Infantile-onset myoclonic developmental and epileptic encephalopathy: A new RARS2 phenotype.

Recessive variants in RARS2, a nuclear gene encoding a mitochondrial protein, were initially reported in pontocerebellar hypoplasia. Subsequently, a recessive RARS2 early-infantile (<12 weeks) developmental and epileptic encephalopathy was described with hypoglycaemia and lactic acidosis. Here, we describe two unrelated patients with a novel RARS2 phenotype and reanalyse the published RARS2 epilepsy phenotypes and variants. Our novel cases had infantile-onset myoclonic developmental and epileptic encephalopathy, presenting with a progressive movement disorder from 9 months on a background of normal development. Development plateaued and regressed thereafter, with mild to profound impairment. Multiple drug-resistant generalized and focal seizures occurred with episodes of non-convulsive status epilepticus. Seizure types included absence, atonic, myoclonic, and focal seizures. Electroencephalograms showed diffuse slowing, multifocal, and generalised spike-wave activity, activated by sleep. Both patients had compound heterozygous RARS2 variants with likely impact on splicing and transcription. Remarkably, of the now 52 RARS2 variants reported in 54 patients, our reanalysis found that 44 (85%) have been shown to or are predicted to affect splicing or gene expression leading to protein truncation or nonsense-mediated decay. We expand the RARS2 phenotypic spectrum to include infantile encephalopathy and suggest this gene is enriched for pathogenic variants that disrupt splicing.

Glycaemic control across the lifespan in a cohort of New Zealand patients with type 1 diabetes mellitus.

BACKGROUND: It is well known that tight glycaemic control reduces all-cause mortality and the development of microvascular complications in patients with type 1 diabetes mellitus (T1D), but that effective glycaemic control is difficult to achieve in different age groups. Currently, the state of glycaemic control across the lifespan in patients with T1D in New Zealand is not known. AIM: To determine the differences in glycaemic control with age, gender, rurality and ethnicity in patients with T1D in the Waikato region of New Zealand. METHODS: Retrospective review of clinical records of all patients with T1D on the Waikato Regional Diabetes Database in December 2017 (n = 1303). Glycaemic control was determined by the most recent HbA1c in the past 2 years. RESULTS: Median (25%, 75%) HbA1c was 67 (59, 81) mmol/mol (8.3%) and highest in those aged 15-29 years. Values exceeded clinical recommendations in 85.3% of all patients. Median HbA1c was lower in patients on insulin pump therapy than on multiple daily injections (63 (7.9%) versus 69 mmol/mol (8.5%); P < 0.001), though insulin pumps were significantly less likely to be used by Maori (P = 0.003) and men (P < 0.0001). Worsening glycaemic control was associated with increasing social deprivation (P < 0.001) but was not influenced by rural/urban living. CONCLUSIONS: Poor glycaemic control in Waikato patients with T1D is likely due to inequities in health care, including reduced access to insulin pump therapy, particularly in Maori and socially deprived populations.

The prevalence of microvascular complications in Waikato children and youth with type 1 diabetes has reduced since 2003.

AIMS: To determine whether glycaemic control and the prevalence of microvascular complications in Waikato children/youth with type 1 diabetes (T1D) has changed since 2003. METHODS: A retrospective review was performed of clinical records of children and youth with T1D who were under the care of the Waikato Paediatric and Young Adult Diabetes Services between March 2016 and March 2017. Comparisons were made to published data from the same service in 2003. RESULTS: Despite a more than two-fold increase in insulin-pump therapy since 2003, glycaemic control was not significantly improved in either children or youth. However, since 2003 there has been a significant reduction in the prevalence of diabetic retinopathy (24.6% vs 6.0%; P=0.003) and nephropathy (6.0% vs 25.4%; P=0.002), while symptomatic diabetic neuropathy remains rare. This reduction occurred despite a significant increase in obesity and hypertension, and no significant difference in the rates of dyslipidaemia or smoking. CONCLUSIONS: There has been a marked reduction in microvascular complications in Waikato youth and young adults with type 1 diabetes, but the reasons for the reduction are not clear given there has been no significant improvements in glycaemic control.

A compact neutron scatter camera for field deployment.

We describe a very compact (0.9 m high, 0.4 m diameter, 40 kg) battery operable neutron scatter camera designed for field deployment. Unlike most other systems, the configuration of the sixteen liquid-scintillator detection cells are arranged to provide omnidirectional (4π) imaging with sensitivity comparable to a conventional two-plane system. Although designed primarily to operate as a neutron scatter camera for localizing energetic neutron sources, it also functions as a Compton camera for localizing gamma sources. In addition to describing the radionuclide source localization capabilities of this system, we demonstrate how it provides neutron spectra that can distinguish plutonium metal from plutonium oxide sources, in addition to the easier task of distinguishing AmBe from fission sources.

Impact of pediatric exclusivity on drug labeling and demonstrations of efficacy.

BACKGROUND: Besides vaccines and otitis media medicines, most products prescribed for children have not been studied in the pediatric population. To remedy this, Congress enacted legislation in 1997, known as pediatric exclusivity (PE), which provides 6 months of additional market protection to drug sponsors in exchange for studying their products in children. METHODS: We reviewed requests for pediatric studies and subsequent labeling for drugs granted PE from 1998 through 2012. Regression analysis estimates the probability of demonstrating efficacy in PE trials. Variables include therapeutic group, year of exclusivity, product sales, initiation process, and small disease population. RESULTS: From 1998 through 2012, the US Food and Drug Administration issued 401 pediatric study requests. For 189 drugs, studies were completed and granted exclusivity. A total of 173 drugs (92%) received new pediatric labeling, with 108 (57%) receiving a new or expanded pediatric indication. Three drugs had non-efficacy trials. Efficacy was not established for 78 drugs. Oncology, cardiovascular, and endocrine drugs were less likely to demonstrate efficacy (P < .01) compared with gastrointestinal and pain/anesthesia drugs. Drugs studied later in the program were less likely to demonstrate efficacy (P < .05). Sales, initiation process, and small disease population were not significant predictors. CONCLUSIONS: Most drugs (173; 92%) granted exclusivity added pediatric information to their labeling as a result of PE, with 108 (57%) receiving a new or expanded pediatric indication. Therapeutic area and year of exclusivity influenced the likelihood of obtaining a pediatric indication. Positive and negative outcomes continue to inform the construct of future pediatric trials.

Photothermoelectric p-n junction photodetector with intrinsic broadband polarimetry based on macroscopic carbon nanotube films.

Light polarization is used in the animal kingdom for communication, navigation, and enhanced scene interpretation and also plays an important role in astronomy, remote sensing, and military applications. To date, there have been few photodetector materials demonstrated to have direct polarization sensitivity, as is usually the case in nature. Here, we report the realization of a carbon-based broadband photodetector, where the polarimetry is intrinsic to the active photodetector material. The detector is based on p-n junctions formed between two macroscopic films of single-wall carbon nanotubes. A responsivity up to ~1 V/W was observed in these devices, with a broadband spectral response spanning the visible to the mid-infrared. This responsivity is about 35 times larger than previous devices without p-n junctions. A combination of experiment and theory is used to demonstrate the photothermoelectric origin of the responsivity and to discuss the performance attributes of such devices.

Atomoxetine use during a period of FDA actions.

CONTEXT: The Food and Drug Administration (FDA) issued a Public Health Advisory entitled "Suicidal Thinking in Children and Adolescents Being Treated with Strattera (Atomoxetine)" on September 29, 2005. At FDA's request, the manufacturer subsequently added a boxed warning to the drug's labeling on November 8, 2005. OBJECTIVE: To evaluate whether the boxed warning for suicidal thinking in atomoxetine's labeling was associated with a change in the pattern of attention-deficit/hyperactivity disorder (ADHD) medication use. METHODS: Patients who had an ADHD diagnosis and were prescribed either atomoxetine or stimulants between January 2004 and December 2007 were selected from IMS LifeLink Health Plan Claims database. In this ecologic analysis, the outcome measure is the incident atomoxetine use rate, defined as the proportion of atomoxetine incident users among all initial ADHD pharmacotherapy users. The impact of the boxed warning was evaluated using interrupted time series analysis. RESULTS: A total of 16,311 patients met the definition of incident ADHD medication users. The incident atomoxetine use rate decreased from January 2004 to September 2005 among all age groups (range, -0.45% to -0.74%); and the rate among adult patients decreased by 11.89% (95% confidence interval, 3.05%-20.74%) from September 2005 to November 2005. No long-term impact was detected. CONCLUSIONS: Significant decline of the atomoxetine use rate was observed before the boxed warning in all age groups. No significant change was detected in the atomoxetine use rate among targeted children or adolescents after the FDA's boxed warning concerning suicidal thinking.

Despite 2007 law requiring FDA hotline to be included in print drug ads, reporting of adverse events by consumers still low.

In 2007 the federal government began requiring drug makers to include in their print direct-to-consumer advertisements information for consumers on how to contact the Food and Drug Administration directly, either by phone or through the agency's website, to report any adverse events that they experienced after taking a prescription drug. Adverse events can range from minor skin problems like itching to serious injuries or illness that result in hospitalization, permanent disability, or even death. Even so, current rates of adverse event reporting are low. We studied adverse event reports about 123 drugs that came from patients before and after the enactment of the print advertising requirement and estimated that requirement's impact with model simulations. We found that if monthly spending on print direct-to-consumer advertising increased from zero to $7.7 million per drug, the presence of the Food and Drug Administration contact information tripled the increase in patient-reported adverse events, compared to what would have happened in the absence of the law. However, the absolute monthly increase was fewer than 0.24 reports per drug, suggesting that the public health impact of the increase was small and that the adverse event reporting rate would still be low. The study results suggest that additional measures, such as more publicity about the Adverse Event Reporting System or more consumer education, should be considered to promote patient reporting of adverse events.

The economic returns of pediatric clinical trials of antihypertensive drugs.

BACKGROUND: Congress has authorized the United States Food and Drug Administration (FDA) to provide industry sponsors with a 6-month extension of drug marketing rights under the Pediatric Exclusivity Provision if FDA-requested pediatric drug trials are conducted. The cost and economic return of pediatric exclusivity to industry sponsors has been shown to be highly variable. We sought to determine the cost of performing pediatric exclusivity trials within a single therapeutic area and the subsequent economic return to industry sponsors. METHODS: We evaluated 9 orally administered antihypertensive drugs submitted to the FDA under the Pediatric Exclusivity Provision from 1997 to 2004 and obtained key elements of the clinical trial designs and operations. Estimates of the costs of performing the studies were generated and converted into after-tax cash outflow. Market sales were obtained and converted into after-tax inflows based on 6 months of additional patent protection. Net economic return and net return-to-cost ratios were determined for each drug. RESULTS: Of the 9 antihypertensive agents studied, an average of 2 studies per drug was performed, including at least 1 pharmacokinetic study and a safety and efficacy study. The median cost of completing a pharmacokinetic trial was $862,000 (range $556,000 to 1.8 million). The median cost of performing safety and efficacy trials for these agents was $4.3 million (range $2.1-12.9 million). The ratio of net economic return to cost was 17 (range 4-64.7). CONCLUSION: We found that, within a cohort of antihypertensive drugs, the Pediatric Exclusivity Provision has generated highly variable, yet lucrative returns to industry sponsors.

Economic return of clinical trials performed under the pediatric exclusivity program.

CONTEXT: In 1997, Congress authorized the US Food and Drug Administration (FDA) to grant 6-month extensions of marketing rights through the Pediatric Exclusivity Program if industry sponsors complete FDA-requested pediatric trials. The program has been praised for creating incentives for studies in children and has been criticized as a "windfall" to the innovator drug industry. This critique has been a substantial part of congressional debate on the program, which is due to expire in 2007. OBJECTIVE: To quantify the economic return to industry for completing pediatric exclusivity trials. DESIGN AND SETTING: A cohort study of programs conducted for pediatric exclusivity. Nine drugs that were granted pediatric exclusivity were selected. From the final study reports submitted to the FDA (2002-2004), key elements of the clinical trial design and study operations were obtained, and the cost of performing each study was estimated and converted into estimates of after-tax cash outflows. Three-year market sales were obtained and converted into estimates of after-tax cash inflows based on 6 months of additional market protection. Net economic return (cash inflows minus outflows) and net return-to-costs ratio (net economic return divided by cash outflows) for each product were then calculated. MAIN OUTCOME MEASURES: Net economic return and net return-to-cost ratio. RESULTS: The indications studied reflect a broad representation of the program: asthma, tumors, attention-deficit/hyperactivity disorder, hypertension, depression/generalized anxiety disorder, diabetes mellitus, gastroesophageal reflux, bacterial infection, and bone mineralization. The distribution of net economic return for 6 months of exclusivity varied substantially among products (net economic return ranged from -$8.9 million to $507.9 million and net return-to-cost ratio ranged from -0.68 to 73.63). CONCLUSIONS: The economic return for pediatric exclusivity is variable. As an incentive to complete much-needed clinical trials in children, pediatric exclusivity can generate lucrative returns or produce more modest returns on investment.

Cruce de curvas: Tuberculosis y Enfisema / Tuberculosis and Emphysema: Cross curves

Publicado en ingles en el Diseases of the chest, 1962