Antibiotic prescribing in primary care and antimicrobial resistance in patients admitted to hospital with urinary tract infection: a controlled observational pilot study

There is growing evidence that primary care prescribed antibiotics lead to antibiotic resistance in bacteria causing minor infections or being carried by asymptomatic adults, but little research to date has investigated links between primary care prescribed antibiotics and resistance among more serious infections requiring hospital care. Knowledge of these effects is likely to have a major influence on public expectations for, and primary care use of, antibiotics. This study aimed to assess the feasibility of recruiting symptomatic adult patients admitted to hospital with urinary infections and to link primary and secondary data information to investigate the relationship between primary care prescribed antibiotics and antimicrobial resistance in these patients. A microbiology database search of in patients who had submitted a urine sample identified 740 patients who were potentially eligible to take part in the study. Of these, 262 patients did not meet the eligibility criteria, mainly due to use of a urinary catheter (40%). Two-hundred and forty three patients could not be recruited as the nurse was unable to visit the patients prior to discharge, as they were too unwell. Eighty patients provided complete information. Results indicate that there is evidence that prior antibiotic use is associated with resistant infections in hospital patients. A fully powered study, conducted using routinely collected data is proposed to fully clarify the precision of the association

Magnetic resonance imaging-guided phase 1 trial of putaminal AADC gene therapy for Parkinson's disease.

ObjectiveTo understand the safety, putaminal coverage, and enzyme expression of adeno-associated viral vector serotype-2 encoding the complementary DNA for the enzyme, aromatic L-amino acid decarboxylase (VY-AADC01), delivered using novel intraoperative monitoring to optimize delivery.MethodsFifteen subjects (three cohorts of 5) with moderately advanced Parkinson's disease and medically refractory motor fluctuations received VY-AADC01 bilaterally coadministered with gadoteridol to the putamen using intraoperative magnetic resonance imaging (MRI) guidance to visualize the anatomic spread of the infusate and calculate coverage. Cohort 1 received 8.3 × 1011 vg/ml and ≤450 μl per putamen (total dose, ≤7.5 × 1011 vg); cohort 2 received the same concentration (8.3 × 1011 vg/ml) and ≤900 μl per putamen (total dose, ≤1.5 × 1012 vg); and cohort 3 received 2.6 × 1012 vg/ml and ≤900 μl per putamen (total dose, ≤4.7 × 1012 vg). (18)F-fluoro-L-dihydroxyphenylalanine positron emission tomography (PET) at baseline and 6 months postprocedure assessed enzyme activity; standard assessments measured clinical outcomes.ResultsMRI-guided administration of ascending VY-AADC01 doses resulted in putaminal coverage of 21% (cohort 1), 34% (cohort 2), and 42% (cohort 3). Cohorts 1, 2, and 3 showed corresponding increases in enzyme activity assessed by PET of 13%, 56%, and 79%, and reductions in antiparkinsonian medication of -15%, -33%, and -42%, respectively, at 6 months. At 12 months, there were dose-related improvements in clinical outcomes, including increases in patient-reported ON-time without troublesome dyskinesia (1.6, 3.3, and 1.5 hours, respectively) and quality of life.InterpretationNovel intraoperative monitoring of administration facilitated targeted delivery of VY-AADC01 in this phase 1 study, which was well tolerated. Increases in enzyme expression and clinical improvements were dose dependent. ClinicalTrials.gov Identifier: NCT01973543 Ann Neurol 2019;85:704-714

Adsorption of Cd(II) and Pb(II) ions from aqueous solutions using mesoporous activated carbon adsorbent: Equilibrium, kinetics and characterisation studies

In this study, cadmium and lead ions removal from aqueous solutions using a commercial activated carbon adsorbent (CGAC) were investigated under batch conditions. The adsorbent was observed to have a coarse surface with crevices, high resistance to attrition, high surface area and pore volume with bimodal pore size distribution which indicates that the material was mesoporous. Sorption kinetics for Cd(II) and Pb(II) ions proceeded through a two-stage kinetic profile-initial quick uptake occurring within 30 min followed by a gradual removal of the two metal ions until 180 min with optimum uptake (qe,exp) of 17.23 mg g1 and 16.84 mg g1 for Cd(II) and Pb(II) ions respectively. Modelling of sorption kinetics indicates that the pseudo first order (PFO) model described the sorption of Pb(II) ion better than Cd(II), while the reverse was observed with respect to the pseudo second order (PSO) model. Intraparticle diffusion modelling showed that intraparticle diffusion may not be the only mechanism that influenced the rate of ions uptake. Isotherm modelling was carried out and the results indicated that the Langmuir and Freundlich models described the uptake of Pb(II) ion better than Cd(II) ion. A comparison of the two models indicated that the Langmuir isotherm is the better isotherm for the description of Cd(II) and Pb(II) ions sorption by the adsorbent. The maximum loading capacity (qmax) obtained from the Langmuir isotherm was 27.3 mg g1 and 20.3 mg g1 for Cd(II) and Pb(II) ions respectively

Probability of sepsis after infection consultations in primary care in the United Kingdom in 2002-17:population-based cohort study and decision analytic model

BackgroundEfforts to reduce unnecessary antibiotic prescribing have coincided with increasing awareness of sepsis. We aimed to estimate the probability of sepsis following infection consultations in primary care when antibiotics were or were not prescribed.Methods and findingsWe conducted a cohort study including all registered patients at 706 general practices in the United Kingdom Clinical Practice Research Datalink, with 66.2 million person-years of follow-up from 2002 to 2017. There were 35,244 first episodes of sepsis (17,886, 51%, female; median age 71 years, interquartile range 57-82 years). Consultations for respiratory tract infection (RTI), skin or urinary tract infection (UTI), and antibiotic prescriptions were exposures. A Bayesian decision tree was used to estimate the probability (95% uncertainty intervals [UIs]) of sepsis following an infection consultation. Age, gender, and frailty were evaluated as association modifiers. The probability of sepsis was lower if an antibiotic was prescribed, but the number of antibiotic prescriptions required to prevent one episode of sepsis (number needed to treat [NNT]) decreased with age. At 0-4 years old, the NNT was 29,773 (95% UI 18,458-71,091) in boys and 27,014 (16,739-65,709) in girls; over 85 years old, NNT was 262 (236-293) in men and 385 (352-421) in women. Frailty was associated with greater risk of sepsis and lower NNT. For severely frail patients aged 55-64 years, the NNT was 247 (156-459) in men and 343 (234-556) in women. At all ages, the probability of sepsis was greatest for UTI, followed by skin infection, followed by RTI. At 65-74 years, the NNT following RTI was 1,257 (1,112-1,434) in men and 2,278 (1,966-2,686) in women; the NNT following skin infection was 503 (398-646) in men and 784 (602-1,051) in women; following UTI, the NNT was 121 (102-145) in men and 284 (241-342) in women. NNT values were generally smaller for the period from 2014 to 2017, when sepsis was diagnosed more frequently. Lack of random allocation to antibiotic therapy might have biased estimates; patients may sometimes experience sepsis or receive antibiotic prescriptions without these being recorded in primary care; recording of sepsis has increased over the study period.ConclusionsThese stratified estimates of risk help to identify groups in which antibiotic prescribing may be more safely reduced. Risks of sepsis and benefits of antibiotics are more substantial among older adults, persons with more advanced frailty, or following UTIs

Serious bacterial infections and antibiotic prescribing in primary care: cohort study using electronic health records in the UK

Objective This study evaluated whether serious bacterial infections are more frequent at family practices with lower antibiotic prescribing rates. Design Cohort study. Setting 706 UK family practices in the Clinical Practice Research Datalink from 2002 to 2017. Participants 10.1 million registered patients with 69.3 million patient-years' follow-up. Exposures All antibiotic prescriptions, subgroups of acute and repeat antibiotic prescriptions, and proportion of antibiotic prescriptions associated with specific-coded indications. Main outcome measures First episodes of serious bacterial infections. Poisson models were fitted adjusting for age group, gender, comorbidity, deprivation, region and calendar year, with random intercepts representing family practice-specific estimates. Results The age-standardised antibiotic prescribing rate per 1000 patient-years increased from 2002 (male 423; female 621) to 2012 (male 530; female 842) before declining to 2017 (male 449; female 753). The median family practice had an antibiotic prescribing rate of 648 per 1000 patient-years with 95% range for different practices of 430-1038 antibiotic prescriptions per 1000 patient-years. Specific coded indications were recorded for 58% of antibiotic prescriptions at the median family practice, the 95% range at different family practices was from 10% to 75%. There were 139 759 first episodes of serious bacterial infection. After adjusting for covariates and the proportion of coded consultations, there was no evidence that serious bacterial infections were lower at family practices with higher total antibiotic prescribing. The adjusted rate ratio for 20% higher total antibiotic prescribing was 1.03, (95% CI 1.00 to 1.06, p=0.074). Conclusions We did not find population-level evidence that family practices with lower total antibiotic prescribing might have more frequent occurrence of serious bacterial infections overall. Improving the recording of infection episodes has potential to inform better antimicrobial stewardship in primary care.</p

Mapping localized surface plasmons within silver nanocubes using cathodoluminescence hyperspectral imaging

Localized surface plasmons within silver nanocubes less than 50 nm in size are investigated using high resolution cathodoluminescence hyperspectral imaging. Multivariate statistical analysis of the multidimensional luminescence dataset allows both the identification of distinct spectral features in the emission and the mapping of their spatial distribution. These results show a 490 nm peak emitted from the cube faces, with shorter wavelength luminescence coming from the vertices and edges; this provides direct experimental confirmation of theoretical predictions

Switching the stereochemical outcome of 6-endo-trig cyclizations; Synthesis of 2,6-Cis-6-substituted 4-oxopipecolic acids

A base-mediated 6-endo-trig cyclization of readily accessible enone-derived α-amino acids has been developed for the direct synthesis of novel 2,6-cis-6- substituted-4-oxo-L-pipecolic acids. A range of aliphatic and aryl side chains were tolerated by this mild procedure to give the target compounds in good overall yields. Molecular modeling of the 6-endo-trig cyclization allowed some insight as to how these compounds were formed, with the enolate intermediate generated via an equilibrium process, followed by irreversible tautomerization/neutralization providing the driving force for product formation. Stereoselective reduction and deprotection of the resulting 2,6-cis-6-substituted 4-oxo-L-pipecolic acids to the corresponding 4-hydroxy-L-pipecolic acids was also performed

Flexible trial design in practice – dropping and adding arms in STAMPEDE: a multi-arm multi-stage randomised controlled trial

The trial recruits men with locally advanced or metastatic prostate cancer starting standard long-term hormone therapy. There are 5 research arms and 1 control arm. The trial has a pilot stage assessing safety and feasibility, 3 intermediate “activity” stages (I-III) where the outcome measure is failure-free survival (FFS) and one final “efficacy” stage (IV) with overall survival as primary outcome measure. At the end of each stage, each research arm is formally compared pairwise to the control arm. Accrual of further patients is discontinued early for any research arm either not showing sufficient evidence of activity or with adverse safety considerations; accrual continues to arms showing activity with acceptable safety. The stopping guideline compares the treatment effect against a pre-defined cut-off value using the hazard ratio when the hazards are proportional and restricted-mean survival time otherwise. This interim hurdle becomes increasingly stringent stage-by-stage. The addition of new research arm(s) can be actively considered when sufficiently interesting agents emerge. New research arms are compared only to contemporaneously-recruited control arm patients using the same intermediate guidelines in a time-delayed manner. The addition of new research arms is independent of any of the original research arms stopping accrual early subject to adequate recruitment to support the overall trial aims

Long-term improvements following a residential combined physical and psychological programme for chronic low back pain

Objectives Evaluate the outcomes and explore experiences of patients undergoing a residential combined physical and psychological programme (CPPP) for chronic low back pain. Design A longitudinal observational cohort design, with a parallel qualitative design using semistructured interviews. Setting Residential, multimodal rehabilitation. Participants 136 adults (62 male/74 female) referred to the CPPP, 100 (44 male/56 female) of whom completed the programme, during the term of the study. Ten (2 male/8 female) participated in the qualitative evaluation. Intervention A 3-week residential CPPP. Outcome measures Primary outcome measures were the STarT Back screening tool score; pain intensity-11-point Numerical Rating Scale; function-Oswestry Disability Index (ODI); health status/quality of life-EQ-5D-5L EuroQol five-Dimension-five level; anxiety-Generalised Anxiety Disorder-7; depression-Patient Health Questionnaire-9. Secondary outcome measures were the Global Subjective Outcome Scale; National Health Service Friends and Family Test;. Results At discharge, 6 and 12 months follow ups, there were improvements from baseline that were greater than minimum clinically important differences in each of the outcomes (with the sole exception of ODI at discharge). At 12 months, the majority of people considered themselves a lot better (57%) and were extremely likely (86%) to recommend the programme to a friend. The qualitative data showed praise for the residential nature of the intervention and the opportunities for interaction with peers and peer support. There were testimonies of improvements in understanding of pain and how to manage it better. Some participants said they had reduced, or stopped, medication they had been taking to manage their pain. Conclusions Participants improved, and maintained long term, beyond minimum clinically important differences on a wide range of outcomes. Participants reported an enhanced ability to self-manage their back pain and support for the residential setting