The service has been in operation since the end of 2015 as an adjunct to face-to-face consultations. A key factor in understanding the barriers and facilitators to the acceptance of the tool is understanding the sociodemographic characteristics of general practitioners who determine its use.This study aimed to analyze the sociodemographic factors that affect the likelihood of doctors using eConsulta.A retrospective cross-sectional analysis of administrative data was used to perform a multivariate logistic regression analysis on the use of eConsulta in relation to sociodemographic variables.The model shows that the doctors who use eConsulta are 45-54 years of age, score higher than the 80th percentile on the quality of care index, have a high degree of accessibility, are involved in teaching, and work on a health team in a high socioeconomic urban setting.The results suggest that certain sociodemographic characteristics associated with general practitioners determine whether they use eConsulta. These results must be taken into account if its deployment is to be encouraged in the context of a public health system. The use of tele-consulting, synchronous or asynchronous consultation using information and communication technologies (ICT) to omit geographical and functional distance between general practitioners and citizens in primary health care, is widespread in both public ,2 and prThe Catalan public health system consists of more than 160 providers that offer universal access to 7.5 million people, making it an integrated public welfare network that guarantees the universal right to health . ShortlyA recent study of factors that influence the use of eConsulta found that the main reason individuals used the service was to resolve administrative matters and because the service has potential for significantly reducing the number of face-to-face visits . AnotherIn light of this evidence, this study aimed to employ a multivariate logistic regression model to analyze the characteristics of GPs that affect their use of eConsulta in the context of the Catalan public health system.This is a retrospective descriptive cross-sectional study of primary health care GPs belonging to the Catalan Health Institute (ICS), the major provider of primary care services in Catalonia . The period of study was between January 1, 2016, and March 31, 2018. The target sample was made up of all 3259 GPs working at ICS from 285 centers. The following exclusion criteria were established: doctors belonging to centers participating in the pilot phase of the study, those belonging to centers that activated eConsulta less than 12 months after activating the electronic clinical IT system, GPs from centers that activated the eConsulta service after January 2018 (thus ensuring a minimum 2-month use of the service), those with more than 100 children assigned to them, and those who changed primary care teams during the study period. This study included a total of 2451 doctors serving 220 centers . Of thesThe main study variable was the use of the eConsulta service. Use was defined as any messages sent during the study period, and nonuse was defined as no messages sent. The following were considered independent variables: age, gender, socioeconomic level of the center, type of center , average number of adults attended, mean age of patients assigned to GP, percentage of patients who have activated their PHF, GPs involvement in teaching (yes or no), QoC score, pharmacy prescription quality standard (PPQS) score as of December 2017, and doctor’s accessibility .t test was used to test the significance for continuous variables, and the Chi-square test was used for categorical variables. To evaluate which variables make a doctor more likely to have used the platform, a multivariate logistic regression analysis was used with a significance level of 95%. R-3.5.1  software was used to conduct the analysis.The descriptive analysis used the mean and standard deviation for continuous variables and numbers and percentages for categorical variables. The The multivariate regression model examined which variables affect the use of eConsulta. These variables, independently related to the outcome, are distinct from those obtained from the bivariate analysis, in which they are combined. This means it was not possible to identify a specific correlation. The odds ratio for each outcome is shown with regard to the reference categories and can be interpreted as probabilities. A coefficient of less than 1 indicates that the use of eConsulta is less likely, while coefficients greater than 1 indicate a greater probability of the tool being used. Therefore, according to the regression model, the characteristics of the doctors that determine the use of eConsulta include the following: 45-54 years of age, a QoC score that is higher than the 80th percentile, a high degree of accessibility, are involved in teaching, and work in a primary care team in an urban area with a high socioeconomic level. All of the variables shown in The results of this study differ from those of previous ones, which did not find significant differences in the gender and ages of doctors who adopted new technologies as part of their clinical practice ,21,22. IIt seems that doctors who use eConsulta more have a higher level of accessibility for face-to-face visits. However, this might be because doctors who use eConsulta are probably more involved in managing their agenda and more prone to meeting QoC and PPQS. The increased waiting time for primary care in Catalonia warrants investigation in other studies.Other policies may have acted as confounding factors that affected the interpretation of the results. For example, in January 2017, doctors in primary care teams in Barcelona were offered an economic incentive to use eConsulta. It should also be considered that in other instances, the Ministry of Health has introduced incentives to primary care teams throughout Catalonia to increase the use of the PHF.In summary, these results show that being 45-54 years of age, having a QoC score higher than the 80th percentile, having a high degree of accessibility, being involved in teaching, and working in a primary care team in an urban area with a high socioeconomic level are characteristics that determine the use of tele-consultation in Catalonia. This study’s data cannot be extrapolated to other health systems; however, the results are critical for digital health policy planners, as the success of the tool will heavily depend on whether GPs promote it.


Although numerous surgical techniques are employed to treat acute Stanford type A aortic dissection (ATAAD), controversy remains over which is the best procedure for aortic root reconstruction. Among the various techniques utilized, neomedia repair is considered to be more promising than adhesive-only repair for the treatment of a dissected aortic root. We experienced a series of neomedia sinus Valsalva repair using woven polyester fabric, and evaluated the aortic root diameter by computed tomography and severity of aortic valve insufficiency by transthoracic echocardiography. The aortic root diameter was well preserved with no progress of aortic valve insufficiency in the long-term period. Furthermore, we found that the fabric looked functioning new media in the findings obtained from the pathological examination of a neomedia repaired aortic wall sample that was obtained by chance from a patient during valve replacement surgery performed 10 years after aortic reconstruction for ATAAD. Neomedia repair using woven polyester fabric for ATAAD might facilitate the long-term durability of the surgically treated aortic root.  For patients with severe preoperative condition, saving the patient’s life is the first priority; however, recent advancements in extracorporeal circulation, brain and heart preservation, and revascularization methods have improved the outcomes of the initial treatment, and the improvement of long-term prognosis should always be kept in mind. Long-term prognosis should be considered for the remaining aortic root and distal aorta separately; however, the prognosis for the aortic root is affected by the enlargement of the sinus of Valsalva caused by recanalization and associated aortic insufficiency (AI). To stabilize the dissected sinus of Valsalva, we performed a series of neomedia repairs using polyester fabric as artificial media inserted into the dissected cavity, which was followed up for as long as 10 years. We presently report that we examined the long-term outcomes and obtained very interesting findings in one patient who underwent repeat surgery.The basic treatment method for acute type A aortic dissection (ATA AD), excluding cases with acute thrombotic occlusion, is emergency surgery,Among 23 consecutive patients with ATA AD treated between November 2008 and December 2012, we included 18 patients who underwent neomedia repair of dissected sinus of Valsalva with aortic root preservation. All patients underwent emergency surgery immediately after ambulance transportation to our hospital for acute aortic dissection. In patients who were directly transported by ambulance, diagnosis could be obtained by contrast-enhanced computed tomography (CT) at our hospital, and therefore, when the previous physician performed the CT, the treatment policy was determined based on such information.Surgery was performed using a median sternotomy approach under general anesthesia with the patient in the supine position. For the extracorporeal circulation blood delivery site, when there is an undissected area on the lesser curvature side of the ascending aorta, that area is selected first, and an 18 Fr blood supply cannula for percutaneous cardiopulmonary support (PCPS) was inserted using the Seldinger technique. When the dissection extended to the lesser curvature side of the ascending aorta, a supply route was established with an end-to-side anastomosis performed using the femoral artery in young patients with mild arteriosclerotic lesions and using an 8-mm prosthetic graft from the right axillary artery for elderly patients and those with the dissection extending to the femoral artery. When malperfusion is observed in the four limbs, these techniques were combined, and at the start of the extracorporeal circulation, we endeavored to correct the malperfusion as much as possible. The extracorporeal circulation was commenced by taking the blood from two vessels, that is, the superior and inferior vena cavae, after which a retrograde coronary perfusion cannula and left ventricle vent were inserted. A cooling period of at least 30 min was left, and after confirming that both the temperature of the blood and tympanic temperature were below 26°C, circulatory arrest was determined. Cerebroprotection was performed by retrograde cerebral perfusion until confirmation of the intra-arch findings, and at the time of determining the surgical procedure, we switched to antegrade selective cerebral perfusion. For the myocardial protection, retrograde coronary perfusion-based antegrade selective coronary perfusion was additionally performed. When a dissection entry was present in the ascending aorta and there was no expansion of the dissection into the arch portion of the aorta, AAR was performed, and when there was an expansion into the aortic arch, with a dissection entry in the arch portion, or in cases of DeBakey type III retrograde dissection, TAR was performed. For all prosthetic grafts, a single-branch or 4-branch polyester graft was used.After performing distal anastomosis, proximal anastomosis followed for AAR and distal anastomosis by stepwise technique for TAR. Anastomosis was performed on the three branches of the arch in a distal-to-proximal order for TAR. Following the completion of distal anastomosis, the circulation of the lower half of the body was recommenced from the lateral branch of the prosthetic graft, and rewarming was slowly started.Neomedia repair was performed on the sinus of Valsalva immediately before the proximal anastomosis. In this series, two types of methods were used. The first method involved inserting polyester fabric  cut to the shape of the dissected sinus of Valsalva into the dissected cavity and pasting with a fibrin glue  . Transthoracic echocardiography was performed in the physiological examination room, and the presence or absence and degree of AI were compared before discharge and at the final examination. AI was evaluated according to the test report standard. When trimming the aortic wall in one patient who underwent long-term repeat surgery, a small sample of the neomedia repair site was taken, and histopathological diagnosis was made using hematoxylin eosin (HE) staining. Continuous variables are presented as mean±standard deviation, and a survival curve was created with the Kaplan–Meier method using JMP . This study was performed with the informed consent of the patient and their family members and with the approval of the ethical review board of Amagasaki General Medical Center, Hyogo .The subject sample included 18 patients with a mean age of 64.5±12.2 years , consisting of 9 male and 9 female patients. Preoperative cardiac tamponade was observed in five patients, and cardiopulmonary resuscitation was performed in one patient. Cerebral malperfusion was observed in two patients, and malperfusion of the lower limbs was observed in two patients. Dissection entries were located in the ascending aorta in 13 patients and in the aortic arch in two patients, with DeBakey type III retrograde dissection in three patients. AIs measured preoperatively using transthoracic and transesophageal echocardiography were mild in four patients and moderate or greater in two patients. One patient underwent maintenance dialysis for chronic renal failure  in one patient. Cardiac interventions included mitral annuloplasty for mitral insufficiency caused by rupture of the chordae tendineae in one patient, and in the patient with congenital bicuspid aortic valve, AI progressed, and 10 years later, aortic valve replacement was performed. In this patient, calcification of the right coronary cusp in the undissected sinus slowly progressed, and rupture of the same site led to AI. No patient required intervention for the aortic root  glue, bovine serum albumin–glutaraldehyde glue , fibrin glue , and fibrin sealant patch , as well as a neomedia repair method by inserting a felt sheet or polyester fabric into the dissected cavity as an artificial membrane. Stump formation was originally developed to prevent bleeding from the artificial anastomosis site and to stabilize the dissected intima so as not to cause a new entry by cutting the intima at the site of anastomosis. Alternatively, the treatment of the side of the dissected aortic root requires stabilization of the dissected sinus of Valsalva and maintenance of the aortic ring morphology in addition to reinforcement of the artificial anastomosis site, which should be considered separately. Biological adhesives such as GRF and BioGlue are injected into the base of the dissected cavity in the aim of total formation of the sinus of Valsalva; however, it has been pointed out that tissue toxicity of such adhesives causes problems. Neomedia repair involves the insertion of an artificial fabric tailored to the shape of the dissected sinus of Valsalva, and adhesion using either biological adhesive enables greater strength to be obtained in the sinus of Valsalva formed. For the material used, Teflon felt and polyester knitted fabrics have been reported.With regard to prosthetic graft replacement in ATA AD, various stump formation methods have been reported in the past. Such methods have long since started with methods for adhering the dissected cavity using an adhesive including a belt-shaped felt sandwich, reported that in AAR with stump formation in the aortic root using felt and aortic commissure lifting in 135 patients with acute and chronic ascending aorta dissections, the rate of avoiding repeat surgery for the aortic valve and aortic root was 96% at 5 years and 93% at 10 years. The reason for repeat surgery was enlargement of the sinus of Valsalva in two patients, infectious endocarditis in two patients, and prosthetic graft infection in one patient. Kirsch et al. performed stump formation in 130 patients, among whom GRF was used in more than two-thirds of the patients, and they reported that repeat surgery was avoided at a rate of 75% at 5 years, 61% at 10 years, and 39% at 15 years, which might have been affected by GRF problems.Regarding the long-term prognosis of the aortic root formed, there is not a single report summarizing surgical procedures. Sabik et al. formed the sinus of Valsalva using neomedia and avoided repeat surgery of the aortic root at a rate of 95% at 5 years and 78% at 10 years. The primary cause of repeat surgery of the proximal aorta was AI and anastomotic false aneurysm. In this study, BioGlue was used in the middle of neomedia fixation, and the effect of which cannot be ruled out. Rylski et al. formed the sinus of Valsalva using BioGlue and felt neomedia in 489 patients and avoided repeat surgery of the proximal side at a rate of 96% at 5 years, 92% at 10 years, and 89% at 15 years. The cause of repeat surgery was AI and anastomotic false aneurysm. Alternatively, Nakajima et al. performed neomedia repair by fixing knitted polyester fabric with fibrin glue and reported good outcomes with repeat surgery of the aortic root avoided at a rate of 98% at 5 years and 98% at 10 years. Although not resulting in repeat surgery, residual dissection of the aortic root was observed on CT during follow-up in three patients. In all reports, repeat surgery was performed for AI, anastomotic false aneurysm, and enlargement of the sinus of Valsalva, and we believe that maintaining the residual sinus of Valsalva and strength of the aortic commissure is the key to avoiding repeat surgery.While the details underlining the cause of repeat surgery are unclear, repeat surgery includes many procedures such as aortic valve replacement, AAR, and the Bentall procedure, and it is thought that AI and proximal aortic enlargement are causes. Geirsson et al. and because there is very little concern of biotoxicity, it is considered useful as an adhesive crosslink.Our method differs to reports to date in terms of the fact that a sheet of the same polyester fabric generally used for prosthetic grafts of the thoracic aorta was used as the neomedia and that in method 2, a fibrin sealant patch was used for adhesion. Polyester woven fabric is thin with moderate tension and has good operability when inserting to the back of the dissected cavity. Based on the histological findings presently obtained at the time of repeat surgery, affinity with the native tissue was also good, and therefore, we believe that it is a suitable material as artificial media. With regard to the difference between methods 1 and 2, repeat surgery was performed for the patient of method 1, and a fibrin glue was used as the bioabsorbable material, and therefore, we believe that if proper adhesion is achieved initially, long-term strength maintenance might lie in the polyester woven fabric, with similar outcomes. However, regarding the surgical technique, the fibrin sealant patch was superior in which the additional application of fibrin glue, which carries concern for embolism, was not needed, and proper adhesion could be obtained in a short time. Furthermore, it has been reported that the fibrin sealant patch is effective as an adhesive material for the dissected cavity when used alone,A limitation of the present study was that it was a retrospective observational study with a small subject sample. However, given that there was neither a single case of aortic root enlargement nor repeat surgery involving the aorta, we believe that this method is an excellent surgical procedure.When performing AAR for ATA AD, we inserted a polyester woven fabric into the dissected sinus of Valsalva and performed neomedia repair using fibrin glue and a fibrin sealant patch as an adhesive crosslink. In the long-term outcomes for up to 10 years, there were no patients with enlargement of the sinus of Valsalva and progression of AI, with repeat surgery of the aorta and aortic valve related to dissection avoided at a rate of 100%. The histopathology of the patient with bicuspid valve who incidentally required repeat surgery revealed that the neomedia completely assimilated with the native tissue, and we believe that this method greatly contributes to the repair and strength maintenance of the dissected sinus of Valsalva.


This paper illustrates the development of Primary Health Care (PHC) public sector in Malaysia, through a series of health reforms in addressing equitable access. Malaysia was a signatory to the Alma Ata Declaration in 1978. The opportunity provided the impetus to expand the Rural Health Services of the 1960s, guided by the principles of PHC which attempts to address the urban–rural divide to improve equity and accessibility. The review was made through several collation of literature searches from published and unpublished research papers, the Ministry of Health annual reports, the 5-year Malaysia Plans, National Statistics Department, on health systems programme and infrastructure developments in Malaysia. The Public Primary Care Health System has evolved progressively through five phases of organisational reforms and physical restructuring. It responded to growing needs over a 40-year period since the Alma Ata Declaration in 1978, keeping equity, accessibility, efficiency and universal health coverage consistently in the backdrop. There were improvements of maternal, infant mortality rates as well as accessibility to health services for the population. The PHC Reforms in Malaysia are the result of structured and strategic investment. However, there will be continuing dilemma between cost-effectiveness and equity. Hence, continuous efforts are required to look at opportunity costs of alternative strategies to provide the best available solution given the available resources and capacities. While recognising that health systems development is complex with several layers and influencing factors, this paper focuses on a small but crucial aspect that occupies much time and energies of front-line managers in the health. Equity and access through Primary Health Care (PHC) have been the main agenda of many countries after the PHC Declaration made in Kazakhstan in 1978. Each country including Malaysia used unique approaches to address this mission, based on its resources and presiding policies. Since independence in 1957, Malaysia has regarded health system development as an integral component of national development as evidenced in successive Malaysia Development Plans . The physical infrastructure of the RHS was a network of rural facility complexes. Each complex consisted of a ‘main health centre’, 4 health sub-centres and 20 ‘midwives’ clinics cum quarters’ (MCQs) and was intended to serve a rural population of 50 000. Each complex would have prescribed norms for staffing consisting of a doctor , dental officer, medical assistants, laboratory technicians, pharmacy assistants, nursing, midwifery and sanitation personnel, vehicles equipment and materials. And they were to provide a standard package of basic preventive and curative health care Ismail, . MaternaFor the MCH component, midwives identified pregnant women in the village community and encouraged them to come to the midwife quarters cum-clinic which was the nearest health facility. Subsequently, a well-defined screening and referral system identified and referred mothers and children who needed more intense or complex supervision to progressively higher levels of care, namely the Public Health Nurse at the health sub-centre or the doctor at the main health centre. A key feature of the physical facilities was that the ‘Midwife Clinic Cum Quarters’ situated within the rural village. It had space for a simple clinic with attached living accommodation that was provided free to the midwife and her family. The MCQ was equipped with water and electricity and midwives were provided bicycles (which in later years were replaced by motorcycles). This living arrangement reduced absenteeism and ensured the availability of the midwife almost any time of the day . Similarly, in the larger villages or small towns, housing was also constructed near the health sub-centre and the main health centre to cater for staff who provided ‘on-call services’ to the population.The main health centres were designed to have two wings namely the MCH unit and the outpatient unit. This separation of function recognised the need or cultural acceptability for the conservative rural population who regarded pregnancy as highly personal. Women needed privacy from the outpatient clinics. MCH staff were able to gradually develop the trust of the female population and ante-natal, post-natal and child health attendances increased rapidly.The shortage of doctors and dentists meant that the bulk of services were provided by allied health personnel, while the doctors and dentists visited on a rotational basis. However, population growth outstripped construction capacity. By 1975, only half of the expected expansion had been achieved with a typical three-tier network serving an average of 112 900 rural populations instead of the planned 50 000, with the average rural midwife serving 4390 populations instead of the planned 2000 Noordin, .The then Director General of Health Malaysia, Dr Raja A. Noordin was an active contributor to the Alma Ata conference and provided the leadership for infusing the concepts central to Health for All into the health system. The Alma Ata Declaration provided an impetus to review the status of equitable access and institute strategies to accelerate progress. Recognising the construction of new physical facilities, each supplied with a standard norm of human resources and equipment was too slow to process, the three-tier system was converted to two tiers whereby existing sub-centres were upgraded to health centres, and midwives’ clinics were converted into multipurpose community clinics that would provide basic curative services in addition to the ongoing MCH care. Massive recruitment and retraining converted midwives into community nurses, and additional living accommodation was constructed adjacent to the multipurpose clinics to cater for new staffing norms with two community nurses per multipurpose clinic. The aim was to have coverage of 20 000 populations by each cluster.Another major contribution of Raja Noordin from Alma-Ata was the spur of mobilisation and active participation of the community in the development of the Malaysian health system. Initially termed a ‘community participation’, the concept was partnership between health services and community volunteers to improve health of communities. During the 1970s–1980s, efforts focussed on nutrition and sanitation Noordin, . Driven An intersectoral approach to improve education, health and living standards using the platform of the Applied Food and Nutrition Programme that had been introduced in 1969 was leveraged Ismail, . OutreacThe MCH was the major beneficiary of the early phase of PHC development. With the pervasive presence of the midwives and community nurses, the antenatal attendances improved each year. See Table The improvements were accompanied with impressive decline of the maternal mortality ratio during the 50-year period, 1957–2013, from 530 deaths  introduced a new policy to extend PHC from just focusing on MCH to include the adolescent, adult and elderly thereby providing preventive services with seamless transition throughout life  services that provided clinical (curative) services to walk-in patients were the domain of hospitals services  was created Jaafar, . It has Driven by the telehealth initiatives  services in primary care  and community clinics (then MCQ) at 15 000–20 000 and 3000–4000, respectively, to the population were not achieved  described the phased implementation by clustering the population in the catchment area of a clinic into zones and registering each zone with a PHC team lead by a medical doctor  suggested that utilisation of health services ‘has reached comparable levels of OECD Countries’. There is adequate protection of financial risk for the poor and simulation model that was performed revealed a fair distribution of resources between the rich and poor households.Lim et al. , howeverThere will always remain a continuing dilemma between cost-effectiveness, access and equity. Services such as the flying doctor service, the birthing centre in the health clinics, are amongst services that have high capex but serving low volume of patients although much desired for the population in remote location. It is inevitable to focus on these few interventions to address equity. However, more efforts are required to look at opportunity costs of alternative activities in altering the behaviour of individuals or institutions. The telehealth and TPC initiatives with the slogan ‘Care Close to Home’ are potential sustainable efforts that may offer innovative ways to improve access to deliver care to the population.Malaysia has made significant strides over the last 40 years in reducing the urban–rural differentials towards accessibly to quality health care. Sivasampu et al.  in their


MicroRNAs or miRNAs are a component of the non-coding RNAs family which is engaged in many cellular functions such as cell proliferation, apoptosis, gene expression, signaling pathways, angiogenesis, and etc. Endometriosis is a malignant gynecologic disorder occurring in women before menopausal age. Pathogenesis of this illness is still a discussion subject between the scientists but in our knowledge, microRNAs can be one of the possible involved factors. The purpose of this paper is to investigate the role of apoptotic activities of miRNAs in endometriosis. Accumulative evidence has demonstrated the role of cell proliferation, apoptosis, and invasion in the progression of these diseases. In this review, we looked into the specific role of apoptosis and its related genes and pathways in endometriosis and tied to present an explanation of how miRNAs can affect endometriosis by their apoptotic activities. What we found is that a great extent of miRNAs is involved in this illness and they are responsible for repressing apoptosis and progression of the disease. As a result, miRNAs have two different usages in endometriosis: biomarkers and potential therapeutic targets. In this review we gathered a great amount of evidence to inquire into the role of micro RNAs in inducing apoptosis and how this mechanism can be exerted for therapeutic purposes for endometriosis. Generally, RNAs which are transcribed from the non-coding parts of the genome can be classified into three classes: housekeeping RNAs, transfer RNAs, and regulatory RNAs. MicroRNAs (miRNAs) are a kind of small regulatory RNAs and are approximately consist of 22 nucleotides , 2. RNA Every month through the menstrual period, endometrium gets prepared for the implantation of embryo by the means of bearing a class of biological alterations. Inflammatory reactions, programmed cell death, proliferation of the cells, angiogenesis, tissue formation or differentiation, and remodeling of the tissues are some examples of the engaged processes in altering the endometrium. These processes are regulated by two elements: sex steroids secreted from ovaries and products of the expression of the local genes. There are also some other regulators which their secretion can be autocrine or paracrine and include several growth factors, cytokines, chemokines, proteases, and extracellular matrix –11. BecaEndometriosis is a condition known by ectopic endometrial glands and stroma which has a dependency to estrogen and is counted as an inflammatory disorder. These ectopic glands and stroma are frequently found in pelvis but there are some other locations in which they have been observed: the bowel, diaphragm, umbilicus, and pleural cavity.According to evidence, three subtypes are observed for endometriosis: superficial injuries in peritoneal area, deep penetrating wounds, and cysts or endometriomas which are consist of blood and endometrium-like tissue . DysmenoGenerally, we put the name of endometriosis on an inflammatory estrogen-dependent condition in which endometrial-like tissues are found in some places other than its real position. Till now, scientists have not come to an agreement about the mechanism by which this condition is caused . Some reIn the immunity point of view, there is also a theory regarding the role of deficient immunity in endometriosis. Haptoglobin and monocyte chemoattractant protein 1 are two agents that might take part in causing endometriosis. In addition, some evidence accounts the abnormal B cell, T cells, or natural killer cells as the responsible factor for this gynecological disease. Moreover, inflammation caused by increased amounts of prostaglandins and cytokines is another possible reason that causes endometriosis , 18.In addition, Arvanitis et al.  showed tGenerally, programmed cell death or PCD was first separated from apoptosis when necrosis was discovered as another pattern for cell death in early 1970s . ApoptosA group of considerable morphological and biochemical alterations happen through this process and thereby cells first shrink and their nuclei condense, and then they disintegrate into well-enclosed apoptotic bodies . In a siIn the intrinsic pathway, two groups of mitochondrial proteins enter the cytosol in response to stimuli such as hypoxia, free radicals, and radiation. The first group of these proteins causes activation in the caspase-dependent mitochondrial pathway which leads to the activation of caspase-9. The other group causes a fragmentation and a condensation in the DNA and peripheral chromatin of the nuclei, respectively , 31–33. As mentioned before, miRNAs are small evolutionary conserved RNAs which are able to alter the gene expression by affecting the gene’s related mRNA . It is eBecause of the important role of p53 and BCL-2 families in regulating the intrinsic pathway, miRNAs can impact intrinsic pathway by changing the expression of the proteins of this two families . AccumulWe can name three stages for the cycle of endometrium in menstruating women: proliferating, secretory, and menstrual stages . The preThere also some other members of the BCL-2 protein family that studies has showed their impact on up or down-regulating the apoptosis in the different layers of endometrium during the endometrial cycle: BAX , BCL‐X , and BAKIn endometriosis, not only the ectopic endometrium-like tissue goes through a bunch of alterations but the eutopic endometrium also have some differences with the normal one . These dWe did not found any study comparing the expression of Fas in women with and without disease but a plenty of studies showed that the expression of FasL is higher in women having the disease . FurtherAs mentioned before, miRNAs are able to affect apoptosis in many ways: they can regulate each step of apoptosis in both stimulatory and inhibitory manners. As a result, not only miRNAs are involved in the pathogenesis of several diseases but they also have the potential of being used as biomarkers or therapeutic targets. Considering the pivotal role of apoptosis in endometriosis, we suggest that these RNAs might start a revolution in our understanding of endometriosis pathogenesis and help us provide more efficient diagnostic and therapeutic procedures. Several kinds of research are conducted about different miRNAs involved in endometriosis by regulating apoptosis which we are going to represent some of them in this section.Zhang et al.  investigConsidering the differences existing between the expressed miRNAs of eutopic and ectopic endometrial tissue, miRNAs have the potential to be used as biomarkers in endometriosis . A studyIn treatment point of view, there are some studies that used miRNAs for targeting different genes and signaling pathways engaged in apoptosis. for instance, adammek et al.  tried onNotwithstanding all these evidence, there are still some obstacles in the way of using miRNAs as a common treatment for endometriosis. Low stability and potential side effects are two major limitations of using these RNAs. Furthermore, the lack of proper route of administration and delivering approaches are some other barriers which nanotechnology is removing them out of the way by providing novel delivery systems . All takFor years, scientists thought that 98% of our DNA was junk and not useful at all  but disc


Background: Our study aimed to test the hypotheses that an increased level of loneliness experienced during coronavirus disease 2019 (COVID-19) confinement was predictive of internalizing symptoms and that this pathway was mediated by emotion dysregulation levels.Methods: To reach this aim, we performed an online longitudinal survey recruiting 1,330 participants at Time 1 (at the beginning of the lockdown) and 308 participants at Time 2 (few days before the end of the lockdown). All filled out a set of questionnaires: demographic data, University of California, Los Angeles Loneliness scale, Difficulties in Emotion Regulation Scale−18 items, and Depression Anxiety and Stress Scale−21 items. Hypotheses were tested using structural equation modeling in two steps and controlling for age. First, hypotheses were tested on cross-sectional data. Then, a cross-lagged panel analysis was performed on longitudinal data.Results: Models obtained a good fit and evidenced the predictive role of loneliness levels on the three outcomes . Moreover, we found that emotion dysregulation levels partially mediated the longitudinal relationship between loneliness and both depression and stress but not between loneliness and anxiety levels.Conclusions: This study points out that a central goal of clinical intervention could be the ability to regulate negative emotional states. The coronavirus disease 2019 (COVID-19) pandemic poses challenges never before faced in society from many angles. It affects not only the state of health and integrity of our body endangered by COVID-19 but also the health and integrity of our mind, and the effects on the mental health of COVID-19 are expected to be diverse , psychological stress, and loneliness  have an unfavorable effect on many health outcomes, including mortality , 21. ForLoneliness, defined as the pain of feeling alone , is a psHowever, research  highlighFrom an individual perspective, emotion regulation, defined as the complex set of psychic processes that translate into one's ability to influence his/her emotions, how he/she experiences them and how he/she expresses them , has a dNevertheless, individuals with the same level of loneliness may not experience similar psychological outcomes . This suIn light of these pieces of evidence, the main purpose of this study was to examine—through a structural equation model—the relationship between loneliness and internalizing symptoms, considering the mediating effect of difficulties in emotion regulation and the longitudinal link between loneliness and internalizing symptoms.For the purposes of the study, an online survey was created and diffused online 3 days after the beginning of the confinement in XXX. At the beginning of the survey, an exhaustive presentation of the study's aims and scopes was delivered and information concerning anonymity and privacy. Then, the participant was asked to sign an informed consent. Three days before the end of the national lockdown, participants were sent an email asking them to fulfill the same battery of self-report questionnaires. The procedure of the study applied with the American Psychological Association official guidelines and was approved by the Ethical Committee of the University of XXX, XXXX (N. 356/20).For the purpose of the study, an initial questionnaire was created to evaluate information such as age, sex, and socioeconomic status.Intimate Others , Social Others , and Affiliative Environment (a lack of belonging to the affiliative environment). In the present study, the instrument showed good internal consistency with a Cronbach alpha coefficient of 0.82.University of California, Los Angeles (UCLA) Loneliness Scale  but was slightly below the acceptable CFI cutoff (0.88). The full model is illustrated in p = 0.043) and stress  but not between loneliness and anxiety levels .The final model  is illustrated in It is widely stated that in times of crisis, psychological research should address and provide answers on risk and protective factors involved in the well-being and adjustment of individuals. Empirical and anecdotal contributions have highlighted that the emergency related to COVID-19 has been very powerful in physical and psychological impacts. In the wide range of sudden changes undergone by the world population, most of them have had to face restrictive measures related to their interpersonal interactions: in many countries, the population has been asked to maintain rigorous and lasting lockdown measures to contain the pandemic. One of the consequences for most people was a reduced frequency of social interactions, which was probably translated into an increase in the level of loneliness perceived for most of them. Our focus on loneliness is linked to results that suggest that one of the most direct consequences of lockdown measures is isolation and the associated feeling of loneliness . BecauseHowever, the available empirical evidence that can provide useful clinical indications for dealing with psychological problems caused by “isolation” is limited. Our study aimed to test the hypotheses that an increase in loneliness levels would predict an increase in internalizing symptom levels and that the ability to regulate emotions may mediate these relationships. Our focus on emotion regulation strategies as a further mediator of these associations has its roots in the widely coherent literature that attests to their association with psychopathology and, more specifically, with reactions to distressing events and situations , 66.The first equation structural model was based on an evaluation of all the variables at Time 1 when 1,323 participants were at the beginning of the lockdown. In this model, a significant relationship has been observed between the dimensions of loneliness, emotional dysregulation, and internalizing symptoms. Specifically, loneliness dimensions directly predicted depression, anxiety, and stress levels. This datum is in line with existing literature concerning the association between loneliness and anxiety, depression and other psychological outcomes, and even suicide , 67. HowFurthermore, we found that loneliness predicts these results in terms of depression, anxiety, and stress levels also indirectly, mediated by emotion regulation strategies. In fact, solitude, in its aspects of the intimate, social, and affiliative components, has its most distressing effect if associated with difficulties in emotion regulation. Other studies have shown this strong association  and haveThe second equation structural model aimed at testing the role of time in a subsample of 308 participants concerning these associations. The results of this model only partially supported what was found in the cross-sectional analysis: the levels of emotion dysregulation mediated only the path that connects perceived loneliness and depression and stress but not anxiety. Regarding anxiety, we may speculate that other factors may explain the longitudinal relationship between loneliness and anxiety levels. For instance, the lack of social confrontation on the topic generating anxiety (such as news related to the pandemic) and the fear of getting sick in a situation of loneliness may better explain the pathways linking perceived loneliness to anxiety. An additional explanation of this result can be found in methodological considerations. Indeed, the important dropout of participants between Time 1 and Time 2 of the study has induced an important loss of statistical power, thus making not significant a precedent significant path. We may speculate so that a bigger sample size at Time 2  would have evidenced a significant influence of emotion dysregulation in the path between perceived loneliness and anxiety, in line with the high number of studies highlighting the role played by this variable in anxiety symptomatology.Regarding the role of emotional dysregulation in the relationship between loneliness and stress levels, several considerations can be made. First, our results are in line with previous literature showing that adaptive emotion regulation strategies, such as reappraisal, may buffer the negative impacts of daily stress on positive emotions  and thatRegarding the mediating role of emotion dysregulation in the relationship between loneliness and depression, several explanations can be provided. For instance, a difficulty to accept negative emotions triggered by loneliness feelings in a non-judgmental way may lead to depressive symptoms, eliciting thoughts on the self-perceived inability to adequately face the situation. In this regard, adequate information provided by the institutions on the potential negative emotional states aroused by the situation can be of great use in legitimizing the onset of this emotion in the entire population. Furthermore, an alleged lack of self-efficacy in regulating emotions can be reasonably explained by our observations. This may be especially true of individuals with low self-efficacy in regulating emotions, who have perceived themselves as accustomed to relying on others to regulate their negative emotional states. Feeling lonely for individuals with a propensity for this emotional regulation deficit can be particularly inspiring. In this regard, a prevention program that aims to provide some tips for regulating negative emotions can help avoid a major increase in psychological distress in the general population. Furthermore, from this perspective of understanding the associations between vulnerability factors and psychological well-being, other interesting discoveries offer ideas for further research on these topics. For example, an interesting fact concerns the role of age in the mediation of these associations. In fact, we have found significant correlations between age and outcomes in terms of depression, anxiety, and stress. Young people show multiple levels of stress during this blocking period. It can be suggested that abandoning important aspects of their daily lives for young people could be more stressful.Other studies , 81 haveDespite the insightful nature of our findings, several limitations of the study need to be considered. First, despite longitudinal studies often suffer from relevant dropout in the participation of subjects, this issue is likely to introduce a bias in our study. Indeed, we are not aware of the reasons for dropping, and dropped participants may be more resilient or, conversely, more vulnerable to some of the mental health issues investigated in our study. This issue may limit the generalizability of our findings. Then, due to the growing research on COVID-19, we have chosen to focus attention on the general population, and we have not been able to define specific reactions between subsamples of more exposed and less exposed people. However, our idea is that it is equally important that research may focus on the most influential risk factors. In this line, as suggested by other authors , the posOverall, our results indicate the need to improve research in defining specific risk factors implicated in well-being and adjustment to this very demanding period. This could suggest implementing intervention programs aimed at improving well-being in population segments most at risk for their functioning and mental health.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Sapienza Ethics Board. The patients/participants provided their written informed consent to participate in this study.PV and RT conceived the presented idea. SB, RC, and GR performed the analysis. All authors discussed the results and contributed to the final manuscript.The 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.


There is tremendous variation in costs of delivering health care, whether by country, hospital, or patient. However, the questions remain: what costs are reasonable? How does spending affect patient outcomes? We look to explore the relationship between cost and quality of care in adult, pediatric and neonatal literature. Health care stewardship initiatives attempt to address the issue of lowering costs while maintaining the same quality of care; but how do we define and deliver high value care to our patients? Ultimately, these questions remain challenging to tackle due to the heterogeneous definitions of cost and quality. Further standardization of these terms, as well as studying the variations of both costs and quality, may benefit future research on value in health care. The Institute for Healthcare Improvement (IHI) launched the term Triple Aim in health care  to encouFrom 1996 to 2013, total health care spending on children increased from USD 149.6 billion to USD 233.5 billion (2015 U.S. dollars). In 2013, the largest health condition leading to health care spending for children was well-newborn care in the inpatient setting . Th. Th42]. Another formula proposed by Kaempf et al.  calculatWhen value is studied in medicine, we are attempting to answer the question: Is it worth the investment? As addressed by Flanagan , the valWhile these formulas neatly summarize and conceptualize that there is a close relationship and interplay between value, cost, quality and outcomes, the question of value of care can be so complex and nuanced to study since either part of the equation: costs (whether in dollars or LOS) and quality  each have their own challenges. Quality and outcomes can have different definitions depending on whether it is from the perspective of a health care provider, health care institution, insurance company, family, patient, or society. For example, LOS, as used in the Kaempf metric, is often simplified to be a marker for cost. However, it does not account for the significant non-medical costs to the family, fixed costs of care in the NICU, including space and staffing, as well as expected LOS for the physiologic maturation ,43,48.There are other considerations when trying to study value. First is the impact on family—with the potential discordance between the value from the hospital perspective and the value from the family perspective . OccasioRecently, there has been a growing body of literature looking at disparities in neonatal care demonstrating that there is variation in terms of clinical outcomes. Using data from the CPQCC, Profit et al. developed a validated tool (Baby-MONITOR) to assess the quality of care at different hospitals and demonstrated hospital-to-hospital variation . FurtherThe large variation in both costs and outcomes coupled with limited evidence in health care to demonstrate the link between spending more money  and better outcomes  presents a dilemma when it comes to investing additional resources in a system that is already constrained. In order to reduce unnecessary health care spending, we must couple cost analyses with outcome studies and evaluate the relationship between the two. While quality improvement initiatives are often used as a tool to improve outcomes, there is also the necessary investment of resources . TherefoChoosing Wisely and EHR to drive down unnecessary spending without affecting outcomes. There are both micro and macro-economic opportunities for cost reduction while allowing additional financial investments as new technologies, drugs and programs are introduced.There is already a model that exists in collaborative quality improvement for centers to learn from best and worst performers in order to learn opportunities for improvement. The same approach should routinely incorporate costs into the conversation in order to allow tools such as Choosing Wisely are built on the premise that eliminating services that are not necessary will not worsen outcomes . Coupled with comparative reports such as Mirror Mirror [The link between health care cost and quality of care is inconsistent across the spectrum of ages and disease processes. Much of the struggle lies in the heterogenous definitions of cost, quality, and value of care. While some studies  supportr Mirror , where t


An ever-increasing technological development in the field of radiology urgesa need for guidelines to provide predictable and just health services. Amusculoskeletal guideline was developed in Norway in 2014, without activeimplementation.To investigate the impact of active guideline implementation on the use ofmusculoskeletal diagnostic imaging most frequently encountered in generalpractice .The total number of outpatient radiological examinations across modalitiesregistered at the Norwegian Health Economics Administration between January2013 and February 2019 was assessed using an interrupted time seriesdesign.p = 0.05). Stratified analysis (MagneticResonance Imaging examination as one group and x-ray examinations as theother) showed that this reduction mainly was due to the reduction in the useof Magnetic Resonance Imaging examinations (shoulder and knee) which wasreduced by 24% at a significant level (p = 0.002), whilex-ray examinations had no significant level change(p = 0.71). No other statistically significant changes werefound.A 12% reduction in the total examination of Magnetic Resonance Imagingshoulder and knee, and x-ray lower back and shoulder was found at asignificant level (The impact of the implementation on the use of imaging of the neck, shoulder,lower back, and knee is uncertain. Significant reductions were demonstratedin the use of some examinations in the intervention county, but similareffects were not seen when including a control group in the analysis. Thisindicates a diffusion of the implementation, or other interventions orevents that affected both counties and occurred in the interventionperiod. Theseadvances have led to new and more information-heavy modalities such as ComputedTomography (CT), Magnetic Resonance Imaging (MRI), ultrasound (US), PositronEmission Tomography, and others. These advances have also led to a stronger need forguidelines, as the complexity of the field has increased, new options for diagnosticimaging has inflated,5 and the iRefer developed by the Royal College of Radiologists.6 In Norway, a guideline for diagnostic imaging for non-traumaticmusculoskeletal diseases was finalized in 2014 as a response to increasing number ofoptions of diagnostic imaging for a large patient group .7 A significant number of these patients are referred to diagnostic imaging,and significant geographical variations are demonstrated in the use of this type ofimaging.810 A highutilization rate of examinations with unclear benefit has been reported, e.g. MRI ofthe shoulder.9Guidelines have mostly been developed to target the referrer’s behavior, such as theAmerican College of Radiologists Appropriateness Criteria,11 This may be because the guideline was implemented by mail and onlinepublishing, and not tailored toward the target group.11 For this evaluation, an implementation strategy tailored to the target groupsof the Norwegian musculoskeletal guideline was developed.12 This was a multifaceted strategy, including educational meetings and videos,as well as a tailored short version of the guideline including recommendations fordiagnostic imaging of the neck, shoulder, lower back and knee, and online publishingin appropriate media.12However, the guideline developed in Norway was neither widely known nor used.6The hypothesis made for this study was that the implementation of the musculoskeletalguideline would lead to a reduction in musculoskeletal imaging, due to theassumption of there being a relatively high rate of unwarranted imaging in thisspecific field of radiology. We here define unwarranted imaging as examinationswhere the results, negative or otherwise, does not lead to a change in the patienthandling (diagnostics or treatment), or when leading to a change in patient handlingresulting in a worse outcome.What is the outcome of active guideline implementation onradiological examinations performed in a Norwegian county, measured overa 12-month period?The aim of the current study was to investigate the effect of this implementationstrategy on the use of diagnostic imaging of the musculoskeletal system for the fourbody parts focused on in the implementation in total, and for some specificexaminations related to unwarranted examinations by using a time series analysis.The research question for this study was as follows:13 where historical data are used to establish underlying trends, interrupted byan intervention at a fixed-point time.14 The data were modeled by segmented linear regression with a discontinuity atthe intervention period. Then the effect of the intervention is estimated byperforming hypothesis tests on the change of the level and the slope of theregression model across the intervention period.15 ITS was used in this study since it is the strongest quasi-experimentalresearch design when randomization is not possible.16 In addition, it can account for natural trends and seasonal variations, whichis expected in the current study.An interrupted time series (ITS) design was used in this study, which is aquasi-experimental design that can be used to estimate intervention effect usinglongitudinal data,The data in this study consisted of the total number of the selected radiologicalexaminations relating to the musculoskeletal system registered at the NorwegianHealth Economics Administration (HELFO) between 1 January 2013 and 28 February2019. This time period was chosen to provide historical data as far back aspossible to establish any underlying trends. The implementation was performedfrom November 2017 to February 2018, which was the interruption, and the periodchosen also provides data over a 12-month period after the implementation.The data used in this study are registered as Norwegian Classification ofRadiological Procedures (NCRP) codes. HELFO registers data of outpatientexaminations performed at public hospitals and private institutions. Anyin-patient examinations and examinations covered by insurance or paid in full bythe patient are not included in this data.17 All modalities are included, i.e. Conventional Radiography (CR), MRI, CT,and US.The NCRP codes included were those related to examinations of the neck, shoulder,lower back, and knee. These body parts were chosen as focus for theimplementation because pain from these locations are highly frequent conditionsmet in primary care.9Raw data were provided by HELFO, on our request, in the form of excel sheets inseparate files for the public and private institutions, as well as for thedifferent years. The data contained information about the treatment institution,the patient’s county of residence, and type of examination. The NCRP codescontained further information about modality (such as CR or MRI) and location resulting in the examinationcode with code explanation. The examination code was the most detailed level andindicated the specific examination performed (e.g. MRI of the knee).1820MRI shoulder7x-ray shoulder21x-ray lower back22MRI kneeThe aim of the intervention was to reduce the extension of unwarranted imagingperformed in the intervention county. Previous studies have identified thefollowing specific examinations to contain a high rate of unwarrantedexaminations: The impact of the intervention on the group of examinations with a high rate ofunwarranted examinations were analyzed , as well asstratified analysis on the subgroups examinations of the neck, shoulder, lowerback, or knee. Finally, the impact of the intervention was analyzed on the totalof the selected examinations .Two counties were studied; the county where the re-implementation were held andan independent control county. This was done to control for any non-randomeffects that may have occurred during the intervention period. A total of139,953 examinations were performed in the intervention county and 259,423examinations in the control county in the specific time-period. The data werethen sorted into their respective counties and sorted into the different imagedbody parts , in addition to respectivemodalities, and finally specific procedures.Inclusion criteria for the implementation were: target groups from the planningstage (radiologists and GP’s) from the intervention county were included in theimplementation, and radiographers and the Norwegian Labour and WelfareAdministration (NAV) were included as well.Exclusion criteria for implementation: radiological personnel or GP’s who werenot employed in a hospital/radiological institution, non-medical members ofstaff from NAV, or not from the intervention county.Inclusion criteria for statistical analysis: examinations of the neck, shoulder,lower back, and knee since these were the focus areas of the intervention, andthe specific examinations within these areas presumed to have a high proportionof unwarranted imaging.Exclusion criteria for statistical analysis: systematic outliers or datapointsclearly violating a linear trend.In order to adjust for population size changes over time and differences in sizebetween intervention and control group, the number of diagnostic imaging werenormalized by dividing on the population size. Only data for annual populationsizes where available, thus a linear change were assumed. All data are expressedas counts per 100,000.The raw data were plotted and assessed for any linear trends, repeating patterns,and outliers. Upon visual inspection of the data, a potential trend change inthe x-ray lower back time series for the intervention county was noticed. Thetrend change was confirmed to be significant by an ITS, and thus data beforeAugust 2016 where excluded for further analysis for this time series. For thedifference time series, it was noticed systematic outliers for all the timeseries, thus the following five datapoints were removed from the analysis:October 2013, January 2014, December 2015, January 2016, and February 2016. See t is the timestep, u(t) is the unit step function, andt. All the noiseterms will be assumed to be independent and identical normally distributed. Theconstants 2 and AkaikeInformation Criterion for small sample size). The residuals (noise) of thismodel are then checked against the assumptions for independence usingautocorrelation- and partial autocorrelation function plots. Normality wasassessed using density plots, Quantile–Quantile plots, and the Shapiro–Wilk’stest. If the regression assumptions where not met, the noise term was furthermodeled by potential Seasonal Autoregressive Integrated Moving Average (SARIMA) processes.23 The most parsimonial model that met the regression assumptions where thenselected as the final model.The statistical analysis will be based on a segmented regression analysis. Thefollowing formula gives the base model p-value of 0.05 or less was consideredstatistically significant. A summary of the final models and results are givenin The effect of the intervention was then estimated by a hypothesis test on theregression coefficients for the level change and slope .5, per month, which is an average reduction of 11.9%the first year after the intervention (p = 0.05). See We found a statistically significant level change for the intervention county for allfour examinations most likely to contain a high degree of unwarranted examinations analyzed together. Thelevel change seen here equates a reduction in the use of these examinations of 62.8examinations per 105 per month, which corresponds toan average reduction of 23.4% per month the forts year after the intervention(p = 0.002), was found for the use of MRI examinationspreviously shown to contain a high rate of unwarranted examinations (MRI shoulderand knee) for the intervention county when analyzed together. These significanteffects were not seen in the comparison between the intervention and control county(see figure 3).A reduction of 70.5 examinations per 10For the analysis of the specific examinations alone, the four subgroups chosen  and the subgroups combined  yielded nostatistically significant results. This was also the case for the analysis of thedifference in use of imaging between the intervention and control county. For anoverview of all the results, see The hypothesis made of this study was that a successful implementation of themusculoskeletal guideline would lead to a reduction in musculoskeletal imaging, dueto a high rate of unwarranted imaging in this specific field of radiology. Since wecannot measure the portion of unwarranted imaging directly in this study, we had toassume that a reduction in unwarranted imaging would lead to a detectable decreasein the use of musculoskeletal imaging. On the other hand, the total use ofdiagnostic imaging would remain stable, if more warranted procedures are performed.However, the reduction found in the total use of MRI shoulder and knee, and x-ray ofthe lower back and shoulder combined indicate a reduction in unwarranted imaging,since these are all examinations that are considered to have a high proportion ofunwarranted imaging.24 Nonetheless, more active approaches to guideline implementation such aseducational meetings and outreach,25 and audit and feedback26 may give approximately 20% reduction passive approaches such as postaldissemination where the effect range from none28 up to 10% difference betweenintervention and control group.29Previous implementation efforts in other contexts have shown that guidelineimplementation is complex, and lasting change is challenging to achieve. Moreover,there is no quick fix as no type of implementation has shown to be the most effective.In the current study, the intervention had a significant reduction in the fourselected unwarranted examinations .1820 The recent focus on reducingsurgeries of both the shoulder and the knee from the government may also have had aneffect on the use of these examinations, commonly used as an evaluation tool priorto surgery.30 There has also been a higher focus on unwarranted tests and examinations ingeneral through the launch of the choosing wisely campaign in Norway,31 which may make referrers and radiological personnel more aware of thisphenomenon.This is most likely due to the reduction in MRI examinations, since the x-rayexaminations increased after the intervention. This reduction may be due to a largerpotential for change in these examinations, especially for MRI of the shoulder,where approximately half have been found to be unwarranted.32The fact that we found no statistical significant change in the use of the x-rayexaminations may be due to an already existing downward trend in the use of theseexaminations. Another factor that can have contributed to this finding may be thatthe changes made on the basis of the implementation did not lead to a reduction inthe use of these examinations, but rather changes like the referrer choosing topostpone a referral for imaging. This means that the imaging is still performed;however, the imaging may be more justified than it would have been if it wasperformed at an earlier stage.33 continued geographical variations,10 and lack of knowledge of the guideline11 after earlier attempts of online dissemination indicate that this may not bethe case in Norway. In addition to this, there may have been efforts performed thatwe are not aware of.However, the significant effects were not reproduced when using the base model foranalyzing the difference between the intervention and control county. This indicatesthat there has been something affecting the use of these examinations in both theintervention and the control county. In addition to the just-mentioned governmentinitiatives, this may be due to the web-based dissemination through publishing theguideline on the Norwegian Electronic Medical manual. This online resource used bymost Norwegian GPs could not be contained to the intervention county only, and sincethis is the measure most likely to lead to this effect, since the governmentinitiatives where started in 2019 and 2018, respectively. Despite web-baseddissemination of guidelines being found to lead to significant change in use ofimaging elsewhere,35 The participants in ourimplementation missed, and would like more feedback. However, the feedback missed bythe GPs in our study was not referral rated, but rather the quality andjustification of their referrals.32 Reminders have also proven to be effective means to changebehavior,36 which potentially could have improved the effect of theimplementation. However, it was chosen not to include reminders on the basis of theinterviews with GPs and radiologists, as well as discussions with a practicecoordinator, where the emphasis was mainly on easy accessibility of guidelines. Inother words, the possible reasons that these approaches achieved greater effect thanwe did could be more concrete guiding approaches and individual attention. Eventhough the target groups were involved in the development of the implementationstrategy to some degree, further involvement of the target groups could haveimproved the implementation strategy by increased tailoring toward the users, whichcould have improved the effect of the implementation. This may also be the case forthe development of the guideline itself, where further involvement of the targetgroups could have improved the composition of the guideline, tailoring it toward theneeds of the target groups and thereby making it easier to use in day-to-daylife.The limited effect of the implementation in the current study compared to previousstudies may be related to differences in the implementation content. For example,the implementation may have had a greater effect if individual feedback on referralrates had been provided to the participants, which has shown potential for reducingreferrals for diagnostic imaging in previous studies.The differences in effect may also be explained in terms of differences in context.For example, it can be assumed that the distribution of power in the decision-makingprocess between the referring physician and the radiologist may differ betweendifferent countries.37 which could have led to a clearer intervention, and improving follow-up inthe intervention county. This includes more extensive inclusion of the target groupsin the planning stage, increased tailoring of the implementation strategy, and moreappropriate style, imagery, and language used for the educational parts of the implementation.37 A more extensive use of CFIR may also have included closer follow-up of theparticipants through group debriefings, which may have further increased awarenessof the guideline, and thereby facilitated guideline use.37 This may in turn have increased the effect of the implementation. It may alsobe the case that CFIR was not the most optimal framework to use, in regards of theconduction of the implementation. Other frameworks, like the Promoting Action onResearch Implementation in Health Service (PARiHS) framework could have drasticallychanged the implementation and target groups included. The PARiHS framework have ahigher focus on research implementation being an organizational issue rather than anindividual issue, and strategies consisting of a range of intervention that addressthe need for education, audit, and the management of change.38 However, CFIR was chosen because it is more comprehensive.32The implementation delivery could also have been improved by further utilization ofthe Consolidated Framework for Implementation Research (CFIR),32 The frequency (or dose) of the implementation may also influence the outcome.In the current study, a repeat of the educational meetings, or other means ofrepeating the information could imply greater effect on the use of unwarrantedimaging, and thereby a significant change in the difference in use of unwarrantedimaging between the intervention and control counties. This lack of change indifference between counties may also be explained by other factors than thefrequency of the implementation, such as the implementation not being comprehensiveenough, or poor coverage of the target groups.Other factors related to the conduction of the implementation that may haveinfluenced the outcome could be the fact that the educational meetings were notinformation that the participants sought out as an answer for a perceived problem.It was offered to a representative of the participating municipality, which may haveled to the information not being perceived as equally interesting for all theparticipants, since some participants viewed the implementation more as aconfirmation that their existing practice was correct, rather than as an opportunityto improve.39 In the current study, a tailored implementation strategy was applied;however, the effect was limited. Another contributing factor to the limitation ofthe effect may be the complexity of the referral context. The ever increasing numberof guidelines may result in “guideline fatigue”27 and may foster a guideline-resistant context. Publication bias may also be anexplaining factor, since studies reporting positive results have historically beenmore likely to be published than studies with null-results.40Guideline implementation in general is complex, where many factors need to be takeninto consideration to accomplish the desired effect, such as the quality of theevidence, readiness for change, and stakeholder involvement. Several types ofintervention may be needed to facilitate guideline use, since a single interventionmay not address all the factors needed for change to be achieved. There is noevidence as to which type of implementation is the most effective; however, it doesseem that the more active approaches of greater duration and frequency areconsistently more successful in achieving change than single interventions, orone-off implementation efforts.Limitations of this study are first, a relatively small sample of observations afterthe implementation, which may affect the result. In addition to this, 42 datapointswere removed for the analysis of the use of x-ray of the lower back, due to asignificant level change Medio 2016, unrelated to the implementation. This may becaused by other and unacknowledged efforts to reduce the number of unwarrantedimaging of the lower back, or increased media attention to excessive x-ray imagingof the lower back at the time. The removal of these datapoints led to a relativelysmall sample of observations for both the period before and after the intervention,which may influence the findings.However, the ITS design is very robust, where other implementation efforts at thesame time are what would have the most negative effect on the reliability of theresults, rather than the number of datapoints. It cannot be ruled out that theobserved effect in this study is only in part related to the implementation. Aspreviously mentioned, other efforts performed in the same period as theimplementation that may explain the lack of difference between the counties.The study is also based solely on the number of examinations, without informationregarding the justification of the examinations. First, some of the examinations maynot have musculoskeletal indications, and second we have no exact number ofunwarranted imaging. Hence, the number of examinations is only an indicator ofunwarranted examinations. Given abundant waiting lists, there may be more indicatedexaminations and less non-indicated examinations resulting from theintervention.Another limitation of the study is that it is a retrospective design. In this case,we had to rely on the accurate coding for the examinations, and we did not havecontrol of any other event possibly influencing the intervention or the controlgroup, as already mentioned. Finally, the intervention performed was relativelysmall, in terms of its duration and the fact that the meetings were not repeated,which can have had an effect on the results.In conclusion, the impact of a multifaceted implementation of musculoskeletalreferral guidelines on the use of diagnostic imaging of the neck, shoulder, lowerback, and knee is uncertain. There was found a significant reduction in the use ofMRI examinations deemed most likely to have a great portion of unwarranted imagingin the intervention county, indicating a reduction in unwarranted imaging. However,a similar effect was not found when including a control county, or otherinterventions or events that affected both counties and occurred in or around theintervention. Further implementation efforts should concentrate not only ontailoring the implementation toward the group, but also on several other factors.Such as adequate covering of the target group(s), ensuring that the users areinvolved in the entire implementation process from defining the problem, todesigning and delivering the implementation, as well as ensuring sufficient uptakeand follow-up.


During the last decades, many novel techniques of food processing have been developed in response to growing demand for safe and high quality food products. Nowadays, consumers have high expectations regarding the sensory quality, functionality and nutritional value of products. They also attach great importance to the use of environmentally-friendly technologies of food production. The aim of this review is to summarize the applications of PEF in food technology and, potentially, in production of functional food. The examples of process parameters and obtained effects for each application have been presented. Development of innovative food processing methods can increase the competitiveness of the food industry by improving product quality, introducing new products to the market and reducing production costs  Pasteurization of liquid foods still remains the main purpose of using PEF technology. The lethal effect of PEF on various vegetative bacteria, mold, and yeast can be strengthen by combining with other physical methods, such as UV radiation  of high voltage  are supplied to the product placed between the electrodes in the chamber  and it is exposed to an external electric field, this results in occurrence of induced transmembrane voltage  leaves. The application of PEF shortened the drying time by 57% for air drying, 33% for vacuum drying and 25% for freeze drying. Samples which were PEF-treated and vacuum dried were found to be the closest to fresh leaves regarding colour and smell determined by sensory panel. Application of PEF accelerates also the drying of carrots, potatoes, apples, coconuts or paprika  lose their shape and become sodden. In this form they are not accepted by the consumers. It has been demonstrated that pulsed electric fields can be used to improve freezing tolerance of baby spinach leaves. PEF was applied with vacuum impregnation in the presence of cryoprotectants such as trehalose, sucrose, glucose, and fructose. The combination of these methods caused that leaf cells remained viable and the leaves retained turgor after the freezing and thawing cycle  resulted in the reduction of E. coli and Listeria innocua, but it did not change the color and appearance of blueberries. The only disadvantage of the process was the softening of the berry structure. Anthocyanins and phenolic compounds increased by 10 and 25%, respectively. Palgan et al.  leaves and increases their antioxidant activity. In addition, it also reduced the extraction time, and the increase in pulse intensity was proportional to the amount of polyphenols extracted, as well as to their antioxidant properties   of the ice cream and did not change the color of the samples. The higher total number of microorganisms was noted in the ice cream than in the starter cultures, however, the viability of these bacteria was lower than in the control samples  by, respectively, 164% and 300%. Lactobacillus rhamnosus B 442 cells enriched with zinc ions were used for the production of two types of ice cream: unfermented and fermented  of C-phycocyanin (C-PC) derived from Ulva sp. Protein extraction from these microorganisms is possible due to the use of chemical substances, however this method has serious consequences, therefore PEF combined with osmotic shock and mechanical press was used as an alternative extraction method. Subsequently, the extracted proteins were identified and a specific allergen was assigned to them. Extracts that were obtained with PEF contained only one food allergen—superoxide dismutase (SOD), however, more research is needed on the allergenicity of proteins extracted from macroalgae to assess the risk for human consumption  of high voltage  are supplied to the product placed between the electrodes in the chamber. This technology can be used alone or in combination with other methods to obtain products in more energy efficient (e.g. by lowering temperature and time of extraction) and environmentally friendly way. PEF can be applied for pasteurization, enhancement of such processes as drying, freezing, or extraction, but can also support development of functional food containing e.g. easily absorbed ions of elements essential for proper functioning of the human body.Research of pulsed electric fields technology is carried out around the world. Although this technology has been investigated extensively and there already are commercial PEF systems working in different countries, the majority of the obtained results still refer to the experiments carried out at laboratory scale.