Synthetic considerations in the self-assembly of coordination polymers of pyridine-functionalised hybrid Mn-Anderson polyoxometalates

The incorporation of polyoxometalates (POMs) as structural units into ordered porous constructs such as metal-organic frameworks (MOFs) is desirable for a range of applications where intrinsic properties inherited from both the MOF and POM are utilised, including catalysis and magnetic data storage. The controlled self-assembly of targeted MOF topologies containing POM units is hampered by the wide range of oxo and hydroxo units on the peripheries of POMs that can act as coordinating groups towards linking metal cations leading to a diverse range of structures, but incorporation of organic donor units into hybrid POMs offers an alternative methodology to programmably synthesise POM/MOF conjugates. Herein, we report six coordination polymers obtained serendipitously wherein Zn2+ and Cu2+ link pyridine-appended Mn-Anderson clusters into two- and three-dimensional network solids with complex connectivities and topologies. Careful inspection of their solid-state structures has allowed us to identify common structure-directing features across these coordination polymers, including a square motif where two Zn2+ cations bridge two POMs. By correlating certain structural motifs with synthetic conditions we have formulated a series of design considerations for the self-assembly of coordination polymers of hybrid POMs, encompassing the selection of reaction conditions, co-ligands and linking metal cations. We anticipate that these synthetic guidelines will inform the future assembly of hybrid POMs into functional MOF materials

Which Way Was I Going? Contextual Retrieval Supports the Disambiguation of Well Learned Overlapping Navigational Routes

Groundbreaking research in animals has demonstrated that the hippocampus contains neurons that distinguish betweenoverlapping navigational trajectories. These hippocampal neurons respond selectively to the context of specific episodes despite interference from overlapping memory representations. The present study used functional magnetic resonanceimaging in humans to examine the role of the hippocampus and related structures when participants need to retrievecontextual information to navigate well learned spatial sequences that share common elements. Participants were trained outside the scanner to navigate through 12 virtual mazes from a ground-level first-person perspective. Six of the 12 mazes shared overlapping components. Overlapping mazes began and ended at distinct locations, but converged in the middle to share some hallways with another maze. Non-overlapping mazes did not share any hallways with any other maze. Successful navigation through the overlapping hallways required the retrieval of contextual information relevant to thecurrent navigational episode. Results revealed greater activation during the successful navigation of the overlapping mazes compared with the non-overlapping mazes in regions typically associated with spatial and episodic memory, including thehippocampus, parahippocampal cortex, and orbitofrontal cortex. When combined with previous research, the current findings suggest that an anatomically integrated system including the hippocampus, parahippocampal cortex, and orbitofrontal cortexis critical for the contextually dependent retrieval of well learned overlapping navigational routes

The US Food and Drug Administration’s expedited approval programs: addressing premarket flexibility with enhanced postmarket evidence generation

When the editors of Clinical Trials solicited our review on the U.S. Food and Drug Administration’s (FDA) expedited development and review programs, we anticipated there would be accompanying commentaries from other academics with differing opinions, or perhaps from the perspectives of industry or venture capital. We hardly expected to initiate a discussion among the former Commissioner of the FDA, the current Director of the Center for Drug Evaluation and Research (CDER), and the Chief Medical Officer of the American Society of Clinical Oncology on the advantages and disadvantages to patients and clinicians of FDA’s expedited approval programs. But we appreciate the opportunity to have done so. To be clear, the goal of our review was to engage in constructive dialogue, discussing the implications of expedited approval programs on premarket and postmarket evidence generation, highlighting some specific concerns, and offering our recommendations for robust medical product evaluations that ensure high-quality clinical evidence is available to inform patient care and clinical decision-making. The FDA faces the challenging task of striking the right balance between ensuring that novel therapeutics are safe and effective and allowing promising new drugs to enter the market as quickly as possible. We agree with Dr. Califf that FDA’s regulatory approach should not ‘revert back to the strategy of the 1970s’.2 Likely in response to the desires frequently expressed by patients and clinicians, the U.S. Congress has enacted laws requiring the FDA to develop expedited development and review pathways to accelerate the availability of novel therapeutics. Some of these pathways necessarily offer potential flexibility with respect to the evidentiary standards that are required to demonstrate medical product safety and effectiveness and secure approval. Accordingly, we believe there is a need for corresponding efforts to strengthen the clinical evidence that is generated after market approval

The US Food and Drug Administration’s expedited approval programs: Evidentiary standards, regulatory trade-offs, and potential improvements

The United States Food and Drug Administration (FDA) has several regulatory programs and pathways to expedite the development and approval of therapeutic agents aimed at treating serious or life-debilitating conditions. A common feature of these programs is the regulatory flexibility, which allows for a customized approval approach that enables market authorization on the basis of less rigorous evidence, in exchange for requiring postmarket evidence generation. An increasing share of drugs approved by the FDA in recent years are associated with expedited programs. In this paper, we provide an overview of the evidentiary standards required by FDA’s expedited development and approval programs, summarize the findings of the recent academic literature demonstrating some of the limitations of these programs, and outline potential opportunities to address these limitations. Recent evidence suggests that therapeutic agents in the FDA’s expedited programs are approved on the basis of fewer and smaller studies that may lack comparator groups and random allocation, and rather than focusing on clinical outcomes for study endpoints, rely instead on surrogate markers of disease. Once on the market, agents receiving expedited approvals are often quickly incorporated into clinical practice and evidence generated in the postmarketing period may not necessarily address the evidentiary limitations at the time of market entry. Furthermore, not all pathways require additional postmarketing studies. Evidence suggests that drugs in expedited approval programs are associated with a greater likelihood that FDA will take a safety action following market entry. There are several opportunities to improve the timeliness, information value, and validity of the pre-and postapproval studies of drugs receiving expedited approvals. When use of nonrandomized and uncontrolled studies cannot be avoided prior to market entry, randomized trials should be mandatory in the postapproval period, unless there are strong justifications for not carrying out such studies. In the premarket period, validity of the surrogate markers can be improved by more rigorously evaluating their correlation with patient-relevant clinical outcomes. Opportunities to reduce the duration, complexity, and cost of postmarketing randomized trials should not compromise their validity and instead incorporate pragmatic ‘real-world’ design elements. Despite recent enthusiasm for widely using real world evidence, adaptive designs, and pragmatic trials in the regulatory setting, caution is warranted until large scale empirical evaluations demonstrate their validity compared to more traditional trial design

Calorimetric and magnetic study for Ni50_{50}Mn36_{36}In14_{14} and relative cooling power in paramagnetic inverse magnetocaloric systems

The non-stoichiometric Heusler alloy Ni$_{50}$Mn$_{36}$In$_{14}$ undergoes a martensitic phase transformation in the vicinity of 345 K, with the high temperature austenite phase exhibiting paramagnetic rather than ferromagnetic behavior, as shown in similar alloys with lower-temperature transformations. Suitably prepared samples are shown to exhibit a sharp transformation, a relatively small thermal hysteresis, and a large field-induced entropy change. We analyzed the magnetocaloric behavior both through magnetization and direct field-dependent calorimetry measurements. For measurements passing through the first-order transformation, an improved method for heat-pulse relaxation calorimetry was designed. The results provide a firm basis for the analytic evaluation of field-induced entropy changes in related materials. An analysis of the relative cooling power (RCP), based on the integrated field-induced entropy change and magnetizing behavior of the Mn spin system with ferromagnetic correlations, shows that a significant RCP may be obtained in these materials by tuning the magnetic and structural transformation temperatures through minor compositional changes or local order changes

Optimizing the Data Available Via Health Canada\u27s Clinical Information Portal

Through its Public Release of Clinical Information initiative, Health Canada has provided public access to a vast repository of data that have been submitted to support market authorization of drugs and medical devices. Health Canada has released data from more than 160 submissions for drugs, biologics, vaccines and medical devices. The regulator is currently in its third year of a 4-year phase-in schedule to release clinical data proactively from submissions for all new active substances, new clinical indications, generic drugs and higher-risk devices that are approved, withdrawn or rejected. Substantial clinical data submitted by the industry sponsor of the application, including summary-level data and metadata are made publicly available by Health Canada as a matter of policy

Physician and Other Healthcare Personnel Responses to Hospital Stroke Quality of Care Performance Feedback: A Qualitative Study

Background Understanding how physicians and other healthcare personnel respond to hospital performance feedback initiatives may have important implications for quality improvement efforts. Our objective was to explore responses to the inaugural feedback of hospital performance on stroke quality of care measures among relevant physicians and personnel at the US Department of Veterans Health Administration (VHA) hospitals. Methods Qualitative interviews with hospital administrators, physicians, nurses and quality managers at 12 VHA hospitals in the USA after the inaugural national release of the report on quality of acute stroke care processes. Interview transcripts were analysed using an immersion/crystallisation approach to identify recurrent themes. Results Interviews were completed with 41 individuals at 12 VHA hospitals from diverse regions of the USA; the majority were clinicians, either physicians or nurses, and nearly all had 20 years of experience or more. Interviewees described general perceptions of internal performance feedback that were both positive and negative, such as the notion that performance feedback could provide value to clinicians and hospitals, but at the same time voiced concerns about being inundated with such data. Interviewees also expressed scepticism about public reporting of performance data, citing numerous concerns and limitations. However, when interviewees described specific experiences with performance feedback, nearly all reactions were positive, including excitement, interest and feeling validated about a job well done. Discussion Physicians and other healthcare personnel described hospital performance feedback on stroke quality of care measures to be broadly valuable but identified areas of concern related to the measurement process and public reporting

Medical school gift restriction policies and physician prescribing of newly marketed psychotropic medications: difference-in-differences analysis

Objective: To examine the effect of attending a medical school with an active policy on restricting gifts from representatives of pharmaceutical and device industries on subsequent prescribing behavior. Design: Difference-in-differences approach. Setting: 14 US medical schools with an active gift restriction policy in place by 2004. Participants: Prescribing patterns in 2008 and 2009 of physicians attending one of the schools compared with physicians graduating from the same schools before the implementation of the policy, as well as a set of contemporary matched controls. Main outcome measure: Probability that a physician would prescribe a newly marketed medication over existing alternatives of three psychotropic classes: lisdexamfetamine among stimulants, paliperidone among antipsychotics, and desvenlafaxine among antidepressants. None of these medications represented radical breakthroughs in their respective classes. Results: For two of the three medications examined, attending a medical school with an active gift restriction policy was associated with reduced prescribing of the newly marketed drug. Physicians who attended a medical school with an active conflict of interest policy were less likely to prescribe lisdexamfetamine over older stimulants (adjusted odds ratio 0.44, 95% confidence interval 0.22 to 0.88; P=0.02) and paliperidone over older antipsychotics (0.25, 0.07 to 0.85; P=0.03). A significant effect was not observed for desvenlafaxine (1.54, 0.79 to 3.03; P=0.20). Among cohorts of students who had a longer exposure to the policy or were exposed to more stringent policies, prescribing rates were further reduced. Conclusion: Exposure to a gift restriction policy during medical school was associated with reduced prescribing of two out of three newly introduced psychotropic medications

Analytic ab initio-based molecular interaction potential for the BrO·H\u3csub\u3e2\u3c/sub\u3eO complex

Radical halogen oxide species play important roles within atmospheric processes, specifically those responsible for the removal of O3. To facilitate future investigations on this family of compounds, RCCSD(T)/aug-cc-pVQZ-level electronic structure calculations were employed to generate individual-molecule optimized geometries, as well as to determine the global minimum energy structure for the BrO·H2O complex. This information facilitated the generation of several one-dimensional potential energy surface (PES) scans for the BrO·H2O complex. Scans were performed for both the ground state and the first excited state; this inclusion is due to a low-lying first electronic excited-state energy. These rigid-geometry PES scans were used both to generate a novel analytic interaction potential by modifying the existing Thole-type model used for water and to the fitted potential function. This interaction potential features anisotropic atomic polarizabilities facilitating appropriate modeling of the physics regarding the unpaired electron residing within the p-orbitals of the oxygen atom of the bromine oxide radical. The intention of this work is to facilitate future molecular dynamics simulations involving the interaction between the BrO radical and water clusters as a first step in devising possible novel chemistries taking place at the water interface of clouds within the atmosphere