Hemato

Hemolytic anemias (HAs) encompasses a heterogeneous group of disorders with either congenital or acquired etiologies. We present a complex case of a 27-year-old woman with hemolytic anemia of multifactorial origin, involving both inherited RBC membrane defects and multiple autoimmune comorbidities. Genetic testing identified heterozygous variants in SPTA1 and SBDS, consistent with carrier status for hereditary elliptocytosis and Shwachman–Diamond syndrome. The patient was also diagnosed with Caspr2-positive Isaacs syndrome, systemic lupus erythematosus, seronegative antiphospholipid syndrome, and anti-aquaporin-4 antibody-positive optic neuritis. Despite extensive immunosuppressive and immunotherapic treatment and splenectomy, the clinical course was marked by recurrent hemolytic crises, thrombotic complications, and progressive neurological involvement, ultimately leading to death. Our experience highlights the challenges posed by the diagnosis and management of HAs, underlining the relevance of a multidisciplinary and personalized approach. Full article

Background: Myeloid-derived suppressor cells (MDSCs) contribute to immune suppression observed in chronic lymphocytic leukemia (CLL). MDSCs are immature myeloid cells that are hijacked during development and further reprogrammed by the tumor microenvironment (TME) to harbor immune-suppressive properties and inhibit T-cell functions. Bromodomain and extraterminal domain (BET) proteins, including BRD4, are epigenetic modulators that regulate genes implicated in CLL pathogenesis and TME interactions. Previously, we investigated how the novel BET inhibitor OPN-51107 (OPN5) prevents CLL disease expansion, modulates T-cell immune function, and alters gene expression related to MDSCs. In turn, we hypothesize that BET proteins such as BRD4 regulate MDSC functions, and subsequent pharmacological inhibition of BRD4 will alleviate MDSC-mediated immune suppression in CLL. Methods: Utilizing the Eµ-TCL1 mouse model of CLL, we evaluated BRD4 protein expression in MDSCs derived from the bone marrow of transgenic and age-matched wild-type (WT) mice. We then investigated the ex vivo functionality of OPN5-treated MDSCs, expanded from Eµ-TCL1 and WT bone marrow in MDSC-supportive medium. Finally, we conducted an in vivo study utilizing the Eµ-TCL1 adoptive transfer mouse model to determine the in vivo effects of OPN5 on MDSCs and other immune populations. Results: Through the course of this study, we found that MDSCs isolated from Eμ-TCL1 mice upregulate BRD4 expression and are more immune-suppressive than their WT counterparts. Furthermore, we demonstrated ex vivo OPN5 treatment reverses the immune-suppressive capacity of MDSCs isolated from leukemic mice, evident via enhanced T-cell proliferation and IFNγ production. Finally, we showed in vivo OPN5 treatment slows CLL disease progression and modulates immune cell populations, including MDSCs. Conclusions: Altogether, these data support BET inhibition as a useful therapeutic approach to reverse MDSC-mediated immune suppression in CLL. Full article

Numerous studies point to the significance of cathepsin B (CTSB) in the development of carcinoma. Therefore, the aim of this pilot study was to investigate the levels of cathepsin B (CTSB) and the expression of CTSB mRNA in the plasma of non-Hodgkin lymphoma (NHL) patients. Methods: The study included 44 newly diagnosed NHL patients and 35 healthy volunteers comprising the control group. CTSB in the plasma samples were detected using the enzyme-linked immunosorbent assay (ELISA). Results: The level of CTSB was significantly higher in NHL patients compared to control subjects: 15.28 (11.68–17.23) versus 11.57 (10.12–13.41), p = 0.003. In addition, a positive correlation between plasma CTSB mRNA and CTSB after therapy was observed (rho = 0.591, p = 0.026). Regarding redox parameters, we found a negative correlation between CTSB and the total antioxidant status (TAS) (rho = −0.499, p = 0.035), as well as a positive correlation with the total oxidant status (TOS) (rho = 0.576, p = 0.012). Conclusions: Targeting CTSB might have significant clinical relevance in the diagnostics of NHL. Full article

Background/Objectives: Classic Hodgkin lymphoma (cHL) is a predominantly curable B-cell malignancy. However, primary refractory and relapsed (R/R) cHL remain therapeutic challenges, especially in regions with high tuberculosis (TB) prevalence, where clinical and radiologic features overlap and can obscure the correct diagnosis. This article, presenting a case of R/R cHL mimicking disseminated TB, reviews the evolving paradigm in R/R cHL management. Methods: A 30-year-old Middle Eastern male with advanced nodular sclerosis cHL initially achieved a complete remission (CR) with escalated BEACOPP chemotherapy. Shortly afterward, he developed respiratory symptoms and diffuse miliary pulmonary nodules, highly suggestive of disseminated TB. Despite extensive negative TB workup, including QuantiFERON-TB Gold testing, sputum acid-fast bacilli (AFB) staining, and PCR, his imaging raised concern for recurrent cHL. Due to the small size and diffuse distribution of nodules, biopsy was unfeasible, prompting empiric salvage therapy with DEHAP-Carbo, brentuximab vedotin (BV), and nivolumab. Results: The rapid and robust metabolic response on PET/CT supported lymphoma relapse rather than TB. Following four cycles of this combined regimen, he proceeded to autologous stem cell transplantation and achieved a second CR. Conclusions: This case highlights the diagnostic difficulties in differentiating cHL relapse from TB in endemic regions, emphasizes the critical role of PET/CT in guiding therapy when histopathological confirmation is impractical, and illustrates the impact of novel immunotherapies in improving outcomes. By underscoring the importance of early diagnostic suspicion and multimodal assessment, this article also reviews the evolving paradigm in R/R cHL management, where personalized approaches and targeted agents increasingly complement or replace traditional chemotherapy regimens. Full article

Background: Hemophilia A is an X-linked recessive bleeding disorder associated with high risk for intracranial hemorrhage, requiring complicated neurosurgical interventions. Perioperative management is based on quick factor replacement therapy, control of hemostasis, and deciding whether surgery will be beneficial. Methods: We report the case of a 49-year-old male with severe hemophilia A who had purulent secernation via a skin fistula as a late complication of decompressive craniectomy for epidural hematoma at younger age. Results: Revision surgery was successfully managed with perioperative administration of clotting factor VIII, and the patient showed indications of titanium cranioplasty. Conclusions: A direct preoperative preparation prior to surgery in a postoperative period with controlled hemostasis has been shown to reduce hemorrhagic complications in hemophilic patients, increasing the quality of life and significant neurological complications. Full article

Clonal hematopoiesis (CH) is an age-related process in which hematopoietic stem/progenitor cells increase their fitness due to the acquisition of mutations that lead to a proliferative advantage and to clonal expansion. Its frequency increases with age, and it mostly affects people older than 70 years. The most mutated genes in CH are epigenetic regulators, DNA damage response genes, and splicing factors, which are all involved in the development of myeloid neoplasia. Some risk factors, including age, smoking, and prior cytotoxic therapy, increase the risk of developing CH or increase the fitness of CH. Various types of CH have been observed, associated or not with cytopenias or monocytosis. CH represents a risk factor for many pathological conditions and particularly for hematologic malignancies. A better understanding of the risks related to CH has triggered the development of research, translational, and clinical programs for the monitoring, prevention, and treatment of CH. Full article

Background: This work presents a mechanistic nonlinear model, formulated as a system of first-order Ordinary Differential Equations, to investigate the dynamics of Chronic Lymphocytic Leukemia (CLL) under combined chemoimmunotherapy using CAR-T cells and chlorambucil. Methods: Leveraging nonlinear dynamical systems theory and a model-based design approach, we derive optimal dosing strategies through extensive in silico simulations, providing hemato-oncologists with actionable tools to refine CLL treatment. The model captures the short- and long-term impacts of both therapies on leukemia cell populations, enabling precise predictions of therapeutic outcomes. Results: By analyzing local and global system dynamics, we establish sufficient conditions for dosing and protocol design, offering a framework to optimize therapies based on individual patient responses. Comparisons of dose-escalation and -de-escalation strategies further demonstrate potential trajectories, such as complete eradication, partial response, or relapse, providing data-driven guidance for improving patient care. Conclusions: This study highlights the power of mathematical modeling in blood cancer research, enhancing the development of personalized and effective CLL treatment regimens. Full article

Background/Objectives: Down syndrome (DS), affecting 1 in 1000 births, has been linked to an increased risk of acute leukemia (AL). Patients with DS–acute lymphoblastic leukemia (DS-ALL) have historically had inferior outcomes when they have received risk-adapted therapy. Transient abnormal myelopoiesis (TAM) constitutes a transient leukemia with spontaneous remission in the neonatal period or represents a preleukemic state, preceding DS–acute myeloid leukemia (DS-AML). DS-AML has a better prognosis than that of AML without DS (NDS-AML) due to genetic and biological underlying features, a better response to chemotherapeutic agents, and a lower frequency of relapses. Methods: This retrospective cohort study presents the DS-AL outcomes from a nationwide survey in pediatric oncology centers. A total of 20 patients were studied, 10 with DS-ALL, 4 with DS-AML, 5 with TAM, and 1 with DS-AML after TAM, at median follow-ups of 9.25 (0.6–17.42) years and 7.25 (0.25–18.25) years for DS-ALL and DS-AML, respectively. Results: The median age at diagnosis was 4.7 (1.16–13.83) and 1.92 (1.25–3) years for ALL and AML, respectively. All DS-ALL patients had B-cell precursor ALL and achieved complete remission (CR). One patient relapsed and succumbed due to a severe infection. Three DS-AML patients had AMKL. All DS-AML patients achieved CR. One patient with TAM demanded treatment, all achieved CR, and one progressed to DS-AML. The overall survival (OS) was 70% and 80% for DS-ALL and DS-AML. Conclusions: The improved survival rates of our patients have been due to new protocols with less toxic therapies and better supportive care. Full article

Thalassemia, once associated with limited survival, now sees extended life expectancy due to treatment advancements, but new complications such as pseudoxanthoma elasticum (PXE)-like syndrome are emerging. In fact, thalassemia patients develop PXE-like features more frequently than the general population. These features include skin lesions, ocular changes, and vascular issues like arterial calcifications, all linked to oxidative damage from iron overload. PXE-like syndrome in thalassemia mimics inherited PXE but is acquired. The underlying cause is thought to be oxidative stress due to iron overload, which induces free radicals and damages elastic tissues. Unlike inherited PXE, this form does not involve mutations in the ABCC6 gene, suggesting different pathogenic mechanisms, including abnormal fibroblast metabolism and oxidative processes. The vascular calcification seen in this syndrome often follows elastic fiber degeneration, with proteoglycans and glycoproteins acting as nucleation sites for mineralization. The condition can lead to severe cardiovascular and gastrointestinal complications. Studies have shown a significant incidence of PXE-like skin lesions in thalassemia patients, with some dying from cardiovascular complications. Research on ABCC6, a transporter protein involved in ectopic mineralization, has highlighted its role in various conditions, including PXE, beta-thalassemia, and generalized arterial calcification of infancy. ABCC6 mutations or reduced expression led to ectopic mineralization, affecting cardiovascular, ocular, and dermal tissues. The exact molecular mechanisms linking ABCC6 deficiency to ectopic mineralization remain unclear, though it is known to influence calcification-modulating proteins. This review focuses on the role of ABCC6 in the pathogenesis of calcifications, especially intracranial vascular calcifications in PXE and beta-thalassemia. Full article

Background: Chronic myeloid leukemia (CML) relates to the abnormal presence of the Philadelphia chromosome, which originates the production of the BCR-ABL1 fusion protein and therefore leads to neoplastic transformation and unregulated cell growth. The advent of tyrosine kinase inhibitors (TKIs) has resulted in tremendous improvements in CML scenarios; however, there are practical difficulties, especially considering the late stages of the disease. This review examines recently developed strategies that are intended to increase the efficiency of treatment by overcoming TKI resistance. Methods: We performed a literature review of such databases as PubMed, Scopus, Web of Science, and Embase for the last ten years. The following keywords were used in the studies: ‘CML’, ‘TKI resistance’, ‘novel therapies’, ‘immunotherapy’, ‘targeted agents’, and ‘combination therapies’. Only those studies were included that were clinical trials and preclinical across-the-board developmental programs that attempt to target the tumor at multiple levels and not just focus on basic first-line TKIs. Results: In CML patients who do not respond to TKIs, novel therapeutics encompass ponatinib, asciminib, CAR-T immunotherapy, and BCL-2 and mTOR inhibition in conjunction with TKI therapy. This addresses both BCR-ABL1-dependent and independent resistance mechanisms, increasing the chance of achieving deeper molecular response and reduced toxicity. Nonetheless, they exhibit diverse characteristics regarding efficacy, safety, cost, and quality of life effects. Discussion: Nonetheless, numerous challenges remain regarding the understanding of the mechanisms of resistance, the long-term efficacy of novel medicines, and the ideal combinations to attain optimal outcomes. Areas of future research include the search for other patterns of molecular resistance, tailoring specific treatments to patients, and incorporating AI to improve diagnosis and monitoring. Conclusion: The introduction of novel therapeutic techniques into clinical practice needs a collaborative approach and persistent dynamism to new findings from research. Our analysis indicates that the challenges posed by resistant CML disease are complex and require further improvements in therapeutic and clinical protocol development. Full article

Background/Aim: Omega-3 fatty acids, a key component of immunonutrition, have been used to modulate immune responses and improve clinical outcomes in various settings, including hematological patients undergoing hematopoietic stem cell transplantation (HSCT). This study aimed to summarize the effects of omega-3 supplementation on inflammation, long-term survival, and post-transplant complications, such as graft-versus-host disease (GVHD) and mucositis. Additionally, its impact on nutritional status and immune function was considered. Methods: A narrative review was conducted. The PubMed, Embase, and CINAHL databases were searched, along with sources of gray literature. From 2607 records, five studies met the inclusion criteria and were analyzed Results: The available literature suggests that omega-3 supplementation provides significant benefits, including reduced inflammation, lower C-reactive protein levels, and improved long-term survival. Furthermore, a reduction in GVHD and mucositis incidence was observed. The safety profile of omega-3 was favorable, with no serious adverse events reported. However, the evidence remains limited and heterogeneous, emphasizing the need for further well-designed trials to validate and expand upon these findings. Conclusions: Omega-3 fatty acids appear to be a promising intervention for improving clinical outcomes in HSCT patients. Additional research is essential to optimize treatment protocols and confirm its immunomodulatory role. Full article

Obesity is among the most prevalent risk factors in the severe forms of Coronavirus disease 2019 (COVID-19) infection. COVID-19 patients with obesity often face severe complications that might be associated with overexpression of adiponectin, inflammatory cytokines, and angiotensin-converting enzyme 2 (ACE2) receptors in visceral fat. The pre-existing subclinical inflammation associated with obesity can also lead to severe inflammatory responses. Elevation of proinflammatory cytokines considerably activates coagulation cascades, including the tissue factor (TF) pathway. The hypercoagulable state in COVID-19 is presented with severe pulmonary complications such as venous thromboembolism (VTE), disseminated intravascular coagulation (DIC), and disruption of vascular endothelial cells, which can lead to severe complications and death. The interaction between inflammatory response and coagulation mechanism in COVID-19 patients with obesity warrants a further understanding of prognosis and potential therapeutic approaches. This review discusses the crosstalk between inflammation and coagulopathy in obesity-related severe COVID-19 infection. Full article

Background: Diffuse large B-cell lymphoma (DLBCL) is the most common diagnosed aggressive B-cell lymphoma, with poor outcomes in those who experience relapsed or refractory (R/R) disease. Landmark clinical trials have demonstrated the efficacy and safety of anti-CD19 chimeric antigen receptor (CAR) T-cell therapy for patients with R/R DLBCL, though further exploration of real-world outcomes (RWOs) and safety data is warranted. Methods: A retrospective chart review was performed to collect patient and disease characteristics from patients with R/R DLBCL receiving CAR T-cell therapy for third-line treatment or beyond at the John Theurer Cancer Center as the standard of care. Results: We report on 82 patients with R/R DLBCL that successfully completed an infusion of an anti-CD19 CAR T-cell product at our institution. Best overall and complete response rates were 74.4% (95% CI, 64.9 to 83.8) and 67.1% (95% CI, 56.9 to 77.2), respectively. From the time of CAR T-cell infusion, median PFS was 26.5 months (95% CI, 8.6 months could not be estimated) and OS was not reached. Subgroup analyses revealed no statistical differences in outcomes by use of bridging therapy, Karnofsky performance status, transformed DLBCL status, and the type of CAR T-cell product used for this study. CAR T-cell therapy was well tolerated, with 58 patients (70.7%) experiencing cytokine-release syndrome and 17 patients (20.7%) experiencing immune effector cell-associated neurotoxicity syndrome. Conclusions: These results of RWOs in third-line patients with R/R DLBCL receiving anti-CD19 CAR T-cell therapy are comparable or superior to prior clinical trials and studies of RWOs, validating the strong efficacy and manageable toxicities of CAR T-cell therapy. Full article

Background: Extracorporeal photopheresis (ECP) consists of the collection of a patient’s peripheral blood mononuclear cells (MNCs) that, after incubation with a photosensitive molecule, are exposed to ultraviolet-A (UVA) and then reinfused into the patient. There are two methods for performing the ECP procedure: the “in-line” methods and the “off-line” methods. In the “in-line” method, all the phases of ECP (leukapheresis, photoactivation, and reinfusion) are achieved sequentially in extracorporeal circulation using a single instrument and a single sterile disposable kit without disconnection from the patient’s blood circulation. In this paper, we report our real-life experience with a recently licensed in-line ECP system proposed by Fresenius-Kabi. Methods: The ECP procedures (n = 211) were performed using an Amicus cell separator and a Phelix UV irradiator with Amicus software 4.51 and Phelix software 1.0. A targeted 2000 mL of whole blood (WB) was processed, and 1.5 J/cm² of UVA light was delivered to the collected mononuclear cells (MNCs). Results: From May 2023 to April 2024, we performed 211 ECP procedures in 11 patients with graft-versus-host disease (GvHD). The processed blood volume was between 1992 and 2000 mL, and the blood flow speed during the procedures was highly variable (from 30 to 50 mL/min), so the total duration of the procedure was quite variable (from 92 to 118 min). The collection efficiency (CE2) for mononuclear cells was always satisfactory (from 55% to 73%), with a minimal presence of RBCs and PLTs. Conclusions: In our experience, the Amicus system-based ECP procedure is safe and well tolerated as we observed only one side effect. The duration of the procedure was always under two hours. The collection efficiency (CE2) for MNCs was satisfactory, with minimal platelet and RBC product contamination. Full article

Background/Objectives: Lutathera^® ([¹⁷⁷Lu]Lu-DOTA-TATE) is the first radiolabelled somatostatin (SST) analog approved for the treatment of patients with well-differentiated (G1 and G2) unresectable or metastatic gastro-entero-pancreatic neuro-endocrine-neoplasms (GEP-NENs). The bone marrow and kidneys are critical organs for RLT with [¹⁷⁷Lu]Lu-DOTA-TATE. Our purpose was to evaluate hematological and renal toxicity in 29 patients (18 males, 11 females) treated with Lutathera^®. Methods: According to standard protocols, four cycles of (¹⁷⁷Lu)Lu-DOTA-TATE were administered every eight/nine weeks. Patients received pre-medication with anti-emetic and anti-acid drugs and a slow amino acid infusion for renal protection. Blood count and serum creatinine data were collected at three time points: before the first cycle, after the second cycle, and at the end of treatment. Results: We found that almost all hematological parameters significantly decreased between the baseline and/or interim and post-therapy evaluation, although without a clinical impact. The presence of total tumor load or bone metastases had no influence on these findings, while male patients showed less hematological toxicity than females. Conversely, creatinine levels did not vary during treatment. Conclusions: Our study confirms that [¹⁷⁷Lu]Lu-DOTATATE RLT is safe and well tolerated despite some minor (grade 1) hematological toxicity. Full article

Hereditary hemochromatosis (HH) related to HFE-gene mutations is a well-known condition, yet its understanding remains complex. The BIOIRON classification emphasizes that only homozygosity for the C282Y mutation should be considered pathogenic. The penetrance of HFE-related HH is highly variable. Symptoms are often challenging to recognize at the time of presentation, and the systemic involvement may overlap with other diseases. Hyperferritinemia and elevated transferrin saturation levels are still the milestones in HH diagnosis, but they are also common findings in many other clinical conditions. Furthermore, current diagnostic and therapeutic guidelines are not always unequivocal in defining HH patients’ characteristics, as well as treatment management and goals. Our work provides a concise overview of the latest evidence regarding pathogenic mechanisms, clinical picture, differential diagnosis and diagnostic tools. Alongside this, it summarizes and compares the main recommendations from principal guidelines issued by the 2017 Hemochromatosis International Meeting, the American College of Gastroenterology, the European Association for the Study of the Liver, the European Molecular Genetics Quality Network, the DUTCH guidelines, and the British Society for Haematology. Summarizing tables for quick consultation are also provided. Full article

Background: Hypophosphatemia is a known side-effect of parenteral iron administration, especially after intravenous ferric carboxymaltose (FCM). Fibroblast growth factor 23 (FGF23) is thought to play an important role in the pathophysiology of serum phosphate homeostasis. This study aimed to investigate the effects of FCM on FGF23 serum levels in FCM-treated pediatric patients with iron deficiency (ID)/iron deficiency anemia (IDA) caused by gastrointestinal diseases. Methods: Over 30 months, FGF23 serum levels were assessed prospectively in children with ID/IDA due to gastrointestinal diseases and treated with FCM infusion. Serum levels of intact FGF23 (iFGF23) were assessed and correlated to phosphate serum levels and factors of bone metabolism. Blood sampling was performed in three phases: before FCM infusion, 7–10 days after FCM infusion, and 6–8 weeks after FCM infusion. Results: A total of 42 FCM infusions were given to 35 children (20 girls) with a mean age (±SD) of 12.2 (±4.03) years (range: 2–16 years). The median levels of iFGF23 did not show a significant difference across the three phases (p = 0.56). No significant correlation was found between iFGF23 levels and 25-hydroxyvitamin D/parathyroid hormone/serum phosphate/serum calcium/alkaline phosphatase. No significant change was noted between pre- and post-treatment serum phosphate levels. However, four children (11.42%) developed asymptomatic and transient hypophosphatemia. Conclusions: No significant difference was found between pre-and post-FCM infusion serum iFGF23 levels and bone metabolism parameters. An increase of iFGF23 serum levels 7–10 days after FCM infusion was noted in patients with hypophosphatemia. Full article

The clinicopathologic spectrum of nodular lymphocyte-predominant Hodgkin lymphoma, now termed “nodular lymphocyte-predominant B-cell lymphoma” (NLPBCL), may include incipient, typical and transformed forms. On the basis of its clinicopathologic spectrum, NLPBCL is very similar to follicular lymphoma not associated with BCL2 translocation. In addition, NLPBCL, based on biopathologic features (gene profiling signature, and phenotypic and morphotypic characteristics), is a germinal center-derived B-cell neoplasm; therefore, it could be included in the follicular lymphoma group of non-Hodgkin lymphoma. Full article

Background: Serum albumin is crucial for critically ill patients. To date, several reports have focused on the influence of lower albumin levels on poorer prognosis and disease outcome in different subsets of critical clinical conditions varying from sepsis, to cirrhosis, renal failure, and cancer. In the last few years, investigators reported the role of serum albumin levels in predicting the thrombotic risk in patients with nephrotic syndrome, and, in particular, the degree of hypoalbuminemia seemed to influence the risk of thromboembolism. Decreased serum albumin has been associated with the risk of venous thromboembolism and mortality in adult cancer patients after ending chemotherapy for different malignancies. Aims: We aimed to investigate the role of serum albumin in a cohort of children diagnosed as having VTE (venous thromboembolism) during their treatment for acute lymphoblastic leukemia (ALL) compared to ALL children who did not experience VTE. Methods: A nested case-control study was conducted at the Pediatric Oncology and Hematology Department, University Hospital of Bari. A total of 167 patients were diagnosed as having ALL and treated according to AIEOP-BFM ALL 2000-R2006 protocol. Among these, 12 cases of VTE were recorded and matched to 31 controls, for a total of 43 ALL patients (30 males, aged 1.2–16.6 years) enrolled in the present study. Serum albumin level was collected at diagnosis—before the start of any treatment—(time point 0) and at the moment of the VTE or corresponding time point of the protocol (time point 1). Information on inherited thrombophilia genotype were also recorded. Results: Patients presenting VTE showed a marked reduction of average albumin levels as compared to the control children: t0–t1 1.1 IC (95%) = (0.55, 1.65) vs. 0.31 IC (95%) = (0.08, 0.55); p < 0.005. Conclusions: The reduction of serum albumin levels in our cohort might be an expression of altered vascular and endothelial homeostasis, likely predisposing to VTE. This important clinical observation warrants further larger studies. Full article