Replacement Products Research Articles

Novel freeze drying based technologies for production and development of healthy snacks and meal replacement products with special nutrition and function: A review

Due to the increased knowledge of nutrients and functional ingredients for their positive effects on health, people are tending to choose healthy food products including the snacks rich in these nutrients and ingredients. Healthy meal replacement products, which are calorie-controlled, nutritionally-balanced or/and functionally-fortified “meals,” are another food product that meets people’s health needs. Novel processing technologies enable the production of new products meeting the expectations of consumers. Among these technologies, freeze drying based processing technologies are especially suitable for producing products containing abundant nutrients and functional ingredients due to the drying environment with lower temperature and oxygen content. In this paper, the characteristics of freeze drying and the novel processing technologies based on freeze drying applied to produce healthy snacks and meal replacement products are critically reviewed, the new freeze dried healthy snacks and meal replacement products enriched with special nutrition and function are also discussed.

Microlite-group minerals: tracers of complex post-magmatic evolution in beryl–columbite granitic pegmatites, Maršíkov District, Bohemian Massif, Czech Republic

AbstractMicrolite-group minerals occur as common replacement products after primary and secondary columbite-group minerals (CGM) in albitised blocky K-feldspar and in coarse-grained, muscovite-rich units of the Schinderhübel I, Scheibengraben and Bienergraben beryl–columbite pegmatites in the Maršíkov District (Silesian Unit, Bohemian Massif, Czech Republic). Textural and compositional variations of microlite-group minerals were examined using electron probe micro-analyses and microRaman spectroscopy (μRS). A complex post-magmatic evolution of the pegmatites and the following microlite populations (Mic) and related processes were found: (1) precipitation of U, Na-rich and F-poor Mic I on cracks in CGM; (2) alteration of Mic I to U-rich together with Na- and F-poor Mic II; and (3) partial replacement of Mic I and II by Mic III with a distinct Na, U and Ti loss and Ca and F gain. Stage (2) includes an extensive leaching of Na, without U loss. The final stage (3) produced euhedral-to-subhedral oscillatory zoned Ca and F enriched Mic III with distinctly different composition to the previous F-poor andA-site vacant Mic II. Aggregates of fersmite are associated commonly with Mic III. Distal Mic IIId occurs locally on cracks in K-feldspar or quartz, with compositions analogous to Mic III. Compositional variations and textural features of microlite-group minerals during dissolution–reprecipitation processes serve as sensitive tracers of post-magmatic evolution in granitic pegmatites recording complex interactions between magmatic pegmatite units and externally derived, hydrothermal metamorphic fluids.

Smoking cessation strategies used by former menthol cigarette smokers after a menthol ban

IntroductionMenthol cigarettes were banned in Ontario, Canada on January 1st, 2017. We used concept mapping, a mixed-method approach, to describe how menthol cigarette smokers quit smoking after the Ontario menthol ban. MethodsPre-ban daily and non-daily menthol cigarette smokers who reported smoking abstinence 24 months after the ban (n = 62; 53.2% women; mean age = 43.6, SD = 12.5) generated statements describing reasons and strategies for smoking cessation/reduction after the menthol ban. Participants sorted a final list of 57 statements into groups of similar content and rated statements on how true each statement was for them and multidimensional scaling analysis identified thematic clusters. ResultsSix clusters were identified: Mental and Environment Changes, Direct Ban Impacts, Health Reasons, Cues to Action, Family and Friends, and Cessation Strategies. The highest rated statements (i.e., most true) suggested many participants were motivated to quit smoking before or after the ban and 30.7% of participants believed the menthol ban helped with smoking cessation. Some of the lowest rated statements included using nicotine replacement therapy products, medication (i.e., Champix), or other tobacco products suggesting these strategies were less common. Statement ratings suggested many smokers quit without using replacement products or medication, but modifying cognitions and avoiding smoking cues were common. ConclusionsThe menthol ban aided some menthol smokers to quit, while others reported the ban did not play a role in smoking cessation. These data suggest the menthol ban had direct and indirect effects on smoking reduction behavior. Campaigns supporting similar bans that target both types of effects will likely be most effective for smoking reduction.

Effects of nano cotton stalk and palm leaf ashes on ultrahigh-performance concrete properties incorporating recycled concrete aggregates

The demand for partial replacement and complementary products of cement to enhance the properties of concrete and reduce the environmental pollution from the cement industry is recently increasing. Nano cotton stalk ash (NCSA) and palm leaf ash (PLA) are agricultural residues resulting from the burning of cotton stalk and palm leaves used as biomass. This investigation aims to study the effect of using NCSA and PLA as partial replacements to cement in ultrahigh-performance concrete (UHPC). As partial replacements for cement mass, 0%, 2.5%, 5, 7.5% and 10% of NCSA and 10%, 20% and 30% of PLA were adopted to produce the UHPC. Sixteen mixtures were prepared to evaluate the new and mechanical properties of UHPC containing the NCSA and the PLA. In addition, NCSA and PLA morphologies were evaluated using a scanning electron microscope, and thermogravimetric analysis with differential thermal analysis and X-ray diffraction was applied to assess ash characteristics. Results of the microstructure tests showed that heat treatment of the ash improved its properties by removing carbon and unburned organic matter with a slight change in the mineral composition of the PLA. The increase in the cement replacement rates by ashes led to a decrease in the slump flow, whilst the largest slump flow reduction was recorded in the mix containing 30% of PLA and 10% of NCSA as a replacement of Portland cement by 14.5% mm compared with the reference mix. The application of replacement rates by 2.5% and 5% of NCSA and 20% of PLA by cement mass to produce UHPC respectively realised the highest compressive strengths of 161.7 and 170.1 MPa at 90 days. Moreover, the mixture containing 20% of PLA with 5% of NCSA achieved the highest values of splitting tensile strength, flexural strength and elastic modulus.

Electronic cigarettes, vaping-related lung injury and lung cancer: where do we stand?

Electronic cigarettes have been considered a promising alternative to nicotine replacement products to help heavy tobacco smokers quit smoking. They work thanks to a heating coil causing evaporation of the liquid rapidly followed by cooling, thus creating an aerosol, a completely different mechanism from the combustion of tobacco in traditional cigarettes. The term 'vaping' indicates the use of electronic cigarettes or other devices to inhale heated, aerosolized nicotine, or other substances like cannabidiol, tetrahydrocannabinol, or butane hash oils together with solvents, mainly propylene glycol and vegetable glycerine or their combination. A very fast increase of vaping among adolescents has been observed since electronic cigarettes and other vaping devices first appeared. Although electronic cigarettes have been advocated as a short-term cessation aid for tobacco smokers or as a long-term alternative, there is the concrete risk that they can be perceived by young nonsmokers as a less dangerous alternative to tobacco smoking, thus stimulating nonsmokers to start smoking rather than helping heavy tobacco smokers to quit smoking. Moreover, several cases of exogenous lipoid pneumonia and diffuse alveolar hemorrhage with proven alveolar injury, as well as vaping-associated bronchiolitis obliterans, have been recently reported among electronic cigarette smokers, with severe clinical impact, thus posing the risk of the life-threatening toxic potential of vaping. At the moment, no definitive assessment can be made about the efficacy of electronic cigarettes as a smoking cessation aid, and further studies are required about vaping-related life-threatening acute lung injury.

Fingerprinting fluid evolution by trace elements in epithermal pyrite, Vatukoula Au-Te deposit, Fiji

Tellurium (Te) is an important element for green technologies, including thin film photovoltaic panels. Stagnating supply caused by its by-product dependency together with an increasing demand will likely lead to a shortage in the near future. Pyrite may represent a potential target for the direct recovery of Te, since the concentrations of Te can reach weight percent levels under specific, but poorly constrained hydrothermal conditions. The Vatukoula (formerly Emperor) epithermal Au-Te deposit is currently mined for Au and ~ 75% are recovered from Au-tellurides and pyrite. Tellurium has been processed in the past, but is now sent to tailings despite of concentrations reaching 1.4 wt. % in pyrite, which makes this system a natural laboratory to investigate key Te enrichment processes.The epithermal mineralisation at Vatukoula consists of an early low-grade disseminated host-rock and a later high-grade Ag-Au-Te vein-type stage. Pyrite occurs in both ore-types with diverse As contents including concentrations < 0.5 wt. % in pure pyrite, 0.5 to 13 wt. % in low-As and 23 to 43 wt. % in high-As pyrite, reflecting increasing fluid As with system evolution towards the high-grade mineralisation. Tellurium contents in pyrite increase from pure pyrite (up to 220 ppm) to low-As pyrite (up to 1.4 wt. %), but with a decrease towards high-As pyrite (up to 185 ppm). This is a yet unknown relation, since trace element incorporation in pyrite is usually facilitated by increasing As. Instead, the presented results suggest a threshold between 13 and 23 wt. % As, above which the incorporation of Te and related elements (e.g., Ag, Au) may be less favourable. Mineral stabilities, trace element ratios (e.g., Sb/Pb, Tl/Pb) and LA-ICP-MS mapping of texturally distinct pyrite indicate that fluid boiling was a critical process for the Ag, Au and Te enrichment in the Vatukoula epithermal system. Fluid sulphidation states decreased with proceeding evolution of the epithermal system from initially intermediate- to late low-sulphidation conditions, which led to the diverse chemical character of pyrite. Early pure pyrite primarily formed as a replacement product of magnetite in the altered host rocks, whereas low- and high-As pyrite precipitated in the direct vicinity of Ag-Au-telluride veins, from which most of the As, Ag, Te and Au hosted in pyrite was derived from. Consequently, the trace element composition of pyrite allows the fingerprinting of the fluid evolution of Te-rich ore-forming systems like Vatukoula, Fiji.

Practical Application of the Athndataset: Evaluating Uptake of Extended Half-Life Factor Concentrates in Patients with Moderate and Severe Hemophilia

IntroductionHemophilia patients and providers have more treatment options than ever before. Integration of extended half-life (EHL) factor products into routine use for hemophilia A or B prophylaxis varies across hemophilia treatment centers (HTCs) and has not been formally described. The ATHNdataset is a national database of bleeding disorder and thrombosis patients who opt-in from 138 ATHN-affiliated HTCs and includes required core data elements. The primary aim of this longitudinal, observational study is to characterize the evolving real-world use of factor VIII (FVIII) and factor IX (FIX) concentrates, including rate of switching from one factor replacement product to another (switch rate), comparative annual factor consumption, and infusion frequency using serial queries of the ATHNdataset. A sub-study of detailed site-level questionnaires, above and beyond the ATHNdataset, including 8 HTCs evaluated the ability of the ATHNdataset to capture changes in EHL product use in real-time and demonstrate the fidelity of the ATHNdataset.MethodsAll patient level data was collected and analyzed under the patient authorization for the ATHNdataset. The selected population for analysis included all patients with moderate and severe hemophilia A or B without active inhibitors. EHL products were defined as those with moieties added with intention of half-life extension. The ATHNdataset was queried at baseline (June 2016) and follow-up 9 months later (March 2017). Sub-study site-level switching data was captured via quarterly RedCap™ questionnaires.ResultsATHNdataset analysisAt baseline, 7,552 patients were analyzed (5,504 FVIII, 1978 FIX). Of 3,163 FVIII patients on prophylaxis 87% were prescribed conventional FVIII concentrates and 13% EHL concentrates. Of the 699 FIX patients on prophylaxis 70% were prescribed conventional FIX concentrates, 30% EHL concentrates. Median dose and infusion frequency for FVIII products were 40 IU/kg/dose and 156 annual infusions and for FIX were 65 IU/kg/dose and 104 annual infusions.The 9-month follow-up analysis yielded 7,864 patients eligible (5,764 FVIII, 2,100 FIX). Frequency of use for both EHL FVIII and FIX is increasing. Baseline use of EHL FIX was substantially higher than that of EHL FVIII and continues to rise. Growth in use of EHL FVIII for prophylaxis was 3 times that of conventional FVIII. In aggregate 17% of patients changed from an on-demand to prophylaxis regimen with 40% of these patients initiating prophylaxis with an EHL product.Table 1: Comparative use of conventional and EHL factor concentrate captured in ATHNdataset.Table 2: Median dose and infusion frequency of conventional and EHL factor concentrates prescribed for prophylaxis.Sub-study analysisEight sites representing 1009 patients with moderate and severe hemophilia A or B from across the U.S. participated in the sub-study analysis. At baseline 8% of these patients were prescribed EHL concentrates. Across sites, the median was 10 patients (range: 0-18). Of the patients on an EHL product participating in the ATHNdataset, 63% were on EHL FVIII. At the 9-month follow-up an additional 33 patients had switched to an EHL product (17 FVIII, 16 FIX) equating to an overall EHL use of only 11.6%. Two patients switched among EHL products and 2 returned to a conventional product. Half of sub-study sites reported routinely obtained blood samples for PK analysis; 6 of 8 sites reported obtaining blood samples for PK analysis for patient switching to EHL products during follow-up period.ConclusionThe ATHNdataset presents a unique opportunity to investigate practice changes among U.S. HTCs. Uptake of EHL FVIII has been modest despite the first product being licensed in 2014. In contrast, the use of EHL FIX has now risen to greater than 40% of patients receiving prophylaxis. The median usage of EHL FVIII results in 27% reduction of annual units of factor prescribed for prophylaxis, and 46% reduction for EHL FIX compared to conventional products. The incremental increase in per unit price of EHL products, 30-72% greater than conventional products, exceeds the annual reduction of product usage. Consistent reporting of bleed events and adherence are not currently available for comparison. The contrast between sub-study uptake results and the ATHNdataset results highlight the practice variability among HTCs with respect to integration of EHL products into clinical care. [Display omitted] DisclosuresCroteau:ATHN/Hemophilia of Georgia: Research Funding; Octapharma: Honoraria; Baxalta, Dimension Therapeutics, Genentech, Pfizer: Research Funding; Aptevo, Baxalta/Shire, Bayer, CSL Behring, Genentech, Novo Nordisk, Octapharma, Pfizer: Consultancy. Raffini:Green Cross Inc: Consultancy; Genetech: Consultancy; CSL Behring: Consultancy; Bayer: Consultancy. Silvey:Pfizer, CSL Behring, Octapharma: Consultancy. Wheeler:NovoNordisk: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Octapharma: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees. Neufeld:Novartis: Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Octapharma: Consultancy, Honoraria.

Real-World Expenditures Associated with Treatment of Hemophilia a and B Patients with Standard and Extended Half-Life Factor Replacement Products in the US

Introduction:Management of Hemophilia A and B require intravenous factor VIII (FVIII) and factor IX (FIX) infusions respectively to replenish missing coagulation factor. We compared real world expenditures in the US for clotting factor concentrates associated with treatment of Hemophilia A and B patients with EHL products versus recombinant standard half-life (SHL) products.Methods:De-identified claims data from the Truven Health MarketScan® Research US claims databases were used to identify male patients with either hemophilia A who received FVIII replacement from August, 2014 (month first EHL FVIII product dispensed) to April 2017; or hemophilia B who received FIX replacement from June 2014 (month first EHL FIX product dispensed) to April 2017 and had data for at least 3 months of dispensation. The two groups of patients (SHL vs EHL) were compared. Key outcome measures were direct expenditures and factor IUs dispensed for factor replacement products. Expenditures and IUs dispensed were measured over quarterly (3-month) increments for 10 quarters in each group (SHL & EHL). Descriptive statistics were used to analyze results. Medians for expenditures and IUs were used to accommodate for the skewness of data distribution.Results:Hemophilia A538 Hemophilia A patients were included in the analysis (437 SHL; 104 EHL), including patients who switched from one class to the other. Quarterly expenditures and IUs dispensed were analyzed for these patients up to 30 months.The median quarterly study period factor per patient expenditure was $72,466 higher (2.15 times) in the EHL cohort ($135,392; IQR: $101,690-$189,501) compared with the SHL cohort ($62,927; IQR: $19,448-$121,192). Median quarterly study period per patient IU dispensation was also higher in the EHL cohort (68,736 IUs; IQR: 49,687-100,883) vs SHL users (48,473 IUs; IQR: 13,396-91,102).Median total Hemophilia A related expenditures were $137,210 and $66,713 in the EHL and SHL cohorts indicating that the total expenditures were chiefly due to factor replacement.In the switch analysis, 35 patients had switched from one of three SHL FVIII products to one of two EHL FVIII products. The total median IU dispensation per calendar quarter increased following the switch from 60,396 IU (pre-switch, SHL) to 78,295 IU (post-switch, EHL; 30% increase), as did the factor-related expenditure ($78,945, SHL, versus $160,008, EHL; 103% increase).Hemophilia B104 Hemophilia B patients that had at least 3 months data were included in the analysis (79 SHL; 25 EHL). Quarterly expenditures and IUs dispensed were analyzed for these patients over up to 30 months.The median quarterly study period factor per patient expenditure was $106,441 higher (2.8 times) in the EHL cohort ($165,022; IQR: $97,444-$260,839) compared with the SHL cohort ($58,580; IQR: $26,864 - $113,959). Median quarterly study period per patient metric IU dispensation was also higher in the EHL cohort (68,541 IUs; IQR: 33,941-97,098) vs SHL users (39,180 IUs; IQR: 19,000-87,550).Median total Hemophilia B related expenditures were $165,188 and $60,713 in the EHL and SHL cohorts indicating that the total expenditures were chiefly due to factor replacement.In the switch analysis, 15 patients with hemophilia B switched from SHL to EHL. Median quarterly per-patient factor expenditure for up to 30 months pre/post-switch was $73,862 (IQR: $54,717-$103,798) in the period pre-switch, and $209,795 (IQR: $124,418-$330,650) after the switch. Median quarterly per-patient metric IUs utilization pre-switch was 62,325 (IQR: 41,223-88,396) and 68,541 (IQR: 26,345-113,144) IUs post-switch.Conclusion:This real-world data analysis, unadjusted for treatment regimen or disease severity, showed a higher expenditure associated with EHL use in both Hemophilia A and Hemophilia B treatment in the US. Median quarterly study period per patient IU dispensation was also higher in the EHL cohort for both Hemophilia A and B. These real-world data may challenge assumptions regarding typical factor usage and expenditures associated with EHL products in patients with hemophilia A and B. Further analyses, incorporating essential clinical characteristics, should be explored. [Display omitted] DisclosuresChhabra:Pfizer Inc: Employment, Other: Stockholder. Alvir:Pfizer Inc: Employment, Other: Stockholder. Spurden:Pfizer Limited: Employment, Other: Stockholder. Fogarty:Pfizer Inc: Employment, Other: Stockholder. Tortella:Pfizer Inc: Employment, Other: Stockholder. McDonald:Pfizer Inc: Employment, Other: Stockholder. Pleil:Pfizer: Employment.

Inhibitor Screening in Severe Hemophilia a: A Six-Year Single Center Experience

Background : Factor VIII (FVIII) inhibitors comprise the most morbid and expensive complication in severe hemophilia A. Inhibitor risk is known to be highest within the first 50 exposures to FVIII replacement products, with greatest risk during the first 20 exposures. Routine inhibitor screening is typically performed frequently with the first 20 to 50 exposures, but screening after 50 exposures is controversial, given the high cost of testing and unknown benefit. Early inhibitor detection allows effective treatment of bleeding with bypassing agents, and prompt initiation of immune tolerance to eradicate the inhibitor. Here we report inhibitor screening results at the University of Colorado Hemophilia and Thrombosis Center. Methods : This is a retrospective review of inhibitor testing data from study participants with severe hemophilia A enrolled, with Institutional Review Board approved informed consent, in the Hemophilia Prospective Inceptional Cohort Study (HEMO-PICS) from April 1, 2011 through April 1, 2017. A positive inhibitor was defined as modified Nijmegen Bethesda titer ≥0.5 confirmed on 2 separate blood draws. Tolerance was defined as a Bethesda titer <0.5 on two or more samples. The clinical protocol prescribed inhibitor screening in severe hemophilia A patients every 3-5 exposures prior to 50, and annually thereafter in accordance with National Hemophilia Foundation and US Centers for Disease Control recommendations. Results : Of 204 participants with severe hemophilia A in the study cohort, 24 had fewer than 50 factor exposures and were inhibitor negative at the start of the study observation period (“<50 Exposures Group”), 13 participants had a positive inhibitor at the start of the observation period (“+ Inhibitor Group”), and 167 had >50 exposures and a history of either no inhibitor or a tolerized inhibitor (“>50 Exposures Group”). Figure 1 shows inhibitor surveillance rates and results. In participants with < 50 exposures, positive inhibitors were detected in 11/42 screening tests, while participants with > 50 exposures had 0 positive inhibitors in 454 screening tests. In the “<50 Exposures Group”, 11 of 24 (45%) developed an inhibitor, 7 high titer (peak range 16.7 - 185 BU/mL) and 4 low titer (peak range 0.7 - 1.8 BU/mL). Six participants achieved 50 exposures without inhibitor development during the observation period, while the remaining 7 had fewer than 50 factor exposures at the end of the study period. The mean (+/- standard deviation) age of inhibitor development was 14.6 (+/- 6.2 [range 3-22]) months, after a mean of 12.8 (+/- 7.9 [range 1-29]) factor exposures. Six of those who developed inhibitors did so prior to starting prophylaxis, and the other 5 patients developed inhibitors within 2 months of prophylaxis initiation. Of those who did not develop inhibitors, 8 have been on prophylaxis for an average of 36 (+/- 23.8 [range 14-80]) months, 3 are planning to start prophylaxis, and 2 have declined. Of the 13 participants in the “+ Inhibitor Group”, 3 were tolerized during the study. Conclusion : We report a high rate of positive inhibitor surveillance tests in severe hemophilia A patients during the first 50 exposures (1 per 3.8 tests), and very low rates of positive inhibitors in this population following 50 exposures (0/454). While our results reinforce the practice of frequent inhibitor screening in patients with < 50 factor exposures, screening for inhibitors in patients with > 50 exposure days and no change in the bleeding phenotype is unlikely to be clinically relevant and should not be routinely performed. [Display omitted] DisclosuresWarren:CSL Behring Heimburger Award: Research Funding; Bayer Hemophilia Awards Program: Research Funding. Ng:CSL Behring Heimburger Award: Research Funding; Shire: Consultancy. Buckner:Shire: Membership on an entity's Board of Directors or advisory committees; Uniqure: Consultancy; Genentech: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees.

An Open-Label Study of the Safety and Efficacy of Morotocog Alfa (AF-CC) in Previously Untreated Patients Aged

Background: Moroctocog alfa (AF-CC) (ReFacto AF), a purified recombinant B-domain deleted factor VIII (FVIII) protein, is indicated for the treatment and prophylaxis of bleeding events in patients (pts) with hemophilia A and is manufactured in the absence of human albumin and purified using an affinity chromatography purification process along with additional filtration. It replaced the predecessor product moroctocog alfa, which was manufactured with human serum album and utilized murine monoclonal antibody purification. Data in previously untreated patients aged <6 years using moroctocog alfa (AF-CC) are lacking.Aims: To fulfill a European Medicines Agency requirement for post-authorization safety surveillance and risk management that moroctocog alfa (AF-CC) was acceptable in terms of efficacy and safety (including inhibitor development) in the usual care setting.Methods: This was a nonrandomized, open-label study that enrolled male patients with severe hemophilia A (FVIII activity <1%) aged <6 years and previously untreated patients (PUP) with a FVIII replacement product. The study was approved by an ethics committee and parents/guardians of all patients provided informed consent. The primary endpoint was the development of clinically significant inhibitors. Secondary endpoints focused on efficacy including the annualized bleeding rate (ABR), incidence of less-than-expected therapeutic effect (LETE), response to first on-demand treatment for new bleeding events (4-point rating scale), number of infusions to treat new bleeding events, and FVIII recovery. Moroctocog alfa (AF-CC) was dosed in accordance with the local prescribing information. Blood samples to test for inhibitors were collected at the 10 - 15 exposure day (ED) and 50 ED visits and at least every 6 months through the final visit. Recovery was performed during the enrolment visit (ED1), ED 10-15 visit, and at the ED 50 visit. Thereafter, recovery studies were recommended by at the investigators' discretion.Results: Twenty-three patients aged <6 years (mean age ± SD 1.0±1.09 years) participated for a median study duration of 476 days (min-max 92 - 1876 days). Dosing and frequency of dosing was at the discretion of the primary investigator in accordance with the moroctocog alfa (AF-CC) package insert. Clinically significant inhibitors were found in 5 (21.7%) patients with inhibitor detection overall in 8 (34.8%) patients. The aggregate ABR of all subjects on the study was 5.9±8.08. The percentage LETE was 0.0 and 0.1 for on-demand and prophylaxis settings, respectively. One infusion led to resolution of 88% of bleeding events and 66.4% of first infusions were rated as excellent or good. Overall, the mean number of infusions for resolution of a bleeding episode was 1.3±1.28. At ED1, recovery was 1.32 ± 0.654 IU/dL/IU/kg in subjects between the ages of 28 days to <24 months and 1.749 and 1.776 IU/dL/IU/kg in the 2 children aged greater than 2 yrs, 2.7 and 5.3 yrs respectively, and generally remained constant over the duration of the study.Conclusions: The clinical inhibitor rate along with the overall safety and efficiacy of moroctocog alfa (AF-CC) is similar to its predecessor product supporting that the change in manufacturing did not alter the overall clinical benefit. These data also support the use of moroctocog alfa (AF-CC) for the treatment of previously untreated hemophilia A patients less than 6 years of age. DisclosuresKavakli:Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Baumann:Inventiv: Other: Contractor working for Pfizer on the submitted study. Huard:Pfizer: Employment. Smith:Pfizer: Employment. Alvey:Pfizer: Other: Retired former employee. Korth-Bradley:Pfizer: Employment. Rendo:Pfizer: Employment. Rupon:Pfizer: Employment.

Defective Early B Cell Tolerance in Primary Immune Thrombocytopenia

AIMs:Primary immune thrombocytopenia (ITP) is a common bleeding disorder characterized by low platelet counts, which could cause serious bleeding. One hallmark of ITP is the production of platelet-specific autoantibodies, resulting in accelerated platelet destruction and impaired platelet production. The anti-platelet antibodies normally react with components of platelet glycoproteins (GPs), which are rich in negatively charged amino acids. However, it is not clear how these autoantibodies are generated in ITP patients. The aim of this study is to investigate the status of B cell central tolerance in ITP.Methods:To gain an insight into the early B cell tolerance in ITP, we investigated the B cell receptor (BCR) specificity and immunoglobulin genes of naïve B cells in ITP patients. Naïve B cells were sorted and distributed into 96-well PCR plates at one single cell per well by single cell flow sorting. Paired immunoglobulin heave (IgH) and light (IgL) chain genes were amplified by reverse transcription PCR from single naïve B cells. The correct PCR products were subcloned into corresponding vectors and sequenced. Matched IgH and IgL genes from the same B cell were co-transfected into HEK293 cells to express recombinant antibodies (Fig. 1). The reactivity of these antibodies against platelet antigens was determined by ELISA, immunofluorescence assays, and flow cytometry. Ig gene sequence features were analyzed by programs including IMGT, IgBLAST, and VHRFA-1.Results:So far, 228 recombinant antibodies were expressed derived from naïve B cells in 4 ITP patients and 4 healthy controls. The absolute numbers of somatic mutations (nucleotide exchanges compared with germ line) of VH and VL between naïve B cells and peripheral memory B cells revealed significant difference (5.1 and 4.4 v.s. 19.0 and 14.8, p < 0.05 in both comparisons), indicating that the sorted cells were actually naive B cells (Fig. 2). ELISA assay showed that 17.0% (21/124) of the ITP-derived naïve B cells were platelet-reactive, in contrast to the 2.8% (3/104) in healthy donor-derived naïve B cells (Fig. 3), suggesting a defective B cell tolerance in the early developing stage. The anti-platelet reactivity was also confirmed by immunofluorescence assays and flow cytometry. Sequence analysis revealed that positively charged amino acids were highly enriched in the complementarity determining region 3 (CDR3) of the anti-platelet antibodies, which possibly generates the potential to interact with the negatively charged glycoproteins. The IgL genes derived from ITP patients preferentially used upstream JΚ segments (25.7% v.s. 49.1 %, p < 0.01) compared with healthy controls, indicating an insufficient IgL receptor editing in ITP patients (Fig. 4). In addition, the frequencies of VH replacement products in ITP were elevated in IgH genes from ITP patients (8.6% v.s. 4.4%, p < 0.05) compared to healthy controls (Fig. 5).Conclusion:In summary, this study provides evidence of defective early B cell tolerance and accumulation of anti-platelet naïve B cells in patients with ITP. This defect might be a result of insufficient receptor editing in IgL as well as excessive VH replacement in IgH. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Patient-Reported Outcomes in Hemophilia B Patients Treated with IB1001 [Coagulation Factor IX (recombinant)

INTRODUCTION. Hemophilia B is a rare bleeding disorder caused by missing or defective factor IX, a clotting protein in the coagulation cascade. Patients with hemophilia B are treated with infusion of concentrated factor IX to replace the deficiency. As a chronic disease, patient quality of life and treatment satisfaction is a fundamental component of overall patient care in hemophilia B. Anecdotal evidence has suggested that some patients experience improved clinical outcomes and increased satisfaction when treated with IB1001, approved in the US as IXINITY®, [coagulation factor IX (recombinant)] (current factor treatment) as compared to their previous treatment. The objective of this study was to undertake a systematic assessment of IB1001 patient responses to measures of clinical care and quality of life that are relevant in hemophilia B in order to provide a more comprehensive description. METHODS. This was a cross-sectional study of hemophilia B patients in the United States currently being treated with IB1001. The study protocol was reviewed and approved by a central IRB. A survey was developed to capture patient-reported responses to clinical and quality of life questions of interest, including demographic characteristics, disease status, bleeding events, treatment, quality of life, and patient satisfaction. Where possible, patients were asked to compare responses on current factor treatment to those while on previous treatment with other available products. Patients were invited to complete the survey online. This was a pilot study to generate a descriptive analysis of patient experience. RESULTS. A total of 17 patients completed the survey. Most patients were male (76.5%) with a mean age of 43.8 years (range 16-73), and had been taking IB1001 for a mean 18 months at the time of this study. The elements most important for patient treatment choice were a high recovery rate, 24-hour half-life, no inhibitor development, and few side effects. Fewer annualized bleeding events were reported with the current factor treatment (mean 3.3 vs 6.7). Joint bleeds were most commonly reported, and most patients stated their bleed frequency was less (41%) or about the same (35%) on their current factor treatment compared to their previous treatment. Most patients reported their activity level as either ‘very active’ (23%), or ‘somewhat active’ (53%), and 47% of patients indicated they are more active now than on prior treatment. Overall, patients were either ‘very satisfied’ (76%) or ‘somewhat satisfied’ (12%) with their current factor treatment, compared with 12% and 23%, respectively, on prior treatment. Patients reported more mobility (29%), less pain (41%), and less anxiety or depression (18%) now than on prior treatment. CONCLUSIONS. In this study, we showed the utility of an online, survey-based instrument in characterizing patient experience with factor replacement products in hemophilia B. This study quantified the details of the patient experience that may have been driving the anecdotes of improved patient satisfaction and quality of life with IB1001. Overall, patients reported increased satisfaction, and improved clinical outcomes on their current factor treatment compared to products they had used in the past. While the data from this pilot study are encouraging, further study is warranted such as linking patient-reported outcomes to medical chart data to validate the clinical response and to better understand the variables that most influence patient satisfaction and quality of life. DisclosuresSchaaf:Aptevo Therapeutics: Employment, Equity Ownership. Lockhart:Aptevo Therapeutics: Consultancy. Fritz:Aptevo Therapeutics: Employment, Equity Ownership. Stromatt:Aptevo Therapeutics: Employment, Equity Ownership.

Evaluation of analytical method for polycyclic aromatic hydrocarbons content in home meal replacement products by GC/MS.

This study analyzed four polycyclic aromatic hydrocarbons (PAHs) from frequently consumed home meal replacement (HMR) products in Korea and evaluated their chemical analysis methods. The PAHs investigated were benzo[a]anthracene, chrysene, benzo[b]fluoranthene and benzo[a]pyrene. Chrysene-d12 and benzo[a]pyrene-d12 served as internal standards. The sample was dissolved in dichloromethane before extraction. Liquid-liquid extraction, microwave extraction, alkali digestion and GC-MS were used for analysis. Method validation was conducted on four matrices: fatty solid, fatty liquid, non-fatty liquid, non-fatty solid. Linear correlation coefficients (R2) were all above 0.99 and accuracy ranged from 80.03 to 119.65%. The LOD and LOQ were in the range of 0.03-0.15 and 0.09-0.44μg/kg, respectively. The recoveries varied from 81.09 to 116.42% and precision ranged from 0.07 to 10.73% in both intraday and interday analysis. All concentrations of total PAHs from HMR products were detected at relatively low concentration. This study could provide the PAHs content from HMR products in Korea.

Botryoidal and Spherulitic Aragonite in Carbonates Associated with Microbial Mats: Precipitation or Diagenetic Replacement Product?

Similar carbonate fabrics may result from different pathways of precipitation and diagenetic replacement. Distinguishing the underlying mechanisms leading to a given carbonate fabric is relevant, both in terms of an environmental and diagenetic interpretation. Prominent among carbonate fabrics are aragonite botryoids and spherulites, typically interpreted as direct seawater precipitates and used as proxies for fluid properties and depositional environments. This study investigated μm to mm-scale Holocene botryoidal and spherulitic aragonite from marine and non-marine carbonate settings associated with microbial mats, and reports two distinct formation mechanisms: 1) early diagenetic replacement, and 2) primary precipitation via nanocrystal aggregation. In the intertidal microbial mats of Khawr Qantur (Abu Dhabi), botryoidal and spherulitic aragonite are replacement products of heavily micritized bioclasts. To form the botryoidal and spherulitic aragonite, skeletal rods and needles, resulting from disintegration of micritized bioclasts, recrystallize into nanocrystals during early marine diagenesis. These nanocrystals then grow into fibrous crystals, forming botryoidal and spherulitic aragonite. In the lacustrine microbial bioherms of the hypersaline Great Salt Lake (United States) and in the hydrothermal travertines of Bagni San Filippo (Italy), botryoidal and spherulitic aragonite evolve from nanocrystals via precipitation. The nanocrystals are closely associated with extracellular polymeric substances in microbial biofilms and aggregate to form fibrous crystals of botryoidal and spherulitic aragonite. The studied fabrics form a portion of the bulk sediment and show differences in terms of their formation processes and petrological features compared to the often larger (few mm to over 1 m) botryoidal and spherulitic aragonite described from open-marine reefal cavities. Features shown here may represent modern analogues for ancient examples of carbonate depositional environments associated with microbialites. The implication of this research is that botryoidal and spherulitic aragonite associated with microbial mats are relevant in paleoenvironmental interpretations, but must be combined with a detailed evaluation of their formation process. Care must be taken as the term “botryoidal and spherulitic aragonite” may in fact include, from the viewpoint of their nucleation and formation mechanism, similar fabrics originated from different pathways. At present, it seems unclear to which degree the μm to mm-scale botryoids and spherulites described here are comparable to their cm-to dm-size counterparts precipitated as cements in the open pore space of reefal environments. However, it is clear that the investigation of ancient botryoidal and spherulitic aragonite must consider the possibility of an early diagenetic replacement origin of these precipitates.

Anatomy of a complex mineral replacement reaction: Role of aqueous redox, mineral nucleation, and ion transport properties revealed by an in-situ study of the replacement of chalcopyrite by copper sulfides

The fluid-driven transformation of chalcopyrite (CuFeS2) into Cu-rich sulfides (e.g., digenite, Cu1.8S; covellite, CuS; and chalcocite, Cu2S) is a complex mineral replacement reaction where the reaction pathway is controlled by the interplay between evolving mineral make-up, texture/porosity, and solution chemistry. This transformation was investigated in CuCl2 + H2SO4 solutions under mild hydrothermal conditions (180 to 300 °C); the reaction kinetics, nature of minerals formed, and oxidation states of aqueous Fe and Cu were followed in-situ in real-time using synchrotron powder X-ray diffraction (PXRD) and X-ray absorption spectroscopy (XAS). These results are corroborated by an analysis of the textures of reaction products from comparative ex-situ quench experiments. The in-situ and ex-situ experiments revealed that: (i) aqueous Cu2+ quickly reduced to Cu+ during chalcopyrite replacement in all experiments, and Fe dissolved as Fe2+; (ii) covellite was the first mineral to form, followed by digenite-high with delayed nucleation; and (iii) a non-quenchable hydrated Fe sulfate mineral (szomolnokite, FeSO4.H2O) formed at 240 °C at relatively low concentrations of added CuCl2, which supressed the formation of digenite-high. The quantitative mineral phase evolution retrieved using in-situ PXRD was modelled using a novel dual power law (dual Avrami approach). Avrami exponents revealed that chalcopyrite replacement proceeded initially via a 3-dimensional growth mechanism, followed by diffusion-controlled growth. This is consistent with initial formation of a porous covellite rim around chalcopyrite, confirmed by the observation of the ex-situ reaction products, followed by a second reaction stage where the transport properties of aqueous Fe (released from the chalcopyrite) and aqueous Cu (added from the initial solution) to and from the reaction front become the rate-limiting step; and these two kinetic stages exist even where covellite was the only replacement product. The activation energies calculated for these two kinetic stages were 42.9 ± 7.4 kJ mol−1 and 39.3 ± 13.1 kJ mol−1, respectively. We conclude that (i) the replacement of chalcopyrite by covellite and digenite proceeds via an interface coupled dissolution and reprecipitation mechanism; (ii) availabilities of aqueous Cu+ and of Fe2+ play a critical role in covellite nucleation and on the sequence of mineral precipitation during chalcopyrite replacement; the Cu+ to Cu2+ ratio is controlled by the kinetics of Cu2+ to Cu+ reduction, which increases with increasing temperature, and by the transport of Cu2+ through the daughter mineral to the reaction front, while Fe2+ availability is limited at high temperature by the formation of insoluble ferrous sulfate; and (iii) this reaction evolves from a bulk fluid-chemistry controlled reaction (initial formation of covellite) to an interface-controlled reaction (digenite-high or further transformation to covellite). The current findings highlight the complex feedback between Cu2+/Cu+ aqueous redox, mineral nucleation, and ion transport properties during replacement reactions, and the applicability of combined in-situ PXRD and XAS techniques in deciphering complex fluid-driven mineral replacement reactions.

The impact of smoking on oral health and patient assessment of tobacco cessation support from Turkish dentists.

INTRODUCTIONDentists are in a critical position to help patients quit smoking. This study analyses the effectiveness of Turkish dentists in smoking cessation as part of routine patient care.METHODSAn in-person cross-sectional survey on previous dental visit experiences was completed by 226 patients recruited from the Department of Periodontology, Eskisehir Osmangazi University, Turkey, from March 2019 to September 2019. The questionnaire included topics on patient’s smoking/quit characteristics, experiences on smoking cessation from their dentists, and willingness for the implementation of smoking cessation advice by dentists.RESULTSIn all, 38% of the patients were current smokers, 8% were former smokers, and 68% tried to quit previously. Smokers demonstrated consistently higher scores for plaque index, gingival index, and probing depth, than former/non-smokers (p<0.05). Patients’ knowledge of adverse effects was high, and the patients presented a positive attitude toward receiving cessation activities from dentists (86.7%). A total of 89% responded positively to be asked about their smoking behavior. However, the dentists’ approach for cessation discussions did not go any further than listing the harmful effects. Only 32% of the patients were informed about side effects of smoking and one-third were encouraged to quit. In general, offering smoking cessation advice was relatively infrequent, and the majority of patients tried to quit smoking by themselves (76%) without using any nicotine replacement product (84%).CONCLUSIONSSmoking leads to oral health problems. Dentists in Turkey may ask their patients’ about their smoking habits but less frequently offer practical help to quit.

Hybrid model for sales forecasts in a context of the consolidation of new products on the market: an application in the agro-industrial sector

Purpose – This paper aims to evaluate the performance of the consolidation process of a product recently included commercially in a portfolio through a sales forecasting model that, focused on several segments of the customer portfolio, supports the commercial decision-making.Design/methodology/approach – This approach uses the ABC Curve methodology to define the analysis in segments of relevance and then integrates two methods: (i) the Markovian models in discrete time and annual step to predict the transition behavior between the new replacement product and the consolidated ones; (ii) first-order and second-order exponential smoothing time series forecasting method to predict products in aggregate demand. This model was applied to a seed distributor company based on its customer portfolio and historical data for sales between 2011 and 2019.Findings – The sales forecasting benchmark scenario, designed for stable conditions in the behavioral adherence of new products and the commercial strategy, resulted in a quantitative support for targeting and monitoring commercial efforts to maximize the global performance for this process.Originality/value – Besides presenting a new Markov Chains commercial management approach, the model developed introduces a quantitative tool into the literature for targeting the customer portfolio management processes in the context of replacement in a product portfolio.Keywords - Curve ABC. Markov Chains. Sales Forecasting. Exponential Smoothing. Customer Portfolio Management.

Food for Thought: The Protein Transformation

Food for Thought: The Protein Transformation

Development of a Home Meal Replacement Product Containing Braised Mackerel (Scomber japonicus) with Radish (Raphanus sativus).

The coronavirus disease pandemic has contributed to increasing convenience in food preferences. Home meal replacement (HMR) products are ready-to-eat, -cook, or -heat foods, providing convenience for consumers. We developed a HMR product containing mackerel as a protein- and lipid-rich source using various food-processing technologies to maintain its nutritional content and prolong shelf life. The HMR product contained mackerel, radish, and sauce in a ratio of 5:1:4. Raw frozen mackerels were thawed by using a high-frequency defroster before being braised using a superheated steam roaster. Response surface methodology was employed to obtain the optimal heating conditions of 181 °C for 9 min. The final test HMR product was packed in a polypropylene plastic bowl prior to freezing at −35 °C for 1 h using a quick freezing system. The HMR product developed using these technologies exhibited stable microbiological and chemical properties for 90 days of storage. Sensory scores gradually decreased with increasing storage temperature and time. Protein content in the HMR product was 13%, 40% of which comprised essential amino acids; lipid content was 13.4%, 18% of which was composed of docosahexaenoic acid. The HMR product can preserve its quality and is considered safe for consumption for up to 40 months of storage at −18 °C.

Assessment of the Implementation of Pharmacists’ Prescriptive Authority to Furnish Hormonal Contraceptives, Naloxone, and Nicotine Replacement Therapy in California

Background California State Board of Pharmacy passed Senate Bill 493 authorizing pharmacists to furnish self-administered hormonal contraceptives, nicotine replacement products, and naloxone. Although California Senate Bill 493 expanded pharmacists’ scope of practice, limited implementation persists. Objective The objectives of this study were to assess the implementation of pharmacists’ prescriptive authority to furnish hormonal contraceptives, naloxone, and NRT in California as allowed by the Board of Pharmacy and availability of these services to patients in order to facilitate the development of strategies to expand them. The objective of the first part was to investigate reported awareness and barriers to implementation of services, while the second part was to report actual implementation rates. Methods This was an IRB-approved two-part cross-sectional survey that explored factors that may be associated with the limited implementation of the expanded scope of practice services. Results The two-part study had a total of 389 respondents. In the first part of the study, there were a total of 84 respondents. The majority reported that they were aware that pharmacists have the authority to furnish hormonal contraceptives, naloxone, and NRT, but services were limited. In the second part of the study, there were a total of 305 respondents, each responding to questions addressing only one of the three services: hormonal contraceptives (104 respondents), naloxone (101 respondents), and NRT (100 respondents). Within those subgroups, 19% of the respondents stated they offer hormonal contraceptives, 10% offer NRT, and 84% offer naloxone. Conclusion The results of the two-part study suggested that pharmacists’ authority to furnish these services were limited, thus patients’ access to these services were also limited.