bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Hydroxyurea Treatment on Body Composition in Children with Sickle Cell Anemia in Uganda Using Bioelectrical Impedance Analysis (BIA)
Authors: Kalibala Dennis , Nabaggala Catherine , Turyagyenda Lynnth , Mboizi Vincent , Naggayi Shubaya Kasule , Kabatabaazi Maxencia , Rosano Caterina , Munube Deogratias , Kasirye Phillip , Ssenkusu John , Opoka Robert , Bangirana Paul , Green Nancy S. , Idro Richard , Mupere Ezekiel
Published: December 2023

Introduction

Children with sickle cell anemia (SCA) experience severe illness and risk of malnutrition in sub-Saharan Africa. Treatment with hydroxyurea (HU) decreases SCA complications. In high-income regions, hydroxyurea also improves pediatric growth and overall quality of life. We assessed the effects of hydroxyurea on growth and body composition of children with SCA in Uganda.

Methods

This study was nested in an open-label, single-arm pediatric clinical trial of hydroxyurea 20-30mg/kg/day for prevention of neurological and cognitive impairment. In all, 267 study participants with SCA, ages 3-9 years, initiated hydroxyurea treatment at the Mulago Hospital SCA Clinic in Kampala, Uganda. Anthropometric measurements (weight, height) were obtained at enrollment and at month 18 of therapy; age- and sex-specific z-scores were assigned, per World Health Organization (WHO) international standards. Non-invasive bioelectric impedance analysis (BIA), was used to estimate total body fat mass (FM) and fat-free mass (FFM) at both timepoints. A control sample of110 siblings/family members without SCA, aged 3-12 years, established local z-scores for BIA assessments.

Results

Among SCA participants and controls, 50.6% and 57.3% were female, respectively. Mean age was younger foror the SCA sample: 5.1±0.1 and 7.1±0.3 years ( p<.001). At trial month 18, mean hydroxyurea dose 25.4mg/kg, SCA hemoglobin rose from 7.8±1.2 to 8.9±1.5 g/dL( p<.001), remaining lower than mean hemoglobin level of non-SCA controls 12.5±1.1 ( p<.001). Using the World Health Organization definition of “wasting,” SCA participants at enrollment had a higher proportion of low weight-for-height than controls: 9.8% vs 3.8%, p=.009). By body composition, the SCA sample also had lower FFM (-0.67±0.56 vs. 0.00 ±1.00, p < .001) and FM (-0.68±0.60 vs. 0.00 ±1.00, p<.001) than controls. At month 18, for the 254 active SCA participants (95.1%), the proportion with wasting was unchanged. In contrast, z-scores for FFM (-0.65±0.57 to -0.16±0.57, p < .001) and FM (-0.66±0.61 to -0.18±0.61, p<.001) significantly increased (Figure) to near control levels.

Conclusion

Hydroxyurea therapy in children with SCA increased hemoglobin yet did not reduce the proportion with wasting after 18 months. Nonetheless, treatment led to significantly improved FM and FFM to near normal levels. These results suggest that hydroxyurea therapy may play a crucial role in enhancing body composition of children with SCA in the region. The ongoing hydroxyurea trial will enable assessment of longer-term impact on health-related growth and body composition in children with SCA in Uganda.
Epidemiological Insights into Large Granular Lymphocyte Leukemia: A Nationwide SEER Database Study
Authors: Yadukumar Lekha , Gogtay Maya
Published: December 2023

Background: Large granular lymphocytic (LGL) leukemia is a rare hematological malignancy that arises from cytotoxic T lymphocytes (T-LGL) or natural killer (NK) cells. LGL leukemia accounts for 2% to 5% of chronic lymphoproliferative disorders in the United States of America. LGL leukemia can either present as an indolent type or an aggressive type. Most patients remain asymptomatic and often have associated autoimmune diseases, such as rheumatoid arthritis and hematologic dyscrasias. We analyzed the demographic characteristics of LGL leukemia patients and investigated the influence of social determinants on their survival.

Methods: We performed a retrospective cohort study of the Surveillance, Epidemiology, and End Results (SEER) database for patients diagnosed with LGL leukemia between years 2000 and 2020. Patient demographics, year of diagnosis, and timeline of treatment were analyzed by descriptive statistics. Cox proportional hazards regression analysis was performed to identify the factors influencing the survival of these patients.

Results: A total of 2589 patients were diagnosed with LGL leukemia. Median age of diagnosis was 67 years. 59.4% were aged more than 65 years of age at the time of diagnosis, 52.7% were males, 81.5% were Caucasians, 64% had an annual income of more than $65,000, and 84.2% lived in metropolitan areas. 91.8% were diagnosed in the past decade after 2010. It is worth noting that 64.5% of the patients received treatment more than six months after diagnosis of LGL leukemia. 81.5% of patients were Caucasians, 9.6% were African Americans, 5.3% were Asians/Pacific Islanders, followed by 2% Hispanics and 1.5% American Indians. At the time of the last follow-up, 65.5% of patients were alive, with an overall median survival of forty months. 70% of patients had LGL leukemia as the only primary malignancy. Age less than 65 years had better outcomes than the older age group (HR 0.32). Female gender was protective (HR 0.69). Poor outcomes were seen in patients with an annual income of less than $65,000 (HR 1.21). The year of diagnosis and residence had no significant effect on survival. Marriage improved the outcomes of patients (HR 0.78) (Table 1). Patients receiving treatment within six months of diagnosis had higher mortality (HR 1.43) than the rest of the population. Caucasians comprised majority of the patient population and had better prognoses (HR 0.11) than Asians/Pacific Islanders (HR 0.49), Hispanics (HR 0.82), and African Americans (HR 0.97) (Figure 1).

Conclusion: We present a population-based analysis and the determinants of survival in patients with LGL leukemia, a rare malignancy. The number of cases has increased in the past decade. Significant patient factors influencing survival in LGL leukemia patients include younger age at diagnosis, female gender, marriage and higher annual income.
Recurrent Thromboembolism in Patients with Congenital Heart Disease and Prior Thromboembolism: A Prospective Cohort Study
Authors: Kiskaddon Amy L , Betensky Marisol , Do Nhue , Stock Arabela , Quintessenza James , Goldenberg Neil
Published: December 2023

Introduction:

Patients with congenital heart disease (CHD) are at increased risk of thromboembolism (TE) due to changes in blood flow, type of cardiac lesion, exposure to cardiopulmonary bypass, and cardiac catheterization. There are limited data describing the rate of and risk factors associated with recurrent TE in pediatric patients with CHD and prior TE. Therefore, the primary aim of this study was to describe the rate of recurrent TE in pediatric patients with CHD and a prior episode of TE. Secondary aims included: characterize the type of index and recurrent TE and site, as well as compare characteristics and risk factors of patients with CHD and history of index TE who developed recurrent TE versus to those who did not develop a recurrent TE.

Methods:

Patients in this study were enrolled and prospectively followed in the Johns Hopkins All Children's (St. Petersburg, FL) Institution-wide Prospective, Inception Multi-Cohort Study of Pediatric TE anytime between 2013 to present. For this analysis, patients were eligible for inclusion if they were <21 years of age, presented with an index TE, and had a diagnosis of CHD. Data collection included patient characteristics, clinical laboratory testing, radiologic results, type and site of TE, acute and chronic risk factors, and treatment agents. Frequencies/proportions were compared between groups by chi-squared or Fisher's exact test, as appropriate.

Results:

Thirty patients with CHD and index TE were included in this study. Of these, 11 (36.7%) patients had a total of 23 recurrent TEs. Five (45.5%) patients had one recurrent TE, 3 (27.3%) had two recurrent TEs, and another 3 patients had >2 recurrent TEs. Of the 23 recurrent TE, 3 events (13%) were arterial and 20 (87%) were venous. All 3 (100%) arterial TEs were provoked, and catheter related. Of the 20 venous TEs, 16 (80) were provoked and of these, 15 (93.8%) were catheter related. When compared to those who did not develop recurrent TE, patients who developed recurrent TE were more likely to have immobility (p=0.005), an arterial TE (p=0.041), or a lower extremity deep venous thrombosis (p=0.045) at the time of index TE. A greater proportion of patients with recurrence had a central catheter-associated TE compared to those with no recurrent TE but this difference was not statistically significant (73% vs 55%, p=0.057).

Conclusions:

In this single center prospective cohort we describe a high rate of recurrent TE (37%) among children with CHD and history of prior TE, and identified risk factors for TE recurrence. The vast majority of recurrent TE was provoked and catheter associated. Identified risk factors include immobility, and type and location of the index TE. Future multicenter prospective cohort studies are needed to validate these findings and identify additional risk factors.
Myeloid Derived Suppressor Cells and Their Potential Impact on Minimal Residual Disease Status and Disease Response in a Cohort of Patients with Plasma Cell Dyscrasias
Authors: Wilks Andrew , Wazir Mohammed , Gerber Jonathan M. , Brehm Michael , Ramanathan Muthalagu
Published: December 2023

Myeloid Derived Suppressor Cells (MDSCs) are known to promote immune-suppressive and tumorigenic effects in plasma cell dyscrasias (PCDs), including multiple myeloma, and may play a role in treatment response and minimal residual disease MRD status in patients undergoing cancer-directed therapies. MDSCs are classified by their granulocyte-like effects (g-MDSCs) or monocyte-like effects (m-MDSCs). To our knowledge, there are no published studies that correlate minimal residual disease (MRD) with the presence of MDSCs and immune effector-cell populations in the blood and bone marrow of patients with PCDs. In 14 patients with PCDs, we defined immune-cell populations in the blood and marrow and correlated them with MRD status, treatment regimens, disease status (stable vs. progressive) and autologous stem cell transplantation status. In the entire cohort, there were a higher proportion of m-MDSCs in blood (blood 5.56%, aspirate 2.47%). There were a higher proportion of g-MDSCs in aspirate (blood 0.04%, aspirate 0.16%). Interestingly, in patients who remained MRD positive (3/13), the proportions were reversed, and we identified more m-MDSC in aspirate than blood, as well as a low proportion of g-MDSCs in both the aspirate and bone marrow. In patients achieving undetectable MRD (10/13) there were higher proportions of CD8 and CD4 T-cells, with no differences in MDSC populations. Not surprisingly, in patients treated with the anti-CD38 antibody daratumumab (5/14), fewer m-MDSCs were isolated in the blood and aspirate, relative to daratumumab-untreated patients (9/14).Daratumumab treatment decreased activated CD4 and CD8 T cells (HLA-DR+/CD38-, HLA-DR-/CD38+ or HLA-DR+/CD38+ CD4 and CD8 T cells) and increased the proportion of inactive HLA-DR-/CD38- CD4 and CD8 T-cells. In patients with progressive disease (3/14), there was a paucity of all immune effector-cells, including MDSCs, T-cells and monocytes with the exception of neutrophils. MDSC populations were no different in pre-transplant patients (3/14) compared to post-transplant (11/14). In this preliminary study, we have enumerated the presence of MDSCs and their potential impact in patients with PCDs undergoing cancer-directed therapy.
ST2/ Rorγt-Dependent Th1/Th2-like CD4 + Trm Cells Mediate Cutaneous Chronic Gvhd
Authors: Li Qinjian , Wang Xiaoqi , Kong Xiaohui , Wang Bixin , Martin Paul J. , Zhang Xi , Zeng Defu
Published: December 2023

Allogeneic hematopoietic cell transplantation (Allo-HCT) is a curative therapy for relapsed hematological malignances, but the same alloreactive T cells that eliminate malignant cells in the recipient also mediate graft-versus-host disease (GVHD), and in long-term Allo-HCT patients chronic GVHD (cGVHD) remains the major cause of morbidity and mortality. Th subsets (i.e., Th1, Th2, and Th17) have been associated with cGVHD in certain tissues, but the Th subsets involved in cutaneous cGVHD remain undefined. In the current studies, with a murine model of C57BL/6 donor to MHC-matched C3H.SW recipient, we observed that although IFN-γ + Th1 cells were dominant in the gut, liver, and skin during early acute GVHD, the skin showed a marked expansion of IFN-γ +IL-13 + Th1/Th2-like cells 30 days after HCT at the onset of cGVHD, while IFN-γ +IL-13 - Th1 cells remained dominant in the liver and intestines. The cutaneous Th1/Th2-like cells exhibited characteristics of Ly108 -CD69 + tissue resident memory T (Trm) cells. The expansion of cutaneous Th1/Th2-like cells was RORγt and ST2-dependent because T cells from RORγt -/- or ST2 -/- C57BL/6 donors did not show expansion of the cutaneous Th1/Th2-like cells or induce cutaneous cGVHD. These results indicate that 1) IFN-γ +/IL-13 + Th1/Th2-like CD4 + Trm cells likely play a critical role in the pathogenesis of cutaneous cGVHD; 2) the differentiation of IFN-γ +CD4 + Th1 cells into IFN-γ +IL-13 + Th1/Th2-like cells is RORγt and ST2-dependent. The molecular mechanisms that underpin this differentiation pathway are under investigation.
Interleukin-17A Directly Signals to Bone Marrow-Derived Hematopoietic Stem and Progenitor Cells to Promote Their Expansion and Differentiation in Vitro
Authors: Losada Cristobal González , Poon William Wai Lam , Salaciak Matthew , Amghar Samy , Johnson Nathalie A. , Sharif-Askari Bahram , Mercier Francois E.
Published: December 2023

Rationale: IL-17 is a family of six pro-inflammatory cytokines (named from A to F) with distinct patterns of cellular expression. Among these, IL-17A is secreted by lymphoid subsets such as T-helper 17 cells and innate lymphoid cells type 3. Through its action on many tissues, IL-17A is recognized as a key mediator of response to infection and pathogenic states such as cancer and auto-immunity. Until now, the main effect of IL-17A on hematopoiesis has been attributed to an indirect loop through IL-17RA signaling on bone marrow stromal cells, which stimulates secretion of hematopoietic factors such as G-CSF. However, we hypothesized that IL-17A can directly signal to hematopoietic stem and progenitor cells (HSPCs) to determine their self-renewal and differentiation.

Methodology: We analyzed the expression of the IL-17 signaling pathway in publicly available human and mouse hematopoietic single-cell RNAseq datasets. Mouse HSPCs were isolated using FACS to perform clonogenic and differentiation assays in Methocult (StemCell Technologies) and StemPro-34 (Gibco). Spectral flow cytometry (SONY ID7000) was used for analysing IL-17RA expression and differentiation of mouse HSPCs. IL-17A levels were measured in blood and bone marrow serum using ELISA (Invitrogen).

Results: IL-17RA is expressed at the surface of mouse HSPCs, with greatest levels in common lymphoid progenitors and granulocyte-monocyte progenitors. mRNA expression of IL-17RA signaling pathway is also detectable in human HSPCs, with greatest levels in young individuals. IL-17A supplementation leads to an increase in clonogenic capacity of mouse HSPCs in methylcellulose colony-formation assays. In liquid culture, supplementation with IL-17A leads to a greater expansion of sorted Lin -/s-kit +/Sca-1 + progenitors, accompanied by an increased proportion of myeloid-committed cells.IL-17A is also detected in the bone marrow serum, with possible production from subsets of cells expressing RORγt, a master regulator in development of T helper 17 (Th17) cells.

Conclusions: Our work suggests the ability of IL-17A to directly promote clonogenic potential of HSPCs and drive a myeloid-biased lineage commitment in progenitor subsets. Additional studies are required to characterize the response of HSPCs to direct IL-17A signaling in vivo. Considering the important role of IL-17A as a mediator of immune response, and tissue repair, further studies are warranted to elucidate whether modulation of this pathway may be therapeutic in the context of hematopoietic failure or malignancy.
Risk and Outcomes of Hospitalizations in Patients with Anti-Phospholipid Syndrome Admitted with Autoimmune Hemolytic Anemia: A Nation-Wide Analysis
Authors: Mahmoud Amir , Orakzai Abdullah , Jain Tripti , Kharel Himal , Srivastava Arnav , Neupane Niraj , Yassin Heba , Eltaher Basant , Abdelhay Ali
Published: December 2023

Introduction: Autoimmune hemolytic anemia (AIHA) can occur as a primary disorder or as a secondary manifestation of an underlying autoimmune condition. The coexistence of anti-phospholipid syndrome (APS) and AIHA can be very complex and challenging to manage given the intertwining of the prothrombotic and hemolytic states. In this study, we explored the outcomes of underlying antiphospholipid syndrome in autoimmune hemolytic anemia hospitalizations.

Method: The National Inpatient Sample (NIS) database was queried using the International Classification of Diseases (ICD) codes to identify hospitalizations for AIHA and then the data was subclassified into hospitalizations with and without APS. Demographics, comorbidities, and outcomes were identified using appropriate ICD 9/10 codes. Propensity score matched cohorts were generated for APS status and adjusted for age, race, sex, smoking, obesity, DM, CHF, CKD/ESRD, and liver disease.

Results: A total of 7,609 AIHA hospitalizations were included, with 76 patients having underlying APS and 7,533 did not have APS. Mean age was younger in the APS cohort and there were also more females, blacks and Hispanics compared to the non-APS cohort. Propensity score matching was used to generate two cohorts, adjusting for age, race, sex, and for co-morbidities including obesity, smoking, DM, CHF, CKD/ESRD and liver disease. The adjusted analysis showed an 8.59 times higher risk of developing venous thromboembolic events (VTE) in AIHA with APS as compared to those hospitalizations without APS (Odds ratio (OR): 8.59, CI: 1.05-70.5; p=0.03). There was also a statistically significant increase in mean hospitalization cost in the APS group (p=0.001). A trend towards more arterial athero-embolic events (AAE), major bleeding events, and AKI as well as longer length of stay was seen in hospitalizations with APS, but it did not reach statistical significance. No significant difference in in-hospital mortality was seen between the two groups. The results are summarized in the Figure 1.

Conclusion: APS confers additional risk to AIHA hospitalizations with significantly higher VTE events and added costs. Further studies should address the complex management of anticoagulation and prothrombotic risk in APS in the setting of active hemolytic anemia.
A Co-Reactivation Model of Cytomegalovirus and Epstein-Barr Virus after Allogeneic Hematopoietic Stem Cell Transplantation Was Constructed to Predict Mortality after Transplantation
Authors: Ren Jinhua , Chen Shaozhen , Hu Jianda , Yang Ting
Published: December 2023

Abstract

Objective: The aim of this study was to create a predictive model for the occurrence of co-reactivation of cytomegalovirus (CMV) and Epstein-Barr virus (EBV) following allogeneic hematopoietic stem cell transplantation (allo-HSCT).

Methods: The study included 373 patients who underwent allo-HSCT. The patient population was randomly divided into two groups: a training cohort comprising 70% of patients (n=261) and a validation cohort comprising 30% of patients (n=112). The predictive model was developed using several variables, including the time of reactivation of CMV and EBV, patient age and gender, presence of hepatitis B core antibody (HbcAb), type of transplant, use of anti-thymocyte globulin (ATG), and the occurrence of acute and chronic graft-versus-host disease (aGVHD and cGVHD, respectively).

Results: The developed predictive model was expressed as y = -6.21338339 + 0.01923832 × (CMV reactivation time) + 0.00362628 × (EBV reactivation time) - 0.57604523 × (patient gender) + 0.01974136 × (patient age) + 0.85514424 × (presence of HbcAb) + 1.13782872 × (transplant type) + 0.95376138 × (use of ATG) - 0.62393602 × (aGVHD) - 1.09485262 × (cGVHD). The model demonstrated a g-mean value of 0.685 and a probability threshold of 0.297, allowing for the classification of patients into high-risk and low-risk groups.

The incidence of co-reactivation of CMV and EBV over 100 days was significantly higher in the high-risk group compared to the low-risk group. In the high-risk group, the incidence was 49.3%, while in the low-risk group, it was 16.9% (P<0.0001, HR 95%CI 3.693(2.493,5.47)). For patients with aGVHD, the incidence was 41.7% in the high-risk group and 17.9% in the low-risk group (P=0.00026, HR 95%CI 2.7473(1.560,4.839)). In patients without aGVHD, the incidence was 53% in the high-risk group and 14.0% in the low-risk group (P<0.0001, HR 95%CI 4.9439(2.347,10.4)). Additionally, the model was able to predict post-transplant mortality and survival.

Conclusion: Overall, the findings of this study suggest that the developed model is a valuable tool for predicting the risk of CMV and EBV co-reactivation following allo-HSCT. By identifying high-risk patients, clinicians can take proactive measures to prevent or manage viral infections, ultimately improving patient outcomes. Therefore, this model can potentially enhance clinical decision-making and optimize post-transplant care.
Impact of Race on Progression-Free Survival and Overall Survival in Patients with Multiple Myeloma
Authors: Wani Kashmira , Gutta Radhika , Mittal Aayush , Jamil Maria , Springer Kylie , Kuriakose Philip
Published: December 2023

Background: Multiple myeloma (MM) is a disorder of plasma cells. Management typically includes induction therapy, autologous stem-cell transplantation (ASCT) and maintenance therapy. Despite significant progress in treatment modalities and improved survival and response rates in patients diagnosed with MM, it remains an incurable disease with a poor outcome, especially in high-risk groups. Black patients have been shown to have a higher incidence of MM than white patients. Multiple studies have been done to examine racial disparities among white and black patients, specifically in overall survival (OS) and progression free survival (PFS). However, data has been overall inconclusive with some studies suggesting there is a difference in survival based on race, while other studies suggesting the opposite. Thus, racial disparities among white and black patients' needs to be further investigated. In our retrospective chart review we reviewed all adult patients with advanced MM within Henry Ford Cancer Institute in the last 10 years to determine the impact of maintenance therapy on PFS and overall survival OS.

Methods: We conducted a retrospective chart review of adult patients with MM who underwent autologous stem cell transplantation (ASCT) between January 1, 2012 to December 31, 2022. Those who received maintenance chemotherapy after transplant were included in the study. Patients who were lost to follow-up or who had largely incomplete records were excluded. Data points including age, gender, race, date of transplant, maintenance chemotherapy regimen, last follow-up, and date of death (if applicable) were recorded. Kaplan-Meier plots were used to illustrate overall survival and time to relapse between various races. Statistical significance was set at p<0.05.

Results: There were 158 patients included in the study. Of the 158 patients, 82 (51.9%) were male, and 76 (48.1%) were female. The average age of patients included was 61.66 + 9.30 years, spanning from 32 to 78 years old. There were 71 (44.9%) White patients, 76 (48.1%) Black patients, and 11 (7.0%) patients that were of another race. There was no statistical significance in PFS and OS between Black, White and Other race categories.

Conclusions: We did not see a difference in outcome based on race and believe all patients would derive equal benefit from maintenance therapy. Further prospective studies are warranted to examine racial disparities in patients with multiple myeloma.
Association between Heavy Metal Exposure and Idiopathic Aplastic Anemia in Adolescents and Adults:a Case Control Study from Northern India
Authors: Jain Arihant , Wadhera Sarthak , Malhotra Pankaj , Singh Charanpreet , Lad Deepesh Pravinkumar , Khadwal Alka Rani , Prakash Gaurav , Varma Neelam , Reddy Prabhakar
Published: December 2023

Introduction:Compared to western world the incidence of AA in South Asian countries is higher. There are studies to suggest that incidence of this disease is 2-3 times higher in LMICs. Besides immune mediated pathophysiology and inherited presdispostion, toxic insult to the hematopoietic elements due to chemotherapy, radiation exposure, drugs,and environmental toxins such as pesticides and heavy metals have been associated with Aplastic Anemia.The higher incidence of AA in lower socio-economic status and its association with drinking water habits, industrial exposure suggests a possible link with heavy metals in the pathogenesis of disease.

Methodology:Fifty patients diagnosed with idiopathic aplastic anaemia and 50 age and gender matched healthy controls were included in the study. 2 ml of blood and 20 hair shafts were collected as samples from each subject for the analysis of arsenic, lead, cadmium, mercury, and thallium in both samples by Inductively Coupled Plasma Mass Spectrometry (ICP-MS).

Results:The total study population consisted of 61 males and 39 females. 42% of the cases were residents of rural areas, and 58% belonged to urban areas. 54% participants among the controls belonged to rural areas. Among the total population, 48% cases and 58% controls were using tap water as major source of water. Out of the total participant in the study, 10% of the cases and 12% of the controls were found to be exposed to pesticides previously, however no direct occupational exposure of heavy metal was found among the study population. Twenty-three patients (46%) had NSAA, and 15 patients had SAA (30%) while 12 patients (24%) had VSAA.Mean values of arsenic in blood of patients and controls are 3.52±2.9mcg/L,and 0.0mcg/L respectively and the difference was statistically significant (p <0.001) however the mean arsenic values in hair of cases and controls were not different significantly(0.13±0.1mg/g and 0.15±0.1mg/g;p=0.16).Mean values of cadmium in blood of patients and controls were 2.5±1.9mcg/L and 0 mcg/L (p <0.001). Mean values of cadmium in hair of patients and controls are 0.10±0.16, 0.13±0.28 respectively.We noticed blood cadmium higher than safer limits in 24% of cases none in the controls.We found 6% of cases had higher than permissible limit of mercury level and 8% of cases have higher than permissible limit of lead level in their hair samples which represent chronic exposure.

Conclusion:

We found higher mean values of blood Arsenic and blood Cadmium in cases compared to controls. Upto one fourth cases had higher than safety levels of cadmium in their blood. Although causal association cannot be determined in this study our results indicate that heavy metal toxicity may be one of the reasons for AA in regions with higher environmental exposure and soil and water contamination.
Tmprss6 siRNA Treatment in Mice Stops Hepcidin Reduction across Pregnancy
Authors: Fielding Katherine , Ataide Ricardo , Bennett Cavan , Pettikiriarachchi Anne , Clucas Danielle , Schaeper Ute , Pasricha Sant-Rayn
Published: December 2023

Aim: Hepcidin levels are suppressed during human and murine pregnancy. It is unknown whether hepcidin levels are primarily the result of iron deficiency/utilisation or whether there is a pregnancy-specific mechanism for hepcidin suppression. We reasoned that Tmprss6 inhibition would cause constitutive BMP-SMAD signalling and help determine the mechanism of antenatal hepcidin suppression.

Method: Female wildtype C57BL/6 mice were treated subcutaneously every 21 days with a GalNAc-siRNA conjugate targeting Tmprss6 (Silence Therapeutics GmbH, Berlin, Germany) or a non-targeting control (NTC) siRNA conjugate. Mice were mated and monitored for pregnancy. Samples were collected from pregnant mice humanely euthanised at E8.5 or E14.5, and unmated controls.

Results: Treatment with Tmprss6 siRNA inhibited hepatic Tmprss6 mRNA expression (unmated fold change 0.077, p<0.0001).

qPCR Hamp expression was significantly increased in Tmprss6 siRNA-treated mice, compared to NTC-treated mice, at all timepoints. Serum hepcidin, by ELISA, was higher in Tmprss6 siRNA-treated mice than in NTC-treated mice at E14.5 (1126ng/ml vs 178.5, p<0.0001). In unmated mice, serum hepcidin was not significantly elevated (640.9 vs 980.1ng/ml, p=0.224).

Across NTC treated pregnancy, Hamp expression and serum hepcidin were reduced at E14.5 compared to unmated ( Hamp fold change E14.5 0.293, p=0.0367; serum hepcidin E14.5 178.5 vs 640.9, p=0.0247). In contrast, Tmprss6 siRNA treatment caused elevated hepcidin through pregnancy (E14.5 1126 vs unmated 980ng/ml, p=0.99); Fig 1a.

Maternal liver iron was unchanged between groups. Tmprss6 siRNA reduced placental iron, fetal liver iron, and fetal weight (0.189 vs 0.226g, p<0.0001), Fig 1b. At E8.5/E14.5, Tmprss6 siRNA reduced Mean Cell Volume (E14.5: 41.42 vs 51.72fL, p<0.0001) and Mean Cell Haemoglobin (E14.5: 11.20 vs 15.68pg, p<0.0001); at E14.5 only, maternal anaemia was seen with Tmprss6 siRNA (haemoglobin 9.4 vs 13.85g/L, p=0.0004).

Conclusion: Disruption of Tmprss6 increased hepcidin and ablated the hepcidin fall over pregnancy. This may suggest that any pregnancy-related factor which directly suppresses hepcidin cannot overcome Tmprss6 knockdown. Tmprss6 siRNA treatment resulted in iron-restricted erythropoiesis, reduced placental iron and impacted fetal development, despite unchanged liver iron stores.
Socioeconomic determinants of the biology and outcomes of acute lymphoblastic leukemia in adults
Authors: Johnston Hannah , Youshanlouei Hamed Rahmani , Osei Clinton , Patel Anand A. , DuVall Adam , Wang Peng , Wanjari Pankhuri , Segal Jeremy , Venkataraman Girish , Cheng Jason X. , Gurbuxani Sandeep , Lager Angela , Fitzpatrick Carrie , Thirman Michael , Nawas Mariam , Liu Hongtao , Drazer Michael , Odenike Olatoyosi , Larson Richard , Stock Wendy , Saygin Caner
Published: December 2023

Various socioeconomic and biologic factors affect cancer health disparities and differences in health outcomes. To better characterize the socioeconomic vs biologic determinants of acute lymphoblastic leukemia (ALL) outcomes, we conducted a single-institution, retrospective analysis of adult patients with ALL treated at the University of Chicago (UChicago) from 2010 to 2022 and compared our outcomes with the US national data (the Surveillance, Epidemiology, and End Results [SEER] database). Among 221 adult patients with ALL treated at UChicago, BCR::ABL1 was more frequent in patients with higher body mass index (BMI; odds ratio [OR], 7.64; 95% confidence interval [CI], 1.17-49.9) and non-Hispanic Black (NHB) ancestry (59% vs 24% in non-Hispanic White (NHW) and 20% in Hispanic patients; P = .001). In a multivariable analysis, age (hazard ratio [HR], 6.93; 95% CI, 2.27-21.1) and higher BMI at diagnosis (HR, 10.3; 95% CI, 2.56-41.5) were independent predictors of poor overall survival (OS). In contrast, race or income were not predictors of OS in the UChicago cohort. Analysis of the national SEER database (2010-2020) demonstrated worse survival outcomes in Hispanic and NHB patients than in NHW patients among adolescent and young adults (AYAs) but not in older adults (aged >40 years). Both AYA and older adult patients with higher median household income had better OS than those with lower income. Therefore, multidisciplinary medical care coupled with essential supportive care services offered at centers experienced in ALL care may alleviate the socioeconomic disparities in ALL outcomes in the United States.
Salmonella enterica in farm environments in the Ashanti Region of Ghana
Authors: Ofori Linda Aurelia , Fosu Dennis , Ofori Seth , Akenten Charity Wiafe , Flieger Antje , Simon Sandra , Jaeger Anna , Lamshöft Maike , May Juergen , Obiri-Danso Kwasi , Phillips Richard , Chercos Daniel Haile , Paintsil Ellis Kobina , Dekker Denise
Published: November 2023

Background

Salmonella enterica are important foodborne pathogens and the third leading cause of death among diarrheal infections worldwide. This cross-sectional study investigated the frequency of antibiotic-resistant Salmonella enterica in commercial and smallholder farm environments in the Ashanti Region of Ghana. A total of 1490 environmental samples, comprising 800 (53.7%) soil (from poultry, pigs, sheep, goats and cattle farms), 409 (27.4%) pooled poultry fecal and 281 (18.9%) dust (from poultry farms) samples, were collected from 30 commercial and 64 smallholder farms. All samples were processed using standard culture methods. Isolates were identified by biochemical methods and confirmed using the VITEK 2 System. Antibiotic susceptibility testing was carried out by disk diffusion following the EUCAST guidelines. Serotyping was performed using the Kauffman White Le Minor Scheme.

Results

The overall Salmonella frequency was 6.0% (n/N = 90/1490); the frequency varied according to the type of sample collected and included: 8.9% for dust (n/N = 25/281), 6.5% for soil (n/N = 52/800) and 3.2% for pooled poultry fecal samples (n/N = 13/409). Salmonella was also recovered from commercial farm environments (8.6%, n/N = 68/793) than from smallholder farms (3.2%, n/N = 22/697) (PR = 2.7, CI: 1.7 – 4.4). Thirty-four different Salmonella serovars were identified, the two most common being Rubislaw (27.8%, n/N = 25/90) and Tamale (12.2%, n/N = 11/90). Serovar diversity was highest in strains from soil samples (70.6%, n/N = 24/34) compared to those found in the dust (35.2%, n/N = 12/34) and in fecal samples (29.4%, n/N = 10/34). Salmonella frequency was much higher in the rainy season (8.4%, n/N = 85/1007) than in the dry season (1.0%, n/N = 5/483) (PR = 8.4, 95% CI: 3.3 – 20.0). Approximately 14.4% (n/N = 13/90) of the isolates were resistant to at least one of the tested antimicrobials, with 84.6% (n/N = 11/13) being resistant to multiple antibiotics. All Salmonella Kentucky (n = 5) were resistant to ciprofloxacin.

Conclusion

This study showed that farm environments represent an important reservoir for antibiotic-resistant Salmonella, which warrants monitoring and good husbandry practices, especially in commercial farms during the rainy season, to control the spread of this pathogen.
The effect of regional transmural agreements on the information transfer of frail older patients
Authors: Fritsche G. , Schoonenboom N. , Van der Kroon H. , Douma CE. , Van der Dussen J. , Verlaan MNE. , Cloosterman B. , Heems M. , Nepal A. , Toor E. J. , de Rooij A. , van Stralen KJ. , Lucke JA.
Published: November 2023

Introduction

Frail older patients are at risk for many complications when admitted to the hospital. Multidisciplinary regional transmural agreements (RTA) in which guidelines were set concerning the information transfer of frail older patients might improve outcomes. We aim to investigate the effect of implementation of the RTA on the completeness of the information transfer of frail older patients when admitted to and discharged from the hospital.

Methods

This is a retrospective cohort study in which we collected data from 400 randomly selected hospitalized frail older patients (70+) before the implementation of the RTA, January through March 2021, and after, October through December 2021. The cohort was split up into four groups, which determined what correspondence would be checked (referral letter by General Practitioner (GP) and three groups of ‘hospital letters’: ED letter upon admittance, clinical discharge letter to the elderly care physician and clinical discharge letter to the GP. We assessed for mention of frailty, a medication list and mention of resuscitation orders.

Results

In the period before implementation the mean age of patients was 82.6 years (SD 7.4) and 101 were female (50.5%), after implementation mean age was 82.3 (SD 6.9) and 112 were female (56.0%). Frailty was mentioned in hospital letters in 12.7% before and 15.3% after implementation (p = 0.09). More GP referral letters were present after implementation (32.0% vs. 54.0%, p = 0.03), however frailty was mentioned only in 12.5% before and 7.4% after (p = 0.58). There was a good handover of medication lists from the hospital (89.3% before, 94% after, p = 0.20) and even better from the GP (93.8% before, 100% after, p = 0.19). Resuscitation orders were mentioned in 59.3% of letters from the hospital before implementation and 57.3% after (p = 0.77), which is higher than in the referral letters (18.8% before and 22.2% after (p = 0.91).

Discussion

The implementation of RTA improved the number of GP referral letters present; however, it did not lead to other significant improvements in communication between the hospital and the GP’s. Frailty and resuscitation orders are still frequently not mentioned in the reports. After a successful reimplementation, the improvements of outcomes could be investigated.
Association between disability in activities of daily living and phase angle in hemodialysis patients
Authors: Li Junhui , Wang Zhi , Zhang Qiannan , Zhang Huiping , Shen Yuxin , Zhang Qi , Jian Guihua , Cheng Dongsheng , Wang Niansong
Published: November 2023

Background

Disability in activities of daily living (ADL) significantly increases the risk of mortality among patients undergoing hemodialysis. Malnutrition and decreased exercise capacity are closely correlated with ADL disability. Phase angle (PhA) has been proposed as a measure of nutritional status and exercise capacity. This study aims to investigate the prevalence of ADL disability in hemodialysis patients and its association with PhA.

Methods

A prospective, observational study was conducted, involving hemodialysis patients treated between November 2019 and January 2020 in an affiliated hospital of Chinese university. ADL was measured using both basic ADL (BADL) scales and instrumental ADL (IADL) scales. PhA measurements were obtained using a BIA device while the patients were in the supine position after dialysis.

Results

A total of 237 hemodialysis patients with a mean age of 60.01 ± 13.55 years were included in this study. The prevalence of disability in ADL was 43.5%. Multivariable analysis results showed a robust association between low PhA and disability in both BADL and IADL (for each unit decrease in PhA: odds ratio 4.83 [95% CI: 2.56–9.0], and 3.57 [95% CI: 2.14–5.95], respectively). The optimal cut-off values of PhA for disability in BADL and IADL were 4.8 and 5.4, with the area under the ROC curve (AUC) were 0.783 (0.727, 0.835) and 0.799 (0.743, 0.848), respectively.

Conclusions

Low PhA is strongly associated with disability in ADL in hemodialysis patients. These findings suggest that PhA may serve as a potentially objective measure of ADL disability in hemodialysis patients.
Genetic detection of two novel LRP5 pathogenic variants in patients with familial exudative vitreoretinopathy
Authors: Li Jiayu , Wang Chanjuan , Zhang Shaochi , Cai Bo , Pan Bo , Sun Caihong , Qi Xiaolong , Ma Chunmei , Fang Wei , Jin Kangxin , Bi Xiaojun , Jin Zibing , Zhuang Wenjuan
Published: November 2023

Background

Familial exudative vitreoretinopathy (FEVR) is a genetic eye disorder that leads to abnormal development of retinal blood vessels, resulting in vision impairment. This study aims to identify pathogenic variants by targeted exome sequencing in 9 independent pedigrees with FEVR and characterize the novel pathogenic variants by molecular dynamics simulation.

Methods

Clinical data were collected from 9 families with FEVR. The causative genes were screened by targeted next-generation sequencing (TGS) and verified by Sanger sequencing. In silico analyses (SIFT, Polyphen2, Revel, MutationTaster, and GERP + +) were carried out to evaluate the pathogenicity of the variants. Molecular dynamics was simulated to predict protein conformation and flexibility transformation alterations on pathogenesis. Furthermore, molecular docking techniques were employed to explore the interactions and binding properties between LRP5 and DKK1 proteins relevant to the disease.

Results

A 44% overall detection rate was achieved with four variants including c.4289delC: p.Pro1431Argfs*8, c.2073G > T: p.Trp691Cys, c.1801G > A: p.Gly601Arg in LRP5 and c.633 T > A: p.Tyr211* in TSPAN12 in 4 unrelated probands. Based on in silico analysis and ACMG standard, two of them, c.4289delC: p.Pro1431Argfs*8 and c.2073G > T: p.Trp691Cys of LRP5 were identified as novel pathogenic variants. Based on computational predictions using molecular dynamics simulations and molecular docking, there are indications that these two variants might lead to alterations in the secondary structure and spatial conformation of the protein, potentially impacting its rigidity and flexibility. Furthermore, these pathogenic variants are speculated to potentially influence hydrogen bonding interactions and could result in an increased binding affinity with the DKK1 protein.

Conclusions

Two novel genetic variants of the LRP5 gene were identified, expanding the range of mutations associated with FEVR. Through molecular dynamics simulations and molecular docking, the potential impact of these variants on protein structure and their interactions with the DKK1 protein has been explored. These findings provide further support for the involvement of these variants in the pathogenesis of the disease.
Endoscopic spinal cord untethering using a 1 cm skin incision technique in pediatrics: a technical case report
Authors: Ishisaka Eitaro , Tahara Shigeyuki , Tsukiyama Atsushi , Nozaki Toshiki , Hattori Yujiro , Morita Akio , Murai Yasuo
Published: November 2023

Background

Spinal cord untethering by sectioning the filum terminale is commonly performed in tethered cord syndrome patients with minor abnormalities such as filar lipoma, thickened filum terminale, and low conus medullaris. Our endoscopic surgical technique, using the interlaminar approach, allows for sectioning the filum terminale through a very small skin incision. To our knowledge, this procedure has not been previously reported. This is the first case report involving a 1 cm skin incision.

Case presentation

A 9-month-old male patient was referred to our neurosurgical department due to a coccygeal dimple. MRI revealed a thickened fatty filum. After considering the treatment options for this patient, the parents agreed to spinal cord untethering. A midline 1 cm skin incision was made at the L4/5 vertebral level. Untethering by sectioning the filum terminale was performed by full endoscopic surgery using the interlaminar approach. The procedure was uneventful and there were no postoperative complications.

Conclusions

In terms of visibility and minimizing invasiveness, our surgical technique of using the interlaminar approach with endoscopy allows for untethering by sectioning the filum terminale through a very small skin incision.
Impairment of delayed recall as a predictor of amnestic mild cognitive impairment development in normal older adults: a 7-year of longitudinal cohort study in Shanghai
Authors: Bao Xiaoqian , Li Wei , Liu Yuanyuan , Li Xia , Yue Ling , Xiao Shifu
Published: November 2023

Background

Amnestic mild cognitive impairment (aMCI) is considered a prodromal phase of Alzheimer’s disease (AD). However, little is known about the neuropsychological characteristic at pre-MCI stage. This study aimed to investigate which neuropsychological tests could significantly predict aMCI from a seven-year longitudinal cohort study.

Methods

The present study included 123 individuals with baseline cognitive normal (NC) diagnosis and a 7-year follow-up visit. All the subjects were from the China Longitudinal Aging Study (CLAS) study. Participants were divided into two groups, non-converter and converter based on whether progression to aMCI at follow-up. All participants underwent standardized comprehensive neuropsychological tests, including the mini-mental state examination (MMSE), Montreal Cognitive Assessment (MoCA), auditory verbal learning test (AVLT), the digital span test, the verbal fluency test, the visual recognition test, the WAIS picture completion task, and WAIS block design. Logistic regression analysis was used to evaluate the predictive power of baseline cognitive performance for the transformation of amnestic mild cognitive impairment. Receiver operating characteristic (ROC) curve was used to test the most sensitive test for distinguishing different groups.

Results

Between the non-converter group and converter group, there were significant differences in the baseline scores of AVLT-delayed recall (AVLT-DR) (8.70 ± 3.61 vs. 6.81 ± 2.96, p = 0.001) and WAIS block design (29.86 ± 7.07 vs. 26.53 ± 8.29, p = 0.041). After controlling for gender, age, and education level, converter group showed lower baseline AVLT-DR than non-converter group, while no significant difference was found in WAIS block design. Furthermore, converter group had lower AVLT-DR score after controlling for somatic disease. The area under the curve of regression equation model was 0.738 (95%CI:0.635–0.840), with a sensitivity 83.9%, specificity of 63.6%.

Conclusions

Our results proved the value of delayed recall of AVLT in predicting conversion to aMCI. Early and careful checking of the cognitive function among older people should be emphasized.
Validation of Chinese version of the 5-item WHO well-being index in type 2 diabetes mellitus patients
Authors: Du Jianhua , Jiang Yinan , Lloyd Cathy , Sartorius Norman , Ren Jie , Zhao Weigang , Wei Jing , Hong Xia
Published: November 2023

Background

For better disease management and improved prognosis, early identification of co-morbid depression in diabetic patients is warranted. the WHO-5 well-being index (WHO-5) has been used to screen for depression in diabetic patients, and its Chinese version (WHO-5-C) has been validated. However, its psychometric properties remain to be further validated in the type 2 diabetes patient population. The aim of our study was to examine the reliability and validity of the WHO-5-C in patients with type 2 diabetes mellitus.

Methods

The cross-sectional study was conducted on 200 patients from July 2014 to March 2015. All patients should complete the WHO-5-C, the Patient Health Questionnaire-9 (PHQ-9), the 20-item Problem Areas in Diabetes Scale (PAID-20), the Mini International Neuropsychiatric Interview (M.I.N.I), and Hamilton Rating Scale for Depression (HAM-D). Internal consistency of WHO-5 was revealed by Cronbach’s alpha, and constructive validity by confirmatory factor analysis (CFA). Relationship with PHQ-9, HAM-D, and PAID-20 was examined for concurrent validity, and ROC analysis was performed for criterion validity.

Results

The WHO-5-C presented satisfactory reliability (Cronbach’s alpha = 0.88). CFA confirmed the unidimensional factor structure of WHO-5-C. The WHO-5-C had significant negative correlation with HAM-D (r = -0.610), PHQ-9 (r = -0.694) and PAID-20 (r = -0.466), confirming good concurrent validity. Using M.I.N.I as the gold standard, the cut-off value of WHO-5-C was 42, with a sensitivity of 0.83 and specificity of 0.75.

Conclusion

The WHO-5-C holds satisfactory reliability and validity that is suitable for depression screening in type 2 diabetes patients as a short and convenient instrument.