APOL1 on patients of African ancestry with hypertension and their clinicians?What are the effects of testing and disclosing the genetic results for APOL1 genotypes had greater improvement in blood pressure from baseline and more lifestyle changes (better dietary and exercise habits) compared with patients with low-risk APOL1 genotypes or waiting list control patients.In this randomized clinical trial of 2050 patients of African ancestry with hypertension without chronic kidney disease in which genetic testing results were disclosed to patients and clinicians, patients with high-risk APOL1 genetic testing results to patients of African ancestry with hypertension and to their clinicians was associated with a greater reduction in blood pressure, kidney disease screening, and self-reported behavior changes in those with high-risk APOL1 genotypes.Disclosing  APOL1 [OMIM 603743]) gene on chromosome 22 are common in individuals of West African ancestry and confer increased risk of kidney failure for people with African ancestry and hypertension. Whether disclosing APOL1 genetic testing results to patients of African ancestry and their clinicians affects blood pressure, kidney disease screening, or patient behaviors is unknown.Risk variants in the apolipoprotein L1  or delayed (waiting list control group) APOL1 genetic testing results from trained staff; their clinicians received results through clinical decision support in electronic health records. Waiting list control patients received the results after their 12-month follow-up visit.Patients randomly assigned to the intervention group received APOL1 genotypes and those with low-risk APOL1 genotypes. Secondary outcomes compared these outcomes between intervention group patients with high-risk APOL1 genotypes and controls. Exploratory analyses included psychobehavioral factors.Coprimary outcomes were the change in 3-month systolic blood pressure and 12-month urine kidney disease screening comparing intervention patients with high-risk APOL1 genotypes vs those with low-risk APOL1 genotypes and controls . At 3 months, the mean (SD) change in systolic blood pressure was significantly greater in patients with high-risk APOL1 genotypes vs those with low-risk APOL1 genotypes  and controls . At 12 months, there was a 12% increase in urine kidney disease testing among patients with high-risk APOL1 genotypes (from 39 of 234 [17%] to 68 of 234 [29%]) vs a 6% increase among those with low-risk APOL1 genotypes  and a 7% increase among controls . In response to testing, patients with high-risk APOL1 genotypes reported more changes in lifestyle  and increased blood pressure medication use  vs those with low-risk APOL1 genotypes; 1631 of 1686 (97%) declared they would get tested again.Among 2050 randomly assigned patients , the baseline mean (SD) systolic blood pressure was significantly higher in patients with high-risk APOL1 genetic testing results to patients of African ancestry with hypertension and their clinicians was associated with a greater reduction in systolic blood pressure, increased kidney disease screening, and positive self-reported behavior changes in those with high-risk genotypes.In this randomized clinical trial, disclosing NCT02234063ClinicalTrials.gov Identifier:  APOL1 genetic results on patients of African ancestry with hypertension and their clinicians.This randomized clinical trial determines the effects of testing and disclosing  High-risk genotypes at the apolipoprotein L1 (APOL1) locus confer a 5-fold to 10-fold increased risk for CKD and end-stage kidney disease attributed to hypertension, although this risk increment is attenuated among individuals with diabetes.6 High-risk variants of APOL1 (OMIM 603743) on chromosome 22 are found in 1 of 7 people of African ancestry but are nearly absent in people of European ancestry7 because they confer resistance to trypanosomal infection and are subject to positive selection in West Africa.9Chronic kidney disease (CKD) affects 26 million US adults.10 racial and ethnic minority populations should not be the last to benefit from scientific advances, including genetic discoveries. There is increasing interest in incorporating genetic testing into primary care.13 The APOL1 risk genotype is common and confers high risk for a serious chronic disease in people of African ancestry, who are disproportionately burdened by chronic diseases, and thus it may be important to incorporate genetic testing into clinical care.12 Blood pressure (BP) control reduces kidney function deterioration,14 but people of African ancestry have the highest age-adjusted prevalence of hypertension and the lowest rates of blood pressure control.15 Kidney function tests, including urine microalbumin testing, aid in risk stratification and clinical staging but are underused among patients at high risk of CKD, especially patients of African ancestry.16Although it is important to avoid overstating the importance of genetic contributions to chronic disease disparities and to acknowledge that social determinants of health are the critical determinants of disparities,APOL1 genotypes,17 but little is known about whether testing patients for APOL1 risk will affect clinical care processes, including appropriate kidney disease screening, or improve outcomes, such as BP control or incident CKD, or how patients will respond to testing. Effective communication of genetic risk to clinicians supported by clinical decision support in electronic health records (EHRs), as well as to patients, may be useful because it has been useful for hypertension control in general.19Stricter BP control may have a mortality benefit for persons with high-risk APOL1 status is being used in niche clinical settings, including for evaluation of living kidney donors.21 To our knowledge, there are no proven interventions at this time, but there appears to be consensus that the presence of high-risk alleles alone does not necessarily lead to kidney failure. Other factors, such as social determinants of health or control or lack of control of BP, may influence the clinical course of persons with high-risk alleles. To determine whether risk disclosure would affect BP and kidney testing, researchers collaborated with a genomics stakeholder board  to conduct the Genetic Testing to Understand and Address Renal Disease Disparities (GUARDD) trial to study the effects of incorporating APOL1 genotype information into primary care management of adults of African ancestry with hypertension.Testing of 22 Inclusion criteria were self-identified African ancestry, being 18 to 70 years of age, hypertension EHR diagnosis and/or taking antihypertensive medications and/or 2 systolic BP (SBP) readings greater than 140 mm Hg at least 6 months apart, community dwelling, English speaking, and receiving primary care at a participating site in the past year. Exclusion criteria were diabetes, CKD, pregnancy, moving away during the study period, and cognitive impairment. This study was approved by the Icahn School of Medicine for Family Health Institutional Review Board. All participants provided written informed consent. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.23This randomized clinical trial  in a 7:1 ratio so that the number of patients with 2 high-risk 22; measured sitting BP with BpTru BPM-200 digital monitors validated against in-office and 24-hour ambulatory BPs; and averaged the second and third of 3 measurements.24 We identified urine protein to creatinine ratio and microalbumin to creatinine ratio testing in EHRs up to 12 months before (baseline) and for 12 months after (postintervention) randomization. For genetic testing at baseline for intervention patients and at 12 months for controls, coordinators collected venous blood samples .During baseline, 3-month, and 12-month study visits, trained coordinators administered a survey ascertaining demographic characteristics, knowledge, attitudes, and behaviors22 A validated assay interrogated APOL1 G1 and G2 alleles7 in a Clinical Laboratory Improvement Amendments, College of American Pathologists–accredited clinical laboratory. Coordinators trained and supervised by a senior genetic counselor returned results to ensure that all patients would receive standardized information in a timely manner. Patients received a result of high-risk APOL1 genotypes if they were homozygous or compound heterozygous carriers of G1 and/or G2 alleles, and patients received a result of low-risk APOL1 genotypes if they were heterozygous G1 or G2 or homozygous wild-type allele carriers. Coordinators returned results of low-risk APOL1 genotypes over the telephone and results of high-risk APOL1 genotypes in person, using “teach back”  to ensure comprehension.25 All patients received a scripted message indicating that it is important to control BP for many reasons, including kidney health; were asked if they wanted to speak to or meet with the study’s genetic counselor; and received a low literacy educational booklet with their results.Our clinical decision support engine provided privacy-protected data flow and real-time communication between the EHR, genetic testing laboratory, and study team.26 Waiting list control patients received the results after their 12-month follow-up visit. The alert included the result, a message that BP control can help forestall kidney failure, the 3 most recent BP readings, and links to information for clinicians and patients with 1-click access and printing. The entire process was informed by formative interviews; developed in partnership with the genomic stakeholder board’s patients, advocates, and clinicians; tailored by and for patients of African ancestry and for low-literate populations; and extensively piloted and revised.27Return of results triggered an EHR best practice alert with results that fired once for every primary care professional (PCP) who opened an encounter in the 1-year follow-up period.APOL1 genotypes with patients with low-risk APOL1 genotypes for the 2 primary end points: 3-month SBP and 12-month urine albumin screening for kidney disease. Secondary outcomes included differences in SBP and urine testing in an enriched intervention group (patients with high-risk APOL1 genotypes) vs controls and psychobehavioral patient factors between groups and over time. We did not focus on kidney screening via serum creatinine testing because it is part of routine panels ordered for reasons often unrelated to CKD screening or assessment.We compared patients with high-risk t test or analysis of variance was used to compare continuous variables, and the χ2 test or the Fisher exact test was used to compare categorical variables by groups. To test significance of changes within groups over time, we used paired t tests for continuous variables and McNemar tests for categorical variables. We used linear mixed models to test the difference in SBP change over time between patients with high-risk APOL1 genotypes and those with low-risk APOL1 genotypes by entering the interaction term of time and APOL1 status and adjusting for confounders, and we used generalized estimating equation methods to test the change in controlled SBP status and kidney function testing over time between patients with high-risk APOL1 genotypes and those with low-risk APOL1 genotypes and similarly between patients with high-risk APOL1 genotypes and controls. Analyses were conducted in SAS, version 9.4 (SAS Institute Inc), and P values were from 2-sided tests, with significance set at P < .05.Statistical analysis was performed from May 1, 2018, to July 31, 2020. We used mean (SD) values to describe continuous variables and proportions to describe categorical variables; the 28 There were no differences in sociodemographic characteristics between intervention and control patients except that control patients had higher educational attainment (more than some college: 162 of 255 [64%] control patients vs 1010 of 1795 [56%] intervention patients). However, patients with high-risk APOL1 genotypes had significantly higher mean (SD) SBP at baseline (137 [21] mm Hg) than those with low-risk APOL1 genotypes  and controls   were enrolled, 2783 (51%) were ineligible, 234 (4%) declined, and 412 (8%) were undecided when enrollment finished . Of 2052 = .001) .APOL1 genotypes  vs those with low-risk APOL1 genotypes  or controls  (APOL1 genotypes (3.6%), those with low-risk APOL1 genotypes , and controls . After adjustment for age, sex, body mass index, comorbidity, income, educational level, and marital status, the decrease in SBP remained statistically significantly different between patients with high-risk APOL1 genotypes and those with low-risk APOL1 genotypes (P = .02). The mean (SD) diastolic BP at 3 months was 83.6 (12.3) mm Hg in patients with high-risk APOL1 genotypes, 83.8 (10.9) mm Hg in those with low-risk APOL1 genotypes, and 83.7 (10.9) mm Hg in controls. There was no significant difference in SBP at 12 months or in the change in SBP from baseline to 12 months between groups.Although all groups had some decrease in SBP, it was greatest in patients with high-risk P = .01) . The perAPOL1 genotypes (12% increase: from 39 of 234 [17%] to 68 of 234 [29%]) compared with those with low-risk APOL1 genotypes (6% increase: from 278 of 1561 [18%] to 377 of 1561 [24%]) and controls (7% increase: from 33 of 255 [13%] to 50 of 255 [20%]), a difference significant between patients with high-risk APOL1 genotypes and controls (P = .01), although, over time across groups, this difference did not remain statistically significant  after receiving APOL1 results , changing how they take their BP medications  and taking BP medications more often   and worried they would develop kidney problems . We offered all patients the opportunity to speak to or meet with a genetic counselor at no cost; however, none chose to do so.A total of 1468 of 1561 patients with low-risk  = .005) . Nearly 31 and BP control is important for reducing the incidence and progression of CKD.32 In partnership with the genomics stakeholder board, we recruited and tested adults with self-reported African ancestry and hypertension for APOL1 alleles that increase the risk of CKD and end-stage kidney disease. We returned genetic test results to them through trained laypersons and to their PCPs via EHR alerts at 15 academic, community, and safety-net practices. Disclosure of APOL1 genetic risk results led to a greater decrease in SBP among those with high-risk APOL1 genotypes vs those with low-risk APOL1 genotypes and among those with high-risk APOL1 genotypes vs controls, as well as a significantly greater increase in urine kidney disease screening in all groups, especially among patients with high-risk APOL1 genotypes. Patients had favorable reactions to testing and return of results, and patients with high-risk APOL1 genotypes reported positive changes in lifestyle and BP medication use compared with patients with low-risk APOL1 genotypes.Chronic kidney disease and its complications are at epidemic levels,APOL1 genetic results to patients of African ancestry with hypertension and their PCPs. Baseline SBP was higher in patients with high-risk APOL1 genotypes (as previously reported33), but the SBP absolute and percentage improvement was higher in this group vs those with low-risk APOL1 genotypes or controls. To our knowledge, few studies disclosing genetic risk of chronic diseases have led to improved outcomes.35 Our findings may be due to the use of EHR alerts, which have previously shown efficacy,19 along with disclosure of genetic results to patients. The magnitude of SBP improvement was small, but we did not provide specific BP target recommendations or BP-lowering strategies to clinicians or patients; future programs may show more benefit with more intense BP-lowering efforts. The SBP improvement may also be the result of the change in behaviors among the patients with high-risk APOL1 genotypes. Health behavior changes were small and, although statistically significant, may have been clinically not meaningful. The increase in urine screening across all groups may be because physicians were aware of being part of a clinical trial and thus may have changed their test-ordering patterns in response. However, this outcome was modified by an awareness of patients’ genetic risk, with a higher increase in kidney disease screening among patients with high-risk APOL1 genotypes vs those with low-risk APOL1 genotypes.This trial tested the effects of disclosing 36 Thus, return of genetic risk results to PCPs with clear care plans, targeted education, and recommended clinical workflows would increase knowledge about and acceptability of genomic medicine in primary care. This study contributes to the evidence base that knowledge of genetic risk in primary care may affect processes and outcomes of care.Translational genomics and clinical informatics may play increasing roles in primary care–based chronic disease prevention and control efforts, but the effect of returning results needs to be tested in rigorous randomized clinical trials. Primary care professionals are central to helping patients understand and address risk and interactions between clinical, genetic, and environmental factors, and they will likely be crucial in efforts to minimize the risk and maximize the benefit of genetic testing in diverse populations and settings.37 and may not be critical in returning results for chronic disease risk. Our stakeholders and formative research38 guided us to have patients tested and receive results in their primary care practices via laypersons who were mainly of African ancestry and trained by genetic counselors to return results and by local stakeholders to be sensitive to the culture and challenges facing patients. We did not rely on PCPs to return test results because they did not order the test and did not feel prepared to return results,39 but we provided them with decision support to discuss results with their patients. This approach was well received by the patients; none chose to meet with a genetic counselor, although we offered the opportunity to all, and they viewed disclosure of results very favorably. Clinician extenders (nurse practitioners and physician assistants) may be useful for other practices to consider to permanently fill this role for busy clinicians or as a bridge while clinicians learn to incorporate information from a relatively new field into their workflow.To date, the optimal way to return genetic results to patients with common diseases in primary care settings is not clear. Genetic counselors have been on the front line of delivering genetic testing results to patients and clinicians regarding mendelian disorders, but PCPs are on the front line of health care for most patients. Genetic counselors are a limited resourceAPOL1 genotypes vs controls. In addition, we did not have comprehensive data on lifestyle and dietary intake or medication refill data. In this pilot trial, the period of outcome assessment was short (1 year). However, this trial has informed a national multicenter trial called GUARDD-US, which is ongoing. We used change in SBP as a primary outcome because of prior strong associations with cardiovascular disease.40 However, diastolic BP is an important risk factor and will be explored in future work. We did not have information on treatment fidelity collected as part of the study protocol, and we did not have significant information on the type and dosage of medication and could only address the changes in broad groups. The upcoming GUARDD-US trial will address these issues in more detail. Confounding  could affect these results. Finally, although we conducted this trial in academic, clinical, and primary care settings, we did so in 1 urban area, and it will be important to validate the findings in other settings.The study has some limitations. We excluded patients with CKD, and it is important to study the effects of genetic testing and disclosure of results on patients with abnormal kidney function. Our intervention had a modest effect size, possibly owing to increase in medication use and/or lifestyle change, which may have substantial benefits at the population level. However, interventions with more robust components and repeated reminders may demonstrate a more significant effect. Our primary outcome was within the intervention group, although we did see effects when comparing patients with high-risk APOL1 genetic testing results combined with EHR-based clinical decision support and disclosure of results to patients using laypersons improved SBP control and increased guideline-appropriate kidney function testing. These results may support an approach of broad implementation of genetic medicine in primary care. This broad implementation will benefit racial and ethnic minority groups that have been traditionally underrepresented in both clinical trials and genetic studies.41 Because it is imperative not to overlook the importance of social determinants of health in affecting chronic disease, it will also be important to understand and address the intersection of social and biological determinants in patient health.Return of


P = 0.007), suffered longer duration of diabetes mellitus  and predominantly female , but also had lower serum levels of creatinine  and albumin  than patients with enlarged or normal kidney size. At the end of analysis, 14 (16.9%) patients died. Patients with small kidney size demonstrated higher all-cause  and infection-related  mortality than patients with enlarged or normal kidney size. In a multivariate-logistic-regression model, small kidney size was a powerful predictor of mortality . Diabetic patients with small kidney size at the beginning of PD carry a substantial risk for mortality.Although patients with diabetes mellitus mostly present with enlarged or normal-sized kidneys throughout their life, a small proportion of patients have small kidneys. This longitudinal study enrolled 83 diabetic patients treated with peritoneal dialysis (PD) between 2015 and 2019. Patients were stratified into two groups, those with enlarged or normal (n = 67) or small (n = 16) kidneys, based on their kidney sizes before dialysis. Patients with small kidney size were not only older (76.63 ± 10.63 vs. 68.03 ± 11.26 years,  The presence of diabetes mellitus was associated with a 1.723-fold risk of having a large kidney. Moreover, Rigalleau et al.2 reported that large kidneys predicted poor kidney outcome in patients with diabetes and chronic kidney disease. In the second manifestations of arterial disease (SMART) study3, large kidney length was found to be associated with higher risk of cardiovascular events and mortality in high-risk patients, irrespective of estimated glomerular filtration rate.It is not uncommon to find enlarged kidneys in patients with diabetes mellitus, and the kidneys could remain large even in the advanced stage of the disease. In a Sardinian population cohort study, Piras et al.4 reported that most of their type 2 diabetes mellitus patients with chronic kidney disease had small kidneys. Notably, Habib5 proposed that both kidney hypertrophy and atrophy can occur in diabetes mellitus. The early changes in diabetic kidneys are mainly due to tubular basement membrane thickening, which leads to kidney hypertrophy. On the other hand, various tubulointerstitial diseases can induce apoptosis in proximal tubular cells, causing tubular atrophy and fibrosis and ultimately kidney atrophy5. Furthermore, atherosclerosis and related ischemic diseases can decrease the blood supply to the kidneys, resulting in kidney atrophy5.Nevertheless, small kidneys could be observed in a small number of diabetic patients with chronic kidney disease. Majdan et al.6. In 2016, Taiwan, the United States, and the Jalisco region of Mexico reported the highest incidences of treated ESKD, with rates of 493, 378, and 355 patients per million general population, respectively. Notably, diabetes is the primary cause of ESKD in 46% of incident dialysis patients in Taiwan. Nevertheless, the majority of uremic patients in Taiwan are treated with hemodialysis rather than peritoneal dialysis (PD)7.Chronic kidney disease is endemic in Taiwan; indeed, the incidence and prevalence of end-stage kidney disease (ESKD) are higher in Taiwan than in any other countryThe rationale for this study was based on an important, but as yet unanswered, question that arose for many diabetic patients treated with PD in our hospital. The majority of diabetic patients had enlarged or normal kidneys when entering dialysis, whereas few diabetic patients were found to have small kidneys at the time of uremia. Therefore, this raises the question of what the impact of kidney size before dialysis on the outcomes of these patients is. Perhaps one of the potential clinical applications of small kidneys is to remind clinicians about diabetic patient care. For example, if small kidney size at the beginning of PD is found to be associated with a greater risk for infection-cause mortality, physicians should be alert of the possibility of occurrence of infection and consider early initiation of antimicrobial therapy in case of infectious symptoms and signs.Diabetes mellitus is the most important cause of ESKD worldwide, but no work has been performed to compare outcomes of diabetic patients with enlarged or normal versus small kidney size, which initiated our interest in this research. Therefore, this study attempted to survey kidney size in diabetic PD patients before the commencement of dialysis and to analyze the association of kidney size with outcomes and laboratory biomarkers.P = 0.007) and suffered longer duration of diabetes mellitus , but also more often female  than patients with enlarged or normal kidney size.This study included 83 diabetic patients receiving long-term PD at Chang Gung Memorial Hospital Table . Most ofP = 0.022) and albumin .Compared with patients with enlarged or normal kidney size Table , patientTable P < 0.001). Moreover, there was more infection-related mortality in the patients with small than in those with enlarged or normal kidney size . The sources of infection-related mortalities were three PD-related peritonitis, three nosocomial pneumonia, two pressure sore infection, one fulminant clostridium difficile colitis, one cellulitis, one diabetic foot wound infection and one pulmonary tuberculosis.At the end of analysis, 14 (16.9%) patients died (Table P = 0.028).In a multivariate logistic regression model Table , it was P < 0.001).Kaplan–Meier analysis revealed that patients with small kidney size had lower cumulative survival than did patients with enlarged or normal kidney size , suffered longer duration of diabetes mellitus (P = 0.006), but also had lower serum levels of creatinine (P = 0.022) and albumin (P = 0.010) than patients with enlarged or normal kidney size. The abovementioned variables, for example older age, longer duration of diabetes mellitus, as well as malnutrition  could attribute to increased mortality.The analytical data from this study suggested that small kidney size at the commencement of dialysis could be a risk factor for mortality in the diabetic PD population. This finding adds new knowledge to the existing dialysis literature. There was no clear explanation for the observation. Nevertheless, patients with small kidney size were not only older . Many groups have confirmed such a positive association between decreasing kidney size and aging18. Hommos et al.16 reported that aging could be associated with considerable changes in kidney parenchymal structure, even in the absence of age-related comorbidities. Gross pathology examination of aged kidneys found a decrease in kidney cortical volume, an increase in surface roughness, and an increase in the number and size of simple kidney cysts with aging. Histopathology examination also found an increase in nephrosclerosis  associated with the aging process.Patients with small kidney size were older than patients with enlarged or normal kidney size (P = 0.017). This positive association between small kidney size and female sex has been confirmed by many independent studies18. In a study of 665 adult volunteers, Emamina et al.17 reported a sex difference in kidney size in adults; the median kidney lengths were 11.0 cm (women) and 11.5 (men) on the left side and 10.7 cm (women) and 11.2 cm (men) on the right side. Therefore, the female kidney was usually smaller than the male kidney. On the other hand, Piras et al.1 revealed that female sex was associated with a 2.035-fold risk of having a large kidney. Finally, it was unclear whether the diabetic females had more history of analgesic use than diabetic males, although there were no medical records for this, and the recall history was subjected to memory bias. A questionnaire survey in Norway revealed19 that women used both more nonprescription analgesics and more prescription analgesics than men.Patients with small kidney size were more often female than patients with enlarged or normal kidney size  did not show higher rates of technical failure, but their survival was shorter than that of the younger group (< 70 years of age). In Taiwan, most families are large families, with three generations living in the same household. Younger family members can take care of their older parents and assist them in performing PD therapy. This may explain the higher age of PD in this study.The average age of patients in this study was 69.70 ± 11.57 years. This figure is close to that of the Japanese study. In Japan, patients are approximately 69 years of age at the initiation of dialysisP = 0.022) and albumin (P = 0.010) than patients with enlarged or normal kidney size. Albumin is the most abundant protein in human serum22. Albumin is produced by the liver and is an indicator of malnutrition. On the other hand, creatinine is the end product of creatine, is mainly present in skeletal muscle and is used as a surrogate measurement of muscle mass23. Creatinine generation is reduced in the setting of low skeletal muscle mass, such as in older patients. Since patients with small kidney size were older and with a predominance of females, it was not surprising that these patients had lower serum levels of creatinine and albumin than the enlarged or normal kidney size group.Patients with small kidney size patients suffered from lower serum levels of creatinine (P < 0.001) and infection-related (P < 0.001) mortality than patients with enlarged or normal kidney size. Diabetics generally have an increased propensity to develop infections. The increased occurrence of infections in diabetic patients is caused by the hyperglycemic milieu, which supports immune dysfunction , angiopathy, neuropathy, a decrease in the antibacterial activity of urine, gastrointestinal and urinary dysmotility, and an increased need for medical interventions24. Diabetes impairs antibacterial defenses and increases the risk of infection25. Furthermore, a high concentration of glucose degradation products in PD solutions could accelerate leucocyte apoptosis and damage peritoneal antibacterial defense26. Previous studies28 have reported diabetes mellitus as a risk factor for PD-associated peritonitis. According to a large retrospective cohort study in China29, peritonitis was always associated with a higher risk of mortality in PD patients, and its influence on mortality was more significant in patients with longer PD durations. The assessment of the immune defense system of the diabetic patients with small kidney size will need further investigation.Patients with small kidney size demonstrated higher all-cause , icodextrin-based (7.5 g/dL) or standard dialysates containing glucose  were used according to the patients' peritoneal transport characteristics and serum calcium levels to maintain adequate ultrafiltration and enlarged or normal calcium levels. Dialysis prescription aimed at obtaining a total Kt/V of at least 1.8 per week.PD prescriptions were based on the peritoneal membrane characteristics determined by the peritoneal equilibration testurea, were surveyed by automated and standardized methods. All blood samples were collected in the morning after at least 10 h of fasting. Serum levels of calcium, phosphate and intact parathyroid hormone were also surveyed, and the corrected serum calcium level was calculated as calcium (mg/dL) = [0.8 ]. All other markers were surveyed via standard laboratory methods using an automatic analyzer.The data represented the last laboratory values prior to the patients being started on PD. All laboratory values, including blood cell count, biochemical data, dialysate/plasma creatinine ratio, peritoneal transport characteristics, weekly creatinine clearance and weekly Kt/V31. For comparison between two groups, Student's t-test was used for quantitative variables, whereas the chi-squared or Fisher's exact test was used for categorical variables. Survival data were analyzed with the Kaplan–Meier method and tested for significance using the log-rank test. A univariate binary logistic regression analysis was performed to compare the frequency of potential risk factors associated with mortality. To control for confounders, a stepwise backward multivariate binary logistic regression analysis was performed to analyze the variables that were significant on univariate analysis. The criterion for significance to reject the null hypothesis was a 95% confidence interval. The statistical analyses were performed using IBM SPSS Statistics Version 25 for Mac .The continuous variables are presented as the means ± the standard deviations for the numbers of observations, whereas the categorical variables are presented as numbers (percentages)This longitudinal observational study complied with the guidelines of the Declaration of Helsinki and was approved by the Medical Ethics Committee of Chang Gung Memorial Hospital. Because this study was a retrospective review of existing data, Institutional Review Board approval was obtained, but without specific informed consent from the patients. The Institutional Review Board of Chang Gung Memorial Hospital specifically waived the need for consent. The Institutional Review Board number assigned to the study was 202000663B0.


It has been demonstrated that glycated albumin (GA) is significantly associated with diabetes complications and mortality. However, among patients diagnosed with non-ST-elevation acute coronary syndrome (NSTE-ACS) administered percutaneous coronary intervention (PCI), the predictive value of GA for poor prognosis is unclear.This study eventually included 2247 NSTE-ACS patients in Beijing Anzhen Hospital, Capital Medical University in January-December 2015 who received PCI. All patients were followed up until death or for 48 months post-discharge. The primary endpoint was major adverse cardio-cerebral events (MACCEs), including all-cause death, non-fatal myocardial infarction, ischemia-induced revascularization and non-fatal ischemic stroke.In total, 547 (24.3%) MACCEs were recorded during the follow-up period. Upon adjusting for potential confounders, GA remained an important risk predictor of MACCEs . GA addition significantly enhanced the predictive ability of the traditional risk model  0.085, P = 0.053; integrated discrimination improvement (IDI) 0.007, P = 0.020).GA is highly correlated with poor prognosis in NSTE-ACS patients undergoing PCI, suggesting that it may be a major predictive factor of adverse events among these individuals.The online version contains supplementary material available at 10.1186/s12933-022-01446-3. Type 2 diabetes mellitus (T2DM) independently and significantly predicts atherosclerotic cardiovascular disease (ASCVD), and increases ASCVD risk by about 2 times . PatientIn recent years, glycated albumin (GA) has attracted widespread attention for being unaffected by food intake and red blood cell lifespan. GA generally reflects the status of blood sugar control in 2–4 weeks. In cases for whom FBG and HbA1c have the above limitations and cannot accurately reflect the patient's blood glucose levels, GA would be a good surrogate indicator . GlycateHowever, the prognostic value of GA in individuals with non-ST-elevation acute coronary syndrome (NSTE-ACS) administered percutaneous coronary intervention (PCI) is largely undefined. In addition, studies comparing the predictive values of FBG, HbA1c and GA in poor cardiovascular prognosis are lacking. Therefore, the current work aimed to assess GA for its predictive value for poor outcomes in NSTE-ACS patients after PCI.2) or kidney replacement treatment, severe liver dysfunction ; (7) PCI failure, PCI-associated complications or in-hospital death. Finally, totally 2247 individuals were included in this study  were based on relevant guidelines . ExclusiPatient baseline data were obtained from the electronic medical information recording system of Beijing Anzhen Hospital. Hypertension was defined as systolic blood pressure (BP) ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg after repeated measurements on different days . CriteriOn the early morning of the operation day, blood samples with fasting time of 8–12 h were taken and sent to the laboratory of the testing center for examination immediately. The GA levels were determined by the enzymatic method using Lucica GA-L kit  . The valEchocardiograms were verified by 2 ultrasound specialists. Coronary angiography, percutaneous coronary intervention and perioperative management were based on current guidelines . ChronicAfter discharge from the hospital, all patients were followed up until death or 48 months after discharge. The primary endpoint was major adverse cardio-cerebral events (MACCEs), including all-cause death, non-fatal myocardial infarction (MI), non-fatal ischemic stroke and ischemia-induced revascularization. MI was reflected by increased cardiac troponin or creatine kinase levels surpassing the upper limits of the reference ranges, with ischemia signs and/or electrocardiogram findings suggesting myocardial ischemia. Stroke definition involved signs of neurological damage, caused by ischemic lesions confirmed by computed tomography or magnetic resonance imaging. Ischemia-induced revascularization was reflected by revascularization in target and/or non-target vessels due to recurring or persistent ischemic symptoms, including PCI and CABG.Cases were assigned to 2 groups based on median GA . Normally distributed continuous variates are mean ± standard deviation, and were compared by two-sample independent t test. Continuous variates with skewed distribution were represented by median and 25th and 75th percentiles, and compared by the Mann–Whitney U test. Nominal variates were described by numbers and percentages, and compared by the Chi-square, continuity-corrected chi-square or Fisher’s exact test.The Kaplan–Meier method was utilized for describing event rates at follow-up and plotting time-to-event curves in both groups, which were compared by the log rank test. The univariable Cox proportional hazards model was used for preliminary assessment of factors associated with MACCEs. Variates with significant associations with MACCEs and those that may be meaningful based on clinical experience were included in five multivariate models. Variates with potential collinearity were not included in the multivariate analysis. GA was tested as nominal and continuous variables, respectively. Hazard ratios (HRs) and 95% confidence intervals (CIs) were used to describe the associations. In multivariable Cox proportional hazard analysis, five models were established for evaluating GA’s predictive value in MACCEs: Model 1, adjustment for age, gender and body mass index (BMI); Model 2, adjustment for Model 1 variables and smoking history, hypertension, T2DM, anemia and previously diagnosed MI, PCI and stroke; Model 3, adjustment for Model 2 variables and TG, TC, creatinine, high-sensitivity C-reactive protein (hs-CRP), HDL-C, left ventricular ejection fraction (LVEF); Model 4, adjustment for Model 3 variables and oral hypoglycemic agent (OHA) and insulin prescriptions at discharge; Model 5, adjustment for Model 4 variables and left main artery (LM) lesion, multi-vessel lesion, SYNTAX score, complete revascularization and drug-eluting stent (DES) amount. According to Model 5, a restrictive cubic spline curve was established to illustrate the dose–response association of GA with MACCEs. Except for variables used for stratification, stratified analysis adjusted for Model 5 variables. Interactions were examined by the likelihood ratio test.Harrell’s C-index, net reclassification improvement (NRI) and integrated discrimination improvement (IDI) were used for investigating the additive effects of GA on the predictive abilities of traditional cardiovascular disease risk factors in MACCEs.P < 0.05 was deemed statistically significant.SPSS v26.0 and R v3.6.3 were used for data analysis. Two-tailed Totally 2247 patients were included, with an average age of 60.1 ± 9.0, and the proportion of males was 71.9% (n = 1616). Patients were assigned to 2 groups based on median GA. Demographic data, clinical features, laboratory results, and medical and procedural details are shown in Tables P < 0.001), all-cause death (P = 0.006), non-fatal MI (P = 0.001) and ischemia-driven revascularization (P < 0.001) were significantly higher in the high GA group compared with the low GA group. However, the incidence rates of non-fatal stroke were comparable in both groups  cases of MACCEs were recorded, including 36 (1.6%) all-cause death, 112 (5.0%) non-fatal myocardial infarction (MI), 45 (2.0%) non-fatal stroke and 354 (15.8%) ischemia-driven revascularization cases. The incidence rates of MACCEs , suggesting that GA had a linear relationship with MACCE risk. This was further confirmed in the non-linear correlation test (P for nonlinear association < 0.001).After adjusting for variates in Model 5, the dose–response relationship between GA level and MACCEs was illustrated by drawing restricted cubic spline curve Fig. . It was 2), smoking history (no or yes), hypertension (no or yes), OHA at admission (no or yes), and insulin at admission (no or yes), there were no differences in the predictive power of GA in MACCEs . It is worth noting that the predictive value of GA seemed to be higher in non-diabetic patients  , age (< 65 or ≥ 65 years), BMI (< 28 or ≥ 28 kg/mP = 0.002). The reclassification and discrimination abilities were significantly improved in comparison with the baseline risk model after addition of GA . In Harrell’s C-index, NRI and IDI analysis, addition of FBG  and HbA1c  also significantly improved the risk prediction ability of the baseline model , addition of GA markedly enhanced the ability of the model to predict risk  Study in 1990–1992, Selvin et al. followed up 11,104 patients for 20 years, and found that GA was associated with vascular outcomes and mortality in the community, and these associations were similar to those observed for HbA1c . HbA1c, Regarding the mechanism-level explanation of GA’s predictive value for poor prognosis in atherosclerotic cardiovascular disease, inflammation has attracted widespread attention. In cultured rat vascular smooth muscle cells (VSMCs), GA can induce the expression of the pro-inflammatory cytokine IL-6 at the mRNA level . The preThere were limitations in this study. First, this was a single-center, retrospective, observational trial, which might reduce the effectiveness and power of these research findings. Therefore, more in-depth prospective, multi-center studies are required to further verify the current findings. Secondly, some patients received anti-diabetic treatment before admission, which may have affected the actual level of GA. Thirdly, factors such as age, obesity, inflammation, etc. may impact GA levels in this work. Fourthly, this study only included Chinese patients, and the generalizability of the findings to other ethnicities requires further investigation. Fifth, in our research population, patients with UA account for the vast majority. Therefore, the predictive value of GA on the prognosis of patients with NSTEMI may not be well shown.In NSTE-ACS patients administered PCI, GA level is significantly correlated with high risk of adverse cardio-cerebral events. Addition of GA significantly improves the ability of traditional risk models to predict poor prognosis. This conclusion needs further prospective, large-scale studies for confirmation.Additional file 1. Additional table.


The incidence of postoperative delirium (POD) after maxillofacial tumors radical surgery is relatively high. There are a number of evidences showing the relationship between hypertension and decreased cerebral blood flow, as well as the relationship between cerebral ischemia and postoperative cognitive impairment. However, the impact of hypertension in the process of POD and related mechanisms remain unclear.This study included 98 elderly patients who underwent maxillofacial tumors radical surgery in our hospital, from June 2020 to December 2020. We collected the general condition of patients and related research factors before surgery, and also collected related intraoperative factors. After that, we would follow up the patients for POD evaluation.P < 0.05). The incidence of POD in the irregular medication group was 62%, compared with 26% in the regular medication group (P < 0.05). Both hypertension  and irregular medication use  were independent risk factors for POD after this type of surgery in elderly patients.The incidence of POD in the hypertension group was 41%, compared with 12% in the nonhypertension group (Hypertension and medication use regularity are closely related to POD. This may be related to the delayed postoperative response caused by intraoperative cerebral ischemia. POD  is an acThe incidence of POD is high in patients undergoing maxillofacial tumor  radical The study cohort consisted of 98 elderly patients undergoing maxillofacial tumors radical surgery; their mean age was 68 years, and 67% were male. We finally enrolled 64 patients in the hypertension group and 34 patients in the nonhypertension group, and 64 patients with hypertension included 38 people in the regular medication group and 26 people in the irregular medication group.P < 0.05, α = 0.05), power (1-β) = 0.89 , power (1-β) = 0.83 , compared with 12% (4 of 34) in the nonhypertension group  = 0.89 ; the inc) = 0.83 .P < 0.05); other variables, such as age, BMI, white blood cell count, hemoglobin, surgery duration, blood loss, fentanyl dosage and intraoperative fluid input and tracheotomy number had no difference between a delirium group and a nondelirium group (P > 0.05). Logistics regression analysis results (As indicated in  results  showed tP > 0.05) across patients undergoing this kind of operation, while irregular medication use, SBP, DBP, and DBP reduction between the two groups had differences (P < 0.05). Logistics regression analysis results , and ASA classification I-II. The exclusion criteria were preoperative cognitive dysfunction . For patients who met the inclusion criteria, we used a cuff blood pressure monitor to measure the patient’s preoperative blood pressure in a calm state at different time periods, and according to the hypertension assessment scale , we diviThe anesthesia process for each patient was completed by a randomly assigned anesthesiologist, and the investigator did not perform any intervention during the perioperative period. After the patient entered the operating room, routine vital sign monitoring  was performed, and the amount of fluid lost according to the preoperative fasting time was replenished. After the induction of anesthesia, arterial puncture and deep venous puncture were conducted. During the operation, two-way venous access was used to infuse fluids. When the amount of bleeding was heavy, the speed of infusion was accelerated, and the urine output was kept within the normal range. General anesthesia was induced with midazolam (0.02–0.04 mg/kg), fentanyl (2 μg/kg), propofol (2.0–2.5 mg/kg), and cisatracurium besylate (0.2 mg/kg) and maintained with remifentanil (0.1–0.2 μg/kg/min), 1% propofol (2–5 mg/kg/h), and isoflurane. Partial pressure of carbon dioxide was maintained between 35 and 45 mmHg. We implemented intraoperative rectal temperature monitoring and we used a thermometer or heating blanket to maintain intraoperative body temperature between 35°C and 37°C.The researchers collected data on intraoperative blood loss, operation time, fentanyl dosage, intraoperative fluid infusion and the invasive arterial pressure value (every 5 minutes) based on the anesthesia record sheet. After the operation, the patient entered the intensive care unit with a tracheotomy or a tracheal tube in place to maintain the patency of the airway. After one night of monitoring in the intensive care unit, the patient would be transferred to the general ward on the first day after surgery. POD was assessed at general ward at 8–10 pm every night from the first day the patient returned to the ward to the third day using the Confusion Assessment Method (CAM) . The CAMWe identified SBP (systolic blood pressure) reduction, DBP (diastolic blood pressure) reduction as the preoperative SBP, DBP value minus the intraoperative SBP, DBP value. All blood pressure data were the mean values of the data collected.The evaluation criteria in this hypertension assessment scale  strictlyWe examined hypertension, medication use regularity as the main research factors of POD in our research. We had to strictly measure the preoperative blood pressure to determine the baseline blood pressure level and collect the blood pressure data in the anesthesia record sheet to calculate the perioperative blood pressure decline value.Other influencing factors for POD were also considered, such as age, surgery duration, blood loss, white blood cell count, hemoglobin, tracheotomy, intraoperative fentanyl dosage and fluid management, preoperative blood pressure and intraoperative blood pressure reduction.2 tests, and the power value was also calculated.The main results of the comparison of POD incidence between a hypertension group and a nonhypertension group, as well as between a regular group and a irregular group were analyzed with χt tests, Fisher exact tests and χ2 tests. The counting data like hypertension number, irregular medication number, sex number and tracheotomy number were analyzed by χ2 tests or Fisher exact tests. Measurement data such as blood pressure, BMI, Hb, WBC, SBP, DBP, DBP reduction and SBP reduction were in accordance with the normal distribution, and they were analyzed by T tests. The statistical analysis of the data in the hypertension subgroup were all the same.Patient related data and surgical characteristics were analyzed between a delirium group and a nondelirium group by P < 0.05 was considered significant. A reliable theory [P < 0.2 into logistics regression analysis. Finally, to find out independent risk factors of POD, we put hypertension, SBP, DBP, and SBP reduction into a logistics regression analysis; and in the hypertension subgroup, we put irregular medication use, SBP, DBP, and DBP reduction into a logistics regression.Analyses were conducted using SPSS 20.0 with 2-sided hypothesis testing (α = 0.05), and e theory  (name: A


Studies have indicated that exaggerated hypertension during activity and stress can be a good predictor of the incidence of hypertension. This study tries to evaluate left ventricular (LV) function by tissue Doppler to assess early changes in ventricular compliance before the onset of Hypertension (HTN) in patients with exaggerated blood pressure response during the exercise test.  In this case-control study, 40 patients without a history of hypertension with systolic blood pressure less than 140/90 which referred for exercise test, were included. The exercise test was performed for all patients. Patients who had exaggerated blood pressure during the stress test were considered as cases and the controls with normal blood pressure responses. Then standard echocardiography and Tissue Doppler imaging performed and indices of LV systolic and diastolic were recorded.  The LV mass in cases and controls were 174.9±50.78 and 152.9±33.59, respectively (P=0.114), and LV mass index in cases and controls were 127.4±13.5 and 79.8±15.75, respectively (P=0.023). Moreover, the LV Myocardial Performance Index were 0.68±0.11 and 0.48±0.06 in cases and controls, respectively (P<0.001). The heart rate, E/A, EE, E Velocity and S velocity were measuremented. Except E/A (P=0.009), there was no significant difference between the other variables measured between the cases and controls (P>0.05).  The results of this study showed that using 2D conventional echocardiography as a noninvasive method if performed in prestigious centers can evaluate systolic and diastolic function Tissue Doppler parameters very well in the early stages of heart disease caused by HTN. The interaction between genetic factors and hemodynamic factors causes heart disease caused by HTN in patients with arterial hypertension ,2. The r The present study is an analytical and descriptive case-control study with the aim of investigating the initial changes of ventricular abnormalities before HTN in these patients and compare them with non-HTN subjects. The entrance of samples to this study was randomized. In this study, all patients admitted to the Exercise Test Department of Ghaem and Imam Reza Hospitals  were studied. All patients were carefully evaluated and examined at the time of referral. Patients with systolic blood pressure between 120 and 139 and diastolic blood pressure between 75 and 89 were included in the study. Patients who had a history of hypertension, taking antihypertensive drugs, initial systolic blood pressure above 140, or diastolic blood pressure above 90, diabetes, positive exercise test, and coronary artery disease were excluded. Written informed consent were obtained from all patients before entering the study. This study approved by Ethics Committee of Mashhad University of Medical Sciences. According to the preliminary criteria for the study, 410 patients were tested for exercise. The exercise test results were interpreted in these specimens. After interpreting the results, 50 patients were excluded from the study due to positive test results. Also, 340 patients were excluded due to their history of hypertension, cad, and dissatisfaction with the study. Finally, 20 patients with exaggerated blood pressure during exercise as a case group were studied. In addition, 20 healthy subjects without any exaggerated blood pressure during exercise as a control group were randomly enrolled and studied. Exercise test  was performed for all subjects. Patients who had exaggerated blood pressure during exercise test were considered as case group and samples with normal blood pressure during exercise test were considered as a control group. In samples with a history of smoking, it was recommended that the patient quit smoking at least 6 hours before the exercise test. The Brouce protocol was used in the exercise test and systolic and diastolic blood pressure were measured during the last minute of each exercise as well as in the peak test. The patients continued the test until they reached the target (heart rate based on age-220), and if the patient had a systolic blood pressure of 200 mmHg or above or a diastolic blood pressure of 15 mmHg higher than the base diastolic pressure, it was considered as exaggerated blood pressure during exercise. All equipment used in this study were calibrated. After identification, patients underwent Tissue Doppler Imaging and standard 2D conventional echocardiography , and the left ventricular systolic and diastolic indexes and other information about age, sex, height, weight, and BMI of patients were recorded in the relevant checklists. After entering the samples in this study, they were all taken to participate in the study of informed consent. The Ethics Committee approval of Mashhad University of Medical Sciences was obtained for this study. The code of ethical approval is IR.MUMS.fm.REC.1394.333. After collected of information, results were evaluated by SPSS13 software . Descriptive data were collected from the frequency distribution table, central indexes, distribution and percentages. Continuous quantitative data were compared between the two groups using the independent t-test and Chi-Square test was used to compare the discrete data between the groups. In addition, the correlations between variatans were performed and 0.05 was considered as the significance level. This study was performed on 40 samples who were referred to Ghaem and Imam Reza hospitals in Mashhad to do exercise tests. The 20 samples were randomly assigned to each of the case and control groups. After performing the exercise test and recording the required data, standard 2D conventional echocardiography and Tissue Doppler Imaging were performed for all patients. The 21 (52.5%) patients in this study were male and the rest were female. The mean age of patients in cases and control groups were 44.05±9.65 and 43.02±7.4 years, respectively. There was no significant difference between the two groups in terms of age and gender (P>0.05). Three (7.5%) patients had a history of smoking, and seven (17.5%) had a history of hyperlipoproteinemia (HLP). The mean BMI of patients was 26.6 . There wet al. et al. [et al. [et al. [et al. [et al. [et al. [et al. found that E / A levels increased significantly in patients with increased BP. Marabotti et al. [et al., patients with borderline hypertension had a lower ejection fraction than the rest of the subjects. But unlike our findings, in the study of Dunn et al. [et al. [et al. in 2014, sample size of our study, 40 patients were determined [The results of this study showed that transthoracic 2D conventional echocardiography, especially Tissue Doppler Imaging, can detect diastolic and systolic changes in patients with exaggerated blood pressure responses. Echocardiography is the primary diagnostic method for left ventricular dysfunction ,23. This. et al.  confirms [et al. , in exam [et al. , it was  [et al. , systoli [et al. , which w [et al.  and the i et al.  also repn et al. , a signi [et al. , on the termined . The results of this study showed that transthoracic 2D conventional echocardiography, especially Tissue Doppler Imaging, as a non-invasive method, can detect diastolic and systolic changes in patients with exaggerated blood pressure responses in the exercise test prior to the onset of HTN, and can detect systolic and diastolic Tissue Doppler parameters of the systolic and diastolic function of the ventricle in the early stages of heart disease caused by hypertension. In addition, our study shows disorders in diastolic function of patients with hypertension in exercise tests compared to controls, which can indicate the incidence of HTN in these individuals in the future. This work was financially supported by the Mashhad University of Medical sciences, Mashhad, Iran (grant number is 940206). The present study extracted from the thesis of Dr. Milad hemati, Resident of Cardiology, atherosclerosis prevention research center, Mashhad University of medical science, Mashhad, Iran. The author(s) indicated no conﬂicts of interest.


Mobile technologies to improve blood pressure control in resource-limited settings are needed. We adapted and evaluated the acceptability and feasibility of PositiveLinks, a mobile phone application for self-monitoring, social support, and engagement in care for people living with HIV, among patients with hypertension in rural Uganda.We enrolled adults on treatment for hypertension at Mbarara Regional Referral Hospital and Mbarara Municipal health center IV, southwestern Uganda. We provided and educated all participants on the use of PositiveLinks application and automated blood pressure monitors. We administered a baseline questionnaire and performed in-depth interviews 30 days later to explore acceptability, feasibility, medication adherence, social support, and blood pressure control.A total of 37 participants completed the interviews, mean age of 58 years (SD 10.8) and 28 (75.7%) were female. All participants embraced the PositiveLinks mobile app and were enthusiastic about self-monitoring of blood pressure, 35 (94.6%) experienced peer to peer support. Among the 35 participants non-adherent to medications at baseline, 31 had improved medication adherence. All except 1 of the 31(83.8%) who had uncontrolled blood pressure at baseline, had self-reported controlled blood pressure after 30 days of use of PositiveLinks.Patients with hypertension in rural Uganda embraced the PositiveLinks mobile application and had improved medication adherence, social support, and blood pressure control. Further assessment of cost-effectiveness of the application in blood pressure control in resource-limited settings will be pursued in future studies. This study evaluated the acceptability and feasibility of the PositiveLinks application, a mobile health technology, among patients with hypertension attending 2 public health facilities in Mbarara, southwestern Uganda. Participants were trained and educated on how to use the application to capture self-reports of medication adherence, mood, social support, and blood pressure. After a month of follow-up, participants showed good acceptability of PositiveLinks and were using the application with ease. This was associated with improvements in self-reported adherence to medication and blood pressure control. Of note, participants expressed access to affordable blood pressure machines and internet as barriers. Overall, PositiveLinks is an easy to use mobile health application associated with improved social support, medication adherence, and blood pressure control among adults with hypertension in a low-resource setting. This was an available solution through a research partnership that required modest modification. Further assessment of cost-effectiveness of PositiveLinks application in blood pressure control in resource-limited settings will be pursued in future studies.,In Africa, the estimated number of people with hypertension has increased steadily from 54.6 million in 1990 to 130.2 million in 2010, and it is projected to rise to 216.8 million by 2030.,Compared to North African countries, countries in SSA have low levels of control of hypertension especially in rural areas.,PositiveLinks is a mobile health application designed to facilitate self-monitoring, social support, and engagement in care initially developed for people living with HIV.This pilot study was a mixed methods cohort study of patients with hypertension, resident and receiving clinical care at Mbarara Regional Referral Hospital and Mbarara Municipal Council Health Center IV, southwestern Uganda. These 2 public health facilities represent the setting where most patients seek clinical care for hypertension and as such the findings may be generalizable to similar public health facilities in SSA. A stratified random sampling was done at baseline for potential participants of the study, the sample size was 206. For PositiveLinks, we used consecutive sampling to enroll adults aged 30 years or greater, who owned an android mobile phone, residents of Mbarara town (5 km), who should have taken antihypertensive medication for at least 4 months, and receiving clinical care for hypertension at the outpatients’ clinics in either of the 2 facilities. Pregnant women were excluded as hypertensive disorders of pregnancy were out of the scope of this study. As a pilot study to demonstrate the acceptability and feasibility of PositiveLinks, we did not carry out a sample size calculation but targeted at least 30 participants.Ethical approval for this study was obtained from the Institutional Review Committee of Mbarara University of Science and Technology and the Uganda National Council for Science and Technology. Participants provided signed informed consent before study participation.A questionnaire was administered at baseline and an in-depth interview was conducted on each participant after 30 days of use of PositiveLinks and blood pressure machine. The 30-day period was used since it coincides with the scheduled clinical visits when medication would be replenished.self-monitoring and these included medication adherence , stress , mood  and blood pressure readings (systolic and diastolic blood pressure). The application was also designed to provide social support through a virtual community message board  with appropriate cuff sizes as per arm circumference i.e., small (<21 cm), normal (22–32 cm), and large cuffs (35–44 cm).Enrolled participants were trained on the standard procedure for blood pressure measurement using automatic sphygmomanometers  carried out individual in-depth interviews to explore detailed participants’ perspectives, understanding, and experiences using the application for hypertension management. The audio-recorded interviews were translated to English to ensure transcription by other investigators who also did reviews for quality, clarity, and detailed information.We used Dedoose software program to analyze the data.Of the 206 patients with hypertension sampled between September 2019 and January 2020, 38 participants were enrolled for the pilot study. We excluded 99 non-residents of Mbarara, 138 had analog/button phones, 18 had <4 months of hypertension diagnosis, and 3 did not own a mobile phone. Among the 38 enrolled, one participant withdrew consent during follow-up and was excluded from analysis. Of the 37 participants who completed the 30-day interviews, the mean age was 58 years (SD 10.8) years, 28 (75.7%) were female, and median duration of hypertension diagnosis was 5 years (interquartile range 3–5 years). All participants actively used the application until study exit .Evaluation of acceptability and feasibility of the application were carried out drawing from the domains of TAMSocial support: 35 (94.6%) experienced peer social support through posts and replies from the virtual community board messages;It’s like a support group, when you are down, you go there, people try to post and you don’t feel down again. If you are having a challenge with your health, with your diet, you go there and there’s always somebody there posting so it’s like a family member whom you have not met but is actually helping, so we have each other’s back, you understand, we help each other. If somebody has a question, there’s always somebody to answer and assist, so it’s really fantastic.” “Improves self-monitoring of BP: Participants found using the mobile health application as a real-time and convenient aid to self-monitoring of their daily blood pressure;“Well, it has helped me in monitoring my high blood pressure and knowing how I am daily. I see my blood pressure is better compared to when I used to go the hospital after a longtime minus monitoring.” Improves self-reported medication adherence: Among the 35 participants who reported missing taking their medications at baseline, 31 reported taking all medication as prescribed at the end of the study. The participants attributed this to reminders that helped them remember to take their medication.we are able to enter our blood pressure readings and monitor it and then it reminds to take our medication because we enter that we didn’t take our medication, it will warn you that it’s important to take your medication and you can also communicate with a doctor in case so I think to me it’s perfect.” “Blood pressure control: Among the 31(83.8%) who uncontrolled blood pressure at baseline, all except 1 had had controlled blood pressure after 30 days. Some participants attributed the stability in their bp to use of the app;“Yes I have seen the change, like I said earlier, my blood pressure has stabilized in good figures because before I started using the application, whenever I would go to the hospital, my blood pressure would be high but now it has stabilized.” Ease of use: Participants found the application easy to use during self-management;“No challenges whatsoever, it’s very easy to use and I know that when my blood pressure is too high, I have to take my medication and not miss it, if the blood pressure stays high even after taking my medication, I have to contact my doctor so there’s really no challenge because it’s very easy to use.” Behavioral intention of use: Participants stated that they became accustomed to self-monitoring through the use of the application, which helped them in managing and controlling their hypertension:“It helped us to be aware of our hypertension, that it’s there yes and also how to manage it, actually we have been forced in a good and cooperative way to manage our blood pressure, because now you observe we have hypertension but knowing you have hypertension, you are forced to take care of it and I have a feeling that it’s going to be a continuous process for us because having experienced this nobody would want to divert back to that period when we were careless about our hypertension.” “It added, like you know, people talk about exercising and walking so we get their other things other than the medication, because nobody there can advise you on what medication to take apart from the doctor but other additional things like dietary, exercise, taking things easy and having enough sleep, all these things, you know people were reminding us on the new fruits to have you know, how to use medication to work better.” Community board messages using the application among participants gave lifestyle tips on diet and exercise to control their hypertension;“Knowing one’s health is very important because now I would get to monitor myself and know how I am feeling, whenever I would take my measurements, knowing that its hypertension may be making me weak and I find it’s normal then I would know its other ailments that are disturbing me and I would know what to treat. This made me very happy.” Usage of the app enabled participants to know their blood pressure status and how best to care for themselves;Automatic blood pressure machine: Participants used the bp machines for daily measurements while using the application;“The advantage was leaving me with the application and machine for a month, because of this I don’t have to borrow the machine from any one because I already have one or go to the hospital! I have this machine here in my house and I can take my measurements anytime of the day.” Internet: Reliable internet access was readily provided to the participants;“I had enough [internet] data and thus nothing could hinder me from seeing the messages or sharing with the members.” Other participants with similar disease conditions: Other participants with similar disease conditions made the use of the application easier;“It was really helpful, it was easy to use, and not difficult and you don’t waste time, the network was cooperative and so it was so easy to use and aah you could also communicate on the platform with other people with a local community, communicating your experiences with each other, comforting each other, yea it was a very good thing, it helped me with my high blood pressure management.” However, participants reported challenges both internal and external, which hindered the use of the PositiveLinks application.Forgetfulness: Participants stated difficulty in using the application sometimes due to forgetfulness;“Well the problem is, I don’t know how to use the application well as I should, sometimes when I forget some things I call my son who helps me to enter my information when such issues arise, so I use a few features in the application.” Fear of knowing daily blood pressure measurements: Some participants felt scared to do self-monitoring using the application daily, for fear of knowing that their blood pressure might be high;Well when you gave me these things I felt happy because my blood pressure usually goes high, sometimes it’s so very bad, but whenever I would take my measurements and its extremely high I would get scared so at some point I stopped monitoring myself because my bp was not going down and I was scared and frustrated, then sometimes I would feel bad.” “High cost of antihypertensive medication or cuffs: Difficulty in affording medication or blood pressure cuffs and trouble accessing medical care were challenges for some participants;“I request that you try to help us access medication or increase the machines in the hospital, because sometimes we don’t have medication which is a problem, sometimes we don’t even have money.” Need for more understanding of application and disease conditions: Some participants stressed the need for extra training on how to exactly use the application in the management of hypertension;“Well I would love much more awareness on these items in as much as I was using the application and the machine, I needed much more information, I suggest that training should involve many things and more information and you give it enough time like an entire day per person so that we get to understand much more about the items and what high blood pressure truly is. We have it but we are not well knowledgeable about it that much.” Healthcare providers’ communication: Participants suggested that health care providers try to communicate and support participants as a form of encouragement using the intervention;“I don’t know because we have really helped each other, I think it may be on your part, we want you to encourage participants for real-time support groups because it really helps not only hypertension but can help even groups with other diseases, most people actually fail in managing themselves because they don’t have such support group but if you start real-time support groups it would help much better, here most people reply at their own time and pace.” ,Drawing from TAM theory,,Acceptability and feasibility of PositiveLinks application were promoted by the perceived usefulness, ease of use, and participants’ satisfaction. Participants pointed out the ability of the PositiveLinks application to establish social networks using the virtual private network (community board messages). The social support improved the relationship among participants, who enjoyed messaging each other, improving their mood, and reducing their stress. Peer to peer support and self-care can help to prevent negative psychological effects,,,,PositiveLinks application showed improvement in health outcomes among patients living with hypertension as evidenced by self-reported adherence to antihypertensive medications and improved blood pressure control. These clinically important findings are in keeping with others that showed that mobile health applications play a major role in treatment and improving blood pressure control and management.Our findings should be appraised within the context of our study limitations. First, this was a 2-center pilot study with a small sample. Second, the application was customized in English only, which limits the generalizability of our results to participants who cannot read English. Third, there was potential for selection bias if participants who chose to enroll in the study differ from others in the population. There were more women than men in the study, which may be due to women being better health seekers than men. Fourth, residing within a 5 km radius from the clinics as an inclusion criterion could have been a proxy for both mobile phone/internet access and use in this group. Fifth, smart phone ownership as our inclusion criterion was a limiting factor to this study considering majority of the potential participants having analogue phones, thus directly limiting the feasibility uptake. Thus, attempts to generalize these results to other populations should be made with caution.However, the current study provides a profile of mobile phone use to inform future mhealth interventions in similar settings. In addition, this study has potential health policy implications in emphasizing the importance of reliable internet access in the management of medical conditions. Efforts to improve internet access in low-resource settings may help reduce health disparities by enabling more equitable participation in mhealth interventions.The strengths of this study include: (1) our sample consisted of adults receiving clinical care for hypertension at one tertiary and one low level public health facilities from peri-urban and rural settings where both mobile phone/internet access and use are expected to be comparable to other parts of the country as such the findings are generalizable to Uganda and other low-income countries; (2) We used the TAM, a standard model theory, to access the technology acceptance of the application.In conclusion, we found that PositiveLinks application, a low cost, low maintenance, and easy to use mobile health application, can be rolled out to improve social support, medication adherence, and blood pressure control among adult hypertensive patients in a low-resource setting. This was an available solution through a research partnership that required modest modification. Further assessment of cost-effectiveness of PositiveLinks application in blood pressure control in resource-limited settings will be pursued in future studies.This work was supported by the center for Global Health, grant number (None) at University of Virginia School of Medicine, Charlottesville, VA, USA.All authors duly contributed to this manuscript and they all certify that they sufficiently participated and are responsible for this work. All authors confirm that this work is not under consideration elsewhere. All authors meet authorship criteria and none have disclosures or conflicts of interest relating to the study. These are the contributions from all authors as follows: Ms. Beatrice Mugabirwe took part in writing the concept and design of the study, data collection, analysis and interpretation of data, drafting of the manuscript, revision and critiquing of the manuscript, and approval of the final version of the manuscript. Dr. Tabor Flickinger took part in analysis and interpretation of data, drafting of the manuscript, revision and critiquing of the manuscript, and approval of the final version of the manuscript. Ms. Lauren Cox took part in analysis and interpretation of data, drafting of the manuscript, revision and critiquing of the manuscript, and approval of the final version of the manuscript. Dr. Pius Ariho took part in analysis and interpretation of data, drafting of the manuscript, revision and critiquing of the manuscript, and approval of the final version of the manuscript. Dr. Rebecca Dillingham took part in writing the concept and design of the study, drafting of the manuscript, revision and critiquing of the manuscript, and approval of the final version of the manuscript. Dr. Samson Okello supervised and was actively involved in writing the concept and design of the study, analysis and interpretation of data, drafting of the manuscript, revision and critiquing of the manuscript, and approval of the final version of the manuscript.


Light chain amyloidosis is one of the most common forms of systemic amyloidosis. The disease is caused by the misfolding and aggregation of immunoglobulin light chains to insoluble fibrils. These fibrils can deposit in different tissues and organs such as heart and kidney and cause organ impairments that define the clinical presentation. In this study, we present an overview of IGLV-IGLJ and IGLC germline utilization in 85 patients classified in three clinically important subgroups with dominant cardiac, renal as well as cardiac and renal involvement. We found that IGLV3 was the most frequently detected IGLV-family in patients with dominant cardiac involvement, whereas in renal patients IGLV1 were most frequently identified. For patients with dominant heart and kidney involvement IGLV6 was the most frequently detected IGLV-family. In more detailed analysis IGLV3-21 was observed as the most dominant IGLV-subfamily for patients with dominant heart involvement and IGLV1-44 as the most frequent IGLV-subfamily in the group of patients with dominant kidney involvement. For patients with dominant heart and kidney involvement IGLV6-57 was the most frequently detected IGLV-subfamily. Additionally, we were able to show an exclusive linkage between IGLJ1 and IGLC1 as well as between IGLJ2 and IGLC2 in the fully assembled IGL mRNA. With an incidence rate of 3–5 patients per million, light chain amyloidosis (AL) is the most common form of systemic amyloidosis (70%) . It is cIn the last decades, several research groups have tried to uncover the causes of fibril formation of LCs using different approaches and it was possible to solve the cryo-EM structures of ex vivo fibrils , 4. FurtIn this study we aimed to enhance the knowledge about the germline usage of the V-segment in three clinically distinct subgroups of AL patients with lambda LC restriction and with dominant heart, dominant kidney or dominant heart and kidney involvement. This is based on the assumption that the use of certain IGLV segments poses a risk for the development of amyloidosis and might explain organ tropism –10. MoreFor sequencing, we used an adapted primer-set which designed for highly sensitive minimal residue disease diagnostics in MM , 18. TheWe included patients which were seen between March 2019 and March 2021 at the Amyloidosis Centre of the University Hospital Heidelberg. This study was approved by the Ethics Committee of the University of Heidelberg  and followed the Helsinki guidelines for research of human subjects. Data was collected for FISH analysis and CD138+ sorting . Clinica10–90 ml BM aspirates were collected from patients with lambda AL Amyloidosis with dominant heart, kidney or heart and kidney involvement. Mononuclear cells were isolated by density gradient centrifugation (Ficoll Paque). After washing the cells, a red cell lysis was performed. CD138+ PC were extracted using magnetic beads-based positive selection . Depending on the cell count of the positive fraction 60 000–30 0000 PC were used for FISH analysis. The highest measured percentage of a genetic aberration in the FISH result was defined as the proportion of the main clone . The remThe isolation of genomic DNA and RNA was performed using the „AllPrep DNA/RNA/Protein Mini Kit”, according the manufactures instructions. To homogenize the lysate a QIAshredder was used and due to the storage of the samples in GTC-buffer no additional RLT-buffer with β-mercaptoethanol was added. To eluate the total RNA, 15 μl RNAse free water was added twice and centrifuged to obtain a final volume of 30 μl total RNA. The reverse transcriptase reaction was performed with the High Capacity cDNA Reverse Transcription Kit with RNAse Inhibitor and Oligo dT18-Primer .The polymerase-chain-reaction (PCR) was performed following the published protocol . Final PFor obtaining a sequence, the ab1-Files from Eurofins were analyzed. For IGLV- and IGLJ-gen family assignment VBase2  was usedBM was collected from 101 patients during the specified period. In five cases we were not able to detect any CD138+ PC. However, these were also used for further LC analysis, since the detection limit of the cell count is 2,5E+04 CD138+ PC and it is assumed that sufficient cells are still available for further molecular biological analysis. Through FISH diagnostics, we can obtain information about the clonality of the samples . In 16 cThe clinical characteristics of the different cohorts are listed in For patients with dominant heart involvement the IGLV3-family was assigned in 49% of the cases, for the patients with dominant kidney involvement in 28% and for patients with dominant heart and kidney involvement only in 8%. Thirty-six percent of the sequences from patients with dominant kidney involvement where attributed to IGLV1 . Concerning the frequency of assignment to IGLV6, a difference was also detected in terms of organ manifestation. For dominant cardiac disease, IGLV6 was assigned in 9%, for dominant renal disease in 12% of the cases, but for dominant heart and kidney involvement in 46% of the cases .Regarding the clonality of the samples, no significant difference was found between the IGLV-families. For samples classified in the IGLV1-family, the average percentage of the main clone was 78% (SD: 16%), for IGLV2-samples 85% (SD: 10%), for IGLV3-samples 85% (SD: 15%) and for samples of the IGLV6-family 74% (SD: 17%).In nine (11%) cases, no clear assignment could be done to an IGLV-gene or family. These included five (11%) cases for dominant heart, two (8%) cases for dominant kidney and two (15%) cases for dominant heart and kidney involvement. These nine samples had an average clonality of 71% (SD: 23%), which was slightly lower than the values of the respective subgroups. In one of these nine cases (dominant heart involvement) the PCR with the multiplex-primer set and the PCR with the IGLV6 specific primer achieved sequences with nearly the same number of blurs. This sequence was not assigned to any IGLV-family in the evaluation and defined as non-evaluable.For patients with dominant heart disease, IGLV3-21 was estimated as the most frequent IGLV-family (28%), while IGLV2-14 was the second most frequent detected (17%), and IGLV3-1 with 13% . For theWe also analyzed the IGLJ and IGLC germline usage  in the dIn the analysis of preferential joining of specific IGLJ- and IGLC-family members, our dataset showed that IGLJ1 and IGLJ2 were exclusively joined to IGLC1 and IGLC2, respectively. In contrast, IGLJ3 was found joined to IGLC2 (40%) or IGLC3 (53%) without any relevant preference for one of the two while joining with IGLC1 has not been detected.Finally, we also analyzed the composition of the IGLV-IGLJ-IGLC germline usage . Due to Several studies have already been conducted on the use of IGLV-germline segments in AL amyloidosis –10, 26 . For thiAnother interesting difference between the three subgroups is that about 40% of the patients with dominant cardiac manifestation presented soft tissue involvement, whereas this was only the case in 4% of the patients with dominant renal involvement, but in 33% of the patients with dominant heart and kidney involvement. This indicates that involvement of the heart also favors soft tissue infestation.For the interpretation of our study and for comparison to the already published data it must be considered that the source of biomaterial, the measurement methods and the composition of the cohort play a crucial role and that the presented results hold true under the specific conditions described above. By a clear clinical classification of the groups and our molecular biological approach of the CD138+ positive selection and the multiplex primer set we tried to exclude as many interfering factors as possible. In general, our IGLV-family identification success rate of 89% is within the range of other cDNA based published data sets (72%-100%).If we hypothesize that different organ tropisms favor certain IGLV germline usage, this is an essential point to compare with existing data. In the study of Perfetti et al. in 2002, a singular organ infestation could only be defined in 38%, a double organ infestation was present in 42% . In the In contrast to all six compared publications, in which IGLV6-57 was identified among the top three most common IGLV-families and especially for dominant renal involvement, our results indicate that this may be only a characteristic of patients with dominant heart and kidney involvement. We were able to detect this family in 46% of this cohort. This is deviating from the data published by Kourelis et al., where also a strict classification for cardiac and renal patients was chosen, but IGLV6-57 was identified as the most dominant family for patients with renal involvement .We were able to detect IGLV3-21 as the most dominant IGLV-family for patients with cardiac involvement and IGLV1-44 for patients with dominant kidney involvement. In 2012, Perfetti et al. detected IGLV1-44 as the most frequent and IGLV3-21 as the second most frequent IGLV-family for dominant heart disease .Another new aspect of our study is, that we examined not only the IGLV-segment, but the composition of the entire LC in more detail. We were able to make statements about the possible connections of the IGLJ and IGLC-segments.Surprisingly, for IGLJ3 a joining between IGLC2 and IGLC3 was found. Due to the genomic loci and the arrangement in IGLJ-IGLC cassettes  a connecFinally, we also investigated the connection of the IGLV-segments with IGLJ and IGLC. For the IGLV1-family, including IGLV1-40, IGLV1-44, IGLV1-47 and IGLV1-51 there was a linkage with IGLJ1 and IGLC1 as well as linkages with IGLJ2/IGLJ3 and IGLC2/IGLC3 detected. This was also shown for the IGLV2-family, including IGLV2-8 and IGLV2-14. In contrast, linkage of IGLJ1 and IGLC1 with IGLV6-57 could not be determined. Interestingly, for the most dominant IGLV-families for dominant heart and dominant heart and kidney involvement IGLV3-21 and IGLV6-57 a linkage to IGLJ2 and IGLC2 was detected most frequent. No uniform statement can be made for the subgroups of the IGLV3-family. For IGLV3-21, IGLV3-19, as well as IGLV3-25, no linkage with IGLJ1 and IGLC1 was detected. Interestingly for IGLV3-1 a linkage with IGLJ1 and IGLC1 could be detected in 75% of the cases. These results suggest that spatial genetic proximity to the IGLJ and IGLC loci may be crucial. The IGLV3-1-locus is located on chromosome 22q11.22 closest to IGLJ1 and IGLV6-57 furthest away. Therefore, our results can give an indication of the possible linkage patterns, but due to the small sample number of individual IGLV-families further investigation are needed to confirm our findings.In conclusion, our method of CD138+ cell sorting not only allows us to achieve a very high purity of the sample, but also provides information on the clonality of the sample via FISH analysis. We were able to confirm a specific enrichment of IGLV-families in relation to organ tropism in systemic AL amyloidosis. We detected IGLV3-21 as the most dominant IGLV-family for dominant heart involvement (28%), IGLV1-44 for dominant kidney involvement (20%) and IGLV6-57 for dominant heart and kidney involvement (46%). In addition, for the first time we took a closer look at the complete LC and the linking of IGLV, IGLJ and IGLC segments. Here, we were able to identify dominant linkage pattern between IGLJ and IGLC. IGLJ1 was found exclusively linked to IGLC1 and IGLJ2 to IGLC2. For IGLJ3 a joining with IGLC2 and IGLC3 could be observed. In the linkage of IGLV-segments with IGLJ and IGLC, a certain genetic proximity seems to play a decisive role.S1 Fig(TIF)Click here for additional data file.S2 Fig(TIF)Click here for additional data file.S3 FigThe highest measured percentage of a genetic aberration in the FISH result was defined as the percentage of the main clone.(TIF)Click here for additional data file.S4 FigAll patients are included regardless of the organ manifestation. The dFLC values were collected at diagnosis.(TIF)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 TableHK = dominant heart and kidney involvement, H = dominant heart involvement, K = dominant kidney involvement.(DOCX)Click here for additional data file.S3 TableHK = dominant heart and kidney involvement, H = dominant heart involvement, K = dominant kidney involvement.(DOCX)Click here for additional data file.