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OBJECTIVE:--To assess long-term weight loss efficacy and safety of pramlintide used at different dosing regimens and in conjunction with lifestyle intervention (LSI). RESEARCH DESIGN AND METHODS--In a 4-month, double-blind, placebo-controlled, dose-ranging study, 411 obese subjects were randomized to receive pramlintide (six arms: 120, 240, and 360 μg b.i.d. and t.i.d.) or placebo in conjunction with a structured LSI program geared toward weight loss. Of the 4-month evaluable subjects (n = 270), 77% opted to continue preexisting treatment during an 8-month single-blind extension (LSI geared toward weight maintenance). RESULTS:--At month 4, mean weight loss from baseline in the pramlintide arms ranged from 3.8 ± 0.7 to 6.1 ± 0.8 kg (2.8 ± 0.8 kg with placebo). By month 12, initial 4-month weight loss was regained in the placebo group but was maintained in all but the 120-μg b.i.d. group. Placebo-corrected weight loss with 120 μg t.i.d. and 360 μg b.i.d. averaged 3.2 ± 1.2 kg (3.1 ± 1.1% body wt) and 3.3 ± 1.1 kg (3.1 ± 1.0% body wt), respectively, at month 4 (both P < 0.01; 4-month evaluable n = 270) and 6.1 ± 2.1 kg (5.6 ± 2.1% body wt) and 7.2 ± 2.3 kg (6.8 ± 2.3% body wt), respectively, at month 12 (both P < 0.01; 12-month evaluable n = 146). At month 12, 40 and 43% of subjects treated with 120 μg t.i.d. and 360 μg b.i.d., respectively, achieved >=10% weight loss (vs. 12% for placebo). Nausea, the most common adverse event with pramlintide in the 4-month study (9-29% pramlintide vs. 2% placebo), was generally mild to moderate and occurred in <10% of subjects during the extension. CONCLUSIONS:--When used over 12 months as an adjunct to LSI, pramlintide treatment, with low-dose three-times-daily or higher-dose two-times-daily regimens, helped obese subjects achieve greater initial weight loss and enhanced long-term maintenance of weight loss.

Metformin use is restricted in patients with renal impairment due to potential excess systemic accumulation. This study evaluated the glycemic effects and safety of metformin delayed-release (Metformin DR), which targets metformin delivery to the ileum to leverage its gut-based mechanisms of action while minimizing systemic exposure. Participants (T2DM [HbA1c 7-10.5%], eGFR ≥60 mL/min/1.73m2, not taking metformin for ≥2 months) were randomized to QD placebo (PBO); QD Metformin DR 600, 900, 1200, or 1500 mg; or to single-blind BID Metformin immediate-release (IR) 1000 mg. The primary endpoint was change in HbA1c for Metformin DR vs. PBO at 16 weeks in the modified intent-to-treat (mITT) population (≥ 1 post-baseline HbA1c while on study drug), using a mixed-effects repeated measures model. 571 subjects were randomized (56 years, 53% male, 80% white; BMI 32.2±5.5 kg/m2; HbA1c 8.6±0.9%; 51% metformin naive); 542 were in the mITT population. Metformin DR 1200 and 1500 mg significantly reduced HbA1c (-0.49±0.13% and -0.62±0.12%, respectively, vs. PBO -0.06±0.13%; p<0.05) and FPG (Caverage Weeks 4-16: -22.3±4.2 mg/dL and -25.1±4.1 mg/dL, respectively vs. -2.5±4.2 mg/dL p<0.05). Metformin IR elicited greater HbA1c improvement (-1.10±0.13%; p<0.01 vs. Placebo and all doses of Metformin DR) but with ~3-fold greater plasma metformin exposure. Normalizing efficacy to systemic exposure, glycemic improvements with Metformin DR were 1.5-fold (HbA1c) and 2.1-fold (FPG) greater than Metformin IR. Adverse events were primarily gastrointestinal but these were less frequent with Metformin DR (<16% incidence) vs. Metformin IR (28%), particularly nausea (1-3% vs 10%). Metformin DR exhibited greater efficacy per unit plasma exposure than Metformin IR. Future studies will evaluate the effects of Metformin DR in patients with type 2 diabetes and advanced renal disease. Clinicaltrials.gov NCT02526524.

The diagnostic process for fetal alcohol spectrum disorder (FASD) involves a multi-disciplinary team and includes neurodevelopmental, physical, and facial assessments and evidence of prenatal alcohol exposure during the index pregnancy. With the increased use of virtual care in health care due to the pandemic, and desire of clinics to be more efficient when providing timely services, there was a need to develop a virtual diagnostic model for FASD. This study develops a virtual model for the entire FASD assessment and diagnostic process, including individual neurodevelopmental assessments. It proposes a virtual model for assessment and diagnosis of FASD in children and evaluates the functionality of this model with other national and international FASD diagnostic teams and caregivers of children being assessed for FASD.

Background Pantothenate kinase-associated neurodegeneration (PKAN) is an autosomal recessive neurodegenerative disorder with brain iron accumulation (NBIA). Objectives To assess PKAN diagnostic pathway, history, and burden across the spectrum of PKAN severity from patient and/or caregiver perspectives. Methods Caregivers of patients ( n  = 37) and patients themselves ( n  = 2) were interviewed in a validation study of the PKAN-Activities of Daily Living (ADL) scale. The current study used quartiles of the PKAN-ADL total score to divide patients by severity of impairment (Lowest, Second Lowest, Third Lowest, Highest). Diagnostic and treatment history, healthcare utilization, disease burden, and caregiver experience were compared between groups. Results The analyses included data from 39 patients. Mean age at PKAN symptom onset ( P  = 0.0007), initial MRI ( P  = 0.0150), and genetic testing ( P  = 0.0016) generally decreased across the PKAN severity spectrum. The mean duration of illness did not differ among PKAN severity groups (range, 9.7–15.2 years; P  = 0.3029). First MRI led to diagnosis in 56.4% of patients (range, 30.0–90.0%). A mean (SD) of 13.0 (13.1) medical and 55.2 (78.5) therapy visits (eg, physical, speech) occurred in the past year. More patients in the higher PKAN severity groups experienced multiple current functional losses and/or earlier onset of problems ( P -values < 0.0500). Over half (56.8%) of caregivers experienced a change in employment because of caregiving. The percentage of patients requiring full-time caregiving increased across the PKAN severity spectrum (range, 11.1–100%; P  = 0.0021). Conclusions PKAN diagnosis was often delayed, most probably due to low awareness. Considerable burden of functional impairment and high healthcare utilization were found across the PKAN severity spectrum.

The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) elicits a wide array of physiological effects by binding to several receptor subtypes. The 5-HT 2 family of receptors belongs to a large group of seven-transmembrane-spanning G-protein-coupled receptors and includes three receptor subtypes (5-HT 2A , 5-HT 2B and 5-HT 2C ) which are linked to phospholipase C, promoting the hydrolysis of membrane phospholipids and a subsequent increase in the intracellular levels of inositol phosphates and diacylglycerol1. Here we show that transcripts encoding the 2C subtype of serotonin receptor (5-HT 2C R) undergo RNA editing events in which genomically encoded adenosine residues are converted to inosines by the action of double-stranded RNA adenosine deaminase(s). Sequence analysis of complementary DNA isolates from dissected brain regions have indicated the tissue-specific expression of seven major 5-HT 2C receptor iso-forms encoded by eleven distinct RNA species. Editing of 5-HT 2C R messenger RNAs alters the amino-acid coding potential of the predicted second intracellular loop of the receptor and can lead to a 10–15-fold reduction in the efficacy of the interaction between receptors and their G proteins. These observations indicate that RNA editing is a new mechanism for regulating serotonergic signal transduction and suggest that this post-transcriptional modification may be critical for modulating the different cellular functions that are mediated by other members of the G-protein-coupled receptor superfamily.

Aims/hypothesis Delayed-release metformin (Metformin DR) was developed to maximise gut-based mechanisms of metformin action by targeting the drug to the ileum. Metformin DR was evaluated in two studies. Study 1 compared the bioavailability and effects on circulating glucose and gut hormones (glucagon-like peptide-1, peptide YY) of Metformin DR dosed twice-daily to twice-daily immediate-release metformin (Metformin IR). Study 2 compared the bioavailability and glycaemic effects of Metformin DR dosages of 1,000 mg once-daily in the morning, 1,000 mg once-daily in the evening, and 500 mg twice-daily. Methods Study 1 was a blinded, randomised, crossover study (three × 5 day treatment periods) of twice-daily 500 mg or 1,000 mg Metformin DR vs twice-daily 1,000 mg Metformin IR in 24 participants with type 2 diabetes conducted at two study sites (Celerion Inc.; Tempe, AZ, and Lincoln, NE, USA). Plasma glucose and gut hormones were assessed over 10.25 h at the start and end of each treatment period; plasma metformin was measured over 11 h at the end of each treatment period. Study 2 was a non-blinded, randomised, crossover study (three × 7 day treatment periods) of 1,000 mg Metformin DR once-daily in the morning, 1,000 mg Metformin DR once-daily in the evening, or 500 mg Metformin DR twice-daily in 26 participants with type 2 diabetes performed at a single study site (Celerion, Tempe, AZ). Plasma glucose was assessed over 24 h at the start and end of each treatment period, and plasma metformin was measured over 30 h at the end of each treatment period. Both studies implemented centrally generated computer-based randomisation using a 1:1:1 allocation ratio. Results A total of 24 randomised participants were included in study 1; of these, 19 completed the study and were included in the evaluable population. In the evaluable population, all treatments produced similar significant reductions in fasting glucose (median reduction range, −0.67 to −0.81 mmol/l across treatments) and postprandial glucose (Day 5 to baseline AUC 0–t ratio = 0.9 for all three treatments) and increases in gut hormones (Day 5 to baseline AUC 0–t ratio range: 1.6–1.9 for GLP-1 and 1.4–1.5 for PYY) despite an almost 60% reduction in systemic metformin exposure for 500 mg Metformin DR compared with Metformin IR. A total of 26 randomised participants were included in study 2: 24 had at least one dose of study medication and at least one post-dose pharmacokinetic/pharmacodynamic assessment and were included in the pharmacokinetic/pharmacodynamic intent-to-treat analysis; and 12 completed all treatment periods and were included in the evaluable population. In the evaluable population, Metformin DR administered once-daily in the morning had 28% (90% CI −16%, −39%) lower bioavailability (least squares mean ratio of metformin AUC 0–24 ) compared with either once-daily in the evening or twice-daily, although the glucose-lowering effects were maintained. In both studies, adverse events were primarily gastrointestinal in nature, and indicated similar or improved tolerability for Metformin DR vs Metformin IR; there were no clinically meaningful differences in vital signs, physical examinations or laboratory values. Conclusions/interpretation Dissociation of gut hormone release and glucose lowering from plasma metformin exposure provides strong supportive evidence for a distal small intestine-mediated mechanism of action. Directly targeting the ileum with Metformin DR once-daily in the morning may provide maximal metformin efficacy with lower doses and substantially reduce plasma exposure. Metformin DR may minimise the risk of lactic acidosis in those at increased risk from metformin therapy, such as individuals with renal impairment. Trial registration: Clinicaltrials.gov NCT01677299, NCT01804842 Funding: This study was funded by Elcelyx Therapeutics Inc.

RNA encoding the B subunit of the α-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid (AMPA) subtype of ionotropic glutamate receptor (GluR-B) undergoes a posttranscriptional modification in which a genomically encoded adenosine is represented as a guanosine in the GluR-B complementary DNA. In vitro editing of GluR-B RNA transcripts with HeLa cell nuclear extracts was found to result from an activity that converts adenosine to inosine in regions of double-stranded RNA by enzymatic base modification. This activity is consistent with that of a double-stranded RNA-specific adenosine deaminase previously described in Xenopus oocytes and widely distributed in mammalian tissues.

The purpose of this study was to provide an overview of the measures used by clinicians in Canada to evaluate brain function among individuals assessed for Fetal Alcohol Spectrum Disorder (FASD). We explored which measures are used by Canadian FASD clinicians, emerging trends in FASD assessment practice, and the extent to which clinicians' choice of measures aligns with those recommended in the current Canadian FASD diagnostic guideline. Data were collected via an online survey sent to all FASD clinics in Canada. The response rate was 75%, with 121 individual respondents from 44 clinics. Clinicians reported using a total of 182 unique measures, some of which were reported to assess function across multiple brain domains. There was a fair amount of consistency in measures reportedly used across the country. Although only 32% of measures aligned with those recommended in the Canadian guideline, almost all of the most frequently reported measures aligned with the guideline. We also identified several commonly reported measures that are not in the guideline but may be useful to consider as the guideline continues to evolve. Overall, this study highlights the importance of clinical consistency, ongoing training, and consideration of the research and clinical evidence base to ensure that clinicians across the country are engaging in rigorous and reliable FASD assessment and diagnostic practice. Cette étude visait à fournir un aperçu des mesures prises par les cliniciens canadiens pour évaluer la fonction cérébrale chez les personnes évaluées pour le trouble du spectre de l'alcoolisation fœtale (TSAF). Nous nous sommes intéressés aux méthodes utilisées par les cliniciens canadiens du TSAF, aux tendances relatives aux pratiques d'évaluation du TSAF, et à la mesure dans laquelle les choix des mesures par les cliniciens concordent avec les recommandations de la ligne directrice diagnostique actuelle pour le TSAF. Des données ont été colligées dans le cadre d'un questionnaire en ligne envoyé à toutes les cliniques du TSAF au Canada. Le taux de réponse était de 75 %, soit 121 répondants dans 44 cliniques. Les cliniciens ont rapporté utiliser au total 182 mesures uniques, certaines desquelles visaient à évaluer la fonction dans de multiples secteurs du cerveau. Un consensus raisonnable a été observé parmi les mesures que les cliniciens ont rapporté utiliser à travers le pays. Bien que seulement 32 % des mesures s'alignaient à celles recommandées par la ligne directrice canadienne, presque toutes les mesures les plus fréquemment rapportées concordaient avec celle-ci. Nous avons aussi relevé plusieurs mesures couramment rapportées qui ne figurent pas dans la ligne directrice, mais qu'il pourrait s'avérer utile de prendre en compte au fil de l'évolution de la ligne directrice. Dans l'ensemble, cette étude met en lumière l'importance du consensus clinique, de la formation continue, et de la prise en compte de la recherche et de la preuve clinique pour veiller à ce que les cliniciens d'à travers le pays mettent en œuvre des pratiques rigoureuses et fiables d'évaluation et de diagnostic du TSAF. Public Significance Statement Fetal Alcohol Spectrum Disorder (FASD) assessment and diagnosis are essential for helping people with FASD to connect with important services and supports. There are different approaches to FASD diagnosis around the world, but Canadian FASD clinicians are encouraged to follow a standard process. In this study, we examined the test use of FASD clinicians across Canada and found good consistency across the country, alignment with the current Canadian FASD diagnostic guideline, and some important areas where FASD clinical practice could be improved.

Metformin use is restricted in patients with renal impairment due to potential excess systemic accumulation. This study evaluated the glycemic effects and safety of metformin delayed-release (Metformin DR), which targets metformin delivery to the ileum to leverage its gut-based mechanisms of action while minimizing systemic exposure. 571 subjects were randomized (56 years, 53% male, 80% white; BMI 32.2±5.5 kg/m.sup.2 ; HbA1c 8.6±0.9%; 51% metformin naive); 542 were in the mITT population. Metformin DR 1200 and 1500 mg significantly reduced HbA1c (-0.49±0.13% and -0.62±0.12%, respectively, vs. PBO -0.06±0.13%; p<0.05) and FPG (C.sub.average Weeks 4-16 : -22.3±4.2 mg/dL and -25.1±4.1 mg/dL, respectively vs. -2.5±4.2 mg/dL p<0.05). Metformin IR elicited greater HbA1c improvement (-1.10±0.13%; p<0.01 vs. Placebo and all doses of Metformin DR) but with 3-fold greater plasma metformin exposure. Normalizing efficacy to systemic exposure, glycemic improvements with Metformin DR were 1.5-fold (HbA1c) and 2.1-fold (FPG) greater than Metformin IR. Adverse events were primarily gastrointestinal but these were less frequent with Metformin DR (<16% incidence) vs. Metformin IR (28%), particularly nausea (1-3% vs 10%). Metformin DR exhibited greater efficacy per unit plasma exposure than Metformin IR. Future studies will evaluate the effects of Metformin DR in patients with type 2 diabetes and advanced renal disease.