Strategies for Success With Umbilical Cord Haematopoietic Stem Cell Transplantation in Children With Malignant and Non-Malignant Disease Indications.

Umbilical Cord blood is an intuitively attractive stem cell source, but its use has declined since it is associated with an increased procedure-related morbidity and transplant related mortality. Some of this reflects that cord blood transplants are more often HLA-mismatched compared to other unrelated donor transplants. The ability to transplant in such a setting, indeed without high rates of chronic Graft versus Host Disease (GVHD), constitutes an advantage compared to other unrelated donor cell sources and there are other advantages specifically associated with cord blood as a donor cell source. These advantages must be weighed against its disadvantage, and we have utilised cord blood preferentially as a donor cell source in certain clinical situations in paediatric medicine. In non-malignant diseases, outcomes in metabolic disease are critically dependent on age at transplant and the enzyme delivered by that transplant, and in cord blood transplantation then the time to transplant can be minimised and the engrafted recipients have higher chimerism that delivers higher enzyme levels. In malignant diseases, studies have described reduced relapse rate and better GVHD-free survival, and so we have prioritised cord as a donor cell source where the risk of relapse is highest, and the effects of higher transplant related mortality is most clearly offset by the reduced relapse rates.

The stroke exercise preference inventory is feasible to use in a community rehabilitation setting.

Exploring exercise preferences may help people to adhere to exercise programs by promoting customized programs to suit the person's choices and concerns. We investigated if the Stroke Exercise Preference Inventory, a questionnaire designed to explore stroke survivors' preferences for exercise and potential barriers, was feasible to use, and whether it assisted physiotherapists to design ongoing exercise programs in a mixed diagnostic convenience sample attending community rehabilitation. Physiotherapy staff interviewed 42 participants, and sought feedback about the questionnaire. Participant responses for exercise preferences and perceived barriers were then summarized. The questionnaire was quick to administer, readily understood, and considered relevant to consider when discussing options for exercise. Clinicians reported the questionnaire was useful for 48% (20/42) of participants, as it engaged the participant, clarified their preferences and allowed problem solving of potential barriers to exercise. Participants expressed strong preferences to be challenged, and to receive supervision and support. Preferences regarding environmental and social context of exercise varied widely. Difficulty getting started was the most common barrier reported. The Stroke Exercise Preference Inventory was feasible to use with a mixed diagnostic group during community rehabilitation, and provides structure to explore preferences and barriers to exercise. It remains to be tested whether use of the questionnaire promotes adherence to exercise programs.

Mild Behavioral Impairment: A New At-Risk State for Alzheimer's Disease?

Improving our response to Alzheimer's disease (AD), including prevention and early intervention, is critical for maximizing healthy aging outcomes. Identifying older adults at highest risk for AD would provide an opportunity to offer support, plan for the future, and implement strategies to enhance cognitive and functional outcomes. The emergence of neuropsychiatric symptoms may be one indicator of early AD-related cognitive decline, but distinguishing symptoms from those due to other causes can be challenging. Mild behavioral impairment (MBI) describes an at-risk state for cognitive decline characterized by the late-life onset of neuropsychiatric symptoms. In this article, we discuss the current conceptualization of MBI, the potential for its characteristic neuropsychiatric symptoms to indicate risk for future cognitive decline, and present potential clinical implications. [Journal of Gerontological Nursing, 47(3), 29-36.].

Recruiting and Retaining Youth and Young Adults in the Policy and Communication Evaluation (PACE) Vermont Study: Randomized Controlled Trial of Participant Compensation.

BACKGROUND: The standard approach for evaluating the effects of population-level substance use prevention efforts on youth and young adult perceptions and behaviors has been to compare outcomes across states using national surveillance data. Novel surveillance methods that follow individuals over shorter time intervals and capture awareness of substance use prevention policy and communication efforts may provide a stronger basis for their evaluation than annual cross-sectional studies. OBJECTIVE: This study aimed to identify a combination of strategies to recruit a sample of youth and young adults sufficiently representative of the Vermont population and determine how best to retain a web-based panel of youth and young adults over a 6-month period. METHODS: Eligible participants were Vermont residents aged 12 to 25 years who were willing to complete three 10 to 15-minute web-based surveys over a 6-month period. Recruitment was conducted via the following three main mechanisms: (1) web-based recruitment (paid and unpaid), (2) community-based recruitment through partners, and (3) participant referrals via a personalized link. Upon completion of the baseline survey, participants were randomly assigned to one of the following three retention incentive conditions: (1) guaranteed incentive (US $10), (2) lottery incentive (US $50 weekly lottery drawing), and (3) preferred method (guaranteed or lottery). Analyses examined cost per survey start by recruitment source, distribution of demographic characteristics across incentive conditions, and retention by study condition at 3-month and 6-month follow-ups. RESULTS: Over a 10-week period in 2019, we recruited 480 eligible youth (aged 12-17 years) and 1037 eligible young adults (aged 18-25 years) to the Policy and Communication Evaluation (PACE) Vermont Study. Facebook and Instagram advertising produced the greatest number of survey starts (n=2013), followed by posts to a state-wide web-based neighborhood forum (n=822) and Google advertisements (n=749). Retention was 78.11% (1185/1517) at 3 months and 72.18% (1095/1517) at 6 months. Retention was equivalent across all incentive study conditions at both waves, despite a strong stated preference among study participants for the guaranteed payment at baseline. Youth had greater retention than young adults at both waves (wave 2: 395/480, 82.3% vs 790/1037, 76.18%; wave 3: 366/480, 76.3% vs 729/1037, 70.30%). Substance use prevalence in this cohort was similar to national and state-level surveillance estimates for young adults, but was lower than state-level surveillance estimates for youth. Most participants retained at wave 3 provided positive qualitative feedback on their experience. CONCLUSIONS: Our study supports the feasibility of recruiting a web-based cohort of youth and young adults with representation across an entire state to evaluate substance use prevention efforts. Findings suggest that a guaranteed payment immediately upon survey completion coupled with a bonus for completing all survey waves and weekly survey reminders may facilitate retention in a cohort of youth and young adults.

A decade of excellent transplant survival in children with inherited metabolic diseases: A report from a single metabolic transplant centre in Europe.

Hematopoietic cell transplantation (HCT) confers a long-term disease-modifying therapy for transplant-permissive inherited metabolic diseases (IMDs). We examined the overall survival (OS) and engrafted survival (ES) of children with IMDs, who received first HCT at Royal Manchester Children's hospital from 1985 to 2016. A total of 137 children with IMDs were included in this analysis (historical cohort [1985-2006], n＝65; current cohort [2007-2016], n＝72). Primary diagnoses included mucopolysaccharidoses (81%), X-linked adrenoleukodystrophy (6%), metachromatic leukodystrophy (4%), mannosidosis (3%), Wolman disease (2%), and other conditions (4%). The five-year OS has increased from 65% (95% confidence interval [CI], 52%-76%) in the historical cohort to 91% (95% CI, 81%-96%) in the current cohort (P<0.001). Moreover, the five-year ES, which was 64% (95 CI%, 56%-72%) for the entire cohort, has doubled from 41% (95% CI, 29%-53%) in the historical cohort to 85% (95% CI, 75%-92%) in the current cohort (P<0.001). The proportion of patients with graft failure has decreased from 37% in the historical cohort to 8% in the current cohort (P<0.001). In patients who received a second transplant, 13 out of 20 patients (65%) in the historical cohort and all four in the current cohort were alive and engrafted. Of 82 survivors followed-up at Manchester, 80% and 20% had full and mixed chimerism, respectively. Although this study was restricted to a single center, our findings show that HCT is an increasingly safe procedure and provides long-lasting endogenous enzyme replacement therapy for children with IMDs in the modern era of HCT.

Glyco-engineered Long Acting FGF21 Variant with Optimal Pharmaceutical and Pharmacokinetic Properties to Enable Weekly to Twice Monthly Subcutaneous Dosing.

Pharmacological administration of FGF21 analogues has shown robust body weight reduction and lipid profile improvement in both dysmetabolic animal models and metabolic disease patients. Here we report the design, optimization, and characterization of a long acting glyco-variant of FGF21. Using a combination of N-glycan engineering for enhanced protease resistance and improved solubility, Fc fusion for further half-life extension, and a single point mutation for improving manufacturability in Chinese Hamster Ovary cells, we created a novel FGF21 analogue, Fc-FGF21[R19V][N171] or PF-06645849, with substantially improved solubility and stability profile that is compatible with subcutaneous (SC) administration. In particular, it showed a low systemic clearance (0.243 mL/hr/kg) and long terminal half-life (~200 hours for intact protein) in cynomolgus monkeys that approaches those of monoclonal antibodies. Furthermore, the superior PK properties translated into robust improvement in glucose tolerance and the effects lasted 14 days post single SC dose in ob/ob mice. PF-06645849 also caused greater body weight loss in DIO mice at lower and less frequent SC doses, compared to previous FGF21 analogue PF-05231023. In summary, the overall PK/PD and pharmaceutical profile of PF-06645849 offers great potential for development as weekly to twice-monthly SC administered therapeutic for chronic treatment of metabolic diseases.

Mechanistic investigation of the preclinical pharmacokinetics and interspecies scaling of PF-05231023, a fibroblast growth factor 21-antibody protein conjugate.

PF-05231023, a long-acting fibroblast growth factor 21 (FGF21) analog, was generated by covalently conjugating two engineered [des-His1, Ala129Cys]FGF21 molecules to a nontargeting human IgG1 κ scaffold. The pharmacokinetics (PK) of PF-05231023 after i.v. and s.c. administration was evaluated in rats and monkeys using two enzyme-linked immunosorbent assays with high specificity for biologically relevant intact N termini (NT) and C termini (CT) of FGF21. Intact CT of FGF21 displayed approximately 5-fold faster systemic plasma clearance (CL), an approximately 2-fold lower steady-state volume of distribution, and at least 5-fold lower bioavailability compared with NT. In vitro serum stability studies in monkeys and humans suggested that the principal CL mechanism for PF-05231023 was degradation by serum proteases. Direct scaling of in vitro serum degradation rates for intact CT of FGF21 underestimated in vivo CL 5-fold, 1.4-fold, and 2-fold in rats, monkeys, and humans, respectively. The reduced steady-state volume of distribution and the bioavailability for intact CT relative to NT in rats and monkeys were compatible with proteolytic degradation occurring outside the plasma compartment via an unidentified mechanism. Human CL and PK profiles for intact NT and CT of FGF21 were well predicted using monkey single-species allometric and Dedrick scaling. Physiologically based pharmacokinetic models incorporating serum stability data and an extravascular extraction term based on differential bioavailability of intact NT and CT of FGF21 in monkeys improved accuracy of human PK predictions relative to Dedrick scaling. Mechanistic physiologically based pharmacokinetic models of this nature may be highly valuable for predicting human PK of fusion proteins, synthetically conjugated proteins, and other complex biologics.

Pharmacokinetics (PK), pharmacodynamics (PD) and integrated PK/PD modeling of a novel long acting FGF21 clinical candidate PF-05231023 in diet-induced obese and leptin-deficient obese mice.

Pharmacological administration of fibroblast growth factor 21 (FGF21) improves metabolic profile in preclinical species and humans. FGF21 exerts its metabolic effects through formation of beta-klotho (KLB)/FGF receptor 1c FGFR1c complex and subsequent signaling. Data from various in vitro systems demonstrate the intact C- and N-terminus of FGF21 is required for binding with KLB, and interaction with FGFR1c, respectively. However the relative roles of the termini for in vivo pharmacological effects are unclear. Here we report PF-05231023, a long-acting FGF21 analogue which is unique in that the half-life and subcutaneous (s.c.) bioavailability of the intact C-terminus are significantly different from those of the intact N-terminus (2 vs. 22 hr for half-life and 4~7 vs. ~50% SC bioavailability). Therefore, this molecule serves as a valuable tool to evaluate the relative roles of intact C-terminus vs. N-terminus in in vivo pharmacology studies in preclinical species. We determined the effects of PF-05231023 administration on body weight (BW) loss and glucose reduction during an oral glucose tolerance test (OGTT) following SC and intravenous (i.v.) administration in diet-induced obese (DIO) and leptin-deficient obese (ob/ob) mice, respectively. Our data show that the intact N-terminus of FGF21 in PF-05231023 appears to be sufficient to drive glucose lowering during OGTT and sustain BW loss in DIOs. Further, PK/PD modeling suggests that while the intact FGF21 C-terminus is not strictly required for glucose lowering during OGTT in ob/ob mice or for BW reduction in DIO mice, the higher potency conferred by intact C-terminus contributes to a rapid initiation of pharmacodynamic effects immediately following dosing. These results provide additional insight into the strategy of developing stabilized versions of FGF21 analogs to harness the full spectrum of its metabolic benefits.

Incarcerated fibroid uterus: the role of conservative management.

BACKGROUND: Uterine incarceration occurs when the gravid uterus remains trapped within the sacral hollow and cannot ascend out of the pelvis as it enlarges. Predisposing factors include uterine fibroids. Optimal management of uterine incarceration involves manual reduction of the uterus because of the significant maternal and fetal risks associated with persistent incarceration. CASE: A nulliparous woman with known uterine incarceration secondary to a large anterior uterine fibroid was managed conservatively throughout her pregnancy after attempts at manual reduction were unsuccessful. CONCLUSION: Conservative management of the incarcerated uterus is a reasonable option if attempts at manual reduction are unsuccessful. Magnetic resonance imaging can be helpful in delineating anatomy and planning for delivery.

Contexte : On parle d'incarcération utérine lorsque l'utérus d'une femme enceinte demeure coincé dans le creux du sacrum et ne peut cheminer hors du bassin au fur et à mesure de son expansion. La présence de fibromes utérins fait partie des facteurs prédisposants. La prise en charge optimale de l'incarcération utérine met en jeu la réduction manuelle de l'utérus, et ce, en raison des risques maternels et fœtaux considérables qui sont associés à la persistance de l'incarcération. Cas : Une nullipare, chez qui la présence d'une incarcération utérine attribuable à un gros fibrome utérin antérieur était connue, a fait l'objet d'une prise en charge conservatrice tout au long de sa grossesse, après l'échec de tentatives de réduction manuelle. Conclusion : La prise en charge conservatrice de l'incarcération utérine constitue une option raisonnable à la suite de l'échec de tentatives de réduction manuelle. L'imagerie par résonance magnétique peut s'avérer utile pour situer l'anatomie et planifier l'accouchement.