Safety and Efficacy of Hizentra® Following Pediatric Hematopoietic Cell Transplant for Treatment of Primary Immunodeficiencies.

Primary immunodeficiency disease (PIDD) comprises a group of disorders of immune function. Some of the most severe PIDD can be treated with hematopoietic cell transplant (HCT). Hizentra® is a 20% liquid IgG product approved for subcutaneous administration in adults and children greater than 2 years of age with PIDD-associated antibody deficiency. Limited information is available on the use of Hizentra® in children following HCT for PIDD. A multicenter retrospective chart review demonstrated 37 infants and children (median age 70.1 [range 12.0 to 176.4] months) with PIDD treated by HCT who received Hizentra® infusions over a median duration of 31 (range 4-96) months post-transplant. The most common indication for HCT was IL2RG SCID (n = 16). Thirty-two patients switched from IVIG to SCIG administration, due to one or more of the following reasons: patient/caregiver (n = 17) or physician (n = 12) preference, discontinuation of central venous catheter (n = 16), desire for home infusion (n = 12), improved IgG serum levels following lower levels on IVIG (n = 10), and loss of venous access (n = 8). Serious bacterial infections occurred at a rate of 0.041 per patient-year while on therapy. Weight percentile increased by a mean of 16% during the observation period, with females demonstrating the largest gains. Mild local reactions were observed in 24%; 76% had no local reactions. One serious adverse event (death from sepsis) was reported. Hizentra® was discontinued in 15 (41%) patients, most commonly due to recovery of B cell function (n = 11). These data demonstrate that Hizentra® is a safe and effective option in children who have received HCT for PIDD.

Investigating the Influence of Aromatic Counterions on the Micellar Structure and Aggregation Behavior of Morpholinium-Based Surface-Active Ionic Liquids in an Aqueous Solution.

Two morpholinium-based surface-active ionic liquids (SAILs) with aromatic counterions were synthesized, namely, n-dodecyl-n-methylmorpholinium salicylate [C12mmor][Sal] and n-dodecyl-n-methylmorpholinium 3-hydroxy-2-naphthoate [C12mmor][3-h-2-n], and explored their aggregation behavior in aqueous solutions systematically. Electrical conductivity, small-angle neutron scattering (SANS), surface tension (ST), and UV-vis spectroscopy measurements were employed to determine various thermodynamic, micellar, and interfacial parameters, like the degree of counterion binding (ß), critical micelle concentration (CMC), minimum area per molecule (Amin), surface excess concentration (Γmax), standard Gibbs free energy of adsorption (ΔGad0), aggregation number (Nagg), standard Gibbs free energy of micellization (ΔGm0), standard enthalpy of micelle formation (ΔHm0), and the standard entropy of micellization (ΔSm0) in an aqueous solution. Incorporating the aromatic counterions favors significantly excellent micellization properties over conventional halogenated SAILs such as [C12mmor][Br]. SANS analysis revealed that upon changing the counterion from salicylate to 3-hydroxy-2-naphthoate, the structure changed from prolate ellipsoidal micelles to large unilamellar vesicles. Also, increasing the concentration in the case of [C12mmor][Sal] resulted in a lower aggregation number.

Cost Effectiveness of Cognitive Behavioral Therapy for the Treatment of Subjective Tinnitus in Australia.

OBJECTIVES: The aim of this study was to conduct an economic evaluation for the treatment of subjective tinnitus using different modalities of cognitive behavioral therapy (CBT) in Australia. DESIGN: A decision tree model was used to conduct a cost-utility analysis for CBT to determine the cost effectiveness for tinnitus treatments, in terms of cost per responder and cost per quality-adjusted life-year (QALY), from a health system perspective using a 2-year time horizon. Meta-analysis was used to differentiate the levels of effectiveness between three delivery methods for CBT: individual face-to-face care (fCBT), group sessions (gCBT), and a supported internet program (iCBT). One-way sensitivity analysis and probabilistic sensitivity analysis (PSA) explored the uncertainty surrounding model inputs and outcomes. Results were presented as incremental cost-effectiveness ratios compared with no treatment, and as net monetary benefit at a $50,000 willingness-to-pay threshold. RESULTS: Compared with no treatment, the incremental cost per responder was $700 for gCBT, $871 for iCBT, and $1380 for fCBT. The base case incremental cost-effectiveness ratio was $35,363 per QALY for fCBT, $17,935 per QALY for gCBT, and $22,321 per QALY for iCBT compared with no treatment, although there was substantial uncertainty around the QALY gain for responders. Net monetary benefit was $356 (fCBT), $555 (gCBT), and $487 (iCBT), indicating the treatments were cost effective compared with no treatment. One-way sensitivity analysis revealed the results were most sensitive to the probability of a positive response to treatment and treatment length. The PSA found the probability of being cost effective compared with no treatment for gCBT was 99.8%, iCBT 98.4%, and fCBT 71.5% at a willingness-to-pay of $50,000 per QALY, although QALY gain remained at a fixed value in the PSA. CONCLUSIONS: CBT for tinnitus was likely to be cost effective compared with no treatment regardless of treatment modality, assuming they are not mutually exclusive. Of the interventions, gCBT was the lowest cost per responder and lowest cost per QALY. Internet CBT obtained comparable economic outcomes due to similar treatment effectiveness and cost. Group CBT and iCBT warrant greater adoption in clinical practice for the treatment of subjective tinnitus. Further research on preference-based utility measures for varying levels of tinnitus severity and the durability of treatment effect is required to enhance the quality of economic evaluation in this field.

Safety and Tolerability of Subcutaneous IgPro20 at High Infusion Parameters in Patients with Primary Immunodeficiency: Findings from the Pump-Assisted Administration Cohorts of the HILO Study.

PURPOSE: To evaluate the safety and tolerability of subcutaneous IgPro20 (Hizentra®, CSL Behring, King of Prussia, PA, USA) administered at high infusion parameters (> 25 mL and > 25 mL/h per injection site) in patients with primary immunodeficiency. METHODS: The Hizentra® Label Optimization (HILO) study was an open-label, parallel-arm, non-randomized study (NCT03033745) of IgPro20 using a forced upward titration design for infusion parameters. Patients experienced with pump-assisted IgPro20 infusions received weekly IgPro20 infusions at a stable dose in the Pump-Assisted Volume Cohort (N = 15; 25-50 mL per injection site) and in the Pump-Assisted Flow Rate Cohort (N = 18; 25-100 mL/h per injection site). Responder rates (percentage of patients who successfully completed ≥ 75% of planned infusions), safety outcomes, and serum immunoglobulin G (IgG) trough levels were evaluated. RESULTS: Responder rates were 86.7% (13/15, 25 mL) and 73.3% (11/15, 40 and 50 mL) in the Volume Cohort, and 77.8% (14/18, 25 and 50 mL/h), 66.7% (12/18, 75 mL/h), and 61.1% (11/18, 100 mL/h) in the Flow Rate Cohort. Infusion compliance was ≥ 90% in all patients in the Volume Cohort and in 83.3% of patients in the Flow Rate Cohort. The number of injection sites (Volume Cohort) and the infusion duration (Flow Rate Cohort) decreased with increasing infusion parameters. The rate of treatment-emergent adverse events per infusion was low (0.138 [Volume Cohort] and 0.216 [Flow Rate Cohort]). Serum IgG levels remained stable during the study. CONCLUSION: Pump-assisted IgPro20 infusions are feasible at 50 mL and 100 mL/h per injection site in treatment-experienced patients, which may result in fewer injection sites and shorter infusion times. TRIAL REGISTRATION: NCT03033745 ; registered January 27, 2017.

Safety and Tolerability of Manual Push Administration of Subcutaneous IgPro20 at High Infusion Rates in Patients with Primary Immunodeficiency: Findings from the Manual Push Administration Cohort of the HILO Study.

PURPOSE: To evaluate the safety and tolerability of IgPro20 manual push (also known as rapid push) infusions at flow rates of 0.5-2.0 mL/min. METHODS: Patients with primary immunodeficiency (PID) with previous experience administering IgPro20 (Hizentra®, CSL Behring, King of Prussia, PA, USA) were enrolled in the Hizentra® Label Optimization (HILO) study (NCT03033745) and assigned to Pump-assisted Volume Cohort, Pump-assisted Flow Rate Cohort, or Manual Push Flow Rate Cohort; this report describes the latter. Patients administered IgPro20 via manual push at 0.5, 1.0, and 2.0 mL/min/site for 4 weeks each. Responder rates (percentage of patients who completed a predefined minimum number of infusions), safety outcomes, and serum immunoglobulin G (IgG) trough levels were evaluated. RESULTS: Sixteen patients were treated; 2 patients (12.5%) discontinued at the 1.0-mL/min level (unrelated to treatment). Responder rates were 100%, 100%, and 87.5% at 0.5-, 1.0-, and 2.0-mL/min flow rates, respectively. Mean weekly infusion duration decreased from 103-108 to 23-28 min at the 0.5- and 2.0-mL/min flow rates, respectively. Rates of treatment-related treatment-emergent adverse events (TEAEs) per infusion were 0.023, 0.082, and 0.025 for the 0.5-, 1.0-, and 2.0-mL/min flow rates, respectively. Most TEAEs were mild local reactions and tolerability (infusions without severe local reactions/total infusions) was 100% across flow rate levels. Serum IgG levels (mean [SD]) were similar at study start (9.36 [2.53] g/L) and end (9.58 [2.12] g/L). CONCLUSIONS: Subcutaneous IgPro20 manual push infusions at flow rates up to 2.0 mL/min were well tolerated and reduced infusion time in treatment-experienced patients with PID. TRIAL REGISTRATION: NCT03033745.

Hemophagocytic Lymphohistiocytosis in Langerhans Cell Histiocytosis: A Case Report and Review of the Literature.

A toddler undergoing treatment for refractory Langerhans cell histiocytosis (LCH) developed concurrent hemophagocytic lymphohistiocytosis (HLH). These are thought to be distinct histiocytic disorders, with different pathophysiologies, diagnostic criteria, and treatments. HLH in a patient with LCH is thought to be quite rare. In this report, we review the presentation of our patient, as well as review the existing literature of other pediatric patients who have been diagnosed with both LCH and HLH.

Professional Women's Softball Injuries: An Epidemiological Cohort Study.

OBJECTIVE: To report the epidemiology of Women's National Professional Fast-Pitch (NPF) softball injuries during the 2017 season. The secondary objective was to evaluate risk factors for pitching injuries. DESIGN/SETTING: Prospective injury data were collected from the primary clinical care of 6 professional softball teams. PARTICIPANTS: The NPF study population consisted of 153 players. INDEPENDENT VARIABLES: Data collection included the following: number of practices each week, diagnosis of the injury, game or practice injury, position played when sustaining the injury, treatment for the injury, number of missed practices and/or games as a result of the injury, and total days until return to play. MAIN OUTCOME MEASURES: Injury rate (IR) overall, IR in position players, and IR in pitchers. Secondary outcomes included risk assessment for injury in pitchers; descriptive statistics on the injuries recorded in all players. RESULTS: Pitchers reported both upper extremity and lower extremity injuries equally, whereas positional players reported more lower extremity injuries. Pitchers were also most likely to be injured during a practice than a game. Overall, there were 3.26 reported game injuries per 1000 athlete exposures (AE) and 4.79 practice injuries per 1000 AE. Pitchers specifically had 1.88 reported game injuries per 1000 AE and 5.66 practice injuries per 1000 AE. CONCLUSIONS: In contrast to previous data, our study showed an increased IR in practice as compared to games in both position players and pitchers. Significant injuries were relatively rare, and most injuries seemed minor, usually with less than 7 days missed, suggesting a relative safety associated with this sport.

Individualized immunoglobulin treatment in pediatric patients with primary humoral immunodeficiency disease.

Primary immunodeficiency diseases (PIDD) are a group of genetic conditions that are generally considered to be under-diagnosed, and gaps may exist in the knowledge of treatment options. This review focuses on the diagnosis of pediatric patients with primary antibody deficiency and considerations for treatment with immunoglobulin (IgG) to optimize multiple dosing variables and minimize adverse events. The possibility of individualizing IgG therapy in clinical practice represents, in this field, the next pivotal step with the goal of improving the quality of life of pediatric patients with PIDD.

Integrated micro-biochemical approach for phytoremediation of cadmium and lead contaminated soils using Gladiolus grandiflorus L cut flower.

The potential of vermicompost, elemental sulphur, Thiobacillus thiooxidans and Pseudomonas putida for phytoremediation is well known individually but their integrated approach has not been discovered so far. The present work highlights the consideration of so far overlooked aspects of their integrated treatment by growing the ornamental plant, Gladiolus grandiflorus L in uncontaminated and sewage-contaminated soils (sulphur-deficient alluvial Entisols, pH 7.6-7.8) for phytoremediation of cadmium and lead under pot experiment. Between vermicompost and elemental sulphur, the response of vermicompost was higher towards improvement in the biometric parameters of plants, whereas the response of elemental sulphur was higher towards enhanced bioaccumulation of heavy metals under soils. The integrated treatment (T7: vermicompost 6g and elemental sulphur 0.5gkg(-1) soil and co-inoculation of the plant with T. thiooxidans and P. putida) was found superior in promoting root length, plant height and dry biomass of the plant. The treatment T7 caused enhanced accumulation of Cd up to 6.96 and 6.45mgkg(-1) and Pb up to 22.6 and 19.9mgkg(-1) in corm and shoot, respectively at the contaminated soil. T7 showed maximum remediation efficiency of 0.46% and 0.19% and bioaccumulation factor of 2.92 and 1.21 and uptake of 6.75 and 21.4mgkg(-1) dry biomass for Cd and Pb respectively in the contaminated soil. The integrated treatment T7 was found significant over the individual treatments to promote plant growth and enhance phytoremediation. Hence, authors conclude to integrate vermicompost, elemental sulphur and microbial co-inoculation for the enhanced clean-up of Cd and Pb-contaminated soils.

Softball Pitching and Injury.

The windmill softball pitch generates considerable forces about the athlete's shoulder and elbow. The injury pattern of softball pitchers seems to be primarily overuse injury, and they seem not to suffer the same volume of injury that baseball pitchers do. This article will explore softball pitching techniques, kinetics and kinematics of the windmill pitch, epidemiology of softball pitchers, and discuss possible etiologies of softball pitching injuries.

Subcutaneous Immunoglobulin Replacement Therapy with Hizentra® is Safe and Effective in Children Less Than 5 Years of Age.

BACKGROUND: Hizentra® (IGSC 20%) is a 20% liquid IgG product approved for subcutaneous administration in adults and children 2 years of age and older who have primary immunodeficiency disease (PIDD). There is limited information about the use of IGSC 20 % in very young children including those less than 5 years of age. METHODS: A retrospective chart review involved 88 PIDD infants and children less than 5 years of age who received Hizentra®. RESULTS: The mean age at the start of Hizentra® was 34 months (range 2 to 59 months). IGSC 20 % was administered weekly to 86 infants (two additional infants received twice weekly and three times weekly infusions, respectively) and included an average of 63 infusions (range 6-182) for an observation period up to 45.5 months. Infusion by manual delivery occurred in 15 patients. The mean dose was 674 mg/kg/4 weeks. The mean IgG level was 942 mg/dL while on IGSC 20 %, compared to a mean trough IgG level of 794 mg/dL (p < 0.0001) during intravenous or subcutaneous IgG administration prior to IGSC 20 %. Average infusion time was 47 (range 5-120) minutes, and the median number of infusion sites was 2 (range 1-4). Local reactions were mostly mild and observed in 36/88 (41%) children. No serious adverse events were reported. A significant increase in weight percentile (7 % ± 19.2, p = 0.0012) among subjects was observed during IGSC 20% administration. The rate of serious bacterial infections was 0.067 per patient-year while receiving IGSC 20%, similar to previously reported efficacy studies. CONCLUSIONS: Hizentra® is effective in preventing infections, and is well tolerated in children less than age 5 years.

Effect of weight loss on magnetic resonance imaging estimation of liver fat and volume in patients with nonalcoholic steatohepatitis.

BACKGROUND & AIMS: Little is known about how weight loss affects magnetic resonance imaging (MRI) of liver fat and volume or liver histology in patients with nonalcoholic steatohepatitis (NASH). We measured changes in liver fat and liver volume associated with weight loss by using an advanced MRI method. METHODS: We analyzed data collected from a previous randomized controlled trial in which 43 adult patients with biopsy-proven NASH underwent clinical evaluation, biochemical tests, and MRI and liver biopsy analyses at the start of the study and after 24 weeks. We compared data between patients who did and did not have at least 5% decrease in body mass index (BMI) during the study period. RESULTS: Ten of 43 patients had at least a 5% decrease in BMI during the study period. These patients had a significant decrease in liver fat, which was based on MRI proton density fat fraction estimates (18.3% ± 7.6% to 13.6% ± 13.6%, P = .03), a relative 25.5% reduction. They also had a significant decrease in liver volume (5.3%). However, no significant changes in levels of alanine aminotransferase or aspartate aminotransferase were observed with weight loss. Thirty-three patients without at least 5% decrease in BMI had insignificant increases in estimated liver fat fraction and liver volume. CONCLUSIONS: A reduction in BMI of at least 5% is associated with significant decrease in liver fat and volume in patients with biopsy-proven NASH. These data should be considered in assessing effect size in studies of patients with nonalcoholic fatty liver disease or obesity that use MRI-estimated liver fat and volume as end points.

Esophageal infections: an update.

PURPOSE OF REVIEW: Infectious esophagitis generally occurs in patients with impaired immunity. Although methods to suppress the immune system evolve, the potential infectious consequences are poorly understood. The purpose of this article is to review the risk factors, diagnosis, and treatment of infectious esophagitis. RECENT FINDINGS: Minimal pediatric data, including a few case reports and series, involve infectious esophagitis. Esophageal infections are usually caused by the following microbes, in order starting with the most common: Candida albicans, herpes simplex virus, and cytomegalovirus. Uncommon risk factors in these and other reports include epidural triamcinolone and oral budesonide in addition to more common risk factors such as HIV infection, chemotherapeutic agents, and transplant immunosuppressive medications. Rare reports involve immunocompetent patients and treatment of these patients is controversial. SUMMARY: Understanding of infectious esophagitis is growing, and risk factors, diagnosis, and treatments are evolving.

Integrated micro-biochemical approach for phytoremediation of cadmium and zinc contaminated soils.

The integrated potential of oilcake manure (OM), elemental sulphur (S(0)), Glomus fasciculatum and Pseudomonas putida by growing Helianthus annuus L for phytoremediation of cadmium and zinc contaminated soils was investigated under pot experiment. The integrated treatment (2.5 g kg(-1) OM, 0.8 g kg(-1) S(0) and co-inoculation with G. fasciculatum and P. putida promoted the dry biomass of the plant. The treatment was feasible for enhanced cadmium accumulation up to 6.56 and 5.25 mg kg(-1) and zinc accumulation up to 45.46 and 32.56 mg kg(-1) in root and shoot, respectively, which caused maximum remediation efficiency (0.73 percent and 0.25 percent) and bioaccumulation factor (2.39 and 0.83) for Cd and Zn, respectively showing feasible uptake (in mg kg(-1) dry biomass) of Cd (5.55) and Zn (35.51) at the contaminated site. Thus, authors conclude to integrate oilcake manure, S(0) and microbial co-inoculation for enhanced clean-up of cadmium and zinc-contaminated soils.

A systematic analysis of recombination activity and genotype-phenotype correlation in human recombination-activating gene 1 deficiency.

BACKGROUND: The recombination-activating gene (RAG) 1/2 proteins play a critical role in the development of T and B cells by initiating the VDJ recombination process that leads to generation of a broad T-cell receptor (TCR) and B-cell receptor repertoire. Pathogenic mutations in the RAG1/2 genes result in various forms of primary immunodeficiency, ranging from T(-)B(-) severe combined immune deficiency to delayed-onset disease with granuloma formation, autoimmunity, or both. It is not clear what contributes to such heterogeneity of phenotypes. OBJECTIVE: We sought to investigate the molecular basis for phenotypic diversity presented in patients with various RAG1 mutations. METHODS: We have developed a flow cytometry-based assay that allows analysis of RAG recombination activity based on green fluorescent protein expression and have assessed the induction of the Ighc locus rearrangements in mouse Rag1(-/-) pro-B cells reconstituted with wild-type or mutant human RAG1 (hRAG1) using deep sequencing technology. RESULTS: Here we demonstrate correlation between defective recombination activity of hRAG1 mutant proteins and severity of the clinical and immunologic phenotype and provide insights on the molecular mechanisms accounting for such phenotypic diversity. CONCLUSIONS: Using a sensitive assay to measure the RAG1 activity level of 79 mutations in a physiologic setting, we demonstrate correlation between recombination activity of RAG1 mutants and the severity of clinical presentation and show that RAG1 mutants can induce specific abnormalities of the VDJ recombination process.

Outcomes of computed tomography and magnetic resonance enterography in clinical practice of inflammatory bowel disease.

BACKGROUND: Computed tomography (CT) and magnetic resonance (MR) enterography are now widely used to diagnose and monitor Crohn's disease. AIM: We sought to assess the use of enterography for management of inflammatory bowel disease (IBD) in our medical center. METHODS: We performed a retrospective review of all patients diagnosed with IBD who underwent MR or CT enterography from November 1, 2010 to October 25, 2012 at our institution. We assessed disease complications identified by enterography, agreement between disease activity determined by endoscopy and enterography, association between inflammatory markers and enterography-determined disease activity and recommended changes in medical and surgical management following enterography. RESULTS: A total of 311 enterography studies (291 MR and 20 CT enterographies) were performed on 270 patients, including 258 (83.0 %) on patients with presumed Crohn's disease and 53 (17.0 %) with presumed ulcerative colitis. Active small bowel (SB) disease was noted in 73/311 (23.5 %) studies. Complications including strictures, perianal fistulas, abscesses and SB fistulas were noted in 108/311 (34.7 %) studies. Endoscopic and enterography defined active disease had an agreement of κ = 0.36 in the ileum (n = 179). A total of 142/311 (45.7 %) enterographies were associated with recommended medication changes within 90 days while surgery or endoscopic dilation of stricture was recommended following 41/311 (13.2 %) enterographies. Enterography resulted in a change in diagnosis from ulcerative colitis to Crohn's in 5/311 (1.6 %) studies. CONCLUSION: Enterography reveals active disease and complications not evident on endoscopy and should be considered in the initial diagnosis, assessment of disease activity, and monitoring of therapy in patients with IBD.

Evidence for the presence of Borrelia burgdorferi in invasive breast cancer tissues.

Borrelia burgdorferi, the causative agent of Lyme disease, has recently been demonstrated to infect and enhance the invasive properties of breast cancer cells, while also influencing the expression of inflammatory chemokines (CXCL8 and CXCL10). This study investigates the presence of B. burgdorferi in invasive breast cancer tissues using commercially available, FDA-approved breast cancer tissue microarrays consisting of 350 ductal, 32 lobular, and 22 intraductal invasive breast carcinomas, alongside 29 normal breast tissues. Employing fluorescent immunohistochemical staining and high-resolution imaging, the findings revealed that approximately 20% of invasive lobular and ductal carcinomas, followed by 14% of intraductal carcinomas, tested positive for B. burgdorferi, while all normal breast tissues tested negative. PCR analysis further confirmed the presence of B. burgdorferi DNA in breast cancer tissues. Moreover, 25% of B. burgdorferi-positive tissues exhibited expression of both chemokines, CXCL8 and CXCL10, which was not observed in B. burgdorferi-negative tissues. Analysis of available patient data, including age, indicated a correlation between older patients and B. burgdorferi-positive tissues. This study validates the presence of B. burgdorferi in invasive breast cancer tissues and highlights the involvement of key CXCL family members associated with inflammatory processes.