Antibiotic use in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) patients during the COVID-19 pandemic has exceeded the incidence of bacterial coinfections and secondary infections, suggesting inappropriate and excessive prescribing. Even in settings with established antimicrobial stewardship (AMS) programmes, there were weaknesses exposed regarding appropriate antibiotic use in the context of the pandemic. Moreover, antimicrobial resistance (AMR) surveillance and AMS have been deprioritised with diversion of health system resources to the pandemic response. This experience highlights deficiencies in AMR containment and mitigation strategies that require urgent attention from clinical and scientific communities. These include the need to implement diagnostic stewardship to assess the global incidence of coinfections and secondary infections in COVID-19 patients, including those by multidrug-resistant pathogens, to identify patients most likely to benefit from antibiotic treatment and identify when antibiotics can be safely withheld, de-escalated or discontinued. Long-term global surveillance of clinical and societal antibiotic use and resistance trends is required to prepare for subsequent changes in AMR epidemiology, while ensuring uninterrupted supply chains and preventing drug shortages and stock outs. These interventions present implementation challenges in resource-constrained settings, making a case for implementation research on AMR. Knowledge and support for these practices will come from internationally coordinated, targeted research on AMR, supporting the preparation for future challenges from emerging AMR in the context of the current COVID-19 pandemic or future pandemics.

The function of exocrine glands depends on signals within the extracellular environment. In the mammary gland, integrin-mediated adhesion to the extracellular matrix protein laminin co-operates with soluble factors such as prolactin to regulate tissue-specific gene expression. The mechanism of matrix and prolactin crosstalk and the activation of downstream signals are not fully understood. Because integrins organize the cytoskeleton, we analysed the contribution of the cytoskeleton to prolactin receptor activation and the resultant stimulation of milk protein gene expression. We show that the proximal signalling events initiated by prolactin (i.e. tyrosine phosphorylation of receptor and the associated kinase Jak2) do not depend on an intact actin cytoskeleton. However, actin networks and microtubules are both necessary for continued mammary cell differentiation, because cytoskeletal integrity is required to transduce the signals between prolactin receptor and Stat5, a transcription factor necessary for milk protein gene transcription. The two different cytoskeletal scaffolds regulate prolactin signalling through separate mechanisms that are specific to cellular differentiation but do not affect the general profile of protein synthesis.

SummaryBackgroundAntibacterial resistant infections are rising continuously, resulting in increased morbidity and mortality worldwide. With no new antibiotic classes entering the market and the possibility of returning to the pre-antibiotic era, the Joint Programming Initiative on Antimicrobial Resistance (JPIAMR) was established to address this problem. We aimed to quantify the scale and scope of publicly funded antibacterial resistance research across JPIAMR countries and at the European Union (EU) level to identify gaps and future opportunities.MethodsWe did a systematic observational analysis examining antibacterial resistance research funding. Databases of funding organisations across 19 countries and at EU level were systematically searched for publicly funded antibacterial resistance research from Jan 1, 2007, to Dec 31, 2013. We categorised studies on the basis of the JPIAMR strategic research agenda's six priority topics (therapeutics, diagnostics, surveillance, transmission, environment, and interventions) and did an observational analysis. Only research funded by public funding bodies was collected and no private organisations were contacted for their investments. Projects in basic, applied, and clinical research, including epidemiological, public health, and veterinary research and trials were identified using keyword searches by organisations, and inclusion criteria were based on the JPIAMR strategic research agenda's six priority topics, using project titles and abstracts as filters.FindingsWe identified 1243 antibacterial resistance research projects, with a total public investment of €1·3 billion across 19 countries and at EU level, including public investment in the Innovative Medicines Initiative. Of the total amount invested in antibacterial resistance research across the time period, €646·6 million (49·5%) was invested at the national level and €659·2 million (50·5%) at the EU level. When projects were classified under the six priority topics we found that 763 (63%) of 1208 projects funded at national level were within the area of therapeutics, versus 185 (15%) in transmission, 131 (11%) in diagnostics, 53 (4%) in interventions, and only 37 (3%) in environment and 39 (3%) in surveillance.InterpretationThis was the first systematic analysis of research funding of antibacterial resistance of this scale and scope, which relied on the availability and accuracy of data from organisations included. Large variation was seen between countries both in terms of number of projects and associated investment and across the six priority topics. To determine the future direction of JPIAMR countries a clear picture of the funding landscape across Europe and Canada is needed. Countries should work together to increase the effect of research funding by strengthening national and international coordination and collaborations, harmonising research activities, and collectively pooling resources to fund multidisciplinary projects. The JPIAMR have developed a publicly available database to document the antibacterial...

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