Early and precocious determination of acute kidney injury (AKI) is essential to prevent morbidity and mortality following coronary artery bypass grafting (CABG). Evaluation of the perioperative renal function is substantial using novel biomarkers other than the late traditional method of using serum creatinine. Plasma neutrophil gelatinase-associated lipocalin (NGAL) is a biomarker investigated for early detection of AKI in patients undergoing coronary artery bypass grafting, and its role has to be determined in this study.p value < 0.001). The cut-off value of plasma NGAL levels measured 6 h postoperatively was 145 ng/ml and the area under the receiver-operating characteristic (ROC) curve was 0.965. Results of this study showed that plasma NGAL is a robust early biomarker of AKI, which preceded the rise in serum creatinine by many hours.Twenty-five patients undergoing elective CABG were enrolled in this cohort study and were assigned into two groups: group I include the patients that did not develop AKI (no AKI group) and group II include the patients that developed AKI (AKI group). Acute kidney injury based on Kidney Disease: Improving Global Outcomes (KDIGO) classification had been developed in 7 patients (28%). Plasma NGAL levels at 6 h were higher in patients who developed AKI compared with those who did not (302 ± 88.02 vs. 116.50 ± 17.33 ng/m, This study revealed that earlier diagnosis of acute kidney injury in patients undergoing CABG can be achieved by measuring postoperative plasma NGAL concentration at 6 h. Acute kidney injury (AKI) is a frequent intricacy after cardiac surgery. Cardiac surgery-associated kidney injury may affect 30% of the patients based on the literature and different definitions of acute kidney injury. Mortality increases from 1% up to half the patients who undergo hemodialysis following cardiac surgery , transfusion of blood products (packed RBCs and fresh frozen plasma), and nephrotoxic drugs administration before or after surgery may as well increase the risk of postoperative AKI . This drawback causes serum creatinine to be a late marker for AKI even after decline in the glomerular filtration rate (GFR) to half , scheduled for elective coronary artery bypass grafting (CABG) using cardiopulmonary bypass (CPB).Exclusion criteria included: age < 18 years, emergency surgery, Redo operations, pre-existing renal impairment, or renal replacement therapy (RRT), low ejection fraction < 30%, the need for postoperative intra-aortic balloon, chronic inflammatory disorders and immunosuppression, corticosteroid therapy, and patient refusal.Demographic data, patients’ risk factors, preoperative evaluation of all the patients enrolled in the study and preoperative routine laboratory test as coagulation profile, CBC, kidney function, and liver function tests were evaluated and recorded. All the patients continued the preoperative medications till the night of surgery with the exception of nephrotoxic drugs. Upon arrival to the operating room, peripheral venous cannula was inserted and radial artery cannulation was done in the non-dominant hand under local anesthesia after checking the patency of the collaterals through the modified Allen’s test. Two milligrams midazolam and 4 mg morphine IV were given for sedation after application of standard monitors to the patient according to the American Society of Anesthesiologist (ASA) recommendations. Induction of anesthesia was done using fentanyl at 5 μg/kg, midazolam at 0.05 mg/kg (titrated dose), thiopental at 3–5 mg/kg (titrated dose), and rocuronium at 0.9 mg/kg to achieve muscle relaxation in order to facilitate tracheal intubation. Blood pressure was maintained within 20% of the baseline with avoiding tachycardia (keeping HR between 60–80 bpm) during induction. Maintenance of anesthesia was done by isoflurane (1.2%), fentanyl and rocuronium.Rt. Central venous line was inserted by the guidance of ultrasound.Anticoagulation was done before cannulation of the aorta using intravenous heparin 300 to 400 units/kg with target ACT between 400 and 480 s.After clamping of the aorta, antegrade cold cardioplegia  was administered in a dose 10 mg/kg. Cardioplegia was given in a dose of 5 mg/kg every 20 minutes.CPB was established to keep the mean arterial pressure (MAP) during full flow between 50 and 70 mmHg. Hematocrit was kept above 20%, fresh packed RBCs were given if needed. CBP time and aortic cross-clamping time were measured and recorded.2O) and fulfillment of the criteria for extubation. Patients were followed up and managed for the 48 h study period as per standard protocols.Patients were weaned from the CPB according to the general condition of the patient and cross-clamp time. After venous and arterial decannulation, protamine was administered for reversal of heparin . The patients enrolled in the study were weaned from the ventilator in the intensive care unit (ICU) after vital data stabilization  within normal range above 60 and below 90 bpm and central venous pressure (CVP) within the range of 10 and 15 cm HNGAL levels were determined at two time points: preoperatively (within 24 h before the surgery) and postoperatively 6 h after arrival to the ICU. Assay of serum NGAL was done by the enzyme-linked immune sorbent assay (ELISA) method, using the kit supplied by Shanghai Sunred Biological Technology Co., Ltd. The kit uses a double-antibody sandwich enzyme-linked immunosorbent assay (ELISA).Serum creatinine levels were measured at five time points: preoperatively before induction of anesthesia and at 6, 12, 24, and 48 h postoperative. Serum creatinine concentration was measured using a Beckman® Analyzer  according to the picric acid colorimetric method.Postoperative AKI during the 48 h follow-up period was determined based on the Kidney Disease: Improving Global Outcomes (KDIGO) classification and the levels of the 6 h postoperative plasma NGAL values for renal impairment were checked. Other variables we included were age, gender, aortic cross clamp time, and CPB time.Stage 1 AKI was defined as rise in serum creatinine by 0.3 mg/dL or by an increase ≥ 1.5-fold from the baseline valueStage 2 AKI classified by a 2–2.9-fold rise in baseline serum creatinineStage 3 AKI by ≥ 3-fold rise in serum creatinine.The primary outcome of this study was to evaluate the efficiency of neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker in predicting AKI in patients scheduled for elective coronary artery bypass grafting (CABG) under cardiopulmonary bypass (CPB).r = 0.8). Based on this and taking in consideration 15% drop out rate, the needed sample is 25 patients.Using MedCalc program version 11 setting alpha error at 5% and power 90% results from previous study, Group II include the patients that developed AKI (AKI group)The patients were assigned into two groups:t test was used to compare quantitative variables between the two study groups when the data were normally distributed. Qualitative data were presented as number and percentage and the differences between the two groups were compared using the chi-square (χ2) test and/or Fisher exact test when the expected count in any cell found less than 5. p < 0.05 will be considered significant.The data was collected, revised, coded, and introduced to a PC using statistical package for social science . Data was presented as mean and standard deviation (±SD) for quantitative prometric data. Independent Pearson correlation coefficient was used to test correlations between serum NGAL and other variables.The receiver operating characteristic (ROC) curve and area under the curve  of plasma NGAL measured 6 h postoperatively were calculated and compared for the assessment of its ability to anticipate acute kidney injury.Twenty-five patients without pre-existing renal dysfunction undergoing elective on pump CABG who did not have exclusion criteria were enrolled in this prospective cohort study.The kidney injury was determined based on kidney disease improving global outcomes (KDIGO) classification in terms of rise in serum creatinine during the first 2 days after surgery.Of the 25 patients studied, 7 (28%) had AKI postoperatively as defined by KDIGO criteria while 18 (72%) did not, by measuring serum creatinine (SCr) 48 h postoperatively.Six patients who had AKI developed stage 1 AKI while only one patient had stage 2 AKI. None of the patients of AKI group developed stage 3 AKI or underwent dialysis.p value 0.136)Average age was 56.54 ± 6.44 years in No AKI Group vs. 60.67 ± 4.51 years in AKI Group with .There is statistically non-significant difference between AKI group and No AKI group as regards age and sex where Patients’ characteristics regarding body mass index, medical history of diabetes mellitus, familial history of coronary artery disease (CAD), history of dyslipidemia, diuretics use before surgery, preoperative hemoglobin, and preoperative left ventricular systolic function were comparable in both groups Table Table 1Bp value = 0.019)The number of hypertensive patients in the AKI group (85%) compared to the no AKI group (33%) was significantly higher  and longer aortic cross-clamp time (93.86 ± 6.77 vs. 69.4 ± 6.49 min)  compared to the other group (Table Patients with AKI had longer CPB time (109.42 ± 7.48 vs. 84.00 ± 6.87 min)  in the two groups for preoperative levels and postoperative creatinine levels at 6, 12, and 24 h. The AKI group had higher postoperative 48 h SCr levels (p < 0.001) as shown in  as shown in Fig. Measurement of plasma NGAL 6 h postoperatively showed higher levels in patients who had AKI during the first 2 days follow-up vs those who did not (302 ± 88.02 vs. 116.50 ± 17.33 ng/mL) (r = 0.857)   Table Table 3CThe cut-off value of the 6 h postoperative plasma neutrophil gelatinase-associated lipocalin levels was 145 ng/ml and the area under the receiver-operating characteristic curve was 0.965 as shown in Fig. Acute kidney injury following cardiac surgery is a frequent and serious complication, it is considered to be independently associated with worse outcomes, increased mortality rate, prolonged ICU, and hospital stay  women and 21 (84%) men patients were enrolled in the study. The mean age was 57.69 ± 6.17 years.In all patients enrolled in our study, serum NGAL was measured at two time points: preoperative within 24 h before surgery and 6 h postoperatively in all patients enrolled in this studySerum creatinine was measured preoperatively at 6 h, 12 h, 24 h, and 48 h after surgery.A total of 7 patients out of 25 (28%) developed AKI according to Kidney Disease: Improving Global Outcomes (KDIGO) KDIGO criteria, plasma NGAL levels at 6 h postoperative were significantly higher in all patients with AKI compared to their baseline levels, whereas only one patient had elevated serum creatinine at 6 h postoperative.Our data suggests that plasma NGAL is a robust early AKI biomarker, which forgoes the rise in serum creatinine by many hours allowing the avoidance of nephrotoxic drugs  and dose adjustment of the antibiotics; therefore, decreasing the morbidity and the necessity of RRT.p value < 0.001). In AKI group, there was a statistically significant correlation between 6 h NGAL level and creatinine measured 48 h after surgery (r = 0.859) Plasma NGAL measured 6 h postoperatively showed higher levels in patients who had AKI during the first 2 days follow-up vs those who did not (302 ± 88.02 vs. 116.50 ± 17.33 ng/mL)  and specificity (88.9%).Our results are in line with several previous studies that suggested NGAL as a highly promising biomarker for predicting AKI early after cardiac operations.Mishra et al. measured NGAL levels in the pediatric population undergoing cardiac surgery and reported that serum NGAL showed a 10-fold increase 2 h postoperative in patients who developed AKI later  curve of 0.75 , NGAL level measured within 6 h postoperative was an adequate biomarker for early detection of AKI  4.76 as compared to 71–140 min and by an OR 6.30 for > 140 min  while for the cross clamp time more than 60 min increased the AKI hazard by an OR of 2.84 as compared to 61–120 min and by an OR 3.64 for > 120 min (p = 0.01)  included in the study is considered to be an important limitation. To evaluate the ability of plasma NGAL for earlier diagnosis of AKI after coronary artery bypass grafting, larger randomized prospective trials are required.The small group number (The other limitation of this study is that the plasma NGAL level was assessed at 6 h postoperatively and not after that, which is considered a short observational period. In spite of the fact that earlier studies on NGAL have showed that AKI and the elevation of plasma NGAL levels occur in the majority of studies during the aforementioned period.Despite normal serum creatinine levels before surgery for all the patients enrolled in the study, measurement of the glomerular filtration rate before surgery to evaluate kidney function was not done.This study revealed that early prediction of acute kidney injury in patients undergoing CABG can be achieved by monitoring plasma NGAL levels at baseline and 6 h after surgery. The early rise in plasma NGAL levels, preceding serum creatinine can be beneficial in providing an early warning to critical care providers allowing the possibility of taking earlier interventions in this high risk population.


Non-communicable diseases are the leading cause of death and disability across India, including in the poorest states. Effective disease management, particularly for cardiovascular diseases, requires the tracking of several biochemical and physiological parameters over an extended period of time. Currently, patients must go to diagnostic laboratories and doctors’ clinics or invest in individual point-of-care devices for measuring the required parameters. The cost and inconvenience of current options lead to inconsistent monitoring, which contribute to suboptimal outcomes. Furthermore, managing multiple individual point-of-devices is challenging and helps track some parameters to the exclusion of others. To address these issues, HealthCubed, a primary care technology company, has designed integrated devices that measure blood glucose, hemoglobin, cholesterol, uric acid, blood pressure, capillary oxygen saturation and pulse rate. Here we report data from clinical studies undertaken in healthy subjects establishing the validity of an integrated device for monitoring multiple parameters.  Non-communicable diseases (NCDs) are now the leading cause of disease burden in India, including in the poorest states. According to the World Health Organization, NCDs accounted for 63% of all deaths in India in 2016 with cardiovascular diseases (CVDs) contributing a major part of the burden (27%), followed by respiratory diseases (11%) . The management of NCDs, particularly CVDs, requires the monitoring of several parameters such as blood pressure, blood glucose and cholesterol. This necessitates multiple visits, to provide a blood sample, receive the report and consult with the physician. Given the long-term nature of the conditions, testing and monitoring has to be undertaken for years. Cost and inconvenience add up; moreover, the lack of high-quality diagnostic laboratories impedes the effective management of these diseases. To address these challenges, point-of-care (POC) tests that can be administered at the site of interest such as a clinic or a home, are rapid, easy to perform, and enable treatment decisions or referrals within a single encounter with the patient, have been introduced ,6,7. HowHealthCubed (HC) has designed a set of devices that measure blood glucose, hemoglobin, cholesterol, uric acid, blood pressure, capillary oxygen saturation and pulse rate, for the simultaneous monitoring of biochemical and physiological parameters relevant to CVDs. They are compact and lightweight (1.7 kgs) and are designed for convenience, ease of use, portability and accuracy. The devices are controlled by an android software application via Bluetooth and offer data storage on the cloud. These features make the devices valuable screening tools in the hands of a healthcare provider such as a general practitioner, particularly in semi-urban and rural areas. While other devices with multiple test offerings exist  and HealthCube-XL (HC-XL) in comparison with individual, comparable POC tests/devices, we undertook a clinical study in healthy subjects. Here we report results demonstrating the validity of these integrated devices.We evaluated the performance characteristics of point-of-care devices, HealthCube SE (HC-SE) and HealthCube XL (HC-XL) compared to equivalent marketed devices. HC-SE was evaluated for blood glucose, hemoglobin, cholesterol, uric acid and HC-XL was evaluated for systolic and diastolic blood pressure, peripheral capillary oxygen saturation and pulse rate. HC-SE has the same functionalities as HC-XL, with the exception of the electrocardiography module.The study was conducted by the Rajalakshmi Hospital, Bengaluru, India, a tertiary care hospital approved by the Central Drug Standards Control Organization (CDSCO) for clinical validations. The study was open label, outcome blinded and conducted in accordance with the Declaration of Helsinki. It was approved by the institution’s Ethics Committee prior to commencement under approval number RH/IEC/AP-024/2018 (approved on 17 September 2018) for HC-SE and RH/IEC/AP-023/2018 (approved on 17 September 2018) for HC-XL. The study was registered under Clinical Trials Registry–India (CTRI) with the number CTRI/2019/01/016905 (approved on 4 January 2019). It was performed in 2 phases; in the first phase, tests for blood glucose (BG), hemoglobin, cholesterol and uric acid were conducted using HC-SE (Study 1). In the second phase blood pressure and pulse oximetry were evaluated using HC-XL (Study 2).Eligible participants were healthy volunteers who were recruited to the study between 11 October 2018 to 15 April 2019. A cohort of 150 subjects participated in Study 1 and subsequently in Study 2. The inclusion criteria were adults, 18 years and above who were able to give consent. The exclusion criteria were known diagnosis of acute or critical illness, participation in any other clinical study and history of blood disorders such as lymphoma, leukaemia, myeloma, polycythaemia, Von Willebrand disease, haemophilia and thrombocythemia. The participants were 70.7% male and 29.3% female. All participants gave informed consent.Each participant was subjected to a fingerstick to obtain capillary blood and tested alternately on the reference device and the HC-SE device. The reference devices were CE certified, BeneCheck Multimonitoring System (BK6-12M) for glucose, cholesterol and uric acid and CE certified Premium Hb monitoring System (BKA-30S) for hemoglobin. The data were recorded for the reference devices manually. The HC-SE device provided a readout on a Bluetooth-enabled tablet device through an android application called EzDx for Easy Diagnostics (version 2.6 demo).(a)Blood Pressure: Each participant was tested while seated and resting with the FDA approved SunTech 247 NIBP Model 551503 (reference device) and HC XL. Three measurements were taken on each device by the same operator, alternating between the devices with a 1-minute gap between readings. The measurements were manually noted and averaged.(b)Pulse oximetry: Peripheral capillary oxygen saturation and pulse rate were measured using FDA approved Choicemmed MD300C2 Pulse Oximeter (reference device) and HC XL using a probe connected to the subject’s index finger. Measurements were taken in 3 replicates, alternating between the devices. Averages were calculated and compared.The results obtained for blood glucose, total cholesterol, uric acid and hemoglobin using the HC-SE device were compared with the respective reference device readings. Standard statistical techniques, such as proportions that fit within specific limits (acceptable tolerance limits), were applied . These lScatter plots were drawn and the Pearson correlation coefficient was derived to describe the relationship between data obtained from the HC-SE device and the reference device.Systolic and diastolic blood pressure values, oxygen saturation and pulse rate were compared between the HC-XL device and the reference device. Proportions that fit within specific limits were determined for each parameter . Like inIn Study 1, biochemical parameters were compared between the HC-SE and reference devices. Of the 150 subjects recruited for the study, 150, 148, 146 and 143 subjects were evaluated for blood glucose, total cholesterol, hemoglobin and uric acid, respectively . PatientBlood pressure, oxygen saturation and pulse rate measured with the HC-XL device were compared with measurements from the appropriate reference devices . 143/150We evaluated the performance characteristics of the HC-SE and HC-XL devices compared to reference devices for glucose, cholesterol, hemoglobin, uric acid, systolic and diastolic pressure, pulse rate and oxygen saturation. The tests were evaluated in two ways. One, the values obtained with the HC devices were compared to reference device values and binned into ranges based on specific tolerance limits. Two, scatter plots were drawn and the correlation between HC and reference device values was analyzed.For all parameters except cholesterol and hemoglobin, more than 95% of the data points fit within acceptable tolerance limits. Of the data points for cholesterol and hemoglobin, 94.6% and 93.8%, respectively, were within acceptable tolerance limits. Furthermore, the Pearson correlation coefficient values were 0.99 for glucose, 0.96 for cholesterol, 0.88 for hemoglobin and 0.96 for uric acid. For blood pressure, pulse rate and oxygen saturation, the Pearson coefficient values were 0.98 for systolic blood pressure, 0.97 for diastolic blood pressure, 0.42 for oxygen saturation and 0.95 for pulse rate, respectively. The Pearson coefficient values for all parameters except hemoglobin and oxygen saturation, were >0.9, suggesting an excellent correlation between the HC and reference devices.The HC-SE and HC-XL devices are intended for screening purposes. Their accuracy needs to be similar to other point-of-care or home-based use devices. Moreover, since the HC devices are aggregates of individual point-of-care tests, the performance characteristics of each test must be in line with disclosures made by the manufacturers for those tests. These expectations were largely met, with inconsistencies noted for cholesterol, hemoglobin and oxygen saturation. The cholesterol test data, although borderline in the range analysis, had an excellent correlation to the reference device. Hence, this test meets one of the key validation criteria. The hemoglobin test appeared to be less robust, both in the range and correlation analysis. However, this test may offer a reasonable estimation in clinical settings where diagnostic laboratories are hard to come by. For oxygen saturation, we note that 96% of the values fell within the allowed range of variability, even though a poor correlation between device values was observed. Since the comparison was between two point-of-care devices, factors such as the calibration of the reference device cannot be ruled out as the cause of the poor correlation. Additional studies comparing HC device values with invasive venous blood oxygen saturation measurements may be needed to confirm the accuracy of this test.One limitation of this study was that it was conducted in healthy subjects. Thus, the spread of values was limited, with the exception of hemoglobin. Given the high incidence of anaemia in India, this is not a surprise . To ensuThe HC-SE and HC-XL devices allow users to obtain data, for several key parameters using a single, integrated device. For clinicians and caregivers in diverse settings, this eliminates the need to invest in multiple devices and train individuals to operate them. It provides convenience and importantly, allows clinicians to make informed decisions for their patients. These are significant benefits, particularly in underserved communities that have poor access to diagnostic laboratories. We believe that the HC devices push the frontiers of disease screening and diagnosis, addressing directly the need for managing chronic conditions in India and other parts of the world equitably.


COVID-19 may lead to severe disease, requiring intensive care treatment and challenging the capacity of health care systems. The aim of this study was to compare the ability of commonly used scoring systems for sepsis and pneumonia to predict severe COVID-19 in the emergency department.Prospective, observational, single centre study in a secondary/tertiary care hospital in Oslo, Norway. Patients were assessed upon hospital admission using the following scoring systems; quick Sequential Failure Assessment (qSOFA), Systemic Inflammatory Response Syndrome criteria (SIRS), National Early Warning Score 2 (NEWS2), CURB-65 and Pneumonia Severity index (PSI). The ratio of arterial oxygen tension to inspiratory oxygen fraction (P/F-ratio) was also calculated. The area under the receiver operating characteristics curve (AUROC) for each scoring system was calculated, along with sensitivity and specificity for the most commonly used cut-offs. Severe disease was defined as death or treatment in ICU within 14 days.38 of 175 study participants developed severe disease, 13 (7%) died and 29 (17%) had a stay at an intensive care unit (ICU). NEWS2 displayed an AUROC of 0.80 , CURB-65 0.75 (0.65−0.84), PSI 0.75 (0.65−0.84), SIRS 0.70 (0.61–0.80) and qSOFA 0.70 (0.61−0.79). NEWS2 was significantly better than SIRS and qSOFA in predicating severe disease, and with a cut-off of5 points, had a sensitivity and specificity of 82% and 60%, respectively.NEWS2 predicted severe COVID-19 disease more accurately than SIRS and qSOFA, but not significantly better than CURB65 and PSI. NEWS2 may be a useful screening tool in evaluating COVID-19 patients during hospital admission.https://clinicaltrials.gov/ct2/show/NCT04345536).: ClinicalTrials.gov Identifier: NCT04345536. ( SepsispneumoniaSeveral tools have been developed for risk stratification in patients with sepsis in the emergency department (ED) include; a) the Quick Sequential Failure Assessment (qSOFA) score ,Commonly applied scoring systems for Quick Sequential Organ Failure Assessment (qSOFA) Altered mental stateSystolic blood pressure ≤100 mmHgRespiratory rate ≥22 breaths/minSystemic Inflammatory Response Syndrome (SIRS) Temperature >38 °C or <36 °CHeart rate > 90 beats/minRespiratory rate >20 breaths/min or PaCO2 < 4.3 kPa3 or < 4000 cells/mm3White blood cell count >12 000 cells/mmCURB-65 ConfusionUrea > 7 mmol/lRespiratory rate ≥30 breaths/minSystolic blood pressure <90 mmHg or diastolic blood pressure ≤ 60 mmHgAge ≥ 65 yearsPneumonia severity index (risk class I–V)Step 1. If any, assign patient to risk class II-V according to step 2. If non, assign patient to risk class IAge > 50 yearsHistory of neoplastic disease, congestive heart failure, cerebrovascular disease, renal disease or liver diseaseAny of the following abnormalities on physical examination: Altered mental status, pulse ≥ 125 beats/min, respiratory rate ≥ 30 breaths/min, systolic blood pressure <90 mmHg or temperature <35 °C or ≥40 °C.Step 2. Point scoring system (point assigned for each characteristic). If the score is ≤70 the patient is assigned to risk class II, 71–90 to risk class III, 91–130 to risk class IV and >130 risk to risk class V.Age (1 point/year)Female sex (10 points)Nursing home resident (10 points)Neoplastic illnesses (30 points)Liver disease (20 points)Congestive heart failure (10 points)Cerebrovascular disease (10 points)Renal failure (10 points)Altered mental state (20 points)Respiratory rate ≥30 breaths/min (20 points)Systolic blood pressure <90 mmHg (20 points)Temperature <35 °C or ≥40 °C (15 points)Pulse ≥ 125 beats/min (10 points)Arterial pH < 7.35 (30 points)Blood urea nitrogen ≥ 11 mmol/l (20 points)Sodium <130 mmol/l (20 points)Glucose >14 mmol/l (10 points)Haematocrit < 30% or Haemoglobin <9 g/dl (10 points)PaO2 < 60 mmHg (>8 kPa) (10 points)Pleural effusion (10 points)National Early Warning Score 2 (NEWS2) (score range 0–20)The following six physiological parameters are scored from 0 to 3.Respiratory RateOxygen Saturations (with lower oxygen saturation targets for patients with confirmed hypercapnia)TemperatureSystolic blood pressureHeart RateLevel of consciousnessAdditional 2 point if any Supplemental Oxygen is administered.In this prospective observational study, we have evaluated and compared the predictive characteristics of commonly used scoring systems for sepsis and pneumonia applied to a cohort of consecutive COVID-19 patients admitted to our hospital. Our aim was to evaluate their accuracy in the ED in predicting the development of severe COVID-19 infection within 14 days after hospital admittance, in order to assist initial triage and allocation of limited monitoring resources.All SARS-CoV2-positive patients >18 years old, admitted to the OUH during the period from 01.03.20 to 30.06.20 were evaluated for study participation. Patients transferred from other hospitals, and patients electively hospitalized for medical conditions unrelated to SARS-CoV-2, were excluded. Since the aim of this study was to evaluate the value of the scoring systems in the ED, only the calculation of qSOFA, SIRS-criteria, CURB-65, PSI, NEWS2 and P/F-ratio from the patient’s first assessment at the hospital were included. Severe disease was defined as death or treatment in ICU within 14 days after admittance. There were no established criteria for ICU admission. The decision to transfer a patient to ICU was taken by experienced intensivist on duty.The included patients were included in the quality registry “Covid19 OUS”, at Oslo University Hospital (OUH). The quality registry was approved by the data protection officer at OUH on March 13th 2020 (Reference number 20/08822). Informed consent was waived in accordance with the data protection officer. Patients were included prospectively, but before March 13th, due to the acute onset of the pandemic in Norway, the first eight patients were included retrospectively. The register contains all patients hospitalized with confirmed SARS-CoV-2 (positive reverse transcriptase polymerase chain reaction (RT-PCR)) regardless of symptoms and clinical findings. Identification of COVID- 19 positive patients admitted to OUH has been done by cross-checking results of positive SARS-CoV-2 RT- PCR provided by the Department of Microbiology at OUH, and by use of the diagnose coding system “International Classification of Diseases” (ICD10) by identifying the diagnosis codes J12.8  in combination with U07.1 (COVID-19 identified). The clinicians who assessed the patients were otherwise unrelated to the study. Data were extracted from patient journals and recorded electronically by register staff in the Medinsight registration tool. The records were controlled by two of the authors .This paper has been developed according to the STARD-guidelines for reporting diagnostic accuracy studies.The area under the receiver operating characteristics curve (AUROC) for severe disease was calculated for each scoring system. Sensitivity, specificity, positive and negative predicative values of the most commonly used cut-off values for SIRS-criteria (2/4), qSOFA (2/3), CURB-65 (2/5), PSI (3/5) and NEWS (5), together with a P/F-ratio less than 300 mmHg (40 K Pa), were determined. Patients with missing data were excluded from the individual calculation.t test. Categorical variables are given in numbers and percentages, and were compared with the chi-square test. Statistical analyses were calculated using the IBM SPSS Statistics (version 26) and GraphPad Prism (version 8). 95% confidence intervals for sensitivity, specificity and positive and negative predicative values were calculated by Medcalc . P-values less than 0.05 were considered significant.Continuous variables are given in median and interquartile ranges, and compared using the independent Student’s A total of 207 adult patients with confirmed COVID-19 were admitted to the hospital from March to June 30th. 19 patients transferred from other hospitals and 13 patients electively admitted for nonCOVID related conditions were excluded , leavingThe patients who developed severe disease were older, had more comorbidity, frailty and limitation of treatment. Baseline characteristics, see NEWS2 displayed an AUROC of 0.80 , CURB-65 0.76 (0.67−0.84), PSI 0.74 (0.64−0.84), SIRS 0.70 (0.61–0.80) and qSOFA 0.70 (0.62−0.78). NEWS2 were significantly better than qSOFA and SIRS , and comThe AUROC for P/F-ratio for predicting severe disease was 0.81, which is comparable with NEWS2, CURB-65 and PSI. The sensitivity and specificity for the P/F-ratio with cut-off ≤300 mmHg (≤40 kPa) were 70% and 73%, respectively.This prospective observational study of five different scoring systems applied on COVID-19 patients at admittance to hospital found that NEWS2 predicts severe disease in COVID-19 patients significantly better than the sepsis scoring systems qSOFA and SIRS. The AUROC was not significantly higher for NEWS2 than for CURB-65 and PSI.,With a cut-off of NEWS2 set to five, the sensitivity of 82% and the NPV of 92% are moderately good. However, the specificity of 60% and PPV of only 37% makes it challenging to use in clinical practice. When the NEWS2 cut-off value is increased, both the specificity and the PPV increase, but at the expense of sensitivity. NEWS2 is currently used in assessing patients with suspected severe infections in several EDs around the world.There have been several attempts at developing new tools to predict development of severe COVID-19.,In contrast to sepsis, which commonly presents with multiorgan failure, COVID-19 is often characterized by solitary respiratory failure.Of the 175 hospitalized COVID-19 patients included in our study, 38 were defined as severe disease; non-survivors or by need of intensive care treatment. Thus, adequate clinical observations are of outmost importance. This is hindered by a multitude of infection control measures such as time-consuming donning and doffing of personal protective equipment. It is therefore important that the routines for observations are simple and well documented. Serial assessments using NEWS2 is a reasonable practical approach, and may possibly identify deteriorating patients. While NEWS2 did not perform significantly better than CURB65 and PSI, it is simple to use, include only easily accessible clinical parameters, while CURB-65 and PSI both include laboratory analyses. P/F-ratio assessment require blood gas analysis, and may therefore be difficult to perform outside of the ICU.It must be emphasized that COVID-19 is mainly a pulmonary disease. We suggest that the NEWS2 score in COVID-19 patients is supplemented with monitoring the degree of oxygen requirement and more detailed grading of respiratory rate and signs of patient exhaustion, as well as the P/F- ratio if feasible.This study has some limitations. It is a single centre study which may limit the generalizability, and the relatively small number of participants limits the certainty of our analysis. The study was conducted in the early phase of the pandemic, and there may have been changes in clinical practice and routines during the study period. However, we do not think this affected data collection. Notable strengths are that all participants are well characterized in a large prospective quality register that comprise a complete consecutive patient set, including the first COVID-19 patients admitted to our hospital.In conclusion, our study revealed that NEWS2 was equivalent to CURB65, PSI and P/F-ratio, but more accurate than SIRS and qSOFA, in predicting severe disease among patients hospitalized for COVID-19. However, the value of single assessments is limited, and hospitalized patients must be adequately monitored for signs of deterioration.Oslo University Hospital. It did not receive any external funding.The study was funded by ClinicalTrials.gov. The ClinicalTrials.gov Identifier is NCT04345536.The study was registered as an observational study in Dr Olasveengen has received research grants from Zoll Foundation and Laerdal Foundation. No other disclosures were reported.Informed consent was waived in accordance with the data protection officer (case number 20/07119) due to the status as a quality register with reporting of aggregated patient data with no risk of identification of personal sensitive information.The publication was approved by data protection officer at Oslo University Hospital .Due to the nature of this research, with data from a quality register with waived consent, data is not available do to ethical and legal restrictions.Not applicable.Aleksander Rygh Holten: Conceptualization, Formal analysis, Writing - original draft, Writing - review & editing, Supervision. Kristin Grotle Nore: Formal analysis, Investigation, Writing - review & editing. Caroline Emilie Van Woensel Kooy Tveiten: Formal analysis, Investigation, Writing - review & editing. Theresa Mariero Olasveengen: Methodology, Formal analysis, Investigation, Writing - review & editing, Resources. Kristian Tonby: Methodology, Formal analysis, Investigation, Writing - review & editing, Resources, Supervision.


The aim of this study was to determine medication‐related problems (MRPs) in primary care patients over 65 years of age.Cross‐sectional study based on the electronic health records of patients (65‐99 years of age) visited in 284 primary health care centers during 2012 in Catalonia. Variables: age, sex, sociodemographic variables, number of drugs, kidney and liver function and MRPs . Unconditional logistic regression models were used to identify the factors associated with MRPs in patients with multimorbidity.916 619 older people were included and 853 085 of them met the criteria for multimorbidity. Median age was 75 years and 57.7% of them were women. High percentages of MRPs were observed: PIMs (62.8%), contraindicated drugs in chronic kidney disease (12.1%), duplicate therapy (11.1%), contraindicated drugs in liver diseases (4.2%), and drug‐drug interactions (1.0%). These numbers were higher in the subgroup of patients with ≥10 diseases. The most common PIMs were connected to drugs that increase the risk of fall (66.8%), antiulcer agents without criteria for gastroprotection (40.6%), and the combination of drugs with anticholinergic effects (39.7%). In the multivariate analysis, the variables associated with all MRPs among the patients with multimorbidity were the number of drugs and the number of visits.The coexistence of multimorbidity and polypharmacy is associated with an elevated risk of MRPs in older people. Medication safety for older patients constitutes a pressing concern for health services. The increase in life expectancy is associated to an increase in multimorbidity.Older people belong to a population subgroup that is very prone to suffering from MRPs.MPRs are very prevalent in older people with multimorbidity, mainly in the subgroup of patients with 10 or more comorbidities, and with polypharmacy.There is a positive correlation between the number of drugs and the number of visits and the risk of MRPs.The clinical approach in older patients with multimorbidity and the safe use of the drugs which are prescribed to them represent two main challenges for health systems in order to reach a balance between the beneficial and drug side effects.1People over 65 years of age are the fastest‐growing segment of the world's population. It is considered that by 2050 one in four persons living in Europe and North America will be 65 or over.Prescription of multiple medicines in older people has been associated with lack of adherence, increase in medication‐related problems (MRPs), the emergence of geriatric syndromes and diminished functional capacity, resulting in a higher consumption of health resources.Some studies show that multimorbidity is closely related to the emergence of MRPs, since multimorbidity often requires the intervention of various specialists and the prescription of multiple drugs.22.1A cross‐sectional study was carried out in Catalonia (Spain), a Mediterranean region of 7 515 398 inhabitants.Inclusion criteria were: individuals between 65 and 99 years old in December 31, 2011 and assigned to a PHC managed by ICS. Only participants that survived until December 31, 2012, were included in the analysis. A total of 916 619 patients were included at baseline. The study period was from January 1, 2012 to December 31, 2012.2.2The Information System for Research in Primary Care (SIDIAP) contains anonymized clinical information originating from the primary care electronic health records (EHR) since 2006.The medication database includes drugs subsidized, dispensed and billed by the national health system. For the purpose of identifying problems related to the most relevant medications, the study only included systemic drugs, and excluded hospital medication, drugs dispensed by hospital pharmacies, drugs not subsidized by public health services and topical medication .2.3All variables were obtained directly from the SIDIAP database.2.3.1In the SIDIAP database, diseases are coded in accordance with the International Classification of Diseases, version 10 (ICD‐10). An operational definition of multimorbidity was used, that is, the presence of two or more chronic diseases, based on the selected 60 groups of chronic diseases determined by the Swedish National study of Aging and Care in Kungsholmen (SNAC‐K),2.3.2The number of different drugs per patient was classified in five categories: 0; 1; 2‐4; 5‐9; ≥10 drugs.Information on drug exposure was obtained from the Pharmacy Invoice Registry, which includes drugs prescribed by primary care and hospital physicians. Drugs were classified according to the Anatomical Therapeutic Chemical Classification System (ATC).2.3.32.Glomerular Filtration Rate (GFR): kidney function was calculated estimating the GFR according to the MDRD‐4 IDMS10 equation.ICD‐10 codes included in chronic kidney disease category according to SNAC‐K criteria , Alanine Transaminase (ALT); and Gamma‐glutamyl Transpeptidase (GGT). Liver dysfunction was considered when at least one value was abnormal: ALP > 2 × 129 IU/L; ALT > 5 × 41 IU/L (men) or ALT > 5 × 33 IU/L (women); and GGT > 61 IU/L.ICD‐10 codes included in chronic liver disease category according to SNAC‐K criteria , sex , socio‐economic status 2.3.6Duplicate therapy: practice of prescribing two or more medications with the same pharmacological activity. Duplicate therapies considered to pose significant clinical risk by professional consensus were included. The associations of active principles with the same pharmacological action that were used jointly to achieve a synergistic effect or to adjust doses were not considered .Drug‐drug interaction: when the activity or effect of one drug is altered by the presence or the action of another. We prioritized interactions that might threaten life due to therapeutic failure or toxicity. We used the Contraindicated drugs in chronic kidney disease: contraindicated medications were based on a consensus recommendation of the Catalan Health Department for patients with chronic kidney disease (see Table Drugs contraindicated in liver disease: were based on the database of the Spanish College of Pharmacists (see Table PIMs in older people (≥65 years old): were considered when the associated risk of adverse events was higher than the expected clinical benefits and when there was not clear scientific evidence for a specific indication or cost‐effectiveness. We mainly used the STOPP/START criteria,The following MRPs were analyzed: duplicate therapy, drug‐drug interactions, potentially inappropriate medications (PIMs) in older people (≥65 years old), contraindicated drugs in chronic kidney disease and contraindicated drugs in liver diseases. To analyze the MRPs, firstly we created the tables that contain the medicines or associations of medicines with potential safety concerns:2.4The protocol of the study was approved by the Clinical Research Ethics Committee of the Fundació Institut Universitari per a la Recerca a l'Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol) (Protocol No: P17/080). All data were anonymized and confidentiality of EHR was guaranteed at all times in accordance with national and international law.2.5U test to assess differences between groups (multimorbidity groups and non‐multimorbidity group).Descriptive statistics were used to summarize overall information. Categorical variables were expressed as frequencies (percentage) and continuous variables as mean (SD) or median . We used the Chi‐square test and Mann‐Whitney Prevalence of MRPs and use of PIMs were compared among groups.Logistic regression models were fitted in order to identify the factors associated with each MRP  in the population with multimorbidity. Odd ratios (OR) and 95% confidence intervals (CI) were calculated. Variables included in the logistic regression models were sex, age, MEDEA index, number of drugs and number of visits.The analyses were carried out using SPSS for Windows, version 25 , Stata 15 Stata/MP, version 15 for Windows  and R version 3.6.1 . The significance level was set at .05.3P < .001). In the multimorbidity group, the mean number of diagnoses per patient was 6.3 (SD: 3.0) and the mean number of medications was 5.6 (SD: 3.9). Table A total of 916 619 patients were included in the analysis. The median age was 75 years (IQR: 69‐81) and 57.7% were women. Out of 853 085 patients, 93.1% met multimorbidity criteria, with a higher prevalence in women , followed by contraindicated drugs in chronic kidney disease (12.1%), and duplicate therapy (11.1%). These percentages were higher in the subgroup of patients with 10 or more comorbidities, with percentages of MRP of 88.0%, 31.3% and 20.1%, respectively. Conversely, these percentages were less in non‐multimorbidity group: 16.1%, 0.06% and 1.86%, respectively , the use of antiulcer agents without criteria for gastroprotection (40.6%), and the combination of drugs with anticholinergic effect (39.7%), for which 34 052 patients (5.9%) presented high anticholinergic load (score ≥ 3). These percentages are higher in the subgroup of patients with ≥10 comorbidities , closely followed by duplicate therapy and PIMs (10.6%)   to 1.24 (95% CI: 1.19‐1.30), except in the case of drugs contraindicated in liver diseases . There was a positive correlation between the number of drugs and the risk of MRPs, particularly between PIMs and the group of patients that were prescribed ≥10 drugs . Finally, a higher number of visits (number of visits from 1 to ≥10) correlated with a higher risk of MRPs, with OR ranging from 2.70 (95% CI: 2.30‐3.17) to 23.74 (95% CI: 16.60‐33.96) , probably attributable to the different criteria used in the various studies.The major strength of this study is the use of a high quality database of primary care records that includes 75% of the Catalan population and is, thus, considered highly representative. This study comprehensively analyses the most commonly prescribed medicines in primary care and provides information on MRPs relating to the use of contraindicated drugs in liver diseases in older people. On the other hand, our analysis excludes hospital medications, drugs dispensed from hospital pharmacies, drugs not subsidized by public health services and medication prescribed for acute conditions, which have the potential to cause MRPs. Moreover, the study uses the billing database for drugs, while actual adherence to medication is not known.In this study, the medication registered in the EHR includes drugs prescribed by family doctors and other specialists. Fragmentation of care is common in patients with multimorbidity, which are frequently referred to specialists, thus increasing the risk of MRPs.There is much diversity among studies which quantify the impact of interventions aimed at reducing MRPs and PIMs. Consequently, there is unclear evidence showing that interventions such as the review of prescriptions actually reduced the number of patients with one or more PIMs or MRPs.Importantly, reduction of MRPs should be assisted by the integration of automated warnings regarding prescriptions and a safe use of medications in the prescription modules of family doctors. The results of this study indicate that the coexistence of multimorbidity and polypharmacy is clinically relevant since it correlates with an elevated risk of MRPs. However, the study cannot specify the individual impact of each of these two factors. Polypharmacy and unsafe medication constitute a risk factor for undesired clinical consequences: falls, fall‐associated variables , adverse drug reactions, general health decline , poor cognitive performance, hospitalization and mortality rates.5The results of this study underscore the clinical significance of polypharmacy and multimorbidity, which correlate with a high risk of MRPs in patients over 65 years of age. The risk of MRPs could be attenuated with periodic reviews of medication and the implementation of automated warnings in the electronic prescription systems although the clinical impact of this reduction is not known. The inappropriately prescribed drugs most commonly related to safety issues were proton pump inhibitors and anxiolytics. With the aging of the population, ensuring safe and effective pharmacological treatment for older patients represents one of the main challenges for health services.www.icmje.org/coi_disclosure.pdf and declare: no support from any organization for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could have influenced the submitted work.All authors have completed the ICMJE uniform disclosure form at All authors contributed to the design of the study, revised the article and approved the final version. Concepción Violán, Albert Roso‐Llorach, Ester Amado‐Guirado and Sergio Fernández‐Bertolin obtained the funding. Concepción Violán, Mariona Pons Vigues, Quintí Foguet‐Boreu, Albert Roso‐Llorach, Amelia Troncoso‐Mariño and Noemí Villén drafted the article. Noemí Villén, Amelia Troncoso‐Mariño, Mariona Pons Vigues, Albert Roso‐Llorach, Concepción Violán and Sergio Fernández‐Bertolin proposed the methodology, conducted the tests and contributed to the analysis and interpretation of data. Amelia Troncoso‐Mariño, Concepción Violán, Quintí Foguet‐Boreu and Noemí Villén wrote the first draft of the manuscript. Noemí Villén, Amelia Troncoso‐Mariño, Albert Roso‐Llorach and Sergio Fernández‐Bertolin wrote the first draft of the supplementary file, and all authors contributed ideas, interpreted the findings and reviewed rough drafts of the manuscript.The protocol of the study was approved by the Clinical Research Ethics Committee, Fundació Institut Universitari per a la Recerca a l'Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol) (Protocol No: P17/080). All data were anonymized in agreement with national and international law.Table S1 Codes ICD 10 included in the diagnosis of chronic kidney disease.Table S2. Codes ICD 10 included in the diagnosis of chronic liver disease.Table S3. List of duplicate therapy.Table S4. List of drug‐drug interaction.Table S5. List of drugs contraindicated in chronic kidney disease by first level of ATC.Table S6. List of drugs contraindicated in liver diseases by first level of ATC.Table S7. List of drugs potentially inappropriate in the elderly (≥65 years).Table S8. Number of contraindicated drugs in chronic kidney disease and liver disease and potentially inappropriate medications in older people by multimorbidity group .Table S9. Twenty most contraindicated drugs in chronic kidney disease by multimorbidity group .Table S10. Twenty most contraindicated drugs in liver disease by multimorbidity group .Table S11. Twenty most potentially inappropriate medications in older people by multimorbidity group .Click here for additional data file.


PD participants were identified through specific PD reported medications. Periodontitis was defined according to the 2012 case definition, using periodontal examination data provided. Then, we compared blood levels and standard chemical laboratory profiles of PD patients according to the presence of periodontitis. Multivariable regression was used to explore this dataset and identify relevant variables towards the presence of periodontitis. According to the medication report, 37 participants were eligible, 29 were secure and 8 were unsecure PD medications regimens. Overall, PD cases with periodontitis presented increased levels of White Blood Cells (WBC) (p = 0.002), Basophils (p = 0.045) and Segmented neutrophils (p = 0.009), and also, lower levels of Total Bilirubin (p = 0.018). In the PD secure medication group, a significant difference was found for WBC (p = 0.002) and Segmented neutrophils (p = 0.002) for the periodontitis group. Further, WBC might be a discriminating factor towards periodontitis in the global sample. In the secure PD medication, we found gender, segmented neutrophils and Vitamin D2 to be potential discriminative variables towards periodontitis. Thus, periodontitis showed association with leukocyte levels alterations in PD patients, and therefore with potential systemic changes and predictive value. Furthermore, Vitamin D2 and gender showed to be associated with periodontitis in with secure medication for PD. Future studies should assess in more detail the potential systemic repercussion of the presence of periodontitis in PD patients.People with Parkinson’s Disease (PD) are associated with the presence of periodontitis. We aimed to compare blood and standard biochemical surrogates of PD patients diagnosed with periodontitis with PD individuals without periodontitis. This retrospective cohort study used a sample from the National Health and Nutrition Examination Survey (NHANES) 2011–2012 that underwent periodontal diagnosis ( Periodontitis is a chronic inflammatory condition that targets the supporting structures of the teeth . Dental Parkinson’s disease (PD) is the second most frequent slowly progressive neurodegenerative condition that mostly affects the central nervous system . Still wTo date, the relationship between PD and periodontitis stands with PD associated motor impairments and cognitive decline that compromises oral hygiene habits and causes the deterioration of patient’s oral status . ConsequTherefore, our primary aim was to compare blood and standard biochemical levels between periodontitis and non-periodontitis cases among Parkinson’s disease patients. Additionally, we aimed to evaluate if such changed biomarkers might contribute to predict the presence of periodontitis in PD patients.https://www.cdc.gov/nchs/nhanes/index.htm. In this retrospective cohort study, periodontal examination data from the NHANES 2011–2012 was extracted. Our analysis deemed the following exclusion criteria: younger than 18 years of age; participants with medical exclusion from periodontal exam; non-complete periodontal status and edentulous patients. The National Health and Nutrition Examination Survey (NHANES) 2011–2012 data is a representative multistage probability sample of non-institutionalized U.S. civilians survey to assess the health status through the Centers for Disease Control and Prevention (CDC) and Prevention National Center for Health Statistics (NCHS) website at Oral health data collection protocols were approved by the CDC, NCHS Research Ethics Review Board, Atlanta (USA), and all participants gave written informed consent. All the examinations were conducted in a mobile examination center (see in detail in ). PD cases were confirmed through specific PD reported medications according to the NHANES database. In this way, patients reporting the use of Benztropine, Carbidopa, Levodopa, Ropinirole, Methyldopa, Entacapone, Cabergoline, Orphenadrine and Pramipexole were categorized as PD cases ,31. ThenPeriodontitis was defined as a minimum of 2 or more sites with clinical attachment loss (CAL) ≥ 3 mm and a periodontal pocket depth (PPD) ≥ 4 mm or one site with PPD ≥ 5 mm, as described by Eke et al. (2012). Data from the Periodontal Examination of NHANES 11–12 were treated through appropriate algorithms in Microsoft Office (MO) Excel to render the respective periodontal diagnosis. From this, we were able to render the number of missing teeth.The demographic variables included were age, gender, smoking status and number of teeth. From the self-reported questionnaire, we categorized smoking status as current smoker (smoked more than 100 cigarettes and currently smoking), former smoker (smoked more than 100 cigarettes and currently not smoking) and non-smoker (never smoked). Diabetes mellitus was categorized as “yes” or “no” according to the self-reported questionnaire. High blood pressure was categorized according to previous medical confirmation of high blood pressure and if taking prescription for hypertension.9/L), percentage of Lymphocyte (%), percentage of Monocyte (%), percentage of Segmented Neutrophils (%), percentage of Eosinophils (%), percentage of Basophils (%), Lymphocyte (109/L), Monocyte (109/L), Segmented neutrophils (109/L), Eosinophils (109/L), Basophils (109/L), Red Blood Cell (RBC) count (million cells/uL), Hemoglobin (g/dL), Hematocrit (%), Mean Cell Volume (MCV) (fL), Mean Cell Hemoglobin (MCH) (pg), Mean Cell Hemoglobin Concentration (MCHC) (g/dL), Red Cell Distribution (RCD) width (%), Platelet count (109/L), Mean Platelet Volume (MPV) (fL).Blood levels data included White Blood Cell (WBC) count , Alanine aminotransferase (ALT) (U/L), Aspartate aminotransferase (AST) (U/L), Alkaline phosphatase (AP) (U/L), Blood Urea Nitrogen (mg/dL), Total Calcium (mg/dL), Creatine Phosphokinase (CPK) (IU/L), Cholesterol (mg/dL), Bicarbonate (mmol/L), Creatinine (mg/dL), Gamma Glutamyl Transferase (GGT) (U/L), Glucose, Serum (mg/dL), Iron (refrigerated) (ug/dL), Lactate Dehydrogenase (LDH) (U/L), Phosphorus (mg/dL), Total Bilirubin (mg/dL), Total Protein (g/dL), Uric Acid (mg/dL), Sodium (mmol/L), Potassium (mmol/L), Chloride (mmol/L), Osmolality (mmol/Kg), Globulin (g/dL), Triglycerides (mg/dL), 25-hydroxyvitamin D2 (25OHD2) (nmol/L), 25-hydroxyvitamin D3 (25OHD3) (nmol/L).n), percentage (%) for categorical variables. The main outcome variable was the presence of periodontitis (P+ vs. P−). We compared baseline variables between periodontitis and non-periodontitis groups. Explicit comparison of mean values was performed by t-Student test when data assumptions for the application of this test were met . Mann–Whitney test was used, as an alternative comparison technique, when those assumptions were not verified. To compare significant variables between the subgroups P(−) and P(+) we graphically computed the tendency of WBC, segmented neutrophils and basophils counts according to age using scatterplots from ggplot2 package for R version 4.0, and tendency was computed and fitted via ‘geom_smooth’. Then, we made regression analyses in the overall and only in secure PD cases. Preliminary analyses were performed using univariate models. Next, a multivariable model was constructed for the presence of periodontitis. Only variables showing a significance p ≤ 0.25 in the univariate model were included in the multivariable stepwise procedure. Predictor variables considered in this procedure were: gender , WBC count (109/L), Segmented neutrophils (109/L) and 25-hydroxyvitamin D2 (25OHD2) (nmol/L). The contribution of each variable to the model was evaluated by Wald statistics. A multivariable stepwise adjusted logistic regression procedure was used to model the influence of the investigated factors towards the presence of periodontitis in PD patients. A significance level of 5% was set in all inferential analyses. Data were uploaded through SAS Universal Viewer for Windows and handled with MS Excel. For each periodontal case definition, specific MS Excel datasets were derived in order to formulate appropriate algorithms to define the periodontal status according to the case definition. Data analysis was performed using IBM SPSS Statistics version 25.0 for Windows . Descriptive measures are reported through mean ± standard deviation (SD) for continuous variables, and number of cases  participants were identified as taking PD medications, 29 secure  and 8 unsecure PD  medications regimens . There wp = 0.002), Basophils (p = 0.045) and Segmented Neutrophils (p = 0.009), also displayed graphically (p = 0.002) and Segmented Neutrophils (p = 0.002) for the periodontitis group .Then, we investigated the standard biochemistry profile levels to investigate the systemic status of these participants according to the presence of periodontitis . The onlp =0.025) (p = 0.026), Segmented Neutrophils  and 25OHD2 . The second model evidenced an improved score for correct classification (89.7%).In order to analyze which factors would discriminate the periodontitis presence, we performed multivariable stepwise regression analyses considering each factor. In the overall sample, blood WBC levels were consistently identified as a discriminative factor towards periodontitis  . Among tIn the present representative study from the NHANES 2011–2012, periodontitis was associated with increased serum levels in PD patients. Therefore, our hypothesis was confirmed, in which leukocyte levels  and bilirubin were increased in periodontitis cases in this particular population. Furthermore, for the overall population WBC count showed potential predictive value towards periodontitis, while for secure PD medications gender, segmented neutrophils and 25OHD2 were the meaningful elements.The link between periodontitis and leukocytosis is well documented ,38,39,40Furthermore, male gender presented a higher risk to have periodontitis, this result being in line with previous reports that show males have a higher prevalence of periodontitis both in representative ,46,47 anAdditionally, the presence of 25OHD2 in the predictive models is also in accordance with previous studies, where individuals with periodontitis were associated with lower levels of Vitamin D, compared to non-periodontitis ,51,52,53The present report has limitations important to mention and discuss. Despite this sample deriving from a large representative U.S. population survey, the final number of included patients was small. However, this small number can be explained by the fact that PD affects 1% of individuals over 60 . In our In spite of these limitations, this article has important strengths. Our report is the first to depict the potential effect of the presence of periodontitis on the systemic status of PD. Further, NHANES is prospectively a reliable source of data to determine associations as previously demonstrated , and pubPeriodontitis was associated with an increase of white blood cells count, segmented neutrophils and basophils in PD patients. Furthermore, white blood cells count, segmented neutrophils, Vitamin D2 and gender showed discriminatory value to predict the existence of periodontitis in PD cases. Future studies should assess in more detail the potential systemic repercussion of the presence of periodontitis in PD patients.


It has been demonstrated that urinary neutrophil gelatinase-associated lipocalin (NGAL) and calprotectin are helpful biomarkers in the differentiation of intrinsic and prerenal acute kidney injury. The present cross-sectional study investigates, whether urinary biomarkers are able to differentiate primarily inflammatory from non-inflammatory entities in chronic kidney disease (CKD).2 in the past 12 months. Pyuria, metastatic carcinoma, and renal transplantation were regarded as exclusion criteria. Diabetic nephropathy, hypertensive nephropathy, and polycystic kidney disease were categorized as ‘primarily non-inflammatory renal diseases’ (NIRD), whereas glomerulonephritis and vasculitis were regarded as ‘primarily inflammatory renal diseases’ (IRD). Urinary calprotectin, NGAL, and kidney injury molecule-1 (KIM-1) concentrations were assessed in a study population of 143 patients with stable CKD and 29 healthy controls. Stable renal function was defined as an eGFR fluctuation ≤5 ml/min/1.73 mp < 0.05 each), whereas KIM-1 concentrations did not (p = 0.84). The three biomarkers did neither show significant differences in-between the individual entities, nor the two categories of IRD vs. NIRD . Albumin exceeds the diagnostic power of the investigated biomarkers by far. Urinary calprotectin and NGAL concentrations significantly differed between CKD and healthy controls ( The urinary biomarkers calprotectin, NGAL, and KIM-1 have no diagnostic value in the differentiation of primarily inflammatory vs. non-inflammatory etiologies of CKD. A kidney biopsy is the only possibility to establish a definite diagnosis of an individual’s renal disease. The histological identification of glomerulonephritis or vasculitis allows the initiation of a specific therapeutic intervention like immunosuppression. In contrast, hypertensive or diabetic nephropathy is primarily managed by unspecific measures like control of blood pressure, diabetes, and hyperlipidemia. Hence, these subjects do not benefit from kidney biopsy. The selection of patients with chronic kidney disease (CKD), who should undergo a kidney biopsy, constitutes an unresolved challenge. Today, the decision to perform a biopsy in a hypertensive or diabetic subject is usually based on clinical scenarios like microscopic hematuria, nephrotic range proteinuria, impairment of renal function with diabetes/hypertension of short duration, or a rapidly worsening glomerular filtration rate (GFR) in previously stable subjects . The defAnalogously, there was a search for a biomarker that differentiates between intrinsic and prerenal acute kidney injury (AKI). A reliable noninvasive test for the differentiation of prerenal and intrinsic AKI was desirable since it would shorten the time to initiation of therapy and it would prevent unnecessary biopsies in prerenal disease. We and others have shown that urinary calprotectin and neutrophil gelatinase-associated lipocalin (NGAL) are helpful biomarkers in this context: Whereas urinary concentrations are substantially increased in intrinsic AKI, concentrations are comparable to healthy controls in the case of prerenal AKI . A recenWhereas these urinary biomarkers have been extensively studied in AKI, it remains elusive, whether they may provide helpful diagnostic information in stable CKD as well. With regard to their role as mediator proteins of the innate immune system and their substantial increase in intrinsic AKI  and the described impact on inflammation and fibrosis (KIM-1), it may be hypothesized that the urinary concentrations of these biomarkers are higher in primarily inflammatory than in primarily non-inflammatory underlying entities of CKD. The present cross-sectional study investigates this hypothesis in a population of stable CKD.2 within the past 12 months. We refrained from including subjects with a higher deterioration of eGFR in order to reliably exclude any states of acute on chronic kidney injury. Exclusion criteria were obstructive uropathy, urothelial carcinoma, metastatic cancer, and pyuria. Etiological entities were categorized in primarily inflammatory renal diseases  and primarily non-inflammatory diseases . This categorization was done despite the fact that inflammatory mechanisms are of relevance in the pathogenesis of these entities as well. The mechanisms, however, can contribute to the progression of the diseases but do not initiate them and do not necessitate immunosuppression. Glomerulonephritis/vasculitis comprised subjects with lupus nephritis, crescentic glomerulonephritis due to polyangiitis with granulomatosis, membranous glomerulonephritis, IgA-nephropathy and mesangioproliferative glomerulonephritis in Schönlein–Henoch purpura, focal segmental glomerulosclerosis, and glomerulonephritis of unknown origin. This study was approved by the local ethics committee of the Charité – University Hospital Berlin (EA4/043/09) and by the ethics committee of the Ruhr-University of Bochum (5019-14). All patients provided written informed consent.The present work constitutes a multicenter study at two nephrological outpatient offices in Berlin, Germany. 143 patients with stable CKD as well as 29 healthy subjects without any medical history serving as control were enrolled. The study population has been described in a former study . CKD was® Calprotectin, catalog number K 6928, Immundiagnostik AG, Bensheim, Germany) according to the manufacturer’s protocol as published previously  ml/min/1.73 m2) compared to NIRD . A body mass index above 30 kg/m2 was seen in 38.8% of the study population. Ferritin , hemoglobin  and C-reactive protein  did not differ between the two groups. 29 healthy controls did not suffer from any preexisting overt medical condition. They included 21 male and 8 female subjects with a median age of 74 (IQR 58–77). Assessment of urinary calprotectin, NGAL, and KIM-1 was successful in the whole study population. Biomarker concentrations in dependence on the underlying etiology of CKD are presented in The study included 143 subjects with stable CKD including 29 female and 114 male patients with a median age of 72 (IQR 67-77). Group 2  than the CKD population . Median concentrations of diabetes (n = 41), hypertension (n = 42), and the combination of these entities (n = 19) fell between the values of these two groups. Analysis of variance showed no intergroup differences in the CKD population . Calprotectin showed a non-significant numerical trend to higher values in IRD compared to NIRD . Diabetes and hypertension led to median concentrations of 10 414 (IQR 5400–27 064 pg/ml) and 13 173 pg/ml (IQR 6567–25 936 pg/ml), respectively. Subjects of IRD had a median concentration of 14 896 pg/ml (IQR 5658–28 881 pg/ml). Patients with ADPKD yielded a urinary NGAL of 16 692 pg/ml (IQR 4153–18 534 pg/ml). The lowest concentrations were measured in the remaining etiologies of CKD . Analysis of variance showed no intergroup differences in the CKD population . NGAL showed a numerical trend to higher values in IRD compared to NIRD without reaching statistical significance  compared to healthy controls , followed by IRD . The lowest concentrations were obtained in the remaining etiologies . Median concentrations of diabetes, hypertension, and the combination of these entities fell between the values of these two groups. Analysis of variance showed no intergroup differences in the CKD population . KIM-1 showed a numerical trend to higher values in IRD compared to NIRD without reaching statistical significance  and the CKD population  and the combined etiology of diabetes and hypertension . Analysis of variance showed an intergroup difference in the CKD population  with a post-hoc analysis yielding significance for pairwise comparison of diabetes and hypertension (p = 0.02) as well as diabetes and ‘others’ (p < 0.001). ACR was significantly higher in IRD compared to NIRD  had a lower ACR than the CKD population . It can be released as a proinflammatory danger signal from both leukocytes (predominantly neutrophils and monocytes) and damaged tissue itself ,22,23. PKIM-1 and NGAL reflect tubular damage. Hence, these molecules may be candidate biomarkers for ADPKD. Indeed, an increase in urinary KIM-1 reflects tubular damage in the proximal S3 tubule segment , and MeiThe study did not evaluate novel glomerular biomarkers like podocin or nephrin. It did include, however, albumin as the most established and widespread biomarker of glomerular injury. In fact, the discriminatory potency of ACR was better than NGAL, calprotectin, and KIM-1. There was a significant intergroup difference compared to the aforementioned biomarkers. The highest values were reached amongst the inflammatory entities and diabetes, CKD due to hypertension reached the lowest concentrations. With an AUC of 0.70 albuminuria had the highest discriminatory potency of all the biomarkers in the differentiation of IRD and NIRD.NGAL, KIM-1, and calprotectin detect acute deteriorations of renal function. There are abundant investigations of NGAL and KIM-1 in various settings of AKI as well as their use as predictors for renal and cardiovascular endpoints, whereas work on its differential diagnostic potential in CKD is extremely scarce. The present study aimed to characterize their diagnostic potency in merely chronic disease. The trial provides information on both a heterogeneous ‘real life’ CKD population and a subgroup of primarily inflammatory renal diseases. Calprotectin was tested for the first time with the aim to discriminate for primarily inflammatory entities. In order to avoid any ‘acute on chronic’ states of kidney disease, we focused on stable CKD with an eGFR loss ≤5 ml in the past 12 months. This aspect in study design was mandatorily for a clear separation of acute from chronic disease. On the other hand, it is a limitation: It cannot be excluded, that there is a diagnostic potency of these biomarkers in progressive CKD. Future studies addressing this question should be welcomed.In summary, urinary calprotectin, NGAL, and KIM-1 were not able to differentiate between various entities of stable CKD. Specifically, IRD could not be discriminated from NIRD. Albumin as a traditional glomerular biomarker exceeds the diagnostic performance of these new biomarkers by far. Their characteristics in ‘unstable CKD’, for example, active glomerulonephritis or vasculitis, remain elusive.Click here for additional data file.


V1: 13.3 ± 6.9 h, V2: 4.9 ± 3.2 days and V3: 93.9 ± 11.5 days post-stroke). (3) Results: In response to GHP, MABPv does not initially increase, but over time MABPv showed a significant increase in response to GHP in AIS (visits 2 and 3) and controls (visit 2). Additionally, in response to GHP in AIS, CBFVv increased in the affected hemisphere. Lastly, in AIS, a significant correlation between CBFVv and MABPv, assessed by SD, was seen in the unaffected hemisphere, whereas this relationship was not demonstrated in the affected hemisphere. (4) Conclusions: To our knowledge, this is the first study to analyse the relationship between CBFVv and MABPv. Shedding light on the effect of head position on the relationship between cerebral blood flow and blood pressure is important to improve our understanding of the underlying effects of cerebral autoregulation impairment. This early mechanistic study provides evidence supporting supine head positioning in healthy controls and stroke patients, through demonstration of a reduction of MABPv and increase in CBFVv. (1) Background: Larger blood pressure variability (BPv) in the first 3 h post-stroke onset increases pathophysiological effects such as infarct size, and leads to greater risk of disability, comorbidities and mortality at 90 days. However, there is limited information on the relationship between systemic and cerebral haemodynamic and variability parameters. (2) Objectives: This study determined the effect of a gradual change in head position (GHP) on cerebral blood flow velocity variability (CBFVv) and mean arterial blood pressure variability (MABPv), in healthy controls and acute ischaemic stroke (AIS) patients. Methods: CBFVv and MABPv were expressed as standard deviation (SD) and coefficient of variation. A total of 16 healthy controls (mean age 57 ± 16 years) were assessed over two visits, 12 ± 8 days apart, and 15 AIS patients (mean age 69 ± 8.5 years) were assessed over three visits ( Ischaem2 . It has 2 . Meng an2 . However2 . CA can 2 . In acut2 ,12.Presently most studies of dCA are based on cerebral blood flow velocity (CBFV) measured with transcranial Doppler ultrasound (TCD), however, there is limited information on the relationship between mean arterial blood pressure variability (MABPv) and cerebral blood flow velocity variability (CBFVv). MABPv is associated with poorer prognosis in AIS, especially in those with severe strokes, as suggested by a higher NIHSS score, and this may be due to greater dCA impairment . Larger Previous studies have been unclear in determining the optimum head position for management of stroke. Currently, the standard post-stroke recovery head position is ≥30°, to reduce the risk of aspiration pneumonia. However, the overall aim of AIS management should be to optimise perfusion to the ischaemic penumbra; therefore, several studies  have been carried out to determine the most beneficial head position for a good prognosis post-stroke, and some suggesting a supine (0° head position) may be advantageous as it improves CBF ,16. A redown) and upright  on beat-to-beat CBFV and cerebral haemodynamic parameters in AIS patients and healthy controls, recruited between December 2015 and March 2017 [The study was approved by the Wales Research Ethics Committee 1 (Reference: 15/WA/0328) and all participants provided written informed consent. Lam et al. 2018) provided the primary data for this analysis, this study aimed to assess and compare the effect of a gradual head position (GHP) change between supine  hyper-acute stroke unit within 24 hrs of symptom onset if they were not eligible to receive intravenous thrombolysis or undergo mechanical thrombectomy. Healthy control subjects were recruited on the basis that they matched in age, sex and BP to recruited AIS patients, recruiting from volunteers within the department or local hospital trust. Participants were excluded from the trial if they were under the age of 18 years, unable or unwilling to give consent to participate in the study, were/planned to be pregnant, and/or lactate during the time period of the study. Other grounds for exclusion included individuals who practiced yoga regularly . AIS patrtension  and comodown and HPup, by changing the angle of the hospital bed, measured using a goniometer.Assessments took place in a dedicated cardiovascular research laboratory at UHL, with the participants on a standard hospital bed. Each participant experienced both HPUsing a UA767 BP monitor, three brachial BP recordings were taken and averaged. Beat-to-beat BP was recorded using a Finometer device  placed on the middle finger of the nondominant/nonhemiparetic arm of control and AIS participants, respectively. Cardiovascular status of the patient was monitored using a three-lead ECG. TCD ultrasonography  was performed with 2 MHz probes, enabling bilateral insonation of the middle cerebral arteries (MCA) of the participant, accessed through the temporal bone window. A head frame was used to secure and maintain the position of the ultrasound probes. Continuous measurements of BP and CBFV were recorded onto a physiological data-acquisition system (PHYSIDAS), at a rate of 500 samples/s and stored for processing data offline.down. Following this, a GHP paradigm was initiated to examine the effect of head position on cerebral haemodynamics, from HPdown to HPup, and this was repeated twice  and another 5-min assessment was carried out. Over a 30-s time period, the angle of the bed was returned to an HPdown, where another 2-min recording was performed. This protocol (timing and degree of head position change) was validated through pilot work [Baseline assessment and recordings of all parameters of each individual were performed over 5-min, while the participant was in an HPed twice . Particilot work , demonstdown and the 5-min assessments in the HPup were analysed and compared. A BP correction for the 30° in head position change was conducted to provide the correct MABP at head height.Healthy controls underwent this procedure twice on two separate visits, approximately 14 days apart. Assessments for AIS patients were taken in three separate visits, for up to three months post-stroke symptom onset. ‘Visit 1’ took place straight after admission into the hospital (acute: within 24 h of symptom onset), ‘visit 2’ was within 7 days ± 24 h post-stroke onset (sub-acute), and ‘visit 3’ was 3 months ± 7 days post-stroke onset (chronic) . Data obdown and HPup Spearman’s rank-order correlation and linear regression tests were also performed on both datasets. All tests were conducted on the dominant/nondominant hemispheres (DH/NDH) for healthy controls and on the unaffected/affected hemispheres (UH/AH) for AIS patients during each visit (p < 0.05 indicates significance).MABPv and CBFVv were expressed by standard deviation (SD) over the 5-min recordings. To standardise the values of SD, the coefficient of variation (CoV = SD/mean), represented as a percentage (CoV (%)), was also calculated. Datasets for healthy controls and AIS patients were independently analysed. For each dataset the Shapiro-Wilks test was first performed, showing that the data for both MABPv and CBFVv were not normally distributed. Therefore, to test whether there was a significant difference in MABPv and CBFVv, in response to GHP change, the nonparametric paired Wilcoxon signed-rank test was conducted for both healthy controls and AIS. All data were analysed separately without the need for multiple testing analyses. In order to investigate the relationship between MABPv and CBFVv for both HPFifteen AIS patients (7 women) were recruited (mean ± SD age of 69 ± 8.5 years), and 11 out of the 15 patients completed all visits. These included two total anterior circulation, five partial anterior circulation, three posterior circulation and five lacunar stroke syndromes. A small number of AIS patients were unable to participate in subsequent visits, due to inpatient transfer for ongoing rehabilitation at another hospital. Eighteen healthy control subjects were recruited, but two were excluded from the study due to poor insonation of their temporal windows . Data frdown and HPup) and 3 (HPup only)  A–C, but  visit 2 D.The three main findings from this study are: (1) in response to GHP, MABPv does not initially increase, but over time, i.e., visit 2 and 3, MABPv shows a significant increase in response to GHP in AIS and control groups; (2) in response to GHP, CBFVv increases in the AH; (3) in AIS, a significant correlation between CBFVv and MABPv, assessed by SD, was seen in the UH, whereas this relationship was not demonstrated in the AH.down versus HPup [down to HPup relaxes baroreceptors, inducing sympathetic stimulation causing vasoconstriction, increased heart rate (HR), cardiac contractility and venous return [An elevated head position in healthy controls significantly decreased MABP. Previous studies have found mean systolic blood pressure (SBP) to be greater in a HPsus HPup ,22,23. Ts return .up in healthy controls [MABPv is found to be significantly different during both visits, which is in agreement with previous studies, suggesting that a greater BPv is produced by an HPcontrols ,24. Sinccontrols , a supinA significant increase in MABPv was observed in visits 2 and 3, but not visit 1, in response to GHP. The initial lack of increase in MABPv in visit 1 could be due to pre-existing BPv. Studies have shown that in the hyperacute, acute and subacute stages of AIS patients, pre-existing BPv is present and therefore insensitive to the effects of changes in head position ,27,28. Hup reducing CPP, and in turn, CBF. Rosner and Coley (1986) studied 18 patients with intracranial hypertension, and showed an increase in head position caused a decrease in intracranial pressure (ICP) and increased the difference between MABP and ICP, therefore increasing the CPP [down may improve cerebral circulation [down maximises CPP, therefore is likely to improve CBF to the ischaemic penumbra [Previous studies have reported that a change in head position affects CBF, through changes in CPP ,31,32. A the CPP . Schneid the CPP . The Heaculation . These spenumbra ,31,32.Unaffected hemisphere. The UH showed no significant results in CBFVv in response to GHP. This could be explained by the fact that there is no pathology present, thus CA is preserved in that hemisphere. This is supported by Panerai et al. (2001) who demonstrated that, intact CA was present in all manoeuvres that induced sudden changes in BP in healthy subjects [subjects . A studysubjects . Additiosubjects .Affected hemisphere. Results showed that in the AH, SD of CBFVv in both visit 1 and 3 significantly increased in response to GHP. However, this was not seen in visit 2. Increase in CBFVv in response to GHP in visit 1 and 3 could be accounted for by pathology present in the AH causing CA impairment. This concept is termed lateralisation, whereby cerebrovascular impairment associates with the affected hemisphere. For example, if intact CA is not present to maintain constant CBF, lack of control of CBF could lead to the increased variation in response to systemic BP changes. This is supported by a study demonstrating that in a large MCA ischaemic stroke, the AH showed significant CA impairment, however, CA was intact in the UH [n the UH . Interesn the UH . Howevern the UH . In contn the UH ,37. up. This suggests the reproducibility of the response to GHP, as inter-visit variability in MABP is similar, which would be expected in a healthy control group, assuming the demographics of the participants remains the same. However, significant decrease in CBFV in upright compared to baseline positions in the nondominant and dominant side was only demonstrated in visit 2. The conflicting results between each visit could be the result of variable predominance of operating physiological mechanisms. During the first visit, the procedure was completely new to participants, which could result in anxious individuals. Anxiety alters ventilation–perfusion patterns, which affects the EtCO2, which was not analysed in this study. Minhas et al. (2018) demonstrated the strong correlation between CBFV and changes in EtCO2 [For healthy controls, results for MABP were consistent between both visits, with a significant increase in MABP found with a supine compared to HPin EtCO2 . In visiResults were not consistent between the SD of CBFV and MABP and CoV (%) of CBFV and MABP, which may be due to SD and CoV (%) measuring different facets of variability. The results observed in visit 1 showed a significant correlation for the SD of MABP and CBFV suggesting intact CA preserved in the UH. However, this relationship was lost in the AH, potentially suggesting CA impairment due to the pathology present A,B,E,F. Several limitations are associated with this study. First, the sample size included is relatively small, though no previous similar studies have been carried out and therefore a formal sample size calculation could not be performed. A sample size of sixteen would have 80% power to detect changes of 2 units in ARI with 5% significance . HoweverTo our knowledge, this is the first study to analyse the relationship between CBFVv and BPv. Shedding light on the effect of head position on the relationship between CBF and BP is important to improve our understanding of the underlying effects of CA impairment. This early mechanistic study provides evidence supporting supine head positioning in healthy controls and stroke patients, through demonstration of a reduction of BPv and increase in CBF. This study, by observing the changes in MABPv and CBFVv in response to GHP was able to investigate CA indirectly in AIS patients. However, future studies should look to investigate CA as well as the clinical effects of CBFVv and their effects over time, in order to fully evaluate these relationships and address any uncertainties in order to confirm the suggested hypotheses.


Lipid abnormalities are associated with diabetic kidney disease and CHD, although their exact role has not yet been fully explained. Sphingomyelin, the predominant sphingolipid in humans, is crucial for intact glomerular and endothelial function. Therefore, the objective of our study was to investigate whether sphingomyelin impacts kidney disease and CHD progression in individuals with type 1 diabetes.n = 1087) from the Finnish Diabetic Nephropathy (FinnDiane) prospective cohort study with serum sphingomyelin measured using a proton NMR metabolomics platform were included. Kidney disease progression was defined as change in eGFR or albuminuria stratum. Data on incident end-stage renal disease (ESRD) and CHD were retrieved from national registries. HRs from Cox regression models and regression coefficients from the logistic or linear regression analyses were reported per 1 SD increase in sphingomyelin level. In addition, receiver operating curves were used to assess whether sphingomyelin improves eGFR decline prediction compared with albuminuria.Individuals (−1 [1.73 m−2] year−1), even after adjustment for classical lipid variables such as HDL-cholesterol and triacylglycerols . Similarly, sphingomyelin increased the risk of progression to ESRD . Moreover, sphingomyelin increased the risk of CHD . However, sphingomyelin did not perform better than albuminuria in the prediction of eGFR decline.During a median (IQR) 10.7  years of follow-up, sphingomyelin was independently associated with the fastest eGFR decline  contains peer-reviewed but unedited supplementary material, which is available to authorised users. Diabetic kidney disease (DKD) is a fundamental risk factor for CVD in individuals with type 1 diabetes  or timed overnight [μg/min] urine collections. Normoalbuminuria was defined when, in at least two out of three urinary samples, UAER was <20 μg/min or <30 mg/24 h; microalbuminuria when UAER was ≥20 and <200 μg/min or ≥30 and <300 mg/24 h; or macroalbuminuria when UAER was ≥200 μg/min or ≥300 mg/24 h. In addition, at baseline, 24 h UAER was also measured centrally from a single sample with an immunoturbidimetric method.−1 1.73 m−2; (3) eGFR halving and eGFR <15 ml min−1 1.73 m−2; (4) eGFR decrease of >20 ml min−1 1.73 m−2; (5) eGFR halving or decrease of >20 ml min−1 1.73 m−2; and (6) eGFR decrease of >25% and change of CKD stage.In 2015, follow-up data on renal function and cardiovascular events were analysed. Individuals included were followed prospectively as part of the FinnDiane study, but laboratory data were also collected from their medical files. Kidney disease progression was assessed as the fastest eGFR decline quartile and as progression from a lower albuminuria stratum to a higher one. The median number of available serial creatinine measurements was 13  per individual included; the median proximity from the baseline visit was on average 10.7 years. From those values, eGFR was calculated. Repeated measurement analysis using mixed models was conducted, resulting in smoothed, predicted eGFR values. As the change in eGFR was used as a dependent variable in the next stage of analysis, no covariates were included in the model. Individual time for eGFR measurements was a random effect in the model. For the purpose of the eGFR change, we calculated the percentage annual change assuming linear decline on the log scale by using the first and last predicted eGFR value according to the formula: [(eGFR last/eGFR first) ^ (1/years elapsed between visits) − 1] × 100. Recently, it was shown that the eGFR slope was a relevant surrogate endpoint for renal outcomes in individuals with type 2 diabetes with a broad range of baseline kidney function . TherefoSimilarly, we had serial measurements of UAER during the follow-up and we also collected data from the medical files. The number of follow-up measurements was dependent upon baseline albuminuria status. Progression in albuminuria was defined as the progression from a lower albuminuria stratum to a higher one, with at least two consecutive measurements needed to confirm the stratum change. UAER measurements were performed annually if an individual had normoalbuminuria; however, they were performed every 3 months in those with microalbuminuria. Data on ESRD were retrieved from the Finnish Care Register for Health Care.Follow-up data on cardiovascular outcomes and death from baseline to the end of 2015 were retrieved from the Finnish Care Register for Health Care and the Cause of Death Register. CHD was defined as patients having had either a myocardial infarction or coronary revascularisation (percutaneous coronary intervention or coronary artery bypass graft) based on ICD-8/9 code 410, ICD-10 codes I21–I22 and the Nordic Classification of Surgical Procedure codes TFN 40, FN1AT, FN1BT, FN1YT, FNF, FNG, FNA, FNB, FNC, FND, FNE and 5311-5315. In addition, data on ischaemic strokes were collected based on ICD-8/9 codes 433 and 434 and ICD-10 code I63.χ2 test for categorical variables. Linear association of serum sphingomyelin with clinical variables was assessed using univariable regression; the strength of association is presented with Pearson r.Analyses were performed using SAS version 9.4  and SPSS Statistics version 21 . Distribution of variables was tested by Kolmogorov–Smirnov test. Continuous variables are given as mean ± SD if normally distributed, and otherwise as median with IQR. Categorical variables are given as percentages. Between-group differences were analysed using ANOVA for normally distributed variables and 1c, HDL-cholesterol and triacylglycerols. Sex and smoking were modelled as categorical, and other variables as continuous variables, respectively. When used in different models, due to low sphingomyelin level and in the absence of a standard concentration range, sphingomyelin level was scaled per its SD, to give more meaningful association measures. The assumption of the proportional hazards was tested by plotting Schoenfeld residuals against time and testing a nonzero slope by including time–covariate interaction. The potential nonlinearity in the relationship between sphingomyelin and different clinical outcomes was tested using generalised additive modelling (GAM) without a priori assumptions of the shape of the relation. GAM is an extension of the generalised linear model and allows the inclusion of nonparametric smoothing functions to identify a potential nonlinearity in the relationship between the independent and the dependent variables [p value of <0.05 was considered statistically significant.For the multivariable analyses of sphingomyelin association with different renal and CVD outcomes, Cox proportional hazard survival regression or logistic regression analysis or linear regression analysis was used, as appropriate. Variables, measured at baseline visit and reported to be associated with renal disease progression or CHD, were selected into the models together with the sphingomyelin level, including sex, time of diabetes onset, diabetes duration, previous or current smoking, systolic blood pressure, BMI, HbAariables . None ofn = 1087) had a median age of 38.1  years, and diabetes duration of 21.9  years at baseline. There were more men included in the study (54%).The participants (r = 0.12), diabetes duration (r = 0.12) and HbA1c (r = 0.18), but decreased with height (r = −0.14)   and standard lipid variables, including total cholesterol , HDL-cholesterol  and triacylglycerols . However, sphingomyelin was not associated with lipid-lowering therapy . ESM Table Serum sphingomyelin concentration was higher in females than in males , and increased with increasing age  and UAER (r = 0.21), with p < 0.001 for both comparisons.At baseline, 778 participants had normoalbuminuria, 148 had microalbuminuria and 161 had macroalbuminuria. According to eGFR, 794 participants were classified into the G1 KDIGO eGFR category, 196 into G2 category, 63 into G3 category , 29 into G4 category and five into G5 category. In the univariable analysis, serum sphingomyelin was associated with eGFR . The association remained significant even when adjusted for other variables known for their association with GFR decline, including sex, diabetes duration, age of diabetes onset, smoking, blood pressure, HbA1c and BMI , even when adjusted for the whole array of established risk factors, including lipid and glycaemic variables. Higher sphingomyelin values also predicted the occurrence of de novo albuminuria, when adjusted for diabetes duration, time of diabetes onset, sex, smoking, blood pressure and HDL-cholesterol, but not after adjustment for BMI, HbA1c or serum triacylglycerols. Of note, serum sphingomyelin increased the risk of progression from microalbuminuria to macroalbuminuria as well, but the HRs did not reach statistical significance , progression from microalbuminuria to macroalbuminuria (p = 0.54) or progression from macroalbuminuria to ESRD (p = 0.10).Furthermore, we used GAM to identify a potential nonlinearity in the relationship between the serum sphingomyelin and albuminuria or ESRD. Although visualising suggested that the risk of ESRD started to increase when the sphingomyelin concentration was around 0.50–0.55 CU, nonlinearity was not significant for any of the outcomes, i.e. progression from normoalbuminuria to microalbuminuria (p < 0.001). Similarly, in the group with the slowest eGFR decline, serum sphingomyelin was significantly higher in the group with macroalbuminuria compared with the group with normoalbuminuria or microalbuminuria .In addition, we analysed whether albuminuria affects the association between serum sphingomyelin and eGFR decline. In the group with the fastest eGFR decline, serum sphingomyelin was higher in those with macroalbuminuria compared with those with normoalbuminuria or microalbuminuria