This case report concerns a 40-year-old male who had previously been treated for an esophageal varix rupture, at the age of 30 years. The medical examination at that time revealed occlusion of the inferior vena cava in the proximity of the liver, leading to the diagnosis of the patient with Budd-Chiari syndrome. The progress of the patient was therefore monitored in an outpatient clinic. The patient had no history of drinking or smoking, but had suffered an epileptic seizure in 2004. The patient's family history revealed nothing of note. In February 2012, color Doppler ultrasonography (US) revealed a change in the blood flow in the right portal vein branch, from hepatopetal to hepatofugal, during deep inspiration. Arrival time parametric imaging (At-PI), using Sonazoid-enhanced US, was subsequently performed to examine the deep respiration-induced changes observed in the hepatic parenchymal perfusion. US images captured during deep inspiration demonstrated hepatic parenchymal perfusion predominantly in red, indicating that the major blood supply was the hepatic artery. During deep expiration, the portal venous blood flow remained hepatopetal, and hepatic parenchymal perfusion was displayed predominantly in yellow, indicating that the portal vein was the major source of the blood flow. The original diagnostic imaging results were reproduced one month subsequently by an identical procedure. At-PI enabled an investigation into the changes that were induced in the hepatic parenchymal perfusion by a compensatory mechanism involving the hepatic artery. These changes occurred in response to a reduction in the portal venous blood flow, as is observed in the arterialization of hepatic blood flow that is correlated with the progression of chronic hepatitis C. It has been established that the peribiliary capillary plexus is important in the regulation of hepatic arterial blood flow. However, this case demonstrated that the peribiliary capillary plexus also regulates acute changes in portal venous blood flow, in addition to the chronic reduction in blood flow that is observed in patients with chronic hepatitis C. The liver receives a dual blood supply from the hepatic portal vein and the hepatic artery. Whilst 70–80% of the supply is provided by the portal vein, which transports nutrients and various other substances to the liver, the remaining 20–30% of the blood supply arrives via the hepatic artery, which mainly nourishes the biliary system . The bloBudd-Chiari syndrome occurs as a result of the congestion of the liver, due to the chronic obstruction of hepatic blood flow draining into the venous system. Long-lasting hepatic congestion has been demonstrated to lead to necrosis of the hepatocytes in the vicinity of the hepatic venules  and sinusoidal enlargement, whilst congestive cirrhosis has been indicated to develop as a result of the progressive fibrosis in the proximity of the hepatic venules . This leWith the aim of gaining a better understanding the pathology of liver disease, the focus of our group is the study of hepatic hemodynamic changes. The present study concerns a case of Budd-Chiari syndrome that may reveal, in part, the mechanism that regulates the blood flow balance between the hepatic artery and the hepatic portal vein.A 40-year-old male had been previously admitted to The Toho University Omori Medical Center  for the treatment of an esophageal varix rupture, at the age of 30 years. At that time, as the physical examination indicated occlusion of the inferior vena cava in the proximity of the liver, a liver biopsy was performed. The biopsy revealed fibrosis in the vicinity of the hepatic venules (zone III), and an enlargement of the sinusoids and portal vein branches, which led to a diagnosis of Budd-Chiari syndrome. The patient was subsequently monitored in the hospital's outpatient clinic. The patient had no history of alcohol consumption or tobacco use, but had suffered a single epileptic seizure in 2004. The patient's family history revealed nothing of note. In February, 2012, the patient underwent a routine abdominal ultrasound, and the color Doppler ultrasonography (US) images revealed a change in the blood flow from hepatopetal (in red) to hepatofugal (in blue) in the right portal vein branch during deep inspiration  and 2. WUS imaging was performed using a Toshiba Aplio XG diagnostic ultrasound system  with a 3.75 MHz convex array probe  at a mechanical index of 0.21. The right main branch of the portal vein was visualized from the right intercostal space, and images displaying the liver parenchyma of the right hepatic lobe (segments 5–8) were selected for analysis. The focal depth was set at 3–10 cm using the dual-focus mode. Subsequent to the selection of the imaging parameters, the recommended dose of Sonazoid , obtained from GE Healthcare , was injected via the cubital vein. Following the Sonaziod infusion, imaging was performed for ∼40 sec to visualize the patient during a period of deep inspiration, and the images were then stored as raw data in the system hardware. The images corresponding with deep expiration were acquired in the same manner. US was performed by the same operator each time to maintain imaging consistency.At-PI images were generated from the stored data using the software interfaced with the ultrasound system. The right branch of the hepatic artery was selected as the region of interest (ROI); thus, the system set the moment at which the ROI was contrasted as time 0, and sequentially calculated the arrival time of individual pixels in the hepatic parenchyma. The system subsequently automatically created and superimposed a color map onto a B-mode image. In the present study, it took ∼10 sec for the contrast agent to completely visualize the liver parenchyma, following its arrival at the hepatic artery. We therefore displayed pixels arriving between 0–5 sec in red, and those arriving between 6–10 sec in yellow –5.For the quantitative evaluation of the At-PI data obtained, the ratio of the area of red pixels, i.e. the pixels with shorter arrival times, to the entire contrast-enhanced area was calculated as the ‘ratio of red’ (ROR), using the image analysis software ImageJ  in October 2010, traces and color codes temporal changes in contrast-enhanced US images. We have previously used At-PI to investigate the influence of the hepatic portal vein and the hepatic artery on hepatic parenchymal enhancement, and have reported its use in the clinical assessment of type C chronic liver disease  and alcoIn the present study, At-PI technology was used to reveal changes in hepatic parenchymal enhancement in a patient whose blood flow balance between the hepatic artery and portal vein was affected by deep breathing. The arrival time of Sonazoid in the liver was the primary element that was considered in the study of this blood flow balance. The contrast agent, injected via the cubital vein, first arrived at the liver via the hepatic artery, having passed through the heart. It was also carried through the venous system to arrive at the liver via the portal vein, once the blood had first nourished the stomach, intestines and spleen. The contrast agent has been demonstrated to arrive at the liver via these two routes ∼5 sec apart, with the hepatic arterial blood flow arriving more rapidly . In At-PBudd-Chiari syndrome occurs as a result of the congestion of the liver, due to the chronic obstruction of hepatic blood flow draining into the venous system. Long-lasting hepatic congestion has been demonstrated to lead to necrosis of the hepatocytes in the vicinity of the hepatic venules , and sinusoidal enlargement, whilst congestive cirrhosis has been indicated to develop as a result of the progressive fibrosis in the proximity of the hepatic venules . This leAs observed in the present case, when the portal venous blood flow is reduced, the hepatic vascular system has a mechanism to compensate for the loss in hepatic parenchymal perfusion –4. HowevBlood flow in the liver, particularly intrahepatic micro-circulation, is important in the study of changes in hepatic parenchymal perfusion. Sonazoid, injected via the cubital vein, arrives at the liver via arterial blood flow. In healthy individuals, the hepatic artery is the blood vessel that feeds the biliary system. Arterial blood flow nourishes large and small bile ducts, while traveling through the liver toward the periphery. The peribiliary capillary plexus is formed around the bile ducts, and a number of the capillaries merge into the terminal portal venules and sinusoids. However, certain branches of the hepatic artery merge directly into the sinusoids, without passing through the peribiliary capillary plexus, or nourish the portal vein by extending into the wall –18.2O, respectively)  . The abictively) , thus coThe investigations in the present study demonstrated that, during deep inspiration, when portal venous blood flow was obstructed by an increase in the intra-abdominal pressure, the reduction in hepatic parenchymal perfusion was immediately counterbalanced by the hepatic artery. As a result of this compensatory mechanism, the portal vein appeared to serve as a drainage vessel for the hepatic artery, and changed the blood flow to hepatofugal. The reduction in the portal venous blood flow may have generated signals to stimulate the precapillary sphincter, which then regulated hepatic parenchymal perfusion by activating an alternative mechanism that enhanced hepatic arterial blood flow into the sinusoids. During expiration, when intra-abdominal pressure was reduced, blood flow through the low-pressure portal vein into the liver parenchyma was facilitated. Consequently, the precapillary sphincter regulated the hepatic arterial blood flow to reestablish the dominance of the portal vein in the hepatic hemodynamics. In the present study, it was possible to establish how hepatic parenchymal perfusion was affected by acute changes in the portal venous blood flow by examining a patient with Budd-Chiari syndrome, who exhibited an inspiration-induced change in the portal venous blood flow, from hepatopetal to hepatofugal. At-PI was utilized as a simple and effective imaging tool for the visualization of these changes in hepatic hemodynamics.et al indicated that the conversion of hepatic blood flow from hepatofugal to hepatopetal occurred following transcatheter arterial embolization therapy (TAE) for hepatocellular carcinoma (Due to the lack of valves, blood flow in the hepatic portal vein is easily converted to hepatofugal blood flow, as the pressure gradient of hepatic parenchymal perfusion is reversed by a change in the hemodynamics. Comprehensive studies of hepatofugal blood flow in the portal venous system, particularly in the main portal vein, have demonstrated that the reversal of portal venous blood flow is rare when the portosystemic shunt is naturally occurring. It is possible that this is due to the fact that hepatic blood flow is maintained by a mechanism that prevents portal venous pressure from decreasing below sinusoidal pressure –29. In tarcinoma . This maTo the best of our knowledge, the present study is the first in which respiration-induced reversible changes in hepatic blood flow, from hepatopetal to hepatofugal, have been investigated with the use of the At-PI technology. The results have provided an insight into the effect of respiration on the hemodynamic changes between the hepatic artery and portal vein.We have previously used At-PI to investigate the hepatic arterial dominance that occurs as a result of disease progression in patients with chronic hepatitis C . The per


Return to work after gynaecological surgery takes much longer than expected, irrespective of the level of invasiveness. In order to empower patients in recovery and return to work, a multidisciplinary care program consisting of an e-health intervention and integrated care management including participatory workplace intervention was developed.We designed a randomized controlled trial to assess the effect of the multidisciplinary care program on full sustainable return to work in patients after gynaecological surgery, compared to usual clinical care. Two hundred twelve women (18-65 years old) undergoing hysterectomy and/or laparoscopic adnexal surgery on benign indication in one of the 7 participating (university) hospitals in the Netherlands are expected to take part in this study at baseline. The primary outcome measure is sick leave duration until full sustainable return to work and is measured by a monthly calendar of sickness absence during 26 weeks after surgery. Secondary outcome measures are the effect of the care program on general recovery, quality of life, pain intensity and complications, and are assessed using questionnaires at baseline, 2, 6, 12 and 26 weeks after surgery.The discrepancy between expected physical recovery and actual return to work after gynaecological surgery contributes to the relevance of this study. There is strong evidence that long periods of sick leave can result in work disability, poorer general health and increased risk of mental health problems. We expect that this multidisciplinary care program will improve peri-operative care, contribute to a faster return to work of patients after gynaecological surgery and, as a consequence, will reduce societal costs considerably.NTR2087Netherlands Trial Register (NTR):  Research on duration of full recovery and Return To Work (RTW) after (laparoscopic) gynaecological surgery has shown large discrepancy between expected physical recovery and actual return to work -3. This The Dutch Health Council stated, in line with the International Classification of Functioning, disability and health (ICF) model that there is a strong need for multidisciplinary recommendations for resumption of postoperative work activities ,15. HoweBased on the results of the modified Delphi study, the outcomes of the focus group discussions, the literature review and considering both the ICF model as well as the Attitude, Social influence and self-Efficacy (ASE) model in which important determinants of recovery and RTW are described ,21, a muThe main objective of this study is to evaluate the effectiveness of the multidisciplinary care program  compared to usual care regarding full sustainable RTW for patients after hysterectomy or laparoscopic adnexal surgery on benign indication. Secondary objectives of the study are 1) to study the effect of the multidisciplinary care program on general recovery, quality of life, pain intensity and complications; 2) to investigate how the program is evaluated by the patients, their health care providers and their employers and 3) to validate the multidisciplinary convalescence recommendations developed in het Delphi study .The CONsolidated Standards Of Reporting Trials (CONSORT) statement was followed to describe the design of this study. This checklist is used worldwide to improve the reporting of Randomized Controlled Trials (RCT) -26.The design of the study is a multicentre prospective RCT in patients undergoing gynaecological surgery and will be conducted in the Netherlands. In this study, the intervention group will receive a multidisciplinary care program  and will be compared with a control group that receives usual given peri-operative care together with a placebo e-health intervention. Figure The seven participating hospitals in this study will be six general (teaching) hospitals and one University hospital, all localized in or nearby Amsterdam: 1)The Amstelland Hospital; 2)The Flevo Hospital; 3) The Kennemer Gasthuis; 4) The Onze Lieve Vrouwe Gasthuis; 5) The Sint Lucas Andreas Hospital; 6) The Spaarne Hospital and 7) The VU University Medical Center.Participants for the study will be recruited from the waiting lists of participating hospitals. Patients scheduled for a hysterectomy or laparoscopic adnexal surgery because of benign disorders will receive an invitation letter on behalf of their gynaecologist, together with an information package consisting of: 1) patient information letter about the study, 2) Informed Consent (IC), 3) reply card to send to the researchers when not interested in participation in the study and finally, depending on the requirements of the particular hospital, 4) a leaflet about participating in scientific research in general.When the researchers do not receive a reply card of the patient within two weeks after the delivery of the information package, they will make contact to evaluate whether she is interested in participation in the study. Phone numbers and addresses of these patients will be send to the researchers by the participating hospitals weekly. Patients willing to participate and meeting the inclusion criteria will be asked to return the signed IC and will receive the baseline questionnaire about four weeks before surgery. Subsequently, when both are filled out and the surgery is scheduled within four weeks, the patient will be randomized for the intervention or usual care group.Eligible patients for this study are women aged between 18-65 years, employed for at least 8 hours per week (paid or unpaid) and scheduled in one of the participating hospitals for a laparoscopic adnexal surgery and/or hysterectomy due to benign disorders. Exclusion criteria for this study are: 1) (suspicion of) malignancy; 2) (ectopic) pregnancy; 3) deep infiltrating endometriosis; 4) concomitant surgical procedures or major health problems/psychiatric disorders affecting recovery or daily activities; 5) being sick listed for more than 4 weeks, or when the surgery is to cure the reason of the absence of work, sick listed for more than 2 months; 6) working temporarily for an employment agency without detachment; 8) dealing with a lawsuit against their employer; 9) not able to understand or complete the questionnaires written in the Dutch language and 10) no access to internet.To prevent unequal randomization between hospitals, patients will be pre-stratified by hospital and type of surgery . A computer-generated block randomization will be performed on individual level. The blocks consist of four characters to ensure roughly equal group sizes with each stratum and are randomly varying in sequence. Randomization will be executed by an (independent) research assistant, after the patient has completed baseline measurements and IC.In the Netherlands, there is a considerable variation in given peri-operative care and convalescence recommendations for gynaecological patients. The number of consultations and also the available time for counselling differs per hospital. After discharge, in general the patient receives one appointment for a post-operative check-up in an outpatients' department for about six weeks after surgery. Other medical care by gynaecologists and GPs is given only on demand. Patients with paid work who do not RTW within six weeks after surgery, are generally consulted by their OPs due to Dutch legislation.In addition to given usual care, patients in the control group of this RCT will get access to a placebo e-health intervention. This website has five unique pages and provides the patient with a patient leaflet and telephone numbers of the participating hospitals. The patient leaflet is derived from The Dutch Society of Obstetrics and Gynaecology (NVOG) website and forms the basis of almost all leaflets provided in Dutch hospitals for hysterectomy or laparoscopic adnexal surgery on benign indication ,28.Patients in the intervention group, receive normal usual peri-operative care with the adjustment that the care providers supply standardized detailed convalescence recommendations to the patients . In addiTo improve peri-operative gynaecological care, an interactive e-health intervention aiming at the empowerment of gynaecological patients during the peri-operative period including return to normal activities and work was developed . This e-This part of the intervention will only be offered to the patient when she is not fully returned to work ten weeks after surgery and consists of two main protocols; 1) Integrated care protocol and 2) Workplace intervention protocol and is based on a previous study of patients with chronic low back pain .A clinical occupational physician will be trained as RTW coordinator to fulfil an intermediate role between the patients' gynaecologist, GP, OP and a trained OT. The clinical occupational physician independently assesses the mental and physical condition of the patient and is responsible for the planning and the coordination of the continuation of care. First consultation of the clinical occupational physician will take place in the tenth or eleventh week after surgery. Table The workplace intervention procedure starts when the clinical occupational physician refers the patient to the OT, an expert to provide work (place) adaptations. The clinical occupational physician will define the conditions  under which the patient may return to work, which should be adopted by the OT and communicated effectively to the patient and the employer. The workplace intervention is based on methods used in 'participatory ergonomics' ,31 and pThe follow-up period will be 26 weeks after surgery (baseline). All the outcome variables are measured using self-report online questionnaires  and will1) The primary outcome measure in this study is sick leave duration until full RTW, defined as: duration of sick leave in calendar days from the day of surgery until full RTW in own or other work with equal earnings, for at least four weeks without  recurrence . This me2) The total duration of sick leave (due to the consequences of the surgery) during the 26 weeks follow-up period; measured by a monthly calendar of sickness absence.3) First RTW; measured by a monthly calendar of sickness absence.4) Recovery; measured by a validated Recovery Specific Quality Of Life questionnaire RS-QOL(RI10) , an exte5) Functional and general health status ; assessed according to the standard Dutch version of the EuroQol  and the 6) Pain intensity; measured using Von Korff questionnaire .7) Empowerment; assessed by the Dutch adaptation of the General Self-Efficacy Scale .8) Health care usage; measured by the Tic-P questionnaire  and valu9) The occurrence of complications in the post-operative period; assessed by questions based on the complication registration form of The Dutch Society of Obstetrics and Gynaecology (NVOG) . Patient10) Socio-demographic data; measured by the standard Dutch version of the EuroQol  and spec11) Type of surgery.12) Complications during surgery; assessed by questions based on the complication registration form of The Dutch Society of Obstetrics and Gynaecology (NVOG) .13) Work-related factors; measured by the Dutch Musculoskeletal Questionnaire (DMQ) , the Job14) Pain perception and fear avoidance belief; assessed by the Tampa scale .15) Sick leave duration in the past 3 months.16) Expectations, intention and motivation of the employee about return to work after surgery .A process evaluation will be performed only in the intervention group according to the Linnan and Steckler model . These p17) Patient's attitudes, opinions and compliance regarding the convalescence recommendations and the tools of the e-health program.18) Physicians' and employers' attitude en opinion regarding the multidisciplinary care program.19) Satisfaction with care program and care providers; measured with the short version of the Patient Satisfaction with Occupational Health Services Questionnaire (PSOHQ)  and spec20) The use of the e-health intervention during the follow-up period .21) Suggestions for improvement of the e-health intervention.22) Provided convalescence recommendations by the care providers according to the patients.Power calculation was performed on the primary outcome . To achieve a power (1-β) of 80%, with a significance level (α) of 5% and considering a HR of 1.5 in favour of the intervention group, approximately 191 patients will be needed. Anticipating a 10% drop out rate, in total a sample size of at least 212 patients will be aimed for. To recruit this number of patients, the study will anticipate on a ten-month inclusion period.Patients will be blinded for the allocated treatment. Treatment allocation (randomization) will take place by computer-generated block randomization after completion of baseline questionnaire and IC. After randomization, all patients will receive access to the e-health intervention. However, after logging into the website with their personal login credentials, the kind of information provided by the e-health intervention will depend on the group the patient is randomized for.During recruitment, the patients will be told that in case they do not RTW within 10 weeks after surgery, they might be approached for supplementary care depending on the care program they are randomized for. Nevertheless, explanation will only be given about the comparison of two different types of information supply and peri-operative guidance and not about the content of peri-operative guidance according to the 'intervention' or 'control' group.Due to the different treatments in both groups, therapists and researchers cannot be blinded for the allocated treatment of the patient.All statistical analyses will be performed at patient level, according the Intention-To-Treat (IIT) principle. To assess whether protocol deviations have caused bias, the results of the ITT analyses will be compared to per protocol analyses in which the patients who were not treated according to the intervention protocol, will be excluded. To examine the success of the randomization, baseline characteristics of the patients in both groups will be compared using descriptive statistics. If necessary, analyses will be adjusted for prognostic dissimilarities.A Kaplan Meier analysis (including the log rank test) will be used to describe the association between the group allocation and the duration of sick leave until the first period of full sustainable RTW. The Cox proportional hazard model will be used to estimate hazard ratios for RTW and the corresponding 95% confidence interval.The study design, protocols, procedures and IC were approved by the Medical Ethics Committees of all participating hospitals: the VU University Medical Center , the Amstelland Hospital , the Flevo Hospital , the Kennemer Gasthuis , the Onze Lieve Vrouwe Gasthuis , the Sint Lucas Andreas Hospital  and the Spaarne Hospital .This paper describes a RCT to study the effect of a multidisciplinary care program on recovery and full sustainable return to work of women who underwent a hysterectomy and/or a laparoscopic adnexal surgery on benign indication. Since work participation contributes to well-being and recovery of illness, the program particularly pays attention to stimulate patients in gradually resuming normal activities including RTW ,55. DuriThe implementation of this study in six general (teaching) and a University hospital is a good reflection of the Dutch health care situation. In addition, the selection bias of patients will be restricted through the proactive way of inviting all patients on the waiting lists to participate in the RCT. Therefore, selection will take place only based on clearly defined in- and exclusion criteria. A third strength is the blinding of the patients, which will minimize the Hawthorne and placebo effect . FurtherThe main limitation of this study is that contamination between the intervention and control group cannot completely be prevented, because the randomization will be performed on patient level. With regard to the health care providers, it is impossible to blind them for the intervention allocation, because the allocation determines the kind of convalescence recommendations that should be given to the patient. Therefore, it is important for them to follow and distinguish consequently the protocol belonging to the intervention versus the control group. Contamination may occur when care providers use acquired insights received through the convalescence recommendations for the intervention group to adapt their usual care and convalescence recommendations given to the control group. To minimize this effect, we will only proactively work on the familiarity of the protocols among the health care providers and not on the detailed contents of the convalescence recommendations for the patients in the intervention group. The patients' gynaecologists will only receive a summary of the guideline by means of their patients' record, in order to pass it on to the patient at discharge from the hospital. GPs and OPs will only receive the guideline when the patient hands over her tailored convalescence recommendations or work reintegration plan to them. A learning curve of the health care providers to flawlessly execute the protocol in the intervention group may be expected. This implementation curve may result in less effect of the intervention during the beginning of the study, which should receive attention during the analysis of the results. To accelerate the implementation of the protocol, pocket maps with the description of the intervention will be distributed, teaching meetings with the health care providers about the protocol will be organized and the protocol will be added to the medical file of the patient. Although therapists and researchers cannot be blinded for the allocated treatment of the patient, they will not be involved in measuring the outcomes, since all outcome measures are self-reported and the questionnaires will be sent by email or post to the patients. Therefore, it is unlikely that the way patients complete the questionnaires, will be influenced by the researcher and care providers. Moreover, the therapists of the multidisciplinary team , will not be involved in the assessment of the outcomes. With concern to contamination between patients of the intervention and control group, a chance meeting cannot be excluded. According to the protocol, patients from different groups should not be placed in the same hospital room, but it cannot be prevented that patients will meet outside the room. Another limitation of this study is the fact that the integrated care management and the workplace intervention will be carried out by one clinical occupational physician and OT, which might affect the execution of the intervention. However, both will work according to a detailed standardized protocol in order to minimize their personal influence on performance of the intervention as much as possible. Compliance to e-health interventions is sometimes low. We tried to minimize the risk of low compliance as much as possible by spending extra effort and time on involving the stakeholders (end-users) in the development of this intervention and adapting it to their specific needs by use of the intervention mapping protocol . FinallyYearly more than 17.500 women receive a hysterectomy or laparoscopic adnexal surgery on benign indication in the Netherlands . These lIf the multidisciplinary guidelines evaluated in this study will bring about a quicker recovery without an increase in complications, they will be implemented broadly in the Netherlands in collaboration with the participating medical board of gynaecologists, OPs and GPs. After implementation, the expectation is that the guidelines will result in more unambiguous detailed convalescence recommendations given by gynaecologists, GPs and OPs, through which patients will be better informed about when it is medically safe to resume daily and work activities after gynaecological surgery and give them the possibility to arrange (workplace) adaptations if necessary. Furthermore, the unambiguous recommendations will likely enhance the compliance to advice given by medical specialists and stimulate the patient to resume activities with increasing gradations of strain, which will presumably bring about a quicker recovery without an increase of complications ,62. TherBQ: Baseline Questionnaire; GP: General Practitioner; IC: Informed Consent; ICF: International Classification of Functioning; ITT: Intention-To-Treat; OP: Occupational Physician; OT: Occupational Therapist; RCT: Randomized Controlled Trial; RTW: Return To workThe authors declare that they have no competing interests.All authors made substantial contributions to this study and manuscript. They participated in the design of the study, the drafting and/or revising of this manuscript. All approve with this version to be published.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6963/12/29/prepub


Osteoma is a benign tumor rarely found in the paranasal sinuses. A 30-year-old female presented with an 8-month history of proptosis of the right eye that was progressing slowly. She was diagnosed with ethmoid osteoma and managed with collaborative surgery at the ophthalmology and otolaryngology departments. After surgery, the patient suffered visual loss that was managed medically. The surgical steps and protocol used for safe removal are discussed in the report. Management of a giaint osteoma extending to orbital tissue needs meticulous dissection through open approach and collaborative surgery by otolaryngologist and ophthalmologist. Osteomas are benign tumors rarely found in the paranasal sinuses  and are Paranasal sinus osteomas have a tendency to grow slowly, and for this reason they are generally asymptomatic and are diagnosed only as a coincidental radiological finding . An osteSurgery is the treatment of choice for symptomatic ethmoid osteoma. However, the approach is under discussion and depends on the extension and occurrence of complications . TraditiCase Description A 30-year-old female was referred to our hospital with an 8-month history of proptosis of the right eye that was progressing slowly. She complained of double vision and pain around the right eye. Her previous medical history was unremarkable. During the previous 2 months she had experienced epiphora, positional headache, and painful eye movements, as well as nasal and post-nasal discharge. The ear, nose, and throat examination revealed only nasal and post-nasal discharge. Ophthalmologic examin- ations showed severe proptosis of the right eye anterolaterally (approximately 3 mm), mild diplopia, and painful motility. Her visual function was mildly disturbed and revealed diplopia on left gaze. Visual acuity was measured as 20/20 in each eye and intraocular pressure (IOP) was normal. Her eye movement had a slight adduction limitation – (−1 grade). Other movements were unaffected. The right globe was pushed downward and laterally. There was mild swelling of the right lower lid. A hard nodular mass could be felt on and below the right medial cantus. Preoperative radiographic diagnostic work-up was axial, while a coronal computed tomography (CT) scan of the paranasal sinuses revealed a radiopaque mass in the right ethmoidal air cells with protrusion to the right orbit arising from anterior ethmoid sinus with extension upwards to the roof of the sinus and posterior ethmoid sinus and laterally in to the right orbital . The ophthalmic side of the tumor was not smooth, with an irregular surface and was posterior laterally close to the optic nerve. Surgical techniqueWe approached the tumor with a right-side Lynch incision. The endoscopic approach was not suitable as the lateral side of the tumor was deeply extended into the orbit. In order to gain better exposure, we removed part of the ascending process of the maxilla and the lacrimal bone. Because of the large size of the tumor, we divided it in two halves by drilling at the narrowest segment in an orbital and ethmoidal portion. The ethmoidal portion was excavated by drilling and then the remaining eggshell of the tumor was separated from the ethmoid roof to prevent damage to the skull base and possible cerebrospinal fluid (CSF) rhinorrhea. The orbital portion had an irregular surface  and the We had to divide the orbital portion into pieces by drilling and freeing the entrapped muscles before removing the tumor. We repeatedly monitored the optic nerve function by observing the pupil size. Post-operatively, the patient’s proptosis disappeared completely. She suffered some limitation of inward eye movement, as well as decreased vision to 5/10 due to macular edema. We initiated oral prednisolone therapy (1 mg/kg daily) for one week. The patient’s condition improved to normal over the course of 4 weeks. The patient was observed at follow-up and was symptom-free after 1 year. Although small frontoethmoidal osteomas are relatively frequent, giant osteomas are a particularly rare finding . EthmoidAny surgical approach has to take into account protection of the vital structures, particularly the optic nerve and cribriform plate, complete resection, and minimal cosmetic deformity. Different approaches have been discussed in the literature for the management of large ethmoidal osteomas; including external frontoethmoidectomy, lateral rhinotomy, midfacial degloving, and osteoplastic flap. An endoscopic approach is used in selected cases . The mosThe endoscopic approach has been used for this purpose recently. A number of reports in the literature describe the use of an endoscope to remove osteomas of ethmoidal origin, but none of these cases had an ophthalmic complication, while in all cases there was access to the tumor for endoscopic dissection ,6.Our case is made distinct by a number of ophthalmic complications due to extension of the tumor to the midsagittal plane of the orbit with a lobulated surface that was extended to the optic nerve and was entrapped into the surrounding fascia. Despite gentle manipulation on the posterior part of the tumor, mild ischemic neuritis of the ophthalmic nerve occurred that responded well to oral prednisolone (1 mg/kg daily) for 3 weeks. Traction of the optic nerve was an inevitable and regrettable consequence in our case as the orbital content was so trapped in the furrows of the tumor surface that we could not free the tumor until we removed it and saw that the orbital structures were on traction. The open approach is the most appropriate way to remove an osteoma extending into the orbit and the cooperation of both otolaryngologists and ophthalmologists is necessary to achieve risk-free surgery. Treatment of large ethmoid osteomas with orbital complications requires meticulous dissection of the surrounding tissues through an open approach to prevent injury to the orbital content. Involving an ophthalm-ologist familiar with orbital surgery supports incident-free surgery.


Home is a special location for many animals, offering shelter from the elements, protection from predation, and a common place for gathering of the same species. Not surprisingly, many species have evolved efficient, robust homing strategies, which are used as part of each and every foraging journey. A basic strategy used by most animals is to take the shortest possible route home by accruing the net distances and directions travelled during foraging, a strategy well known as path integration. This strategy is part of the navigation toolbox of ants occupying different landscapes. However, when there is a visual discrepancy between test and training conditions, the distance travelled by animals relying on the path integrator varies dramatically between species: from 90% of the home vector to an absolute distance of only 50 cm. We here ask what the theoretically optimal balance between PI-driven and landmark-driven navigation should be. In combination with well-established results from optimal search theory, we show analytically that this fractional use of the home vector is an optimal homing strategy under a variety of circumstances. Assuming there is a familiar route that an ant recognizes, theoretically optimal search should always begin at some fraction of the home vector, depending on the region of familiarity. These results are shown to be largely independent of the search algorithm used. Ant species from different habitats appear to have optimized their navigation strategy based on the availability and nature of navigational information content in their environment. Path integration (PI) is a strategy used by many animals to return home by the shortest possible route. In path integration, animals compute a home vector (HV) by integrating the angles steered and distances travelled on the outward journey Cataglyphis fortis see Melophorus bagoti see Melophorus bagoti) relying on their HV differs even within the same species: fractional use of the HV increases from 40% in landmark-rich habitats to 70% in landmark-poor habitats Desert ants and most likely other ants too possess a path integration system. In landmark-poor habitats ants return home by taking the shortest possible route, thus relying on path integration e.g., . In landGiven these differences in the distance travelled relying on the HV, we here ask what the theoretically optimal balance between PI-driven and landmark-driven navigation should be. In the presence of a familiar route, we investigate the possibility that initiating search prior to running off the entire HV may be a robust solution to minimize the expected cost and maximize the probability of success in finding the familiar route.Two models are used to determine the theoretically optimal point, according to the path integrator, at which to begin searching for home. In both models, it is assumed that.the navigating agent is familiar with an entire foraging route, i.e., if it is somewhere along a familiar route, it is able to find its way directly to its nest;the familiar route is approximately a straight line extending from its nest to some distance at some point prior to the homeward journey, the navigating agent is displaced from its familiar route (otherwise it would not need to search according to assumption (i));at the beginning of the homeward journey, the expected displacement is zero, i.e., over a large number of trials, the centre of the displacement distribution is unbiased.The cause of displacement is not important to the theoretical modelling in this work but two scenarios are presented to motivate the need for an effective coupling between search and PI strategies for animal homing . There aTwo models are used to determine the ideal HV distance to follow before initiating search, given that the true homing trajectory is displaced according to some error distribution . In this way, the expected cost is found over all points along the familiar route. Secondly, the expected cost is found over the angular extent of the familiar route, subtended at the point of  start of search (Model 1b). In effect, the latter analysis provides a reweighting of points along the familiar route, reducing the contribution of points which are far away at the start of search.The major advantage of these two ways of modelling the expected cost function is that they do not require a particular search strategy or distribution to be assumed. A disadvantage is that neither explicitly account for the probability distribution of points along the familiar route being found. The latter requires specification, at the very least, of a search distribution (see later).The second model finds the fraction of the HV corresponding to the maximum likelihood of finding any point along the familiar route. This is based on finding the prior distribution of the target, the familiar route. This is done by combining three results.Firstly, from the well known optimal search theory of Koopman These three results are combined to give the optimal search distribution, given a familiar route, and therefore the position where maximum search effort should be placed. This position is compared with the optimal position(s) under the minimum expected cost models.A geometric construction illustrating the following analysis is shown in It is assumed that the cost of searching, From the midpoint i.e., Shifted by some distance i.e., It can be seen thatBy symmetry of construction, equivalent arguments apply It is important to note that this result is independent of the search distribution or search algorithm.A similar argument applies in considering the maximum cost of search rather than the expected cost of search. The monotonicity of However, the minimum cost It can also be shown that the expected cost of search with respect to the angular extent of the familiar route is also minimized when The validity of the above theoretical assumptions is illustrated using three simple search algorithms, in simulation .From the searcher’s perspective, the above problem is similar to the original problem of finding a single target whose position is uncertain. Firstly, for the purpose of target search, the relative uncertainty between searcher and target can be considered to be independent of whether positional uncertainty is associated with the searcher or the target. That means the uncertainty in allocentric position of the searcher (due to cumulative PI errors) can be considered to be equivalent to the uncertainty in position of the target The probability of Strictly, maximizing the expected number of targets detected in the two-target problem is not mathematically equivalent to optimizing the probability of detecting either target. For example, if the probability of detecting both targets is increased without affecting the probability of detecting individual targets, the expected number of targets detected is increased, without increasing the probability of detecting either target. However, by maximizing the expected number of targets detected, it is likely that a realization of the search distribution will detect a target early, providing benefit to the searcher. Furthermore, this formulation of the problem provides a simple mathematical solution for the optimal search effort distribution which can be found directly following Koopman From the earlier example, the combined density function is,An analogous More generally, the convolution may be written asFor instance, if Similarly if The bivariate Gaussian is a good approximation of the positional uncertainty distribution of a PI system which has a compass Following Koopman Two important consequences of Eq 16 are as follows. Firstly, if It is worth noting that the arguments presented above may be generalized to alternative target detection models. For instance, Wehner & Srinivasan The distance individual ants travel relying on their path integrator in an unfamiliar terrain decreases from landmark-poor saltpans, to landmark-rich desert scrub and to landmark-dense rainforest. The fractional read-out of HV information shown by ants occupying landmark rich and dense habitats may be related to the range over which these ants know the visual scene around their nests. Here, we used two theoretical analyses to find the optimal start of search, given an accurate HV obtained through PI, and a familiar route. The first analysis assumed that the cost of search is monotonically dependent on the distance to the search target. For a homogeneous set of points along the familiar route, the optimal position was shown to be the midpoint of the familiar route according to the PI system. The second analysis assumed that the start of optimal search should begin at the mode of the optimal search density function. For any symmetrical unimodal positional uncertainty distribution, the modal position is the midpoint of the familiar route according to the PI system. The start of search according to both the cost minimization and optimal search distribution models is in agreement, and corresponds to the midpoint of the familiar region according to the PI system.Melophorus bagoti trained to a feeder 20 m away from the nest returned home in a narrow 0.5 m wide corridor of landmarks  is provided later with a food source at midway  for a few trials. If these ants are displaced, a dynamically optimized homing system should begin search immediately to minimize expected cost and maximize expected probability of finding the familiar route of 20 m. Alternatively, if M. bagoti runs off approximately half its HV  prior to searching, this may suggest a strategic optimization for commonly encountered conditions rather than dynamic adaptation from one foraging trip to the next  caught close to the nest (zero-vector ants), when displaced far away from their familiar region, search more or less symmetrically around the release location To further complicate matters, experimental evidence suggests that the available visual information may directly influence the search strategy The experimental and theoretical results described here also have implications on the nature of the neural networks subserving path integration. From a computational perspective, there needs to be an accurate path integration system and, if the familiar route is to be (approximately) bisected, then there needs to be metric properties associated with the familiar region. It is unclear at present whether a decentralized neural architecture such as Cruse & Wehner Figure S1The familiar region affects the optimal homing strategy. A. When the foraging journey (blue) extends beyond the familiar region (grey), the optimal homing animal follows the direction of its HV (dotted line) to the middle of the familiar range, from where it finds its home directly. A sudden displacement (red dashed) results in the homing animal unable to reach the familiar region following running off nearly 100% of its HV (red solid line), at which point it initiates search. B. As per (A) but with a typical foraging journey within the familiar range. The optimal homing animal follows the direction of its HV to the middle of the familiar range, which now corresponds to just under halfway along the full HV. C. Proposed experiment to test whether the fraction of HV used adapts dynamically to the familiar region or is tightly coupled to the magnitude of the HV at the start of homing.(TIFF)Click here for additional data file.Figure S2Geometric construction showing angular extent of different segments of the familiar route  These represent two possible locations to begin searching for the familiar route, one exactly midway along a line (TIFF)Click here for additional data file.Figure S3Correlated random walk search model. A. Three random search trajectories (rows) are shown for four different fractional HVs (columns) used. The home (light red dot), familiar route (black line), last known location (cyan dot), random displacement (red dashed line), fractional use of the ideal HV (solid red line) are superimposed. B. Top left panel shows the frequency histogram of positions of first detection of the familiar route, pooled from the frequency distributions at each of eleven ideal search initiation position (TIFF)Click here for additional data file.Figure S4Archimedean spiral search model – otherwise as per (TIFF)Click here for additional data file.Figure S5Modified Cataglyphis search model – otherwise as per (TIFF)Click here for additional data file.Figure S6Cost of search. Mean ± s.e.m. of the number of steps needed to detect the familiar route as a function of the distance r between the start of search and detection point, pooled over all trials in bins of 0.2 linear units, are shown for the correlated random walk search (A), Archimedean spiral search (C) and modified Cataglyphis search (E). Mean ± s.e.m. of the number of steps needed to detect the familiar route as a function of the ideal search initiation position 5 search steps. Using these models it is not possible to assign a probability of failure to a particular radial distance since no particular point along the familiar route can be associated with the failure to detect the familiar route.(TIFF)Click here for additional data file.Table S1Search model descriptions.(TIFF)Click here for additional data file.Table S2Simulation parameters common to all search models.(TIFF)Click here for additional data file.Text S1Model (1b): Cost Minimization.(DOC)Click here for additional data file.


In the current study, a non-invasive technique for systolic blood pressure (SBP) measurement based on the detection of photoplethysmographic (PPG) pulses during pressure-cuff deflation was compared to sphygmomanometry—the Korotkoff sounds technique. The PPG pulses disappear for cuff-pressures above the SBP value and reappear when the cuff-pressure decreases below the SBP value. One hundred and twenty examinations were performed on forty subjects. In 97 examinations the two methods differed by less than 3 mmHg. In nine examinations the SBP value measured by PPG was higher than that measured by sphygmomanometry by 5 mmHg or more. In only one examination the former was lower by 5 mmHg or more than the latter. The appearance of either the PPG pulses or the Korotkoff sounds assures that the artery under the cuff is open during systolic peak pressure. In the nine examinations mentioned above the PPG pulses were observed while Korotkoff sounds were not detected, despite the open artery during systole. In these examinations, the PPG-based technique was more reliable than sphygmomanometry. The high signal-to-noise ratio of measured PPG pulses indicates that automatic measurement of the SBP by means of automatic detection of the PPG signals is feasible. In sphygmomanometry (SPM), an external pressure cuff is used, and the commencement and the cessation of the Korotkoff sounds when the cuff pressure decreases below the SBP and DBP values, respectively, are identified. Auscultatory SPM uses audible detection of Korotkoff sounds, and, when performed by a trained listener, is considered to be the most accurate non-invasive method, and is accepted as a reference standard for evaluating the accuracy of other non-invasive methods for blood pressure measurement. However, the auscultatory SPM is not convenient to use, depends on the experience of the user and only provides single measurements. Furthermore, the presence of the physician can influence blood pressure level, which is known as the white coat effect –3.In order to avoid the drawback of the auscultatory SPM, non-invasive automatic blood pressure (NIBP) meters have been developed. The automatic SPM detects the Korotkoff sounds by means of a microphone but is prone to artifacts due to external noise and vibrations ,5. OscilThe low accuracy of the available automatic NIBP meters can be deduced from the standards imposed by the Association for the Advancement of Medical Instrumentation , the proHypertension [Nevertheless several recent Editorial Commentaries in rtension –15 emphartension ,15. Somertension .1.2.Several techniques have been developed for the measurement of SBP by using the collapse of the artery under the cuff when the cuff pressure is above the SBP value. The reopening of the artery when the cuff pressure decreases below the SBP value can be detected by a distal flow or pulse detector, such as manual palpation, Doppler ultrasound, photoplethysmography (PPG) or strain gauge –25. EachIn a former study , we presThat study considered the auscultatory method as the reference standard and tried to find another technique, with measurement results as close as possible to those of the reference standard. The determination of the pulses as PPG pulses was based on empirical criteria and was therefore of a statistical nature, which is a potential source of error, similar to oscillometry. Furthermore, the auscultatory technique has its own inaccuracies, and these inaccuracies are also involved in the PPG-based technique which is based on the auscultatory SPM.In the current study, an improved noninvasive PPG-based method for the measurement of SBP is presented and compared to auscultatory SPM. The PPG signal downstream to the cuff disappears when the cuff pressure is greater than the SBP value and reappears when the cuff pressure decreases below the SBP value. In the current study the PPG signal-to-noise ratio was increased relative to the former study  and the 2.2.1.PPG examinations and auscultatory SPM measurements were performed on 42 male subjects aged 25–73 years. We preferred to perform the examinations on male subjects, since in a previous study  we foundThe subjects were seated during the examination. Their forearms were placed comfortably on a table, and the measurement was begun after a rest period of 10 min. A pressure cuff was applied to the left arm and an electronic pump raised the air pressure to 140, 160 or 180 mmHg (according to the SBP of the subject) at a rate of 15 mmHg per second. Then the air pressure decreased at a constant rate of 1.5 mmHg per second. The cuff air pressure was measured by a piezoelectric transducer which was calibrated by a mercury manometer. The SBP of each subject was measured five times, simultaneously by auscultatory SPM and by the PPG method, using the same pressure-cuff. Korotkoff sounds were detected by two researchers (MN and YA), using a double stethoscope. Each investigator pressed a button when the first 4–5 Korotkoff sounds were heard and each button-press caused a notation (star) to be inserted into the recording of the PPG  and stored for further processing. The output of the piezoelectric transducer for the cuff air pressure measurement was simultaneously digitized and stored.The PPG signal in the hand distal to the cuff was used for the determination of the cuff pressure at which the PPG pulses reappeared during cuff deflation. The PPG signal in the free hand was utilized for the determination of the time-segments in which the PPG signal distal to the cuff was expected to appear. In previous studies ,27 we haThe increase of the cuff pressure was relatively slow, at a rate of 15 mmHg per second—it took more than 10 s to raise the pressure to a value of 160 mmHg. In an earlier study it was found that when the cuff is inflated at a higher rate, 10%–20% of subjects show no PPG pulses until the pressure has decreased significantly below the true SBP value (as measured by Korotkoff sounds). This effect probably originates from the collapse of the finger arteries under the PPG sensor due to their drainage into the veins when the cuff air pressure increases above SBP. When the cuff air pressure is slightly below the SBP value the blood volume pulses entering the arteries distal to the cuff are small and cannot open the collapsed arteries under the sensor . Increas2.3.Five examinations were taken for each subject. The first examination was only a practice run and was not used in the analysis. In general the next three examinations were analyzed for the determination of the SBP value; if one of these examinations could not be used because of movement noise, the fifth examination was used instead.K) was determined off-line by the indications (stars) marked by the two investigators. In order to compensate for the reaction time of the investigators (of about 1/3 s), the SBPK value was determined as the cuff air pressure value, PC, at the start time of the free-hand PPG-pulse in which the first star appeared  in each examination was obtained off-line by two observers (SE and EH) from the value of the cuff air pressure, PC, at which the PPG pulses reappeared during the deflation period. The two observers were blind to the corresponding pressure values determined by auscultation. At cuff pressures slightly below the SBP value, the artery is only open for a short time—when the arterial blood pressure is higher than PC—and the corresponding PPG pulses are smaller than the corresponding pulses in the cuff-free hand. However the characteristic pattern of these PPG pulses was distinct from the noise in most cases, and the first pulse was easily recognized. The criterion used in our study to determine the reappearance of the first PPG pulse was qualitative as is the criterion for the Korotkoff sounds. Only pulses whose appearance resembled the PPG pattern, that showed significant decrease starting 100–300 ms after the start time of the PPG signal in the free hand, were accepted. Only pulses that were recognized as PPG pulses by both observers were accepted. The SBPPPG value was determined as the cuff air pressure value at the start time of the PPG pulse in the cuff-free hand in which the first PPG pulse had clearly reappeared.The PPG-based SBP value  curves during the cuff deflation. Note the oscillations in the decreasing pressure curves that appear before the SBP values, both those obtained by Korotkoff sounds and those obtained by the PPG pulses reappearance. These oscillations are used in oscillometry to determine the systolic and diastolic blood pressure values through empirical criteria.The curves below the PPG curves are the air pressure (PPPG-SBPK for the 120 examinations was 0.81 (±2.49) mmHg, which is significantly higher than zero (p < 0.001 in t-test). K differed from SBPPPG by 3, 4, 5, 6 and 7 mmHg or more.In 97 out of 120 examinations of the 40 subjects, the difference between SBP values, measured by PPG, and SBP values measured by Korotkoff sounds was less than 3 mmHg. The mean (±SD) of the difference SBPPPG-SBPK, was zero.PPG-SBPK differed from zero, SBPPPG was higher than SBPK. As was claimed above, in a given examination in which SBPPPG and SBPK differed, detection of the PPG signal before the Korotkoff sounds during the cuff deflation indicates higher accuracy of the PPG-based technique relative to the Korotkoff based-technique and vice versa.In the majority of the examinations in which SBPPPG-SBPK for each subject. The maximal intra-subject difference between the three values of SBPPPG-SBPK was 0–9.4 mmHg (mean and SD 3.4 ± 2.5 mmHg).Intra-subject variability is demonstrated in 3.2.The various indirect non-invasive techniques for the measurement of systolic blood pressure are based on applying decreasing external pressure by means of a pressure cuff on an underlying artery and determining the systolic blood pressure by measuring some physiological parameter that changes when the cuff pressure decreases from above the SBP value to below it. The indirect techniques assume that the counter-pressure applied on the arterial wall causes it to collapse when the cuff pressure is higher than the arterial blood pressure, and the artery reopens when the arterial blood pressure is higher than the cuff pressure. The arterial wall itself is assumed to be compliant when the trans-mural pressure is zero and to exert negligible resistance force. In stiffened atherosclerotic arteries, higher pressure than the arterial blood pressure is required to occlude the artery, and it affects blood pressure measurement ,8,28. ThSBP meters based on detection of a pulsatile parameter that is directly induced by blood flow and can be detected non-invasively. These pulsatile parameters include pulse palpation, ultrasound Doppler, PPG and strain gauge. SBP is determined from the cuff pressure at which the pulsatile parameter reappears when the external pressure decreases below the SBP value and the artery reopens.Auscultatory sphygmomanometry based on Korotkoff sounds. Korotkoff sounds are also assumed to start when the external pressure decreases below the SBP value and the artery reopens. However, they cannot be classified as directly induced by blood flow, since they are not heard when no external pressure is applied on the artery, when blood flows uninterruptedly.Oscillometry, which is based on the dependence on time of the air pressure pulses in the cuff during cuff deflation—the oscillometric curve. The air pressure pulses appear even when the cuff pressure is above SBP value, and the SBP is determined by the analysis of the oscillometric curve using empirical criteria. Those empirical criteria are probably responsible for the low accuracy of oscillometry ,7–9, sinThe cuff-based indirect techniques can be classified into three classes according to the type of these physiological parameters:Korotkoff sounds appear only when the cuff pressure is between the systolic and diastolic blood pressure. The arterial blood flow itself does not generate these sounds, as they are not heard when the cuff pressure is below the diastolic blood pressure value. Several effects have been suggested as the origin for Korotkoff sounds: turbulence due to partial occlusion of the artery, flutter of the arterial wall, impact of the pulsating blood on the stationary distal column of blood and more ,29–31. IAuscultatory sphygmomanometry, based on the detection of Korotkoff sounds, has been accepted as the preferred non-invasive technique for the measurement of arterial blood pressure. Auscultatory sphygmomanometry has been compared to direct intra-arterial measurement of SBP, and it provided, in several examinations, significantly lower values than those obtained by the invasive gold-standard ,6,32–34.PPG differed from SBPK, SBPPPG was higher than SBPK  was higher than the corresponding number of examinations in which SBPK was higher than SBPPPG. Detection of the PPG signal before the Korotkoff sounds during cuff deflation indicates the greater accuracy of the PPG-based technique relative to the Korotkoff based-technique in that measurement, and vice versa. In the current study, the PPG-based measurement of the SBP was found to be more accurate than the Korotkoff sounds-based technique of the SBP measurement. It should be emphasized that the current study cannot provide information regarding the absolute accuracy of the two techniques: in order to make such a determination, comparison to intra-arterial measurement is required.The PPG-based technique belongs to the first class, since the PPG signal can appear only when the cuff pressure decreases below the SBP value, and it continues to appear when there is no external pressure. In the current study we compared the PPG-based technique with auscultatory sphygmomanometry, which is considered to be the most accurate non-invasive method for blood pressure measurement and is accepted as the method of choice. In our study we have found that during cuff deflation, in the majority of the examinations in which SBPSBPK see . The meaThe study also showed that in some cases the PPG-based technique did not provide an accurate SBP measurement. In those examinations in which Korotkoff sounds were heard before the reappearance of the PPG signals, the latter were not detected despite the reopened artery, as proved by the detection of the Korotkoff sounds. The small volume of blood added to the whole arm and hand during the short time in which the arterial blood pressure was above the instantaneous cuff pressure could not create a detectable change in light transmission in several examinations. It is reasonable, however, to assume that increase of the PPG signal-to-noise ratio and more reliable detection of the PPG signal can provide higher accuracy in the measurement of the SBP by the PPG-based technique. It is not reasonable to expect that after 100 years of extensive use, the Korotkoff sounds-based technique can be significantly improved.4.The current study shows that the PPG-based technique for the measurement of SBP is of comparable accuracy to the Korotkoff sound-based technique, and probably of higher accuracy, though this last claim should be validated in more comprehensive studies. It should be emphasized that the study was performed on male subjects, who have PPG signal greater than that for female subjects. In general, the typical pattern of the PPG signals can be clearly recognized even when the cuff pressure is slightly below the SBP value, indicating that automatic measurement of SBP by means of automatic detection of the PPG signals is feasible. The absolute accuracy of the automatic measurement of the SBP by means of PPG-based technique has to be determined experimentally by comparing it to invasive intra-arterial blood pressure measurements.The main limitation of the PPG-based technique is that it only measures SBP but not diastolic blood pressure. However, a blood pressure meter, that provides automatic and accurate measurement of SBP together with diastolic blood pressure measurement either by the manual Korotkoff sound-based technique or by the automatic oscillometry, seems to be of clinical merit.During the long period since the invention of the Korotkoff sounds-based technique, efforts have been made to use the technique automatically, using a microphone instead of a stethoscope, but the automatic technique has not been shown to be accurate enough to replace auscultatory sphygmomanometry. Audible artifacts are more reliably rejected by the human ear-brain combination than by sophisticated algorithm designed to analyze the microphone signals and to differentiate between Korotkoff sounds and artifacts. The PPG signal seems to be more suitable for automatic detection because in most cases the pattern of the PPG signals is conserved throughout the whole deflation period and can be easily recognized.


Since medication nonadherence is considered to be an important health risk, numerous interventions to improve adherence have been developed. During the past decade, the use of Internet-based interventions to improve medication adherence has increased rapidly. Internet interventions have the potential advantage of tailoring the interventions to the needs and situation of the patient.The main aim of this systematic review was to investigate which tailored Internet interventions are effective in improving medication adherence.We undertook comprehensive literature searches in PubMed, PsycINFO, EMBASE, CINAHL, and Communication Abstracts, following the guidelines of the Cochrane Collaboration. The methodological quality of the randomized controlled trials and clinical controlled trials and methods for measuring adherence were independently reviewed by two researchers.A total of 13 studies met the inclusion criteria. All included Internet interventions clearly used moderately or highly sophisticated computer-tailored methods. Data synthesis revealed that there is evidence for the effectiveness of Internet interventions in improving medication adherence: 5 studies  showed a significant effect on adherence; 6 other studies  reported a moderate effect on adherence; and 2 studies  showed no effect on patients’ adherence. However, most studies used self-reported measurements to assess adherence, which is generally perceived as a low-quality measurement. In addition, we did not find a clear relationship between the quality of the studies or the level of sophistication of message tailoring and the effectiveness of the intervention. This might be explained by the great difference in study designs and the way of measuring adherence, which makes results difficult to compare. There was also large variation in the measured interval between baseline and follow-up measurements.This review shows promising results on the effectiveness of Internet interventions to enhance patients’ adherence to prescribed long-term medications. Although there is evidence according to the data synthesis, the results must be interpreted with caution due to low-quality adherence measurements. Future studies using high-quality measurements to assess medication adherence are recommended to establish more robust evidence for the effectiveness of eHealth interventions on medication adherence. Recent reports of the World Health Organization and the National Institute for Health and Clinical Excellence reveal that 30%–50% of patients with chronic illnesses do not adhere to prescribed medication . Other sAdherence is defined as the extent to which the patient’s behavior matches the agreed recommendations of the prescriber ..7].Online assessment and feedback are used in interventions with single-incident computer-assisted risk or health assessments. For example, feedback is emailed to the patients or provided online . In addiWith tailored content a program provides (1) tailored text messages composed in a unique way according to how patients respond to certain questions, or (2) restricted access to content sections per patient . TailoreInterventions that provide not only tailored content but also individualized instructions for meeting certain health goals, self-management goals, or goal-setting activities are so-called customized health programs , used byInterventions also differ in the type and extent of health provider involvement. User control allows individuals to take a major role in managing their own care, whereas in expert control an expert or therapist takes a more directive role .Only 4 of the interventions were based on user control and 9 interventions used contact with the health provider. A Web-based asthma management program was developed in 1 study . The proIn contrast, in the Blue Angel for Asthma Kids, a customized educational and monitoring website site providing secure email contact between patients and their therapist, the therapist had a more directive role . Like thSeveral interventions used a special device to exchange information between patients and health care providers. The Med-eMonitor recorded data and answers to questions that could be uploaded by the health provider. Based on these outcomes, the health provider provided advice and updated the treatment regimens . The PATOur analysis to examine the extent to which medication adherence is determined by different tailoring levels revealed no clear relationship between the intervention’s level of sophisticated tailoring and the extent to which the intervention was effective .We found 5 studies with a significant effect on adherence (3 HQ studies and 2 LQ studies) ,34,35,38A moderate effect on adherence was reported in 6 studies (4 HQ studies and 2 LQ studies). The SPPARO proved to be feasible and improved general adherence. Adherence to medication showed a similar trend but these results did not reach significance . The secNo significant results on patients’ adherence were found in 2 studies (1 HQ and 1 LQ) ,39.Regarding the measurement of adherence, the 13 studies we reviewed showed a large variability of methods: 12 studies used a low-quality measurement to assess adherence and 1 used a combination of these methods  .In 10 studies, self-reported scales were used to obtain the adherence rate. Although 5 studies ,34,36,37One study used a combination of methods. This study  used a dOur investigation of the relationship between the quality of the adherence measurement and the effectiveness of the interventions revealed no clear relationship , although self-reported adherence measurements seemed to result more often in significant effects than did pill counts and pharmacist adherence measurements . Of the There was no clear relationship between the timing of the adherence measurements and the effectiveness of the intervention. The intervals between baseline and follow-up measurements differed between projects. Short-term adherence  was measured in 6 studies. The first study  showed tLong-term adherence was measured in 7 studies—that is, adherence with an interval of 6 months or longer, mostly of 1 year or more. Two studies ,36 reporUsing the principles of the best-evidence synthesis see , taking The sensitivity analysis showed the same results as the best-evidence synthesis. The results remained the same when the analysis was repeated with the 6 LQ studies excluded . Moreover, when studies were rated to be HQ if 4 instead of 6 criteria of interval validity were met, results stayed the same.First, our objective was to gain insight into the current state of the use of Internet interventions to improve medication adherence. Results of this review indicate that this is still a new field. This is visible in the differences in interventions with respect to crucial aspects such as the level of sophisticated tailoring and the role of health care providers. Despite the differences, it is remarkable that none of the interventions used a low level of tailoring and the majority (9 of 13) provided the opportunity to contact a health provider.Second, the studies were assessed on their effectiveness on medication adherence. There is evidence that Internet interventions can improve medication adherence. This evidence comes from 3 HQ studies and 2 LQ studies, finding significant results on medication adherence.Third, we wanted to investigate to what degree adherence is determined by the characteristics of the intervention. All interventions discussed in this review used tailored methods and used a moderately or highly sophisticated tailored intervention. These types of health programs, especially customized health programs, are more complex, generally long-term, allowing the patients to access the programs several times , and areLast, we wanted to investigate whether there is a relationship between the characteristics of a study and the reported effectiveness of the interventions. We found that there was variation not only in the level of tailoring, but also in the measurement of adherence, the timing of measuring adherence, and the intensity of the intervention. The included studies used self-reporting measurements  or pill counts, or prescription refills, or a combination. No study used electronic monitoring, which is perceived as a high-quality method for assessing adherence . Of the There is evidence that Internet interventions can be effective in improving medication adherence. The evidence comes from 3 HQ studies. However, the results should be interpreted with caution. Self-reported scales were used in 10 studies, which is considered a low-quality adherence measurement: 5 reported a significant effect of the intervention on adherence, 4 a moderate effect, and 1 no effect. Self-measurements can contribute to overestimating of the effects of interventions . This coElectronic monitoring or observation is considered to be more accurate. It electronically records the time and date of the actual dosing events. Because every single method has its limitations, the best approach is to use multiple assessment techniques concurrently, as a way to improve the accuracy of adherence assessment . One stuOf the studies we reviewed, 6 measured short-term adherence that varied from 6 weeks to 4 months: 4 of them were found highly effective and 1 moderately effective regarding adherence. The question is whether adherence improved in the long term, because the period was too short to measure persistence. According to an international expert forum on adherence , it is nThe search method was top-down in that we relied on existing databases and search terms. This approach has the possibility of missing important articles due to miscoding of search terms. A bottom-up strategy is more time consuming but has the advantage of being more comprehensive.Monitoring adherence to optimize effects and minimize nonadherence could be time consuming. Computers, however, are very good at collecting data concerning the monitoring of adherence. Internet interventions can be tailored, collect data, and monitor adherence. In addition, based on this systematic literature review, there is evidence that tailored Internet interventions can be an effective method to improve medication adherence. This means that Web-based interventions can be effective at increasing medication adherence among chronically ill patients. Health providers, who want to enhance patients’ adherence, are encouraged to use tailored websites or reminder systems. They could use these interventions in addition to their everyday work.Because we did not find a clear relationship between the effectiveness and the degree of tailoring, we recommend that future studies should be conducted with variation in the level of sophistication of tailoring to further test which characteristics of the tailored messages have the most positive effects on adherence. Moreover, website compliance is often not completely reported. While the frequency in which the patient used the website is often reported, studies do not describe how exactly patients used the website. Therefore, it is difficult to compare the results of different interventions, because the way patients use the website can have implications for the effectiveness of the website.With more than 40 million people using the Internet for a variety of purposes, health communication programs in the future are more likely to be delivered online . These t