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The regulatory standards of the United States Food and Drug Administration (FDA) require substantial evidence of effectiveness from adequate and well-controlled trials that typically use a valid comparison to an internal concurrent control. However, when it is not feasible or ethical to use an internal control, particularly in rare disease populations, relying on external controls may be acceptable. To better understand the use of external controls to support product development and approval, we reviewed FDA regulatory approval decisions between 2000 and 2019 for drug and biologic products to identify pivotal studies that leveraged external controls, with a focus on select therapeutic areas. Forty-five approvals were identified where FDA accepted external control data in their benefit/risk assessment; they did so for many reasons including the rare nature of the disease, ethical concerns regarding use of a placebo or no-treatment arm, the seriousness of the condition, and the high unmet medical need. Retrospective natural history data, including retrospective reviews of patient records, was the most common source of external control (44%). Other types of external control were baseline control (33%); published data (11%); and data from a previous clinical study (11%). To gain further insights, a comprehensive evaluation of selected approvals utilizing different types of external control is provided to highlight the variety of approaches used by sponsors and the challenges encountered in supporting product development and FDA decision making; particularly, the value and use of retrospective natural history in the development of products for rare diseases. Education on the use of external controls based on FDA regulatory precedent will allow for continued use and broader application of innovative approaches to clinical trial design, while avoiding delays in product development for rare diseases. Learnings from this review also highlight the need to update regulatory guidance to acknowledge the utility of external controls, particularly retrospective natural history data.

International audience

Despite much progress, few genetic findings for schizophrenia have been assessed by functional validation experiments at the molecular level. We previously reported evidence for genetic linkage of broadly defined schizophrenia to chromosome 17q25 in a sample of 24 multiplex families. 2,002 SNPs under this linkage peak were analyzed for evidence of linkage disequilibrium using the posterior probability of linkage (PPL) framework. SNP rs1060120 produced the strongest evidence for association, with a PPLD|L score of 0.21. This SNP is located within the 3'UTR of the histone gene H3F3B and colocalizes with potential gene target miR-616. A custom miRNA target prediction program predicted that the binding of miR-616 to H3F3B transcripts would be altered by the allelic variants of rs1060120. We used dual luciferase assays to experimentally validate this interaction. The rs1060120 A allele significantly reduced luciferase expression, indicating a stronger interaction with miR-616 than the G allele (p = 0.000412). These results provide functional validation that this SNP could alter schizophrenia epigenetic mechanisms thereby contributing to schizophrenia-related disease risk.

Intravenous epoprostenol improves exercise capacity and survival in patients with pulmonary arterial hypertension (PAH); however, chemical instability and a short half-life have caused limitations in its use. The chemically stable prostacyclin analogue treprostinil has a longer half-life, and improves hemodynamics and signs/symptoms of PAH. This study investigated the feasibility of transitioning patients with PAH from intravenous epoprostenol to intravenous treprostinil using a rapid switch protocol. Twelve PAH patients were enrolled in a 12 week prospective open label study. Patients were switched from intravenous epoprostenol to intravenous treprostinil (1:1 ng/kg/min) by a direct switch of the medication reservoir from epoprostenol to treprostinil. The dose of treprostinil was adjusted throughout the study to achieve a 2-fold increase of treprostinil compared with the baseline epoprostenol dose. Rapid transition to treprostinil was achieved without serious adverse events and, baseline clinical status was maintained over 12 weeks. The mean baseline epoprostenol dose was 28 +/- 14 ng/kg/min. At week 12, the mean treprostinil dose was 62 +/- 30 ng/kg/min. All patients reported less prostacyclin-related side effects with treprostinil and remained on treprostinil after study completion. Selected patients with PAH can be safely transitioned from intravenous epoprostenol to intravenous treprostinil using a rapid switch protocol.

Chronic wounds heal poorly and can have a huge impact on a sufferer’s life. They are caused by a number of factors, one of which is the presence of persistent infections. Many standard treatments are unsuccessful at destroying these infections as the bacteria form a biofilm. Biofilms encase the bacteria, preventing immune cells from destroying them. There are multiple bacterial species within a biofilm, sometimes with antibiotics resistance, and which species are present changes over time. The changing, multi-species nature of biofilms can make finding an effective antibiotic treatment difficult. Also, bacteria in biofilms genetically differ from planktonic bacteria, and are often less susceptible to antibiotics. Additionally, biofilms are thought to reduce the access of antibiotics to the bacteria within. These reasons are discussed in further detail in this review, along with some of the reasons why bacteria can prevent wound closure.

TUTORIAL Noise and Digital Signal Processing, Stephan Weiss, Robert W. Stewart, Gillian M. Davis SYSTEM ASPECTS Analogue Techniques, Malcolm Hawksford Hardware Design Considerations, Robert S. Oshana Software Design Considerations for Real-Time DSP Systems, Elizabeth Keate Evaluating the Effects of Noise on Voice Communication Systems, William D. Voiers, Alan D. Sharpley, Ira L. Panzer DIGITAL ALGORITHMS AND IMPLEMENTATION Single Channel Speech Enhancement, Graham P. Eatwell Microphone Arrays, Stephen J. Leese Echo Cancellation, Stephen J. Leese SPECIAL APPLICATIONS Signal and Feature Compensation Methods for Robust Speech Recognition, Rita Singh, Richard M. Stern, Bhiksha Raj Model Compensation and Matched Condition Methods for Robust Speech Recognition, Rita Singh, Bhiksha Raj, Richard M. Stern Noise and Voice Quality in VoIP Environments, Dennis Hardman Noise Canceling Headsets for Speech Communication, Lars Hakansson, Sven Johansson, Mattias Dahl, Per Sjoesten, Ingvar Claesson Acoustic Crosstalk Reduction in Loudspeaker-Based Virtual Audio Systems, Darren B. Ward Interference in Telephone Circuits, George Keratiotis, Larry Lind, Minesh Patel, John W. Cook, Peter Whelan An Adaptive Beamforming Perspective on Convolutive Blind Source Separation, Lucas Parra, Craig Fancourt Use of DSP Techniques to Enhance the Performance of Hearing Aids in Noise, Douglas Chabries, Victor Bray

The Royal Numismatic Society, London special publication n°56; International audience; The Laurion district was one of the most important mining centres of ancient Greece during the fifth and fourth centuries BC, and the minerals extracted were a foundation of Athenian power. On the surface, remains associated with the whole mining process including adits, mineral processing and metallurgical workshops extend over tens of kilometers. The Laurion lead-silver mines are the only ones known from the ancient world where vertical shafts reach as far as 100m deep to connect underground networks dug to exploit ore deposits. These mines required sophisticated organisational, engineering and technological capabilities, and an excellent understanding of geology. Recently, field investigation has been carried out into these shafts and mines. Analysis of traces found on the walls of the ancient mining galleries and works is providing new information and insights about the structures and technology of the mining industry during antiquity.