Prioritizing vaccine development to focus on pathogens that drive the most antibiotic prescribing will have multiple advantages: reducing the burden of disease, reducing the extent of antibiotic use, and thus reducing the selective pressures driving antimicrobial resistance. In this proposal, we will (1) test the hypothesis that recent declines in outpatient antibiotic prescribing in the US are associated with reductions in pneumococcal disease attributable to PCV13 uptake and (2) estimate the antibiotic prescribing attributable to the most common pathogens and variation by age, demographic, and geography. To do so, we will use large representative nationwide datasets from the US, including insurance claims, public health surveillance, and a national immunization survey. The deliverables from this project will include estimates of the impact of PCV13 on outpatient prescribing and quantification of the expected reductions in antibiotic prescribing given vaccines for common pathogens. We expect that the results from these studies will establish (1) robust estimates of the reductions in outpatient antibiotic prescribing achieved by PCV13, as an exemplar of what vaccines can accomplish; and (2) priorities for vaccines to target in terms of impact on antibiotic prescribing and thus on antimicrobial resistance.

Circadian rhythms are endogenously generated by the suprachiasmatic nuclei (SCN) of the hypothalamus and are entrained to the 24 h day primarily by the light-dark cycle (the major environmental time cue) and, to a lesser extent, by non-photic time cues (e.g. social interaction, novel activity, exercise). Outputs from the SCN control the rhythmicity of many physiological and behavioural processes (e.g. hormone secretion, core body temperature, sleep, activity). Disorders of circadian system may have serious consequences. Shift-work and jet-lag are examples in which the endogenous circadian system is desynchronised from the external environment. Blind individuals are also likely to suffer from circadian rhythm disorders (abnormal sleep, hormonal and behavioural rhythms) as they lack the eye-mediated photic input to the SCN required to entrain endogenous rhythms to the light-dark cycle. In order to resynchronise disordered rhythms, treatment (e.g. light or exogenous melatonin) must be given at an appropriate time according to each individual's circadian system. It is not yet established how similar circadian period (t) is between individuals. An assessment of period, unaffected by the external environment, is required in order to evaluate how robust and repeatable the measurement of human circadian rhythms are. A recent publication by Harvard Medical School has proposed that t = 24.18 h in sighted subjects studied in a laboratory-based 'forced desynchrony' protocol whereas our field studies of blind people at the University of Surrey suggest a higher average (=24.5h). The forced desynchrony protocol tightly controls the subjects' exposure to external influences by maintaining them on a 28 hour sleep-wake schedule and keeping them in constant dim light (15 lux) for 30 days. As 28 hours is beyond the range of entrainment for human rhythms, the circadian system reverts to its endogenous periodicity. This is in contrast to the field studies of totally blind individuals where light cannot influence the subjects, no restrictions are placed on them and exposure to non-photic time cues is unrestricted. The variation in experimental techniques used in these studies has prevented a definitive consensus on the value of t. Whether the inconsistencies observed between the two approaches are due to differences in experimental technique, the use of sighted and blind subjects or exposure to photic and non-photic time cues is unknown. Thus, the overall aim of the project is to define the endogenous period (t) of the human circadian system and to examine the influence of non-photic time cues on rhythmicity. The proposed study will assess the circadian period of six totally blind subjects in the laboratory using the forced desynchrony protocol and will be compared to the period measured in field studies in the same individuals. By studying blind subjects, the potentially confounding influences of light are removed, allowing an assessment of the effects of an altered distribution of non-photic time cues between the two methods. The findings will be used to assess the stability and precision of the human circadian pacemaker and to evaluate the potential of a general model to treat circadian rhythm disorders.

Vaccines against viruses can reduce antibiotic prescribing by reducing the incidence of viral infections that are inappropriately treated with antibiotics, as well as by reducing the incidence of secondary bacterial infections caused by viral infections. We will estimate the magnitude of this effect for influenza vaccination and the potential magnitude for Respiratory Syncitial Virus (RSV) vaccination and enhanced influenza vaccination. First, we willestimate the antimicrobial prescribing attributable to RSV and influenza in the Kaiser Permanente population in Northern California, USA, in total and by drug class and age group. Next, we will estimate the antimicrobial prescribing currently averted by influenza vaccination by comparing antimicrobial prescribing in (1) persons who have not received influenza vaccine vs. (2) persons who have, controlling for age and location within northern California, in aggregate and stratified by age and antimicrobial class. Using these results, we will estimate the number and proportion of antimicrobial prescriptions that may potentially be averted by improved influenza vaccines and (separately) by RSV vaccines that are now investigational, assuming various possible levels of coverage and effectiveness. Notable features of our analysis will be extensive measures to avoid confounding and an examination of waning of influenza prescribing effects with time since vaccination.