (2.9 times per week) and participated for approximately two hours (122-min) per rehabilitation session . The sixOur hypotheses were supported in that emotional changes were moderately correlated with functional progressions; a single-session of rehabilitation resulted in a slight emotional improvement and there was emotional fluctuation along with consistent functional progression. The results of our descriptive data offer a better understanding of how collegiate student-athletes psychologically and physically progress during postoperative rehabilitation. Our study supports that, when patients appear to experience emotional struggle or remain at a low emotional status for a long time period, clinicians could initiate open communication with them in a manner that may have a positive effect. Explaining the interactive relationship between emotion and function and that emotional ups and downs are common during the rehabilitation process could help patients adhere to rehabilitation, achieve emotional improvement and stay at a higher emotional status.r = 0.41; emotion before session vs. function: r = 0.62) correlation (time-collapsed: r = 0.58). Our observation is consistent with those of previous reports [r-values indicate that at least 17% up to 38% of the variation in functional progression can be explained by variation in emotional change. Emotion is difficult to define and/or measure. Overtime, researchers have tested many different approaches with various measurement tools. Emotion can be measured by physiological responses such as autonomic nervous system [Between emotion and function, there was a moderate , the amount of emotional improvement measured on a VAS was 3 mm (51 to 54 mm). Although limited to quantifying pain, previously established minimal differences on VAS were at least 15 mm  or 18 mmWhile function consistently improved, emotional fluctuation was observed during the rehabilitation period. The first emotional improvement (time-collapsed) appeared at the time point corresponding to 24% of the rehabilitation period. Afterwards, patients experienced six emotional deteriorations , which is corresponding to 28% of the entire rehabilitation period C. The emn = 4), which limits generalization of the results. When considering an expected change in the VAS of 16.8 mm with a standard deviation of 19.1 mm (an ES of 0.88) based on our data, the minimum number of subjects need to detect clinically meaningful effect was calculated as ten . Along with the internal and external psychosocial factors above, degree of heterogeneity in terms of gender, family, sport, performance level, previous history of surgery and rehabilitation, characteristics  of the lower-extremity pathology or other medical condition in our patients certainly impact our results. Based on the results of this preliminary analysis, data from a larger number of patients from a narrow population should be analyzed in the future. Since emotion is complex, as stated above, it should be measured and analyzed by a multidimensional approach. There are emotionally mediated contributing factors that can potentially affect clinical function. For example, level of certain hormones  due to emotional changes can influence the healing process and functional outcomes. Therefore, we acknowledge that our assessment using the VAS cannot fully reflect emotional response. The nature of rehabilitative treatment and communication with clinicians in terms of quantity and quality across patients may have varied, which could have affected the study results. According to the chi-square test, specific therapeutic rehabilitative interventions were different. However, maintaining similar proportions of therapeutic interventions in patients with different pathologies is not possible. The sampling frequency in main outcomes was different in that emotion measurements were obtained each session while function was assessed every eight sessions; as such, the average numbers of measurements for emotion and function were 50 and seven, respectively. For functional outcome measures, however, the time course of change should be considered for determining the optimal measurement frequency [Several important limitations and assumptions of our study should be addressed. First, our study has a small sample size (requency .n = 4), which has a limitation for generalizing the results. Future researchers should conduct a study with a larger number of participants from the homogenous clinical population.We observed a moderate linear relationship between emotional changes and functional progression in collegiate student-athletes during the postoperative rehabilitation period. A single session of rehabilitation resulted in slight emotional improvement. After the first emotional improvement, patients experienced six instances of emotional deterioration (37% of the time), while function consistently progressed. The results of our preliminary data have several clinical implications: clinicians should be aware of the relationship between emotion and function and the potential existence of emotional ups and downs throughout the rehabilitation period; psychological consultation focusing on these topics could help patients advance to an emotional improvement and remain at positive emotional status. It should be noted that we only provided preliminary data (


The main subjects were the three-component systems composed either by one fluorocarbon component  with Ar and O2 or by two fluorocarbon components with one additive gas. The investigation scheme included plasma diagnostics by Langmuir probes and model-based analysis of plasma chemistry and heterogeneous reaction kinetics. The combination of these methods allowed one (a) to figure out key processes which determine the steady-state plasma parameters and densities of active species; (b) to understand relationships between processing conditions and basic heterogeneous process kinetics; (c) to analyze etching mechanisms in terms of process-condition-dependent effective reaction probability and etching yield; and (d) to suggest the set gas-phase-related parameters (fluxes and flux-to-flux ratios) to control the thickness of the fluorocarbon polymer film and the change in the etching/polymerization balance. It was shown that non-monotonic etching rates as functions of gas mixing ratios may result from monotonic but opposite changes in F atoms flux and effective reaction probability. The latter depends either on the fluorocarbon film thickness (in high-polymerizing and oxygen-less gas systems) or on heterogeneous processes with a participation of O atoms (in oxygen-containing plasmas). It was suggested that an increase in O2 fraction in a feed gas may suppress the effective reaction probability through decreasing amounts of free adsorption sites and oxidation of surface atoms.This work summarizes the results of our previous studies related to investigations of reactive ion etching kinetics and mechanisms for widely used silicon-based materials (SiC, SiO In particular, silicon carbide is a very promising semiconductor featuring high thermal conductivity, high breakdown voltage and wide bandgap [xNy films which also exhibit a dielectric nature and are characterized by both low density of surface states and high dielectric permittivity [xNy is a very attractive material for optical devices due to having quite low optical loss (less than 0.2 dB/cm at 1550 nm [2 and 2.0 for Si3N4) which may be adjusted through a change in the O/N ratio [In our days, silicon-based electronics still keep the dominant position in the worldwide production of various integrated circuits and discrete electronic devices. The chemical base of such devices is represented by the silicon itself, which is normally plays the role of the substrate material, as well as by three main silicon-based substances, such as SiC, SiO bandgap . Accordi bandgap ,2,3. Sil bandgap . In addiittivity . It was  1550 nm ,8) and a3N4 and/or SiOxNy layers. Recently, strong requirements to devise dimension and performance pre-determine the use of “dry” patterning techniques, namely the reactive ion etching (RIE) method. The main feature of RIE is the simultaneous action of two parallel etching mechanisms, such as physical sputtering and ion-assisted chemical reaction [xHyFz [4 exhibits the highest z/x ratio and, thus, is characterized by the domination of etching over surface polymerization for typical RIE conditions [4F6, C4F8, CHF3 and CH2F2) exhibit a high polymerization ability that results in the deposition of a fluorocarbon polymer film on the treated surface. Though the last phenomenon lowers absolute etching rates and causes etching residues, it positively influences the etching anisotropy for silicon  as well as allowing one to obtain noticeably higher etching selectivity for couples of SiO2/Si and SiO2/Si3N4 (due to different thicknesses of polymer films on oxygen-free and oxygen-containing surfaces) [Obviously, since most real devices have complicated multi-layer structures, the corresponding device fabrication process needs the precision patterning of both the silicon substrate and preliminary deposited SiC, SiO, Sireaction ,10. In sn [xHyFz ,12,13,14nditions ,13. At turfaces) ,11. TherUntil now, there have been many experimental studies  belongs to F atoms. The role of CFx (x = 1–3) radicals as etchant species is almost negligible; it works only through the ion-induced defluorination of deposited fluorocarbon polymer film [The main contribution to the chemical etching pathway for all above-mentioned materials under typical RIE conditions  and C–F2 plasma ,27 that 2 plasma ,29,30. A2 plasma . Similar2 plasma .3N4 can also follow a spontaneous mechanism  an increase in Si3N4 etching with increasing gas pressure and input power [2) Si3N4 etching rate in the CF4 + O2 plasma [The chemical interaction of F atoms with Si0 kJ/mol  is small0 kJ/mol . This isut power ,32 and  SiO2 etching rate in the CF4 + O2 plasma [3N4 [The chemical interaction of F atoms with SiO9 kJ/mol ). That iompounds ,14. The 2 plasma ,23, simi2 plasma  and Si3Nsma [3N4 ,33,34.Analysis of the above data allows one to formulate at least two serious problems which require additional justifications and research efforts. Firstly, a significant part of published works have a mostly experimental nature and, thus, discuss both etching and polymerization effects without data on plasma parameters and plasma chemistry. As such, even the very detailed and accurate studies , ternary mixtures which combine the fluorocarbon component with Ar and O2 (as gas systems where reactions involving O and O(1D) species influence the densities of active species and polymer decomposition rates [In recent years, we performed a series of research works dealing with effects of gas mixing ratios in two- and three-component fluorocarbon gas mixtures ,41,42,43on rates ,10,11,12To understand how the chemical nature of the fluorocarbon component and corresponding To figure out differences in steady-state densities of F atoms and polymerizing radicals under the same processing conditions in light of their formation/decay kinetics as well as to evaluate the ability of additive gases  to adjust gas-phase compositions in corresponding gas systems;To compare RIE performances for both non-oxygenated and oxygenated gas systems with respect to various silicon-based materials in terms of etching rates and etching selectivity as well as to suggest corresponding etching mechanisms and limiting stages through correlations between fluxes of active species and obtained etching kinetics.Experiments were carried out in a planar inductively coupled plasma (ICP) reactor , the sam2 plasma before and after each measurement. From our previous works  provided experimental data on electron- and ion-related plasma parameters such as electron temperature , it 2 and Si3N4 (or the non-stoichiometric SiNx) were studied using fragments of Si (100) wafers without or with a preliminary deposited layer of the corresponding material. SiC films with a thickness of ~150 nm were produced by rf magnetron sputtering of 99% SiC target in Ar plasma. The substrate surface was preliminarily cleaned from organic contaminations through consequent washing in trichloroethylene, acetone, methanol and deionized water. More details about the deposition method and regimes are available in Ref. [2 films with a thickness of ~500 nm were produced using the low-pressure chemical vapor deposition (LPCVD) technique. The precursor gases were SiH4 and O2, and the substrate temperature was 425 °C. More details about the deposition method and regimes may be found in Ref. [x films with a thickness of ~400 nm were produced by the plasma-enhanced chemical vapor deposition (PECVD) method. The precursor gases were SiH4, He, NH3 and N2. The deposition process was carried out in an rf (13.56 MHz) plasma source operated at 300 W and 800 mTorr. The substrate temperature was 150 °C. More details about the deposition method and regimes may be found in Ref. [3N4  kinetic model ,48. A se + Ar/O2 ,48,49,50 + Ar/O2 ,52,53 an + Ar/O2 ,43,48,544–, CHF3– and C4F8– based plasmas has been demonstrated in several works [The electron energy distribution function (EEDF) has a nearly Maxwellian shape. The applicability of Maxwellian EEDFs to describe electron-impact kinetics in low-pressure CFal works ,56,57,58exp−C/Te ,56,58 baThe dependence of gas temperature, geometry ,51,52,53geometry .The heterogeneous loss of atoms and radicals is described by first-order recombination kinetics with k≈γυT/Λ ,37,38, wn length  and υT=8om Refs. ,56,58,604–, CHF3– and C4F8– based plasmas, even with addition of O2, is low enough to assume The electronegativity of low-pressure CFme ne≈n+ ,56,57,58The effective ion mass was evaluated according to Blank’s law as yX/1/mX+ , where yt of kiz ,58.The output model parameters were the volume-averaged steady-state densities of plasma active species and their fluxes to the etched surface. It should also be noted that the combination of the used modeling algorithm and kinetic scheme provides an adequate description of the plasma chemistry in the given gas systems ,56,57,582 and Si3N4 have been discussed in detail in Refs. [The basic features of reactive ion etching processes in fluorocarbon-based plasmas as well as related reaction mechanisms for Si, SiOin Refs. ,39,61,62Under reactive ion etching conditions , the measured etching rate, ys+Rchem ,61. ThesThe ion-assisted chemical reaction has the rate of γRΓF ,38, wherγR≈s01−θ  depends nterface .The physical sputtering  has the rate of YSΓ+ ,63, wher ~  Miεi ,36,37 isr MiεiΓ+ . Obviousx  radicals, and the polymerization ability increases in fluorine-poor plasmas [4- and C4F8- based plasmas while 3- based plasmas). Accordingly, parameters The growth of the fluorocarbon polymer film is provided by the CF plasmas ,24. AccoΓF ratio ,36,37, wectively ,36,40,484, CHF3 and C4F8 gases has been studied in earlier works [4 + Ar, CHF3 + Ar and C4F8 + Ar plasmas under the condition of The influence of input RIE process conditions  on electron- and ion-related plasma parameters in CFer works ,64,65,66-4–C4F8–CHF3, while the shapes of 3 plasma results from low electron energy losses for the ionization of the dominant neutral component HF (Hydrogen Fluoride) compared with that for CF4 molecules in the CF4 plasma and CF2 radicals in the C4F8 plasma (+ + 2e (−10 cm3/s at 4 + e → CF3+ + F + 2e (−9 cm3/s at 2 + e → CF2+ + 2e (−9 cm3/s at 4) < 4F8) is connected with higher electron energy losses for vibrational and electronic excitations for CF4 compared with CF2. An increase in 4 + Ar gas mixture causes a nearly proportional decrease in electron energy losses for vibrational and electronic excitations of CFx species as well as leads to the opposite change in energy losses for ionization due to R4: Ar + e → Ar+ + 2e . Mechanisms providing such a phenomenon are the condition m + e → Ar+ + 2e, where Arm = Ar  are the metastable Ar atoms. Accordingly, it is analogous for ion current densities 2 for CF4 + Ar; 1.55–2.20 mA/cm2 for CHF3 + Ar and 1.05–2.36 mA/cm2 for C4F8 + Ar at 0–75% Ar) that determine ion fluxes to the etched surface 4 + Ar and C4F8 + Ar plasmas at The plasma density increases in the sequence of CCF4–CHF3  due to t3–CF4–C4F8 as well as decreases with increasing Ar fraction in a feed gas . Quite close values of 3 + Ar and CF4 + Ar plasmas, respectively. At the same time, an increase in Ar fraction above 60% changes the situation due to the rapid increase in 4F8 + Ar plasma.The negative dc bias at feed gas . This re4 + Ar, CHF3 + Ar and C4F8 + Ar plasmas. From 4 plasma are original CF4 molecules and F atoms [3–CF2–CF [x + e → CFx−1 + F + e as well as higher heterogeneous loss probabilities for less saturated species. The main source of fluorine atoms  is represented by R6 for 4 + e → CF3+ + F + 2e. Accordingly, the decay of atomic species is provided by heterogeneous processes R8: F + F(s) → F2 and R9: F + CFx(s) → CFx+1, where index “(s)” points out the adsorbed state of corresponding particles. According to 3 plasma are HF, CHF3 and CFx (x = 1–3). The high density of HF  the high efficiency of gas-phase reactions R11: CHFx + F → CFx + HF . F atoms ,53,55. T3–CF2–CF  are due th Refs. ,66,67) i = 3, 4) ,58,60. TWhen analyzing data of 4 + Ar and C4F8 + Ar plasmas while 3 + Ar plasma) increases in the sequence of CF4–CHF3–C4F8, and the gap between first and last gas systems reaches two orders of magnitude. Such a phenomenon is because the C4F8+Ar plasma provides the maximum production rate of CF2 radicals by R16, R18 and R20. An increase in 3 + Ar (by ~4.2 times at 0–75% Ar) and C4F8 + Ar (by ~3.8 times at 0–75% Ar) plasmas but produces a much slower effect in the case of the CF4 + Ar gas system (by ~1.4 times at 0–75% Ar). The reason is the increasing dissociation frequencies for multi-atomic fluorocarbon species  due to an increase in both electron temperature and electron density. Accordingly, similar behaviors were also obtained for the total flux of polymerizing radicals to the etched surface The total density of polymerizing radicals ace Γpol a.4–C4F8–CHF3, and the gap between first and last gas systems reaches around three times. The lowest 3 plasma results from the (a) low F atom formation rate because 4 + Ar and C4F8 + Ar plasmas , the reason for this phenomenon is the same behavior of the F atom formation rate in R6 and R7 due to increasing process frequencies, as was mentioned above. Oppositely, CHF3 + Ar and C4F8 + Ar plasmas exhibit nearly constant frequencies for R6, R7 and R14 (due to opposite changes in electron temperature and electron density) and, thus, a nearly proportional decrease in F atom formation rate with increasing Ar fraction in the feed gas. As such, the slow change in 12 cm−3–3.0 × 1012 cm−3, or by ~1.3 times in CHF3 + Ar and 7.1 × 1012 cm−3–4.1 × 1012 cm−3, or by ~1.7 times in C4F8 + Ar at 0–75% Ar) is not connected with electron impact kinetics but results from rapidly decreasing F atom decay frequencies in gas-phase reactions R11 and R20. Similar tendencies were also obtained for the flux of fluorine atoms to the etched surface The density of fluorine atoms ith Ref. ) is only4F8 + Ar plasma and reaches the minimum in CF4 + Ar plasma. Therefore, the same order is also followed for the steady-state thicknesses of polymer films, as follows from 4 + Ar plasma is that it provides nearly constant values for 4/Ar mixing ratio on both surface polymerization rate and residual amount of polymer on the plasma-treated surface. Similar results were obtained in Ref. [3 + Ar and C4F8 + Ar plasmas leads to a nearly proportional decrease in the parameter 4F8 + Ar plasma compared with CHF3 + Ar one has the direct experimental confirmation. In particular, Ref. [3 plasma causes 1.5–2 times lower 2 and Si3N4 surfaces compared with those after C4F8 plasma. The almost identical value of ~2.1 follows from the ratio of The comparison of  in Ref.  by experar, Ref.  reported4 + Ar and C4F8 + Ar plasmas. Since these ones represent gas systems with the maximum difference in polymerizing ability, corresponding data may serve for better understanding the features of low- and high-polymerizing plasmas. Analysis of Experiments with pure Ar plasma indicated that etching rates for all four materials  or the etching regime controlled by the polymer thickness through the transport of etchant species to the film/etched surface interface (in the case of high-polymerizing C4F8 + Ar plasma).Quite similar t et al.  for Si, 2 and SiC etching rates from 4 + Ar plasma cannot be associated with the change in 2/SiC reaction kinetics are not influenced by surface polymerization but are sensitive to ion bombardment through desorption of reaction products and the formation of adsorption sites for F atoms. In fact, such a situation represents a typical case of ion-assisted chemical reaction in non-polymerizing gas systems [2 surely mean that the production of adsorption sites for F atoms in the ion-assisted process SiOx(s.) → Si(s.) + xO does not limit the SiO2 etching rate. In our opinion, such a situation is due to high ion bombardment intensity.The non-monotonic Si, SiORchem/ΓF b. Obviou Γpol/ΓF b and ΓpoMiεiΓ+ΓF d in the f MiεiΓ+ c that re systems ,69,70. O2 and SiNx etching rates from 4F8-based plasmas, one can reasonably suggest that (a) the RIE process in pure C4F8 plasma is limited by the transport of etchant species through the thick polymer film and (b) the transition to Ar-rich plasmas activates a chemical reaction by providing better access of F atoms to the etched surface. As such, the formally similar changes in 4 + Ar and C4F8 + Ar plasmas are caused by different mechanisms.The monotonically increasing Si, SiOaterials d. The ma4F8 + Ar plasma, one can simply correlate our experimental data with those from published works [x, SiO2 and Si are nearly equal to ratios of corresponding reaction probabilities. In particular, x and SiO2/SiNx etching rate ratios  → Si(s.) + xO and the increasing amount of adsorption sites for F atoms. Obviously, the latter increases the probability of chemical reaction Si(s.) + xF → SiFx. In addition, x, SiO2 and Si in C4F8 + Ar plasma are influenced by the polymer film thickness and are characterized by the In order to confirm the above assumption on etching mechanisms in the Ced works ,21,22,23 hpol,Si ,20. In opol,SiNx ,20 but abardment ,12,13. Tin Refs. ,16,20,714 + Ar and C4F8 + Ar plasmas are influenced by different factors, one can suggest that the CF4/C4F8 mixing ratio in the three-component CF4 + C4F8 + Ar gas system may also be used to adjust the output characteristics of the RIE process. From 4 for C4F8) leads to a noticeable increase in both electron temperature and ion current density. An increase in 4F8-rich plasmas may result from decreasing electron energy losses for vibrational and electronic excitation of dominant neutral species, as the gas phase is enriched by less saturated radicals (2F4 + e → C2F3+ + F + 2e) and (b) an increase in ionization rate coefficients for all neutral components together with 4F8) intensification of ion bombardment.Since effective probabilities of ion-assisted chemical reactions in CFradicals a. The gr4 molecules as well as leads to the rapid growth of 11 cm−3–3.3 × 1013 cm−3, or by ~100 times at 0–50% C4F8) and 10 cm−3–2.3 × 1013 cm−3, or by ~330 times 0–50% C4F8). The reason is that both species directly appear from C4F8 in R15 and R16, while CF2 is also the main dissociation product of C2F4 in R18. The decreasing dissociation rate of CF4 molecules  suppresses the formation of CF3 radicals but does not result in a decrease in 12 cm−3–9.2 × 1012 cm−3, or by ~4 times at 0–50% C4F8. The reason is the increasing rate of R9 that rapidly transforms CF2 into CF3. The increasing rate of R6 for 4 + Ar and C4F8 + Ar plasmas. In particular, an increase in electron density toward C4F8-rich plasmas as well as higher x species provide a change in the dominant formation mechanism for F atoms . The opposite change in F atoms’ density (by ~2 times 0–50% C4F8) is due to the rapid increase in their decay frequency in both heterogeneous (R9) and gas-phase (R20 and R22: C2F3 + F → C2F4) processes. This fact is in good agreement with experimental results for CF4 + Ar and C4F8 + Ar plasmas at input powers below 1000 W [The data of w 1000 W . Accordi2 etching rates  as well as a more than twofold increase in SiO2/Si etching selectivity (1.2–2.8 at 0–50% C4F8). Considering that corresponding etching processes are provided by the ion-assisted chemical reaction of F atoms, the obtained differences in etching kinetics may be related to different behaviors of effective reaction probabilities. In fact, the data of 4F8) as well as the rapid fall of 4F8). Obviously, the behavior of 4 for C4F8 changes the limiting stage for the Si etching process from the chemical reaction itself (in the case of low 4 + 50% Ar plasma) to the transport of F atoms through the thick polymer film. Accordingly, the continuously increasing 4F8- rich plasmas lowers 2. As such, one can obtain a nearly constant 4/C4F8 mixing ratio in the CF4 + C4F8 + Ar gas system increases the differences between Si and SiO2 etching mechanisms as well as providing an effective tool to adjust the SiO2/Si etching selectivity.From etching experiments a, it was4 + O2 + Ar, CHF3 + O2 + Ar and C4F8 + O2 + Ar gas mixtures with a constant 50% fraction of the fluorocarbon component. Accordingly, the main variable parameter in all three cases was the O2/Ar mixing ratio in order to illustrate how the substitution of inert gas for the chemical active one influences gas-phase plasma parameters and RIE process characteristics. It is important to note that such a gas mixing regime is different compared with that studied for many binary fluorocarbon + O2 gas systems where an increase in The subjects of this chapter are the ternary CF2 in all three gas mixtures results in similar changes in electron- and ion-related plasma parameters. Corresponding results may be briefly commented as follows:From 2-rich plasmas results from an increase in electron energy losses in low-threshold inelastic processes, such as vibrational and electronic excitations of both O2 itself and molecular products of plasma chemical reactions—CO, CO2, FO and CFxO  + e → O2 (V > 0) + e (2 + e → O2 (a1∆) + e (2 + e → O2(b1∑) + e (A decrease in and CFxO . In partA decrease in plasma density toward higher 12–15 eV ) exceed 2-rich plasmas (An increase in negative dc bias is mainly due to the opposite change in ion flux. The reason is that the lower ion flux leads to weaker compensation for the excess negative charge provided by bias power source at  plasmas .2-rich plasmas (a) suppresses densities of fluorocarbon radicals and (b) provides the formation of CO2, CO, FO and CFxO molecules, with CF2O as a dominant component. At the same time, the kinetics of F atoms exhibit principal differences and are worth brief discussion.4 + O2 + Ar plasma, the substitution of Ar for O2 noticeably reduces the F atom formation rate in R6 and R7 even under the condition of 3 radicals is the result of their conversion into CFxO species through R26: CFx + O → CFx−1O + F, R27: CFx + O(1D) → CFx−1O + F, R28: CF3 + CFO → CF4 + CO and R29: CF3 + CFO → CF2O + CF2 with the participation of O, O(1D), and CFO itself. The change in 4 molecules in both gas-phase and heterogeneous recombination pathways. In addition to R26 and R27, an increase in 2O + e → CFO + F + e and (b) increasing efficiency of R32: F2 + e → 2F + e. High formation rates and densities for CFO species are provided by R31 and R33: CO + F → CFO, while the same effect for CF2O molecules results from R29, R34: 2CFO → CF2O + CO and R35: CFO + F → CF2O. The acceleration of R32 results from the rapidly increasing F2 density due to R36: CF2O + O(1D) → F2 + CO2 and heterogeneous recombination of F atoms. The transition to highly oxygenated plasmas (2-rich plasmas are provided mainly by R38: F2 + O(1D) → FO + F and the heterogeneous interaction between F and O atoms. As a result, the total effect from R30, R31 and R37 becomes greater than the sum of R6 and R7. Apart from these, the rates of the atom molecular processes R38, R39: FO + O → F + O2, R40: FO + O(1D) → F + O2, R41: 2FO → 2F + O2 and R42: CFO + O → CO2 + F increase together with 2 leads to the monotonic increase in the F atom production rate as well as causing the same change in the F atom density  is connected with increasing their decay rates due to R26 and R27 as well as decreasing formation rates in CHFx + F → CFx + HF (R11). Accordingly, the total effect of CFx + e → CFx−1 + F + e (R6) and R45: CHFx + e → CHFx−1 + F + e in respect to the production of F atoms shows a decrease with increasing 2). Therefore, the substitution of Ar for O2 strongly suppresses all F atom formation pathways which work in the CHF3 + Ar plasma. Another remarkable fact is the much lower efficiency of additive F atom formation pathways with a participation of oxygen-containing species. In particular, the non-principal contributions of R31 and R23 are because corresponding rates are limited by the formation of CF2O species in R35 and the corresponding heterogeneous counterpart. Their total rate reaches the maximum at 20–30% O2 and remains lower compared with that for R14. Similarly, contributions of R37 and R39–R41 are limited by the formation rate of FO molecules in heterogeneous recombination of atomic species. The latter is also less effective compared with previous gas systems due to (a) lower O and O(1D) production rates in R46: O2 + e → 2O + e and R47: O2 + e → O + O(1D) + e and b) faster decay of oxygen atoms in R26, R27, R43 and R44. All of these result in a decrease in the total F atom formation rate toward O2-rich plasmas . At the same time, rapidly decreasing densities of CHFx and CFx radicals reduce the effective decay frequency for F atoms in both heterogeneous (R9) and gas-phase (R11) reactions. Since the last tendency appears to be faster compared with a decrease in the F atom formation rate, a monotonic increase in both F atom density  and CFx + O(1D) → CFx−1O + F (R27). This provides the monotonic decrease in 13 cm−3–1.2 × 1013 cm−3 for x = 2 and 2.9 × 1013 cm−3–1.3 × 1012 cm−3 for x = 1 at 0–50% O2, see 4 + O2 + Ar and CHF3 + O2 + Ar plasmas. The reason is that the effective loss of O2 molecules through R48: CF + O2 → CFO + O (−11 cm3/s) and R49: C + O2 → CO + O (−11 cm3/s) limits the formation rates for O and O(1D) species in R46 and R47. The luck of oxygen atoms reduces the effect of R26, R27, R30 and R31 on the F atom formation kinetics  and, thus, leads to monotonically decreasing F atom density and flux. Though changes in In the CΓF ratio a that po4-, CHF3- and C4F8- based plasmas in the presence of oxygen exhibit the same order of their polymerizing abilities, as was mentioned for non-oxygenated binary mixtures with Ar. As such, the addition of O2 up to 50% does not change the basic rule concerning the correlation between the polymerizing ability and the xHyFz molecules. Second, the substitution of Ar for O2 in all three gas systems suppresses the polymer deposition rate through increasing the gap between densities of F atoms and polymerizing radicals. The stronger effect for CF4 + O2 + Ar and CHF3 + O2 + Ar plasmas is because of the increasing density of F atoms and opposite changes in 2 in all three gas systems results in decreasing polymer film thickness. Again, the stronger change in 4 + O2 + Ar and CHF3 + O2 + Ar plasmas is due to the simultaneous acceleration in physical  but shows formal agreement with 2 mean identical mechanisms are influencing the behaviors of effective reaction probabilities for these materials, while spontaneous F + Si reaction kinetics are less sensitive to the ion bombardment intensity.From and SiO2 b contrad2-rich plasmas reduces the amount of free adsorption sites for etchant species and suppresses xOy and SiBrxOy compounds have much lower volatility compared with SiClx and SiBrx. Therefore, if the same rule works for the fluorine-based etching chemistry, the oxidation of reaction products R52: SiFx(s.) + yO → SiFxOy(s.) must assume their ion-stimulated desorption pathway R53: SiFxOy(s.) → SiFxOy, which is less effective compared with both spontaneous desorption of SiFx (x = 4) and ion-stimulated desorption of SiFx (x < 4). As such, the acceleration of R52 together with decreasing efficiency of R53 increases the residual amount of reaction products on the etched surface and, thus, reduces In our opinion, the similar decrease in both om Refs. ,73,74, i4F8 + O2 + Ar plasma, an increase in 2 and Si3N4  in multi-component fluorocarbon gas mixtures. The latter were represented either by one fluorocarbon component  with Ar and O2 or by two fluorocarbon components with one additive gas. In contrast to “classical” works [In this work, we summarized and re-discussed, on a comparative scale, the results of our previous studies related to reactive ion etching kinetics and mechanisms for silicon and silicon-based materials  are strongly dependent on individual properties of the corresponding fluorocarbon component. In CF4 + Ar, CHF3 + Ar and C4F8 + Ar plasmas, an increase in Ar fraction in the feed gas always (a) results in sufficient changes in electron temperature and plasma density ; (b) increases the intensity of ion bombardment; and (c) causes a lower-than-proportional decrease in F atom density. The last feature is due to either an increase in electron impact dissociation frequencies for CFx species (in the case of CF4 + Ar plasma) or a decrease in F atom loss frequencies in gas-phase reactions (in the case of CHF3 + Ar and C4F8 + Ar plasmas). In CF4 + O2 + Ar, CHF3 + O2 + Ar and C4F8 + O2 + Ar gas mixtures, the substitution of Ar for O2 causes similar changes in electron- and ion-related plasma parameters and suppresses densities of polymerizing radicals but has a different impact on F atom kinetics. As such, even the formally similar changes in F atom density for CF4 + O2 + Ar and CHF3 + O2 + Ar plasmas result from different plasma chemical reaction mechanisms.It was demonstrated that in both non-oxygenated and oxygenated gas systems, plasma polymerization ability (the deposition rate and the steady-state thickness of polymer film) correlates with the It was found that the dominant etching mechanism in all cases is represented by the chemical etching pathway , while the latter does not follow the behavior of F atom flux. This fact points out the process-condition-dependent effective reaction probability for F atoms. The analysis of correlations between the effective reaction probability and fluxes (or flux-to-flux ratios) of plasma active species allows one to suggest the limiting stage of the etching process. Depending on the gas system, this may be the ion-stimulated desorption of reaction products, the transport of F atoms through thick polymer film or heterogeneous reactions with the participation of oxygen atoms under the condition of thin polymer film. Most of the model-predicted results are in good agreement with published experimental data on etching and polymerization kinetics in various fluorocarbon-based plasmas.


Serial analysis of circulating tumor cells (CTCs) such as androgen receptor splice variant 7 is useful in selecting treatments for castration-resistant prostate cancer (CRPC). We report a case who had been positive for androgen receptor splice variant 7 in CTCs before docetaxel, and was subsequently treated with abiraterone rechallenge because of the negative conversion of androgen receptor splice variant 7 following docetaxel. Although, the rechallenge of anti-androgen agent based on CTCs analysis is expected to be an effective approach, it is yet to be reported. Thus, we chose the candidate for abiraterone rechallenge based on serial CTCs analyses by the AdnaTest. As a result, the patient responded to abiraterone that he once had developed resistance to. Our findings reinforce the utility of AR-V7 as a biomarker in the setting of post-chemo androgen-targeted-therapy rechallenge. Most metastatic prostate cancers are treated with androgen deprivation therapy (ADT) at the outset. Nevertheless, most of them progress to acquire resistance to the primary ADT, which is a state called castration-resistant prostate cancer (CRPC). Novel anti-androgen agents , CYP17A1 inhibitor that inhibit the production of testosterone (abiraterone), two taxane-based chemotherapies (docetaxel and cabazitaxel) and radium-223 have been approved by the US Food and Drug Administration for CRPC treatments  and circulating tumor DNA are drawing attention in recent years. In terms of CTCs, Antonarakis's study propounded testing androgen receptor splice variant 7 (AR-V7) expression in CTCs , 6. In tTo this end, we performed a feasible bedside CTC testing for CRPC patients. Herein, we report a case of a CRPC patient who was successfully treated based on sequential CTC analysis .This study was approved by the institutional review board of Juntendo hospital (admission number: 14-052), and all experiments were carried out in accordance with approved guidelines. Written informed consent was obtained from the patient for the publication of any potentially identifiable images or data included in this article.2) and a total of six cycles was given. Radiofrequency ablation (RFA) was performed for a liver metastasis since it was a singular and small lesion (<30 mm), which is the indication for RFA. After the administration of docetaxel, PSA declined to 0.166 ng/dl. Furthermore, CTC analysis confirmed the negative conversion of AR-V7 in CTCs. Due to the favorable response to docetaxel, docetaxel treatment was suspended and only LH-RH antagonist was continued for the following 5 months as a drug holiday. Subsequently, when PSA rose to the pre-docetaxel level (2.29 ng/dl), we tested AR-V7 expression again. Resultantly, because AR-V7 still remained negative, we opted for abiraterone rechallenge based on the following discussion with patient. The attending physician explained to the patient that enzalutamide may cause adverse events, such as fatigue and anorexia. Because the patient had no adverse events during the administration of abiraterone, he wanted to resume abiraterone. Also, because he had experienced symptoms of alopecia and numbness that adversely affected his job at the time of docetaxel administration, he did not want to be treated with chemotherapy while at work.In November 2007, a 62-year-old man was diagnosed as localized prostate cancer with no metastasis  and underwent radical prostatectomy. In April 2008, he had a PSA recurrence (2.4 ng/dl) and the combination androgen blockade therapy  was initiated. In March 2015, he presented a local recurrence, and the treatment was switched to abiraterone  combined with LH-RH antagonist and prednisolone. In addition, radiation therapy (60 Gy/30 fr) was done against the local recurrence, which resulted in marked tumor disappearance. His disease was well-managed with abiraterone for 13 months. In June 2016, he showed PSA progression and a liver metastasis occurred. At this point, AR-V7 was positive by the AdnaTest . Therefore, we selected docetaxel of every 4 week  than the level before abiraterone rechallenge. In line with this, no other metastases were found. PSA elevation was not observed for 8 months. Afterward, when PSA rose to 4.00 ng/dl 10 months after abiraterone rechallenge, we analyzed AR-V7 expression in CTC again. CTC analysis showed that the expression of AR-V7 was converted to positive. Based on the CTC analysis, subsequent cabazitaxel was started. Although, PSA was well-controlled for 9 months after cabazitaxel administration, PSA rose continually after 10 cycles of cabazitaxel, and computed tomography image showed the emerge of the bladder invasion.Here, we reported the case of a CRPC patient with liver metastases, who was treated with abiraterone rechallenge based on AR-V7 status in CTCs.Nakazawa et al.  reportedThe clinical outcome of treatment with abiraterone or enzalutamide for patients who progressed on abiraterone has been shown in COU-AA-302 trial. Most of these patients received chemotherapy before subsequent abiraterone or enzalutamide. PSA response (defined as a PSA reduction of at least 50% from baseline) was observed in 24 of 55 patients who received subsequent abiraterone and in 22 of 33 patients who received subsequent enzalutamide . BesidesIn our report, changes in AR-V7 expression appeared to be reflective of the treatment effect. For example, the negative conversion of AR-V7 occurred after docetaxel and RFA for liver metastasis, both of which could have eliminated AR-V7-positive CTCs. Then, the withdrawal of docetaxel possibly stimulated the expansion of AR-V7-negative cells expressing full-length AR, which might have resulted in regained susceptibility to abiraterone rechallenge. Although, PSA elevation was observed after the abiraterone rechallenge, this treatment was able to suppress the increase in PSA for the following 8 months and delay the initiation of subsequent cabazitaxel treatment. Furthermore, abiraterone was effective only when AR-V7 was negative. These findings reinforce the utility of AR-V7 as a biomarker in the setting of post-chemo androgen-targeted-therapy rechallenge.On the other hand, we have a variety of issues we need to address in CTC research. Firstly, whether CTCs represent the entire tumor characteristics is questionable. Secondly, AR-V7 is not the only mechanism driving CRPC progression. The states of other mechanisms responsible for treatment resistance in CRPC such as dysregulated PI3K–AKT signaling, WNT signaling pathway and DNA repair defects need to be elucidated . ThirdlyTo the best of our knowledge, this is the first reported case of regaining susceptibility to the post-chemo anti-androgen agent with the concurrent negative conversion of AR-V7. Our result suggests that the rechallenge of post-chemo AR-targeted therapy based on AR-V7 testing can be a good strategy in treating CRPC.Written informed consent was obtained from the patient for the publication of any potentially identifiable images or data included in this article.All authors have significantly contributed to the study and are in agreement with the content of the manuscript. Each author's contribution is as follows: NN and MK performed the experiments. NN, MK, MN, and SH designed the study. NN and MK wrote the manuscript, and MN and SH revised it.SH has research grants from Astellas and Sanofi Aventis, honorarium from Astellas, Takeda, Astrazeneca and Sanofi Aventis and Janssen. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


In this review, we will look into the existing methods to study treatment resistance to androgen receptor targeted therapies in prostate cancer. This will encompass both the different existing preclinical models as well as the role specific models have played in the current understanding of resistance mechanisms. Prostate cancer is an androgen-driven tumor. Different prostate cancer therapies consequently focus on blocking the androgen receptor pathway. Clinical studies reported tumor resistance mechanisms by reactivating and bypassing the androgen pathway. Preclinical models allowed the identification, confirmation, and thorough study of these pathways. This review looks into the current and future role of preclinical models to understand resistance to androgen receptor-targeted therapies. Increasing knowledge on this resistance will greatly improve insights into tumor pathophysiology and future treatment strategies in prostate cancer. The androgen receptor (AR) is the main driver of proliferation in prostate cancer (PCa) cells, and thus is an important therapeutic target ,2. It coClinical targeting of the AR is achieved by LHRH agonists/antagonists and abiraterone or by blocking the AR ligand binding pocket with anti-androgens . Unfortunately, curative treatment of advanced PCa by these AR signaling inhibitors is prevented by the occurrence of resistance mechanisms ,2.To become resistant against these therapies, PCa cells have to overcome the lack of growth signals. The mechanisms can be broadly categorized into two groups: (1) mechanisms that reactivate AR signaling output ; and (2) mechanisms that bypass the AR by providing growth signals via other means .Different cell types are used as preclinical PCa models, each with their distinct features. The most commonly used PCa cell lines and their characteristics are shown in LNCaP is a cell line derived from a lymph node metastasis. It harbors a T877A AR mutation, with ligand promiscuity and has only a modest potential to form xenografts in nude mice . It has The big advantages of these cell lines are their relative simplicity and ease of culturing in different conditions. This enables the rapid validations of hypotheses and the simultaneous testing of multiple compounds. Also beneficial is the high amount of data that are already available on them  ,22. EachFor example, in Tran et all., they used LNCaP cells with increased expression of wild type AR and VCaP cells. In these cells, together with the derived xenograft model, the AR inhibitor MDV3100 was identified, which was later renamed to enzalutamide . PCa celDe novo resistance mechanisms can be studied in cellular models generated via genetically modifying PCa cells , but this largely limits their use in validation studies. In contrast to de novo resistance studies, cell lines with acquired resistance may lead to the discovery of novel resistance mechanisms, but it is challenging to identify the underlying mechanism . More reMouse xenografts are commonly created by transplanting human cell lines in mice. This can be performed in different locations: subrenal , orthotopic (in the mouse prostate), and subcutaneous (under the skin), each with its specific characteristics . CreatinFor example, in Nguyen et al., multiple PDX were developed, reflecting prostate cancer features such as AR amplification, PTEN deletion, TP53 deletion/mutation, RB1 loss, TMPRSS2-ERG rearrangements, SPOP mutation, MSH2/MSH6 genomic aberrations, and BRCA2 loss . From thThree-dimensional cell cultures can similarly be valuable in creating a basis to investigate cell–cell interactions. Cell lines can consequently be studied in a tumor microenvironment ,28. ThisFor example, in the spheroids of Eder et al., cancer-associated fibroblasts were co-cultured with LNCaP, LAPC4, and DuCaP. This made DuCaP resistant to enzalutamide, by increasing the Akt PI3K pathway (see further). Novel treatments can be proposed and tested in these resistant tumors .Transgenic technology has enabled mimicking genetic changes that have been discovered in PCa. The genes under investigation can be knocked out or altered specifically in mouse prostate luminal cells. In this way, GEMMs of different pathways that lead to treatment resistance in humans have been recreated, of which the most commonly altered mechanisms are represented in As a consequence, human PCa phenotypes can be mimicked in GEMMs, and murine metastatic signatures that can be relevant in humans can be discovered . While iBesides mimicking PCa phenotypes, GEMMs can also be used to study non-cancerous targets of hormone therapy. Multiple models studying the AR have been created from this perspective. Although these models do not directly result in novel prostate cancer treatments, their impact is indirect by improving the understanding of the AR and its pathways ,35 Tabl.For example, in the TRAMP model, researchers altered the expression of SV40 antigens to create prostate cancer models reflecting the heterogeneous AR and p53 expression and castration response seen in patients .Different patient-derived models have been reported, including primary cell cultures, patient-derived explants, and patient-derived xenografts . These mAt first, primary cells were grown in 2D cultures much like the cell lines discussed in Patient-derived explants consist of primary tumor biopsies that are kept in their integrity in culture ex vivo. The culture conditions have been optimized considerably so that these models retain the functional and structural characteristics of the tissue, which enables their successful use in preclinical studies ,42. ConsPatient-derived xenograft models are created by inserting tumor tissue in nude mice , C4-2b, ResA/B, and 22Rv1 ,45,46,47As the discussed preclinical models suggest that AR overexpression develops in settings with some remaining AR activity, more potent AR inhibition may prevent PCa cells from acquiring this mechanism of resistance. This could be achieved by highly potent anti-androgens  that block AR activity even upon AR overexpression, and combination treatments . Pre-cliAnother therapeutic possibility in AR-overexpressing tumors consists of supraphysiological androgen treatment. In PCa cell lines and PDX models, high testosterone concentrations inhibit the MYC-E2F pathway and induce DNA damage ,51. A reSeveral mutations in the AR have been found in AR signaling inhibitors-resistant disease. Many of these mutations are located in the ligand binding pocket within the AR ligand binding domain. AR ligand binding domain mutations can either broaden the agonist spectrum (ligand promiscuity), prevent the binding of anti-androgens, or even convert anti-androgens into agonists ,54. ThisAR signaling inhibitor treatment has been shown to induce truncated versions of the AR in cell cultures as well as in patient material. The AR-V7 variant is most frequently expressed in mCRPC tissue and associated with a lower response to abiraterone and enzalutamide treatment . DiffereThus, drugs that target the transcription activation function in the amino terminal domain of the AR might provide a new therapeutic strategy. Such compounds are in the preclinical phase . Other wNR3C1 or GR) and AR correlates was found upon proteasome inhibition, where there was an accumulation of GR with a lowering of AR [The first evidence of glucocorticoid receptor  showed reduced sensitivity to enzalutamide . This waA recent study in mCRPC patients found IL6 levels to be associated with de novo abiraterone and enzalutamide resistance . CytokinIL6 is a well-established regulator of PCa progression and circulating IL6 levels are a predictive biomarker for poor prognosis ,87. In LMany unsolved questions remain. For instance, there is conflicting evidence with regards to the exact mechanisms of AR outlaw activation. In addition, there is no information available if outlaw activation alters the cistrome of the AR and thus changes the growth signals in the cells. This is further complicated by the fact that most pre-clinical research on this topic is limited to the LNCaP cell line, and it is thus difficult to generalize the findings. For instance, an ex vivo study with prostate tissue cultures of treatment-naive patients undergoing radical prostatectomies found that galiellalactone consistently reduces AR activity in benign tissue but has mixed effects in cancerous tissue . FurtherNeuroendocrine prostate cancer (NEPC) is an aggressive, AR-negative form of PCa associated with poor prognosis for the patient. However, NEPC is an umbrella term that actually describes two very different kinds of cancer: (1) neuroendocrine carcinoma that developed within the prostate, or (2) prostate adenocarcinoma cells that transdifferentiated into a neuroendocrine-like PCa cells ,97. ThesEtiologically, GEMMs with a prostate-specific knock out of p53 and RB1 showed more neuroendocrine transdifferentiation, suggesting that this process is caused by cumulative mutations . This se+/alpha2beta1hi/CD133+) [Stem cells and stem-like signatures reflect a regenerative and aggressive PCa phenotype. These tumors are characterized by specific surface markers  . There i/CD133+) ,105.Stemness signatures are commonly associated with low AR signaling. Commercial cell lines PC 3 and DU 145 cells are AR-negative and express stemness markers ,107. TheStemness markers moreover increase in hormone treated models. After androgen deprivation, increased stemness was seen in LuCaP35 prostate tumor explants . Upon enSince several AR-targeted therapies  have been introduced in the clinic, it is crucial to know whether there is cross-resistance or whether there is an optimal sequence of treatments .Hereby, preclinical studies were crucial to support the development of clinical trials. In cell lines, cross-resistance between AR-targeted therapies is commonly observed ,46. SequIn conclusion, preclinical models show a strong cross resistance to AR targeting therapies. Clinical trials confirm the response to androgen deprivation treatment to be associated to the response to the new AR-targeting therapies, strengthening this hypothesis .Cell culture experiments showed a clear cross resistance to the taxanes docetaxel and cabazitaxel in hormone refractory cell lines ,112. XenAs prostate cancer is a heterogeneous disease, clinical samples should be analyzed in depth to yield strong and highly specific markers that predict treatment response ,120,121.For example, in Karthaus et al., the regenerative potential of prostate cells was studied at the single cell level at different time points after castration. By doing so, they investigated the changes and regenerative potential of murine and human cells ,122.Novel targeted therapies are being developed to treat patients based on their individual molecular profile . By reveAs an example, the AR overexpressing LNCaP cell line contributed to the development of AR signaling inhibitors .Although the value of novel treatments is determined in clinical trials, a tight association between preclinical treatment response and the clinical response of PCa patients is seen . Novel tPreclinical models are a fundamental aspect in prostate cancer research and often start as proof of principle (cell lines), to be replicated in animal models and finally in clinical trials. As translational studies unravel novel possibilities for targeted therapy, preclinical models will be essential in the development of these therapies.Basic and translational insights in the molecular mechanisms of androgen synthesis and AR action all started from cell lines, together with biophysical studies of the AR (like DNA and ligand binding) and, more recently, complex formation with coregulators . The AR-Preclinical models will prove to be important in assessing what therapies are likely to be effective based on the patient profile. Before we will be able to run clinical trials with drugs likely to be effective, thorough insights in the underlying prostate cancer biology and treatment resistance are needed.


The reliability of the questionnaire was tested using Cronbach’s alpha and intraclass coefficient (ICC). Results: The questionnaire was found to be reliable (α ≥ 0.6), with “social disability” having the highest score (α = 0.868). All domains showed an improvement (α < 0.005) in OHRQoL scores after treatment. Conclusions: the novel questionnaire tested in this study was found to be reliable and convenient to use, and demonstrated that prosthetic treatments have a significant positive effect on OHRQoL post-treatment scores.Objectives: the aims of this study were the development of a novel questionnaire to assess the impact of prosthetic treatments on oral health-related quality of life (OHRQoL) and the performance of a prospective pilot study. Background: the currently preferred OHRQoL measurement tool is the oral health impact profile-49 (OHIP-49), a self-report questionnaire which mainly focuses on general effects related to oral health. Materials and methods: A total of 24 adult participants  were recruited and asked to complete the novel questionnaire twice: once before the prosthetic treatment began and 4–6 weeks post-treatment. The assessment of the change in OHRQoL was based on the differences in participants’ answers before and after treatment. Data were analyzed using ANOVA with a repeated-measures method and  Dental and oral health both seem to have a significant impact on self-perception, psychological status, and human social status ,2. TheseOral health related quality of life (OHRQoL) is a broad term which deals with such psychological, social and emotional aspects of oral health ,8, and iDental prosthetic treatments may help in dealing with concerns regarding lack of aesthetics or dysfunctions, as most patients report high levels of satisfaction and increase in OHRQoL, as demonstrated in various studies ,17,18,19In light of the above, there seems to be a need to evaluate a tool that can used in routine dental care and assess the psychosocial effects of dental prosthetic treatments. Such a tool may help dental practitioners to better evaluate the importance of mental and social aspects of dental prosthetic treatments and their effects on their patients. In turn, it may lead to a better communication between the patient and the dental practitioner and ultimately lead to a better treatment outcome ,4,20. ThThe novel questionnaire was developed based on a systemic literature review and meta-analysis on articles published in Medline between the years 1985–2016 and included two search engines—PubMed and Ebsco—with initial filtering of the system by language (English), followed by a manual search using the keywords: psychological impacts, prosthodontics, oral health-related quality of life (OHRQoL), aesthetics, and combinations of the abovementioned.The literature lists were reviewed in order to determine which articles have the potential to identify metrics for the psychosocial effects on dental rehabilitation outcomes. The potential articles were those that reviewed and/or provided information about the indicators relevant to the effects we have defined, in the context of two main treatment modalities: removable versus fixed rehabilitations. Based on the conclusions that emerged from the literature review and the meta-synthesis process, a new questionnaire based on the relevant psychological metrics was formulated. The questionnaire is based largely on questions from the OHIP-49 and PIDAQ questionnaires. The novel questionnaire was developed by three authors: an oral rehabilitation specialist (EM), a clinical psychologist (JM), and a dental student (YL). The guidelines for writing the questionnaire were: contain fewer questions than OHIP-49 in order to be more convenient to use, rephrasing of questions whose answers were restrictive so that more patients will be able to agree with the saying, and removal of questions which were too specific, such as “have you had sore jaw” and “have you had painful gums”; the latter of these was replaced by a single question: “Do you have any pain in your mouth?” In addition, questions that were similar in meaning were deleted .The questionnaire contains 31 questions and statements, which are divided into six dimensions: functional disability, physiological pain, psychological discomfort, physiological disability, psychological disability, and social disability . The ansThe final questionnaire is attached to this work as After approval of the constructed questionnaire by the Tel-Aviv University Ethical Committee, a preliminary research was conducted to test the research hypothesis.The sample included 24 Israeli adults  who were treated by students at the Tel Aviv University School of Dentistry and underwent a dental rehabilitation process (lasting between 6–26 months), due to complete/partial tooth loss or teeth discoloration. Over 18 years of age and under 75 years.Patients at the School of Dentistry at Tel Aviv University.Good general health, no medical risks, including past or present chemotherapy or radiation.Ability to understand, respond, and complete the questionnaire.At least one tooth in need of prosthetic treatment: fixed partial denture (FPD), implant-supported, full or partial removable restorations, full or partial removable restorations supported by implants.Inclusion criteria:Exclusion criteria:Systemic illnesses that will prevent research participation.Oral disease that directly or indirectly affects rehabilitation.Oral disease that directly or indirectly affects OHRQoL.Failure to complete prosthetic treatments.Patients were asked to complete the new questionnaire twice: once prior to the onset of rehabilitation and approximately 6 weeks after the treatments’ completion. The internal consistency of the questionnaire before and after prosthetic treatments was statistically examined, being divided into the sub-topics, according to Cronbach’s alpha (α ≥ 0.6). The reliability of the different domains was calculated and presented as intraclass coefficient (ICC) .Assessment of the psychological implications and improvement in the patients’ QoL indices were made based on the answers given to the same question before and after treatment and were measured in specific patient-based measurements, which examined (for each of the questionnaires) differences between before and after prosthetic treatment as well as differences between the different types of treatment.The questionnaires and informed consent forms were provided directly to the patients during their visit to the university student clinics or in a personal meeting with them at the end of the rehabilitation and were manually filled.The gathered information was stored in an Excel file; data was stored in an examiner computer (Y.L) without enclosing any identifying details of the participants. The data included serial number of the respondent, age, gender, type of treatment, duration of treatment, and answers to the different items of the novel questionnaire. Statistical analysis was performed using the Statistical Package for Social Sciences for Windows Release 23.0 .The answers given to the questionnaires were analyzed using ANOVA with repeated measures analysis in order to evaluate the differences between before and after treatment, as well as differences between the permanent and removable rehabilitation groups. T-test and variance analysis were used to examine the relationships between subjects’ characteristics  and their effects on patients responses to the questionnaire.The internal consistency for the different questionnaire domains was found to be above 0.6, as detailed in Most treatments appeared to be under the subsection of fixed rehabilitation (16 patients) versus removable rehabilitation (8 patients). Under the removable rehabilitation sub-subject: full and partial removable dentures were included, and under the fixed rehabilitation sub-subject: crowns and bridges, implant supported crowns and bridges, implant supported fixed partial dentures, and implant supported partial dentures.The changes in OHRQoL values before and after treatment, combined with the effect of the type of prosthetic rehabilitation on this change, were subdivided into the sub-themes in the questionnaire and tested using ANOVA with repeated measures.An improvement in OHRQoL was achieved for each of the indices at the end of treatment. The degree of satisfaction  obtained at the end of rehabilitation was significantly higher than that measured before the start of treatment for both types of rehabilitations (D < 0.005). The two-factor ANOVA did not demonstrate a significant difference in the relationship between the type of rehabilitation and the degree of improvement in patient satisfaction at the end of rehabilitation. See The reported pain at the end of rehabilitation was significantly lower than that measured before the start of treatment for both types of rehabilitation (D < 0.005). The two-way ANOVA did not show a significant difference in the relationship between the type of rehabilitation and the degree of pain reduction of the patient at the end of rehabilitation. Moreover, the sum of the scores obtained for each type of rehabilitation (before and after rehabilitation) was very similar for both groups, meaning the degree of pain and the degree of pain improvement is very similar between the two groups at the two time points examined. See p ≤ 0.05). It can be seen that removable rehabilitation group) showed higher pre-treatment values. However, the degree of improvement for this measure at the end of rehabilitation appears to have been slightly more in the removable rehabilitation group than the degree of improvement in the permanent rehabilitation group. See The difference between rehabilitation types and their effect on the change in the psychological discomfort index was found to be insignificant  between treatment type and its effect on the degree of improvement in the physiological disability index were not significant. As can be seen in Interaction results , while the fixed rehabilitation group showed a marked improvement in the psychological limit at the end of treatment. See Social limitation reporting values obtained at the end were significantly lower than those measured before treatment, for both types of rehabilitation (D < 0.005). The two-factor ANOVA did not demonstrate a significant difference in the relationship between the type of rehabilitation and the degree of improvement in the patient’s social disability at the end of rehabilitation. Moreover, the summary of the value gaps obtained for each type of rehabilitation (before and after rehabilitation) was very similar for both groups. Thus, the degree of improvement in this measure is very similar between the two groups at the two time points examined. See There was no correlation between the degree of satisfaction with the physician and the change in OHRQoL values at the end of treatment. This may be explained by the specific dental care given by students at the dental clinics at Tel Aviv University. The degree of satisfaction with the treatment was very high  for all patients.p = 0.035). The latter suggests that men exhibit a greater degree of satisfaction with the physician.A total of 15 male and 9 female adults participated in this study. The improvement in OHRQoL before and after rehabilitation was not certain on any of the measures in the questionnaire, except for the last measure: describing the degree of satisfaction with the physician (for which p = 0.024). For this measure, the duration of treatment appeared to have a negative effect on the OHRQoL values tested in the questionnaire, so that patients whose treatment duration was shorter exhibited a significant improvement in the oral QoL values reported at the end of rehabilitation.Dental rehabilitation times were divided into: up to 18 months of treatment , and over 18 months (7 patients). In analyzing the results obtained in relation to the relationship between duration of rehabilitation and degree of change in OHRQoL values, even in this case, t-test analysis did not show a significant relationship for any of the measures defined in the questionnaire, with the exception of the last measure, which describes the degree of satisfaction with the physician  and only two articles published their research based on the complete questionnaire (OHIP-49). Only one study out of the nine added to the source questionnaires another questionnaire that examined patient satisfaction with treatment . In each and onlyThe impact of each of the QoL metrics, as well as the additional clinical parameters examined and their effect on the change in OHRQoL at the end of rehabilitation, along with other information clarified by the results of the study, may help the physician to choose the type of rehabilitation that will produce the best result .Because of the variability of results in each of the reviewed studies, it can be concluded that in this context there is also room for modification of the questionnaires, which will lead to greater and unambiguous clarity on important criteria and metrics.Despite the differences in the aims of the studies, the types of rehabilitation and the additional variables examined, most of the articles we reviewed (66%) reached the same central conclusion: all patients demonstrated higher post-treatment satisfaction and OHRQoL ,17,18,19The new questionnaire contained 31 questions, divided into six pre-defined sub-groups: ‘functional disability’, ‘physiological pain’, ‘psychological discomfort’, ‘physiological disability’, ‘psychological disability’, and ‘social disability’, and achieved satisfactory results.Our study indicates that dental rehabilitation has a positive effect on OHRQoL across all metrics tested. Patients required to undergo removable rehabilitation treatment exhibited a lower initial status and, therefore, greater improvement at the end of the rehabilitation.In our attempt to identify different factors that may affect the QoL change  in relation to dental rehabilitation, we found that neither gender nor duration of treatment was found to improve OHRQoL before and after treatment. We did observe a significant relationship between gender and duration of treatment, and the degree of satisfaction with the physician . However, in examining whether there was a relationship between the patient’s satisfaction with the physician and the change in quality of life indicators related to oral health, we did not find a significant correlation. The results of our study are in line with findings of other studies, especially those reviewed in our work. Bramanti et al.  also fouLimitations to this study include its relatively small size, presumably due to reluctance of patients to participate, and since many of those who attend university clinics suffer from various medical conditions and therefore did not meet the inclusion criteria. In order to better assess its suitability for widespread use by dental practitioners, future studies should be conducted on larger sample sizes. It may also opt to explore additional factors, such as the correlation between material improvement in the appearance of teeth at the end of rehabilitation and the ability to make social connections, or to construct a psychological profile for the patient (pre-questionnaire) at the beginning of the treatment and adjusting the type of rehabilitation that will be most appropriate for him.This study demonstrated the importance of a novel questionnaire developed to assess psychosocial aspects of dental prosthetic treatments. It was found to be reliable and convenient to use as part of routine dental care. It also allowed for accurate assessment of the psychosocial conditions of patients prior to dental treatments initiation, thus enabling awareness of the dental practitioner towards the patients’ needs, and lead to a positive dental treatment outcome.


Background: Rehabilitation is an important health strategy. Due to the lack of rehabilitation professionals  and lack of rehabilitation services , the need to strengthen rehabilitation in Albania was pronounced. Therefore, this project aimed at rehabilitation service assessment and workforce capacity building in Albania. Methods: The World Health Organization’s Template for Rehabilitation Information Collection was used to collect available data related to rehabilitation services. Additionally, two site visits to different rehabilitation centers including interviews with relevant stakeholders were performed. A stakeholders’ workshop to prioritize recommendations was also performed before finalizing the report. Results: In Albania, rehabilitation service delivery, rehabilitation workforces, and financing in rehabilitation need to be strengthened. Conclusions: The project achieved the intended objectives. Additionally progress has been occurring in the development and implementation of the Physical and Rehabilitation Medicine specialization at the University of Medicine, Tirana. Rehabilitation is a health strategy that enables people experiencing disability to achieve and maintain optimal functioning . From a The World Report on Disability (WRD)  has showResponding to the GDAP, several activities have been initiated in different countries including Mongolia , MalaysiIn 2017, the World Health Organization (WHO) started the Initiative “Rehabilitation 2030—a call for action”  and publThis project aimed at rehabilitation service assessment and workforce capacity building in Albania based on existing data and compared with the standard given in the recommendation by the World Health Organization ,6,13. ThIn this study, a civil society approach was performed, it means that this study was done neither by nongovernmental nor commercial for profit actors . In thisBased on previous experiences ,18,19,20Phase 1: Collecting general information about the country  5], and RThis project aimed at an estimation of the need for rehabilitation in Albania and an analysis of the existing rehabilitation services. This was not the National Strategic Plan for Rehabilitation according to the standards of the WHO  that staAs aforementioned in the results, the need to strengthen rehabilitation services in Albania is pronounced. It includes the rehabilitation service provision, rehabilitation workforces, and financing for rehabilitation services. Realizing the importance of rehabilitation, some hospitals and polyclinics are organizing self-financing mechanisms for rehabilitation.Recommendations were derived either from objective data in relation to internationally accepted standards for rehabilitation service provision , this mainly includes implementation of rehabilitation professions not yet existing in Albania  and establishment of rehabilitation services that do not exist . Other recommendations are to respond to qualitative information such as the attitude of the majority of the population with regard to people with disabilities and understanding of full participation, the lack of understanding in the need of persons with disability among health professionals, and the lack of quality controls and CME for rehabilitation practitioners.Union Européenne des Médecins Specialistes (UEMS)-PRM Section. To implement other health related professions such as OT, and P&O, the authors also recommend that the University of Medicine Tirana collaborate with other international organizations such as the World Federation of Occupational Therapy and International Society of Prosthetists and Orthotists, respectively.During the first site visit, one of the discussions was with the university and faculties that concluded that having education in the specialization of PRM at the University of Medicine Tirana was one of the priorities. Additionally, the need to include rehabilitation in the undergraduate module is also very high. Therefore, the curriculum for PRM specialization and the module for rehabilitation in an undergraduate degree were proposed to the University of Medicine Tirana. It was also discussed of how to get support for implementing the PRM specialization from the international PRM community, particularly from the Due to the lack of the examples of strengthening rehabilitation at the health system level, the methodology of this project was based on our previous experiences in establishing a National Disability and Rehabilitation Action Plan in different countries ,18,19. AAlthough this study addressed Albania, it can be applied as learning experience for other countries worldwide where governments have not initiated strengthening rehabilitation and the civil society can initiate such projects. Of course, it should be done systematically and with sound methodology. Therefore, our approach for Albania was to use the WHO’s tool and previous experiences ,19,27. TLimitations. In spite of the achieved of intended objectives of this project, some limitations can also be observed. These include: (1) the site visits were only performed in two cities, Tirana and Durres; (2) during the stakeholders workshop, there was no equal representation of different health professionals in rehabilitation, this was due to the lack or even non-existing rehabilitation professionals in the country, such as PRM, OT, P&O and rehabilitation nurse. We tried to compensate it optimally by involving representatives from different institutions who worked in the field Rehabilitation. Although there was lacking official support from the government, this project achieved the intended objectives . This civil society approach can be performed as a model and alternative for such purpose and might lead to more objective results. The authors hope that the results and recommendations in the final report will represent a milestone in the improvement of rehabilitation services in Albania.