Regulators, Pivotal Clinical Trials, and Drug Regulation in the Age of COVID-19

Medicine regulators rely on pivotal clinical trials to make decisions about approving a new drug, but little is known about how they judge whether pivotal trials justify the approval of new drugs. We explore this issue by looking at the positions of 3 major regulators: the European Medicines Agency, Food and Drug Administration, and Health Canada. Here we report their views and the implications of those views for the approval process. On various points, the 3 regulators are ambiguous, consistent, and demonstrate flexibility. The range of views may well reflect different regulatory cultures. Although clinical trial information from pivotal trials is becoming more available, regulators are still reluctant to provide detailed information about how that information is interpreted. As medicines and vaccines come up for approval for treatment of COVID-19, transparency in how pivotal trials are interpreted will be critical in determining how these treatments should be used

Regulators, Pivotal Clinical Trials, and Drug Regulation in the Age of COVID-19

Medicine regulators rely on pivotal clinical trials to make decisions about approving a new drug, but little is known about how they judge whether pivotal trials justify the approval of new drugs. We explore this issue by looking at the positions of 3 major regulators: the European Medicines Agency, Food and Drug Administration, and Health Canada. Here we report their views and the implications of those views for the approval process. On various points, the 3 regulators are ambiguous, consistent, and demonstrate flexibility. The range of views may well reflect different regulatory cultures. Although clinical trial information from pivotal trials is becoming more available, regulators are still reluctant to provide detailed information about how that information is interpreted. As medicines and vaccines come up for approval for treatment of COVID-19, transparency in how pivotal trials are interpreted will be critical in determining how these treatments should be used

Working Together: Building K-12/College Mentor Partnerships to Support Students with Learning Differences

In an interactive discussion with audience members, presenters will share ideas for developing positive mentor-mentee partnerships between K-12 schools and colleges; discuss the impact of two recently established mentor partnerships, as well as perspectives from college student mentors and K-12 teachers of student mentees with learning differences; collaboratively examine data to discuss potential program adaptations; and provide mentoring activities that audience members can utilize

Employee motivation, external orientation and technical efficiency of foreign-financed firms in China: a stochastic frontier analysis

By using a stochastic frontier model, we have identified several firm-specific attributes as determinants of technical efficiency in foreign-financed manufacturing firms in southern China. The empirical results suggest a strong association between efficiency and employee motivation, which includes the use of bonus incentives and flexibility in employment policy. In terms of the external orientation behavior of firms, the findings do not support the export/efficiency relationship. Sample firms with a high degree of export-orientedness were less efficient, possibly due to the high transaction costs in China of exportation. As for the effects of expatriate input on production, our empirical evidence revealed that firms with a relatively high expatriate ratio performed less efficiently than others did. These two findings may have significant implications for the marketing strategies and management (including the localization) of human resources of foreign-financed firms in China

Underwater remote skimming of slow sand filters for sustainable water production

Slow sand filters (SSF) are a simple water treatment technology providing an important alternative to conventional drinking water treatment. SSF are extensive in terms of carbon cost and chemical use but require a large land area and are complex to operate, as periodic cleaning is required to prevent filter clogging. Therefore, redundant SSF beds are required to enable water production to occur during long cleaning downtimes. Underwater skimming (UWS) is a cleaning innovation where the foulant layer (containing sand and particles) is removed using a skimmer consisting of a shrouded blade mounted on a vehicle platform. Sand, particles, and biofilm are skimmed prior to ex situ washing of the recovered sand. In this Viewpoint, we posit that the introduction of an in situ underwater skimmer operated remotely can substantially help to offset the aforementioned challenge of downtime, with its associated loss of production, enabling the technology to operate more efficiently and remain a pertinent and advantageous process option within modern water treatment facilities or possibly resource constrained settings. Otherwise, this resilient biotechnological process could be replaced by chemical and energy-intensive processes which increase the entropy of water treatment more than SSF. The anticipated benefits and challenges of UWS of SSF are discussed

Accidental hepatic artery ligation in humans

Despite the vast amount of information from experimental animals, it has been difficult to obtain a clear-cut picture of the effects of ligation of the hepatic artery in humans with relatively normal livers. The last complete review of this subject in 1933 indicated that a mortality in excess of 50 per cent could be expected in non-cirrhotic patients with injury of the hepatic artery or its principal branches. Five cases of dearterialization of the normal human liver have been observed. These were due to accidental interruption of the right hepatic artery in four and the proper hepatic artery in one. The injured vessel was repaired in one case and ligated in the others. In four of the five patients the vascular disruption was the sole injury. In the other the common bile duct was also lacerated. There was no evidence of hepatic necrosis in any case although one patient died from complications of common duct repair. Transient changes in SGOT and temporary low grade bilirubinemia were commonly noted. In addition, all cases of ligation of the hepatic artery reported since 1933 have been compiled. On the basis of reviewed, as well as the presently reported cases, it is concluded that ligation of the hepatic artery or one of its branches in the patient with relatively normal hepatic function is not ordinarily fatal in the otherwise uncomplicated case. Adequate perfusion of the liver can usually be provided by the remaining portal venous flow and whatever arterial collaterals are present, unless additional factors further reduce the portal venous flow or increase hepatic oxygen need. These factors include fever, shock and anoxia. The key to therapy in unreconstructed injuries to the hepatic artery is avoidance of these secondary influences. © 1964

An assessment of aerosol‐cloud interactions in marine stratus clouds based on surface remote sensing

An assessment of aerosol-cloud interactions (ACI) from ground-based remote sensing under coastal stratiform clouds is presented. The assessment utilizes a long-term, high temporal resolution data set from the Atmospheric Radiation Measurement (ARM) Program deployment at Pt. Reyes, California, United States, in 2005 to provide statistically robust measures of ACI and to characterize the variability of the measures based on variability in environmental conditions and observational approaches. The average ACIN (= dlnNd/dlna, the change in cloud drop number concentration with aerosol concentration) is 0.48, within a physically plausible range of 0–1.0. Values vary between 0.18 and 0.69 with dependence on (1) the assumption of constant cloud liquid water path (LWP), (2) the relative value of cloud LWP, (3) methods for retrieving Nd, (4) aerosol size distribution, (5) updraft velocity, and (6) the scale and resolution of observations. The sensitivity of the local, diurnally averaged radiative forcing to this variability in ACIN values, assuming an aerosol perturbation of 500 c-3 relative to a background concentration of 100 cm-3, ranges betwee-4 and -9 W -2. Further characterization of ACI and its variability is required to reduce uncertainties in global radiative forcing estimates

Tandem quadruplication of HMA4 in the zinc (Zn) and cadmium (Cd) hyperaccumulator noccaea caerulescens

Zinc (Zn) and cadmium (Cd) hyperaccumulation may have evolved twice in the Brassicaceae, in Arabidopsis halleri and in the Noccaea genus. Tandem gene duplication and deregulated expression of the Zn transporter, HMA4, has previously been linked to Zn/Cd hyperaccumulation in A. halleri. Here, we tested the hypothesis that tandem duplication and deregulation of HMA4 expression also occurs in Noccaea. A Noccaea caerulescens genomic library was generated, containing 36,864 fosmid pCC1FOSTM clones with insert sizes ~20–40 kbp, and screened with a PCR-generated HMA4 genomic probe. Gene copy number within the genome was estimated through DNA fingerprinting and pooled fosmid pyrosequencing. Gene copy numbers within individual clones was determined by PCR analyses with novel locus specific primers. Entire fosmids were then sequenced individually and reads equivalent to 20-fold coverage were assembled to generate complete whole contigs. Four tandem HMA4 repeats were identified in a contiguous sequence of 101,480 bp based on sequence overlap identities. These were flanked by regions syntenous with up and downstream regions of AtHMA4 in Arabidopsis thaliana. Promoter-reporter b-glucuronidase (GUS) fusion analysis of a NcHMA4 in A. thaliana revealed deregulated expression in roots and shoots, analogous to AhHMA4 promoters, but distinct from AtHMA4 expression which localised to the root vascular tissue. This remarkable consistency in tandem duplication and deregulated expression of metal transport genes between N. caerulescens and A. halleri, which last shared a common ancestor >40 mya, provides intriguing evidence that parallel evolutionary pathways may underlie Zn/Cd hyperaccumulation in Brassicaceae

Openings and closings in Spanish email conversations

Despite the increasing interest scholarly research has shown in the study of computer-mediated communication, there is still a need to investigate the empirical validity of assumed homogeneity of language usage over the net and focus on the social diversity and variation that characterizes any communication. With this in mind, the present paper is an investigation into the stylistic choices that a particular group of email users made when engaged in a specific activity type. More specifically, it explores the variation in the discourse practices employed to open and close emails in conversation alongside the institutional power of participants and the interactional position of each email contributing to the conversation. To carry out this study a corpus of short email conversations in Peninsular Spanish was collected (n = 240). The analysis focused on the opening and closing sequences of the emails that made up the conversations and considered opening and closing linguistic conventions as discursive practices that members of a community may use strategically. The findings revealed that the discursive practices under scrutiny were subject not only to technological but also to social and interactional constraints and thus highlighted contextual variability. Further, the high degree of sociability in the electronic episodes studied was interpreted as reflecting a ¿people first, business second¿ communicative style

Hemocyanin facilitates lignocellulose digestion by wood-boring marine crustaceans

Woody (lignocellulosic) plant biomass is an abundant renewable feedstock, rich in polysaccharides that are bound into an insoluble fiber composite with lignin. Marine crustacean woodborers of the genus Limnoria are among the few animals that can survive on a diet of this recalcitrant material without relying on gut resident microbiota. Analysis of fecal pellets revealed that Limnoria targets hexose-containing polysaccharides (mainly cellulose, and also glucomannans), corresponding with the abundance of cellulases in their digestive system, but xylans and lignin are largely unconsumed. We show that the limnoriid respiratory protein, hemocyanin, is abundant in the hindgut where wood is digested, that incubation of wood with hemocyanin markedly enhances its digestibility by cellulases, and that it modifies lignin. We propose that this activity of hemocyanins is instrumental to the ability of Limnoria to feed on wood in the absence of gut symbionts. These findings may hold potential for innovations in lignocellulose biorefining