Asthma that is poorly controlled and undertreated can progress to more severe disease that is associated with high levels of unscheduled care that requires high-cost therapy, leading to a significant health economic burden. The identification and appropriate referral to a specialist asthma service is also often delayed by several months or years because of poor recognition and understanding of symptom severity. Current severe asthma services may take several months to provide a comprehensive multidisciplinary assessment, often necessitating multiple hospital visits and costing up to £5000 per patient.This study aims to evaluate whether a new service model could identify poorly controlled and potentially severe asthma much earlier in the patient pathway, and then compare clinical outcomes between this new care model with standard care.Modern Innovative Solutions to Improve Outcomes in (MISSION) Severe Asthma is a novel service model developed by asthma specialists from Portsmouth and Southampton severe asthma services. MISSION Severe Asthma identified patients with poorly controlled disease from general practice databases who had not been under secondary outpatient care in the last 12 months or who were not known to secondary care. In 1- or 2-stop assessments, a thorough review of diagnosis, disease phenotype, and control is undertaken, and clinical outcomes collected at baseline.A variety of clinical outcomes will be collected to assess the service model. The results will be reported in February 2020.This protocol outlines a mixed methods study to assess the impact on disease control, unscheduled health care usage, and quality of life in patients seen in the MISSION clinic compared with a closely matched cohort who declined to attend.DERR1-10.2196/9585 Asthma affects 5.4 million patients in the United Kingdom with the majority of costs (nearly 80%) relating to treating poorly controlled asthma, amounting to over £1 billion per annum as a direct cost and an indirect cost to society (time off work and lost productivity) of £6 billion. In the past year, the Wessex Region has seen over 1800 emergency adult hospital admissions because of asthma , costing over £2.1 million to the local health authority.Asthma UK highlights that over half of the people with asthma suffer debilitating symptoms despite being prescribed treatment . Poorly The Specialised Services Pathway for Severe Asthma recognizes the burden of uncontrolled disease ordinarily amenable to antiinflammatory medications and the progression to longer term “severe” disease, necessitating high-cost therapies  . The ideCurrent severe asthma services may take several months to provide a comprehensive multidisciplinary assessment often necessitating multiple hospital visits and costing up to £5000 per patient. The report “Fighting for Breath” highlighted these issues with service delivery recommending that referral pathways to severe asthma services should be improved .Modern Innovative Solutions to Improve Outcomes in (MISSION) Severe Asthma is a novel service model pilot that took place in June and July 2014. MISSION was developed by asthma specialists from Portsmouth and Southampton asthma services.The MISSION concept involved a “carousel clinic” which brings together all the assessments and investigations a patient requires into one clinic—the patient moved around each assessment or “investigation station” in a serial fashion. This allowed the research team to efficiently gather all the data required for both staff and the patient. This severe asthma patient journey was mapped and opportunities for improvement were identified such as earlier diagnosis by active case finding of at-risk patients, followed by a swift multidisciplinary assessment which meant patients could be seen sooner and assessed more effectively. Patients attending standard outpatient services undergo basic lung function, chest x-ray, and medical review. They are then referred for other tests or specialist opinions as required at different time-pointsMISSION Severe Asthma identified patients with poorly controlled disease from general practice (GP) databases who had not been under secondary outpatient care in the last 12 months or who were not known to secondary care. The patients were then invited to Rapid Access Asthma Clinics (RAACs) for assessment at their GP surgery on a Saturday, at a time convenient for them. The clinics were held on Saturdays at a time better suited to the needs of asthma patients, many of whom are working or studying full-time.The RAAC delivered a comprehensive asthma review including assessments of allergic status, airway inflammation, education, self-management planning, and smoking cessation leading to a written personalized 1-year asthma management plan for their GP providing clear treatment recommendations for those with uncontrolled but treatable asthma see . TreatmeAt the end of the RAAC, a multidisciplinary team (MDT) meeting was held and treatment plans were discussed. The possible outcomes for patients included increasing or decreasing medication, referral for research study, referral to other medical teams, or a need for further assessment as the patient has potentially severe and uncontrolled asthma. Patients with potentially severe and uncontrolled asthma were invited for a more detailed multidisciplinary specialist assessment at a Severe Asthma Assessment Clinic (SAAC) again on a Saturday, held at Queen Alexandra Hospital.MISSION SAAC included multidisciplinary assessment respiratory specialists, dieticians, physiotherapists, ear, nose, and throat (ENT) consultants, physiologists, psychologists, and pharmacists. Computed tomography (CT) scanning of the chest and sinus as well as flexible nasendoscopy to assess for sinus change and nasal polyps was available on that day. Patients saw the appropriate specialists based on the clinical history from the RAAC and a medical assessment on arrival to the SAAC. This ensured full lung function, inhaler technique, and medical exam for all patients, and physiotherapy, dietician, ENT, CT chest or sinus were performed where needed see . RepreseAt the end of the clinic, a full MDT meeting was held to discuss each case. Patients and their GP received a detailed letter with all the test results and treatment changes as well as plans for follow-up. Follow-up referrals were made to specialists as needed, and treatment changes were made on the day of the clinic visit with support from the pharmacy for new treatment prescriptions.In summary, the difference of the MISSION clinic from standard care was in 2 areas: First the active case finding of patients who are not already known to secondary care but are potentially uncontrolled. The second is the model of the clinic. Patients seen at the RAAC only will undergo more extensive testing and review of their asthma than primary care can provide and will have their comorbidities identified, asthma phenotyped, and treatment changes made appropriately.MISSION is a new and novel way of delivering highly specialized asthma care and has the potential to change the way asthma care is delivered across the United Kingdom as well as services for other long-term health conditions. The MISSION model is the first model of this type, and this study aimed to evaluate its success and compare the MISSION service with current care delivery. This will be done in several different ways. The study is a mixed methods evaluation of the new service comparing outcomes before and after the MISSION clinic using retrospective data analysis and prospective qualitative interviews. A control arm of patients not exposed to, but eligible for, the new MISSION clinic will also be included.Using quantitative and qualitative methods, our objective is to explore the impact of the MISSION service on clinical outcomes and patient experience. Using quantitative methods, we will (1) retrospectively analyze data collected as part of routine clinical care from all patients attending MISSION e.g. asthma control, medication usage and technique, exacerbations, comorbidities, allergies, and investigations  and (2) retrospectively compare the assessment of comorbidities, investigations, and treatments between MISSION SAAC patients and standard outpatient care.The primary objectives of this study are as follows:To assess whether asthma control , health care utilization, and short-acting beta-agonist (SABA) usage) is improved in MISSION SAAC patients compared with patients undergoing standard outpatient secondary asthma care at 6 months.To assess whether asthma control  is improved in MISSION RAAC patients compared with those who were eligible for MISSION but did not attend.To assess whether asthma control  is improved after attending the MISSION RAAC and SAAC.To conduct a prospective qualitative study exploring patients’ experience, understanding and perceptions of their asthma as well as views on MISSION.To explore the acceptability of MISSION as a service model for patients, staff, and the NHS.To retrospectively compare a clinical case finding approach in primary care with a computer-assisted interrogation on primary care records.To assess the health economic impact of the MISSION service.To phenotype patients with uncontrolled or severe asthma in primary care and gain more information about the asthma population in Wessex.To assess whether asthma comorbidities are assessed in standard outpatient care.To assess waiting times and times to specialist referral in MISSION and standard outpatient care.A mixed methods observational study evaluating the new service, comparing outcomes before and after the intervention, and including a control arm of patients not exposed to, but eligible for, the new intervention is included. This will include analyses of the MISSION participants (attending both the RAAC and SAAC clinics), patients from the existing asthma service (from outpatient severe asthma clinics), and data from patients on GP records who were eligible to attend MISSION but did not (primary care patients). Finally, qualitative methods will be used to explore participant and health care professionals’ views on MISSION. The MISSION Severe Asthma project has not been designed as a randomized controlled trial (RCT) but designed to evaluate a novel service model (the intervention) in participants with uncontrolled and potentially severe asthma, to assess whether it is deliverable and acceptable by participants and health care professionals, and to explore the barriers that would need to be addressed before a larger RCT.A patient advisor reviewed all patient-facing documentation for the study and will give advice and feedback on the structure of the qualitative interviews.Participants with uncontrolled or potentially severe asthma were identified from GP records by the MISSION team and new referrals to an asthma specialist clinic at Queen Alexandra Hospital between May and August 2014.Study participants for qualitative interview will be recruited from patients who attended MISSION SAAC days and staff who attended MISSION RAAC or SAAC days. Qualitative one-to-one interviews will be held over the telephone.Data for quantitative analysis will be collected from records made by the clinical team during the MISSION RAACs and SAACs and asthma outpatient clinics. GP records will be entered as usual by the GP. No extra data will be collected.The participant must meet all of the following criteria to be considered eligible for the study:Male or female, aged 18 years or older.Is in one of the following population groups:Attended the MISSION RAAC orAttended the MISSION SAAC orIdentified as uncontrolled asthma by record searches and invited to the MISSION RAAC but did not attend “primary care patients” orHas been referred to the specialist asthma clinic at Queen Alexandra Hospital “outpatient severe asthma patients” orAttended the MISSION RAAC or SAAC as a health care professionalParticipant is willing and able to give informed consent for participation in the study.The primary endpoint is asthma control as measured by exacerbation frequency .SABA use measured by the number of inhalers prescribed in 6 months pre- and post-MISSION or outpatient clinic.Exacerbation frequency  in 6 months pre- and post-MISSION or outpatient clinic.Health care usage costs for asthma and number of contacts  over 6 months pre- and post-MISSION or outpatient clinic.Assessment of comorbidity  and method of assessment.Assessment of inhaler technique and recommendations for inhaler devices.Smoking cessation advice.Investigations performed during 6 months in secondary care, for example, full lung function, sputum induction, and performing a high-resolution CT scan of the chest.Time from GP referral to first clinic visit in secondary care.Time between first and second visit in secondary care.Time to appointment with other specialists for asthma-related comorbidity where indicated, for example, dietician, ENT, physiotherapist, psychologist, and CT imaging.Assessment of eosinophilic airways inflammation through measurement of fractional exhaled nitric oxide (FeNO).The frequency of nonattendance at clinic.SABA use measured by the number of inhalers prescribed in 6 months pre- and post-MISSION clinic.Exacerbation frequency  during the 6 months pre- and post-MISSION.Frequency and severity of comorbidities.Frequency and type of allergy.Measurement of exhaled nitric oxide.Measurement and variation of lung function.Frequency and type of additional asthma control medication.Disease control and quality of life as assessed by ACQ and Asthma Quality of Life Questionnaire (AQLQ).Number of patients having measurement of forced expiratory volume in 1 second (FEV1)÷forced vital capacity (FVC) as a proxy for asthma control and severity.Prescription of SABAs during last 6 months at baseline and 6 months.Exacerbation rates  during the last 6 months at baseline and 6 months.ED attendances, OOH contacts, and hospital admissions during the last 6 months at baseline and 6 months.Inhaled steroid doses and usage.Number of patients having measurement of FEV1÷FVC as a proxy for asthma control and severity.The sensitivity and specificity of the PRIMIS  Asthma Audit Tool in identifying the patients compared with gold standard specialist assessment and interrogation of primary care records.All patients from the RAACs and all primary care patients will be approached for consent to use their anonymized data from the MISSION clinics or from GP records for research purposes. No extra data for research purposes will be collected for the quantitative analysis from patients at MISSION assessments, asthma outpatient clinics, or GPs.All patients who attended MISSION SAACs will be approached to take part in qualitative one-to-one telephone interviews.Health care professionals who worked at the MISSION clinics from both primary and secondary care will be approached for qualitative interview. All health care professionals will be approached with an estimated 10 to be interviewed from primary care and 10 from secondary care. They will be contacted by email or telephone and, if interested, they will be sent a written information sheet by email or post. They will also be given contact details if they have any further questions regarding what is required to take part. If willing to take part, they will be sent a consent form to fill in and return to the study team.All patients who attended the MISSION RAACs (quantitative) and SAACs  will be contacted by telephone to discuss the study and then, if they are interested, will be sent a patient information sheet (PIS) and consent form with a covering letter.If the patient is unable to be contacted by telephone, they will be sent a covering letter from the MISSION team inviting them to take part in the study. They will be provided with a number to contact if they have any questions. They will be given the opportunity to read the PIS, and if they agree to take part in the study, they can return the consent form by post in a stamped addressed envelope.Patients in primary care will be contacted as described above.Patients who attended outpatient clinics as new referrals in June and July will be approached by telephone after being identified from the clinic attendance list. If the patient is willing, they will be sent a PIS and consent form to send back to the study team in a stamped addressed envelope.Health care professionals who attended the MISSION RAACs or SAACs will be contacted by email or telephone to explain the study and then sent a PIS by email or post if they are interested in taking part. They will be given time to read the PIS, and if they wish to take part, they will be asked to return a consent form in a stamped addressed envelope.Retrospective notes review at 6 months after the MISSION clinics will be performed to collect the following data. Data collected by study group are detailed in Retrospective notes review at 6 months after the MISSION clinics will be performed to collect the following data for MISSION SAACs and asthma outpatients. The clinical record form used for the MISSION SAACs is shown in Where information is not written in medical notes or clinic letters, it will be marked as not assessed. Information will include the following:Medical history including asthma history, asthma triggers, allergy history, past medical history, family history, and occupation.Lung function including peak flow, FEV1, FVC, transfer factor of the lung for carbon monoxide, CO transfer coefficient, and FeNO.Medication history including asthma and non-asthma medication.Exacerbation history including number of steroid courses, hospital admissions, and intensive treatment unit admissions.Health care usage including nonroutine GP attendances, OOH contacts, and ED attendances in 6 months pre- and post-MISSION SAAC or outpatient clinic.Allergy testing results and whether done.Smoking status, and if current smoker, whether any smoking cessation advice or referral was done.Inhaler technique—whether checked, any improvements made, and recommendations for inhaler devices.Investigations performed and time in days after first visit.ACQ score.AQLQ score.Sino nasal outcome test-22  score.Epworth sleepiness score .Hospital anxiety and depression scale score.Nijmegen (assessment of hyperventilation syndrome) score.Gastroesophageal Reflux Disease Questionnaire  score.Time of GP referral, first clinic visit, and second clinic visit.Time of referral and appointment with other specialities, for example, ENT, dietician, and physiotherapy.Lung function including FEV1, FVC, peak flow, and FeNO.ACQ and AQLQ at baseline, 3 months, and 6 months in MISSION RAAC patients.Medication history for the last 12 months.Exacerbation history for the last 12 months.OOH, hospital, and emergency department attendancesThe target population for the qualitative telephone interviews is all of the 20 patients who attended the MISSION SAACs. All patients in this group will be approached for an interview. Participants from MISSION SAACs who are taking part in qualitative interviews will have 1 telephone interview as part of this evaluation research study.Interviews will be arranged at a mutual date and time of convenience. The researcher will make the telephone calls to minimize costs to the participants and facilitate audio recordings. Interviews will be held in a semistructured manner using a topic guide with relevant prompts. This will allow patients to focus discussion on the issues important to them and hear their experiences and views in their own words with free discussion guided by the patient.The areas explored will include the patients’ perceptions, understanding, fears, and concerns about their asthma as well as their views on MISSION—problems, barriers, and positive experiences. The interview will explore asthma and asthma service delivery.The topic guide will be developed in conjunction with the payment protection insurance advisor.Telephone interviews will also be held with medical staff from both primary and secondary care who worked at the clinics. The anticipated number of participants will be 10 from primary care and 10 from secondary care. All staff who attended the MISSION clinics will be approached for consent. The interviews will explore the health care professionals’ thoughts on MISSION and its strengths and weaknesses as well as any suggestions for improvement. The interviews will also explore the health care professionals’ understanding and training in severe asthma and any areas where they would wish to see improvement.The semistructured interviews will be conducted by telephone and audio-recorded with notes taken. Telephone interviews have been chosen as participants live over a wide geographical area, and it will allow flexibility with interview times to accommodate participants’ work and other commitments.The interviews will be conducted by one of the health care professionals involved in the clinic. By having an existing relationship with the study participants and by the interviewer being a health care professional, the participant may be more willing to share experiences and personal views ,8. The rAt the beginning of the interview, patient participants will be reminded that the interview topic guide can be deviated, that they are free to suggest topic areas relevant to their experience and tell their experiences in their own words, and that there are no right or wrong answers but to share with the interviewer their thoughts, both the positives and negatives about MISSION, living with asthma, and asthma care.There is also a concern that the patient participants may raise health questions or ask for health care advice. This will be addressed by explaining at the beginning of the interview that the interview is not a clinical consultation; however, any questions can be answered at the end of the interview.The interviews will be digitally audio-recorded and transcribed by a professional transcription company. The data will be entered into a software program to facilitate qualitative analysis  Ltd, London, UK). All participants’ names will be removed from the transcripts to retain confidentiality. When writing the results, no quotes will be directly attributed to participants. Participants will be given the opportunity to read and approve the transcript. The transcript will be sent to participants, and if no response is heard within 2 weeks, the transcript will be included in the analysis.The results from the interview will be analyzed using a thematic and framework analysis, which uses a 5-step approach to analyzing and writing up data . This inThe interviews will take between 45 min to 1 hour to complete depending on what the participants share with the interviewer. The interview can be terminated at any point the participant wishes to stop, and this will not influence their subsequent treatment.The study was powered to show a difference between the MISSION group and the primary care group for the primary outcome, exacerbation frequency. The sample size was based on an analysis of covariance (ANCOVA) approach, with the outcome being exacerbation frequency in the second 6-month period and with the exacerbation frequency in the first 6-month period being the covariate. Baseline data suggest a mean number of exacerbations for this group of 1.29, with an SD of 1.30. There is expected to be no change in exacerbation frequency between time periods for the primary care group, whereas it is anticipated that exacerbations in the MISSION group may reduce by 50% to 0.65 exacerbations. A correlation between the exacerbation rates in the 2 time periods of 0.5 is assumed. The primary care group will be larger, with an anticipated 3:1 ratio. To show a difference between groups with a 5% significance level and 90% power, it is calculated that 44 subjects in the MISSION group and 132 in the primary group are required.All data collected will be analyzed. There will be an analysis of the MISSION and outpatient groups separately. We will analyze 4 groups of participants: (1) qualitative assessments in participants attending the severe clinic, (2) health professionals attending either of the rapid or severe clinics, (3) quantitative assessments between those attending the rapid clinic in primary care to those invited but did not attend, and (4) those who attended the severe clinic compared with those routinely attending the outpatient severe asthma clinics in hospital.The analyses will compare the study outcomes between the 4 study groups.The primary outcome is exacerbation frequency. This outcome will be analyzed using ANCOVA, with the outcome variable being exacerbation frequency in the second 6-month period and the exacerbation rate in the first 6-month period treated as the covariate. Owing to the likely skewed distribution of the exacerbation frequency, it may be necessary to perform a log transformation of the outcome before analysis. Comparisons will be made overall between the 3 groups, and specifically between the MISSION group and each of the other 2 groups.The analysis of secondary outcomes measured on a categorical scale during the second 6-month period will be compared between groups using Fisher exact test. Continuous variables will be compared between groups using analysis of variance, if found to be normally distributed, or the Kruskal-Wallis test, if not found to be normal.Comparisons between groups will also be made accounting for the values during the first time period. ANCOVA will be used for continuous variables, whereas logistic regression will be used for binary outcomes.Participants may withdraw at any point in either the qualitative or quantitative aspects of the study.The end of study is the date of the last qualitative interview of the last participant.All data collected will be included in the analysis.The study will analyze observational data retrospectively, and so we do not anticipate any significant deviations as would be expected in a longitudinal study.No interim analyses will be performed.Patient volunteers and patients who have taken part in the qualitative interviews will be invited to help with dissemination events. The results will be submitted for presentation at national conferences. There will also be reports on the Wessex Asthma Network website for patients and public to access . All stuThe MISSION team screened GP records to identify uncontrolled asthmatics to invite to MISSION clinics. There were 369 patients identified who had one or more of the criteria that suggest uncontrolled or potentially severe asthma  , 2 or more exacerbations in the last 12 months requiring steroids for more than 3 days, any hospital, ED or OOH contact in the last 12 months, and high SABA usage—>6 inhalers in the last 12 months or reduced lung function FEV1 ≤70%). All patients who were identified were approached for the MISSION project.The MISSION service: The searches identified 1436 patients who were manually reviewed by the MISSION team and 460 patients met the criteria. All these patients were invited to the clinic; 125 were booked in, and 84 attended the RAACs, of whom 22 were identified for the SAACs.All patients identified by the GP search but who did not attend the MISSION clinics will be approached for the study to maximize the chance of getting the same number of participants to the number who consents from the MISSION group.The severe asthma outpatient clinic at Portsmouth Hospitals NHS Trust sees 16 new referrals per month. The sample will be matched to the same as the number of patients attending the SAACs, that is, 20 patients. All new referrals to the asthma clinic who meet the inclusion criteria will be included until the sample size is reached.All 20 patients from the MISSION SAACs will be approached for a qualitative interview. Furthermore, all clinical staff who attended the MISSION RAACs or SAACs will be approached for an interview with an anticipated number of 10 interviewed from primary care and 10 from secondary care.The clinical intervention has been performed and the study has been ethically approved by the Yorkshire & The Humber-Leeds East Research Ethics Committee (Reference 15/YH/0136) and sponsored by Portsmouth Hospitals NHS Trust. The results will be reported in February 2020.


Objective: We report one case of malignant high blood pressure with no systemic signs but with ocular complaints.Methods: The paper presents the case of a 31-year-old male who complained of sudden loss of visual acuity in both eyes. The ophthalmological examination revealed bilateral papillary oedema. General and cardiological examinations revealed he was suffering from malignant high blood pressure. Results: The pathogenic treatment resulted in resolution of signs and symptoms with favourable ophthalmological evolution and almost entirely functional recovery. Clinical, paraclinical and imagistic data suggested the diagnosis of pheochromocytoma.Conclusion: This case highlighted ocular complications of high blood pressure. The paper summarizes the differential diagnosis and management of high blood pressure and reviews the most common causes of secondary hypertension in young patients.  In Romania, there are no studies regarding the prevalence of hypertensive neuroretinopathy, but, doubtless, their existence would be necessary.High blood pressure is a major cause of worldwide mortality. According to SEPHAR study, the prevalence of primary and secondary high blood pressure in Romania is 40% [2]: There are three important factors that play a key role in hypertensive retinopathy pathogenesis [Vasoconstriction:- 3]. Arteriosclerosis is irreversible and does not regress under treatment. It occurs both in young individuals and in the elderly, who suffer from pre-existing vascular involutional sclerosis.o The first response of retinal arterioles to increased blood pressure is the narrowing of the lumen (vasoconstriction), which is proportional to the severity of hypertension. Over time, elevated pressure damages vascular endothelium. Degeneration of smooth muscle fibers in the vascular wall leads to breaks and leakage of plasma into the vessel wall; plasma clotting within the vessel wall produce mural thickening and luminal narrowing, process called fibrinous necrosis :o Switching from hypertensive angiopathy to retinopathy is confronted with rupture of the blood-retinal barrier. The blood-retinal barrier consists of vascular endothelial cells and pigmented epithelial cells connected by tight junctions that form a selective barrier, restricting ions transfer, substrate and water permeability, allowing a proper neuronal function. Therefore, there are two components [- Inner barrier  – tight junctions between capillary endothelial cells- Outer barrier  – tight junctions between pigmentary epithelial cells5-7]:o In hypertensive retinopathy, the outer barrier is spared, while the inner barrier is not. It is responsible for . They are superficial, perivascular and respect the macula.• Cotton wool spots – areas of ischemia in the nerve fibre layer. Ischemia to the nerve fibres leads to decreased axoplasmic flow, nerve swelling and ultimately fluffy opacification . The presence of papillary oedema is manifested by the decrease of the visual acuity and requires immediate antihypertensive treatment.- Papillary oedema – due to leakage and ischemia of arterioles supplying the optic disc that undergo necrosis. The ischemia causes swelling and blurred disc margins and the leakage causes peripapillary haemorrhage and disc oedema [8] of retinal manifestations in high blood pressure:Classification [1. Hypertensive angiopathy – includes angiosclerosis with its four stages (it may pre-exist in elderly)6]:Retinal angiosclerosis . Patient evaluation begins with visual acuity testing and examination of the anterior and posterior segment using the biomicroscope. An optical coherence tomography (OCT) is necessary in order to evaluate the severity of retinal damage. Also, a fluorescein angiography could be necessary to discriminate between ischemic macular disorders, which cannot be evaluated by OCT, and non-ischemic macular disorders. Finally, a complete anamnesis and referral to other medical specialities, like cardiology, endocrinology, internal medicine, etc. is essential.Patients are generally asymptomatic in early stages and have bilateral ophthalmoscopic changes. If papillary and macular oedema occurs, in later stages, the patient complains of visual acuity loss [4].Differential diagnosis includes diabetic retinopathy, retinal vein occlusion, anaemia, syphilis, irradiation retinopathy and papillary oedema caused by intracranial high pressure [5].The treatment’s purpose is an optimum diet and weight, a normal value of the blood pressure by referral to the cardiologist and regular ophthalmoscopic examinations to follow retinal changes [9]. Ophthalmologic prognosis depends on the evolution of the underlying disease. High blood pressure can induce numerous retinal severe complications: retinal vein occlusion, retinal artery occlusion, retinal aneurysms, decrease of visual acuity in time due to lesions in the optic nerve and macula. Also, high blood pressure can determine: intravitreal bleeding, oculomotor paralysis by stroke, horizontal diplopia due to sixth nerve palsy caused by stretching of one or both abducens nerves over the petrous tip because of the papillary oedema or hemianopathic deficiencies by affecting intracranial optic nerves pathways [6].Without treatment, the general prognosis is difficult to assess, because a number of systemic complications may occur over time: stroke, acute myocardial infarction, heart failure, rhythm disorders , chronic kidney disease, peripheral vascular disease [5].The ophthalmological prognosis is good with the treatment of the high blood pressure, although the general prognosis remains uncertain .• Retinal vein occlusion – due to the presence of retinal haemorrhages in the context of an acute condition. It cannot be excluded, being frequently associated. It should also be noted that in retinal vein occlusion, the outer barrier is affected, leading to neurosenzorial retinal detachment. Due to that, if the neurosenzorial retinal application occurs after medical treatment, the diagnosis of hypertensive retinopathy is supported at the expense of retinal vein occlusion . Based on the confirmation of adrenal gland nodule, the patient was suspected of pheochromocytoma. Further blood tests and imagistic investigation were needed in order to assess the certain aetiological diagnosis. The patient was followed-up further by the endocrinologist and cardiologist.The differential diagnosis of the aetiology is between essential and secondary high blood pressure. Secondary high blood pressure can be caused by numerous diseases, such as renal artery stenosis, parenchymal kidney disease, coarctation of the aorta, pheochromocytoma, hyperaldoseronism, etc. .Regarding the frequency, it was noted in literature that the low incidence of pheochromocytomas in the hypertensive population was estimated at 0.1%-1%; only 10% of them appearing in young people, the rest being diagnosed starting with the 5th decade [We noticed many case particularities such as the following:• Young age of high blood pressure debut• The ocular complaints have led to medical presentation, although high blood pressure is a systemic disease • The correct and complete diagnosis required a multidisciplinary management • Patient nonadherence to the antihypertensive treatment prescribed before ophthalmological initial presentation led to the appearance of ocular complications of high blood pressure • Poor patient compliance, as he refused MRI investigation due to anxious syndrome, had an unfavorable impact on etiological diagnosing • Patient had a favorable evolution under antihypertensive treatment with quasi-integral functional and structural ophthalmological recovery• Further medical evaluation is needed to assess if there are any other complications of high blood pressure


Hypertension is a rapidly growing problem in developing countries. At the same time, due to its asymptomatic nature, the afflicted population is largely unaware of being hypertensive. Due to a lack of resources, routine medical exams are very rare in developing countries and many sick individuals remain undiagnosed. Using a large sample of hypertensive individuals from Indonesia, we show the importance of being diagnosed. Diagnosed individuals exhibit lower systolic and diastolic blood pressure, and overall lower probability of remaining hypertensive than undiagnosed individuals. We also show the main channels through which this is achieved: taking medication, routinely monitoring one’s blood pressure, and engaging in moderate physical activities. We also point to channels through which additional benefits could be realized, but that are currently ineffective: dietary changes and maintaining a healthy body weight. Combined, these results point to the importance of directing public policy towards addressing the under-diagnosis problem and educating the public of the benefits of adopting a healthy life-style. Periodic health screening is a routine that most people living in developed economies have grown accustomed to. Medical professionals everywhere recommend routine screenings that can discover chronic diseases in their infancy and allow for adequate interventions to be formulated and prescribed. However, due to a multitude of socio-economic deficiencies, this practice is less common in underdeveloped or developing economies. Due to a general lack of resources, routine medical exams are very rare in developing countries. Furthermore, due to a historical struggle to fight infectious diseases, many health care providers and even governments in developing countries are underestimating the severity and prevalence of chronic diseases. This leads to extremely high rates of chronic diseases under-diagnosis, which can further lead to more serious health problems and ultimately increase mortality rates.The problem is even more pronounced for asymptomatic health conditions, such as hypertension. Hypertension can go unnoticed for years, but can have major and even fatal consequences if left untreated. Elevated blood pressure is a major risk for coronary heart disease and can lead to stroke and organ damage while being either symptomatic or asymptomatic . The WorUnder-diagnosis has been linked to a variety of possible causes like socio-economic indicators such as income and education, community characteristics and infrastructure, and even individual risk and time preferences  3] 4]. [4].3] [. [4].3] We argue that meaningful empirical studies addressing this issue should be more narrowly defined and more carefully constructed from a theoretical perspective. The theoretical benefits of screening and diagnosis are primarily informational and by itself diagnosis does not improve outcomes. But when treatments are available, the diagnosis information can further work towards improving one’s health through two distinct channels which can be loosely referred to as professionally directed treatment and self-directed treatment. By professionally directed treatment we mean to include things like medication, medical interventions, and things that generally require the assistance of a health-care professional. By self-directed treatment we mean to include things like adopting a better diet, quitting smoking and drinking, and other life-style changes that a health-care professional might recommend but that are ultimately personal choices that generally require a significant behavioral effort. When discussing the effect of diagnosis on health outcomes it is therefore important to evaluate the existence, efficacy, and cost for both types of treatments, which implies that different health conditions might present extremely different results. We might not observe the desirable effects when looking at mortality rates of a hard to cure condition or when considering the incidence of smoking, which is highly addictive and hard to quit. But we might observe such effects with other health issues that are easier to address.For the case of hypertension, it is generally cheap to both screen and diagnose it and also to treat it or at least control it using a variety of available medication. Hypertensive patients are also recommended to maintain a normal body weight, engage in moderate physical activities, change their diets, and limit the intake of certain substances like alcohol or sodium . HoweverUsing recent data from Indonesia, we estimate significant benefits of screening and diagnosis on the prevalence and severity of hypertension. Hypertensive patients who are diagnosed are more likely to take medication, engage in routine blood pressure checks, quit smoking, and engage in moderate physical activities. While major life-style changes prompted by diagnosis are somewhat limited and do not include healthier dietary changes, diagnosis has a clear beneficial role on lowering both systolic and diastolic blood pressure, and ultimately reducing the incidence and severity of hypertension.In order to estimate the effects of being previously diagnosed on later blood pressure, we use data from the Indonesia Family Life Survey (IFLS). IFLS is a large longitudinal survey spanning over 20 years and containing a representative sample of Indonesian households. IFLS collects a vast number of demographic and socio-economic indicators at the individual, household, and community level. For our study, we use data from the latest IFLS wave, which was fielded in 2015. The data used is fully anonymized, survey data, made publicly available by the Rand Corporation. IRB approval was obtained both at Rand and in Indonesia when the surveys were fielded.As part of collecting health data, trained nurses took the blood pressure of all IFLS respondents 15 years or older. These blood pressure measurements were taken three times. We dropped the first measurement in order to alleviate measurement errors due to respondents’ nervousness, then took the average of the last two measurements to construct our systolic and diastolic blood pressure variables. Using these blood pressure measurements, we assembled our sample by including all respondents who according to the WHO definition can be classified as hypertensive. In addition to this, we added to the sample those respondents who were previously diagnosed as hypertensive and those respondents who were found taking hypertension medication at the time of the survey, even though their measured blood pressure would not qualify them as hypertensive. The reasoning is that medication or other types of treatment following diagnosis might bring blood pressure to normal levels, but these patients are still hypertensive. All the patients were asked if they had been previously diagnosed with hypertension by a medical professional.Our sample contains 7585 hypertensive individuals between the ages of 15 and 103, out of which only 3242 were previously diagnosed with hypertension. That implies about 57% of the hypertensive individuals were not aware of their condition. This under-diagnosis rate figure is quite high but in line with previous findings from the literature. The raw IFLS sample contains more hypertensive respondents than reported here, but some contain missing information and cannot be used in our regression analysis. We only report here the full sample of individuals for which all the information is available and can be used in the regression analysis. Diagnosisi is an indicator variable equal to 1 if respondent i has been diagnosed with hypertension in the past and 0 oherwise, Xi represents a vector of characteristics specific to respondent i, and εi is the error term that is assumed to be uncorrelated with the diagnosis status.Our outcome variables will be the two blood pressure measures (systolic and diastolic) and an indicator variable that takes value 1 if the respondent is currently hypertensive according to the WHO definition (140 mm HG systolic/90 mm Hg diastolic), and 0 otherwise. While it may seem redundant to report both the hypertensive status and the systolic/diastolic blood pressures separately, these measures can tell different stories. Heart attack risks for instance are more closely related to the systolic numbers, and isolated systolic hypertension can be quite common. We then estimate the effect of having been previously diagnosed on these current measures of health status, while controlling for a series of individual specific socio-economic and health characteristics. For each of the aforementioned 3 blood pressure measures, we hence estimate the following equation:Xi, we use respondent’s age and age squared (to account to possible non-linearities with respect to age), respondent’s years of formal education, the log of per capita expenditures (logPCE) to proxy for household income, an indicator for being overweight, an indicator for poor general health status, and an indicator for sex. Bound and Krueger [As control variables that are included in the vector  Krueger  show thaNote that some previous research shows an association between height and hypertension  and betwEstimating these equations will yield the association of a prior diagnosis with current health outcomes. However, as argued before, the diagnosis is merely informational and does not treat the affliction by itself. It needs to be followed by treatment. In order to see the channels through which potential health improvements are realized, we estimate the effect of a prior diagnosis on a series of potential courses of treatment and control. We want to see if a prior diagnosis leads to taking medication, increasing engagement in physical activity, changing ones dietary habits, reducing body weight, quitting smoking, etc. These equations are similar with the main equation involving the blood pressure measures and are explained in more detail in the results section.First, we estimated the effect of a prior diagnosis on the probability of currently being hypertensive. We coded an indicator variable as 1 if the individual was considered hypertensive according to the WHO definition during the 2015 survey and 0 otherwise. We then estimated this equation using a linear probability model and reported the effects in the second column of Second, we estimated the effect of a prior diagnosis on systolic and diastolic blood pressure directly. These effects are presented in columns 3 and 4 of Interestingly, the effects of education and per capita expenditures (which proxies for income) are mostly insignificant. Socio-economic indicators such as education and income are often cited in the literature as important determinants of health. The lack of statistical significance in our estimates does not invalidate their importance, but rather points to the main channel through which socio-economic factors affect health. At least when it comes to hypertension, it seems that education and economic well being mostly work through screening and diagnosis. Individuals with higher education and incomes are more likely to engage in screening and prevention and are therefore more likely to be diagnosed and treated for hypertension, which results in overall better health. The fact that income in particular has virtually zero direct effect on blood pressure is also most likely due to the fact that hypertension treatment is generally cheap and so once diagnosed, economic factors are not a barrier for getting treatment. As a direct policy recommendation, this implies that public spending should be mainly directed towards improving diagnosis rates. It is very likely however, that for other health conditions there might be additional direct effects of socio-economic status, especially so for health conditions where treatment is expensive. In such cases, spending on treatment, in addition to screening, might prove beneficial and even preferred.To further investigate any potential differential impacts across demographic groups, we disaggregate the sample by gender and age and report the results of these estimations in The results of these disaggregations are qualitatively in line with the full-sample results. A prior diagnosis leads to lower incidence of hypertension in both men and women, and in both young and old. A few interesting differences in magnitudes do emerge however. Men seem to benefit from a prior diagnosis slightly better than women, while the young benefit significantly more than the old. The coefficient for the below 40 years of age sub-sample is more than double in magnitude than the coefficient for the 40 and above sub-sample.Our next efforts go towards investigating the responsible channels of disease treatment and control. As mentioned before, diagnosis itself has a simple informational role. How this information is actually used is important in understanding health patterns and eventually formulating policy. At the health care provider level, hypertension is relatively easy to get under control using a variety of prescription medication. At the individual level, hypertension can further be managed through a series of life-style changes. Patients are advised to maintain a healthy body weight, engage in moderate physical activity, reduce the intake of alcohol, saturated fat and salt, and closely monitor their blood pressure. Some of these life-style changes are costlier than others, and so we want to investigate which ones are actually followed through by diagnosed patients.To answer these questions, we perform a series of additional regressions that estimate the effect of a prior diagnosis on a variety of variables that can lead to lower blood pressure. The results in On the other hand, there do not seem to be any major dietary changes after being diagnosed. We do not have precise data on the consumption of saturated fat or salt, but we proxy it with fast food and soft drinks consumption. Diagnosed respondents do not consume less fast food and soft drinks than undiagnosed ones, nor do they present any statistically significant differences in terms of BMI or being overweight. Note that Indonesia is a predominantly islamic country, and so alcohol consumption is not something that we can meaningfully investigate. A possible explanation for the lack of a statistically significant effect on dietary habits and BMI is the interplay between BMI and social status in developing countries. Previous studies  do indeeA direct policy implication of these results is that the public health education programs and the health care professionals who diagnose hypertensive patients should stress more the importance of a healthy diet and maintaining a healthy weight, as patients can realize additional benefits in terms of disease management through these channels. Even more so, stressing the additional benefits of all life-style factors can further enhance disease management and should be pursued through public policy. Even though diagnosed patients seem to be responsive in terms of smoking, physical activity, and monitoring their blood pressure regularly, this responsiveness seems to be pretty low overall, and much lower than the medication responsiveness. While diagnosed patients are 25.9% more likely to take medication than undiagnosed ones, they are only about 10% more likely to quit smoking and check their blood pressure regularly and only 3.6% more likely to engage in physical activity. These results are to be expected given the low cost of medication and the high cost of hard-to-make life-style changes, but they are far from ideal from a population health perspective. If we assume that all patients who are prescribed medication are also advised to adopt certain life-style changes, but some mildly hypertensive patients might only be encouraged to these changes without being prescribed medication, we would ideally like to see the magnitudes of these effects reversed.Using a large sample of hypertensive respondents from a longitudinal data set in Indonesia, we estimated the effect of a prior hypertension diagnosis on current incidence and severity of hypertension. We found that screening and diagnosis has significant positive effects and results in a lower systolic and diastolic blood pressure and in a lower overall incidence of hypertension. These results are contrary to the strand of literature that is arguing that screening and diagnosis are often ineffective and/or much more expensive than treatment. We argue that the role of diagnosis is purely informational and it is therefore essential to distinguish between different types of afflictions when performing such studies. Since different health problems have different available courses of treatment, the effects of a prior diagnose on current or future health outcomes are highly dependent on the availability and overall cost of these treatments.We also investigated the channels through which hypertension diagnosis leads to lowering blood pressure and found medication to be the most important one. Some patients who are diagnosed are prescribed medication which then directly leads to lower blood pressure. We also found modest but significantly higher rates of certain life-style changes among diagnosed patients. Being diagnosed results in less smoking, more physical activity, and more regular monitoring of blood pressure. On the other hand, we found no significant effects on diet, BMI, and overweight status. We find these results as expected, since hypertension medication is relatively cheap, while life-style changes are often hard and costly to adopt. An interesting avenue for future research might be to consider the role of mental health and social interactions in managing hypertension. Arguably there is quite a bit of interplay between these and maintaining healthy dietary habits, smoking, and even exercising. For instance, Bustamante et al.  find thaThat being said, given the extent of the medical literature that documents the importance of such life-style changes in managing hypertension, we argue that these should be first order items on the agenda of public policy as it relates to public health. Our overall results suggest dedicating resources both towards improving diagnosis rates and also towards education regarding the importance of adopting a healthy life-style and not only relying on medication.As developing countries go through a health transition, from dealing mainly with infectious diseases to dealing mainly with chronic diseases, large countries like Indonesia or China have seen rapidly rising rates of hypertension among their populations. At the same time, due to the asymptomatic nature of hypertension and to a lack of resources and established medical routines, much of the afflicted population is not diagnosed and are largely unaware of being hypertensive. Given our results, it is therefore imperative for public policy in such countries to dedicate more resources towards addressing the under-diagnosis problem and educating the public on how to adopt a healthy life-style in the face of a rapidly changing economy.


To develop human space exploration, it is necessary to study the effects of an isolated and confined environment, as well as a microgravity environment, on cerebral circulation. However, no studies on cerebral circulation in an isolated and confined environment have been reported. Therefore, we investigated the effects of a 14-day period of confinement in an isolated environment on dynamic cerebral autoregulation.We participated in an isolation and confinement experiment conducted by the Japan Aerospace Exploration Agency in 2016. Eight healthy males were isolated and confined in a facility for 14 days. Data were collected on the days immediately before and after confinement. Arterial blood pressure waveforms were obtained using a finger blood pressure monitor, and cerebral blood flow velocity waveforms in the middle cerebral artery were obtained using transcranial Doppler ultrasonography for 6 min during quiet rest in a supine position. Dynamic cerebral autoregulation was evaluated by transfer function analysis between spontaneous variability of beat-to-beat mean arterial blood pressure and mean cerebral blood flow velocity.Transfer function gain in the low- and high-frequency ranges increased significantly  after the confinement.The increases observed in transfer function gain may be interpreted as indicating less suppressive capability against transmission from arterial blood pressure oscillation to cerebral blood flow velocity fluctuation. These results suggest that confinement in an isolated environment for 14 days may impair dynamic cerebral autoregulation.UMIN000020703, Registered 2016/01/22. For human space exploration, orthostatic intolerance after spaceflight , 2 and vTherefore, in the present study, we investigated the effects of confinement in an isolated environment for 14 days on dynamic cerebral autoregulation using transfer function analysis.We participated in an isolation and confinement experiment conducted by the Japan Aerospace Exploration Agency (JAXA). The protocol was approved by the Institutional Ethical Committee of Nihon University School of Medicine (27-7-0-1) and JAXA (79-4-1). We investigated eight healthy males . Written informed consent and medical histories were obtained from all participants before the study began. All participants were screened in regard to their medical history and given physical examinations, including blood pressure measurement. Additional screening included an electrocardiogram (ECG), a psychological test, and an interview. None of the participants had any known medical problems or a history of recreational drug use.The participants were isolated and confined for 14 days at the “Confinement Environment Adaptation Training Facility” in Tsukuba Space Center. This facility, the details of which have been described by Inoue et al. , consistThe following restrictions were placed on the participants in the facility. Participants were requested to refrain from leaving the facility or engaging in recreational activities such as drinking alcohol and smoking; communication was limited to telecommunication with researchers in the control room; and meals basically consisted of preserved foods that mimicked astronaut foods. In addition to predetermined daily schedules, several group and personal tasks were assigned, including previously reported tasks simulating the selection of astronaut candidates . No exer2) was measured using pulse oximetry . Continuous arterial blood pressure waveforms were obtained noninvasively in the middle finger using photoplethysmography  at the heart level on a beat-to-beat basis. The absolute value of arterial blood pressure was measured at heart level via intermittent arterial blood pressure measured using the oscillometric method with a cuff sphygmomanometer placed over the right brachial artery . Cerebral blood flow (CBF) velocity waveforms in the middle cerebral artery were obtained continuously by transcranial Doppler (TCD) ultrasonography  at a depth of 50–60 mm using a 2 MHz probe. This probe was positioned on the right temporal window and fixed at a constant angle, where the highest CBF velocity and appropriate Doppler signal were obtained. To achieve TCD monitoring with high repeatability, we developed a custom probe holder made of a polymer mold to fit the facial bone structure and ear of each participant [2) and respiratory rate were monitored continuously using capnography by nasal cannula .On the days immediately before and after the 14-day confinement period, data for estimating cerebral circulation were measured while participants were lying in a supine position on a comfortable bed. All participants refrained from engaging in heavy exercise and consuming caffeinated or alcoholic beverages for at least 24 h before the measurements. All measurements were conducted in a quiet, environmentally controlled laboratory at an ambient room temperature of 23–26 °C. Heart rate (HR) was measured using a three-lead ECG, and arterial oxygen saturation  was estimated using the values of intermittent blood pressure measured using the cuff sphygmomanometer. Mean values for steady-state HR and mean CBF velocity (MCBFV) were obtained by averaging the 6-min data segments. SpO6 min of continuous arterial blood pressure and CBF velocity waveforms were used for spectral and transfer function analyses during spontaneous respiration of room air. The beat-to-beat values of MAP and MCBFV were obtained by integrating analog signals with each cardiac cycle using the PC-based Notocord software. The beat-to-beat values of MAP and MCBFV were then linearly interpolated and resampled at 2 Hz. The MAP and MCBFV time series were first detrended with third-order polynomial fitting using a previously validated algorithm , 10. Thet test. A P value < 0.05 was considered statistically significant. Statistical analysis was performed using SygmaStat software .Data are presented as mean ± standard error of the mean. Variables between before and after the 14-day period of confinement were compared using a two-tailed and paired All participants completed the protocol for the 14-day confinement period.2, ETCO2, or respiratory rate.Changes in steady-state hemodynamics and respiratory condition are shown in Table t (7) = − 2.4, P = 0.048; high-frequency t (7) = − 2.4, P = 0.046). The percentage changes of transfer function gain were 30% in the low-frequency range and 14% in the high-frequency range (Fig. Changes in frequency analysis indexes are shown in Table To the best of our knowledge, no previous studies have reported the effects of an isolated and confined environment on dynamic cerebral autoregulation. Therefore, we studied the effects of a 14-day confinement period in an isolated environment on dynamic cerebral autoregulation using transfer function analysis. The main finding of the present study was that the 14-day confinement period resulted in increased transfer function gain in the low- and high-frequency ranges, despite no changes being observed in steady-state MAP or MCBFV. Increased transfer function gain means that transmission from arterial blood pressure oscillation to CBF velocity fluctuation is amplified with less suppressive capability, suggesting the impairment of dynamic cerebral autoregulation after confinement in an isolated environment; this finding was similar to those in previous studies reporting that increased transfer function gain by hypercapnia impairs cerebral autoregulation , 14.Cerebral autoregulation maintains steady-state CBF by adjusting arteriolar resistance in the brain despite changes in arterial blood pressure. Moreover, the ability of a rapid cerebrovascular response to buffer changes in CBF velocity induced by transient changes in arterial blood pressure is referred to as dynamic cerebral autoregulation. In addition to the assessment of steady-state CBF, transfer function analysis allows the dynamic relationship between arterial blood pressure oscillation and CBF velocity fluctuation to be evaluated. Previous studies have shown that several clinical conditions affect dynamic cerebral autoregulation, but not steady-state MCBFV –17. In tA number of studies have reported that confinement in an isolated environment can lead to various psychological and physiological changes . However2 or steady-state MCBFV were found between before and after confinement in the present study, suggesting that the concentration of carbon dioxide inside the facility was not likely to influence the impairment of dynamic cerebral autoregulation.In addition, it is possible that the concentration of carbon dioxide inside the facility could have affected dynamic cerebral autoregulation in the preset study. Generally, exposure to high concentrations of carbon dioxide leads to hypercapnia, which induces increased steady-state CBF and impairs dynamic cerebral autoregulation . HoweverThe main limitation of the present study is that the 14-day confinement period took place in a multi-factorial environment. It is assumed that the 14-day confinement period consisted of some factors that might have affected dynamic cerebral autoregulation. As mentioned above, the present study did not attempt to identify the factors underlying the impairment of dynamic cerebral autoregulation. Another limitation is the small number of participants. Conceivably, some of our results might have been different with a larger study population, implying a type I and/or II error.Another limitation of the present study is that we chose only men as participants for the purpose of simplifying the experimental stress model for confinement in an isolated environment, as some physiological measures, such as cerebral circulation, can be influenced by the menstrual cycle and female sex hormones , 19. TheIt is well known that some astronauts experience orthostatic intolerance upon return to Earth , 2. The The results of the present study showed that transfer function gain in the low- and high-frequency ranges increased after the 14-day confinement period. Increased transfer function gain would indicate that transmission from arterial blood pressure oscillation to CBF velocity fluctuation is amplified with less suppressive capability. Therefore, the present results suggest that confinement in an isolated environment may impair dynamic cerebral autoregulation.


Patients with chronic kidney disease are at higher risk of developing cardiovascular disease. Chronic exposure to intermittent hemodialysis may be a source of added stress to the cardiovascular system; intradialytic hypotension is a common complication of hemodialysis, and repeated events may lead to hemodynamic stress and ischemic injuries. Administration of non-pneumatic compression stockings to the lower limbs has demonstrated hemodynamic stabilizing effects in other settings and may provide similar benefits in the kidney disease population. Therefore, we conducted this pilot study assessing the feasibility and tolerability of the application of non-pneumatic compression stockings to patients with kidney disease. We also assessed the changes in hemodynamic measurements following the application of the compression stockings to explore the biological feasibility of this being an effective intervention for intradialytic hypotension.Fifteen individuals were enrolled in the study . Outcomes including hemodynamic parameters such as cardiac output, peripheral vascular resistance, and blood pressure were measured using continuous pulse wave analysis. Changes in global longitudinal strain were measured via echocardiography. These outcome measurements were made before and after the application of compression stockings.All study participants tolerated the compression garments well and without complication. Hemodynamic response to lower body compression caused varying effects on cardiac output, mean arterial pressure and global longitudinal strain. Some individuals saw large improvements in hemodynamic parameters while in others the opposite effect was observed. No consistent response was elicited.Application of compression stockings to patients with renal dysfunction is well-tolerated. However, significant variations in hemodynamic outcomes exist, and may be a barrier for larger scale trials without prior identification of specific patient characteristics indicating likely benefit from the application of external compression.NCT02915627, Registration Date: Sept 27, 2016.ClinicalTrials.gov, Identifier:  It is well recognized that patients with end stage renal disease (ESRD) requiring intermittent hemodialysis (HD) suffer excess cardiac morbidity and mortality . There aIntra-dialytic hypotension is one of the most common complication of HD treatment, occurring in approximately 20–30% of HD sessions . ClinicaOne such approach to the management of IDH is mechanical augmentation via the application of lower limb compression stockings during dialysis –10. ThesIn contrast to pneumatic compression stockings which provide thigh high intermittent compression, non-pneumatic anti-shock compression garments apply continuous pressure to not only the lower limbs but also upper thigh and abdomen. The ZOEX Non-Inflatable Anti-Shock Garment (NASG) is a specific type of anti-shock garment originally developed from NASA anti-G-force technology which received FDA device approval for management of haemorrhagic shock in 1991. They are a lightweight neoprene garment that is made up of six segments that close tightly with Velcro. This garment is worn on the lower extremities (legs) and applies 20–40 mmHg pressure to the lower body and abdomen.The utility of NASG to raise systemic blood pressure is already well established through work done on obstetrical haemorrhages in remote locations. Two independent groups working in Pakistan report a marked elevation in systolic blood pressure within minutes of application of NASG to patient suffering from obstetrical haemorrhage , 16. LatWe therefore conducted this pilot study to examine the effects of non-pneumatic compression garments on individuals with varying degree of renal dysfunction. Through this small and focused trial. We aim 1) to assess the tolerability of these garments, 2) to examine the hemodynamic effects of these compression garments through continuous hemodynamic monitoring using the Finapres technology, and 3) to assess the feasibility for potential larger scale clinical trials.In this prospective, interventional, pilot study, non-pneumatic anti-shock compression garments were applied to individuals with varying degrees of renal disease. Three groups of participants were analyzed: 1) Healthy participants with no known kidney disease which served as a control group, 2) participants with stage 4 or 5 chronic kidney disease (CKD) not receiving dialysis, and 3) individuals with end stage renal disease currently receiving intermittent hemodialysis.Five patients were recruited for each arm of the study. Healthy participants were recruited via poster board advertisement at London Health Science Centre (LHSC), Victoria Campus, London, Ontario, while CDK patients were recruited from the LHSC CKD clinic based at a community dialysis site. Dialysis patients were recruited from the Victoria Hospital dialysis unit population, also at LHSC.All participants were required to be over the age of 18 and were of both sexes. Healthy participants had no clinical diagnosis of CKD. Non-dialysis CKD patients were required to have diagnosed stage 4 or 5 CKD but were not receiving and had never had any form of dialysis. Dialysis patients were required to be undergoing active intermittent hemodialysis at the time of the study protocol. Participants were excluded if they had New York Heart Association Class IV heart failure, absence of lower limbs or lower limb injury, or individuals with established peripheral vascular disease or clear symptoms of claudication. Additionally, patients who declined participation, were pregnant, or did not meet inclusion criteria were excluded.ZOEX Non-Inflatable Anti-Shock Garment (NASG), supplied by ZOEX NIASC, Coloma, CA, USA were used for all participants of this study. They are a compression garment consisting of 6 segments that close tightly with Velcro that applies a continuous pressure of 20–40 mmHg to the lower limbs and abdomen.The use of the Finometer  in dialysis patients has been described in detail elsewhere  and was On the day of the study visit, participants were subjected to a basic history review and a baseline set of routine vitals were taken to calibrate the Finometer. Patients were weighed, and their current weight was compared against their ideal weight as an estimate of fluid balance  and dialysis participants (D) were weighted on the day of study. This weight was compared to their ideal weight, obtained from their recent nephrology clinic notes. The difference between study weight and ideal weight is intended to provide an estimate to the fluid balance of the study participant on the day of study.


Empagliflozin has been shown to reduce cardiovascular mortality, but the underlying pathogenetic mechanisms are poorly understood. It was previously demonstrated that empagliflozin improved arterial stiffness.http://www.ClinicalTrials.gov: NCT02471963, registered 15th June 2015, retrospectively registered) and received either 6-weeks treatment with 25 mg empagliflozin orally once daily or placebo (crossover). Central systolic pressure and central pulse pressure were recorded by the SphygmoCor System . Now, we investigated the impact of parameters of glucose metabolism, volume status, sympathetic activation, lipids, uric acid, blood pressure and inflammation on vascular parameters of arterial stiffness using multivariate regression analysis.Our analysis comprising 58 patients with type 2 diabetes mellitus identifies factors triggering the improvement of arterial stiffness. All patients participated in an investigator-initiated, prospective, double-blind, randomized, placebo-controlled, interventional clinical trial , central pulse pressure  forward  as well as reflected wave amplitude  compared to placebo. The multivariate regression analysis included age, sex and change between empagliflozin and placebo therapy of the following parameters: HbA1c, copeptin, hematocrit, heart rate, LDL-cholesterol, uric acid, systolic 24-h ambulatory blood pressure and high sensitive CRP (hsCRP). Besides the influence of age , sex  and change in systolic 24-h ambulatory blood pressure , the change of hsCRP  emerged as a significant determinant of the empagliflozin induced reduction in arterial stiffness (placebo corrected). When replacing HbA1c with fasting plasma glucose in the multivariate regression analysis, a similar effect of the change in hsCRP  on arterial stiffness parameters was found.Besides age and sex, change in systolic 24-h ambulatory blood pressure and change in hsCRP were determinants of the empagliflozin induced improvement of vascular parameters of arterial stiffness, whereas parameters of change in glucose metabolism and volume status had no significant influence. Our analysis suggests that empagliflozin exerts, at least to some extent, its beneficial vascular effects via anti-inflammatory mechanisms.Trial registrationhttp://www.ClinicalTrials.gov: NCT02471963, registered 15th June 2015, retrospectively registered Treatment of type 2 diabetes should aim at improving vascular structure and function in the micro- and macrocirculation besides metabolic control . ArteriaIn the EMPA-REG OUTCOME study  treatment with the selective sodium-glucose cotransporter 2 inhibitor (SGLT2-inhibitor) empagliflozin reduced the primary combined cardiovascular end point as well as secondary end points of hospitalization due to heart failure, cardiovascular morbidity, total mortality and renal end points . The undhttp://www.crc-erlangen.de) . The principal findings of the clinical trial have been previously published [This is a prespecified analysis of patients, who participated in an investigator initiated prospective, double blind, randomized, placebo-controlled, cross-over, interventional single center study conducted at the Clinical Research Center of the Department of Nephrology and Hypertension, University of Erlangen-Nuremberg, Germany , fasting plasma glucose > 240 mg/dl, any history of stroke, transient ischemic attack, instable angina pectoris or myocardial infarction within the last 6 months prior to study inclusion, uncontrolled hypertension (office blood pressure ≥ 180/110 mmHg), congestive heart failure (CHF) NYHA stage III and IV, use of loop diuretics and pregnancy. Eight patients from the original study cohort (71 patients) were excluded because they presented with hsCRP values above 5 mg/l. Another five patients from the original study cohort showed a clinical infect correlate such as cystitis, vaginal infection, cold or gout. Even though these patients did not present with hsCRP above 5 mg/dl, they were excluded from our analysis based on the clinical investigation. Conventional blood pressure and heart rate measurements in the office and during 24-h were carried in standard fashion by validated devices.Characteristics of the study population have been previously published . In briePatients underwent a run-in/wash-out phase of 4 weeks if pretreated with any antidiabetic agent, or 2 weeks if not pretreated with any antidiabetic agent and afterwards were randomized to either empagliflozin 25 mg orally once daily or placebo. Following 6 weeks of treatment with either of these drugs, the patient underwent a wash-out phase of 1 week. Then the patient received the other substance for another 6 weeks of intervention (cross-over).To derive the central (aortic) arterial waveform, a validated system  was applied , 7, 20 bOffice blood pressure measurement was performed in a standardized fashion according to guideline recommendations . During All blood samples were measured centrally at the biochemistry laboratory of the University of Erlangen-Nuremberg according to established methods. In particular, hsCRP was measured via particle-reinforced nephelometry. Copeptin was analysed by lab MVZ Dr. Limbach GbR using Time Resolved Amplified Cryptate Emission method. Coefficient of variation of measurements was below 10%.Normal distribution of data was confirmed by histogram and Kolmogorov–Smirnov test prior to further analysis. Data were compared by paired and unpaired t-tests and expressed as mean ± standard deviation (SD) in text and tables. A two-sided p-value < 0.05 was considered statistically significant. Bivariate correlation analyses were performed using Pearson’s test. Multivariate regression analysis was performed including the parameters sex, age and change of the following parameters under treatment with empagliflozin: HbA1c (model 1), copeptin concentration, hematocrit, 24-h ambulatory heart rate, LDL-cholesterol, uric acid, 24-h ambulatory blood pressure and hsCRP. A second multivariate regression analysis model included besides the other previously mentioned parameters fasting plasma glucose instead of HbA1c (model 2). Vascular stiffness parameters entered our model as an independent variable, namely as first change in central systolic blood pressure, second change in pulse pressure, third change in forward wave amplitude and fourth change in reflected wave amplitude. A separate multiple regression analysis was performed for each of the four independent variables mentioned. Potential collinearity between the dependent variables in our model has been excluded by calculating correlation coefficients between the dependent variables. There is no correlation between change in systolic 24-h ambulatory blood pressure and sex , age  and change of the following parameters: uric acid , hsCRP , LDL-cholesterol , fasting plasma glucose , hematocrit  and copeptin . All analyses were performed using IBM SPSS Statistics 22 .2. None of the patients were on any antidiabetic medication (85% were on metformin prior to study inclusion), whereas 50 patients received antihypertensive medications at baseline (84% received an angiotensin receptor blocker or an ACE-inhibitor), without any changes in medication throughout the study period.Characteristics of the study cohort have been previously published . In brieConsistent with our previous results , after tFurther analysis now included volume parameters such as copeptin and hematocrit, parameters of glucose metabolism such as HbA1c and fasting plasma glucose, hsCRP as parameter of inflammation, LDL-cholesterol, uric acid, and heart rate as parameter of sympathetic activation  glycated hemoglobin plasma levels and was associated with small decreases in body weight, plasma insulin and blood pressure , 24. HowOur study suggests that hsCRP might be a determinant of the empagliflozin induced improvement of central pulse pressure and reflected wave amplitude. It has been previously shown in rat models that therapy with empagliflozin reduces inflammatory processes in the diabetic kidney via suppression of the advanced glycation end product receptor axis , 34. In The increase in copeptin levels and hematocrit measured after empagliflozin therapy compared to baseline mirrors volume depletion due to osmotic diuresis caused by glucosuria and natriuresis. It has been previously shown that SGLT2 inhibitors have a modest osmotic diuretic and natriuretic effect, which can reduce extracellular volume, blood pressure and body weight . In the In our study population there was a small, but significant increase in LDL- and HDL-cholesterol, which has also been previously described in the EMPA-REG-OUTCOME study . This efIt has been recently shown in a post hoc analysis of the EMPA-REG OUTCOME trial that changes in uric acid mediated 24.6% of the effect of empagliflozin versus placebo on the reduction in risk of cardiovascular death . We therOne major selection bias limits the generalization of the study: only patients with normal kidney function were included and most patients with cardiovascular disease or advanced diabetes were excluded. Therefore the investigated relations only apply to patients in the early stage of diabetes without relevant end-organ damage.The markers for volume status (copeptin and hematocrit) as well as sympathetic activation (heart rate) are only crude biomarkers with a lot of background variation, especially in a small study population like this. Therefore, based on the results of this study, it cannot be concluded that volume status and sympathetic activation are not important mediators in the effects of SGLT-2 inhibitors.Of course, though prespecified, such an analysis of potential outcome determinants can only be the first step in the identification of factors explaining the vasoprotective potential of empagliflozin. We used placebo corrected changes in our analysis, since the differences between empagliflozin and placebo induced changes observed in the same patient entered our multiple regression analysis. The correlations between markers of vascular stiffness and hsCRP were statistically significant, but very weak and therefore clinical significance is unsure. Nevertheless, the signal that inflammation might influence empagliflozin induced reduction of arterial stiffness was present in two different statistical methods  and might therefore be an interesting target for future investigations. Further clinical trials with detailed parameters of volume status, inflammation and sympathetic activation are needed to better understand the precise mechanism of empagliflozin-induced vasoprotection.Besides age and sex, change in systolic 24-h ambulatory blood pressure and change in hsCRP were determinants of the empagliflozin induced improvement of vascular parameters of arterial stiffness, whereas parameters of change in glucose metabolism, lipid metabolism, uric acid, sympathetic activation as assessed by heart rate and volume status had no significant influence. Our analysis found a signal that empagliflozin may exert, at least to some extent, its beneficial vascular effects via anti-inflammatory mechanisms.


Body composition assessment, measured using single‐slice computed tomography (CT) image at L3 level, and aerobic physical fitness, objectively measured using cardiopulmonary exercise testing (CPET), are each independently used for perioperative risk assessment. Sarcopenia , myosteatosis [i.e. low skeletal muscle radiation attenuation (SM‐RA)], and impaired objectively measured aerobic fitness (reduced oxygen uptake) have been associated with poor post‐operative outcomes and survival in various cancer types. However, the association between CT body composition and physical fitness has not been explored. In this study, we assessed the association of CT body composition with selected CPET variables in patients undergoing hepatobiliary and pancreatic surgery.V˙O2 at AT), oxygen uptake at peak exercise (V˙O2 peak), skeletal muscle mass, and SM‐RA.A pragmatic prospective cohort of 123 patients undergoing hepatobiliary and pancreatic surgery were recruited. All patients underwent preoperative CPET. Preoperative CT scans were analysed using a single‐slice CT image at L3 level to assess skeletal muscle mass, adipose tissue mass, and muscle radiation attenuation. Multivariate linear regression was used to test the association between CPET variables and body composition. Main outcomes were oxygen uptake at anaerobic threshold  and V˙O2 at AT  while skeletal muscle mass was only weakly associated with V˙O2 peak . In the multivariate analysis, only SM‐RA was associated with V˙O2 peak  and V˙O2 at AT .Of 123 patients recruited , 113 patients had good‐quality abdominal CT scans available and were included. Of the CT body composition variables, SM‐RA had the strongest correlation with V˙O2 at AT and at peak). This study demonstrates that myosteatosis, and not sarcopenia, is associated with reduced aerobic physical fitness. Combining both myosteatosis and physical fitness variables may provide additive risk stratification accuracy and guide interventions during the perioperative period.There is a positive association between preoperative CT SM‐RA and preoperative physical fitness ( Despite improvement in surgical techniques, multimodal cancer therapies and perioperative care, morbidity, and mortality after major hepatobiliary and pancreatic (HPB) cancer surgery still pose substantial challenges. Accurate perioperative risk assessment prior to major cancer surgery is not personalized and is still substantially variable in the precision of outcome prediction. Identifying patients who are at risk of poor outcomes is a priority in order to facilitate shared decision making, inform prehabilitation and co‐morbidity management initiatives before surgery, and guide intra‐operative and post‐operative care. Various scoring systems exist for the risk stratification of these patients; however, few are objective. The importance of objectively measured aerobic physical fitness [using cardiopulmonary exercise testing (CPET)]CPET provides an objective assessment of physical fitness through evaluating cardio‐respiratory function under the stress of exercise mimicking the stress of major surgery. This has been widely adopted in the UK as a preoperative test to objectively evaluate perioperative risk,V˙O2 at AT) and at peak exercise (V˙O2 peak) are associated with worse outcome following colorectal surgeryBody composition analysed by using a single‐slice CT image at the third lumbar vertebra (L3) is strongly correlated with total body skeletal muscle mass.clinicaltrials.gov (NCT03641118). All patients had a histological or radiological diagnosis of operable liver metastases , periampullary carcinoma, hepatocellular carcinoma, or benign disease necessitating major liver or pancreas resections. A minority of patients underwent neoadjuvant cycles of capecitabine and oxaliplatin prior to colorectal liver metastasis surgery. This represented a pragmatic prospectively collected patient cohort reflecting a busy tertiary HPB referral centre. All patients underwent CPET before surgery. Body composition was assessed using a preoperative single‐slice CT image at the level of the third lumbar vertebra (L3). Patients without a good‐quality preoperative abdominal CT scan were excluded. CT scans were defined as poor quality if they had large radiation artefacts or profound muscle oedema. Preoperative plasma levels of haemoglobin, creatinine, albumin, and C‐reactive protein were assessed within 7 days of the planned surgery. The albumin and C‐reactive protein levels were used to calculate the modified Glasgow prognostic score (mGPS).V˙O2 at AT and V˙O2 peak (mL·kg−1·min−1). Secondary outcomes included 1 year all‐cause mortality and length of hospital stay; both were measured from day of surgery.All consecutive patients undergoing CPET and HPB surgery between January 2014 and January 2018, at the University Hospital Southampton NHS Foundation Trust HPB Unit, UK, were included in a prospective cohort and were eligible for inclusion. The study was reviewed and approved by the South East Scotland Research Ethics Committee (16/SS/0188) and is registered with .gov NCT041118. AlCPET was conducted according to standardized methods published elsewhere by the Perioperative Exercise Testing and Training Society and endorsed by the Association for Respiratory Technology & Physiology in the UK.V˙O2, predicted V˙O2 peak, height, and age with the aim of achieving a 10 min ramp stage. All CPETs were analysed by experienced accredited perioperative CPET practitioners (D. Z. H. L./M. R. E.) who were blinded to CT scan variables and clinical outcome variables.2) of skeletal muscle , VAT (−150 to −50 HU), and SAT (−190 to −30 HU) were assessed. The cross‐sectional area was then adjusted for height squared to calculate the L3 index (cm2·m−2), which is strongly correlated with total body SM and adipose tissue mass.The preoperative CT scan performed nearest to the date of surgery was selected for analysis (max 4 weeks before surgery and after completion of neoadjuvant chemotherapy). Abdominal CT scans were analysed in an anonymized and blinded format by one researcher trained in body composition analysis (D. P. J. V. D.) as described before.t‐test, the Mann–Whitney U‐test was used for non‐parametric variables, and the χ2 test was used for categorical variables. As the cohort size was too small for cut‐point finding approaches such as optimum stratification, gender‐specific cut points were set at the median for each CT body composition and CPET variable.V˙O2 at AT and V˙O2 peak was assessed using linear regression. First, all clinical variables were tested separately in an unadjusted univariate model (Model 1). Then, variables were ordered from lowest to highest P‐value from Model 1 and were added one by one to the multivariate linear regression model (Model 2). After each addition, an F‐test was performed to test whether the added variables significantly improved the model fit. If the F‐test P‐value was <0.05, the variable was kept in the model; otherwise, it was removed. Univariate and multivariate Cox regression and logistic regression were used for, respectively, overall survival and 1 year survival. Variables with a P < 0.1 in the univariate analysis were included into the multivariate analysis. For correlations, Pearson's correlation coefficient was used (r) for normally distributed data and the Spearman correlation coefficient (rs) for non‐normally distributed data.Data were analysed using IBM SPSS Statistics 23 for Microsoft Windows. Continuous data were compared using an independent Table2·m−2; SM‐RA, 37.1 and 30.4 HU; V˙O2 at AT, 9.4 and 9.3 mL·kg−1·min−1; and V˙O2 peak, 16.0 and 14.3 mL·kg−1·min−1. Patients with low skeletal muscle mass, SM‐RA, low V˙O2 at AT, and low V˙ O2 peak were significantly older. No significant differences could be detected in body composition or fitness variables when comparing benign vs. malignant or liver vs. pancreas groups. Significantly lower haemoglobin was seen in the low V˙O2 at AT and V˙O2 peak groups; however, no difference was found in skeletal muscle mass and SM‐RA. No significant differences could be detected in C‐reactive protein, GPS, and white cell counts. However, there were weak correlations between SM‐RA and both acute phase proteins C‐reactive protein  and albumin .One hundred twenty‐three patients were included during the study. Liver resections consisted of liver metastases , hepatocellular carcinoma (5 patients), and other major liver resections . Pancreatic resections consisted of pancreatic neoplasms , ampullary carcinoma (16 patients), cholangiocarcinoma , and intraductal papillary mucinous neoplasm (3 patients). Ten patients were excluded for CT scan analysis because they did not have a suitable preoperative CT scan available. Patient characteristics are shown in P < 0.001), VAT (P < 0.001), SM‐RA (P = 0.001), and SAT‐RA (P = 0.048), while women had higher SAT (P < 0.001); see FigureV˙O2 at AT (P < 0.001), oxygen pulse (V˙O2/Heart RateR) at AT (P < 0.001), ventilatory equivalent for carbon dioxide at AT (V˙E/V˙CO2 at AT) (P < 0.001), work rate at AT (P < 0.001), V˙O2 peak in litres per minute (P < 0.001), V˙O2 peak adjusted for weight (P = 0.033), V˙O2/Heart Rate at peak (P < 0.001), and work rate at peak (P < 0.001). TableV˙O2 at AT for men (P = 0.019) but not for women (P > 0.05) was significantly higher in the high SM‐RA group. Weight‐adjusted V˙O2 peak was higher in the high SM‐RA grouped for both men and women . A higher work rate at AT and peak was also seen in both groups at high SM‐RA values, with significant differences in women (AT P = 0.030 and peak P = 0.016). Furthermore, a significantly lower V˙E/V˙CO2 slope for both men and women  and V˙E/V˙CO2 at AT and peak (P = 0.018 and P = 0.025) for men were observed in the higher SM‐RA groups.All 123 patients underwent CPET, of which six patients were not able to achieve an anaerobic threshold . No CPET‐related adverse events occurred. For both CT and CPET assessments, there were significant differences between genders. In short, men had higher SM . Other significant variables in the univariate analysis were age, BMI, ASA > 2, VAT, and SAT. However, in the multivariate analysis, only SM‐RA and age were added to the model because adding additional variables did not result in a significant F change (P > 0.05). In the multivariate analysis, SM‐RA was significantly associated with both weight‐adjusted V˙O2 at AT  and V˙O2 peak ; see TableUnivariate and multivariate linear regression results are shown in V˙O2 peak was associated with increased 1 year mortality  and increased length of hospital stay  in the univariate analysis  2.10, 95% CI 0.98–4.51, P = 0.056]. As there was an association between V˙O2 peak and SM‐RA, we wanted to test whether a combination of low physical performance and myosteatosis would be a better predictor of overall survival and mortality. We therefore identified three patient phenotypes based on V˙O2 peak and SM‐RA: (i) high V˙O2 peak, (ii) low V˙O2 peak only, and (iii) low V˙O2 peak and myosteatosis (low SM‐RA). Indeed, patients with both low V˙O2 peak and myosteatosis had significantly lower survival in the multivariate Cox regression analysis ; see TableP = 0.021).Low‐weight‐adjusted V˙O2 at AT, V˙O2 peak, and V˙E/V˙CO2 slope) in both men and women, while sarcopenia  was not. SM‐RA was associated with both weight‐adjusted V˙O2 at AT and V˙O2 peak in the multivariate analysis. Furthermore, combining low V˙O2 peak with myosteatosis (low SM‐RA) was found to be a better predictor of overall survival than was low V˙O2 peak or low SM‐RA alone. Additionally, an elevated mGPS was associated with lower overall survival. This novel finding demonstrates that CT‐derived SM‐RA data are associated not only with SM structure but also with SM functioning.In this study, myosteatosis (low SM‐RA) was associated with reduced fitness  in both multivariate analyses. Myosteatosis is generally regarded as the result of a pathologic process involving systemic inflammation and insulin resistance in disease states such as cancer cachexia or obesity.Although the relationship between myosteatosis, sarcopenia, and poor fitness was assumed, no study had ever set out to test this hypothesis. Interestingly, we observed that sarcopenia was only significantly associated with weight‐adjusted inactivity is one of the leading public health issues we face,V˙O2 peak was the strongest predictor of adverse outcome . Combining CPET with CT data could provide a better prediction of clinical outcome compared with either of them alone, as we found that patients with both low V˙O2 peak and myosteatosis had significantly lower overall survival while low V˙O2 peak only was not significantly associated with overall survival. Evidence has shown that a higher physical activity and fitness after a cancer diagnosis and its treatments reduce perioperative risk and improve quality of life and post‐operative outcomes including survival.Lack of physical activity and fitness is a major modifiable risk factor of ill healthSuch data raise the obvious hypothesis: Can health outcomes be improved by perioperative interventions targeted at improving body composition and physical fitness? Body composition and fitness modulation as a concept in surgical risk prediction is attractive due its potential reversibility. In elective surgical patients, there is a small window of opportunity from contemplation of surgery and tumour staging to the date of surgery. Tailored programmes during this period should be multi‐faceted and targeted at individual patients' needs. A combination of strategies targeting poor muscle function, reduced physical fitness, secondary anorexia, inflammation, psychological health, and poor nutrition has been suggested in the context of multimodal prehabilitation prior to cancer and major intra‐abdominal surgery.In conclusion, we found that myosteatosis and not sarcopenia (assessed by CT scan) was associated with physical fitness (assessed with CPET) in a surgical HPB population. These data suggest that a simple and fast analysis of myosteatosis on a single‐slice CT image provides information  on the patients' physical fitness. CT body composition combined with objectively measured fitness (CPET) might provide additive risk stratification benefits and guide personalized multimodal interventions during the perioperative period.Malcolm A. West was supported by a National Institute for Health Research Academic Clinical Lecturer Award (CL‐2016‐26‐002) and declares that he has no conflict of interest. David P. J. van Dijk was supported by the Netherlands Organisation for Scientific Research (NWO Grant 022.003.011) and declares that he has no conflict of interest. Fredrick Gleadowe declares that he has no conflict of interest. Thomas Reeves declares that he has no conflict of interest. John Primrose declares that he has no conflict of interest. Mohammed Abu Hilal declares that he has no conflict of interest. Mark R. Edwards declares that he has no conflict of interest. Sandy Jack declares that she has no conflict of interest. Sander S. S. Rensen declares that he has no conflict of interest. Michael P. W. Grocott declares that he has no conflict of interest. Denny Z. H. Levett declares that she has no conflict of interest. Steven W. M. Olde Damink declares that he has no conflict of interest.


N = 20) compared to patients without (N = 10) and an association with SAKI. Closer scrutiny reveals that patients with SAKI trended to higher doses of noradrenaline, lower mean arterial pressure (MAP), and lower cardiac index (CI), without reaching statistical significance. Lactate was significantly higher in SAKI patients.With interest, we read the recent publication by Harrois et al. correlating low cortical blood flow with the risk of septic acute kidney injury (SAKI) . SAKI isIn a sheep model, Lankadeva demonstrated hemodynamic and oxygenation mismatch between the cortex and medulla, before SAKI became evident. Despite large increases in global RBF and renal oxygen delivery, significant hypoperfusion and hypoxia were detected at the medulla but not at the cortex . This maLankadeva initiated treatment with noradrenaline, restoring MAP to normal and strongly enhancing RBF, however with the effect of further reducing medullary perfusion and oxygenation .Medullar oxygenation, subject to macrocirculatory   and micr