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Background: Accelerometer-measured physical activity is an increasingly used endpoint in heart failure (HF) trials. We investigated the determinants of accelerometer-measured physical activity and the relationship with patient-reported health status., Methods: Post-hoc analysis of the Empire HF trial, including outpatients with HF with reduced ejection fraction (HFrEF). Physical activity was quantified as average accelerometer counts per minute (CPM) with higher values representing higher activity. We investigated associations between activity level and clinical variables, including age, sex, and body mass index, as well as patient-reported health status assessed by Kansas City Cardiomyopathy Questionnaire (KCCQ)., Results: Complete data were available in 180 (95%) patients (86% male, mean age 65 year). Baseline median physical activity level was 1,318 CPM (Q1-Q3 1,111-1,585). Age and anemia were independently associated with activity level (β-coefficients: -10 CPM per year age increase [95% CI -16 to -5.1], P = .00015, and -126 CPM for anemia [95% CI -9.1 to -244], P = .035). Significant independent associations were observed between activity level and all KCCQ summary scores (β-coefficient point estimates of 3.7, 4.6, and 4.9 CPM, all P < .02). For 12-week changes in KCCQ-summary scores, only the KCCQ-CSS was associated with activity level; mean increase of 17.5 CPM [95% CI 1.5 to 34.0], P = 0.032, per 5-point increase in KCCQ-CSS. Associations were not modified by treatment allocation (interaction P-values > .05)., Conclusions: In patients with HFrEF, older age and anemia were independently associated with lower activity. Moreover, physical activity only weakly increased with better health status, suggesting that changes in physical activity reflect improvements in patients' health status to a limited degree. This highlights the need to better understand the endpoint with regards to all other health parameters to ease interpretation in future HF trials., Competing Interests: Conflict of Interest C.F.A. reports grant from the Danish Heart Foundation, Toyota-Fonden Denmark, Arvid Nilsson's Foundation, Aase & Ejnar Danielsen's Foundation, Fru Asta Florida Bolding's Memorial Grant, KV Foundation and The Research and Innovation Foundation of the Department of Cardiology (FUHAS, formerly FUKAP), Herlev and Gentofte University Hospital, Herlev, Denmark; personal fees from AstraZeneca, all outside the submitted work. J.J. reports grants from The Danish Heart Foundation, Denmark, and The CARDIOHGH at the Department of Cardiology, Herlev and Gentofte University Hospital, Denmark, during the conduct of the submitted work; personal fees from scientific advisory board from AstraZeneca and Boehringer Ingelheim, outside the submitted work; grants from The Research Council at Herlev and Gentofte University Hospital, Denmark, grants from The CARDIOHGH (formerly FUHAS), Herlev and Gentofte University Hospital, Denmark, and grants from The A.P. Møller Foundation for the Advancement of Medical Science, Denmark [as sub-investigator of the Empire HF trial]. M.A.O reports grants from the Danish Heart Foundation, grants from The Steno Diabetes Center Odense, Denmark and grants from A.P. Møller Foundation during the conduct of the study. C.T. reports speaker fees from Orion Pharma, personal fees for advisory board participation from Boehringer Ingelheim and Bayer A/S, all outside the submitted work. F.G. reports speaker fees from Orion Pharma, Vifor Pharma and Novartis, and personal fees for advisory board participation from Abbott, Pfizer, Astra-Zeneca, Ionis, Alnylam and Bayer, all outside the submitted work. J.E.M. reports speaker fees from Novartis, Boehringer Ingelheim, Abiomed, Orion and Abbott, advisory board from Orion and Boehringer Ingelheim, and research grant Abiomed and Roche, all outside submitted work. M.S. reports grants from The Capital Region of Denmark, grants from The Danish Heart Foundation, during the conduct of the study; personal fees and nonfinancial support from AstraZeneca, personal fees from Novo Nordisk and Boehringer Ingelheim, outside the submitted work., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

To investigate noninvasive pressure-strain loop (PSL) combined with two-dimensional speck tracking imaging and left ventricular pressure measurement in the evaluation of cardiac function changes in anemia of prematurity (AOP) with different modes of respiratory support, and to explore its value in detecting subclinical myocardial injury in preterm infants. This retrospective study included 79 preterm infants with anemia, according to different modes of respiratory support, who were divided into invasive respiratory support group (39 cases) and noninvasive respiratory support group (40 cases). A control group of 40 nonanemic preterm infants with matched age, sex, and gestational age were also included. Complete echocardiography was performed for each included infant. There are PSL parameters that used to evaluate cardiac function, including global longitudinal strain (GLS), global work index (GWI), global constructive work (GCW), global wasted work (GWW), and global work efficiency (GWE) among the three groups were compared. Compared with the control group, the value of GWI, GCW, and GWE were significantly lower and GWW was higher in the AOP groups (P < 0.05), and GWI, GCW and GWE were much significantly lower in the invasive respiratory support group than in the noninvasive respiratory support group (P < 0.05). There was no significant difference in GLS among the three groups (P > 0.05). Noninvasive PSL analysis can quantitatively assess myocardial work in AOP with different respiratory support, which is more sensitive than other conventional echocardiographic indices. This technique may provide a new method for monitoring subclinical myocardial injury with AOP., (© 2024. The Author(s).)

Anemia and renal failure are independent risk factors for perioperative stroke, prompting us to assess the combined impact of acute hemodilutional anemia and bilateral nephrectomy (2Nx) on microvascular brain Po 2 (P Br o 2 ) in a rat model. Changes in P Br o 2 (phosphorescence quenching) and cardiac output (CO, echocardiography) were measured in different groups of anesthetized Sprague-Dawley rats (1.5% isoflurane, n = 5-8/group) randomized to Sham 2Nx or 2Nx and subsequently exposed to acute hemodilutional anemia (50% estimated blood volume exchange with 6% hydroxyethyl starch) or time-based controls (no hemodilution). Outcomes were assessed by ANOVA with significance assigned at P < 0.05. At baseline, 2Nx rats demonstrated reduced CO (49.9 ± 9.4 vs. 66.3 ± 19.3 mL/min; P = 0.014) and P Br o 2 (21.1 ± 2.9 vs. 32.4 ± 3.1 mmHg; P < 0.001) relative to Sham 2Nx rats. Following hemodilution, 2Nx rats demonstrated a further decrease in P Br o 2 (15.0 ± 6.3 mmHg, P = 0.022). Hemodiluted 2Nx rats did not demonstrate a comparable increase in CO after hemodilution compared with Sham 2Nx (74.8 ± 22.4 vs. 108.9 ± 18.8 mL/min, P = 0.003) that likely contributed to the observed reduction in P Br o 2 . This impaired CO response was associated with reduced fractional shortening (33 ± 9 vs. 51 ± 5%) and increased left ventricular end-systolic volume (156 ± 51 vs. 72 ± 15 µL, P < 0.001) suggestive of systolic dysfunction. By contrast, hemodiluted Sham 2Nx animals demonstrated a robust increase in CO and preserved P Br o 2 . These data support the hypothesis that the kidney plays a central role in maintaining cerebral perfusion and initiating the adaptive increase in CO required to optimize P Br o 2 during acute anemia. NEW & NOTEWORTHY This study has demonstrated that bilateral nephrectomy acutely impaired cardiac output (CO) and microvascular brain Po 2 (P Br o 2 ), at baseline. Following acute hemodilution, nephrectomy prevented the adaptive increase in CO associated with acute hemodilution leading to a further reduction in P Br o 2 , accentuating the degree of cerebral tissue hypoxia. These data support a role for the kidney in maintaining P Br o 2 and initiating the increase in CO that optimized brain perfusion during acute anemia.

Background: We hypothesized that oxidative stress in Ugandan children with severe malaria is associated with mortality., Methods: We evaluated biomarkers of oxidative stress in children with cerebral malaria (CM, n = 77) or severe malarial anemia (SMA, n = 79), who were enrolled in a randomized clinical trial of immediate vs delayed iron therapy, compared with community children (CC, n = 83). Associations between admission biomarkers and risk of death during hospitalization or risk of readmission within 6 months were analyzed., Results: Nine children with CM and none with SMA died during hospitalization. Children with CM or SMA had higher levels of heme oxygenase-1 (HO-1) (P < .001) and lower superoxide dismutase (SOD) activity than CC (P < .02). Children with CM had a higher risk of death with increasing HO-1 concentration (odds ratio [OR], 6.07 [95% confidence interval {CI}, 1.17-31.31]; P = .03) but a lower risk of death with increasing SOD activity (OR, 0.02 [95% CI, .001-.70]; P = .03). There were no associations between oxidative stress biomarkers on admission and risk of readmission within 6 months of enrollment., Conclusions: Children with CM or SMA develop oxidative stress in response to severe malaria. Oxidative stress is associated with higher mortality in children with CM but not with SMA., Clinical Trials Registration: NCT01093989., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The ASTRIO study was a randomised, multicentre, 24-week study that compared the effects of ferric citrate hydrate (FC) and non-iron-based phosphate binders (control) on anaemia management in haemodialysis (HD) patients receiving erythropoiesis-stimulating agents (ESAs). In that study, FC reduced the doses of ESAs and intravenous iron without affecting haemoglobin (Hb); however, the cost-effectiveness of FC was unclear. We retrospectively implemented a cost-effectiveness analysis comparing the incremental cost-effectiveness ratios (ICERs) in FC (n = 42) and control (n = 40) groups in patients with serum phosphate and Hb controlled within the ranges of 3.5-6.0 mg/dL and 10-12 g/dL, respectively. Costs included drug costs of phosphate binders, ESAs, and intravenous iron. Elevated red cell distribution width (RDW) has been reported to be associated with mortality in HD patients and was therefore used as an effectiveness index. The mean (95% confidence interval) differences in drug costs and RDW between the FC and control groups were US$ - 421.36 (- 778.94 to - 63.78, p = 0.02) and - 0.83% (- 1.61 to - 0.05, p = 0.04), respectively. ICER indicated a decrease of US$ 507.66 per 1% decrease in RDW. FC was more cost-effective than non-iron-based phosphate binders. Iron absorbed via FC could promote erythropoiesis and contribute to renal anaemia treatment., (© 2022. The Author(s).)

Sickle cell disease (SCD) is associated with haemolytic anaemia and secondary activation of leucocytes and platelets, which in turn may further exacerbate haemolysis. As cytokine signalling pathways may participate in this cycle, the present study investigated whether pharmacological blockade of the interleukin-1 receptor (IL-1R) would mitigate anaemia in a murine model of SCD. Within 2 weeks of treatment, reduced markers of haemolysis were observed in anakinra-treated mice compared to vehicle-treated mice. After 4 weeks of anakinra treatment, mice showed increased numbers of erythrocytes, haemoglobin, and haematocrit, along with reduced reticulocytes. Blood from anakinra-treated mice was less susceptible to ex vivo erythrocyte sickling and was resistant to exogenous IL-1β-mediated sickling. Supernatant generated from IL-1β-treated platelets was sufficient to promote erythrocyte sickling, an effect not observed with platelet supernatant generated from IL-1R -/- mice. The sickling effect of IL-1β-treated platelet supernatant was inhibited by a transforming growth factor-β (TGF-β) neutralising antibody, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibition, and superoxide scavengers, but replicated by recombinant TGF-β. In conclusion, pharmacological IL-1R antagonism leads to improved anaemia in a murine SCD model. IL-1β stimulation of platelets promotes erythrocyte sickling. This effect may be mediated by platelet-derived TGF-β-induced reactive oxygen species generation though erythrocyte NADPH oxidase., (© 2021 British Society for Haematology and John Wiley & Sons Ltd.)

Background: The definition for anemia in pregnancy is outdated, derived from Scandinavian studies in the 1970's to 1980's. To identity women at risk of blood transfusion, a common cause of Severe Maternal Morbidity, a standard definition of anemia in pregnancy in a modern, healthy United States cohort is needed., Objective: To define anemia in pregnancy in a United States population including a large county vs. private hospital population using uncomplicated patients., Materials and Methods: Inclusion criteria were healthy women with the first prenatal visit before 20 weeks. Exclusion criteria included preterm birth, preeclampsia, hypertension, diabetes, short interval pregnancy (<18 months), multiple gestation, abruption, and fetal demise. All women had iron fortification (Ferrous sulfate 325 mg daily) recommended. The presentation to care and pre-delivery hematocrits were obtained, and the percentiles determined. A total of 2000 patients were included, 1000 from the public county hospital and 1000 from the private hospital. Each cohort had 250 patients in each 2011, 2013, 2015, and 2018. The cohorts were compared for differences in the fifth percentile for each antepartum epoch. Student's t-test and chi-squared statistical tests were used for analysis, p-value of ≤0.05 was considered significant., Results: In the public and private populations, 777 and 785 women presented in the first trimester while 223 and 215 presented in the second. The women at the private hospital were more likely to be older, Caucasian race, nulliparous, and present earlier to care. The fifth percentile was compared between the women in the private and public hospitals and were clinically indistinguishable. When combining the cohorts, the fifth percentile for hemoglobin/hematocrit was 11 g/dL/32.8% in the first trimester, 10.3 g/dL/30.6% in the second trimester, and 10.0 g/dL/30.2% pre-delivery., Conclusions: Fifth percentile determinations were made from a combined cohort of normal, uncomplicated pregnancies to define anemia in pregnancy. Comparison of two different cohorts confirms that the same definition for anemia is appropriate regardless of demographics or patient mix., Competing Interests: The authors have declared that no competing interests exist.

Background: Pregnant women are often susceptible to anemia, which can damage the thyroid gland. However, compared with moderate and severe anemia, less attention has been paid to mild anemia. The purpose of this study was to evaluate the effect of mild anemia on the thyroid function in pregnant women during the first trimester., Methods: A total of 1,761 women in the first trimester of their pregnancy were enrolled from Shenyang, China, and divided into mild anemia and normal control groups based on their hemoglobin levels. Thyroid-stimulating hormone (TSH), free thyroxine (FT4), and free triiodothyronine (FT3) levels were compared between the two groups., Results: The TSH levels of pregnant women with mild anemia were higher than those of pregnant women without mild anemia (p < 0.05). Normal control women were selected to set new reference intervals for TSH, FT3, and FT4 levels during the first trimester, which were 0.11-4.13 mIU/l, 3.45-5.47 pmol/l, and 7.96-16.54 pmol/l, respectively. The upper limit of TSH 4.13 mU/l is close to the upper limit 4.0 mU/l recommended in the 2017 American Thyroid Association (ATA) guidelines, indicating that exclusion of mild anemia may reduce the difference in reference values from different regions. Mild anemia was related to 4.40 times odds of abnormally TSH levels (95% CI: 2.84, 6.76) and 5.87 increased odds of abnormal FT3 (95% CI: 3.89, 8.85). The proportion of hypothyroidism and subclinical hypothyroidism in patients with mild anemia was higher than that in those without anemia (0.6% vs. 0, p = 0.009; 12.1% vs. 1.9%, p < 0.001). Mild anemia was related to 7.61 times increased odds of subclinical hypothyroidism (95% CI: 4.53, 12.90)., Conclusions: Mild anemia may affect thyroid function during the first trimester, which highlights the importance of excluding mild anemia confounding when establishing a locally derived specific reference interval for early pregnancy., Competing Interests: 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., (Copyright © 2021 Nie, Wang, Liu, Li and Sun.)

Allograft and xenograft transplantation into a mouse host is frequently utilized to study cancer biology, tumor behavior, and response to treatment. Preclinical studies employing these models often focus solely upon the intra-tumoral effects of a given treatment, without consideration of systemic toxicity or tumor-host interaction, nor whether this latter relationship could modulate the toxicologic response to therapy. Here it is demonstrated that the implantation and growth of a range of human- and mouse-derived cell lines leads to structural vascular and, potentially, functional changes within peripheral endocrine tissues, a process that could conceivably ameliorate the severity of anti-angiogenic-induced fenestrated vessel attenuation. Observations suggest a multifactorial process, which may involve host- and tumor-derived cytokines/growth factors, and the liberation of myeloid-derived suppressor cells. Further investigation revealed a structurally comparable response to the administration of exogenous estrogen. These findings, in addition to providing insight into the development of clinical anti-angiogenic "adaptation," may be of significance within the "cancer-cachexia" and cancer-related anemia syndromes in man., (© 2021 The Authors. Journal of Applied Toxicology published by John Wiley & Sons Ltd.)

Molidustat, an orally administered hypoxia-inducible factor prolyl-hydroxylase inhibitor, is under development for the treatment of anemia of CKD. This 24-week, phase 3, single-arm, multicenter study evaluated the efficacy and safety of molidustat in Japanese patients with renal anemia who were undergoing hemodialysis and who were not receiving an erythropoiesis-stimulating agent. Twenty-five patients received molidustat at a starting dose of 75 mg once daily, which was adjusted to maintain a Hb target of ≥10.0 to <12.0 g/dL. The mean rates of Hb increase from baseline and week 0 to the first dose change up to week 8 were -0.030 and 0.080 g/dL/week, respectively. By week 24, 89% of patients had a Hb level within target range. No adverse events of special interest were reported. Treatment with dose-titrated molidustat for 24 weeks was well tolerated in Japanese patients undergoing hemodialysis, and no new safety signal was observed. Clinicaltrials.gov identifier: NCT03351166., (© 2021 Bayer Yakuhin Ltd. Therapeutic Apheresis and Dialysis published by John Wiley & Sons Australia, Ltd on behalf of International Society for Apheresis, Japanese Society for Apheresis, and Japanese Society for Dialysis Therapy.)

Low birth weight (LBW) is associated with a higher risk of neonatal mortality and the development of adult-onset chronic disease. Understanding the ongoing contribution of maternal hemoglobin (Hgb) levels to the incidence of LBW in South Asia is crucial to achieve the World Health Assembly global nutrition target of a 30% reduction in LBW by 2025. We enrolled pregnant women from the rural Tangail District of Bangladesh in a Maternal Newborn Health Registry established under The Global Network for Women's and Children's Health Research. We measured the Hgb of pregnant women at enrollment and birth weights of all infants born after 20 weeks gestation. Using logistic regression to adjust for multiple potential confounders, we estimated the association between maternal Hgb and the risk of LBW. We obtained Hgb measurements and birth weights from 1,665 mother-child dyads between July 2019 and April 2020. Using trimester-specific cutoffs for anemia, 48.3% of the women were anemic and the mean (±SD) Hgb level was 10.6 (±1.24) g/dL. We identified a U-shaped relationship where the highest risk of LBW was seen at very low (< 7.0 g/dL, OR = 2.00, 95% CI = 0.43-7.01, P = 0.31) and high (> 13.0 g/dL, OR = 2.17, 95% CI = 1.01-4.38, P = 0.036) Hgb levels. The mechanisms underlying this U-shaped association may include decreased plasma expansion during pregnancy and/or iron dysregulation resulting in placental disease. Further research is needed to explain the observed U-shaped relationship, to guide iron supplementation in pregnancy and to minimize the risk of LBW outcomes.

Pregnancy after bariatric surgery is known to be associated with a higher risk of small for gestational age infants (SGA) and maternal anemia. 71 patients with a history of bariatric surgery, who had at least one pregnancy ended with a delivery of a single live-born neonate after the bariatric surgery were included in the study. The main endpoints were gestational weight gain (GWG), GWG as % of the maternal weight at the beginning of pregnancy (GWG%), maternal anemia, SGA and large for gestational age infants (LGA), neonatal intensive care unit admission (NICU). GWG% was 23.8% ± 14.1 in the LGA group vs 13.9% ± 11.0 in the normal weight neonates group; p < 0.03. Patients diagnosed with anemia before pregnancy had higher GWG% than patients without pre-pregnancy anemia (20.1% ± 11.1 vs 13.4% ± 11.6); p < 0.05. GWG% was higher in patients, whose infants were admitted to NICU (25.3% ± 17.6 vs 14.1% ± 11.0; p < 0.04). GWG% can be considered a risk predictor of the LGA and NICU admissions in bariatric patients. Anemia diagnosed before pregnancy is associated with higher GWG%., (© 2021. The Author(s).)

Anemia is very common in patients with inflammatory disorders. Its prevalence is associated with severity of the underlying disease, and it negatively affects quality of life and cardio-vascular performance of patients. Anemia of inflammation (AI) is caused by disturbances of iron metabolism resulting in iron retention within macrophages, a reduced erythrocyte half-life, and cytokine mediated inhibition of erythropoietin function and erythroid progenitor cell differentiation. AI is mostly mild to moderate, normochromic and normocytic, and characterized by low circulating iron, but normal and increased levels of the storage protein ferritin and the iron hormone hepcidin. The primary therapeutic approach for AI is treatment of the underlying inflammatory disease which mostly results in normalization of hemoglobin levels over time unless other pathologies such as vitamin deficiencies, true iron deficiency on the basis of bleeding episodes, or renal insufficiency are present. If the underlying disease and/or anemia are not resolved, iron supplementation therapy and/or treatment with erythropoietin stimulating agents may be considered whereas blood transfusions are an emergency treatment for life-threatening anemia. New treatments with hepcidin-modifying strategies and stabilizers of hypoxia inducible factors emerge but their therapeutic efficacy for treatment of AI in ill patients needs to be evaluated in clinical trials.

Background: Anemia is a common complication of chronic kidney disease (CKD). Blood urea nitrogen (BUN) in CKD represents nitrogenous uremic toxin accumulation which could be involved in anemia of CKD. We investigated the effects of BUN independent of estimated glomerular filtration rate (eGFR) on anemia in non-dialysis CKD (NDCKD)., Methods: This prospective study included 2,196 subjects enrolled in the KoreaN Cohort Study for Outcome in Patients With Chronic Kidney Disease (KNOW-CKD) cohort with BUN and hemoglobin level data. Initially, we investigated the association between BUN and hemoglobin level. To examine the impact of baseline BUN on the incident anemia, a longitudinal study was performed on 1,169 patients without anemia at study enrollment. BUN residuals were obtained from the fitted curve between BUN and eGFR. Anemia was defined as a hemoglobin level of <13.0 g/dL for men and <12.0 g/dL for women., Results: BUN residuals were not related to eGFR but to daily protein intake (DPI), while BUN was related to both eGFR and DPI. BUN was inversely associated with hemoglobin level (β -0.03; 95% confidence interval [CI] -0.04, -0.03; P <0.001) in the multivariable linear regression analysis adjusted for multiple confounders including eGFR, and BUN residual used instead of BUN was also inversely associated with hemoglobin level (β -0.03; 95% CI -0.04, -0.02; P <0.001). Among the 1,169 subjects without anemia at baseline, 414 (35.4%) subjects newly developed anemia during the follow-up period of 37.5 ± 22.1 months. In the multivariable Cox regression analysis with adjustment, both high BUN level (Hazard ratio [HR] 1.02; 95% CI 1.01, 1.04; P = 0.002) and BUN residual used instead of BUN (HR 1.02; 95% CI 1.00, 1.04; P = 0.031) increased the risk of anemia development. Moreover, BUN, rather than eGFR, increased the risk of anemia development in patients with CKD stage 3 in the multivariable Cox regression., Conclusion: Higher BUN levels derived from inappropriately high protein intake relative to renal function were associated with low hemoglobin levels and the increased risk of anemia independent of eGFR in NDCKD patients., Competing Interests: The authors have declared that no competing interests exist.

Background: The present study investigated factors associated with pre-neoadjuvant chemotherapy (NAC), and pre-operative anaemia, and examined their impact on outcomes in patients with oesophago-gastric cancer treated with curative intent., Methods: Patients diagnosed with oesophago-gastric cancer (January 2010 to December 2015) and treated with curative intent by NAC then surgery at a tertiary centre were included. Patients were grouped by the presence of anaemia (haemoglobin <130 mg/L in males and <120 mg/L in females) and into microcytic (MCV <80 fL), normocytic (80-100 fL) and macrocytic (>100 fL) subgroups. Categorical data were analysed by chi-squared test and overall survival by univariate and multivariate Cox regression., Results: 99/295 (34%) patients who received NAC were diagnosed with pre-NAC anaemia, and 157/268 (59%) of patients who subsequently underwent surgery were diagnosed with pre-operative anaemia. Normocytic anaemia was the most common, with 76 (26%) in pre-NAC and 107 (40%) in pre-operative groups. Pre-NAC anaemia was associated with increasing clinical N stage (p = 0.022), higher modified Glasgow Prognostic Score (mGPS) (p = 0.006), and a higher rate of intra-operative transfusion (p = 0.030). Pre-operative anaemia was associated with pre-NAC anaemia (p = 0.004), increasing age (p = 0.026), higher pre-operative mGPS (p = 0.021), and a higher rate of intra-operative transfusion (p = 0.021). Anaemia before NAC and surgery was associated with poorer overall survival in patient following R0 resection, independent of stage (HR 1.26, 95% CI 1.02-1.54, p = 0.030)., Conclusion: Anaemia was associated with poorer overall survival and greater requirement for intra-operative blood transfusion in oesophago-gastric cancer patients undergoing treatment with curative intent., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Splenomegaly can be due to several mechanisms but is almost always a sign of a systemic condition. Patient habits, travel, and medical conditions can increase risk of splenomegaly and suggest etiology. Symptoms can suggest infectious, malignant, hepatic, or hematologic causes. Physical examination will typically reveal splenomegaly, but abdominal ultrasonography is recommended for confirmation. Physical examination should also assess for signs of systemic illness, liver disease, and anemia or other hematologic issues. The most common causes of splenomegaly in the United States are liver disease, malignancy, and infection. Except for apparent causes such as infectious mononucleosis, basic laboratory analysis and ultrasonography are the first-line steps in determining etiology. Malaria and schistosomiasis are common in tropical regions, where as many as 80% of people may have splenomegaly. Management of splenomegaly involves treating the underlying disease process. Splenectomies and spleen reduction therapies are sometimes performed. Any patient with limited splenic function requires increased vaccination and prophylactic antibiotics for procedures involving the respiratory tract. Acute infections, anemia, and splenic rupture are the most common complications of splenomegaly, and people with splenomegaly should refrain from participating in contact sports to decrease risk of rupture.

Anaemia is a common and multifactorial blood disorder in elderly individuals. This condition may be a significant barrier to pressure ulcers healing as it is associated with a decreased level of oxygen being supplied to body tissues. Some nutritional deficiencies such as iron, vitamin B12 and folate may also cause anaemia and have a negative impact on pressure ulcer healing. An increased iron demand in hard-to-heal pressure ulcers is a significant factor associated with the risk of anaemia of chronic disease in elderly patients. Anaemia screening and correction may need to be considered as well as iron supplementation if required in pressure ulcer prevention and management.

Anemia has been acknowledged as worldwide problem, including in Indonesia. This cross-sectional study aims to explore dietary determinants as risk factors for anemia in children aged 6-36 months living in a poor urban area of Jakarta. The study was done in Kampung Melayu sub-district in Jakarta, Indonesia. Data was collected within two weeks in September-October 2020. A structured questionnaire for a 24-h recall and a semi-quantitative Food Frequency Questionnaire (FFQ) were used to collect the dietary intake data, and venous blood was withdrawn to determine the hemoglobin levels. Bivariate chi-square and multiple logistic regression tests were executed to explore the dietary determinant factors for anemia. We recruited 180 subjects. The average hemoglobin concentration was 11.4 ± 1.7 mg/dL; the anemia prevalence was 29.4%. The following variables were significantly associated with higher risk of anemia: no cow's milk formula consumption, inadequate intake of fats, protein, calcium, vitamin D, iron, zinc, vitamin A, vitamin C, vitamin B6, and vitamin B12. Only cow's milk formula consumption and zinc intake were revealed as the determinant factors of anemia. In conclusion, the prevalence of anemia was 29.4% among children aged 6-36 months old. Anemia was significantly associated with two dietary determinants as risk factors that are cow's milk formula consumption and zinc intake.

Background: The anti-M antibody can lead to hemolytic disease of the fetus and newborn (HDFN) and adverse fetal outcomes, especially in the Asian population. However, fetal erythropoiesis resulting from M alloimmunization needs further investigation., Study Design and Methods: We analyzed erythropoiesis in eight fetuses with M alloimmunization and compared them with the fetuses affected by anti-D. They were matched as pairs according to the gestational age of diagnosis and the hematocrit before treatment. Paired t-tests or paired Wilcoxon rank-sum tests were conducted to compare the difference in the cord blood indexes. Pearson correlation analysis was used to evaluate the correlativity between hematocrit and the reticulocyte percentage in the two groups., Results: The fetuses in the MN group had lower reticulocyte count and percentage than those in the RhD group (p < .05). All of the fetal reticulocyte production indexes (RPIs) in the MN group were less than 2, indicating an inadequate hemopoietic response to anemia, while the majority of the RPIs in the RhD group (85.7%) were significantly higher (p = .003), with 6 cases greater than 2.5. Hematocrit was negatively correlated with reticulocyte percentage (y = 54.7-171.7x, r 2  = 0.825, p = .005) in the RhD group, while no significant correlation was found in the MN group. No difference in the number of IUT, interval, or the fetal outcome was found between the two groups., Conclusion: Fetal reticulocytopenia provided direct evidence of an inadequate hemopoietic response in HDFN due to anti-M, leading to hyporegenerative anemia. Once the IgG component of anti-M is detected, close monitoring should be considered., (© 2021 AABB.)

Diastolic dysfunction is a known cause of mortality in adults with sickle cell disease (SCD). Left atrial function (LAf) and strain (LAS) are novel echocardiographic parameters to assess early diastolic dysfunction, which have not been assessed in pediatric SCD. Through a retrospective single-center study, we describe echocardiographic parameters of diastology in children with SCD and evaluate their relationship with clinical variables including anemia and blood pressure. Baseline clinical data, 24-hour ambulatory blood pressure monitoring data and echocardiography results were collected. LAf and LAS were measured using volumetric data and speckle-tracking echocardiography, respectively. Sixty-seven children with SCD (13.5±7 y, 47% male, 7% hypertensive) with a mean hemoglobin of 8.8±1.3 g/dL, LAf of 61±8% (n=53) and LAS of 46.3±7.4% (n=28) were included. LAS was significantly associated with hemoglobin (ρ=0.43, P=0.022) but not with maximal left atrial (LA) volume (ρ=-0.05, P=0.79) or any blood pressure parameters. On multivariate analysis, LAS decreased by 3.2% (1.3, 5.1) and LA volume increased by 1.6 mL/m2 (3.1, 0.08) for every 1 g/dL decrease in hemoglobin. Thus, severity of baseline anemia in pediatric SCD correlates with diastolic function as measured by LAS, independent of LA dilation., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Sphingosine-1-phosphate lyase insufficiency syndrome (SPLIS) is a rare metabolic disorder caused by inactivating mutations in sphingosine-1-phosphate lyase 1 (SGPL1), which is required for the final step of sphingolipid metabolism. SPLIS features include steroid-resistant nephrotic syndrome and impairment of neurological, endocrine, and hematopoietic systems. Many affected individuals die within the first 2 years. No targeted therapy for SPLIS is available. We hypothesized that SGPL1 gene replacement would address the root cause of SPLIS, thereby serving as a universal treatment for the condition. As proof of concept, we evaluated the efficacy of adeno-associated virus 9-mediated transfer of human SGPL1 (AAV-SPL) given to newborn Sgpl1-KO mice that model SPLIS and die in the first weeks of life. Treatment dramatically prolonged survival and prevented nephrosis, neurodevelopmental delay, anemia, and hypercholesterolemia. STAT3 pathway activation and elevated proinflammatory and profibrogenic cytokines observed in KO kidneys were attenuated by treatment. Plasma and tissue sphingolipids were reduced in treated compared with untreated KO pups. SGPL1 expression and activity were measurable for at least 40 weeks. In summary, early AAV-SPL treatment prevents nephrosis, lipidosis, and neurological impairment in a mouse model of SPLIS. Our results suggest that SGPL1 gene replacement holds promise as a durable and universal targeted treatment for SPLIS.

Background: Anemia is one of the world's leading cause of disability and the most serious global public health issues. This systematic review and meta-analysis was conducted very carefully in order to give up the pooled compliance of Iron and Folic-Acid Supplementation in Sub-Saharan Africa., Methods: To conduct this brief systematic review and meta-analysis, a related literature search was done from different sources, PubMed Medline and Google Scholar Journals. Then IFA Supplementation related searching engine was used to make the work more meaningful and intensive. Moreover, we used modified Newcastle-Ottawa quality assessment scale for cross sectional studies to assess the quality of the study in terms of their inclusion. Then, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline was followed to carry out the work in a carful manner. Finally, the pooled effect size was computed using the review manager and Compressive Meta-analysis software., Results: Twenty-three studies, which encompassed 24272 pregnant women, were chosen for the analysis. From those an overall prevalence of compliance with Iron and Folic Acid Supplementation (IFAS) in pregnancy in SSA was 39.2%. However, the result from meta-analysis showed that women who were counseled on IFAS in their courses of pregnancy were 1.96 times more likely to adhere to IFAS compared to those who were not counseled [OR:1.96, 95% CI (1.76-,5.93)]. Moreover, it showed that women who had knowledge of IFAS were 2.71 times more likely to have compliance with IFAS as compared to those who had no knowledge of IFAS [OR:2.71, 95% CI (1.33,5.54)]. Also it revealed that those women who had knowledge of anemia were 5.42 times more likely to have compliance with IFAS as compared with those who had no knowledge of anemia [OR5.42, 95% CI (1.52, 19.43)]. Furthermore, women who had received fourth visit for ANC were 1.54 times more likely to have compliance with IFAS as compared to those who had not received for ANC [OR 1.54, 95% CI (0.66, 3.58.43)]., Conclusions: Our finding from this systematic review and meta-analysis shows the low case in prevalence of compliance to IFAS among pregnant women in SSA. Predictors for this includes: knowledge about anemia, knowledge about IFAS, counseling on IFAS and receiving fourth antenatal care visit were statistically correlated positively with compliance to IFAS. This demands careful appraisal of effect of prevention work for functioning policy, programs and plan nutrition intrusions for refining maternal dietary intake in gestation. Also dietary education intrusion requires to be planned to satisfy the needs of pregnant women. So we hope that the result of this study might be essential as a bridging stone for policy makers of Africa; exclusively for maternal and child health care. Finally, we recommended further studies to be conducted in the area of the study for more intensive and detailed suggestions., Competing Interests: The authors have declared that no competing interests exist.

Objective: Deficiency of adenosine deaminase 2 (DADA2) is a potentially fatal monogenic syndrome characterized by variable manifestations of systemic vasculitis, bone marrow failure, and immunodeficiency. Most cases are diagnosed by pediatric care providers, given the typical early age of disease onset. This study was undertaken to describe the clinical phenotypes and treatment response both in adults and in children with DADA2 in India., Methods: A retrospective analysis of pediatric and adult patients with DADA2 diagnosed at various rheumatology centers across India was conducted. Clinical characteristics, diagnostic findings, and treatment responses were analyzed in all subjects., Results: In total, 33 cases of DADA2 were confirmed in this cohort between April 2017 and March 2020. Unlike previous studies, nearly one-half of the confirmed cases presented during adulthood. All symptomatic patients exhibited features of vasculitis, whereas constitutional symptoms and anemia were more common in pediatric patients. Cutaneous and neurologic involvement were common, and 18 subjects had experienced at least one stroke. In addition, the clinical spectrum of DADA2 was expanded by recognition of novel features in these patients, including pancreatic infarction, focal myocarditis, and diffuse alveolar hemorrhage. Treatment with tumor necrosis factor inhibitors (TNFi) was initiated in 25 patients. All of the identified disease manifestations showed marked improvement after initiation of TNFi, and disease remission was achieved in 19 patients. Two cases were complicated by tuberculosis infection, and 2 deaths were reported., Conclusion: This report presents the first case series of patients with DADA2 from India, diagnosed by adult and pediatric care providers. The findings raise awareness of this syndrome, particularly with regard to its presentation in adults., (© 2020, American College of Rheumatology.)

Anemia is a common condition in HIV-infected children; however, its pathophysiology and the contribution of frequent causes of anemia such as iron deficiency (ID) and malaria are poorly understood. We carried out an ancillary study on the effect of HIV on anemia as part of a case-control study on risk factors of anemia among Mozambican children aged 1-59 months with documented HIV status. Of them, 390 children were admitted to the hospital with anemia (hemoglobin [Hb] < 11 g/dL), whereas 272 children without anemia (Hb ≥ 11 g/dL) were recruited in the community. We assessed differences by HIV status in the presentation of anemia etiological factors and the effect of HIV infection on the association of each factor with anemia. Among the 99 HIV-infected and 563 uninfected children included, HIV-infected anemic children had an increased risk of undernutrition (P < 0.0001), Epstein-Barr virus infection (P < 0.0001), bacteremia (P = 0.0060), a decreased risk of malaria (P < 0.0001), and a similar risk of ID (P = 0.7371) compared with anemic-uninfected children. HIV-infected children were significantly less likely to have anemia associated with Plasmodium falciparum hyperparasitemia (P = 0.0444) and had a lower prevalence of parasitemia in the bone marrow (BM) (P < 0.0001) than anemic-uninfected children. Levels of BM erythropoiesis and dyserythropoiesis were comparable between groups. These findings suggest that the pathophysiology of anemia among HIV-infected malaria-exposed children is not related to HIV-specific effects. For unclear reasons, HIV-infected children had reduced risk of malaria infection, whereas ID prevalence was comparable in HIV-infected and uninfected children, suggesting that iron supplementation recommendations should not be different in HIV-infected children.

&lt;b&gt;Background and Objective:&lt;/b&gt; Vitamin A Deficiency (VAD) is a critical public health problem that affects the health of kids worldwide and may induce anemia and oxidative stress. The current study aimed to pre-clinically assess the effect of a cupcake, prepared to be served for primary school children, on vitamin A deficiency and related anemia and oxidative stress in rats. &lt;b&gt;Materials and Methods:&lt;/b&gt; Flour of flash orange sweet potatoes, as a rich source of pro-vitamin A, was used to prepare the cupcake. The chemical composition, amino acids and sensory evaluation of the cupcake were done. The biological evaluation was carried out using 18 weaning rats in three groups (control group, vitamin A-deficient group and vitamin A-deficient group fed on a diet fortified with 20% of the prepared cupcake for two months). &lt;b&gt;Results:&lt;/b&gt; The results indicated the high value of vitamin A in the prepared cupcake. Excellent sensory characteristics were noticed. Feeding on the VDA diet fortified with the prepared cupcake suppressed the reduction in Retinol-Binding Protein (RBP), hemoglobin and iron. Total Iron Binding Capacity (TIBC) increased in the VAD group. Also, feeding on the prepared cupcake suppressed the reduction in Superoxide Dismutase (SOD) and Glutathione Peroxidase (GPx) and the elevation of Malondialdehyde (MDA). &lt;b&gt;Conclusion:&lt;/b&gt; It can be suggested that the prepared cupcake is promising in preventing of vitamin A deficiency and related anemia and oxidative stress. Thus, the prepared cupcake may be efficient for children to prevent vitamin A deficiency.

Excessive gestational weight gain (GWG) increases the risk of maternal anaemia during pregnancy, but whether it is associated with offspring anaemia has not been investigated. We aimed to prospectively investigate the association of GWG rate in the second/third trimester with infant Hb concentration and anaemia risk. The present study comprised 13 765 infants born during 2006-2009 to mothers who participated in a trial on prenatal micronutrient supplementation. The GWG was calculated by subtracting the maternal weight at enrolment from that at end-pregnancy. The GWG rate was calculated as dividing the GWG by number of weeks between the two measurements and classified into quintiles within each category of maternal BMI. Infant Hb concentrations were measured at 6 and 12 months of age, and anaemia was defined as an Hb concentration <110 g/l. Of the 13 765 infants, 949 (6·9 %) were anaemic at 6 months and 728 (5·3 %) at 12 months. The GWG rate was inversely and linearly associated with the infant Hb concentrations at both 6 and 12 months (P < 0·001 for linearity). Compared with the middle quintile of GWG rate, the highest quintile was associated with an increased risk of anaemia at 6 months (adjusted OR 1·30, 95 % CI 1·07, 1·59) and 12 months (adjusted OR 1·74, 95 % CI 1·40, 2·17). The associations were consistently mediated by maternal anaemia during pregnancy (P < 0·001). In conclusion, excessive GWG rate appears to be associated with an increased risk of infant anaemia, partly independent of maternal anaemia during pregnancy that mediates the association.

Objectives: Although anemia is a widespread condition that leads to an increase in morbidity and mortality, particularly as people age, little information on anemia in centenarians is available. The objective of this study was to determine the prevalence of anemia and examine the relationship between anemia and a decline in kidney function in Chinese centenarians. Methods: We conducted a population-based cross-sectional study of a sample of 1002 Chinese centenarians (180 men and 822 women) from 2014 to 2016. Anemia was defined as a hemoglobin level of <130 g/L for men and <120 g/L for women. Results: The prevalence of anemia and severe anemia (<100 g/L) were 68.5% (men, 76.1%; women, 66.8%) and 19.6% (men, 16.1%; women, 20.3%), respectively. The risk of anemia and estimated glomerular filtration rate (eGFR) showed a nonlinear relationship (nonlinear P  = 0.021). The interaction analysis revealed that ethnicity and diabetes mellitus played a role in the association between the eGFR (<60 mL/min/1.73 m 2 ) and anemia. Conclusion: Anemia is highly prevalent in Chinese centenarians, particularly among men. Decreased kidney function was an independent determinant of anemia, especially in Han participants and participants with diabetes mellitus. The possibility of decreased kidney function needs to be considered in the evaluation and treatment of anemia in centenarians.

Background: ESRD (End-stage renal disease) treatment is a comprehensive medical process and requires numerous serological biochemical tests (SBTs) in diagnosis. To reduce these invasive, expensive, cumbersome, and time-consuming SBTs, there is a need to develop an alternative serological biochemical composition evaluation method. Bioelectrical impedance analysis (BIA) is affected by body's chemical and physical components, which might be correlated with serological biochemical composition and can be potentially used to evaluate biochemical composition in hemodialysis patient treatments. In this work, the relationship of classic and specific bioelectrical impedance vector analysis (BIVA) with major serological biochemical indexes in maintenance hemodialysis (MHD) patients was examined., Methods: Bioelectrical and biochemical datasets were measured from 280 women and 408 men and formed 3872 effective biochemical-bioelectrical records in total. Statistical analysis was performed., Results: The results show that BIVA vectors have strong relationship with phosphorus, hemoglobin, and PTH in both male and female groups. Strong correlation was also observed between Ca, albumin, CHOL, LDLC, and BIVA vectors in the male group. In the female group, a significant correlation was observed between classic BIVA values and NT-proBNP. SVM models are effective for classifying biochemical indexes., Conclusions: The obtained correlations and SVM classification models imply that BIVA can be used as a preliminary tool to evaluate and classify the degree of anemia, malnutrition, fluid overload, and mineral and bone disorder (MBD) in MHD patients by reducing the number of SBTs.

Background: Anemia is a major public health problem in both developed and developing countries especially among pregnant women. Nearly half of pregnant women in Ethiopia have anemia which has both health and economic impacts. Therefore, this study is aimed at identifying nutritional-related predictors of anemia among pregnant women attending antenatal care in Central Ethiopia, 2019., Methods: An unmatched case-control study was conducted at public hospitals in Central Ethiopia from February to April 2019. The consecutive sampling technique was used to select study participants. Data were collected by a structured questionnaire, and the collected data were entered into Epi Info version 7 and SPSS version 23 for analysis. Binary and multiple logistic regression analyses were computed to identify predictors of anemia. Adjusted odds ratio (AOR) with 95% confidence interval (CI) and p value < 0.05 was used to determine the presence of an association., Result: A total of 426 pregnant women (142 cases and 284 controls) had participated in this study. Taking tea/coffee immediately after food (AOR = 2.35, 95% CI: 1.39-3.99), mid-upper arm circumference (MUAC) of mothers of <23 centimeters (AOR = 3.83, 95% CI: 2.26-6.49), the presence of forbidden food during pregnancy (AOR = 2.21, 95% CI: 1.24-3.88), not taking additional food (AOR = 1.99, 95% CI: 1.17-3.40), unable to take fruit (AOR = 4.05, 95% CI: 1.3-15.47), loss of appetite (AOR = 2.28, 95% CI: 1.28-4.09), low dietary diversity score (DDS) (AOR = 3.29, 95% CI: 1.83-5.90), and medium DDS (AOR = 2.88, 95% CI: 1.46-5.70) were found to be determinants of anemia., Conclusions: Taking tea or coffee immediately after food, MUAC of mothers, the presence of forbidden food, not taking additional food, frequency of taking fruit, and dietary diversity were predictors of anemia among pregnant women. Therefore, interventions targeted at prevention of anemia among pregnant mothers should emphatically consider those identified determinants. This finding also highlights the need for strong nutritional counseling to prevent anemia among pregnant mothers during antenatal care follow-ups along with other interventions., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2020 Berhanu Senbeta Deriba et al.)

Background: Even though anemia was highly targeted in different global strategies, many pregnant and/or lactating women and children were suffering from it and its complications. Besides this, prior trend analysis has not been conducted among pregnant and/or lactating women in Ethiopia. Therefore, this study aimed to assess the trend and determinants of anemia change among pregnant and/or lactating women in Ethiopia., Methods: The study utilized two consecutive Ethiopia Demographic and Health Survey (EDHS) datasets. A total of 6,106 and 5,641 pregnant and/or lactating women in 2011 and 2016 survey respectively were included in the analysis. The data were analyzed by using Stata version 14.0. Logit based decomposition analysis was done to identify contributing factors for anemia change and statistical significance was determined by using P-value., Results: The trend of anemia was increased from 19% in 2011 to 29% in 2016 EDHS. The analysis revealed that, 8% of the overall change in anemia was because of the change in women's composition. Changes in the composition of pregnant and/or lactating women according to region, economic status and tobacco and/or cigarette use were the major sources of the change. Greater than 90% of the increase in anemia was due to differences in the coefficient. Mostly, the change in behaviors of the Amhara population, those who had a history of terminated pregnancy and use tobacco and/or cigarette were the sources of the change., Conclusions: Anemia among pregnant and/or lactating women was increased against government interventions over the last half-decade in Ethiopia. Programmatic interventions targeting Somali and Dire Dawa regions are still needed to decrease anemia., Competing Interests: The authors have declared that no competing interests exist.

Background: Severe anaemia is a common clinical problem among young children in sub-Saharan Africa. However, the effect of severe anaemia on neurodevelopment of these children is not well described. Therefore, we assessed the neurodevelopmental performance of preschool children diagnosed with severe anaemia in Northern Uganda., Methods: We conducted a prospective cohort study among children < 5 years of age 14 days post discharge after an episode of severe anaemia (Hb < 5.0 g/dl; n = 171; mean Hb = 3.9g/dl) at Lira Regional Referral Hospital, Uganda. Neurodevelopmental outcomes (cognitive, language and motor) were assessed using Bayley Scales of Infant and Toddler Development, 3rd edition (Bayley-III). Age-adjusted z-scores for each domain were calculated using scores from healthy community control children (n = 88) recruited from the same environment for each age category. Multiple linear regression was used to compare z-scores in the cognitive, language and motor scales between the two groups after adjusting for weight-for-age z-score, socioeconomic status, mother's education, and father's employment on all the scales., Results: The prevalence of neurodevelopmental impairment was 2.3% (95% CI: 0.8-6.1) for cognition, 1.7% (95%: 0.6-5.3) for language and 3.5% (95% CI: 1.6-7.6) for motor scales and 4.6% (95% CI: 2.3-9.1) for deficits in ≥1 area of neurodevelopment. Significant differences were observed between the two groups with the SA group performing worse on cognition [adjusted mean score, (Standard error, SE), P-value] [-0.20, (0.01) vs. 0.00, (0.01), P = 0.02]; language [-0.25, (0.01) vs. 0.00, (0.01), P< 0.001]; and motor [-0.17, (0.01) vs. 0.00, (0.01), P = 0.05] scales., Conclusion: In children < 5 years of age, severe anaemia was associated with neurocognitive (cognition, language and motor) deficits in the immediate period post treatment. Further research is needed to identify risk factors and determine the long-term effects of poor neurodevelopment in young children with severe anaemia., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Past studies have shown that maternal anemia is associated with a heavy placenta or a higher placental weight/birthweight (PW/BW) ratio. Although these findings suggest a non-linear relationship between maternal hemoglobin concentration and PW/BW ratio, this relationship has not been closely examined., Methods: We evaluated 83,354 singletons and their mothers in a nation-wide birth cohort study, the Japan Environment and Children's Study (JECS). The associations between maternal hemoglobin concentration and placental weight, birthweight, and PW/BW ratio were assessed., Results: Mean placental weight was significantly higher in women with moderate or severe anemia (576 [183] g), but not in women with elevated hemoglobin levels (564 [117] g), compared with in women with normal hemoglobin levels (560 [115] g). In contrast, mean PW/BW ratio was significantly higher in women with moderate or severe anemia (0.190 [0.049]) or elevated hemoglobin levels (0.189 [0.033]) than in women with normal hemoglobin levels (0.185 [0.033]). In a regression analysis with cubic spline, a U-shaped relationship was found between maternal hemoglobin concentration and PW/BW ratio., Discussion: We demonstrated non-linear and concentration-dependent relationships between maternal hemoglobin concentration and placental weight, birthweight, and PW/BW ratio. Although the mechanisms underlying these associations are not fully understood, we suggest that low or elevated hemoglobin concentration may lead to placental compensatory hypertrophy and fetal growth restriction. Prevention and proper management of anemia before and during pregnancy are important for a well-functioning placenta and favorable fetal growth., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction: Anemia has and will continue to be a central theme in medicine particularly as clinicians are treating a burgeoning population of complex multi-organ system processes. As a result of multiple randomized controlled trials (RCTs), meta-analyses, and societal recommendations overly restrictive paradigms and under-administration of erythropoiesis stimulating agents (ESAs) have likely been followed by clinicians among all specialties., Areas Covered: A review of anemia in the context of chronic kidney disease, hematologic malignancies, and cancer is presented with focus on the establishment of ESAs as integral in the treatment of anemia. Multiple RCTs and meta-analyses studying the use of ESAs are presented with focus upon their application to clinical practice. A 'compendium' is proffered describing the evolution, establishment, and implications of ESA administration initially among those with CKD with rapid subsequent application to the Hematology-Oncology population of patients. Literature search methodologies have included MEDLINE (1985-2020), PubMed (1996-2020), Cochrane Central Trials (1985-2020), EMBASE (2000-2020), and ClinicalTrials.gov (2000-2020)., Expert Opinion: Upon evaluation of risks and benefits of ESAs focused opinion and commentary is made supporting more liberal use of these agents and strongly suggesting that the current underlying treatment 'pendulum' has perhaps shifted too far to the 'under-treatment' side in many cases.

Background: The composite Model for End-Stage Liver Disease Excluding International Normalized Ratio Score (MELD-XI) is a novel tool to evaluate cardio-renal and cardio-hepatic interactions in patients with advanced heart failure (HF). However, its prognostic ability remains unclear in elderly HF patients., Methods and Results: From July 2014 to July 2018, patients hospitalized for HF were prospectively recruited at 16 centers. Clinical features, laboratory findings, and echocardiography results were assessed prior to discharge. Cardiovascular (CV) death and HF re-hospitalization were recorded. Of the 676 patients enrolled, 264 (39.1%) experienced CV events throughout a 1-year median follow-up period. Patients with high MELD-XI were predominantly male and had a higher prevalence of NYHA III/IV, history of HF admission, hyperuricemia, ventricular tachycardia, anemia, and ischemic heart disease. In Kaplan-Meyer analysis, patients with higher MELD-XI (≥11) scores showed a worse prognosis than did those with lower (<11) scores (log-rank p≤0.001). Multivariate Cox proportional hazards testing revealed MELD-XI as an independent predictor of CV events (HR: 1.033, 95% CI: 1.006-1.061, p = 0.015) after adjusting for age, gender, body mass index, NYHA III/IV, prior HF hospitalization, systolic blood pressure, ischemic etiology, ventricular tachycardia, anemia, BNP, and left ventricular ejection fraction., Conclusions: Cardio-renal and cardio-hepatic interactions predicted CV events in aged HF patients., Competing Interests: No authors have competing interests.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) deficiency leads to lower cholesterol and is associated with reduced vascular complications in the general population. Cholesterol lowering may also have beneficial effects in sickle cell disease (SCD). The objective of this study was to determine effects of PCSK9 deficiency in a mouse model of SCD. Bone marrow transplantation (BMT) was performed from donor SCD mice to wild-type, PCSK9-deficient, and LDLR-deficient recipients to generate SCD controls (Pcsk9 +/+ , SCD bmt ) with preserved PCSK9 status, SCD mice with deficiency of PCSK9 (Pcsk9 -/- , SCD bmt ), and SCD mice with deficiency of LDLR (Ldlr -/- , SCD bmt ). Although cholesterol levels were lower in Pcsk9 -/- , SCD bmt mice compared to Pcsk9 +/+ , SCD bmt mice, anemia was more severe in Pcsk9 -/- , SCD bmt mice. Increased reticulocytosis, enhanced ex vivo erythrocyte sickling, and increased erythrocyte phosphatidylserine exposure was also observed. Livers, spleens, and kidneys contained increased iron in Pcsk9 -/- , SCD bmt mice compared to Pcsk9 +/+ , SCD bmt mice consistent with greater hemolysis. SCD mice with deficiency of LDLR (Ldlr -/- , SCD bmt mice) had similar anemia as Ldlr +/+ , SCD bmt mice despite higher serum cholesterol. In conclusion, deficiency of PCSK9 is associated with worsened anemia in SCD mice due to increased hemolysis. These findings may have implications for lipid-lowering strategies in patients with SCD, as well as for potential novel modifiers of anemia severity.

According to European Union directive 2010/63/EU a severity classification of experimental procedures performed on laboratory animals is mandatory. This includes a prospective evaluation of all interventions performed within the experiment, as well as an assessment of the actual burden of each animal during the experiment. In this regard, the evaluation and scoring of defined criteria regarding the health state of animals could help to early identify deteriorations in animal health and facilitate the application of humane endpoints. This article discusses the applicability of an adapted score sheet in BALB/cAnNRj mice receiving either cisplatin, doxorubicin or busulfan, three chemotherapeutic agents with different toxicological profiles and longitudinal non-invasive molecular imaging. The health state was investigated by score sheets documenting general state, body weight, spontaneous behaviour and treatment specific parameters (e.g. anaemia, neurotoxicity, persistent diarrhoea). Although blood and serum analyses clearly indicated various organ damage, most scoring parameters except for body weight did not report on the deceasing animal health state. Thus, there is need for more sensitive observational parameters to judge the animal's health state and welfare.

Introduction: The association of patients with heart failure (HF) and preserved ejection fraction (HFpEF) and with type 2 diabetes mellitus (T2DM) is strong and related additionally to blood pressure (BP)., Aims: To analyze distinctive clinical profiles among patients with HFpEF both with and without T2DM., Methods: The study was based on a Spanish National Registry (multicenter and prospective) of patients with HF (DICUMAP), that enrolled outpatients with HF who underwent an ambulatory BP monitoring (ABPM) and then were followed-up for 1 year. We categorized patients according to the presence/absence of T2DM then building different clusters based on K-medoids algorithm., Results: 103 patients were included. T2DM was present in 44.7%. The patients with T2DM were grouped into two clusters and those without T2DM into three. All patients with T2DM had kidney disease and anemia. Among them, cluster 2 had higher systolic blood pressure and pulse pressure (PP) with a bad outcome (p = 0.03) regarding HF mortality and readmissions, influenced by eGFR (HR 0.93, 95% CI 0.97-0.87, p = 0.04), and hemoglobin (HR 0.65, 95% CI 0.71-0.63, p = 0.03). Among those without T2DM, cluster 3 had a pathological ABPM pattern with the highest PP, cluster 4 was slightly similar to cluster 2, and cluster 5 expressed a more benign pattern without differences on both, HF mortality and readmissions., Conclusions: Patients with HFpEF and T2DM expressed two different profiles depending on neurohormonal activation and arterial stiffness with prognostic implications. Patients without T2DM showed three profiles depending on ABPM pattern, kidney disease and PP without prognostic repercussion.

Maternal alloantibody-mediated hemolytic disease of the fetus and newborn (HDFN) ranges from no or mild symptoms to severe hydrops and intrauterine fetal demise. Hemolytic anti-D-mediated HDFN proceeds via a long-known mechanism, to which three other pathways to fetal/neonatal anemia may be added: (0) Fetal erythrocyte destruction can proceed by extravascular phagocytosis. (1) An apoptotic pathway has been described for anti-Kell, and anti-Ge3. (2) Erythropoietic suppression may arise from altered or deformed erythroblast architecture in anti-M-mediated disease. (3) Clonal escape from erythropoietic suppression is hypothesized to arise from maternal anti-Jr a immune pressure, albeit this requires further elucidation. Alloantibody-mediated anemic disease of the fetus and newborn (ADFN) is a designation we favor for cases when hemolysis or hyperbilirubinemia are not the dominant features, such as those provoked by anti-Kell, anti-Ge3, anti-M, and anti-Jr a ., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Anemia is highly prevalent in people with chronic kidney disease (CKD), and CKD patients always have lower plasma but higher erythrocyte Zn levels than healthy people. To date, no satisfactory mechanism has explained these Zn metabolism abnormalities. We collected blood samples from patients on hemodialysis, 5/6 nephrectomized rats and phenylhydrazine (PHZ)-induced anemic mice and rats and compared them with their normal counterparts. We found that all the anemic animals had significantly decreased plasma Zn levels but elevated erythrocyte Zn levels. We also found that in anemic mice, new red blood cells (reticulocytes) had a ~7-fold higher Zn concentration than mature erythrocytes. When excess Zn was supplied to the rats, there was a ~1.2-fold increase in the Zn level in the rat bones. When Zn was depleted in the rats, the bones lost the greatest amount of Zn in the body (a 45% decrease). We prepared Zn-depleted rats and rendered these rats anemic by treating them with PHZ, and we compared them with normal rats. We found that in PHZ-induced anemia, rats released ~16% of Zn from their bones. Rat bones not only act as a 'reservoir' to adjust the excess or deficient Zn levels but also release Zn in anemia, and the released Zn stimulates erythropoiesis in the bone marrow. In anemia, Zn is redistributed from the plasma (causing the plasma Zn level to decreases) and bones to the bone marrow to produce reticulocytes (causing erythrocyte Zn level elevation)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Preeclampsia and eclampsia are common complications of pregnancy globally, including sub-Saharan African (SSA) countries. Although it has a high burden on maternal and neonatal mortality and morbidity, evidence on the risk of the problem is limited. Therefore, the aim of this review was to examine the factors associated with preeclampsia and eclampsia among mothers in SSA countries., Methods: We searched article from SSA countries using electronic database MEDLINE, EMBASE, PubMed, CINAHL published in English from January 2000 to May 2020. Two reviewers independently screened, extracted and assessed the quality of the articles. Both random and fixed effect model were used for analysis. Heterogeneity of the studies and publication bias were checked. STATA 16 used for analysis., Results: Fifty-one studies met the inclusion criteria and included in this review. The following factors were identified through meta-analysis: being primiparous (OR: 2.52; 95% CI:1.19, 3.86), previous history of maternal preeclampsia/eclampsia (OR:5.6; 95% CI:1.82, 9.28), family history of preeclampsia/eclampsia (OR:1.68; 95% CI:1.26, 2.11), high maternal body mass index (OR: 1.69; 95% CI:1.17, 2.21), chronic hypertension (OR: 2.52; 95% CI:1.29, 3.74), anaemia during pregnancy (OR: 3.22; 95% CI:2.70, 3.75) and lack of antenatal care visits (OR: 2.71; 95% CI:1.45, 3.96). There was inconclusive evidence for a relationship with a number of other factors, such as nutrition and related factors, antenatal care visits, birth spacing, and other factors due to few studies found in our review., Conclusions: The risk of preeclampsia and eclampsia is worse among women who have a history of preeclampsia/eclampsia (either themselves or family members), primiparous, obesity and overweight, living with chronic disease, having anaemia during pregnancy and absence from ANC visits. Therefore, investment must be made in women's health needs to reduce the problem and health service providers need to give due attention to high-risk women., Competing Interests: The authors declare no conflicts of interest.

Objectives: To identify maternal and perinatal risk factors associated with childhood anaemia., Methods: A retrospective cohort study was conducted in three remote Katherine East Aboriginal communities in Northern Territory, Australia. Children born 2004-2014 in Community A and 2010-2014 in Community B and C, and their respective mothers were recruited into the study. Maternal and child data were linked to provide a longitudinal view of each child for the first 1000 days from conception to 2-years of age. Descriptive analyses were used to calculate mean maternal age, and proportions were used to describe other antenatal and perinatal characteristics of the mother/child dyads. The main outcome was the prevalence of maternal anaemia in pregnancy and risk factors associated with childhood anaemia at age 6 months., Results: Prevalence of maternal anaemia in pregnancy was higher in the third trimester (62%) compared to the first (46%) and second trimesters (48%). There was a strong positive linear association (R 2  = 0.46, p < 0.001) between maternal haemoglobin (Hb) in third trimester pregnancy and child Hb at age 6 months. Maternal anaemia in pregnancy (OR 4.42 95% CI 2.08-9.36) and low birth weight (LBW, OR 2.62, 95% CI 1.21-5.70) were associated with an increased risk of childhood anaemia at 6 months of age., Conclusions for Practice: This is the first study to identify the association of maternal anaemia with childhood anaemia in the Australian Aboriginal population. A review of current policies and practices for anaemia screening, prevention and treatment during pregnancy and early childhood would be beneficial to both mother and child. Our findings indicate that administering prophylactic iron supplementation only to children who are born LBW or premature would be of greater benefit if expanded to include children born to anaemic mothers.

Background: The Japan Chronic Kidney Disease Database (J-CKD-DB) is a nationwide clinical database of patients with chronic kidney disease (CKD) based on electronic health records. The objective of this study was to assess the prevalence of anemia and the utilization rate of erythropoiesis-stimulating agents (ESAs) in Japanese patients with CKD., Methods: In total, 31,082 adult outpatients with estimated glomerular filtration rates of 5-60 ml/min/1.73 m2 in seven university hospitals were included this analysis. The proportions of patients with CKD stages G3b, G4, and G5 were 23.5%, 7.6%, and 3.1%, respectively., Results: The mean (standard deviation) hemoglobin level of male patients was 13.6 (1.9) g/dl, which was significantly higher than the mean hemoglobin level of female patients (12.4 (1.6) g/dl). The mean (standard deviation) hemoglobin levels were 11.4 (2.1) g/dl in patients with CKD stage G4 and 11.2 (1.8) g/dl in patients with CKD stage G5. The prevalences of anemia were 40.1% in patients with CKD stage G4 and 60.3% in patients with CKD stage G5. Logistic regression analysis showed that diagnoses of CKD stage G3b (adjusted odds ratio [95% confidence interval]: 2.32 [2.09-2.58]), G4 (5.50 [4.80-6.31]), and G5 (9.75 [8.13-11.7]) were associated with increased prevalence of anemia. The utilization rates of ESAs were 7.9% in patients with CKD stage G4 and 22.4% in patients with CKD stage G5., Conclusions: We determined the prevalence of anemia and utilization rate of ESAs in Japanese patients with CKD using data from a nationwide cohort study., Competing Interests: The authors have declared that no competing interests exist.

The main inherited cardiac arrhythmias are long QT syndrome, short QT syndrome, catecholaminergic polymorphic ventricular tachycardia and Brugada syndrome. These rare diseases are often the underlying cause of sudden cardiac death in young individuals and result from mutations in several genes encoding ion channels or proteins involved in their regulation. The genetic defects lead to alterations in the ionic currents that determine the morphology and duration of the cardiac action potential, and individuals with these disorders often present with syncope or a life-threatening arrhythmic episode. The diagnosis is based on clinical presentation and history, the characteristics of the electrocardiographic recording at rest and during exercise and genetic analyses. Management relies on pharmacological therapy, mostly β-adrenergic receptor blockers (specifically, propranolol and nadolol) and sodium and transient outward current blockers (such as quinidine), or surgical interventions, including left cardiac sympathetic denervation and implantation of a cardioverter-defibrillator. All these arrhythmias are potentially life-threatening and have substantial negative effects on the quality of life of patients. Future research should focus on the identification of genes associated with the diseases and other risk factors, improved risk stratification and, in particular for Brugada syndrome, effective therapies.

Background: The impact of anemia treatment with erythropoietin stimulating agents (ESA) on health-related quality of life (HRQOL) in chronic kidney disease (CKD) patients is controversial, particularly regarding optimal hemoglobin (Hb) target ranges., Methods: We conducted a systematic review and meta-analysis of observational studies and randomized controlled trials (RCT) with ESA to estimate the effect of different achieved Hb values on physical HRQOL and functionality. We searched PubMed, EMBASE, CENTRAL, PEDro, PsycINFO and Web of Science databases, until May 2020. Two authors independently extracted data from studies. We included observational and RCTs that enrolled CKD patients undergoing anemia treatment with ESA with different achieved Hb levels among groups. We excluded studies with achieved Hb < 9 g/dL. For the meta-analysis, we included RCTs with control groups achieving Hb 10-11.5 g/dL and active groups with Hb > 11.5 g/dL. We analyzed the standardized mean difference (SMD) between groups for physical HRQOL., Results: Among 8496 studies, fifteen RCTs and five observational studies were included for the systematic review. We performed the meta-analysis in a subset of eleven eligible RCTs. For physical role and physical function, SMDs were 0.0875 [95% CI: - 0.0025 - 0.178] and 0.08 [95% CI: - 0.03 - 0.19], respectively. For fatigue, SMD was 0.16 [95% CI: 0.09-0.24]. Subgroup analysis showed that trials with greater achieved Hb had greater pooled effects sizes - 0.21 [95% CI: 0.07-0.36] for Hb > 13 g/dL vs. 0.09 [95% CI: 0.02-0.16] for Hb 11.5-13 g/dL. Proportion of older and long-term diabetic patients across studies were associated with lower effect sizes., Conclusion: Achieved hemoglobin higher than currently recommended targets may be associated with small but potentially clinically significant improvement in fatigue, but not in physical role or physical function. Younger and non-diabetic patients may experience more pronounced benefits of higher Hb levels after treatment with ESAs.

Background and Purpose: Hemoglobin (Hbg) is often thought to impact cerebral blood flow velocity (CBFV). This study was performed to investigate the relationship between Hbg value and CBFV in African children with malaria., Methods: In this prospective, observational study, children aged 3 months to 18 years with malaria and a normal Blantyre coma score underwent a single transcranial Doppler ultrasound (TCD) examination with a concurrent Hbg check., Results: One hundred fifty-six children with a mean age of 43 months were enrolled. Thirty-three children (21%) had severe anemia (Hbg <5g/dL), 46 (29%) had moderate anemia (Hbg 5-6.9 g/dL), 63 children (41%) had mild anemia (7-9.9 g/dL), and 14 children (9%) had no anemia (Hbg >10 g/dL) at the time of TCD examination. Mean averaged CBFV in the middle cerebral artery (MCA) for the cohort was 99% of predicted based on normative values standardized for age. There was no significant correlation between Hbg levels and measured CBFV in the MCA (r = -.09; 95% CI, -.24-.07; P = .29)., Conclusion: In a large sample of African children with malaria, Hbg did not correlate with CBFVs as measured by TCD. Future work that includes baseline TCD measurements and Hbg values as well as other physiological parameters known to influence CBFVs is necessary to confirm these findings., (© 2020 American Society of Neuroimaging.)