Psychosocial Outcomes Among Users and Nonusers of Open-Source Automated Insulin Delivery Systems: Multinational Survey of Adults With Type 1 Diabetes.

BACKGROUND: Emerging research suggests that open-source automated insulin delivery (AID) may reduce diabetes burden and improve sleep quality and quality of life (QoL). However, the evidence is mostly qualitative or uses unvalidated, study-specific, single items. Validated person-reported outcome measures (PROMs) have demonstrated the benefits of other diabetes technologies. The relative lack of research investigating open-source AID using PROMs has been considered a missed opportunity. OBJECTIVE: This study aimed to examine the psychosocial outcomes of adults with type 1 diabetes using and not using open-source AID systems using a comprehensive set of validated PROMs in a real-world, multinational, cross-sectional study. METHODS: Adults with type 1 diabetes completed 8 validated measures of general emotional well-being (5-item World Health Organization Well-Being Index), sleep quality (Pittsburgh Sleep Quality Index), diabetes-specific QoL (modified DAWN Impact of Diabetes Profile), diabetes-specific positive well-being (4-item subscale of the 28-item Well-Being Questionnaire), diabetes treatment satisfaction (Diabetes Treatment Satisfaction Questionnaire), diabetes distress (20-item Problem Areas in Diabetes scale), fear of hypoglycemia (short form of the Hypoglycemia Fear Survey II), and a measure of the impact of COVID-19 on QoL. Independent groups 2-tailed t tests and Mann-Whitney U tests compared PROM scores between adults with type 1 diabetes using and not using open-source AID. An analysis of covariance was used to adjust for potentially confounding variables, including all sociodemographic and clinical characteristics that differed by use of open-source AID. RESULTS: In total, 592 participants were eligible (attempting at least 1 questionnaire), including 451 using open-source AID (mean age 43, SD 13 years; n=189, 41.9% women) and 141 nonusers (mean age 40, SD 13 years; n=90, 63.8% women). Adults using open-source AID reported significantly better general emotional well-being and subjective sleep quality, as well as better diabetes-specific QoL, positive well-being, and treatment satisfaction. They also reported significantly less diabetes distress, fear of hypoglycemia, and perceived less impact of the COVID-19 pandemic on their QoL. All were medium-to-large effects (Cohen d=0.5-1.5). The differences between groups remained significant after adjusting for sociodemographic and clinical characteristics. CONCLUSIONS: Adults with type 1 diabetes using open-source AID report significantly better psychosocial outcomes than those not using these systems, after adjusting for sociodemographic and clinical characteristics. Using validated, quantitative measures, this real-world study corroborates the beneficial psychosocial outcomes described previously in qualitative studies or using unvalidated study-specific items.

Venous Thromboembolism Prophylaxis in Pediatric Inflammatory Bowel Disease Patients Hospitalized With a Central Line.

OBJECTIVES: Patients hospitalized with inflammatory bowel disease (IBD) have increased risk of venous thromboembolism (VTE). The aim of this study was to determine whether the adoption of a VTE protocol would change rates of medical VTE prophylaxis (low molecular weight heparin) in patients with IBD and a central venous catheter (CVC), while subsequently decreasing the incidence of VTE in this population. METHODS: A protocol for VTE prophylaxis in IBD was established in March of 2018. Every patient hospitalized with an IBD flare and central venous access from March 2013 to March 2020 was identified. Study data, including patient demographics, rates of Doppler ultrasound (US), and rates of VTE were collected using International Classification of Diseases (ICD)-10 codes, CPT codes, and chart review retrospectively. Determination of an IBD flare was based on physician global assessment. Groups were compared with independent-sample t tests and chi-squared tests. RESULTS: A total of 313 hospitalizations across 187 different patients were identified that met criteria including IBD and central venous access. VTE prophylaxis increased from 5.24% (n = 12) prior to the intervention to 63.10% (n = 53) after the intervention [chi-square (1, N = 313) = 125.0192, P < 0.001]. Rate of Doppler US increased from 9.17% (n = 21) prior to the intervention to 17.86% (n = 15) after the intervention [chi-square (1, N = 313) = 4.5562, P < 0.05]. Diagnosis of VTE increased from 0.87% (n = 2) prior to the intervention to 7.14% (n = 6) after the intervention [chi-square (1, N = 313) = 9.6992, P < 0.01]. There were no significant differences in the demographic characteristics pre- versus post-intervention. CONCLUSIONS: Rates of Doppler US and VTE prophylaxis use increased significantly after implementation of a VTE protocol. Rates of VTE diagnosis also increased, though we suspect this may be due to missed diagnoses prior to implementation of the protocol and increased risk awareness after the protocol was established.

Quality of life and psychological well-being among children and adolescents with diabetes and their caregivers using open-source automated insulin delivery systems: Findings from a multinational survey.

BACKGROUND: Open-source automated insulin delivery (AID) systems have shown to be safe and effective in children and adolescents with type 1 diabetes (T1D) in real-world studies. However, there is a lack of evidence on the effect on their caregivers' quality-of-life (QoL) and well-being. The aim of this study was to assess the QoL of caregivers and children and adolescents using open-source AID systems using validated measures. METHODS: In this cross-sectional online survey we examined the caregiver-reported QoL and well-being of users and non-users. Validated questionnaires assessed general well-being (WHO-5), diabetes-specific QoL (PAID, PedsQL) and sleep quality (PSQI). RESULTS: 168 caregivers from 27 countries completed at least one questionnaire, including 119 caregivers of children using open-source AID and 49 not using them. After inclusion of covariates, all measures but the PAID and one subscale of the PedsQL showed significant between-group differences with AID users reporting higher general (WHO-5: p = 0.003), sleep-related (PSQI: p = 0.001) and diabetes-related QoL (PedsQL: p < 0.05). CONCLUSIONS: The results show the potential impact of open-source AID on QoL and psychological well-being of caregivers and children and adolescents with T1D, and can therefore help to inform academia, regulators, and policymakers about the psychosocial health implications of open-source AID.

Variability of Glycemic Outcomes and Insulin Requirements Throughout the Menstrual Cycle: A Qualitative Study on Women With Type 1 Diabetes Using an Open-Source Automated Insulin Delivery System.

BACKGROUND: The impact of hormone dynamics throughout the menstrual cycle on insulin sensitivity represents a currently under-researched area. Despite therapeutic and technological advances, self-managing insulin therapy remains challenging for women with type 1 diabetes (T1D). METHODS: To investigate perceived changes in glycemic levels and insulin requirements throughout the menstrual cycle and different phases of life, we performed semi-structured interviews with 12 women with T1D who are using personalized open-source automated insulin delivery (AID) systems. Transcripts were analyzed using thematic analysis with an inductive, hypothesis-generating approach. RESULTS: Participants reported significant differences between the follicular phase, ovulation, and luteal phase of the menstrual cycle and also during puberty, pregnancy, and menopause. All participants reported increased comfort and safety since using AID, but were still required to manually adjust their therapy according to their cycle. A lack of information and awareness and limited guidance by health care providers were frequently mentioned. Although individual adjustment strategies exist, achieving optimum outcomes was still perceived as challenging. CONCLUSIONS: This study highlights that scientific evidence, therapeutic options, and professional guidance on female health-related aspects in T1D are insufficient to date. Further efforts are required to better inform people with T1D, as well as for health care professionals, researchers, medical device manufacturers, and regulatory bodies to better address female health needs in therapeutic advances.

Emotional and Physical Health Impact in Children and Adolescents and Their Caregivers Using Open-source Automated Insulin Delivery: Qualitative Analysis of Lived Experiences.

BACKGROUND: Given the limitations in the access and license status of commercially developed automated insulin delivery (AID) systems, open-source AID systems are becoming increasingly popular among people with diabetes, including children and adolescents. OBJECTIVE: This study aimed to investigate the lived experiences and physical and emotional health implications of children and their caregivers following the initiation of open-source AID, their perceived challenges, and sources of support, which have not been explored in the existing literature. METHODS: Data were collected through 2 sets of open-ended questions from a web-based multinational survey of 60 families from 16 countries. The narratives were thematically analyzed, and a coding framework was identified through iterative alignment. RESULTS: A range of emotions and improvements in quality of life and physical health were reported, as open-source AID enabled families to shift their focus away from diabetes therapy. Caregivers were less worried about hypoglycemia at night and outside their family homes, leading to increased autonomy for the child. Simultaneously, the glycemic outcomes and sleep quality of both the children and caregivers improved. Nonetheless, the acquisition of suitable hardware and technical setup could be challenging. The #WeAreNotWaiting community was the primary source of practical and emotional support. CONCLUSIONS: Our findings show the benefits and transformative impact of open-source AID and peer support on children with diabetes and their caregivers and families, where commercial AID systems are not available or suitable. Further efforts are required to improve the effectiveness and usability and facilitate access for children with diabetes, worldwide, to benefit from this innovative treatment. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/15368.

A proposed algorithm for evaluation and management of pediatric hemophilia patients who present to the emergency department with head trauma.

Hemophilia is the deficiency of plasma clotting factor VIII (hemophilia A) or IX (hemophilia B) where management focuses on the prevention and treatment of acute bleeding symptoms and their sequelae. The most concerning risk is for life-threatening bleeding, including intracranial hemorrhage (ICH), which is caused by head trauma. Guidelines exist for the evaluation and management of pediatric head trauma, including the Pediatric Emergency Care Applied Research Network (PECARN) protocol, but limited evidence exists for when hemophilia patients present to the emergency department (ED), specifically with head trauma. Literature is limited regarding ICH and hemophilia, which further supports the culture of uncertainty among providers. The objective of this study is to conduct a retrospective chart review to determine the prevalence and clinical characteristics of ICH, and to describe computed tomography (CT) scan use in hemophilia patients who present to Phoenix Children's Hospital (PCH) ED with head trauma from January 1, 2007 to June 1, 2019. A total of 89 ED visits and 43 patients met inclusion criteria, and prevalence of ICH was determined to be 4% with the patients presenting with varied clinical characteristics and few commonalities. Using these data, we propose a new algorithm to aid clinicians in determining the need for CT scan in pediatric hemophilia patients who present to the ED with head trauma.

Open-source Web Portal for Managing Self-reported Data and Real-world Data Donation in Diabetes Research: Platform Feasibility Study.

BACKGROUND: People with diabetes and their support networks have developed open-source automated insulin delivery systems to help manage their diabetes therapy, as well as to improve their quality of life and glycemic outcomes. Under the hashtag #WeAreNotWaiting, a wealth of knowledge and real-world data have been generated by users of these systems but have been left largely untapped by research; opportunities for such multimodal studies remain open. OBJECTIVE: We aimed to evaluate the feasibility of several aspects of open-source automated insulin delivery systems including challenges related to data management and security across multiple disparate web-based platforms and challenges related to implementing follow-up studies. METHODS: We developed a mixed methods study to collect questionnaire responses and anonymized diabetes data donated by participants-which included adults and children with diabetes and their partners or caregivers recruited through multiple diabetes online communities. We managed both front-end participant interactions and back-end data management with our web portal (called the Gateway). Participant questionnaire data from electronic data capture (REDCap) and personal device data aggregation (Open Humans) platforms were pseudonymously and securely linked and stored within a custom-built database that used both open-source and commercial software. Participants were later given the option to include their health care providers in the study to validate their questionnaire responses; the database architecture was designed specifically with this kind of extensibility in mind. RESULTS: Of 1052 visitors to the study landing page, 930 participated and completed at least one questionnaire. After the implementation of health care professional validation of self-reported clinical outcomes to the study, an additional 164 individuals visited the landing page, with 142 completing at least one questionnaire. Of the optional study elements, 7 participant-health care professional dyads participated in the survey, and 97 participants who completed the survey donated their anonymized medical device data. CONCLUSIONS: The platform was accessible to participants while maintaining compliance with data regulations. The Gateway formalized a system of automated data matching between multiple data sets, which was a major benefit to researchers. Scalability of the platform was demonstrated with the later addition of self-reported data validation. This study demonstrated the feasibility of custom software solutions in addressing complex study designs. The Gateway portal code has been made available open-source and can be leveraged by other research groups.

Quality of life in a large multinational haemophilia B cohort (The B-Natural study) - Unmet needs remain.

INTRODUCTION: The B-Natural study is a multicentre, multinational, observational study of haemophilia B (HB) designed to increase understanding of clinical manifestations, treatment and quality of life (QoL). AIM: To characterise and compare QoL in HB across disease severity groups and individuals with inhibitors to identify gaps in treatment. METHODS: A total of 224 individuals from 107 families were enrolled from a total of 24 centres in North America (n = 16), Europe (n = 7) and Asia (n = 1). Of these, 68 (30.4%) subjects had severe (<1 IU/dL), median age 15.6 years, 114 (50.9%) moderate (1-5 IU/dL), age 13.3 years, and 42 (18.8%) mild (>5-< 40 IU/dL), age 12.1 years, disease. Twenty-nine participants had inhibitors or a history of inhibitors. Three versions of the EQ-5D instrument were used as a measure of QoL: proxy (ages 4-7), youth (ages 8-15) and self (age 16+). Each instrument included a visual analogue scale ranging from 100 (best health) to 0 (worst health) to assess current day's health (EQ VAS). Range-of-motion (ROM) for elbows, knees and ankles was assessed using a four-point scale, from which a composite score was calculated. RESULTS: In all severity groups, a proportion of subjects showed less than optimal QoL. The majority of the mild and moderate severe participants reported a normal EQ-5D health profile (79% and 72%, respectively), whereas about half (47%) of the severe participants and only 13% of the inhibitor participants reported this profile. CONCLUSION: The B-Natural study reveals impacted QoL in all disease severities of HB including those with inhibitors. Unmet needs remain and include nonsevere HB.

Current practices in pediatric hospital-acquired thromboembolism: Survey of the Children's Hospital Acquired Thrombosis (CHAT) Consortium.

Background: A rise in hospital-acquired venous thromboembolism (HA-VTE) in children has led to increased awareness regarding VTE prophylaxis and risk assessment. Despite no consensus exists regarding these practices in pediatrics. Objective: To describe common practices in VTE prophylaxis, VTE risk assessment models, and anticoagulation dosing strategies in pediatric hospitals that are members of the Children's Hospital Acquired Thrombosis (CHAT) Consortium. Methods: An electronic survey of 44 questions evaluating practices surrounding pediatric HA-VTE risk assessment and prevention was distributed between August 9, 2021, and August 30, 2021, to the primary investigators from the 32 institutions within the CHAT Consortium. Results: The survey response rate was 100% (n = 32). In total, 85% (n = 27) of the institutions assess HA-VTE, but only 63% (n = 20) have formal hospital guidelines. Within the institutions with formal guidelines, 100% (n = 20) include acute systemic inflammation or infection and presence of a central venous catheter (CVC) as risk factors for VTE. Pharmacologic prophylaxis is prescribed at 87% (28) of institutions, with enoxaparin being the most frequent (96%, n = 27). Variability in responses persisted regarding risk factors, risk assessment, thromboprophylaxis, dosing of prophylactic anticoagulation or anticoagulant drug monitoring. A majority of providers were comfortable providing thromboprophylaxis across all age groups. In addition, the global coronavirus disease 2019 increased the providers' use of prophylactic anticoagulation 78% (n = 25). Conclusion: Practices among institutions are variable in regard to use of HA-VTE prophylaxis, risk assessment, or guideline implementation, highlighting the need for further research and a validated risk assessment model through groups like the CHAT Consortium.

Real-world evidence on clinical outcomes of people with type 1 diabetes using open-source and commercial automated insulin dosing systems: A systematic review.

AIMS: Several commercial and open-source automated insulin dosing (AID) systems have recently been developed and are now used by an increasing number of people with diabetes (PwD). This systematic review explored the current status of real-world evidence on the latest available AID systems in helping to understand their safety and effectiveness. METHODS: A systematic review of real-world studies on the effect of commercial and open-source AID system use on clinical outcomes was conducted employing a devised protocol (PROSPERO ID 257354). RESULTS: Of 441 initially identified studies, 21 published 2018-2021 were included: 12 for Medtronic 670G; one for Tandem Control-IQ; one for Diabeloop DBLG1; two for AndroidAPS; one for OpenAPS; one for Loop; three comparing various types of AID systems. These studies found that several types of AID systems improve Time-in-Range and haemoglobin A1c (HbA1c ) with minimal concerns around severe hypoglycaemia. These improvements were observed in open-source and commercially developed AID systems alike. CONCLUSIONS: Commercially developed and open-source AID systems represent effective and safe treatment options for PwD of several age groups and genders. Alongside evidence from randomized clinical trials, real-world studies on AID systems and their effects on glycaemic outcomes are a helpful method for evaluating their safety and effectiveness.

Natural history study of factor IX deficiency with focus on treatment and complications (B-Natural).

INTRODUCTION: Haemophilia B (HB) is less well studied than haemophilia A (HA); despite similarities between the two inherited bleeding disorders, important differences remain that require further research. AIM: B-Natural is a multi-centre, prospective, observational study of HB, designed to increase understanding of clinical manifestations, treatment, quality-of-life (QoL), inhibitor development, immune tolerance induction (ITI) outcome, renal function and create a biorepository for future investigations. METHODS: Participants include sibling pairs/groups without a current/history of inhibitors and singletons or siblings with a current/history of inhibitors followed for six months. Demographics, medical, social history and treatment were recorded. A physical examination including joint range of motion (ROM) was performed; QoL was assessed. Samples were collected for F9 gene mutation, HLA typing, non-inhibitory antibodies and renal function testing. RESULTS: Twenty-four centres enrolled 224 individuals from 107 families including 29 with current/history of inhibitors. Of these, 68, 30.4%, had severe (<1% FIX level of normal); 114, 50.9%, moderate (1%-5%); and 42, 18.8%, mild (>5-<40%) disease. At enrolment, 53.1% had 50 + exposure days to exogenous FIX. Comparison of joint scores showed significant (P < .05) differences between those with severe (with/without inhibitors), and those with moderate/mild disease. The majority with severe disease, 80.0% with current/history of inhibitors and 64.3% of those without, were treated with prophylaxis. CONCLUSION: B-Natural provides data supporting an increased understanding of HB and its impact throughout life. The need for optimal disease control to normalize physical and psychosocial outcomes is underscored, and further analyses will contribute to an increased understanding of critical issues in HB.

L-leucine improves anemia and growth in patients with transfusion-dependent Diamond-Blackfan anemia: Results from a multicenter pilot phase I/II study from the Diamond-Blackfan Anemia Registry.

BACKGROUND: Diamond-Blackfan anemia (DBA) is an inherited bone marrow failure syndrome characterized by anemia, short stature, congenital anomalies, and cancer predisposition. Most cases are due to mutations in genes encoding ribosomal proteins (RP) leading to RP haploinsufficiency. Effective treatments for the anemia of DBA include chronic red cell transfusions, long-term corticosteroid therapy, or hematopoietic stem cell transplantation. In a small patient series and in animal models, there have been hematologic responses to L-leucine with amelioration of anemia. The study objectives of this clinical trial were to determine feasibility, safety, and efficacy of L-leucine in transfusion-dependent patients with DBA. PROCEDURE: Patients ≥2 years of age received L-leucine 700 mg/m2 orally three times daily for nine months to determine a hematologic response and any improvement in growth (NCT01362595). RESULTS: This multicenter, phase I/II study enrolled 55 subjects; 43 were evaluable. There were 21 males; the median age at enrollment was 10.4 years (range, 2.5-46.1 years). No significant adverse events were attributable to L-leucine. Two subjects had a complete erythroid response and five had a partial response. Nine of 25, and 11 of 25, subjects experienced a positive weight and height percentile change, respectively, at the end of therapy. CONCLUSIONS: L-leucine is safe, resulted in an erythroid response in 16% of subjects with DBA, and led to an increase in weight and linear growth velocity in 36% and 44% of evaluable subjects, respectively. Further studies will be critical to understand the role of L-leucine in the management of patients with DBA.

Clinical spectrum of pyruvate kinase deficiency: data from the Pyruvate Kinase Deficiency Natural History Study.

An international, multicenter registry was established to collect retrospective and prospective clinical data on patients with pyruvate kinase (PK) deficiency, the most common glycolytic defect causing congenital nonspherocytic hemolytic anemia. Medical history and laboratory and radiologic data were retrospectively collected at enrollment for 254 patients with molecularly confirmed PK deficiency. Perinatal complications were common, including anemia that required transfusions, hyperbilirubinemia, hydrops, and prematurity. Nearly all newborns were treated with phototherapy (93%), and many were treated with exchange transfusions (46%). Children age 5 years and younger were often transfused until splenectomy. Splenectomy (150 [59%] of 254 patients) was associated with a median increase in hemoglobin of 1.6 g/dL and a decreased transfusion burden in 90% of patients. Predictors of a response to splenectomy included higher presplenectomy hemoglobin (P = .007), lower indirect bilirubin (P = .005), and missense PKLR mutations (P = .0017). Postsplenectomy thrombosis was reported in 11% of patients. The most frequent complications included iron overload (48%) and gallstones (45%), but other complications such as aplastic crises, osteopenia/bone fragility, extramedullary hematopoiesis, postsplenectomy sepsis, pulmonary hypertension, and leg ulcers were not uncommon. Overall, 87 (34%) of 254 patients had both a splenectomy and cholecystectomy. In those who had a splenectomy without simultaneous cholecystectomy, 48% later required a cholecystectomy. Although the risk of complications increases with severity of anemia and a genotype-phenotype relationship was observed, complications were common in all patients with PK deficiency. Diagnostic testing for PK deficiency should be considered in patients with apparent congenital hemolytic anemia and close monitoring for iron overload, gallstones, and other complications is needed regardless of baseline hemoglobin. This trial was registered at www.clinicaltrials.gov as #NCT02053480.

The Role of Thromboelastography in Pediatric Patients with Sinusoidal Obstructive Syndrome Receiving Defibrotide.

Sinusoidal obstructive syndrome (SOS) is a potentially fatal form of hepatic injury after hematopoietic stem cell transplantation. Patients can develop liver dysfunction, portal hypertension, ascites, coagulopathies, and multisystem organ failure. The mortality rate of severe SOS has been reported as high as 98% by day 100 after transplantation. Defibrotide, which is now approved for the treatment of SOS, has significantly decreased mortality. Defibrotide is a polynucleotide with profibrinolytic, anti-ischemic, and anti-inflammatory activity. These properties can increase the risk of life-threatening bleeding in this patient population. Previous protocols have suggested maintaining international normalized ratio ≤ 1.5, platelets > 30 k/uL, and fibrinogen ≥ 150 mg/dL to minimize this risk of bleeding. However, this can be challenging in fluid-sensitive patients with SOS. Thromboelastography (TEG) is a functional assay that evaluates the balance of procoagulant and anticoagulant proteins. In this series, TEG was used to guide defibrotide therapy as well as blood product transfusions in SOS patients with abnormal coagulation studies. Each patient recovered from SOS and had no bleeding complications. A randomized clinical trial is the next step in supporting the use of TEG in SOS patients with abnormal coagulation studies receiving defibrotide therapy.

Treatment, survival, and thromboembolic outcomes of thrombotic storm in children.

OBJECTIVE: To describe the course and management of thrombotic storm in 8 children. STUDY DESIGN: Clinical data were collected and analyzed for consecutive children diagnosed with thrombotic storm, aged 6 months to 21 years inclusive, in the context of a single-institution prospective inception cohort study. Thrombotic storm was defined as newly diagnosed multisite venous thromboembolism (VTE) with acute thrombus progression despite conventional or higher than conventional dosing of heparin or low molecular weight heparin. All evaluations and therapies were ordered by the treating physicians in the context of clinical decision making. RESULTS: Eight of the 178 children with VTE enrolled in the cohort between March 2006 and November 2009 were diagnosed with thrombotic storm. Antiphospholipid antibodies were acutely positive in 6 children, of whom heparin-induced thrombocytopenia was confirmed by serotonin release assay in 2 and atypical in 1. One child died. Five children received a direct thrombin inhibitor, titrated to achieve normalization of markedly elevated D-dimer levels. All children were transitioned to fondaparinux or enoxaparin before receiving extended anticoagulation with warfarin. Immunomodulatory therapy was instituted in all children. During follow-up (median duration, 3 years; range, 2-6 years), 3 of the 7 surviving children experienced recurrent VTE, and 4 children had clinically significant postthrombotic syndrome. CONCLUSION: Thrombotic storm is an infrequent but potentially fatal presentation of VTE in children. Administration of direct thrombin inhibitors and immune modulation can achieve quiescence, although long-term adverse outcomes are common.

Fibronectin bridges monocytes and reticulocytes via integrin alpha4beta1.

Leucocytes are emerging as critical determinants in the severity of the pathology associated with sickle cell disease (SCD) and recent studies have shown that they can bind to sickle red blood cells (SS RBCs). However, the mechanism of this interaction is unclear. The alpha4beta1 integrin on monocytes and SS reticulocytes was found to mediate the interaction of these cells in in-vitro adhesion assays and in the blood of SCD patients. Plasma fibronectin (Fn), a ligand for alpha4beta1, could link SS RBCs to monocytes, as peptides derived from both the Arg-Gly-Asp-Ser (RGDS) and CS-1 site in Fn disrupted the reticulocyte/monocyte interaction. It was further shown in whole blood that 70% of the interacting monocytes were also bound to platelets, suggesting the existence of multi-cellular aggregates in SCD. Platelet inclusion in these aggregates was mediated by a P-selectin/P-selectin glycoprotein ligand-1 interaction, which has been demonstrated to activate the monocyte. These results suggest a new model for understanding the mechanism of attachment of SS RBCs to monocytes and implicate the platelet as a component and contributor to potentially occlusive aggregates that circulate in the blood of SCD patients.

Hearing genes and cisplatin deafness: a pilot study.

OBJECTIVE: Cisplatin commonly is used to treat pediatric solid tumors. A major dose-limiting toxicity is sensorineural hearing loss. Which patients experience ototoxicity after treatment with cisplatin must reflect individual susceptibility, since it is not seen in all similarly treated patients. We hypothesized that mutations or polymorphisms in hearing genes are more common in patients who experience ototoxicity than in the general population. STUDY DESIGN: We completed retrospective mutation screening of GJB2 and SLC26A4 and screened for three mtDNA mutations in patients with a history of childhood cancer who developed severe hearing loss at cumulative cisplatin doses of less than 400 mg/M2. MATERIALS AND METHODS: Patients younger than 21 years of age who experienced severe hearing loss after cisplatin were identified using the Childhood Cancer Survivor Study database. Archival DNA from buccal washes of 11 patients was used for mutation screening and detection. RESULTS: With the exception of one patient (9.1%) who was a carrier for the 35delG mutation, no mutant alleles were found. Given the reported prevalence of the 35delG mutation in the general population of 2.5%, this result is not significant (P = .35). CONCLUSIONS: It is not likely that any of the five hearing genes we examined contribute to cisplatin ototoxicity. Further study may be warranted to look at other hearing genes as possible predictors of cisplatin ototoxicity.