Histiocytic sarcoma (HS) is a rare tumor that may result from the transdifferentiation of preexisting hematolymphoid neoplasms in a subset of patients. There are instances of correlation or concurrence between HS and a number of cancers, particularly B-cell-associated hematopoietic tumors. Only three cases of HS occurring subsequent to or concurrently with gastrointestinal stromal tumors (GIST) have been recorded. Our main objective was to give an overview of demographics, clinical signs and symptoms, histopathological findings, and immunohistochemical and molecular analysis when HS develops secondary to or concurrently with GIST. A search of PubMed, Google Scholar, and ScienceDirect was undertaken using Medical Subject Headings (MeSH) keywords. According to the findings of our review, there were two males (66.6%) and one female (33.3%). The average age of patients at presentation was 59.6 years. On the immunohistochemistry, three patients were positive for cluster of differentiation (CD) 68 (100%), two patients were positive for CD 163 (67%), one patient was positive for leukocyte common antigen (LCA) (33%), and only one patient was positive for CD 4, CD 10, CD 31, CD 45, human leukocyte antigen (HLA)-DR, lysozyme, and vimentin (33%). On molecular investigation, the gastric mass of only one patient (33.33%) contained a KIT mutation on exon 11. Emperipolesis was observed in one patient (33.33%) on histological examination. Our study provides an important overview of the available literature and gives insight into important diagnostic markers of HS when it occurs secondary to or concurrently with GIST. Histiocytic sarcoma is an extremely rare tumor with an incidence of 0.17 per million individuals . In 2016Histiocytic sarcoma often involves extranodal regions, including the digestive tract, soft tissue, lung, and nasal cavity . There hGrossly, a fleshy mass with a well-circumscribed or infiltrative border, fluctuating bleeding, or necrosis frequently characterizes the presentation of histiocytic sarcoma . HistoloDiagnostic fine-needle aspiration is frequently performed on patients with extranodal histiocytic sarcoma. The cytologic characteristics include lymphoplasmacytic or neutrophilic background with lymphoglandular bodies, and emperipolesis . While cGastrointestinal stromal tumors (GIST) are the most common mesenchymal tumor of the gastrointestinal tract and are located in the stomach (56%), followed by small bowel (32%), colorectum (six percent), and esophagus (less than one percent) . The omeSeveral studies report an association or concurrence of HS with a number of malignancies -37.To daMethodologyTo investigate cases of histiocytic sarcoma occurring secondary or concurrently to GIST, we used PubMed, Google Scholar, and ScienceDirect. We collected all relevant reports electronically by entering the necessary keywords. The search cutoff date for databases was July 10, 2022. We implemented a Boolean approach using Medical Subject Heading (MeSH) keywords. When establishing the inclusion/exclusion criteria listed below, article titles and abstracts were evaluated. In this review, Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards for 2020 were followed .Inclusion and exclusion criteriaWe included only English-language case reports and conference abstracts with unrestricted access to full-text reports and with only human subjects. We excluded all other study designs. MeSH keywords searched in PubMed are summarized in Table The search strategy in ScienceDirect and Google Scholar is summarized in Table ResultsThis review's search approach includes the aforementioned databases and generated 208 articles, of which 10 duplicates were eliminated using Zotero. A total of 198 records were reviewed, and 150 were discarded based on the inclusion/exclusion and relevance criteria. The final screening yielded 48 reports for quality and eligibility evaluation. Lastly, one conference abstract and two case reports were included in this review. A quality assessment tool using the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Case Reports was performed. The PRISMA flowchart is illustrated in Figure In our review, there were two males (66.6%) and one female 33.3%) as per gender distribution. The mean age of presentation was 59.6 years. On the immunohistochemistry panel, all three patients were positive for CD 68 (100%), two patients were positive for CD 163 (67%), one patient was positive for leukocyte common antigen , and only one patient was positive for CD 4, CD 10, CD 31, CD 45, HLA-DR, lysozyme, and vimentin (33%). Two patients (66.6%) were positive for both CD 68 and CD 163, and one patient (33.3%) was positive for CD 68 and LCA. On molecular analysis, the gastric mass was positive for a KIT mutation on exon 11 in one patient (33.33%). In two patients (67%), there was no BRAF mutation, and molecular analysis was not done in one patient (33.3%). On histopathological findings, emperipolesis was seen in one patient (33.33%). The results of our review are summarized in Table 3.3% as pReview of literatureTransdifferentiation is the process of changing a cell type from one tissue or organ into a cell type from a different tissue or organ directly without going through any intermediate cell lineage. It is also called lineage reprogramming . AccordiHistiocytic sarcoma is characterized by a broad age distribution and a significant predominance of males . This coIn order to confirm histiocytic differentiation with positive markers and to rule out morphologically similar entities with negative markers, immunohistochemistry is crucial for the diagnosis of histiocytic sarcoma. A small percentage of instances of histiocytic sarcomas additionally express CD 31, CD 4 (cytoplasmic), and CD 45RO ,10,21. TPatients with follicular lymphoma and histiocytic sarcoma have both been identified as having immunoglobulin H (IgH)-BCL2 fusions ,26. In bUsing targeted next-generation sequencing, Hornick's team has discovered various activating mutations in the RAS-MAPK, PI3K-AKT-MTOR, and CD KN2A tumor-suppressor gene in the majority of histiocytic sarcomas . FurtherLimitationsThe biggest limitation of our literature review was the presence of only two case reports and one conference abstract with a sample size of three, due to which we can't draw any significant conclusion. The ethnicity of patients was missing in all reports. There were no significant details on the management and follow-up of the patients. Therefore, future cases should include detailed parameters to add value to the literature.Our review summarizes available data when HS occurs secondary to or concurrently with GIST. All three patients had confirmed HS in our review and were positive for CD 68. Only two patients were positive for CD 163. Two patients had HS with GIST treated previously, and one patient had concomitant GIST with positive CD 68, CD 117, and CD 34. The most common clinical presentation was abdominal pain. Only one patient had emperipolesis on histopathological examination. Our knowledge of the exact relationship between HS and GIST is limited given less sample size and needs to be supplemented by a large sample size; therefore, rare cases like these need to be reported. Our review is important in the sense that it provides an overview of the current available literature and gives insight into important diagnostic markers when HS occurs secondary to or concurrently with GIST.


Non-alcoholic fatty liver disease (NAFLD) is closely related to cardiovascular diseases (CVD). A newly proposed definition is metabolic dysfunction-associated fatty liver disease (MAFLD), which was changed from NAFLD. The clinical effect of this change on abnormalities of cardiac structure and function is yet unknown. We aimed to examine whether MAFLD is associated with left ventricular (LV) diastolic dysfunction (LVDD) and cardiac remolding and further identify the impact of different subgroups and severity of MAFLD.®) with a controlled attenuation parameter (CAP), and patients with MAFLD were divided into normal, mild, moderate, and severe hepatic steatosis groups based on CAP value. Cardiac structure and function were examined by echocardiography.We evaluated 228 participants without known CVDs. Participants were categorized by the presence of MAFLD and the normal group. Then, patients with MAFLD were subclassified into three subgroups: MAFLD patients with diabetes (diabetes subgroup), overweight/obesity patients (overweight/obesity subgroup), and lean/normal-weight patients who had two metabolic risk abnormalities (lean metabolic dysfunction subgroup). Furthermore, the severity of hepatic steatosis was assessed by transient elastography (FibroScanp < 0.001) compared to the normal group. The overweight subgroup and diabetes subgroup were significantly associated with signs of cardiac remolding, including interventricular septum thickness, LV posterior wall thickness, left atrial diameter , relative wall thickness, and LV mass index . Additionally, moderate-to-to severe steatosis patients had higher risks for LVDD and cardiac remolding .LVDD was significantly more prevalent in the MAFLD group (24.6% vs. 60.8%, MAFLD was associated with LVDD and cardiac remolding, especially in patients with diabetes, overweight patients, and moderate-to-to severe steatosis patients. This study provides theoretical support for the precise prevention of cardiovascular dysfunction in patients with MAFLD. Non-alcoholic fatty liver disease (NAFLD) has become a common metabolic disease worldwide, with the estimated prevalence of a quarter of the population  and is aImportantly, the main cause of death in patients with NAFLD is CVDs, rather than hepatic causes . MAFLD iThis cross-sectional study population consisted of patients who visit the metabolic disease center in Hangzhou Normal University Affiliated Hospital and were enrolled between March 2021 and May 2022 in the Hangzhou Normal University Affiliated Hospital for health examinations. The baseline characteristics were compared among the groups. All subjects were assessed by imaging techniques to investigate the clinical association between MAFLD and LV diastolic dysfunction (LVDD) and cardiac remolding. This study protocol and analysis of the data were approved by the institutional review board of the hospital.A total of 332 participants were initially evaluated, 30 (9.04%) individuals were excluded because of the absence of the echocardiographic images, 28 (8.43%) individuals were removed because of lack of complete laboratory tests, and 46 (13.86%) individuals were excluded because of history of CVDs including heart failure, ischemic heart disease, severe arrhythmia, and moderate or severe valvular heart disease. Finally, a total number of 228 subjects were included in this study. The evaluation of screening programs is presented in via an outpatient collection at the first visit. Smoking status was categorized into never, past, or current smoking. Current smoking was defined as having smoked at least 1 cigarette per day; history of alcohol consumption was categorized into never, past, little drinking (1–19 g/day), moderate drinking (20–39 g/day), and excessive drinking (≥40 g/day). Body mass index (BMI) was calculated as weight (kg) divided by the square of the height (m). Waist circumference was measured at the midpoint between the lower ribs and the iliac crest after normal expiration. Blood pressure was measured on both sides and read by a mercury sphygmomanometer after at least 5 min of rest, and systolic and diastolic blood pressure was recorded. Blood samples were collected from all participants after overnight fasting to determine laboratory parameters, such as cholesterol level, plasma glucose, related indexes of liver function, and inflammation.Demographics, medical history, waist circumference, and social habits including smoking and alcohol consumption, were obtained Hypertension was defined as blood pressure ≥ 140/90 mmHg and/or current antihypertensive therapy. Diabetes was defined according to the 2020 China Guideline for Type 2 Diabetes. It mainly includes typical diabetes symptoms and one of the following conditions: fasting plasma glucose (FPG) level ≥7.0 mmol/L or random and postprandial blood glucose level ≥11.1 mmol/L or glycosylated hemoglobin (HbA1c) level ≥6.5%. Participants with a previous history of diabetes or the current use of glucose-lowering agents were also regarded as current diabetic patients.® 501, Echosens, Paris, France) was used to diagnose fatty liver, and it was also confirmed that it was done by trained radiologists who were blinded to the data of all participants, including general information, laboratory data, and echocardiography. The severity of hepatic steatosis was estimated using controlled attenuation parameter (CAP) values, which were examined by FibroScan®. According to CAP value, the severity of fatty liver was categorized into three grades, which have respectively established cutoff values of 248, 268, and 280 dB/m for >S0, >S1, and >S2 and described as mild, moderate, or severe hepatic steatosis  or transient elastography (FibroScanteatosis . The livteatosis .2), presence of type 2 diabetes mellitus (T2DM), or lean/normal subjects with metabolic dysregulation. Metabolic dysfunction was defined as the concurrence of at least two metabolic risk abnormalities , non-diabetes but overweight/obesity patients (overweight/obesity subgroup), and lean/normal-weight patients who had two metabolic risk abnormalities (lean metabolic dysfunction subgroup). Since the histological steatosis severity is closely associated with CVD , 17, pat3. The relative wall thickness (RWT) was calculated by the formula (2 × PWT)/LVEDD, and increased RWT was defined as RWT > 0.42  probe. Before the examination, the patients were instructed to be quiet for at least 15 min while in a supine position or left decubitus position and to perform calm breathing. The measurement method was in accordance with the Chinese Adult Echocardiography Measurement guidelines. The images were analyzed by another experienced echocardiographer, blinded to who has hepatic steatosis. The parameters of cardiac structure, including left atrial diameter (LAD), LV end-diastolic diameter (LVEDD), interventricular septum thickness (IVST), and LV posterior wall thickness (LVPWT) were routinely measured. LV mass (LVM) was calculated with following formula: LVM= 0.8 X {1.04[(LVEDD+IVST+PWT)3 -(LVEDD)3 ]} + 0.6 g. Body suT > 0.42 . Peak veAll continuous variables were expressed as mean and SD (mean ± SD). The proportions for categorical variables were represented as the number of cases in each category and percentages. Two data groups were compared using Student’s t-test and the ANOVA test when it was necessary to compare at least three data groups for continuous variables. The prevalence of LVDD was presented as the number of cases in each category and percentage using the chi-square test for linear-by-linear association. Additionally, the trend in the proportion of each subgroup in MAFLD and the prevalence of LVDD in MAFLD subgroups were analyzed using the Jonckheere–Terpstra test Figure 2p-values in all cases were calculated, and it was considered that there is a statistically significant difference between the means of the compared groups when the p-value was less than 0.05. Statistical analyses were performed using SPSS version 21.0 software .The analysis of the impact of hepatic steatosis on the cardiac structure was done in 2 steps. First, differences in the echocardiographic parameters between groups of patients with hepatic steatosis and no steatosis were analyzed using Student’s t-test Table 2 p < 0.05), compared to normal people. Patients with MAFLD had significantly higher BMI, waistline, white blood cell count, neutrophil count, and metabolic parameters, such as triglyceride, fasting blood glucose (FBG), serum uric acid (UA), and HbA1c and lower levels of high-density lipoprotein cholesterol (HDL-cholesterol) as compared to those without MAFLD .In the final analysis, a total of 228 participants were stratified by presence or absence of MAFLD, and their clinical, laboratory, and metabolic characteristics are stated in p < 0.000, p for trend < 0.000). As expected, there were differences in some pronounced metabolism abnormalities among the three subgroups, such as BMI, FBG, HbA1c, uric acid, and HDL-cholesterol , 32 patients with diabetes mellitus (diabetes subgroup), and 31 lean or normal-weight patients but with at least 2 metabolic risk abnormalities (lean metabolic dysfunction subgroup), according to the above method. Overweight/obesity MAFLD patients account for the largest proportion as shown in p < 0.05 Table 3)p = 0.001).Next, an analysis of the severity of hepatic steatosis found that moderate and severe hepatic steatosis had more undesirable clinical characteristics when compared to the mild steatosis group Table 4.p < 0.001 [p = 0.1785, p for trend = 0.8677). In addition, we investigated the relationship between the severity of hepatic steatosis with MAFLD and LVDD by the same method as above. Moderate-to-to severe hepatic steatosis had higher prevalence of LVDD as shown in p < 0.0001, p for trend < 0.0001).When compared to the normal group, more patients with MAFLD had LVDD p < 0.05 [p < 0.05 [p < 0.05 [p < 0.05 [Some markers of cardiac remolding demonstrated alterations in patients with MAFLD, manifested by increased IVST, LVPWT, LAD, RWT, LVM, and LVMI p < 0.05 [p < 0.05 [p < 0.05  and the Hangzhou City Health Science and Technique Program (OO20190126).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Anastomotic blood supply is vital to anastomotic healing. The aim of this study was to demonstrate the effect of the left colic artery (LCA) on blood supply in the anastomotic area, explore the relationship between individual differences in the LCA and blood supply in the anastomotic area, and elucidate the relevant indications for LCA retention during radical resection for sigmoid or rectal cancer.Radical sigmoid or rectal cancer resection with LCA retention was performed in 40 patients with colorectal cancer who participated in this study. Systemic pressure, LCA diameter, and the distance from the root of the LCA to the root of the inferior mesenteric artery were measured and recorded. The marginal artery stump pressure in the anastomotic colon before and after the LCA clamping was measured, respectively.p < 0.001). The anastomotic blood supply positively and linearly correlated with body mass index and systemic pressure. Receiver-operating curve analysis revealed that LCA diameter  was an effective predictor of LCA improving anastomosis blood supply. No relationship was found between the LCA root location and anastomotic blood supply.There is a significant difference between the marginal artery stump pressure before LCA ligation and after ligation (53.1 ± 12.38 vs 42.76 ± 12.71, Preserving the LCA is effective in improving blood supply in the anastomotic area, and larger LCA diameters result in a better blood supply to the anastomotic area.The online version contains supplementary material available at 10.1186/s12957-022-02774-0. One of the most serious complications of colorectal cancer surgery is anastomotic leakage. It occurs in 1 to 30% of all cases , with thThe IMA and its branches have large individual differences, for example, the origin of the LCA can be 15 to 88 mm from the root of the IMA . There iInvasive arterial pressure measurement is the direct determination of intravascular pressure, which is the “gold standard” for blood pressure measurement, and can reflect pressure changes in the arteries in a timely and accurate manner and objectively reflect blood supply. In this study, we measured the marginal artery stump pressure (MASP) in the anastomotic colon to reflect the blood supply of the anastomotic area, explore the correlation between individual differences in the LCA and blood supply in the anastomotic area, with an aim to determine the relevant indications for LCA retention during radical resection of sigmoid or rectal cancer, and provide a theoretical basis for developing a personalized surgical protocol for colorectal cancer.This study was approved by the Institutional Review Board of Ningbo Medical Center Li Huili Hospital. Patients consecutively recruited from February 2022 to June 2022 with sigmoid or rectal cancer diagnosed by pathological biopsy, colonoscopy, and enhanced computed tomography were treated at the Department of Colorectal Anorectal Surgery of the Ningbo Medical Center Li Huili Hospital. This study considered only solitary radical resectable sigmoid or rectal cancers 5–25 cm from the anus. The inclusion criteria were as follows: (1) patients with sigmoid or rectal cancer who required surgery; (2) patients aged > 18 years and ≤ 85 years; and (3) patients without distant metastases of the tumor. The exclusion criteria were as follows: (1) pregnant patients or patients requiring emergency surgery; (2) patients who had not undergone intestinal anastomosis (such as Hartmann’s or Miles’s procedure); (3) patients who do not have the LCA; and (4) patients in whom LCA retention has been advised against because of a high metastasis risk of the root lymph nodes of the IMA confirmed intraoperatively. This was a controlled before-and-after study, and overall, 40 patients were selected from among the patients admitted for surgical treatment according to the inclusion and exclusion criteria. The investigators explained the purpose, significance, process, precautions, and other relevant issues pertaining to the study to the patients, and the patient decided on whether to participate in the study of their own will. The patients enrolled provided signed informed consent.In laparoscopic surgery for sigmoid or rectal cancer, after carefully dissecting the IMA root Fig. a, the arHeparin saline (500 mL of 5 U/mL) was placed into a pressurized bag and connected to a pressure sensor. Then, the vital signs monitor was connected to the pressure sensor and the arterial pressure mode was used. Then, the pressure sensor was emptied of air, placed at the same height as the right atrium, and zeroed. The vascular indwelling needle was placed in the edge arterial arch, fixed, and connected to the pressure sensor once the blood flowed out. MASP was recorded when the pressure stabilized. After the LCA was clipped, the MASP was re-recorded after the pressure stabilized.The LCA diameter was measured using enhanced computed tomography of the abdomen within 3 cm after it was given off. To reduce measurement bias, two researchers who chose not to participate in the surgeries measured the LCA diameter before surgery in patients with colorectal cancer. If the difference in the measurements was less than or equal to 0.2 mm, the average of the measurements was considered as the patient’s LCA diameter. If, on the other hand, the difference was greater than 0.2 mm, a third researcher who was not involved in surgeries was selected to measure the LCA diameter, and the average of the two most similar values was considered as the patient’s LCA diameter.t test was used to analyze the effect of clinically relevant factors on the MASP in the anastomotic colon before and after LCA clipping and the amplitude of MASP change. The paired samples t test was used to analyze the differences in anastomotic blood supply when the LCA was or was not retained and assess independent factors in subgroup that influence the change magnitude of MASP after LCA clamping. The independent predictors that influence the change magnitude of MASP after LCA clamping were identified using linear regression. Pearson correlation analysis was performed to evaluate the relationship between clinically relevant factors and the MASP in the anastomotic colon and explore the relationship between LCA diameter and the amplitude of MASP change after LCA clamping. Considering the degree of blood pressure decrease after LCA clamping as an effect evaluation, an increase in blood pressure greater than 10 mmHg (the median amplitude of MASP change) after LCA opening was regarded as a good improvement in anastomotic blood supply. Receiver operating characteristic (ROC) curve was used to determine the critical value of the minimum LCA diameter for retaining LCA with high sensitivity and specificity. Statistical analysis was performed using SPSS software . The significance level was set at a p value of less than 0.05.The independent samples In all, 40 patients participated in the study, including 26 and 14 patients with rectal and sigmoid colon cancer, respectively, of which 6 had partial intestinal obstruction before surgery. Eighteen patients underwent protective ileostomy. One patient developed an anastomotic abscess. Each anastomosis was tension free, and no patient required mobilization of the splenic flexure. During surgery, the marginal arteries were well protected. Patients’ anastomosed colons did not appear to have macroscopic ischemic changes under the near-infrared system.p < 0.001) . In the subgroups of patients with SP < 80 mmHg, hypertension, diabetes and LCA diameter < 2 mm, the MASP when LCA was open showed no statistical differences compared with the MASP when LCA was clamped (Table p < 0.001), which indicated that LCA diameter was an independent predictor that influence the change magnitude of MASP after LCA clamping.All participants underwent radical resection for sigmoid or rectal cancer with LCA retention. Furthermore, the MASP in the anastomotic colon was measured when the LCA was clamped and open in every patient. The mean MASP (± standard error) when the LCA was clamped was 53.10 ± 12.38 mmHg, while that when the LCA was open was 42.73 ± 12.71; there was a significant difference between the two values (r = 0.891)  Fig. d.Fig. 4SA MASP change amplitude of ≥ 10 mmHg after LCA clamping was considered to have a large impact on the blood supply in the anastomotic area. Further, ROC analysis was performed to determine the LCA threshold diameter that would predict a significant effect on the anastomotic blood supply. LCA diameter was found to be a valuable predictive test factor for whether the LCA can affect the anastomotic blood supply , larger sample sizes in later studies are expected to eliminate systematic errors. The MASP was significantly lower in male than in female. This is consistent with the finding that male gender is a known risk factor for leakage [Studies have shown that the arterial stiffness index is significantly higher in obese patients than in healthy individuals. Therefore, the blood pressure in obese patients is also higher than that in non-obese individuals , which i leakage . Further leakage . This alThere was a positive linear relationship between patients’ systemic blood pressure and their MASP; this finding is consistent with those of Guo et al. .By comparing MASPs when LCA is in different states, we found that the overall MASP when the LCA was open was significantly higher than that when the LCA was clamped. These data verify that LCA retention is effective in improving blood supply to the anastomosis area. In addition, our findings confirmed a positive correlation between the amplitude of MASP change in the anastomotic colon after LCA clamping and the LCA diameter, in that the larger the LCA diameter, the drop in the MASP in the anastomotic colon after LCA clamping was greater than that before LCA clamping. Therefore, colorectal cancer patients with larger LCA diameters also derive greater benefits from intraoperative preservation of the LCA. For patients with LCA stenosis, the middle colic artery is the dominant blood vessel that supplies blood to the left colon, and the LCA has little effect on the blood supply to the left colon. Therefore, retention of the LCA is of little significance in these patients. The middle colic artery is an important branch of the superior mesenteric artery (SMA) and an important source of blood supply to the marginal artery. The middle colic arteries are missing in 3–5% of patients . In thesThere was a large variation in the track of the LCA: in more than half of the patients, the LCA are able to reach the splenic flexure, and approximately 20% of the patients, the LCA only reached the lower section of the descending colon or even lacked , 26. ThiThere are some limitations of this study. Firstly, the sample size of this study was small, with only 40 patients included in the study. As a result, we were not able to perform external validation of our results. Secondly, the variables included in this study may be inadequate, such as the track of the LCA, which may have an effect on MASP of anastomotic colon and should be included in future research. What’s more, this study only included patients with colorectal tumors 5–25 cm from the anus. This may not reflect the effect of LCA on blood supply of anastomotic colon when tumor location is biased toward descending colon.Taken together, our results indicate that retaining LCA did effectively enhance the anastomotic blood supply. Furthermore, LCA diameter was an important factor affecting blood supply in the anastomosis area, and a lager LCA diameter seemed a greater effect the LCA had on the blood supply in the anastomotic area. While the LCA root location was not related to the anastomotic blood supply.Additional file 1: Figure S1. ROC curve for the LCA diameter in predicting the ability of the LCA to affect the anastomotic blood supply.Additional file 2: Table S1. ROC curve coordinates of LCA diameter.


Acute kidney injury (AKI) is a common and severe complication of community acquired infection, but data on impact in sub-Saharan Africa (SSA) are lacking. We determined prevalence, risk factors and outcomes of infection associated kidney disease in adults in Malawi.A prospective cohort study of adults admitted to hospital with infection, from February 2021 to June 2021, collecting demographic, clinical, laboratory and ultrasonography data.Adults admitted to a regional hospital in Southern Region, Malawi.The primary outcomes were prevalence of kidney disease and mortality by Cox proportional hazard model. AKI was defined according to Kidney Disease Improving Global Outcomes (KDIGO) guidelines. Secondary outcomes were risk factors for AKI identified by logistic regression and prevalence of chronic kidney disease at 3 months.We recruited 101 patients presenting to hospital with infection. Median age was 38 years (IQR: 29–48 years), 88 had known HIV status of which 53 (60%) were living with HIV, and of these 42 (79%) were receiving antiretroviral therapy. AKI was present in 33/101 at baseline, of which 18/33 (55%) cases were severe (KDIGO stage 3). At 3 months, 28/94 (30%) participants had died, while 7/61 (11%) of survivors had chronic kidney disease. AKI was associated with older age , and HIV positivity . Living with HIV was independently associated with death .Kidney disease is common among hospitalised adults with infection in Malawi, with significant kidney impairment identified at 3 months. Our study highlights the difficulty in diagnosing acute and chronic kidney disease, and the need for more accurate methods than creatinine based estimated glomerular filtration rate (eGFR) equations for populations in Africa. Patients with kidney impairment identified in hospital should be prioritised for follow-up. We provide data on prevalence, risk factors and consequences of acute kidney injury (AKI), which are scarce in sub-Saharan Africa (SSA).We make use of the expanding availability of point of care ultrasound in Malawi and assess its role in the AKI assessment.This is the first AKI study in Malawi reporting outcomes at 3 months, identifying significant kidney impairment and likely undiagnosed chronic kidney disease (CKD).Diagnosis of AKI and the distinction between CKD is a challenge when baseline kidney function is unknown; pre-existing CKD may have been misclassified as AKI.Our estimate of baseline kidney disease may be lower than actual prevalence, as eGFR equations and creatinine-based methods consistently underestimate kidney disease in SSA, making our findings even more serious and highlights the difficulties in using standard definitions of kidney impairment in this context.Globally, 1.7 million people die from acute kidney injury (AKI) every year, 80% of deaths are in low-income and middle-income countries (LMICs).2 underestimates AKI incidence by>50%.6The International Society of Nephrology initiative aims that ‘no one should die of untreated AKI in low resource regions by 2025’.Kidney ultrasound is standard practice in Malawi as part of the AKI assessment to identify chronic damage in the face of competition for dialysis beds. Patients with evidence of chronic kidney impairment are unlikely to be prioritised for kidney replacement therapy. In addition, kidney ultrasound may be used to identify those at increased risk of AKI, through assessment of kidney morphology, or by Doppler estimation of the Renal Resistive Index (RI), which directly correlates with intrarenal arterial resistance.A systematic review of 176 patients found that raised RI values on ultrasound were associated with increased odds of persistent AKI.We aimed to estimate the prevalence of kidney disease at presentation and 3-month follow-up in non-hospital-acquired infection in Malawian adults. Second, we evaluated risk factors for kidney disease and outcomes of mortality.Zomba Central Hospital (ZCH) is a regional hospital in Southern Malawi serving both urban and rural populations with 60 adult medical inpatient beds. Healthcare is provided free at this government institution at the point of delivery. Approximately half of the patients usually present directly to the hospital and the other half are referred from primary or secondary care. Adults are triaged by a nurse and then reviewed by a doctor or clinical officer. If admission under a specialty team is deemed appropriate, they will be reviewed by an intern or registrar from the admitting specialty, and by a consultant usually within 24 hours.Limited medical investigations are available on clinician request. Depending on availability, standard of care includes tuberculosis (TB) diagnostics , malaria testing , plain film radiography, full blood counts and serum creatinine ascertainment. Inpatient HIV services include provider-initiated HIV testing and counselling, with CD4 count and viral load available on clinician request. A four-bed enhanced observation unit exists on the medical ward with provisions for oxygen therapy, but no cardiac monitoring or defibrillator. There is a five-bed intensive care unit, mostly used for surgical postoperative patients. Local HIV prevalence is estimated at 17% among 15–49 year olds.8At ZCH, we performed a prospective observational study recruiting adults (≥18 years) with suspected infection and a medical decision to admit to hospital. Suspected infection was deliberately broad to incorporate a wide spectrum of presenting physiology, and to be consistent with ongoing studies. This includes reporting in the last week any of: fever; rigours; night sweats and treatment with antibiotics. All patients in the admissions unit were approached for screening, Monday–Friday, 07:00–17:00.Exclusion criteria were any of: people lacking capacity to consent, with no proxy consent available; pregnancy; non-severe uncomplicated localised infection with only local symptoms apparent on clinical examination by the screening clinical officer (such as cellulitis); detainees; trauma; admission to surgical or obstetric/gynaecological ward and previously recruited to the study. Responsibility for care and treatment decisions remained with the usual clinical team. Participants were followed-up as inpatients at 48 hours, and at 3 months in the community.Patients provided blood and urine at baseline, 48 hours and 3 months. Creatinine, blood urea nitrogen, glucose, ionised calcium, sodium, potassium, chloride and bicarbonate were assessed by iSTAT CHEM8 cartridges . The handheld iSTAT system measures creatinine using an enzymatic assay traceable to the US NIST Standard Reference material SRM909 with a reportable range of 0.20–20.0 mg/dL. Standard of care for measurement of serum creatinine in ZCH is using a sarcosine oxidase (enzymatic) method on a Mindray BS360-E machine. Often this test is unavailable due to reagent stock outs which are supplied by the government.Point of care HIV testing was done for those with unknown status or no recent negative test. Urine was tested by dipstick for blood and protein, and positive samples further quantified using a laboratory analyser (Mindray BS360).Point of care ultrasound assessed kidney size, corticomedullary differentiation, echogenicity and the presence of any hydronephrosis defined as a dilated appearance of the collecting system. Assessment was made by a clinical officer who underwent dedicated training, including direct supervision by a consultant radiologist before study commencement.RI was measured at each pole of each kidney  and an average taken across poles and between kidneys giving one RI value per participant. A portable Mindray DP-50 machine with 5MHz convex probe was used throughout. The assessor was blinded to the kidney diagnosis.Creatinine was measured on admission, at 48-hour and at 3-month follow-up.AKI was defined according to Kidney Disease Improving Global Outcomes (KDIGO) as a 1.5-fold increase in baseline creatinine from the estimated baseline.We refer to incident AKI at 48 hours if AKI criteria were not met at baseline, but there was a creatinine rise within 48 hours. AKI recovery was defined as a decrease of 0.3 mg/dL between baseline and 48 hours or a normal creatinine (<1.3 mg/dL) at 3 months.2 or decrease in GFR by ≥35% or increase in creatinine by>50% and/or albuminuria/haematuria.Acute kidney disease (AKD) was assessed on admission and at 3 months and defined according to KDIGO as: under 3 month duration, glomerular filtration rate (GFR) <60 mL/min/1.73 mAKI associated with infection, particularly in LMICs, affects patients unlikely to have a documented baseline creatinine, necessitating estimation through back-calculation.11–13The full-age spectrum equation was used to back calculate an estimate of baseline creatinine: using MDRD may be imprecise in estimating baseline creatinine in older adults, resulting in lower baseline estimates and more AKI diagnosis at older ages.Illness severity was measured by quick Sepsis-related Organ Failure Assessment (qSOFA) score, which uses three criteria: one point for low blood pressure (systolic blood pressure ≤100 mm Hg), high respiratory rate (≥22 breaths/min) or altered mental state .2 calculated using combined results from the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and the 4-parameter MDRD study equation, for a non-IDMS (isotope-dilution mass spectrometry)-traceable creatinine method, without race adjustment.2 at presentation were excluded from the CKD definition as the 3-month duration had not been proven. Those with an eGFR <60 mL/min/1.73 m2 at presentation and 3-month follow-up were given a diagnosis of CKD.Mortality was defined as death by 48 hours or 3 months. CKD was assessed at 3 months and defined as an eGFR of <60 mL/min/1.73 mStatistical analyses were performed in R (V.4.0.2).20A directed acyclic graph was used to examine the hypothesised causal relationship between HIV exposure and AKI , and to 10.1136/bmjopen-2022-065649.supp1Supplementary dataAge was included in the adjusted model as a cubic spline term with three knots, meaning that we used age as a continuous variable rather than categorising it into a limited set of age bands. The effect of age on probability of AKI was modelled using predicted probabilities from the adjusted model . ORs for different ages were generated by comparing odds to the reference age, chosen here to be 40 years.Kaplan-Meier survival analysis was conducted using Cox proportional hazards adjusted for age and qSOFA score.A power calculation for specific risk factors was not performed before initiation of this exploratory study. However, a post-hoc power calculation was performed in G Power (V.3.1), given the achieved sample size (88 participants with recorded HIV and AKI status), using HIV as the risk factor.Missing data were less than 18% across all variables , so resuAt the end of the study period, participants, patients and staff at ZCH were invited to a kidney awareness day, where key results were disseminated using simple leaflets, presentations and a group discussion.Between 3 February 2021 and 19 July 2021, 101 eligible patients admitted with infection were recruited. The study flow diagram is summarised in For those who HIV status was known (88/101), 53/88 (60%) of participants were people living with HIV. Among people living with HIV, 42/53 (79%) were receiving antiretroviral therapy, 40/53 (75%) co-trimoxazole preventive therapy and 11/53 (21%) isoniazid preventive therapy. Among all participants recruited, 11/101 (11%) had a history of receiving treatment for tuberculosis and 21/101 (21%) for malaria within the past month. The majority, 80/101 (79%), reported antibiotic use prior to presentation and 4/101 (4%) reported using over the counter medications or traditional medicines. No participants had a known prior diagnosis of CKD, 1/101 (1%) reported a history of diabetes, and 7/101 (7%) a history of hypertension.A histogram of baseline creatinine values in mg/dL is presented in Outcomes, and the effect of different methods to estimate baseline creatinine on AKI prevalence, are presented in Demographic univariable associations with AKI status are summarised in Multivariable associations with AKI status (based on estimated baseline creatinine assuming GFR: 100 mL/min) identified by logistic regression are presented as unadjusted and adjusted ORs and 95% CIs in Increasing age, living with HIV, microscopic haematuria and proteinuria were most associated with AKI on logistic regression analysis. Time-to-event analysis, adjusted for age and qSOFA score demonstrated an increased hazard of death for HIV positive participants  , and mortality at 3 months was 28/94 (30%). Living with HIV and increasing age were risk factors for presentation to hospital with AKI, and there was a significant prevalence of kidney disease at 3 months (11% CKD and 18% AKD). Living with HIV was independently associated with death at 3 months.Other limited studies examining kidney impairment in Blantyre, Malawi found 21% of medical admissions had evidence of kidney disease on admission (17% AKI and 3% AKD), which is lower than our reported prevalence for both, particularly AKD.Worldwide, the incidence of AKI is not well known. One report of 312 studies, including >3.5 million patients mostly from hospitals in high-income countries, suggests a pooled incidence of 22% (95% CI 19 to 24) and a mortality rate of 23%.2 is an appropriate definition of CKD.27To the best of our knowledge, this is the first AKI study in Malawi to obtain creatinine values at 3 months post discharge. Our data suggest a CKD prevalence of 7/61 (11%). How our data compares to the true community population prevalence of CKD in Malawi is not known. Normative ranges for GFR have not been established in African populations, including whether a cut-off of GFR of less than 60 mL/min/1.73 m2 using iohexol plasma clearance was 19%. This is nearer our estimate of AKD prevalence at 3 months, than our estimate of CKD.2 of 1%, and a systematic review of 13 countries in SSA estimated the pooled prevalence of CKD to be 14%.28 29In a recently published cohort, the African Research on Kidney Disease (ARK) study, in populations from Malawi, Uganda and South Africa, the prevalence of measured GFR<60 mL/min/1.73 mPrevalence reported by eGFR equations rather than measured GFR are likely to be significant underestimates, as highlighted by the important findings from the ARK study. Estimating GFR using serum creatinine substantially underestimates the population level burden of impaired kidney function in Africa.An additional complication is that patients presenting with infections in Malawi do not have documented baseline creatinine values, which can be addressed by back-calculation estimation by GFR equations. However, the optimal equation to accurately estimate GFR in Malawi (and across SSA) is uncertain. In studies from SSA, coefficients for African–American ethnicity consistently overestimate GFR.12We compared the different equations for estimating baseline creatinine and prevalence of AKI. Using lowest creatine during admission as a baseline identified fewer cases of AKI (17%) than the MDRD and full age spectrum back calculation equations (28%–36%), but may have been less likely to misclassify CKD as AKI. Comparatively, AKD encompasses a much broader definition and identified many more cases of kidney impairment (62%). Mortality at 3 months was similar for each AKI definition except lowest creatinine as baseline, for which there were no deaths, likely because this definition excluded participants with the most severe but unchanged kidney impairment.In this context, the inherent limitations of creatinine based AKI definitions are likely to substantially underestimate actual prevalence. Despite using high-income country based ‘normal’ eGFR values, this study still shows a high proportion of likely baseline kidney disease. Even if a substantial proportion of the baseline AKI was in fact undiagnosed CKD, this still represents a significant burden of kidney disease in adults in Malawi who present to hospital with infections. Furthermore, the binary AKI/CKD definitions are difficult, and dichotomisation may not even be meaningful or helpful in this context.We did not find ultrasound to be useful in identifying patients at risk of AKI in our cohort. Furthermore, resistive indices can be technically challenging to obtain and are not commonly practiced in Malawi, and we note the wide CI around our OR estimates. Our data does not support use of the RI in the AKI assessment and further investigation, with larger datasets, is needed. We suggest point-of-care ultrasound use as part of the AKI assessment, but not as a surrogate for serum creatinine measurement.Most deaths occurred after discharge rather than in hospital, indicating long-term mortality associated with hospitalisation with infection. Combined with the high prevalence of kidney disease identified at 3 months, community follow-up of patients is essential. To reduce post-discharge deaths, patients should be counselled on avoiding nephrotoxic medications which are commonly used , and advice given on how to prevent future episodes of AKD. Due to limited resources, follow-up should be prioritised for those identified with kidney impairment. Outpatient review after discharge should include assessment for recovery of kidney impairment, new AKD or formal diagnosis of CKD. Those identified with AKD/CKD will need ongoing follow-up for CKD assessment and management to prevent progression to kidney failure.2 at both presentation and 3-month follow-up) were misclassified as both AKD and AKI at presentation. Evidence of recovery at 3 months was seen in 18/33 (55%) of those with AKI and 38/63 (60%) with AKD, suggesting true AKI/AKD rather than misclassified CKD.Our study has several limitations. We do not know the true prevalence of CKD at presentation, given there were no historical serum creatinine results and patients did not report known CKD. This may have resulted in misclassification of CKD as AKI and AKD. It is reasonable to assume that the 7 cases of CKD (eGFR <60 mL/min/1.73 m2) at presentation at follow-up as the 3-month rule would not be observed. However, there was frequent AKD at 3 months, 18% new kidney impairment in patients who had normal kidney function on admission. This study also highlights the significant prevalence of undiagnosed CKD (eGFR <60 mL/min/1.73 m2 at both presentation and 3-month follow-up), of which none of the participants had prior knowledge. The high prevalence of HIV in the cohort increases the likelihood of baseline kidney disease, and indeed the majority of the CKD at 3 months was in people living with HIV (5/7 (71%)). Estimates for CKD prevalence in people living with HIV across Africa are between 1% and 46% with a pooled prevalence of 6%.31We were unable to identify incident CKD in those who had normal kidney function (eGFR >60 mL/min/1.73 m2 (72–100 mL/min/1.73 m2) and 92 mL/min/1.73 m2 (77–104 mL/min/1.73 m2) for women and men, respectively.27The other significant limitation is related to there being no validated method to estimate GFR and baseline creatinine for Africans, in health or acute illness. We estimated baseline creatinine using an assumed eGFR of 100 mL/min, which resulted in a 5% difference in AKI prevalence compared with an assumed eGFR of 75 mL/min. An assumed eGFR between 75 mL/min and 100 mL/min is supported by the median (IQR) iohexol measured GFR in Malawians reported in the ARK study: 86 mL/min/1.73 m2 body surface area; however, adults in Malawi may have a smaller body surface area. The median (IQR) body surface area for Malawian females and males in the ARK study was 1.70 m2 (1.50–1.80 m2) and 1.70 m2 (1.60–1.80 m2), respectively.2) was not measured, preventing correction of iSTAT measurements for PCO2. It was not possible to ascertain causes of death, and our study was not powered to detect moderate or small associations.We used MDRD and CKD-EPI equations to report eGFR normalised to 1.73 mTo prevent deaths from untreated AKI in low-resource regions by 2025, diagnosis of AKI and kidney disease needs to be appropriate for the local context. We urgently need more accurate methods to assess kidney function for specific African populations. eGFR and creatinine-based equations underreport the burden of kidney disease and the distinction between AKI and CKD is difficult.


The objective of this meta-analysis was to compare the efficacy and drug safety of tolvaptan with placebo for autosomal dominant polycystic kidney disease (ADPKD).The PubMed, Embase, and Cochrane Library databases were searched from inception to September 10, 2021. Eligible studies comparing tolvaptan and placebo in the treatment of patients with ADPKD were included. Data were analysed using Review Manager Version 5.3.P < 0.01) and TKV increase  in ADPKD treatment. Additionally, tolvaptan reduced the incidence of complications such as renal pain , urinary tract infection , haematuria , and hypertension . However, tolvaptan was associated with a higher incidence rate of adverse events such as thirst , polyuria , and hepatic injury .Thirteen studies involving 3575 patients were included in the meta-analysis. Compared with placebo, tolvaptan had a better effect on delaying eGFR decline (MD 1.27, 95% CI 1.24–1.29, Tolvaptan can delay eGFR decline and TKV increase and reduce complications such as renal pain, urinary tract infection, haematuria, and hypertension in the treatment of ADPKD. However, tolvaptan increases the adverse effects of thirst, polyuria and hepatic injury. Autosomal dominant polycystic kidney disease (ADPKD) is a single-gene disease and the most common inherited progressive kidney disease, characterized by the progressive development of bilateral kidney cysts and variable progression to end-stage kidney disease renal disease (ESRD) , 2. AccoOur meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Assessing the methodological quality of systematic review guidelines. We searched the PubMed, Embase, and Cochrane Library databases from inception to September 10, 2021. The combined text and MeSH terms included autosomal dominant polycystic kidney disease, tolvaptan, and placebo. In addition, the reference lists of the included papers were manually searched to identify eligible studies. There were no language restrictions.The inclusion criteria were as follows: (i) randomized controlled trials (RCTs), cohort or case–control studies; ii) studies of patients with ADPKD; (iii) studies designed to compare tolvaptan with placebo; and (iV) primary end points of this review were recorded, including total kidney volume (TKV) and estimated glomerular filtration rate (eGFR), and the secondary end points were reported, including the incidence rates of renal pain, urinary tract infection, haematuria, and hypertension. Adverse events such as thirst, polyuria, and hepatic injury were also examined.2, anticipation of renal replacement therapy, systolic blood pressure < 90 mmHg, and serious cardiac or hepatic disease.The exclusion criteria were as follows: (i) case series, comments, and reviews; (ii) lack of relevant outcome data; (iii) age < 18 years, eGFR < 15 ml/min per 1.73 mData were extracted independently by two investigators using standard data extraction forms. In the case of disagreement, a third investigator was consulted. We extracted the following data: first author, year of publication, location, study design, follow-up period, age, sex, sample size, and outcomes. The Cochrane assessment tool was used to evaluate the quality of RCTs . The NewP < 0.05 was considered statistically significant. We used the I2 statistic to assess heterogeneity among studies. We considered I2 > 50% and P < 0.10 to indicate significant heterogeneity. Meta-analysis with insignificant heterogeneity was performed using the fixed effects model. For meta-analyses with significant heterogeneity, the random effects model was used. Publication bias was assessed using subgroup analysis or sensitivity analysis.This meta-analysis was performed using Review Manager Version 5.3 (Cochrane Collaboration). We summarized treatment outcomes as odds ratios (ORs) for categorical variables and weighted mean differences for continuous variables with 95% confidence intervals (CIs). A flow diagram of the selection process is shown in Fig. eGFR Data about eGFR slope were reported in seven articles. Subgroup analysis revealed that there was no significant difference between tolvaptan and placebo on the eGFR slope at chronic kidney disease (CKD) stage 1 . The eGFR slope in the tolvaptan-treated patients was lower than that in the placebo-treated patients at CKD stages 2, 3 and 4   . Overall, tolvaptan had a better effect on the rate of eGFR decline    . As a whole, tolvaptan had a better effect on the annual rate of change in the TKV   for the tolvaptan group and 214/1212 (17.7%) for the placebo group. Tolvaptan-treated patients had a lower incidence rate of renal pain   for the tolvaptan group and 131/1212 (10.8%) for the placebo group. Tolvaptan-treated patients had a lower incidence rate of urinary tract infection   for the tolvaptan group and 104/1169 (8.9%) for the placebo group. Tolvaptan-treated patients had a lower incidence rate of haematuria   for the tolvaptan group and 168/1212 (13.8%) for the placebo group. Tolvaptan-treated patients had a lower incidence rate of hypertension  , polyuria , and hepatic injury  , which did not rise to a level indicating disruption of the quality of life . TolvaptThere were some limitations in our meta-analysis. First, in recent years, tolvaptan was approved for the treatment of rapidly progressive ADPKD in adults . Age, heIn the treatment of ADPKD, tolvaptan can delay eGFR decline and TKV increase. Additionally, tolvaptan reduced complications of renal pain, urinary tract infection, haematuria, and hypertension. However, tolvaptan increases the adverse effects of aquaresis and hepatic injury. To further confirm this conclusion, additional large multicentre randomized controlled trials are necessary.


Background and objectives: We aimed to evaluate the effects of the water drinking test (WDT) on several systemic and ocular parameters, including choroidal thickness, which was assessed through optical coherence tomography angiography (OCTA), in glaucoma suspects. Materials and Methods: A total of 40 eyes from 20 glaucoma suspects without any systemic or ocular diseases were included in this prospective observational study. All the participants undertook the WDT, which required the drinking of 1 L of table water in 5 min. The outcome measures included IOP, systolic and diastolic blood pressure (SBP and DBP), mean arterial pressure (MAP), mean ocular perfusion pressure (MOPP), ocular pulse amplitude (OPA), and subfoveal and peripapillary choroidal thickness, which were assessed at baseline and at four 15 min intervals after the WDT. Generalized least squares models and mixed model analyses that take into account repeated measurements were used to assess the changes over time of these parameters. Results: All the ocular and systemic parameters showed statistically significant changes at all time points compared to baseline apart from choroidal thickness. The peak changes were an IOP of 20.1 mmHg versus 17.3 mmHg at 45 min, an SBP of 137.6 mmHg versus 125 mmHg at 30 min, a DBP of 95.9 mmHg versus 85.7 mmHg at 15 min, and an MOP of 53.51 mmHg versus 48.89 mmHg at 15 min. Conclusions: Despite elevations in IOP and significant changes in all the assessed systemic parameters, the WDT was not associated with changes in choroidal thickness in glaucoma suspects. The water drinking test (WDT)’s application has been subject to debate in regard to its diagnostic and clinical utility over the last 80 years.Initially, in the 1970s, it failed to meet the criteria of a diagnostic procedure for glaucomatous optic neuropathy because of its low sensitivity and specificity . Based on recent evidence, it has been gaining popularity as a provocative procedure with high reproducibility for the detection of peak IOP. Several publications have suggested that the peak IOP revealed by the water drinking test is strongly correlated and is in agreement with the IOP peaks that occur during the day ,4,5,6. FConsidering the recent bibliography, there are different plausible mechanisms which are responsible for the acute IOP increase, one of which being the choroidal engorgement following the water load.A study by De Moraes et al.  related Therefore, the purpose of our study was to investigate whether similar changes took place in glaucoma suspect patients following the WDT. In addition, we aimed to correlate these changes with variations in choroidal thickness using new imaging techniques.The advent of the SS-OCTA has enabled better documentation of the choroidal layer. With the application of a longer wavelength (1050 nm) and the presence of the automated segmentation software, variations in the choroidal volume can be assessed in fine detail and with better accuracy .This study aimed to investigate, in glaucoma suspects, the response of systemic and ocular parameters following the water drinking test and, in particular, adds information on the extent of the variation in choroidal thickness and its correlation with IOP and the other variables in question.This prospective study followed the principles of the Declaration of Helsinki and was approved by the institutional ethics committee of the General Hospital of Athens “G. Gennimatas”.Individuals who met the criteria to participate in our research project were informed about the study procedure and provided written informed consent.The investigation was conducted on patients that were referred to our tertiary glaucoma unit. Thirty Glaucoma Suspects who met the study criteria were recruited from the Department of Glaucoma of the 1st Ophthalmology Clinic of the National and Kapodistrian University of Athens from January 2018 to June 2018. All patients were Caucasian; eighteen subjects were female, and twelve were male. Glaucoma suspects were defined, according to the American Academy of Ophthalmology Guidelines, as individuals with characteristic clinical features in at least one eye, such as elevated intraocular pressure (IOP ≥ 21 mmHg) on diurnal tension curve or an appearance of the optic disc or retinal nerve fibre layer (RNFL) that is suspicious for glaucomatous damage. In conjunction, they presented normal open angles through gonioscopy, normal visual fields through achromatic automated perimetry, and normal or borderline retinal nerve fibre layers through optical coherence tomography (OCT).Both visual field examination  and peripapillary RNFL thickness were evaluated on the day of the clinical examination. Unreliable visual fields with more than 33% fixation losses, false-negative errors, or more than 15% false-positive errors were excluded. The thickness of the RNFL was documented using a swept-source technology OCT (1050 nm wavelength light source) and, in particular, the 3D wide scan (12 mm × 9 mm) of the DRI OCT Triton series .16 Accurate high speed choroidal thickness maps can be produced.The measurement of choroidal thickness was performed with the same instrument, (SS-OCT DRI Triton series) which, due to the optimized long-wavelength scanning light (1050 nm), permits better penetration of the deeper layers of the eye.In order to eliminate possible factors that could affect ChT, we had strict inclusion criteria avoiding glaucoma suspects who had any systemic or ocular pathologic condition, were on any systemic medication, or had high refractive errors (>3D). Furthermore, we included subjects that were not using any topical or systemic glaucoma treatment. In particular, exclusion criteria included the use of any antiglaucoma treatment; history of systemic hypertension with or without treatment; history of congestive heart disease; presence of opaque refractive media causing inability to obtain reliable OCT scans; corneal pathology causing inability to measure IOP and OPA; and, finally, refractive error of more than ±3 dioptres. All measurements were obtained at the same time of day, during clinic hours from 1 pm to 3 pm, by two experienced masked technicians. Furthermore, patients who had undergone intraocular surgery within the last year were also excluded from the study. If both eyes of a participant met the inclusion criteria, one was randomly chosen; otherwise, only the glaucoma suspect eye was included in the study.All subjects were asked to perform water and food deprivation for 3 h before the WDT, and the procedure was performed at the same time of day for all participants (between 1 and 2 pm) with the ingestion of 1 litre of table water within 5 min.Axial length of the eyes and anterior chamber depth were documented once before the provocative test with the use of the IOLMaster .The rest of the ocular and systemic parameters were measured before water ingestion to establish a baseline (0 min) and at 15, 30, 45, and 60 min after water ingestion.Intraocular pressure was documented using both the Goldmann applanation tonometer  and the DCT . To avoid corneal and angle deformation, which could lead to false IOP results, Pascal tonometry preceded GATT by 2 min, and only measurements with a quality score of 1 and 2 (Q1/Q2) were accepted.Both techniques of IOP measurement were carried out at each time point by two experienced examiners following the same order (FP and KA).Blood pressure (BP) was measured with a brachial sphygmomanometer  and a single head stethoscope (MDF 740) after the individuals were seated for at least 5 min. Two measurements were taken at an interval of 5 min, and the average value was recorded.The vascular factors related to glaucomatous neuropathy, such as mean ocular perfusion pressure (MOPP) and ocular pulse amplitude (OPA), were recorded as well. OPA values were given by the Pascal tonometer, and MOPP was calculated with the formula MOPP = 2/3 MAP − IOP , where mean arterial pressure was calculated with the formula MAP = DBP + [1/3 × (SBP − DBP)] .Finally, ChT was measured by two experienced technicians at baseline and at each time point following the WDT . As final measurement, the mean value of the two measurements was used. Subfoveal and peripapillary choroidal thickness were measured using Topcon automated OCT software. Peripapillary thickness consisted of four zones . The demarcation of the choroidal borders in each location was completely automated.p values less than 0.05 were considered statistically significant, and all the statistical tests were two-sided. Data extraction in Microsoft Excel was performed separately by two authors (SAK and AK), who did not find any discrepancies in their final documents. Moreover, we performed manual data validation by manually inspecting the column cells as well as by utilizing the data validation tools in Excel.Microsoft Excel was utilized to gather the data, and all the statistical analyses were performed using statistical software R . The baseline descriptive statistics of the study participants were reported as percentage values for the categorical variables and as mean ± standard deviation (minimum–maximum) for the continuous variables. To detect the changes over time in IOP, systolic and diastolic blood pressure, mean ocular perfusion pressure, and mean arterial pressure, generalized least squares models were used (with a compound symmetry correlation structure) that take into account repeated measurements. Since the choroidal thickness of both the eyes of the participants was assessed, a linear mixed model analysis with a random intercept on the individual level was used to assess the relationship between choroidal thickness and the minutes after the WDT. Therefore, by using a mixed model analysis, we adjusted for the relationship between the choroidal thickness of different eyes from the same participants. A total of 20 patients (40 eyes) met the inclusion criteria and were enrolled in our study between 2016 and 2017. The patients were all Caucasian; 14 were female, and 6 were male. The mean age of the individuals considered to be glaucoma suspects was 65.45 years (±8.2). A total of 7 subjects were pseudophakic, and 13 were phakic. The average anterior chamber depth was 3.2 mm (±0.7), and the mean axial length was 23.3 mm (±1.0). The demographics of the patients included in the study are summarized in p < 0.05).Following the water load, dynamic contour tonometry  showed a statistically significant rise at all the time points compared to baseline, with peaks of their mean values at 45 min (20.1 mmHg ± 3.4 mmHg) (p < 0.05).The Goldmann applanation tonometry values were higher than those at baseline at all the time points but only reached statistical significance at 30 min (18.4 mmHg ± 4.5 mmHg) and 45 min (18.4 mmHg ± 4.4 mmHg)  to 2.7 mmHg (±1.1) at 15 min after the WDT and then remained stable. The increase was statistically significant at all the time points. The mean values of IOP both with Goldman applanation tonometry and Pascal tonometry and of OPA are included in p < 0.05). Peak mean systolic pressure (137.6 mmHg ± 10.3) was reached at 30 min, whereas peak mean diastolic pressure (95.9 mmHg ± 10.7) was reached at 15 min after the WDT.  compared to baseline  and to document their correlation with the modification of ChT.Previous studies evaluated the modification of systemic and ocular hemodynamic parameters following the WDT. Most of them were held in healthy or glaucomatous subjects. In the present cohort of glaucoma suspects, we observed that the vascular factors studied were also altered.Systolic blood pressure and diastolic blood pressure were significantly increased at all the time points, and the resulting MAP was also increased. Recent studies ,25,26 shMoreover, confirming the parasympathetic activation following the WDT, a study  on healtAnother study  evaluateMOPP was significantly increased at all the time points after the water load. As MAP increased proportionally more than IOP, OPP was increased as well and remained increased until the 45′ time point. One hour after the water load, it started decreasing.Since ChT seems to be influenced by OPP , the patOPA is believed to represent a surrogate of the uveal blood volume during each cardiac circle .Following the water load, the OPA values increased significantly from baseline and remained increased until the 60′ time point. This was reasonable since the ocular pulse is created by the pulsatile blood flow in the choroid, which, in turn, is increased following the hypervolemia and the increased vascular resistance caused by the autonomic activation provoked by the acute water load.p = 0.016) with the increased thickness of the superior peripapillary choroid, but they did not correlate at a statistically significant level with the variation in the other choroidal areas.Furthermore, the increased values of OPA were positively associated at a significant level  and the modification of choroidal thickness as documented with the SS-OCTA.


Unlike in adults, there are limited pediatric data exploring the association between acute respiratory illnesses and blood pressure abnormalities. The aim of our study was to explore the association of bronchiolitis, a common respiratory illness, with elevated blood pressure in hospitalized children.In this single center retrospective case–control study, we evaluated the association between bronchiolitis and elevated blood pressure and hypertension in hospitalized children, compared to a control group admitted with nonrespiratory conditions, using multivariate regression analyses. Standard published normative data on pediatric blood pressure were used to classify children in various blood pressure categories.P-values, 0.71 and 0.53, respectively). On multivariate regression analyses, only length of stay was associated with hypertension. No patient with blood pressure abnormalities received antihypertensives nor were any nephrology consults documented.A high prevalence of elevated blood pressure (16%) and hypertension (60%) was noted among children with bronchiolitis; this was not statistically different from the control group (18% for elevated blood pressure; 57% for hypertension; A high prevalence of blood pressure abnormalities, without documentation of their recognition, was noted in hospitalized children regardless of diagnosis, pointing to the need for more data on outcomes-driven significance of pediatric inpatient blood pressure measurements. The literature provides evidence of a theoretical link between the lungs and blood pressure (BP). Studies in adult patients have shown a strong comorbidity between bronchial asthma, a respiratory illness, and hypertension (HTN) . StrengtWhile there is literature to support an association between respiratory illnesses and HTN in adults, there have been no studies investigating the association of acute respiratory illnesses with the development of BP abnormalities, either in adults or in children. Based on our personal observations of frequent BP abnormalities in children admitted to our hospital with bronchiolitis and the frequent questions related to these abnormalities to the pediatric nephrology team by treating health care providers, we conducted our current study to explore this association. Bronchiolitis is the leading cause of hospitalization in US infants, accounting for 16% of all hospital admissions in patients in the first year of life , 6. RhinGiven the high volume of patients hospitalized for bronchiolitis each year and the dearth of scientific investigation into the association between bronchiolitis and HTN, we conducted a retrospective case–control study with the primary aim of determining the prevalence of BP abnormalities in children admitted for bronchiolitis; in order to explore whether BP abnormalities in these children were related to pulmonary inflammation or a consequence of the stress response related to the febrile illness and/or hospitalization, we compared BP data in children admitted for other common nonrespiratory conditions. We hypothesized that hospitalized children with bronchiolitis would have a higher prevalence of BP abnormalities, HTN and elevated BP (HBP), compared to children hospitalized for other acute illnesses. Our secondary objective was to identify clinical and patient demographic factors associated with HBP and HTN and to characterize the management and follow-up of BP abnormalities in the outpatient setting.The study was approved by the Institutional Review Board of the University of California Davis. An exemption for the need for written informed consent was granted by the Institutional Review Board of the University of California Davis due to the study's retrospective nature. All methods were performed in accordance with the relevant guidelines and regulations.Children < 3 years of age admitted to either the pediatric wards or intensive care unit (ICU) services between January 2017 and January 2019 with a discharge diagnosis of bronchiolitis were included in this study. An age and sex-matched control group, consisting of children admitted to the aforementioned services with one of the following medical conditions: skin and soft tissue infection, urinary tract infection, or seizure was included for comparison. These diagnoses were chosen for the control group as they are common reasons for admission in children < 3 years, do not affect respiratory status, and may be distressing in terms of pain and discomfort. The intent of this control group was to explore whether there was a specific link between bronchiolitis and BP abnormalities that may be attributed to the disease process itself rather than the agitation associated with an inpatient hospitalization or the discomfort of having respiratory distress unrelated to the underlying diagnosis .Subjects needed to have at least 1 day of a minimum of two “legitimate” BP readings recorded in the flowsheet. Measurements were deemed “legitimate” if there was no nursing documentation that the patient was agitated or moving during the reading, or that the BP was measured on a lower extremity. Notably, those measurements not specifying from which extremity they were obtained were assumed to be taken from an upper extremity, as is standard practice in our hospital, and included in the analysis. Patients were excluded from the study if they had previously diagnosed HTN or were on antihypertensive medications prior to admission, or if they were intubated at any point during the hospitalization, as many sedation medications have vasoactive properties that can affect BP. Other exclusion criteria included a diagnosis of bronchopulmonary dysplasia, presence of acute kidney injury, electrolyte abnormalities, a comorbid acute process overlapping with one of the other inclusion diagnoses, and absence of a recorded height in children as this is needed for determination of BP percentiles.This was a single center retrospective case–control study. HBP and HTN were defined as at least one inpatient day of either averaged diastolic BP (DBP) or averaged systolic BP (SBP) readings above the 90th and 95th percentile, respectively, determined by using age-appropriate BP charts. Standard published normative pediatric reference charts were used based on the age of the child –10. The Sample size calculations were based on our assumption that children admitted with bronchiolitis would have a tenfold higher prevalence of HTN (10%), compared to the control groups (1%). To achieve a power of 80% to detect this difference and an α of 0.05, we needed 100 children in each of the two groups. Multivariate logistic regression analyses were performed using Stata MP ver. 16 . Regressions were estimated separately for the three different primary outcome measures: HTN, HBP, and the composite of HBP or HTN. Model specification was tested by performing linktests, comparing Bayesian information criteria, and computing the area under the model’s receiver operating characteristic curve. HTN and HBP were defined as the dependent variable outcomes of the following independent variables: sex, corrected gestational age, normative chart used, BMI > 90th percentile, level of care, length of stay, a diagnosis of bronchiolitis, prematurity, and use of albuterol or steroids as a part of inpatient treatment. Comparisons of HTN indices for bronchiolitis and control groups was performed using the Student t-test.During the study period, there were 370 children admitted to the hospital with a discharge diagnosis of bronchiolitis. Charts were reviewed in reverse chronology until the target sample size was reached. A total of 129 patient charts were reviewed to reach the target of 100 patients meeting inclusion criteria. The same method was used for the control group with a target of 99 total controls consisting of an equal distribution from each diagnosis category. The most common reasons for exclusion were inadequate BP readings and omission of recorded height; of patients with a diagnosis of seizures, a high proportion was excluded due to their intubation status . The OR of observing either HBP or HTN with bronchiolitis was 0.27 . To determine whether the severity of respiratory illness is associated with HTN, we compared the prevalence of HTN between patients with bronchiolitis requiring ward versus ICU levels of care. As compared to children admitted to the wards, those who initially went to the ICU were older  and had a greater length of stay. Both groups demonstrated a male predominance. The prevalence of HTN was 48% versus 76% for patients admitted to the wards and ICU, respectively. When comparing all bronchiolitis and control patients, ICU status was not found to be significantly associated with HTN (P = 0.95). The SBP and DBP HTN indices were not significantly different between the patients with bronchiolitis and the control group (data not shown).The prevalence of HBP and HTN in patients with bronchiolitis was 14% and 62%, respectively, as compared to the prevalence of 18% and 57% in the combined control group. A diagnosis of bronchiolitis was not found to be significantly associated with HBP or HTN. The odds ratio (OR) of observing HTN in patients with bronchiolitis as compared to those without was 0.63 , with a corresponding The multivariate logistic regression models also accounted for several other patient and clinical management factors that were identified as possible contributors to HTN. As seen in Table For the 199 inpatient encounters included in the analysis, there were no pediatric nephrology consultations placed and very rare documentation addressing abnormal BP values. There were no instances of pharmacotherapy being initiated for the treatment of HTN. Of the 160 patients identified as having HBP or HTN, only 19 (12%) received at least one outpatient BP measurement within 3 months of hospital discharge. Sixteen of these 19 patients (68%) had outpatient measurements also in the HBP or HTN range with no documented normotensive recordings. Within the bronchiolitis group, 20% of those categorized as hypertensive during their hospitalization received outpatient BP measurement following discharge. Of those, 83% never had a normotensive reading; 75% of this group had received steroids. However, all but one measurement was done > 1 week after discharge after which any steroid burst would have been completed .In our study, we evaluated a possible association between bronchiolitis in hospitalized children and BP abnormalities. We found that, compared to control subjects admitted for nonrespiratory illnesses, those with bronchiolitis did not have a higher prevalence of HBP or HTN after controlling for clinical and demographic factors. Among children admitted for bronchiolitis, those with a greater severity of illness were likewise no more likely to be hypertensive than their lesser sick counterparts. The only significant correlations with HTN were greater length of stay.The prevalence of HBP and HTN in our study was surprising to us and is strikingly high. The explanation for this is likely multifactorial and could include agitation resulting from the process of obtaining BP measurements and underlying illness (akin to white coat HTN effect seen in the outpatient setting), BP measurements obtained on the lower extremity or using an inappropriate technique, or inaccurate height recordings making assessments of BP abnormalities erroneous. Our definition of HTN in this study is likely prone to overestimating the prevalence and necessarily differs from the definition conventionally used for diagnosis, which is based on the outpatient setting (auscultatory-confirmed BP readings ≥ 95th percentile on three different visits) .Although these high prevalence rates likely do not reflect the actual prevalence of HTN in this population, they do underscore several challenges that pediatric providers face in detecting clinically significant BP elevations in the inpatient setting. Despite increasing investigations into the incidence, diagnosis, and treatment of inpatient HTN, we have yet to reach a consensus definition and guidelines for monitoring and management of BP abnormalities in this population. Presently, the best estimate for the prevalence of inpatient HTN based upon the literature is somewhere between 1 and 25% . The widWhile our study hypothesis was not confirmed, i.e., that bronchiolitis is associated with BP abnormalities in hospitalized children, we cannot entirely refute that an association between acute respiratory illnesses and BP abnormalities exists. This stems from the aforementioned issues pertaining to absence of normative BP data and the lack of an evidence base behind BP screening in hospitalized children, who are a very different population compared to children seen in the ambulatory setting; differences that arise, as mentioned previously, from the anxiety, stress and agitation of the underlying illness and the need for hospitalization. The very limited documented postdischarge follow-up on BP abnormalities that were noted during the hospital stay is further cause for concern. Our observations open up new questions and areas of potential investigation that are worthy of attention, not only for their implications on patient care but also due to the cost involved with interventions and provision of nursing care (involved in BP measurements) and the additional stress, both physical and psychological, imposed on children and their families with frequent measurement of vital signs and BP determinations.Limitations of this study include the fact that it was conducted in a single center and its retrospective design, which precludes standardization of nursing documentation pertaining to BP records. Thus, abnormal BPs were not confirmed using manual BP measurement, which is the recommended protocol as oscillometric readings are known to overestimate both DBP and SBP . MoreoveOur study highlights the profound need for additional studies to establish evidence-based and clinical outcome-driven guidelines for defining BP and categorizing BP abnormalities in the inpatient setting. The issue of diagnosing white coat hypertension in this population  remains challenging and worthy of investigation. Whether there is a role for ambulatory BP monitoring in hospitalized patients  and the interpretation of the data obtained through such means, are additional questions to consider.