Nicotinamide adenine dinucleotide (NAD) extends longevity in experimental organisms, raising interest in its impact on human health. De novo NAD biosynthesis from tryptophan is evolutionarily conserved yet considered supplanted among higher species by biosynthesis from nicotinamide (NAM). Here we show that a bottleneck enzyme in de novo biosynthesis, quinolinate phosphoribosyltransferase (QPRT), defends renal NAD and mediates resistance to acute kidney injury (AKI). Following murine AKI, renal NAD fell, quinolinate rose, and QPRT declined. QPRT mice exhibited higher quinolinate, lower NAD, and higher AKI susceptibility. Metabolomics suggested an elevated urinary quinolinate/tryptophan ratio (uQ/T) as an indicator of reduced QPRT. Elevated uQ/T predicted AKI and other adverse outcomes in critically ill patients. A phase 1 placebo-controlled study of oral NAM demonstrated a dose-related increase in circulating NAD metabolites. NAM was well tolerated and was associated with less AKI. Therefore, impaired NAD biosynthesis may be a feature of high-risk hospitalizations for which NAD augmentation could be beneficial.

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Because injured mitochondria can accelerate cell death through the elaboration of oxidative free radicals and other mediators, it is striking that proliferator γ coactivator 1-α (PGC1α), a stimulator of increased mitochondrial abundance, protects stressed renal cells instead of potentiating injury. Here, we report that PGC1α’s induction of lysosomes via transcription factor EB (TFEB) may be pivotal for kidney protection. CRISPR and stable gene transfer showed that PGC1α-KO tubular cells were sensitized to the genotoxic stressor cisplatin, whereas Tg cells were protected. The biosensor mitochondrial-targeted Keima (mtKeima) unexpectedly revealed that cisplatin blunts mitophagy both in cells and mice. PGC1α and its downstream mediator NAD + counteracted this effect. PGC1α did not consistently affect known autophagy pathways modulated by cisplatin. Instead RNA sequencing identified coordinated regulation of lysosomal biogenesis via TFEB. This effector pathway was sufficiently important that inhibition of TFEB or lysosomes unveiled a striking harmful effect of excess PGC1α in cells and conditional mice. These results uncover an unexpected effect of cisplatin on mitophagy and PGC1α’s reliance on lysosomes for kidney protection. Finally, the data illuminate TFEB as a potentially novel target for renal tubular stress resistance.

Acute kidney injury (AKI) arising from diverse etiologies is characterized by mitochondrial dysfunction. The peroxisome proliferator-activated receptor γ coactivator-1alpha (PGC1α), a master regulator of mitochondrial biogenesis, has been shown to be protective in AKI. Interestingly, reduction of PGC1α has also been implicated in the development of diabetic kidney disease and renal fibrosis. The beneficial renal effects of PGC1α make it a prime target for therapeutics aimed at ameliorating AKI, forms of chronic kidney disease (CKD), and their intersection. This review summarizes the current literature on the relationship between renal health and PGC1α and proposes areas of future interest.

BackgroundThe Health (Pricing and Supply of Medical Goods) Act 2013 passed into law in July 2013 and legislated for generic substitution in Ireland. The aim of the study was to ascertain the knowledge and perceptions of stakeholders i.e. patients, pharmacists and prescribers, of generic medicines and to generic substitution with the passing of legislation.MethodsThree stakeholder specific questionnaires were developed to assess knowledge of and perceptions to generic medicines and generic substitution. Purposive samples of patients, prescribers and pharmacists were analysed. Descriptive quantitative and qualitative analyses were undertaken.Results and discussionA total of 762 healthcare professionals and 353 patients were recruited. The study highlighted that over 84 % of patients were familiar with generic medicines and are supportive of the concept of generic substitution. Approximately 74 % of prescribers and 84 % of pharmacists were supportive of generic substitution in most cases. The main areas of concern highlighted by the healthcare professionals that might impact on the successful implementation of the policy, were the issue of bioequivalence with generic medicines, the computer software systems used at present in general practitioner (GP) surgeries and the availability of branded generics. The findings from this study identify a high baseline rate of acceptance to generic medicines and generic substitution among patients, prescribers and pharmacists in the Irish setting. The concerns of the main stakeholders provide a valuable insight into the potential difficulties that may arise in its implementation, and the need for on-going reassurance and proactive dissemination of the impact of the generic substitution policy.ConclusionThe existing positive attitude to generic medicines and generic substitution among key stakeholders in Ireland to generic substitution, combined with appropriate support and collaboration should result in the desired increase in rates of prescribing, dispensing and use of generic medicines.

The delivery of healthcare including the provision of pharmacy services globally is highly regulated internationally in order to protect public health and welfare. However, the onset of the COVID-19 pandemic has precipitated the need internationally to amend the model of regulation in order to ensure that people were able to continue to access a range of healthcare services in a timely and effective manner. Many of the changes introduced to the regulation of pharmacy services in Ireland have been replicated in other countries. These include the introduction of electronic means to transmit prescriptions and other orders for medications, relaxing the legal restrictions in place controlling the emergency supply of prescription only medicines and more fully utilizing the professional competency of pharmacists by empowering them to use their expertise and judgment to support their patients accessing the healthcare services that they need. Many of the regulatory changes that have been introduced to support the COVID-19 public health emergency effort are ones that pharmacists have previously sought to enable them provide a more effective and expanded model of pharmaceutical care to their patients. Accordingly, many pharmacists will want these regulatory changes to be retained and further expanded in the aftermath of the COVID-19 public health emergency in order to extend their scope of practice and support them in the care of their patients.

No abstract

Background: Relative to the oral contraceptive pill, uptake of long-acting reversible contraceptive methods (LARCs) in Australia continues to be lower than might be suggested by the evidence on their clinical and economic benefits. Aim:To undertake a critical appraisal of published economic evaluations of LARCs to assess the generalisability of their results to the Australian healthcare context. Materials and Methods:A search of the literature was conducted to identify studies of economic evaluations of LARCs using the Medline, Embase and PubMed databases. The quality of the studies was evaluated using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist. Results: A total of 1009 citations were screened, from which 20 papers, typically reporting the cost per pregnancy avoided, were reviewed. The overall quality of the studies varied but was generally poor (average score of 62/100). To aid comparisons, results have been grouped under the headings IUS (all hormonal intrauterine systems), IUDs (all non-hormonal intrauterine devices), injectables (all contraceptive injections) and implants (all subdermal contraceptive implants).Overall, the results indicated that LARCs were more effective and less costly than oral contraceptives. Conclusions:Despite evidence that LARCs represent value for money, limitations in study quality and approaches must be taken into account when applying these results to Australia. Differences in healthcare settings aside, LARCs may also have benefits beyond their effect on pregnancy that might be captured in broader analyses, such as cost-benefit analyses using willingness to pay methods. These would capture benefits beyond health, which seem to be particularly relevant to contraception. K E Y W O R D Scontraception, cost-effectiveness, costs, literature review, long-acting reversible contraceptive methods