Is regulatory innovation fit for purpose? A case study of adaptive regulation for advanced biotherapeutics

The need to better balance the promotion of scientific and technological innovation with risk management for consumer protection has inspired several recent reforms attempting to make regulations more flexible and adaptive. The pharmaceutical sector has a long, established regulatory tradition, as well as a long history of controversies around how to balance incentives for needed therapeutic innovations and protecting patient safety. The emergence of disruptive biotechnologies has provided the occasion for regulatory innovation in this sector. This article investigates the regulation of advanced biotherapeutics in the European Union and shows that it presents several defining features of an adaptive regulation regime, notably institutionalized processes of planned adaptation that allow regulators to gather, generate, and mobilize new scientific and risk evidence about innovative products. However, our in-depth case analysis highlights that more attention needs to be paid to the consequences of the introduction of adaptive regulations, especially for critical stakeholders involved in this new regulatory ecosystem, the capacity and resource requirements placed on them to adapt, and the new tradeoffs they face. In addition, our analysis highlights a deficit in how we currently evaluate the performance and public value proposition of adaptive regulations vis-à-vis their stated goals and objectives

The UK’s emerging regulatory framework for point-of-care manufacture: insights from a workshop on advanced therapies

Point-of-care (POC) manufacture can be defined as the production of therapies in clinical settings or units close to hospitals and patients. This approach is becoming increasingly via- ble due to the emergence of flexible manufacturing technologies. Expecting an increase in this kind of production, the UK’s regulatory agency, the Medicines and Healthcare products Regulatory Agency (MHRA) is proposing a regulatory framework specifically designed for POC manufacture. To discuss the challenges of POC manufacture and the MHRA’s pro- posal, the EPSRC Future Targeted Healthcare Manufacturing Hub (FTHMH) organized a workshop drawing insights from specialists in cell and gene therapy manufacture. Through presentations and discussion roundtables, the workshop highlighted the challenges for the UK and other countries implementing POC manufacture. The workshop attendees stressed four main issues: quality control; standardization and equipment use; availability of qualified personnel; and the challenges to be met by hospitals participating in POC manufacture systems. This commentary provides a summary of the points discussed in this workshop

Voice Flows To And Around Leaders: Understanding When Units Are Helped Or Hurt By Employee Voice

In two studies, we develop and test theory about the relationship between speaking up, one type of organizational citizenship behavior, and unit performance by accounting for where employee voice is flowing. Results from a qualitative study of managers and professionals across a variety of industries suggest that voice to targets at different formal power levels (peers or superiors) and locations in the organization (inside or outside a focal unit) differs systematically in terms of its usefulness in generating actions to a unit's benefit on the issues raised and in the likely information value of the ideas expressed. We then theorize how distinct voice flows should be differentially related to unit performance based on these core characteristics and test our hypotheses using time-lagged field data from 801 employees and their managers in 93 units across nine North American credit unions. Results demonstrate that voice flows are positively related to a unit's effectiveness when they are targeted at the focal leader of that unitwho should be able to take actionwhether from that leader's own subordinates or those in other units, and negatively related to a unit's effectiveness when they are targeted at coworkers who have little power to effect change. Together, these studies provide a structural framework for studying the nature and impact of multiple voice flows, some along formal reporting lines and others that reflect the informal communication structure within organizations. This research demonstrates that understanding the potential performance benefits and costs of voice for leaders and their units requires attention to the structure and complexity of multiple voice flows rather than to an undifferentiated amount of voice.Business Administratio

A Bichromatic Incidence Bound and an Application

We prove a new, tight upper bound on the number of incidences between points and hyperplanes in Euclidean d-space. Given n points, of which k are colored red, there are O_d(m^{2/3}k^{2/3}n^{(d-2)/3} + kn^{d-2} + m) incidences between the k red points and m hyperplanes spanned by all n points provided that m = \Omega(n^{d-2}). For the monochromatic case k = n, this was proved by Agarwal and Aronov. We use this incidence bound to prove that a set of n points, no more than n-k of which lie on any plane or two lines, spans \Omega(nk^2) planes. We also provide an infinite family of counterexamples to a conjecture of Purdy's on the number of hyperplanes spanned by a set of points in dimensions higher than 3, and present new conjectures not subject to the counterexample.Comment: 12 page

A New Approach to Low Temperature Embedding: Quick Freezing, Freeze-Drying and Direct Infiltration in Lowicryl K4M

Lowicryl resins are most commonly used for low temperature embedding by progressively lowering the temperature during dehydration. Freeze-substitution has also been successfully used with Lowicryl, but both of these techniques generally rely on chemical fixation and prolonged incubations in organic solvents. Freeze-drying may be combined with embedding in Lowicryl K4M. This technique eliminates all chemical fixation and exposure to organic solvents since the samples are quick-frozen, dried in vacuo and directly infiltrated in pure Lowicryl resin. If a primary aldehyde fixation is desired, freeze-drying may be used as an alternative to dehydration with organic solvents. These new approaches may be of significance for histochemistry and immunohistochemistry

A Rule-Based Approach to Analyzing Database Schema Objects with Datalog

Database schema elements such as tables, views, triggers and functions are typically defined with many interrelationships. In order to support database users in understanding a given schema, a rule-based approach for analyzing the respective dependencies is proposed using Datalog expressions. We show that many interesting properties of schema elements can be systematically determined this way. The expressiveness of the proposed analysis is exemplarily shown with the problem of computing induced functional dependencies for derived relations. The propagation of functional dependencies plays an important role in data integration and query optimization but represents an undecidable problem in general. And yet, our rule-based analysis covers all relational operators as well as linear recursive expressions in a systematic way showing the depth of analysis possible by our proposal. The analysis of functional dependencies is well-integrated in a uniform approach to analyzing dependencies between schema elements in general.Comment: Pre-proceedings paper presented at the 27th International Symposium on Logic-Based Program Synthesis and Transformation (LOPSTR 2017), Namur, Belgium, 10-12 October 2017 (arXiv:1708.07854

GTP and Ca2+ Modulate the Inositol 1,4,5-Trisphosphate-Dependent Ca2+ Release in Streptolysin O-Permeabilized Bovine Adrenal Chromaffin Cells

The inositol 1,4,5-trisphosphate (IP3)-induced Ca2+ release was studied using streptolysin O-permeabilized bovine adrenal chromaffin cells. The IP3-induced Ca2+ release was followed by Ca2+ reuptake into intracellular compartments. The IP3-induced Ca2+ release diminished after sequential applications of the same amount of IP3. Addition of 20 μM GTP fully restored the sensitivity to IP3. Guanosine 5'-O-(3-thio)triphosphate (GTPγS) could not replace GTP but prevented the action of GTP. The effects of GTP and GTPγS were reversible. Neither GTP nor GTPγS induced release of Ca2+ in the absence of IP3. The amount of Ca2+ whose release was induced by IP3 depended on the free Ca2+ concentration of the medium. At 0.3 μM free Ca2+, a half-maximal Ca2+ release was elicited with ∼0.1 μM IP3. At 1 μM free Ca2+, no Ca2+ release was observed with 0.1 μM IP3; at this Ca2+ concentration, higher concentrations of IP3 (0.25 μM) were required to evoke Ca2+ release. At 8 μM free Ca2+, even 0.25 μM IP3 failed to induce release of Ca2+ from the store. The IP3-induced Ca2+ release at constant low (0.2 μM) free Ca2+ concentrations correlated directly with the amount of stored Ca2+. Depending on the filling state of the intracellular compartment, 1 mol of IP3 induced release of between 5 and 30 mol of Ca2+

The prevalence and awareness of sleep apnea in patients suffering chronic pain: an assessment using the STOP-Bang sleep apnea questionnaire.

Purpose: Some patient subsets are at higher risk of sleep apnea, including patients with chronic pain. However, it is unclear whether patients and their caregivers are aware of the possibly increased risk of sleep apnea in this population. Chronic pain is often treated with opioids which may decrease both the central respiratory drive and the patency of the upper airway, potentially contributing to this sleep disorder. Using a self-reporting questionnaire approach in the chronic pain population, this study surveyed patient and caregiver awareness surrounding the risk of sleep apnea. In addition, we looked at the influence of opioid therapy on the prevalence of sleep apnea. Participants and methods: Consecutive patients presenting to a pain clinic were invited to participate anonymously in a survey that included the STOP-Bang sleep apnea questionnaire, which assesses patients\u27 knowledge, testing, diagnosis, or treatment of sleep apnea and whether their caregivers had discussed with them their increased risk of sleep apnea and opioid use. Results: Among 305 participating patients, 58.2% (n=173) screened positive for sleep apnea. Among the 202 patients on opioid therapy, 59.2% (116/202) were STOP-Bang positive (score ≥3). However, only 37.5% (n=72/173) of these patients had discussed their risk of sleep apnea with a caregiver and only 30.7% (n=59) underwent testing. Against expectation, opioids did not increase the prevalence of sleep apnea in our study population. Conclusion: Chronic pain patients had a high risk of sleep apnea, regardless of opioid prescription. Most patients were unaware of their increased risk and denied undergoing the necessary testing. Greater attention to screening, testing, and education for sleep apnea needs to be paid in chronic pain patients, especially given the potentially dangerous ramifications of opioid-induced sleep apnea

New Developments in WHIZARD Version 2.6

We describe recent additions to the WHIZARD 2 Monte-Carlo event generator which improve the physics description of lepton-collider event samples and speed up the calculation time required for cross sections and event generation.Comment: Talk presented by W. Kilian at the International Workshop on Future Linear Colliders (LCWS2017), Strasbourg, France, 23-27 October 2017. C17-10-23.