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Abstract Background This study was conducted to determine whether patients with Gaucher disease had significant dental pathology because of abnormal bone structure, pancytopenia, and coagulation abnormalities. Methods Each patient received a complete oral and periodontal examination in addition to a routine hematological evaluation. Results Gaucher patients had significantly fewer carious lesions than otherwise healthy carriers. Despite prevalence of anemia, there was no increase in gingival disease; despite the high incidence of thrombocytopenia, gingival bleeding was not noted; and despite radiological evidence of bone involvement, there was no greater incidence loss of teeth or clinical tooth mobility. Conclusions These data represent the first survey of the oral health of a large cohort of patients with Gaucher disease. It is a pilot study of a unique population and the results of the investigation are indications for further research. Based on our findings, we recommend regular oral examinations with appropriate dental treatment for patients with Gaucher disease as for other individuals. Consultation between the dentist and physician, preferably one with experience with Gaucher disease, should be considered when surgical procedures are planned.

Abstract Background Disease-specific patient-reported outcome measures (PROMs) are fundamental to understanding the impact on, and expectations of, patients with genetic disorders, and can facilitate constructive and educated conversations about treatments and outcomes. However, generic PROMs may fail to capture disease-specific concerns. Here we report the development and validation of a Gaucher disease (GD)-specific PROM for patients with type 1 Gaucher disease (GD1) a lysosomal storage disorder characterized by hepatosplenomegaly, thrombocytopenia, anemia, bruising, bone disease, and fatigue. Results and discussion The questionnaire was initially developed with input from 85 patients or parents of patients with GD1 or GD3 in Israel. Owing to few participating patients with GD3, content validity was assessed for patients with GD1 only. Content validity of the revised questionnaire was assessed in 33 patients in the US, France, and Israel according to US Food and Drug Administration standards, with input from a panel of six GD experts and one patient advocate representative. Concept elicitation interviews explored patient experience of symptoms and treatments, and a cognitive debriefing exercise explored patients’ understanding and relevance of instructions, items, response scales, and recall period. Two versions of the questionnaire were subsequently developed: a 24-item version for routine monitoring in clinical practice (rmGD1-PROM), and a 17-item version for use in clinical trials (ctGD1-PROM). Psychometric validation of the ctGD1-PROM was assessed in 46 adult patients with GD1 and re-administered two weeks later to examine test–retest reliability. Findings from the psychometric validation study revealed excellent internal consistency and strong evidence of convergent validity of the ctGD1-PROM based on correlations with the 36-item Short Form Health Survey. Most items were found to show moderate, good, or excellent test–retest reliability. Conclusions Development of the ctGD1-PROM represents an important step forward for researchers measuring the impact of GD and its respective treatment.

Polycythemia vera (PV) is a chronic myeloproliferative neoplasm. Virtually all PV patients are iron deficient at presentation and/or during the course of their disease. The co-existence of iron deficiency and polycythemia presents a physiological disconnect. Hepcidin, the master regulator of iron metabolism, is regulated by circulating iron levels, erythroblast secretion of erythroferrone, and inflammation. Both decreased circulating iron and increased erythroferrone levels, which occur as a consequence of erythroid hyperplasia in PV, are anticipated to suppress hepcidin and enable recovery from iron deficiency. Inflammation which accompanies PV is likely to counteract hepcidin suppression, but the relatively low serum ferritin levels observed suggest that inflammation is not a major contributor to the dysregulated iron metabolism. Furthermore, potential defects in iron absorption, aberrant hypoxia sensing and signaling, and frequency of bleeding to account for iron deficiency in PV patients have not been fully elucidated. Insufficiently suppressed hepcidin given the degree of iron deficiency in PV patients strongly suggests that disordered iron metabolism is an important component of the pathobiology of PV. Normalization of hematocrit levels using therapeutic phlebotomy is the most common approach for reducing the incidence of thrombotic complications, a therapy which exacerbates iron deficiency, contributing to a variety of non-hematological symptoms. The use of cytoreductive therapy in high-risk PV patients frequently works more effectively to reverse PV-associated symptoms in iron-deficient relative to iron-replete patients. Lastly, differences in iron-related parameters between PV patients and mice with JAK2 V617F and JAK2 exon 12 mutations suggest that specific regions in JAK2 may influence iron metabolism by nuanced changes of erythropoietin receptor signaling. In this review, we comprehensively discuss the clinical consequences of iron deficiency in PV, provide a framework for understanding the potential dysregulation of iron metabolism, and present a rationale for additional therapeutic options for iron-deficient PV patients.

Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T-cell (CAR T) therapy shows remarkable efficacy in patients with relapsed and/or refractory (R/R) multiple myeloma (MM). HBI0101, a novel second generation optimized anti- BCMA CAR T-cell therapy, was developed in an academic setting. We conducted a phase I dose-escalation study of HBI0101 (cohort 1: 150x106 CAR T cells, n=6; cohort 2: 450x106 CAR T cells, n=7; cohort 3: 800x106 CAR T cells, n=7) in 20 heavily pre-treated R/R MM patients. Grade 1-2 cytokine release syndrome (CRS) was reported in 18 patients (90%). Neither grade 3-4 CRS nor neurotoxicity of any grade were observed. No dose-limiting toxicities were observed in any cohort. The overall response rate (ORR), (stringent) complete response (CR/sCR), and very good partial response rates were 75%, 50%, and 25%, respectively. Response rates were dose-dependent with 85% ORR, 71% CR, and 57% minimal residual disease negativity in the high-dose cohort 3. Across all cohorts, the median overall survival (OS) was 308 days (range 25-466+), with an estimated OS of 55% as of June 27th (data cut-off). The median progression-free survival was 160 days, with 6 subjects remaining progression free at the time of data cut-off. Our findings demonstrate the manageable safety profile and efficacy of HBI0101. These encouraging data support the decentralization of CAR T production in an academic setting, ensuring sufficient CAR T supply to satisfy the increasing local demand. Clinicaltrials.gov NCT04720313.

Gaucher disease (GD) is a rare autosomal recessive disorder arising from bi-allelic variants in the GBA1 gene, encoding glucocerebrosidase. Deficiency of this enzyme leads to progressive accumulation of the sphingolipid glucosylsphingosine (lyso-Gb1). The international, multicenter, observational “Lyso-Gb1 as a Long-term Prognostic Biomarker in Gaucher Disease”—LYSO-PROOF study succeeded in enrolling a cohort of 160 treatment-naïve GD patients from diverse geographic regions and evaluated the potential of lyso-Gb1 as a specific biomarker for GD. Using genotypes based on established classifications for clinical presentation, patients were stratified into type 1 GD (n = 114) and further subdivided into mild (n = 66) and severe type 1 GD (n = 48). Due to having previously unreported genotypes, 46 patients could not be classified. Though lyso-Gb1 values at enrollment were widely distributed, they displayed a moderate and statistically highly significant correlation with disease severity measured by the GD-DS3 scoring system in all GD patients (r = 0.602, p < 0.0001). These findings support the utility of lyso-Gb1 as a sensitive biomarker for GD and indicate that it could help to predict the clinical course of patients with undescribed genotypes to improve personalized care in the future.

Objectives: Gaucher disease’s (GD) pathophysiology generates anesthetic concerns in total hip joint arthroplasty (THA), and due to its rareness, data on perioperative risks are scarce. This 22-year study at a large reference center addresses anesthetic management and perioperative outcomes in GD. Methods: This retrospective-cohort study assessed anesthetic success and safety in 30 THA patients, comparing them with a control-matched group. Data on clinical characteristics, perioperative events, and outcomes were collected. The primary outcome was the success rate of anesthesia induction performance at first attempt. Secondary outcomes were difficult intraoperative course and hemodynamic management, and the development of postoperative complications. The age, sex, weight, body mass index, and primary-to-revision hip arthroplasty ratio were similar in both groups. Results: There was no significant difference at all-type anesthesia first initiation attempt success. No particular preference by staff anesthetists for general anesthesia or neuraxial procedures was observed. The GD group showed a significantly higher mean of intraoperative packed Red Blood Cell units administered ((0.73 vs. 0.18); (p = 0.038)), higher intraoperative and postoperative platelet transfusion incidence ((5/30 [16.7%] vs. 0/56 [0.00%]; p = 0.004) and (3/30 [10%] vs. 0/56 [0%]; p = 0.040)), and longer mean recovery room length of stay (426 ± 412 vs. 175 ± 140; p = 0.004). Postoperative complications were not significantly different.

Gaucher disease (GD) is one of the most common lysosomal storage disorders. Bone complications are the most critical irreversible consequence of GD. Osteonecrosis (ON) of the femoral head inevitably leads to osteoarthritis and may be managed by hip arthroplasty. The introduction and worldwide use of therapeutic agents (specifically enzyme replacement therapies (ERT)) lowered the prevalence of osteonecrosis events per patient. We present the cases of two female patients who sustained simultaneous bilateral femoral head osteonecrosis after receiving ERT for long periods while exposed to concomitant risk factors related to femoral head ON. Both patients suffered severe pain and deterioration of their daily activity capabilities, and thus, were offered bilateral hip arthroplasty. Surgery was performed in both hip joints during the same procedure. The current report highlights several key aspects of femoral head ON in young patients with GD.

I study native-born white men's internal migration in the United States over all possible 10- and 20-year periods between 1850 and 1940. Inter-county migration rates—after implementing a new method to correct for errors in linkage—were stable over time. Migrant selection on the basis of occupational status was neutral or slightly negative and also largely stable. But the orientation of internal migration changed over time, declining in distance and increasingly driving urbanization. In the 1930s, migration became less common and less urban oriented. These results provide a clearer understanding of historic U.S. internal migration than previously possible. [ABSTRACT FROM AUTHOR]

Taliglucerase alfa is the first available plant cell-expressed human recombinant therapeutic protein. It is indicated for treatment of patients with type 1 Gaucher disease (GD) in adult and pediatric patients in several countries. Study PB-06-002 examined the safety and efficacy of taliglucerase alfa for 9 months in patients who previously received imiglucerase. The results of adult patients from Study PB-06-002 who continued receiving taliglucerase alfa in extension Study PB-06-003 for up to 36 months are reported here. Eighteen patients received at least one dose of taliglucerase alfa in Study PB-06-003; 10 patients completed 36 total months of therapy, and four patients who transitioned to commercial drug completed 30-33 months of treatment. In patients who completed 36 total months of treatment, mean percent (±standard error) changes from baseline/time of switch to taliglucerase alfa to 36 months were as follows: hemoglobin concentration, -1.0% (±1.9%; n = 10); platelet count, +9.3% (±9.8%; n = 10); spleen volume measured in multiples of normal (MN), -19.8% (±9.9%; n = 7); liver volume measured in MN, +0.9% (±5.4%; n = 8); chitotriosidase activity, -51.5% (±8.1%; n = 10); and CCL18 concentration, -36.5 (±8.0%; n = 10). Four patients developed antidrug antibodies, including one with evidence of neutralizing activity in vitro. All treatment-related adverse events were mild or moderate and transient. The 36-month results of switching from imiglucerase to taliglucerase alfa treatment in adults with GD provide further data on the clinical safety and efficacy of taliglucerase alfa beyond the initial 9 months of the original study. www.clinicaltrials.gov identifier NCT00705939. Am. J. Hematol. 91:661-665, 2016. © 2016 Wiley Periodicals, Inc.

Abstract Background It is now acknowledged that the input of patients in health outcome assessment is vital to understanding the impact of diseases and interventions for those diseases. This study is the first report of patient-reported outcome measures (PROM) in a large cohort of patients with type 1 Gaucher disease (GD1) enabling us to study predictors of the reported outcomes. Method The PROM was sent via a mobile phone survey to 405 adult patients with GD1. Demographics, clinical data, and treatment status were extracted from clinic charts. Age, sex, severity score index (SSI) at presentation and treatment status were used as variables to assess outcomes. Results A total of 192 patients with GD1 (111 females) responded (47.4% response rate), of whom 124 (64.5%) had received GD1-specific therapy. Around 40% of patients reported that GD had restricted their education/job and fun activities and were concerned about being emotional and financial burdens on others. Concerns regarding the risk of bone disease and Parkinson disease were also high (60%). The severity of GD1 (reflected by the need for GD1-specific therapy and a high SSI) was associated with GD1-related restrictions and concerns, fatigue, physical weakness, bone pain, and worry regarding the future. Conclusions The use of GD1 specific PROM highlights personal problems that are not captured by traditional outcome parameters and that need to be addressed to improve health-related quality of life. Validated PROM should be included among the outcome measures in clinical practice and future prospective studies for patients with chronic and rare diseases.

Abstract Attempts to expand ex vivo the numbers of human hematopoietic stem cells (HSCs) without compromising their marrow repopulating capacity and their ability to establish multilineage hematopoiesis has been the subject of intense investigation. Although most such efforts have focused on cord blood HSCs, few have been applied to adult HSCs, a more clinically relevant HSC source for gene modification. To date, the strategies that have been used to expand adult HSCs have resulted in modest effects or HSCs with lineage bias and a limited ability to generate T cells in vivo. We previously reported that culturing umbilical cord blood CD34+ cells in serum‐free media supplemented with valproic acid (VPA), a histone deacetylase inhibitor, and a combination of cytokines led to the expansion of the numbers of fully functional HSCs. In the present study, we used this same approach to expand the numbers of adult human CD34+ cells isolated from mobilized peripheral blood and bone marrow. This approach resulted in a significant increase in the numbers of phenotypically defined HSCs (CD34+CD45RA‐CD90+D49f+). Cells incubated with VPA also exhibited increased aldehyde dehydrogenase activity and decreased mitochondrial membrane potential, each functional markers of HSCs. Grafts harvested from VPA‐treated cultures were able to engraft in immune‐deficient mice and, importantly, to generate cellular progeny belonging to each hematopoietic lineage in similar proportion to that observed with unmanipulated CD34+ cells. These data support the utility of VPA‐mediated ex vivo HSC expansion for gene modification of adult HSCs.

This article redefines the theme, structure, and ideology of Amos 3:1–8. First, the article demonstrates the essential relationship between the unit’s boundaries, structure, content, and theme through a comprehensive research review. Next, the article offers a unique approach to the questions that remain open-ended to date. The article argues that Amos 3:1–8 should be regarded as a single unit comprised of three sub-units linked by one element. It considers the unit’s structure and the verses in their entirety as the foundation for understanding the unit’s complex content.

Abstract A 61‐year‐old male presented with progressive generalized weakness, myalgia, diaphoresis, fever, episodic chills and rigors that had started 4 days previously. Chest x‐ray (CXR) showed overlying curvilinear radio‐opacities. Abdominal computed tomography revealed liver and bilateral adrenal lesions. Empiric 7‐day intravenous Piperacillin / Tazobactam (Zosyn) was initiated, and he was admitted for sepsis. After an episode of rigors on Day 2, he developed acute hypoxic respiratory failure with inspiratory stridor. CXR revealed new, bilateral airspace disease. Racemic Epinephrine, Solumedrol, Ketorolac (Toradol) and Diphenhydramine were given, and he was transferred to the intensive care unit with presumptive diagnosis of foreign body aspiration or allergic reaction. With each subsequent episode of rigor and chills, he continued developing hypoxic respiratory failure with stridor and an incremental increase in pulmonary oedema on imaging. Pulmonologist concluded it likely secondary to negative pressure pulmonary oedema caused by transient laryngeal dyskinesia induced by the increased work of breathing associated with rigors. Symptoms resolved after the complete course of antibiotics along with supportive therapy.

Background: Long-term patient registries are important for evaluating treatment outcomes in patients with rare diseases, and can provide insights into natural disease history and progression in real-world clinical practice. Initiated in 2010, the Gaucher Outcome Survey (GOS) is an ongoing, international, multicenter, observational registry (ClinicalTrials.gov Identifier: NCT03291223) for patients with a diagnosis of Gaucher disease (GD), irrespective of treatment type or status, with a primary objective to monitor safety and long-term effectiveness of velaglucerase alfa. Methods: Here, we evaluated the GOS population 12 years after the registry initiation. Results: As of 25 February 2023, 2084 patients enrolled in the GOS and 1643 received GD-specific treatment. Patients exhibited broad heterogeneity at baseline: age of diagnosis (0 to 85.3 years), hemoglobin concentrations (<80.0 g/L to >150 g/L), platelet counts (<50 × 109/L to >450 × 109/L), and liver and spleen volumes. Most patients treated with enzyme replacement therapy or substrate reduction therapy reported improvements in clinical parameters within 1 year of treatment initiation, maintained over the course of treatment up to 12 years, whereas untreated patients had baseline values closer to standard reference thresholds and showed stability over time. Conclusion: The 12-year data from the GOS confirm the impact of long-term treatment with GD-specific agents and offer insights into disease progression and outcomes in a real-world setting. [ABSTRACT FROM AUTHOR]