Aim: The purpose of this study was to systematically review clinical studies examining the survival and success rates of implants placed with intraoral onlay autogenous bone grafts to answer the following question: do ridge augmentations procedures with intraoral onlay block bone grafts in conjunction with or prior to implant placement influence implant outcome when compared with a control group ? Material and Method: An electronic data banks and hand searching were used to find relevant articles on vertical and lateral augmentation procedures performed with intraoral onlay block bone grafts for dental implant therapy published up to October 2013. Publications in English, on human subjects, with a controlled study design –involving at least one group with defects treated with intraoral onlay block bone grafts, more than five patients and a minimum follow-up of 12 months after prosthetic loading were included. Two reviewers extracted the data. Results: A total of 6 studies met the inclusion criteria: 4 studies on horizontal augmentation and 2 studies on vertical augmentation. Intraoperative complications were not reported. Most common postsurgical complications included mainly mucosal dehiscences (4 studies), bone graft or membrane exposures (3 studies), complete failures of block grafts (2 studies) and neurosensory alterations (4 studies). For lateral augmentation procedures, implant survival rates ranged from 96.9% to 100%, while for vertical augmentation they ranged from 89.5% to 100%. None article studied the soft tissues healing. Conclusions: Survival and success rates of implants placed in horizontally and vertically resorbed edentulous ridges reconstructed with block bone grafts are similar to those of implants placed in native bone, in distracted sites or with guided bone regeneration. More surgical challenges and morbidity arise from vertical augmentations, thus short implants may be a feasible option. Key words:Alveolar ridge augmentation, intraoral bone grafts, onlay grafts, block grafts, dental implants. Localized or generalized bone defects of the alveolar ridge, due to atrophy, periodontal disease and trauma sequelae, may provide insufficient bone volume or unfavorable vertical, transverse, and sagittal inter arch relationship, which may render implant placement impossible or incorrect from a functional and esthetic viewpoint . A varieHowever, despite a relevant number of publications reporting favorable results with these different surgical procedures, considerable controversy still exists as far as the choice of the most reliable technique is concerned; this is frequently due to the lack of comparative studies . Six sysThe aim of this study was to systematically review the following question: In patients with localized alveolar ridge defects, how do clinical and radiographic outcomes obtained with augmentation with intraoral autogenous block bone grafts compare with those of other techniques ? This was done by assessing the complications related to the augmentation procedure, graft success, implant survival, implant success, and radiographic peri-implant marginal bone loss.This systematic review complies with the PRISMA statement  .- Inclusion criteria Inclusion and exclusion criteria were established before carrying out the literature search. Inclusion criteria were as follows:  publicatExclusion criteria were: case reports, reviews, or technical notes; studies on sinus bone grafting, studies only providing histological data or volumetric measurements ; patients affected by bone defects following ablation due to tumors or osteoradionecrosis; bone defects related to congenital malformations , as the initial clinical situation is very different and not comparable to defects following atrophy, periodontal disease, or trauma; studies including both lateral and vertical augmentation procedures but which did not separate dental implant data according to augmentation procedure and studies with missing data.No restrictions were placed on the year of publication. Authors were contacted for clarification of missing information when necessary.- Outcome measures and follow-up periodThe survival rate was presented (when possible) as a cumulative survival percentage rate indicating that a certain percentage of implants were still present in the mouth at the end of the observation period. Any other definitions of implant survival, as described in individual studies, were also considered. Due to the lack of consensus regarding a set of universally accepted success criteria, all definitions of implant success were considered according to the criteria of each individual study. Mean marginal peri-implant bone loss was collected (when possible). All intra or postoperative complications reported in the studies were collected.- Initial literature search The Pubmed (MEDLINE) database of the United States National Library of Medicine was used for a literature search of articles published until October 2013. The following terms were used in different combinations: ‘bone grafts,’ AND ‘dental implants’ AND ‘humans’ AND ‘augmentation’, NOT ‘sinus’. This search was combined with the following search terms: ‘simultaneous’, ‘delayed’, ‘intraoral’, ‘onlay’, ‘block’, ‘horizontal’, ‘vertical’. Duplicates were removed from the search.The search was completed by a review of the references given in each of the studies found in order to identify any additional studies that the initial search might have missed. In addition, a manual search in the private library of MP which included the following journals: British Journal of Oral and Maxillofacial Surgery, Clinical Oral Implants Research, Clinical Implant Dentistry and Related Research, International Journal of Oral and Maxillofacial Implants, International Journal of Oral and Maxillofacial Surgery, Oral Surgery Oral Medicine Oral Pathology Oral Radiology and Endodontology, Journal of Oral and Maxillofacial Surgery, and Medicina Oral Patología Oral y Cirugía Bucal.- Searching for relevant studies.The comprehensive nature of the search methodology produced a large volume of published studies related to the topic. A three-stage screening process was then performed independently in duplicate to maximize the reliability of the extracted data Fig. . Indepen- Quality and risk of bias assessmentTwo reviewers independently and in duplicate evaluated the quality of the included studies as part of the data extraction process. Four main quality criteria were examined:  concealm- Data synthesis and analysis Evidence tables were created with the study data. An initial descriptive analysis (summary) was performed to determine the quantity of data, at the same time assessing variations in study characteristics. The following information was collected from the publications: type of study, type of procedure, number of treated patients (gender and age), number of implants, donor site of the grafts, delayed or simultaneous implant placement, follow-up (months), implant survival and success rates, mean marginal bone loss (mm), number and type of intra/postoperative complications.- Study selection and descriptionThe electronic and hand searches yielded a total of 608 articles. 453 studies were excluded after screening the titles and 92 after reading the abstracts. Overall, 63 full articles were retrieved for more detailed evaluation but only 4 fulfilled the inclusion criteria for data extraction Fig. . The k v- Horizontal augmentationPatient and intervention characteristicsFour studies were identified involving a total of 167 patients and 254 implants. A total of 160 patients with 216 dental implants received lateral ridge augmentation with intraoral block bone grafts: 38 were placed simultaneously and 216 delayed to the bone grafting procedure  ,14. In met al. . The samet al.  also repet al. ,16. Noneet al. (et al. (Implant survival for delayed implant placement varied from 96.9% at one year post-loading  to 100% et al.  applied  (et al.  applied  (et al. . Success (et al. . The mar (et al.  to 0.20± (et al.  for dela (et al. . So, des- Vertical augmentationPatient and intervention characteristicsTwo studies included 54 patients with 120 dental implants. A total of 28 patients with 64 dental implants underwent vertical ridge augmentation with intraoral onlay block bone grafts, all with delayed placement ,18 (see Outcomeset al. (et al. (With regard to postoperative surgical complications, Chiapasco et al.  reported (et al.  reportedet al. (et al. (et al. (et al. (et al. (et al. (et al. (Implant survival varied from 95.6% after one year post-loading  to 100% et al.  obtained (et al. , the suc (et al. . Due to  (et al.  obtained (et al.  obtained (et al. . The dif (et al.  placed d (et al.  submerge (et al.  did not - Quality assessment of trials and risk of biasOne study  had a loThe data reported in the literature seem to demonstrate that bone augmentation by means of the positioning of intraoral onlay grafts can be considered a reliable surgical technique for obtaining sufficient bone volume for the placement of dental implants where it would not otherwise be possible . HoweverCommon techniques introduced for horizontal bone augmentation are guided bone regeneration, ridge splitting and expansion, and block grafts . In a syMore challenging is the vertical augmentation procedure; a variety of surgical procedures have been proposed, such as: autogenous bone grafts, vertical guided bone regeneration, and alveolar distraction osteogenesis. As many atrophic alveolar ridges are deficient in height and width, they may require flattening for better graft adaptation . A seconet al. (et al. (et al. (et al. (et al. (et al. (Among the disadvantages of lateral or vertical bone grafting procedures is the resorption of a significant proportion of the graft ,22-24. Aet al. . Maioran (et al.  added a  (et al. . Regardi (et al. ,25. Rocu (et al.  reported (et al.  and Chia (et al.  studied  (et al.  found th (et al.  and Bren (et al.  wound de (et al. ,30.The main limit encountered in this literature review was the lack of studies with a comparative design and randomized controlled studies. Future research must include control groups and standardized criteria for defining implant success or failure for both simultaneous and delayed protocols, in order to obtain rigorous evidence-based results. In this way, the data presented in this review should be considered indicative rather than conclusive.Survival and success rates of implants placed in horizontally and vertically resorbed edentulous ridges reconstructed with block bone grafts are similar to those of implants placed in native bone, in distracted sites or with guided bone regeneration. More surgical challenges and morbidity arise from vertical augmentations, thus short implants may be a feasible option. Our recommendations for future research focus on the performance of large-scale randomized controlled studies with longer follow-ups involving the assessment of esthetic parameters and hard and soft peri-implant tissue stability.


To evaluate some forage feeds of ruminants in terms of their carbohydrate (CHO) and protein fractions using Cornell Net Carbohydrate and Protein System (CNCPS).1 - intermediate degrading, CB2 - slow degrading and CC - non-degrading or unavailable) and protein  fractions of test feeds.Eleven ruminant feeds  were selected for this study. Each feed was chemically analyzed for proximate principles , fiber fractions , primary CHO fractions  and primary protein fractions . The results were fitted to the equations of CNCPS to arrive at various CHO (CA - fast degrading, CB1 content of all feeds was low but similar. All feeds except cowpea, berseem, and hedge lucerne contained higher CB2 values. Oat among green fodders and hybrid napier among range herbages had lower CC fraction. Feeds such as bajra, cowpea, berseem and the setaria grass contained lower PA fraction. All green fodders had higher PB1 content except maize and cowpea while all range herbages had lower PB1 values except hedge lucerne. Para grass and hybrid napier contained exceptionally low PB2 fraction among all feeds. Low PC contents were reported in oat and berseem fodders.Among green fodders, cowpea and berseem had higher CA content while except hedge lucerne all range herbages had lower CA values. CBBased on our findings, it was concluded that feeds with similar CP and CHO content varied significantly with respect to their CHO and protein fractions. Due to lower CC fraction, oat and hybrid napier were superior feeds in terms of CHO supply to ruminants. Similarly, among all feeds oat and berseem had a lower PC fraction, thus were considered good sources of protein for ruminants. Difference between total CHO and NSC was the indirect measure of structural CHO (SC) content of test feeds. Starch estimation in the feeds was done as per the procedure of Sastry  [et al.  were useet al. [et al. [1 (globulins mainly), PB2 , PB3  and PC .NDICP, acid detergent insoluble CP (ADICP), non-protein nitrogen (NPN) and soluble protein (SP) content of test feeds were estimated as per Licitra et al. . ADICP f [et al.  were useThe results obtained were subjected to statistical analyses using software package SPSS version 16.0 . Means wet al. [et al. [et al. [et al. [et al. [et al. [et al. [et al. [et al. [et al. [et al. [Chemical constituents of forage feeds  revealedet al.  reported [et al.  reported [et al.  evaluate [et al.  evaluate [et al.  were in  [et al.  was high [et al.  reported [et al. , it was  [et al.  were in  [et al. , Mahala  [et al. , Subhala [et al.  and Teka [et al. .et al. [et al. [Total CHO content  of all fet al. . The quaet al.  regardin [et al.  were preet al. [et al. [Primary protein fractions  of forage feeds are presented in et al.  and Gupt [et al.  regardinet al. [et al. [1 was comparable between green fodders and range herbages. Sorghum and bajra among green fodders had lower CB1 content while among range herbages para and guinea grass had lower CB1 content. In typical ruminant diet, the amount of fraction CB2 is very important as this fraction represents the available cell wall portion of ruminant feeds. Obviously legume forages contained lower CB2 fraction as these feeds are high in protein content and low in NDF content. Among other feeds, range herbages contained higher fraction CB2 than green fodders reflecting their high cell wall availability to ruminants. Fraction CC is the lignin bound cell wall content of a feed. Hence this fraction is indigestible both by ruminal microbes and the animal itself. Feeds with low CC fraction will be of superior quality in terms of CHO supply to ruminants and vice-versa. On this aspect, forages like oat and hybrid napier were found to be better feeds. Findings of Trivedi et al. [2 and PB3 are degraded in the rumen to a lesser extent than PA and PB1, thus feeds with high PB2 and PB3 content will have more by-pass protein value. All legume forages had higher PB2 + PB3 content while among non-legume feeds maize fodder, and the setaria grass contained higher PB2 + PB3 content. Very similar observations were made by Kamble et al. [et al. [When CNCPS CHO fractions of forage feeds  were intet al.  and Gupt [et al. . Para ani et al.  regardini et al. . Averagee et al.  and Gupt [et al. .Based on the findings of the above study it was concluded that among typical ruminant forage feeds, oat fodder and hybrid napier grass were better feeds of ruminants from CHO supply point of view while oat and berseem fodders were found to be good forage protein sources to ruminants. Maize fodder was evaluated to be a good feed with more by pass protein value. All the above feeds are extensively used in our country as forages for ruminant feeding and their preferential selection as animal forage sources are established by CNCP system. Therefore, this CNCPS model could be successfully implemented for nutritive evaluation of forage feeds of Indian origin in terms of their CHO and protein fractions though sufficient database should be developed before its applicability in dairy ration formulation.SSK and CD designed the plan of the present study. LKD and DK carried out the experimental work. Manuscript preparation along with data analysis was done by LKD. All authors read and approved the final manuscript.


Tick-borne encephalitis virus (TBEV) and Crimean-Congo haemorrhagic fever virus (CCHFV) are important tick-borne viruses. Despite their wide geographical distribution and ease of acquisition, the prevalence of both viruses in Malaysia is still unknown. This study was conducted to determine the seroprevalence for TBEV and CCHFV among Malaysian farm workers as a high-risk group within the population.We gave questionnaires to 209 farm workers and invited them to participate in the study. Eighty-five agreed to do so. We then collected and tested sera for the presence of anti-TBEV IgG (immunoglobulin G) and anti-CCHFV IgG using a commercial enzyme-linked immunosorbent assay (ELISA) kit. We also tested seroreactive samples against three other related flaviviruses: dengue virus (DENV), West Nile virus (WNV) and Japanese encephalitis virus (JEV) using the ELISA method.The preliminary results showed the presence of anti-TBEV IgG in 31 (36.5 %) of 85 sera. However, when testing all the anti-TBEV IgG positive sera against the other three antigenically related flaviviruses to exclude possible cross reactivity, only five (4.2 %) sera did not show any cross reactivity. Interestingly, most (70.97 %) seropositives subjects mentioned tick-bite experience. However, there was no seroreactive sample for CCHFV.These viruses migrate to neighbouring countries so they should be considered threats for the future, despite the low seroprevalence for TBEV and no serological evidence for CCHFV in this study. Therefore, further investigation involving a large number of human, animal and tick samples that might reveal the viruses’ true prevalence is highly recommended. Ixodes ricinus is the main vector for TBEV-EU, while the other two subtypes are transmitted mainly by I.persulcatus [Ticks are important and prevalent vectors for several animal and human infectious diseases, carrying harmful pathogens such as Borrelia spp, Rickettsia spp, Babesia spp, and various viruses including TBEV and CCHFV. TBEV is a member of the genus Flavivirus within the Flaviviridae family. This etiologic agent of tick-borne encephalitis can cause a potentially fatal neurological infection affecting the human central nervous system. TBEV has three subtypes: European (TBEV-EU), Far Eastern (TBEV-Fe) and Siberian (TBEV-Sib) . Ixodes sulcatus . The vecsulcatus . The virsulcatus . Severalsulcatus , 5.CCHFV is a tick-borne virus belonging to the genus Nairovirus in the Bunyaviridae family and a causative agent for a deadly viral haemorrhagic fever. Despite a history of isolation from many genera and species of ticks, the main vector for this virus is a tick from the Hyalomma genus . SimilarAlthough TBEV and CCHFV are not endemic in Malaysia, circulation of other vector borne viruses are reported in this country, including DENV, WNV, JEV and the Langat virus (LGTV) –15. FlavSeroepidemiological studies related to the prevalence of TBEV and CCHFV have been widely performed, especially among high-risk groups including farmers. To date, there is no reported case or outbreak of those viruses in Malaysia, but there was a study by Thayan and colleagues on screening for TBEV antibodies  among MaThe study’s protocol was approved by the Ethics Committee Universiti Malaya Medical Centre (MEC Ref. 824.11 and MEC Ref. 944.20). Participation in the study was entirely voluntary. Potential participants were briefed on the project and given sufficient time for consideration. All subjects gave written informed consent for inclusion before they participated in the study. The blood samples were handled with strict anonymity. All participants gave written consent for the samples to be used after anonymisation.Eleven cattle and goat farms in Peninsular Malaysia were identified from information from the Department of Veterinary Services (DVS), Ministry of Agriculture and Agro-based Industry, Malaysia. All were contacted and invited to take part in the project. Eight of the 11 farms agreed to participate in the study. These eight farms were located in different regions of Peninsular Malaysia  and VectoCrimean-CHF-IgG kit  in accordance with the manufacturers’ instructions. We then tested positive sera for the presence of anti-DENV, anti-WNV and anti-JEV IgG antibodies to exclude cross reactivity with the positive sera for TBEV IgG. Finally, we performed cross reactivity tests using the DENV IgG ELISA kit , the WNV IgG capture DxSelect ELISA kit  and the JEV IgG ELISA kit .p < 0.05 is considered significant.All data were analysed using the Fisher exact test for analysis of contingency table. We determined the correlations between seropositivity and different age groups using Spearman non-parametric correlation. All statistical analyses were conducted using GraphPad Prism 6 , where P = 1.0000 by Spearman correlation test). when seropositivity was analysed between different age groups, the outcome showed no significant difference (P = 0.5889). The highest reactivity towards anti-TBEV IgG ELISA was 68.4 % (13/19) in males aged 51–60 years and 50 % (2/4) in females in the same age group.Seroprevalence data for TBEV and CCHFV are shown in Table et al. [et al. [et al. [We have shown the seropositivity for TBEV among a small group of farm workers in Peninsular Malaysia. Although our initial data showed that the prevalence of IgG against TBEV was 36.5 %, after testing the positive sera we found that only five (4.2 %) samples could be linked to the presence of TBEV. It was not surprising that there was cross reactivity between TBEV, WNV and DENV because they are all flaviviruses that share a complex antigenic relationship . Our finet al.  in whichet al. . Anotheret al. . LGTV iset al. . Our dat [et al.  showed a [et al. . However [et al. . A possi [et al. . By keep [et al. . Accordi [et al. . However [et al. . Tick ma [et al. . There i [et al. . The out [et al. . Althoug [et al. . This fi [et al. . Youngst [et al. . Certain [et al. . Healthc [et al. . Nabeth  [et al.  suggeste [et al. . As ment [et al. . In Japa [et al. .Our study showed a low seroprevalence for TBEV (4.2 %) among animal farm workers, after ruling out possible cross reactivities, and no correlation with age or gender. We also found no serological evidence of CCHFV transmission among Malaysian farm workers. Further studies involving a larger sample size, and also considering LGTV as a Malaysian counterpart of TBEV that might lead to false positivity, are highly recommended to provide sufficient evidence and reflect the true state of TBEV and CCHFV prevalence in Malaysia.


The current study explored this decision regarding exclusionary illnesses using the SEID criteria with four distinct data sets involving patients who had been identified as having CFS, as well as healthy controls, community controls, and other illness groups. The findings indicate that many individuals from major depressive disorder illness groups as well as other medical illnesses were categorized as having SEID. The past CFS Fukuda et al. prevalence rate in a community based sample of 0.42 increased by 2.8 times with the new SEID criteria. The consequences for this broadening of the case definition are discussed.The Institute of Medicine recently proposed a new case definition for chronic fatigue syndrome (CFS), as well as a new name, Systemic Exertion Intolerance Disease (SEID). Contrary to the Fukuda  In reacfinition , the Canfinition  was devefinition  were devfinition . Each ofet al. [Recently, the IOM  issued aet al.  CFS critet al. , and theet al.  excludedet al.  had a diet al.  p. 186)86et al. et al.  (p. 4), etc.). Thus, according to the above IOM guidelines, if these illnesses account for the SEID symptoms, then it is another illness and not SEID. Therefore, many illnesses are now considered a comorbid condition with SEID. However, trying to determine whether an illness is exclusionary vs. comorbid is a challenging diagnostic task. The IOM [The problem for diagnosticians in interpreting these guidelines is that the core IOM symptoms are not unique to SEID, as other illnesses have comparable symptoms In addition, Ze-dog  pointed In the first study, a CFS screening questionnaire had a combination of existing and new measures including: (1) several demographic related items; (2) The Fatigue Scale ; and (3)et al. [et al. [A total of 60 individuals , and 15 with Lupus) were recruited from the greater Chicago area for the present study. Fifteen of the participants were diagnosed by a physician in Chicago with experience in diagnosing and treating CFS. Each of these participants met the Fukuda et al.  definiti [et al.  criteriaet al.’s [Fifteen healthy control participants had not been diagnosed with CFS or any other illness that could cause significant fatigue. These participants had also been seen by a physician, and no illnesses that could cause fatigue were found . In addition, fifteen participants with a diagnosis of Multiple Sclerosis (MS) were recruited from self-help groups in the Chicago area. Each of these participants met Poser et al.’s  criteriaet al.’s . There wTo meet the SEID criteria  within tn = 15) of those in the CFS group met the SEID criteria, whereas 47% (n = 7) in the Lupus group, 33% (n = 5) in the MS group, and 0% in the control group met the SEID criteria. In an effort to compare this new SEID case definition to the older Fukuda et al. [As indicated in a et al.  criteriaet al. [In the second study, participants were screened by a trained interviewer to determine if they met the inclusion and exclusion criteria for CFS, MDD, or healthy controls . As paret al.  case defet al.  found thThe Structured Clinical Interview for the DSM-IV (SCID) is a valid and reliable semi-structured interview guide that closely resembles a traditional psychiatric interview . The SCIThe SF-36 is 36-item instrument that is comprised of multi-item scales that assess physical functioning, role limitations, social functioning, bodily pain, general mental health, vitality, and general health perceptions. Higher scores indicate better health, lower disability, or less impact of health on functioning. Reliability and validity studies have demonstrated that the 36-item version of the SF-36 has high reliability and validity in a wide variety of patient populations .et al.’s [et al. [A total of 45 individuals  were recruited from the greater Chicago area [et al.’s  diagnost [et al.  case defFifteen participants with a diagnosis of MDD were solicited from a local chapter of the National Depressive and Manic Depressive support group in Chicago. Participants were required to have been diagnosed with major depression by a licensed psychologist or psychiatrist. All participants were screened with the SCID-IV to ensure that they met criteria for a current (active) case of major depression and did not have any other current psychiatric illnesses. Individuals who had other current psychiatric conditions in addition to major depression were excluded. Individuals who reported having uncontrolled or untreated medical illnesses  were also excluded. In the MDD group, all 15 (100%) participants met DSM-IV diagnostic criteria for MDD. None of the participants in the MDD group met criteria for MDD with catatonic, melancholic, psychotic, or atypical features. Participants in the MDD group did not meet criteria for any other Axis I disorders.Finally, fifteen healthy control participants were solicited from the greater Chicago area. Individuals who did not have any medical illnesses or who did not have any uncontrolled or untreated illnesses  were allowed to participate. All participants were screened with the SCID-IV to ensure that they did not have any current psychiatric illnesses. Individuals with current psychiatric conditions were excluded. Sociodemographic data were compared across the three groups, and there were no significant differences with respect to gender, race, age, SES, education, marital status, occupation, work status, and additional roles .To meet the SEID criteria  within tn = 14) of those in the CFS group, 27% (n = 4) in the MDD group, and 0% in the control group met SEID criteria. In an effort to compare this new SEID case definition to the older Fukuda et al. [As indicated in et al. [The data were derived from a larger community-based study of CFS that was carried out in three stages . Stage 1et al.  criteriaAccording to the Phase 1 screen, of the 18,675 interviewees, 16,453 (88%) had no prolonged or chronic fatigue, 1435 (7.7%) had prolonged fatigue, and 780 (4.2%) had chronic fatigue (seven cases refused to answer the fatigue questions). Among those 780 respondents with chronic fatigue, at Phase 1; 304 had ICF-like illness , 68 had a CF-explained-like condition, and 408 had CFS-like profiles. All 408 members of the CFS-like group were invited to participate in Phase 2. Of this group of 408 individuals with CFS-like symptoms, the physician review team reviewed data on 166 individuals, who provided data during the Phase 2 evaluation. There were 47 individuals who were evaluated in a control group, and these individuals screened negative for CFS-like illness during Phase 1.et al. [i.e., melancholic depression, bipolar disorders, anorexia nervosa/bulimia nervosa, psychotic disorders, drug or alcohol related disorders, or medical explanations for their fatigue).A team of four physicians and a psychiatrist were responsible for making a final diagnosis with two physicians independently rating each file using the current U.S. case definition of CFS . Where pet al.  case defTo meet the SEID criteria  within tt). The proportion of screened positives  is PI (π), and the proportion of screened negatives  is 1 − PI (1 − π). The proportion of screened positives evaluated in Phase 2 who were diagnosed with SEID (Number of cases with SEID/166) is L1 (λ1), and the proportion of screened negatives evaluated in Phase 2 who were diagnosed with SEID (0/47 = 0.0) is L2 (λ2).Prevalence, which is the number to be estimated, is represented by P (p). The total number of respondents screened in Phase 1  is N (Nn = 24) of those in the CFS group met the SEID criteria, whereas 47% (n = 42) for the CF group, 44% (n = 20) for the ICF group, and 6% (n = 3) for the controls. Within the Chronic Fatigue explained by medical or psychiatric illness (CF), of those 19 with Melancholic Depression, 47% (n = 9) met the SEID criteria. In addition, for those with a medical reason for their fatigue, 48% (n = 16) met SEID criteria. In an effort to compare this new SEID case definition to the older Fukuda et al. [As indicated in et al. [This data set had been previously used to estimate the prevalence of CFS , which wet al.  prevalenet al. [etc.). For each of the eight Fukuda et al. [et al. [et al. [et al. [We solicited participants with a diagnosis of MDD and CFS to participate in this study . We admiet al.  symptomsa et al.  symptoms [et al.  symptoms [et al.  criteria [et al. .et al. [et al. criteria. We excluded individuals who had other current psychiatric conditions in addition to major depression or who reported having untreated medical illnesses .We recruited 64 individuals, 27 with CFS and 37 with MDD. We obtained our sample of participants with CFS from two sources, local CFS support groups in Chicago and a previous research study conducted at DePaul University. To be included in the study, participants were required to have been diagnosed with CFS, using the Fukuda et al. [For the MDD group, we found participants from three sources, local chapters of the Depression and Bipolar Support Alliance group in Chicago; Craigslist—a free local classifieds ad forum that is community moderated; and online depression support groups. To be included in the study, all participants were required to have been diagnosed with a MDD by a licensed psychologist or psychiatrist. We excluded individuals who had other current psychiatric conditions in addition to a MDD  or who reported having untreated medical illnesses were also excluded. We carefully screened participants to ensure that participants from the MDD group did not have CFS as defined by the Fukuda et al.  criteriaet al. [To meet the SEID criteria  within tet al. , when uset al. .n = 22) of those in the CFS group met the SEID criteria, whereas 24% (n = 9) of those in the MDD group met SEID criteria. In an effort to compare this new SEID case definition to the older Fukuda et al. [As indicated in et al. [et al. [et al. [et al. [Rates of SEID could increase due to the reduction of many exclusionary criteria. Based on study 3, using the Jason  [et al.  criteria [et al.  criteria [et al. , then th [et al.  criteria [et al. .et al. [et al. [et al. [The current study suggests that the core SEID symptoms are not unique to SEID, as some patients with other illnesses, such as those evaluated in this study, have comparable symptoms. As a consequence, some patients with illnesses that had previously been exclusionary under past case definitions such as Fukuda et al.  will nowet al. , rather  [et al.  CFS crit [et al.  CFS critThe current study suggests that some patients with MDD, who also have chronic fatigue, sleep disturbances, and poor concentration, will be misdiagnosed as having SEID. MDD can occur for anyone with a serious medical illness. Some patients might have been depressed prior to becoming ill with SEID, and probably others as a reaction to this illness . Howeveret al. [et al. [et al. [Mood disorders are the most prevalent psychiatric disorders after anxiety disorders: for major depressive episode, the one-month prevalence is 2.2%, and lifetime prevalence is 5.8% . The erret al.  found th [et al. . Fortuna [et al.  empiric  [et al.  has cons [et al.  reviewedvs. orthostatic intolerance [There are additional aspects of the IOM  case defolerance . We beliolerance .There are a number of limitations in the present study. As we used archival data sets, some of the questions that have been proposed to define SEID were not available. Clearly, the current study needs to be replicated with questions that are now proposed , howeverThe recent IOM report  is being


After more than two decades of research, the efforts to translate the concept of RNA based vaccination have reached a critical mass. Several preclinical and clinical projects located in the academic or industrial setting are underway and the coming years will allow us to get broad insight into clinical feasibility, safety, and first efficacy data. It can be anticipated that some RNA based vaccines will be approved within the near future. in vitro transcribed RNA is now viewed as an attractive approach for vaccination therapies, with several features contributing to its favorable characteristics. RNA allows expression of molecularly well-defined proteins and its half-life can be steered through modifications in the RNA backbone. Moreover, unlike DNA, RNA does not need to enter the nucleus during transfection and there is no risk of integration into the genome, assuring safety through transient activity. Rapid design and synthesis in response to demand, accompanied by inexpensive pharmaceutical production, are additional features facilitating its clinical translation.The use of ex vivo transfection of mRNA into autologous dendritic cells (DCs) which was initially described by Boczkowski et al. [The seminal work of Wolff et al. which showed that RNA injected directly into skeletal muscle can lead to protein expression opened the era of RNA based therapeutics . This obi et al. . Along wi et al. , severali et al. . In a dii et al. –10. Persi et al. , 12 are i et al. –15. in vitro analytics such as cytotoxicity  or effects of RNA on transcriptome of DCs . Finally, E. Hattinger et al. will also demonstrate, with a different disease focus, the efficacy of prophylactic RNA vaccination against allergy.In this special issue, a number of papers will illustrate and summarize the advances in this emerging field. M. A. McNamara et al. will provide a comprehensive review on RNA based vaccines in cancer immunotherapy, which is further detailed for the use of mutanome engineered RNA by M. Vormehr et al. These will be complemented by a review from K. K. L. Phua describing targeted delivery systems for RNA based nanoparticle tumor vaccines. Other contributions will describe RNA based methods forIn conclusion, this special issue covers many aspects of RNA based vaccines. As RNA based vaccination is not the only application of the RNA technology , we hope to have sparked the readers interest in RNA based therapies in general.Sebastian KreiterSebastian KreiterMustafa DikenMustafa DikenSteve PascoloSteve PascoloSmita K. NairSmita K. NairKris M. ThielemansKris M. ThielemansAndrew GeallAndrew Geall


Since the introduction of engine-driven nickel-titanium (NiTi) instruments, attempts have been made to minimize or eliminate their inherent defects, increase their surface hardness/flexibility and also improve their resistance to cyclic fatigue and cutting efficiency. The various strategies of enhancing instrument surface include ion implantation, thermal nitridation, cryogenic treatment and electropolishing. The purpose of this paper was to review the metallurgy and crystal characteristics of NiTi alloy and to present a general over review of the published articles on surface treatment of NiTi endodontic instruments.  In addifracture . NiTi infracture , 5. Thusfracture .3N4) particles [Improvement of the cutting efficiency of NiTi instruments especially through their surface treatment has been the subject of numerous investigations. The implantation of boron ions on the surface of the instruments increases their surface hardness . Also, iarticles . The aimRetrieval of literatureAn English-limited Medline search was performed through the articles published from May 1988 to May 2014. The searched keywords included “electropolishing AND NiTi rotary instruments”, “thermal nitridation”, “cryogenic treatment AND nickel-titanium”, “plasma immersion ion implantation AND nickel-titanium”, and “endodontic treatment AND nickel-titanium”. Then, a hand search was done in the references of result articles to find more matching papers.A total of 176 articles were found which according to their related keywords were “10-electropolishing AND NiTi rotary instruments”, “29-thermal nitridation”, “3-cryogenic treatment AND nickel-titanium”, “135-plasma immersion ion implantation AND nickel-titanium”, and “endodontic treatment AND nickel-titanium”.Metallurgy of NiTiThe NiTi alloys used for manufacturing of the endodontic instruments contain approximately 56% (wt) nickel and 44% (wt) titanium. In some NiTi alloys, a small percentage (<2% wt) of nickel can be substituted by cobalt. The resultant combination is a 1:1 atomic ratio (equiatomic) of the major components. The generic term for these alloys is 55-nitinol and as other metallic systems, the alloy can exist in various crystallographic forms. NiTi has inherent ability of shape memory (SM) and super-elasticity (SE)  that steThe concept of SM was first described by Ölander  during eUnder low tensile loading, the superelastic NiTi alloy shows a normal elastic behavior. At higher tensile loading, the elastic stress reaches plateau at which there is an extended horizontal region of elastic strain. Elastic deformation in SS and NiTi is 3% and 7%, respectively. The atoms in SS can move against each other by a small specific amount before plastic deformation occurs which is called the Hookean elasticity . Crystal characteristics of NiTi alloys) and finish (Mf) temperature. Likewise the temperatures at which the austenite starts and finishes are called the As and Af points, respectively. The event causes alterations in the physical properties of the alloy and allows SM [All the alloys with SM show a change in their lattice structure or atomic arrangement, characterizing a phase change while receiving or releasing thermal energy. The critical deformation and shape recovery are explained according to the changes in the lattice parameters through a transformation between the austenite and martensite phases and the characteristics of the crystal structure . At highllows SM , 12, 13.Surface of NiTi instrument2) and smaller amounts of nickel oxides (NiO and Ni2O3) and metallic nickel (Ni) [The surface of NiTi instrument mainly consists of oxygen, carbon, and titanium oxides (TiOkel (Ni) -19. The kel (Ni) . Ni may kel (Ni) .et al. [et al., the surface of titanium-aluminum-vanadium alloy (Ti6Al4V) had amounts of aluminum similar to the amount of Ni in NiTi, even though the bulk material of Ti6Al4V had only 6% Al and NiTi had 50% Ni. There was no Ni on the surface of SS, but some amounts of Cr and Fe were found.Shabalovskaya  found thet al.  were sim2. In other words, calcium phosphate formed on an inert oxide layer. This layer was thicker on pure titanium than on titanium alloys (including NiTi), and the Ca:P ratio of the film was close to that of hydroxyapatite. The calcium phosphates formed on NiTi or Ti6Al4V were less similar to hydroxyapatite. The presence of Ni in the surface of NiTi alloy and aluminum in the surface of Ti6Al4V may have caused these results. SS also has a calcium phosphate layer of this kind. However, the formation of this layer is slower and differs from NiTi [Pure Ti and some of its alloys are amongst the most biocompatible materials . Their from NiTi , 21, 22.Surface treatment of NiTiAttempts to enhance the surface of NiTi instruments, minimize or eliminate their inherent defects, increase the surface hardness/flexibility and improve the resistance to cyclic fatigue and cutting efficiency of endodontic instruments have resulted in a variety of strategies . Plasma immersion ion implantationThere have been several attempts to reduce the release of Ni from NiTi, without deteriorating the mechanical properties of the bulk. This has been done by coating technologies either with titanium nitride (TiN) or with polymers . The polet al. [et al. [Plasma immersion ion implantation (PIII) was first introduced in the late 1980s by Conrad et al.  and Tend [et al. . This te [et al. .During PIII, the specimen is placed in a chamber and immersed in the plasma; then a highly negative pulsating voltage is applied to the sample. PIII is regularly performed to modify the surface of metals and to improve the mechanical properties such as hardness, friction coefficients, and wear/corrosion resistance , 31. Briet al. [et al. [Gavini et al.  showed t [et al.  evaluate [et al.   atoms diffuse into the samples and atmospheric oxygen is stopped by a steel foil consisting of a notable amount of Cr. The modified surface consists of a thin outer layer of TiN and a thicker Ti2Ni layer underneath [TiN belongs to the refractory transition metal family  and consderneath , 35.et al. [et al. [et al. [et al. [Shenhar et al.  and Huan [et al.  showed t [et al.  showed t [et al.  revealed [et al.   involves submersing metal in a super-cooled bath containing liquid N (-196˚C/-320˚F) , 37 and Two mechanisms can change the properties of metal during CT. First is a more complete martensite transformation from the austenite phase following CT  and secoet al. [et al. [et al. [There are few studies on the CT of NiTi rotary instruments. Kim et al.  evaluate [et al.  showed t [et al.  reportedElectropolishingaka electrochemical polishing, electro-lytic polishing and reverse plating, is an electrochemical process for removal of the material layer from a metallic surface. It often acts against electroplating. It may be used in lieu of abrasive fine polishing during microstructural preparation [Electropolishing (EP), paration . 2, which protects the underlying material from further corrosion. Generally, EP removes the native oxide layer and sinters a more homogeneous and stable passive TiO2 layer. In this process, the amount of Ni on the surface decreases [EP is a standard surface treatment process employed as a final finish during manufacturing of NiTi instruments. An electric potential and current are applied, which result in ionic dissolution of the surface. In this process, the surface chemistry and morphology are altered while surface imperfections are removed as dissolved metal ions. Simultaneously, Ti is oxidized to TiOecreases -47.Typically, the instrument is immersed in a temperature-controlled bath of electrolyte and serves as the anode when it is connected to the positive terminal of a direct current power supply, and the negative terminal is attached to the cathode. As the current passes the surface of metal oxidizes and dissolves in the electrolyte. At the cathode, a reduction reaction occurs, which normally produces hydrogen. Electrolytes used for EP are most often concentrated acid solutions with a high viscosity, such as mixtures of sulfuric/phosphoric acid. Other EP electrolytes include mixtures of perchlorates with acetic anhydride and methanolic solutions of sulfuric acid , 46.EP of NiTi instruments is efficient for the elimination of defective surface layers through surface oxidizing. Owing to a gain in total energy caused by the differences in the enthalpy of Ti and Ni oxides forming, the preferential oxidation of Ti on NiTi surface always occurs . Therefoet al. [et al. [et al. [Using scanning electron microscopy (SEM), Herold et al.  showed t [et al.  EP may h [et al.  investiget al. [et al. [et al. [et al. [et al. [et al. [However, the torque at failure and amount of unwinding were decreased. Cheung et al.  showed tet al. . Boessle [et al.  showed t [et al.  demonstr [et al.  showed t [et al.  revealed [et al.  showed t1. Argon implantation caused a moderate improvement in the performance of S1 files, whereas nitrogen ion-implanted files performed worse in the fatigue test. Furthermore, nitrogen ion implantation improves the cyclic fatigue of instruments.2. Thermal nitridation increases the cutting efficiency and corrosion resistance of NiTi files in contact with NaOCl. 3. Cryogenic treatment improves the cutting efficiency, cyclic fatigue resistance and microhardness of NiTi instruments.


Anatomic variation can potentially impact the surgical safety.The purpose of this cross-sectional study was to assess the prevalence of ostiomeatal complex variations based on cone beam computed tomography (CBCT) images of the patients seeking rhinoplasty.p< 0.05 was considered to be statistically significant.In this cross-sectional study, CBCT images of 281 patients including 153 female and 128 male with Mean±SD age of 26.97±7.38 were retrieved and analyzed for presence of variations of ostiomeatal complex and mucosal thickening. All CBCT images were acquired by NewTom VGi scanner with 15×15 field of view, as a part of preoperative recording of patients seeking rhinoplasty in an otolaryngology clinic. Chi- square test and Odds ratio were used for statistical analysis of the obtained data and Agger nasi cells which were seen in 93.2% of the cases were the most common anatomic variation. It was followed by Haller cells (68%), concha bullosa (67.3%), uncinate process variations (54.8%), nasal sepal deviation (49.5%) and paradoxical curvature of middle turbinate (10%). Mucosal thickening were detected in 60.7% of the studied cases.Ostiomeatal complex variations and mucosal thickening are considerably prevalent among the patients seeking rhinoplasty. This study also revealed that CBCT evaluation of paranasal sinuses has comparable result in delineation of the sinonasal anatomy. Otolaryngologists are interested in radiological assessment of paranasal regional anatomy. Certain aRegardless of the controversy about the role of anatomic variations of ostiomeatal complex in inducing rhinosinusitis, being aware of prevalence of these variations might be influential during surgical procedures that involve paranasal sinuses such as Functional Endoscopic Sinus Surgery (FESS) and rhinoplasty. -11For avoiding dissatisfaction after esthetic rhinoplasty, focus on esthetic improvement of the nasal shape should not sacrifice sinonasal health,  and in tComputed tomography (CT) scan is the method of choice for evaluation of paranasal sinuses and the coronal plane is the preferred imaging plane that best displays the ostiomeatal complex. Moreover, since introducing the first cone beam computed tomography (CBCT) system for dentomaxillofacial imaging in 2001 researches have focused on the feasibility of CBCT in several applications including diagnosis of the problems of nose and paranasal sinuses. Considering sinus scanning protocol, the CBCT systems provide comparable high-contrast resolution and inferior low-contrast resolution relative to those obtained with the multi detector CT scanners )MDCT, with 15×15 field of view, taken as a part of preoperative recording of patients seeking rhinoplasty in an otolaryngology clinic over a 1-year period. Coronal cross sections for each patient were reviewed in NNT workstation by authors, for the following features:The incidence of anatomical variations affecting the ostiomeatal complex including the presence of Concha bullosa , Haller cells , nasal septum deviation, paradoxical middle turbinate , Agger nasi , as well as variations in the shape direction and attachment of uncinate process.The incidence of mucosal thickening.Any alteration of the paranasal sinus anatomy resulting from previous surgery, benign tumors of sinonasal mucosa and facial trauma were considered as exclusion criteria. Data were statistically analyzed using SPSS Software, Version 15 . Chi- square test was used for statistical comparison of ostiomeatal anatomic variations between the two genders and between the two sides. Odds ratio was used to assess the significance of association between each of the anatomic variations and the presence of mucosal thickening. A total of 281 subjects who met the study criteria including 153 female (54.44%) and 128 male (45.55 %) patients were included in this study. The subjects were 17-52 years old with the Mean±SD age of 26.97±7.38 years. Various degrees of mucosal thickening were detected in 60.7% of the studied cases. According to p= 0.02).As represented in Prevalence of mucosal thickening was also significantly higher in men than women.There was also significant relation between the presence of Agger nasi cells and absence of mucosal thickening .There was significant relation between the uncinate process variations and presence of mucosal thickening .Regardless of the controversy about the possible role of anatomic variations of paranasal sinus structures in predisposing the patients to recurrent rhinosinusitis, -8, 11-12et al. [et al.  which evAccording to et al. [et al. [As displayed in et al.  and Math [et al.  The variet al. [et al. [et al. [et al., [Agger nasi was the most prevalent among the cases investigated in the present study (93.2%); which is comparable with the results of Bolger et al.  Perez-Pi [et al.  Zinreich [et al.  Much les [et al.  and Wani[et al.,  The vari[et al., , 29et al. (65%); [et al. (4.5%), [et al. (3%). [The prevalence of uncinate process variations in this study was 54.8% which correlated with the results of the studies performed by Wanamaker (45%),  Mamatha . (65%);  but high. (65%);  Perez-Pi (4.5%),  and Zinrl. (3%). et al. (53%), [et al. (67%), [et al. (73%). [et al. (36%), [et al. (15%). [The prevalence of concha bullosa in this study was 67.3% and correlated to Bolger . (53%),  Scribano. (67%),  Perez-Pi. (73%).  It is hi. (73%).  Zinreich. (36%),  and Mama. (15%). et al. [et al. [It is important to note that the degree of pneumatization could be attributed to racial factors.  Badia etet al.  reported [et al.  evaluate [et al. et al. (10%) [The prevalence of paradoxical middle turbinate in this study was 10% which is in line with the study performed by Perez-Pinas l. (10%)  and Lloyl. (10%) , 31et al. [et al. [As shown in et al.  were uni [et al. reported et al.; [et al., [et al. [et al. [Nearly all Agger nasi cells detected in the current study were bilateral (97.33% vs. 2.67%). This variation was also more bilateral among the cases investigated by Fadda et al.;  whereas  [et al. studies iet al. [et al. Bilateral and unilateral occurrence of uncinate process variations was almost similar in our cases (47.40% vs. 52.60%) while in the studies by both Wani et al. [et al. [In this study, unilateral paradoxical curvature of middle turbinate 85.71%) were detected to be more than bilateral ones; which was in accordance with the studies by Wani et al.  and Faddi et al.  and Fadd.71% wereet al. [Picavet et al. performedet al. [In addition, we found mucosal thickening in 60.7% of cases while Picavet et al.  found muet al., [Based on Mathew et al.,  there waet al., , 26, 30 et al., , 8-9 AccConsidering odds ratio, uncinate process variations predisposed the cases to mucosal thickening which is in accordance with the previous studies. , 5, 8 AdOstiomeatal complex variations and mucosal thickening have considerable prevalence among patients seeking rhinoplasty. To reduce the possible complications of the surgery and to achieve optimum satisfactory results, these structural and mucosal alterations could deliberately be evaluated by CBCT with relatively lower radiation exposure.


Regional climate modeling using convection‐permitting models  emerges as a promising framework to provide more reliable climate information on regional to local scales compared to traditionally used large‐scale models . CPMs no longer rely on convection parameterization schemes, which had been identified as a major source of errors and uncertainties in LSMs. Moreover, CPMs allow for a more accurate representation of surface and orography fields. The drawback of CPMs is the high demand on computational resources. For this reason, first CPM climate simulations only appeared a decade ago. In this study, we aim to provide a common basis for CPM climate simulations by giving a holistic review of the topic. The most important components in CPMs such as physical parameterizations and dynamical formulations are discussed critically. An overview of weaknesses and an outlook on required future developments is provided. Most importantly, this review presents the consolidated outcome of studies that addressed the added value of CPM climate simulations compared to LSMs. Improvements are evident mostly for climate statistics related to deep convection, mountainous regions, or extreme events. The climate change signals of CPM simulations suggest an increase in flash floods, changes in hail storm characteristics, and reductions in the snowpack over mountains. In conclusion, CPMs are a very promising tool for future climate research. However, coordinated modeling programs are crucially needed to advance parameterizations of unresolved physics and to assess the full potential of CPMs. Convection‐permitting climate models reduce errors in large‐scale modelsAdded value in convective processes, regional extremes, and over mountainsDiscusses challenges/potentials of convection‐permitting climate simulations Although climate mitigation and adaptation measures are evaluated and applied at local to regional level, current state‐of‐the‐art large‐scale models (LSM)  and regional climate model (RCM)) operate at horizontal grid spacing   that operates on the kilometer scale. Several different terms have been used for CPMs throughout the literature. Terminologies such as cloud‐resolving, convection‐resolving, cloud‐permitting, or convection‐permitting simulations have been frequently used interchangeably [e.g., Weisman et al., Prein et al., Lauwaet et al., Trusilova et al., In mesoscale atmospheric research, CPMs have been used for decades in studies of idealized cloud systems and real weather events. Since the beginning of the 21st century, advances in high‐performance computing allowed steady refinement of the numerical grids of climate models well beyond 10 km. At these scales, convection parameterization schemes may eventually be switched off as deep convection starts to be resolved explicitly [e.g., Bernardet et al., Done et al., Schwartz et al., Weusthoff et al., Davis et al., Grell et al., x = 1 km and showed drastic changes in the seasonal average precipitation patterns compared to LSM simulations. More recent studies have performed CPM simulations on time scales longer than 1 year to investigate climatological features in CPM simulations [e.g., Brisson et al., Chan et al., Ban et al., Fosser et al., Kendon et al., Junk et al., Tölle et al., Prein et al., Rasmussen et al., Ikeda et al., Gensini and Mote, Chan et al., Kendon et al., Knote et al., Rasmussen et al., Four basic modeling approaches used to perform CPM climate simulations are visualized in Figure Miura et al., Satoh et al., Putman and Suarez, Miyamoto et al., Moore, The second approach is to run global integrations at convection‐permitting grid spacing Figure b. This aGrabowski and Smolarkiewicz, Khairoutdinov and Randall, Li et al., Benedict and Randall, Pritchard et al., Kooperman et al., Goswami et al., Stan et al., Randall et al. [2 to 103 larger than the costs for traditional large‐scale model (LSM). However, this technique is still computationally inexpensive compared to the second approach using global CPMs, which is 106 times more expensive than traditional LSM [Randall et al., To reduce the computational challenges of global CPMs, the third approach uses GCM with the so‐called superparameterizations Figure c [Grabowl et al.  estimateSchmidt, Staniforth and Mitchell, Skamarock et al., Rauscher et al., Hagos et al., Tang et al., x = 17 km is refined to Δx = 4 km over Europe and to Δx = 1.4 km over the British Isles. Using this stretched‐grid approach, Tang et al. [Skamarock et al., Wan et al., Slingo et al., Cornford et al., The fourth approach uses stretched‐grid models [e.g., g et al.  showed tOnly the first approach, grid telescoping, is considered in this review, and various forms of this methods will be studied and compared in Since the beginning of the 21st century more and more studies have focused on CPM climate simulations and there is now a strong need to synthesize these studies and to build the foundation and common basis for future advances in climate modeling. Furthermore, impact researchers and stakeholders should be informed of what to expect from CPM climate simulations. This review paper aims to provide this kind of scientific basis by summarizing the knowledge acquired up to now and by highlighting existing challenges and important research questions in this field. In particular, we review the following: (1) What grid spacing is needed for CPM climate simulations ? (2) Wha2Grell et al., Gensini and Mote, In this section, we provide a brief summary of the most important CPM climate simulations reviewed in this paper. Their selection is based on a careful literature review. Figure Gensini and Mote, Additionally, the parent‐grid ratios, i.e., the integer parent‐to‐nest ratios of the horizontal grid spacing, differ widely among individual experiments. Most studies use a parent‐grid ratio between 1:3 and 1:9, except one study that used a parent‐grid ratio of 1:38 [3Gage, Nastrom and Gage, Wyngaard, Moeng et al., Pielke, The energy spectrum of deep convective clouds is continuous across kilometer scales without an apparent energetic gap indicating a scale separation [Weisman et al. [Deng and Stauffer, Lean et al., Roberts and Lean, Done et al., Weisman et al., Schwartz et al., Prein et al., The upper bound on the horizontal grid spacing of convection‐permitting simulations was investigated by n et al.  using idBenoit et al., Richard et al., Lean et al., Skamarock and Klemp, Schwartz et al., Weusthoff et al., Baldauf et al., Kendon et al., Ban et al., Fosser et al., Dai et al., Randall et al., Guichard et al., Bechtold et al., Brockhaus et al., Hohenegger et al., Wyngaard, Moeng et al., Indeed, the explicit treatment of convection using models with grid spacings less than 4 km has led to considerable improvements of quantitative precipitation forecasts [Bryan et al., Cullen and Brown, Khairoutdinov et al., Craig and Dörnbrack [Petch et al., Adlerman and Droegemeier, Bryan et al., Petch, Lang et al., Fiori et al., In the limit of extremely fine horizontal grid spacings, CPMs are thought to converge to large‐eddy simulations [örnbrack  found thLorenz, Zhang et al., Hohenegger and Schär, It is here important to distinguish the purpose and concept of CPM climate simulations from that of weather forecasts or studies of individual cloud systems. At kilometer scales, deterministic predictability is limited to a few hours and small‐scale structures are dominated by stochastic processes [Schwartz et al. [Kain et al. [Langhans et al. [This question was addressed by z et al.  who analn et al. . Similars et al.   of 4.4 km, 2.2 km, 1.1 km, and 0.55 km. Figure The minimum requirement on the horizontal grid spacing to simulate the bulk heat and moisture tendencies and surface precipitation from an ensemble of convective cells has been addressed by s et al.   might modulate locally the dynamics in the boundary layer [Segal and Arritt, Taylor et al., Froidevaux et al., Lauwaet et al., It is of interest to point out that simulations on even finer numerical grids will certainly benefit from better resolved topographic features . Sufficient horizontal grid spacing is of particular importance to simulate the small‐scale variability of surface precipitation over complex terrain [Wang et al., Roh and Satoh, Varble et al. [Miyamoto et al. [Certainly, the question emerges of how much deviation from the converged solution is tolerated in CPMs. Considering the weak grid sensitivity reported above from models running with grid spacings below 4 km and the fact that physical parameterizations result in a similar or even larger spread [e et al.  or Miyamo et al. ) could o4Dickinson et al., Giorgi and Bates, Anthes et al., Dynamical downscaling is conceptually based on the generation of fine scales with RCM simulations initialized and driven by a coarse‐mesh GCM [In this section, we review the rationale behind specific downscaling strategies. Aspects addressed here include the nesting technique including the parent‐grid ratio, the effect of two‐way nesting, domain size, and nudging.4.1Antic et al., Denis et al., Brisson et al. [x = 80 km). They concluded that an intermediate nesting step with Δx = 25 km was essential for the correct representation of precipitation in the CPM. Introducing an additional nest with Δx = 7 km did not improve the results while both directly nesting the CPM into ERA‐Interim and replacing the Δx = 25 km with the Δx = 7 km nest lead to a strong dry bias. The deterioration in the ERA‐Interim to CPM nesting is probably related to the small parent‐grid ratio of 1:30 and the small domain size, while the deterioration in the intermediate Δx = 7 km experiment is probably related to its grid spacing that is in the gray zone where assumptions of convection parameterizations starts to break down.How to downscale large‐scale GCM output to regional and local scales over a limited area is a common challenge of LSM and CPM. Usually, multiple nested limited‐area domains at decreasing horizontal grid spacings are applied until the convection‐permitting scale is reached. However, there is no common agreement on how many steps are needed and how small the parent‐grid ratio between the individual nests could be  because they might be too small to allow the RCM to spin‐up. To provide a smoother transition between the lateral boundary conditions and the RCM simulation, a boundary relaxation zone with typically exponentially decreasing weights in the outermost ∼10 grid cells is applied [Davies, Marbaix et al., Regional climate models (RCMs) and CPMs need some spatial spin‐up  for the generation of fine‐scale features because they are forced by lateral boundary conditions which are given on a coarser scale and which are often physically inconsistent with the RCMs physics . The extent of this spatial spin‐up depends on the speed of the flow, the parent‐grid ratio, hydrodynamic instabilities, nonlinear processes, and surface processes Laprise, . It is ht al.'s,  estimateBrisson et al. [x = 3 km simulation. This was partly related to the morphogenesis of hydrometeors  which were not considered in the driving model.n et al.   to about eight horizontal grid spacings (Δx). This reduces the effective resolution of such models  implicitly diffuse the prognostic variables at scales ranging from two horizontal grid spacings . This w5.2Pruppacher et al., Adams‐Selin et al., Since convection parameterization schemes are not used in convection‐permitting models (CPMs), cloud microphysical processes and processes that contribute to the explicit triggering of deep convection on the grid gain in relevance. Microphysical processes in convective clouds are much more complicated than in stratiform clouds [e.g., Van Den Heever and Cotton, Cohen and McCaul, Adams‐Selin et al., Van Weverberg et al., Morrison and Milbrandt, Adams‐Selin et al. [Brisson et al. [Li et al., Several studies examined the effect of including graupel or hail to the microphysics scheme of convection‐permitting models (CPMs). It is not clear if introducing graupel or hail weakens [n et al.  found thn et al.   in CPM Tao et al., Karydis et al., Koren et al., Fan et al., Ekman et al., Lee et al., The limited knowledge about these processes and their interactions can have far‐reaching consequences. In particular, the representation of cloud‐radiative feedbacks relies heavily on accurate representations of cloud cover and cloud‐radiative properties . Most importantly, the parameterization of cloud‐aerosol interactions remains poorly understood and a key uncertainty in both global models and CPMs [e.g., Tao et al., Rosenfeld et al., Wang et al., Levin and W. R. Cotton [Tao et al. [Because of the widespread effect of aerosols on the climate system, it is important to improve the prescription of aerosols in climate models. Therefore, coupling CPM with aerosol modules that are able to model properties such as particle size, chemical composition, and mixing state [. Cotton  and Tao Liu et al. [Not only convective precipitation is sensitive to the representation of cloud microphysics. u et al.   remain considerably larger than those due to a mesh refinement at kilometer scales [oncrieff  or textb [Straka .Colette et al., Gu et al., Liou et al., Since CPM climate simulations have a more realistic representation of orography, topographic shading, and differential heating in narrow valleys can be simulated. Nonhydrostatic climate models, such as the COSMO‐CLM and the Weather Research and Forecasting Model (WRF) offer an option to include orographic shading and slope effects on radiative transfer. Including those effects delays the breakup of valley inversion layers [5.3Stull, Bryan et al., The planetary boundary layer is the part of the atmosphere that is directly influenced by the Earth's surface and where turbulent processes act on time scales shorter than 1 h [e.g., x)) [e.g., Skamarock, Smagorinsky, Lilly, Deardorff, Bryan et al., Basically, two conceptually different approaches for turbulence parameterizations might be considered relevant to CPM simulations. Mesoscale models and GCM solve for the ensemble‐averaged Navier‐Stokes equations, and the mean flow can be considered laminar. All turbulent kinetic energy and all turbulent fluxes remain unresolved and need to be parameterized. The grid spacing and the effective resolution  with the land surface and atmosphere are generally neglected or oversimplified [e.g., Freeze and Harlan [Gochis et al., Maxwell et al., Leung et al., Miguez‐Macho et al., Niu et al., Shrestha et al., York et al., Maxwell et al., Shrestha et al., 0 m in the lateral and 10−2 m in the vertical direction [Vogel and Ippisch, Based on the early blueprint for integrated hydrologic response models by d Harlan , a numbe5.5Cosgrove et al., Prein et al., Rasmussen et al., Ban et al., A challenging task for CPM climate simulations is the initialization of slow varying fields such as soil moisture and deep soil temperature. While the atmospheric component of climate models reaches an equilibrium state after a few days (spin‐up time) it can take several years for deep surface layer properties [e.g., Kantha and Clayson, Carton and Giese, Even longer spin‐up times are needed for coupled ocean models. In coupled GCM ocean models, deep ocean layers require hundreds of years to adjust while the upper ocean only requires about 50 years [5.6Loveland et al., Masson et al., Arino et al., Sanchez et al., Sanchez et al., Mironov, Kumar et al., Subin et al., Martynov et al., To explore the full potential of CPM climate simulations, high gridded surface fields are necessary. Land cover information is typically provided on grids between 1 km and 300 m [Hastings and Dunbar, Suwandana et al., Messmer and Bettems, Suwandana et al., Another precondition for CPMs are highly resolved digital elevation models. State‐of‐the‐art digital elevation models have sufficiently high grid spacing between 1 km and 30 m [5.7Navarra et al., Smari et al., http://www.top500.org).CPM climate simulations pose a number of high‐performance scientific computing challenges. The continuous weather and climate model development that makes CPM climate simulations possible is concurrent to considerable progress of highly scalable supercomputing infrastructure with high‐bandwidth and low‐latency network connections (interconnects), multicore CPUs, or parallel file systems leading to ever‐increasing computational resources [6 grid elements, e.g., for mesoscale river catchments to up to more than 130×106 for continental domains, CPM climate simulations are computationally very demanding and require specific approaches and solutions that also enable them to efficiently run on next‐generation exascale computing systems (>1018 floating point operations per second) [Attig et al., Keyes, Davis et al., Michalakes et al., Primarily, due to their small horizontal grid spacing, which demands small time steps below 60 s in combination with many model levels , and domain sizes that may range from overall 8×10Geimer et al., Carns et al., The speedup  and parallel efficiency  are measures to evaluate the success of a parallelization effort of an application, for example, in strong scaling studies with a constant problem size during the experiment. Figure Geer, Michalakes et al., Jin et al., Michalakes et al., Jin et al., Today's high‐performance computing systems are massively parallel distributed memory multicore supercomputers with very fast communication networks for data exchange between the individual compute nodes with a shared memory [e.g., Brodtkorb et al., Liu et al., Davis et al., Hwu, x = 2.5 km for a continental U.S. model domain [Meadows, Michalakes and Vachharajani [Lapillonne and Fuhrer, A development in supercomputing that seems especially relevant for highly scalable resource‐intensive CPM climate simulations is the evolution of hybrid or heterogeneous high‐performance computing architectures where multicore CPUs are combined with accelerators (either graphic processing units (GPUs) or Many Integrated Core chip designs) on a single compute node [Meadows, . Michalaharajani  reach anAloisio and Fiore, −1, i.e., 204 Tb for a single decadal run. Data input and output operations, handling and transfer, and analysis as well as storage and archival of such data volumes therefore become a grand challenge [Overpeck et al., NAFEMS World Congress, Clyne and Norton, Zhang et al., Childs et al., The small spatial grid spacing of the CPM climate simulations and necessary frequent output intervals  combined with increasing ensemble sizes pose a substantial big data challenge [Steed et al., Generally, efficient generic analysis frameworks for big geoscience data are still rare, leading to a disparity between parallel, highly scalable model simulations and file systems versus serial analysis/postprocessing tools and often still serial input and output [5.8Kirchengast et al., Haiden et al., Wüest et al., Golding, Lin and Mitchell, Overeem et al., Mass and Madaus, Smith et al., Many of the above described model developments, the evaluation, and assignment of added value in CPM climate simulations are crucially dependent on high‐quality subdaily observational data sets with grid spacings at the kilometer‐scale. The high temporal and spatial resolution is needed to examine the simulation of small‐scale extreme events; an area where CPM climate simulations have high potentials to improve LSM simulations see . GloballBougeault et al., Grubišic et al., Wulfmeyer et al., Alternatives for model development are observations derived from measurement campaigns like the Mesoscale Alpine Programme [66.1As already discussed in Denis et al., x = 4 km) and with two LSMs is shown in Figure x). The higher variability at small wavelengths is a precondition for potential added value in CPM climate simulations, but no guaranty. The form of the spectra also indicates that spatial or temporal averaging of the CPM climate simulation's precipitation will smooth out the potential added value. The variance spectra of other atmospheric variables have similar characteristics [e.g., Skamarock, Horvath et al., Prein et al. [A useful tool to investigate the potential added value is the decomposition of the variance of atmospheric fields into contributions from different wavelengths [e.g., n et al. .6.2Frei and Schär, Isotta et al., This section gives an overview of studies that have evaluated precipitation in CPM climate simulations against LSMs and observations. The observations used for validation are fine‐gridded precipitation data sets, mostly based on radar and rain gauge measurements. Thus, during the evaluation one should account also for the uncertainties in the observations [6.2.1Langhans et al., Langhans et al., Prein et al., A major added value using CPMs is the improved diurnal cycle of summer precipitation. Figure Fosser et al. [Baldauf et al., Fosser et al., r et al.  . Applyin et al.   of the applied CPM. However, Langhans et al. [Ban et al., Fosser et al., CPMs have a tendency for too intense daily heavy precipitation in mountainous regions [s et al.  found noBan et al., Fosser et al., Chan et al., Gensini and Mote [The largest differences between LSM and CPM climate simulations occur on short (subdaily) time scale and for summertime high‐precipitation intensities. Heavy hourly precipitation is typically underestimated in LSM, while large improvements were found in CPM climate simulations [and Mote   and a high vertical resolution in the boundary layer because of the small‐scale processes involved. Short‐term convection‐permitting model (CPM) simulations are able to realistically simulate valley inversions and the related temperature and wind structures [Zhong and Whiteman, Vosper et al., Wei et al., Daly et al., Simulating inversions in CPM climate simulations usually demands subkilometer‐scale horizontal grid spacing  with the WRF model. They found that decreasing horizontal grid spacing (Δx) from 8 km to 1 km leads to a drop in minimum central pressure of 30 hPa attributed to small‐scale physical processes, which are important for tropical cyclone intensity. The domain size of the CPM should not be smaller than 500 km to simulate realistic small‐ and large‐scale features of the storm.Although tropical cyclones are synoptic‐scale objects with spatial extents of several hundreds to thousands of kilometers, small‐scale features such as deep convection or narrow wind systems are crucial for their formation and characteristics such as maximum wind speed and central pressure. Several studies indicate improvements in the simulation of tropical cyclones when CPMs are used [e.g., Lackmann  tested tTaraphdar et al. [x = 1.1 km with LSM simulations and found improvements in the observed tracks and intensities in their CPM simulations.r et al.  compared6.7Seager et al., The decrease in grid spacing of RCM to the CPM scale has important benefits for the representation of the local city climate. This opens the way for an improved assessment of the climate change impact due to urbanization. It is important that this impact is included in climate projections for the future: For example, for North America, urban‐induced climate change is of the same order of magnitude as that due to long‐lived greenhouse gases [Gimeno et al., Grossman‐Clarke et al., Masson, For numerical weather prediction, the typical convection‐permitting model (CPM) spatial scale has already been reached a decade ago, implying that some grid cells are completely urbanized [Trusilova et al. [x = 10 km), indicating a reduced diurnal temperature range in urbanized regions. Zhang et al. [Van Weverberg et al., Hamdi and Vyver, Grossman‐Clarke et al., Grawe et al., Bohnenstengel et al., Wouters et al., x > 10 km) [Trusilova et al., Wouters et al., One of the first to assess how urbanization affects climate in Europe was a et al.  . Therefore, our understanding of how those processes are acting on climate time scales is very limited.7IPCC, As shown in the previous sections, CPM climate simulations facilitate the understanding of the climate system's behavior at scales most relevant to policy makers and citizens. Additionally, climate models are used to make projections of possible future evolutions of the climate system, typically up to 2100 IPCC, . In thisNakicenovic and Swart, Van Vuuren et al., Rogelj et al., Climate projections are based on possible future evolutions of the emissions of greenhouse gases, aerosols, and precursor gases as well as land use/land cover changes, which are derived based on socioeconomic and technological assumptions. As future anthropogenic choices cannot be predicted, different projections covering a range of possible scenarios are used to make projections for the future climate [IPCC, Cholette et al., Hohenegger et al., These scenarios are used to prescribe atmospheric composition in general circulation models, which in turn, simulate the response of the climate system to these changes. Due to their coarse grid spacings  and the7.1Junk et al. [Tölle et al. [Tölle et al. [k et al.  and Tölle et al.  show thae et al.  shows thKnote et al. [e et al.   between 60 km and 20 km results shows an increase in the number of intense cyclones [e.g., Bengtsson et al., Knutson et al., x) around 20 km can simulate tropical cyclone with central pressures below 900 hPa [Murakami et al., Braun and Tao, Gentry and Lackmann, The skill in simulating tropical cyclones depends on the horizontal grid spacing of climate models see . There iKanada et al. [Kanada et al. [a et al.  .8.1x) for which numerical weather and climate models start to permit deep convection sufficiently to avoid the use of error‐prone deep convection parameterization schemes is around 4 km. The physical justification for the application of convection parameterizations starts to break down for horizontal grid spacing (Δx) approximately smaller than 10 km such that parameterizations have to be either reformulated or switched off. Simulations with horizontal grid spacing (Δx) in between the convection‐permitting (Δx < 4 km) and the convection‐parameterized scale (Δx≥10 km), called “gray zone,” should be avoided before suitable scale‐aware parameterizations are designed. Several studies report minor sensitivities for grid spacings smaller then 4 km, especially when compared to the sensitivities stemming from physical parameterizations such as microphysics. A more stringent upper bound on the horizontal grid spacing of CPM climate simulations will have to be enforced if small‐scale topographic features or land surface heterogeneities need to be resolved.The horizontal grid spacing  should be kept larger than 1:12 but also smaller ratios have already been applied with success.x < 10 km. (2) CPM simulations demand higher accuracy and stability of numerical discretization schemes because of steeper slopes (better resolved orography). (3) The effective resolution, which is largely set by the implicit diffusion of discretizations, needs to be high in order to prevent too strong smoothing of the small‐scale dynamics and in order to not unnecessarily waste computational resources.Several approximations and simplifications in the numerics of LSMs lose their validity or cause instabilities when convection‐permitting grid spacings are approached. (1) CPM simulations demand a nonhydrostatic formulation of the dynamical core since the hydrostatic approximation is no longer valid for ΔThe setup of CPM climate simulations is often adapted from numerical weather prediction models because of the high computational costs of testing the physical settings in CPM climate simulations. Whether these settings are appropriate for simulations on climate time scales is, however, largely unknown.8.2Since in CPM climate simulations deep convection is explicitly modeled on the numerical grid, the initiation of convection as well as the evolution and morphology of individual clouds becomes overall more dependent on parameterizations of microphysical processes. The introduction of additional hydrometeor species, such as graupel and hail, or the simulation of the number concentration of cloud particles using two‐moment microphysics schemes can be beneficial for the representation of wintertime orographic precipitation and high cloud cover. However, several physical processes in convective and mixed‐phase clouds and their interaction with aerosols are not well understood and somewhat constrain the full potential of two‐moment schemes. Sensitivities related to cloud microphysical parameterizations and the related sensitivity of the cloud‐radiative feedback remain considerably larger than those due to mesh refinement at kilometer scales.Since soil‐atmosphere interactions are important for many atmospheric processes, from energy fluxes at the surface that interact with near‐surface fields  to the boundary layer dynamics (including the initiation of convection), the introduction of more advanced representations of soil and vegetation processes seems to be crucial in CPM climate simulations.8.3Houze, [Romps, Edman and Romps, There is clear evidence that CPM climate simulations are able to add value to LSMs. However, it is also important to mention that CPM climate simulations are not the cure for all model biases. The largest added value can be found on small spatial and temporal scales (<100 km and subdaily), in regions with steep orography, and higher‐order statistics . High potential for added value lies in process‐based analyses such as analysis of storm dynamics, local wind systems, and the interaction of atmospheric flows with orography  representation of extreme precipitation on hourly time scales; (2) timing (onset and peak) of the diurnal cycle of summertime convection; (3) improved structures of  precipitation objects ; (4) improved simulation of wet‐day frequencies; (5) the added value for precipitation is smaller for winter than for summer except in mountainous regions because of the stronger orographic forcing and reduced role of convection; (6) improved simulations of the buildup and melting of snowpack; (7) improvements in temperature at a height of 2 m related to improved representation of orography; and (8) simulation of the center pressures and small‐scale processes in tropical cyclones.Due to the high computational costs, only a small number of groups investigated climate change issues using CPM climate simulations. All these studies show highly relevant differences in the regional to local climate change signals between CPM climate simulations and LSM simulations. In addition, these studies delivered insights into changes of some meteorological processes which would not have been gained with LSM. Those differences are as follows: (1) a significant increase of short‐duration extreme precipitation events during summer; (2) hail storms over mountains are likely to produce more hail in the upper parts of clouds in a warmer climate, but the amount of hail reaching the surface is likely reduced to zero due to an average increase of the melting level by 500 m; (3) stronger decrease of central pressures and stronger maximum 10 m wind speed in extreme intense tropical cyclones in the northwestern Pacific Ocean; (4) decreases in the future runoff from the Colorado Headwaters due to increased evapotranspiration which counteracts the predicted increase in runoff due to increased precipitation; (5) decreased snowfall to precipitation fraction reduces the snowpack especially in lower elevated areas and late spring; and (6) stronger increase of the daily minimum/maximum temperature in mountain/valley areas of Western Germany and parts of Luxemburg.Climate‐relevant feedback mechanisms not only reveal different magnitudes but some even differ in sign depending on whether a LSM or a CPM was used: (1) in LSMs the soil moisture‐precipitation feedback depends on the used convection parameterization, while CPMs are able to simulate this feedback more realistically; (2) a potential increase in future forest cover, as a result from converting agricultural land to bioenergy plantations, could cause a vegetation‐atmosphere interaction which cools down regional maximum temperature at a height of 2 m.The inability of LSMs to replicate climate‐relevant feedback mechanisms casts doubt on the reliability of regional‐scale information from LSM projections of future climates.8.4Mölg and Kaser [Simulations with LSMs typically have to be statistically downscaled to generate information relevant for impact models . Because of the fine grid spacing of CPM climate simulations, this statistical postprocessing can be avoided as shown in a study by nd Kaser . A direc9Soares et al. [Bogenschutz and Krueger [Moeng et al. [Moeng [Turbulent parameterizations have to be developed to accurately represent the planetary boundary layer, shallow convection, subgrid‐scale cloud cover, and turbulent fluxes related to deep convective systems at kilometer scales. Recent developments, such as those by s et al. , Bogensc Krueger , Moeng eg et al. , and Moe. [Moeng , show prMicrophysics schemes applicable in CPMs are able to simulate additional hydrometeors such as graupel or hail. While this can be beneficial for the simulation of precipitation, their interaction with radiation is often neglected because of the poorly understood optical properties of those hydrometeors.Two‐moment microphysics schemes allow for a more realistic distribution of hydrometeors. However, those schemes are highly tunable, and many key processes such as drop‐drop interactions, the formation of ice particles, or the shape of the particle size distributions are not well known. To unfold the full potential of these schemes, further research is necessary to improve the representation of these processes.There is very limited knowledge about cloud‐aerosol interactions with far‐reaching consequences on the development of deep convection, cloud cover, and precipitation. Cloud‐aerosol interactions are a major source of uncertainties in future climate projections. Besides coupling CPM climate simulations with aerosol modules that are able to describe particle sizes, chemical compositions, and mixing states, basic research on cloud‐aerosol interactions is needed.x). Reducing the numerical diffusion can therefore save computational resources. Numerical schemes with higher order of accuracy like those suggested by Morinishi et al. [Ogaja and Will [CPM climate simulations demand for high accuracy and stability of the numerical solver to avoid instabilities and numerical diffusion. Numerical diffusion leads to effective model resolutions that are many times greater than horizontal grid spacing . An efficient performance on such architectures demands a restructuring or rewriting of parts of the model code. This may lead to speedups of up to 7X for dedicated parts of the code [e.g., Overpeck et al., Zhang et al., Childs et al., Not only the computational time but also the data amount processed during CPM climate simulations is challenging. Data input/output operations, handling and transfer, analysis as well as storage, and archival of such data volumes become a grand challenge [A frequently limiting factor for the detection of added value and the evaluation of CPM climate simulations is the availability of suitable observational data sets. Since the potential added value is expected at small temporal and spatial scales and for extremes, fine‐gridded observational data sets in high temporal resolution are needed. In addition, such measurements are required to cover long temporal and spatial scales in order to be utilized in climate model evaluations.Detecting added value in CPM climate simulations demands suitable evaluation methods. Traditional statistics used in climate research such as climatological mean values, or annual to decadal variabilities are mostly not suitable. The new methods should be able to decompose the spectrum of variability in order to isolate small‐scale features, to analyze the tails of climatological distributions, the extreme value statistics, or to investigate joint distributions . Furthermore, process‐based analysis methods can reveal deeper insights into the more physically and dynamically consistent atmospheric phenomena in CPM climate simulations.Meehl et al., Giorgi et al., Most of the studies presented in this review are based on results derived from a single model and/or considerably short simulation periods. Therefore, assessing the reliability and uncertainty in the presented results is challenging. More decadal‐scale CPM climate simulations are needed to improve our understanding of the climate system and involved feedbacks. A joint effort to address both added value and climate change signals in CPM climate simulations in an organized and coordinated way comparable to other programs like the coupled model intercomparison project [Although CPM climate simulations already have proven to add value to LSM simulations and to provide better insights in regional processes that are highly relevant for society and policy makers, there are several challenges which have to be addressed to exploit their full potential.


A minimum duration of 10–15 min may result in increased cortisol levels with peak concentrations 20–30 min after the cessation of the exercise bout  led to an increase in cortisol levels contrasted to a group exercising with moderate intensity (50–65% HRmax) , and 45 min of intense strengthening . They limited their findings by suggesting that the diurnal timing of the exercise session may be partially responsible for the observed decrease in cortisol levels. The 36% decrease during the first sampling interval (7:45–9:05 a.m.) was significantly higher than the 14% decrease during the longer second interval (9:05–11:00 a.m.). Thus, the reported cortisol data in the paper by Tsai et al. (These results confirm the threshold phenomenon for adults also in adolescents of late puberty stages and indicate that the concentration of cortisol after acute bouts of exercise is intensity dependent. In contrast to these results Tsai et al.  found thy et al.  formulatr et al.  used acui et al.  lack supi et al.  is the di et al.  reportedi et al.  waited fi et al. . Most ofThe 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.