Stemming the Global Trade in Falsified and Substandard Medicines

Drug safety and quality is an essential assumption of clinical medicine, but there is growing concern that this assumption is not always correct. Poor manufacturing and deliberate fraud occasionally compromises the drug supply in the United States, and the problem is far more common and serious in low- and middle-income countries with weak drug regulatory systems. An Institute of Medicine consensus committee report identified the causes and possible solutions to the problem of falsified and substandard drugs around the world. The vocabulary people use to discuss the problem is itself a concern. The word counterfeit is often used innocuously to describe any drug that is not what it seems, but some NGOs and emerging manufacturing nations object to this term. These groups see hostility to generic pharmaceuticals in a discussion of counterfeit medicines. These groups see hostility to generic pharmaceuticals in a discussion of counterfeit medicines. Precisely speaking, a counterfeit drug infringes on a registered trademark, and trademark infringement in not necessarily a problem of public health consequence. Instead of talking broadly about counterfeit drugs, the WHO and other stakeholders should consider two main categories of drug quality problems. Falsified medicines misrepresent the product’s identity or source or both. Substandard drugs fail to meet the national specifications given in an accepted pharmacopeia or the manufacturer’s dossier. In practice, there is often considerable overlap between categories. There is considerable uncertainty about the size of the falsified and substandard drug market. Improved pharmacovigilance, especially in developing countries, give a better picture of the scope of the problem. In the United States, tighter regulatory controls on the wholesale market and a mandatory drug tracking system would improve drug safety. In developing countries, development finance organizations should invest in small- and medium-sized pharmaceutical manufacturers, and governments should use tools such as franchising, accreditation, low-interest loans, and task shifting to encourage private sector investment in drug retail. Finally, the WHO should work with stakeholders such as the UNODC and the WCO to develop an international code of practice on falsified and substandard drugs

The Dodd-Frank Wall Street Reform and Consumer Protection Act: unresolved issues of regulatory culture and mindset

The Dodd-Frank Act constitutes the most significant reform of financial regulation in the United States since the 1930s. Some of its provisions are bold, particularly in the areas of consumer protection and derivative trading. However, the political challenges for law reformers and regulators in the wake of the global financial crisis are far from over. The Act is inchoate. The full scope and nature of the new financial regulatory system will take several years to evolve as the mandated studies and rule making are completed and implemented. We argue that the extent to which the reforms achieve their stated objectives will depend most critically on three factors: (i) the competency, integrity and forcefulness of the federal regulators, (ii) their ability and willingness to supervise the finance industry on an integrated basis, and (iii) a fundamental change in the regulatory culture and mindset

Acceptability and Effectiveness of NHS-Recommended e-Therapies for Depression, Anxiety, and Stress: Meta-Analysis.

BACKGROUND: There is a disconnect between the ability to swiftly develop e-therapies for the treatment of depression, anxiety, and stress, and the scrupulous evaluation of their clinical utility. This creates a risk that the e-therapies routinely provided within publicly funded psychological health care have evaded appropriate rigorous evaluation in their development. OBJECTIVE: This study aims to conduct a meta-analytic review of the gold standard evidence of the acceptability and clinical effectiveness of e-therapies recommended for use in the National Health Service (NHS) in the United Kingdom. METHODS: Systematic searches identified appropriate randomized controlled trials (RCTs). Depression, anxiety, and stress outcomes at the end of treatment and follow-up were synthesized using a random-effects meta-analysis. The grading of recommendations assessment, development, and evaluation approach was used to assess the quality of each meta-analytic comparison. Moderators of treatment effect were examined using subgroup and meta-regression analysis. Dropout rates for e-therapies (as a proxy for acceptability) were compared against controls. RESULTS: A total of 24 studies evaluating 7 of 48 NHS-recommended e-therapies were qualitatively and quantitatively synthesized. Depression, anxiety, and stress outcomes for e-therapies were superior to controls (depression: standardized mean difference [SMD] 0.38, 95% CI 0.24 to 0.52, N=7075; anxiety and stress: SMD 0.43, 95% CI 0.24 to 0.63, n=4863), and these small effects were maintained at follow-up. Average dropout rates for e-therapies (31%, SD 17.35) were significantly higher than those of controls (17%, SD 13.31). Limited moderators of the treatment effect were found. CONCLUSIONS: Many NHS-recommended e-therapies have not been through an RCT-style evaluation. The e-therapies that have been appropriately evaluated generate small but significant, durable, beneficial treatment effects. TRIAL REGISTRATION: International Prospective Register of Systematic Reviews (PROSPERO) registration CRD42019130184; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=130184

New Class of Precision Antimicrobials Redefines Role of Clostridium difficile S-layer in Virulence and Viability

There is a medical need for antibacterial agents that do not damage the resident gut microbiota or promote the spread of antibiotic resistance. We recently described a prototypic precision bactericidal agent, Av-CD291.2, which selectively kills specific Clostridium difficile strains and prevents them from colonizing mice. We have since selected two Av-CD291.2–resistant mutants that have a surface (S)-layer–null phenotype due to distinct point mutations in the slpA gene. Using newly identified bacteriophage receptor binding proteins for targeting, we constructed a panel of Avidocin-CDs that kills diverse C. difficile isolates in an S-layer sequence-dependent manner. In addition to bacteriophage receptor recognition, characterization of the mutants also uncovered important roles for S-layer protein A (SlpA) in sporulation, resistance to innate immunity effectors, and toxin production. Surprisingly, S-layer–null mutants were found to persist in the hamster gut despite a complete attenuation of virulence. These findings suggest antimicrobials targeting virulence factors dispensable for fitness in the host force pathogens to trade virulence for viability and would have clear clinical advantages should resistance emerge. Given their exquisite specificity for the pathogen, Avidocin-CDs have substantial therapeutic potential for the treatment and prevention of C. difficile infections

2D nanosheet paint from solvent-exfoliated Bi2Te3 ink

Embedding 2D layered materials into polymers and other materials as composites has resulted in the development of ultrasensitive pressure sensors, tunable conductive stretchable polymers, and thermoelectric coatings. As a wettable paint or ink, many 2D materials may be penciled, printed, or coated onto a range of surfaces for a variety of applications. However, the intrinsic conductive properties of painted coatings using 2D and layered materials are not completely understood, and conductive polymer additives may mask underlying properties such as directional conductivity. We report a process for making a paint from solvent-exfoliated Bi2Te3 into solution-dispersible 2D and few-layer (multiple quintuple) nanosheet inks, that form smooth, uniform paint blends at several concentrations of Bi2Te3. The individual solvent-exfoliated nanosheets are edge-coated by (poly)ethylene glycol to produce a paint, stable over extended period in solution. Electrical transport is found to be sensitive to aspect ratio, and conduction along the painting direction is suppressed for longer strips so long as the aspect ratio is high (4–10× or more), but for short and wide paint strips (aspect ratio ≤1), conductance is improved by a factor of 3×. Square 2D paint regions show no clear directional preference for conductance at room temperature but are markedly affected by higher temperatures. Conductivity along a preferential conduction pathway through the nanosheet ensemble is modulated by 2D nanosheet stacking along the direction of paint application for a given aspect ratio. This paint and insights into geometrical 2D composite conduction may have implications for conductive composites, thermoelectrics, and writable circuits using 2D material paints or inks

Paintable films from chemically exfoliated 2D bismuth telluride nanosheets.

This work highlights a method whereby solvent exfoliation of Bi2Te3 into solution-dispersible 2D nanosheets can form a practical thin film that can be distributed across a surface. Optimized exfoliated suspensions are also shown to form smooth, uniform blends when mixed with poly ethylene glycol and other polymers to produce a paintable Bi2Te3 film that can be applied to surfaces using an innovative painting technique. Atomic force microscopy, transmission electron spectroscopy, Raman scattering spectroscopy and scanning electron spectroscopy are used to examine the structure of the 2D nanosheets and the Bi2Te3 thin films. Electrical transport studies show that the films have conductive pathways over a range of surfaces and various structural formations, linking the conductivity to the percolating conduction through the nanosheet ensemble

Semiconducting metal oxide photonic crystal plasmonic photocatalysts

Plasmonic photocatalysis has facilitated rapid progress in enhancing photocatalytic efficiency under visible light irradiation. Poor visible‐light‐responsive photocatalytic materials and low photocatalytic efficiency remain major challenges. Plasmonic metal–semiconductor heterostructures where both the metal and semiconductor are photosensitive are promising for light harvesting catalysis, as both components can absorb solar light. Efficiency of photon capture can be further improved by structuring the catalyst as a photonic crystal. Here, the synthesis of photonic crystal plasmonic photocatalyst materials using Au nanoparticle‐functionalized inverse opal (IO) photonic crystals is reported. A catalyst prepared using a visible‐light‐responsive semiconductor (V2O5) displayed over an order of magnitude increase in reaction rate under green light excitation (λ = 532 nm) compared to no illumination. The superior performance of Au‐V2O5 IO is attributed to spectral overlap of the electronic bandgap, localized surface plasmon resonance, and incident light source. For the Au‐TiO2 catalyst, despite coupling of the LSPR and excitation source at λ = 532 nm, this is not as effective in enhancing photocatalytic activity compared to carrying out the reaction under broadband visible light, which is attributed to improved photon adsorption in the visible by the presence of a photonic bandgap, and exploiting slow light in the photonic crystal to enhance photon absorption to create this synergistic type of photocatalyst

Photon migration of Raman signal in bone as measured with spatially offset Raman spectroscopy

Spatially offset Raman spectroscopy (SORS) is currently being developed as an in vivo tool for bone disease detection, but to date, information about the interrogated volume as influenced by the light propagation and scattering characteristics of the bone matrix is still limited. This paper seeks to develop our general understanding of the sampling depths of SORS in bone specimens as a function of the applied spatial offset. Equine metacarpal bone was selected as a suitable specimen of compact cortical bone large enough to allow several thin slices (600 μm) to be cut from the dorsal surface. Photon migration at 830-nm excitation was studied with five bone slices and a 380 μm-thin polytetrafluoroethylene (PTFE) slice placed consecutively between the layers. To optimize Raman signal recovery of the PTFE with increasing depth within the bone stack required a corresponding increase in spatial offset. For example, to sample effectively at 2.2-mm depth within the bone required an optimal SORS offset of 7mm. However, with a 7-mm offset, the maximum accessible penetration depth from which the PTFE signal could be still recovered was 3.7mm. These results provide essential basic information for developing SORS technology for medical diagnostics in general and optimizing sampling through bone tissue, permitting a better understanding of the relationship between the offset and depth of bone assessed, in particular. Potential applications include the detection of chemically specific markers for changes in bone matrix chemistry localized within the tissue and not present in healthy bone