Background & Aims: Although the clinical phenotype of Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer) has been well described, little is known about disease in PMS2 mutation ...carriers. Now that mutation detection methods can discern mutations in PMS2 from mutations in its pseudogenes, more mutation carriers have been identified. Information about the clinical significance of PMS2 mutations is crucial for appropriate counseling. Here, we report the clinical characteristics of a large series of PMS2 mutation carriers. Methods: We performed PMS2 mutation analysis using long-range polymerase chain reaction and multiplex ligation-dependent probe amplification for 99 probands diagnosed with Lynch syndrome-associated tumors showing isolated loss of PMS2 by immunohistochemistry. Penetrance was calculated using a modified segregation analysis adjusting for ascertainment. Results: Germ-line PMS2 mutations were detected in 62% of probands (n = 55 monoallelic; 6 biallelic). Among families with monoallelic PMS2 mutations, 65.5% met revised Bethesda guidelines. Compared with the general population, in mutation carriers, the incidence of colorectal cancer was 5.2-fold higher, and the incidence of endometrial cancer was 7.5-fold higher. In North America, this translates to a cumulative cancer risk to age 70 years of 15%–20% for colorectal cancer, 15% for endometrial cancer, and 25%–32% for any Lynch syndrome-associated cancer. No elevated risk for non-Lynch syndrome-associated cancers was observed. Conclusions: PMS2 mutations contribute significantly to Lynch syndrome, but the penetrance for monoallelic mutation carriers appears to be lower than that for the other mismatch repair genes. Modified counseling and cancer surveillance guidelines for PMS2 mutation carriers are proposed.
To examine variations across general practices and factors associated with antibiotic prescribing for common infections in UK primary care to identify potential targets for improvement and ...optimization of prescribing.
Oral antibiotic prescribing for common infections was analysed using anonymized UK primary care electronic health records between 2000 and 2015 using the Clinical Practice Research Datalink (CPRD). The rate of prescribing for each condition was observed over time and mean change points were compared with national guideline updates. Any correlation between the rate of prescribing for each infectious condition was estimated within a practice. Predictors of prescribing were estimated using logistic regression in a matched patient cohort (1:1 by age, sex and calendar time).
Over 8 million patient records were examined in 587 UK general practices. Practices varied considerably in their propensity to prescribe antibiotics and this variance increased over time. Change points in prescribing did not reflect updates to national guidelines. Prescribing levels within practices were not consistent for different infectious conditions. A history of antibiotic use significantly increased the risk of receiving a subsequent antibiotic (by 22%-48% for patients with three or more antibiotic prescriptions in the past 12 months), as did higher BMI, history of smoking and flu vaccinations. Other drivers for receiving an antibiotic varied considerably for each condition.
Large variability in antibiotic prescribing between practices and within practices was observed. Prescribing guidelines alone do not positively influence a change in prescribing, suggesting more targeted interventions are required to optimize antibiotic prescribing in the UK.
Abstract
Objectives
To identify the rates of potentially inappropriate antibiotic choice when prescribing for common infections in UK general practices. To examine the predictors of such prescribing ...and the clustering effects at the practice level.
Methods
The rates of potentially inappropriate antibiotic choice were estimated using 1 151 105 consultations for sinusitis, otitis media and externa, upper respiratory tract infection (URTI) and lower respiratory tract infection (LRTI) and urinary tract infection (UTI), using the Clinical Practice Research Datalink (CPRD). Multilevel logistic regression was used to identify the predictors of inappropriate prescribing and to quantify the clustering effect at practice level.
Results
The rates of potentially inappropriate prescriptions were highest for otitis externa (67.3%) and URTI (38.7%) and relatively low for otitis media (3.4%), sinusitis (2.2%), LRTI (1.5%) and UTI in adults (2.3%) and children (0.7%). Amoxicillin was the most commonly prescribed antibiotic for all respiratory tract infections, except URTI. Amoxicillin accounted for 62.3% of prescriptions for otitis externa and 34.5% of prescriptions for URTI, despite not being recommended for these conditions. A small proportion of the variation in the probability of an inappropriate choice was attributed to the clustering effect at practice level (8% for otitis externa and 23% for sinusitis). Patients with comorbidities were more likely to receive a potentially inappropriate antibiotic for URTI, LRTI and UTI in adults. Patients who received any antibiotic in the 12 months before consultation were more likely to receive a potentially inappropriate antibiotic for all conditions except otitis externa.
Conclusions
Antibiotic prescribing did not always align with prescribing guidelines, especially for URTIs and otitis externa. Future interventions might target optimizing amoxicillin use in primary care.
Targeted α therapy (TAT) of soft-tissue cancers using the α particle-emitting radionuclide 223Ra holds great potential because of its favorable nuclear properties, adequate availability, and ...established clinical use for treating metastatic prostate cancer of the bone. Despite these advantages, the use of 223Ra has been largely overshadowed by other α emitters due to its challenging chelation chemistry. A key criterion that needs to be met for a radionuclide to be used in TAT is its stable attachment to a targeting vector via a bifunctional chelator. The low charge density of Ra2+ arising from its large ionic radius weakens its electrostatic binding interactions with chelators, leading to insufficient complex stability in vivo. In this study, we synthesized and evaluated macropa-XL as a novel chelator for 223Ra. It bears a large 21-crown-7 macrocyclic core and two picolinate pendent groups, which we hypothesized would effectively saturate the large coordination sphere of the Ra2+ ion. The structural chemistry of macropa-XL was first established with the nonradioactive Ba2+ ion using X-ray diffraction and X-ray absorption spectroscopy, which revealed the formation of an 11-coordinate complex in a rare anti pendent-arm configuration. Subsequently, the stability constant of the Ra(macropa-XL) complex was determined via competitive cation exchange with 223Ra and 224Ra radiotracers and compared with that of macropa, the current state-of-the-art chelator for Ra2+. A moderate log K ML value of 8.12 was measured for Ra(macropa-XL), which is approximately 1.5 log K units lower than the stability constant of Ra(macropa). This relative decrease in Ra2+ complex stability for macropa-XL versus macropa was further probed using density functional theory calculations. Additionally, macropa-XL was radiolabeled with 223Ra, and the kinetic stability of the resulting complex was evaluated in human serum. Although macropa-XL could effectively bind 223Ra under mild conditions, the complex appeared to be unstable to transchelation. Collectively, this study sheds additional light on the chelation chemistry of the exotic Ra2+ ion and contributes to the small, but growing, number of chelator development efforts for 223Ra-based TAT.
Fatigue syndromes (FSs) affect large numbers of individuals, yet evidence from epidemiological studies on adverse outcomes, such as premature death, is limited.
Cohort study involving 385 general ...practices in England that contributed to the Clinical Practice Research Datalink (CPRD) with linked inpatient Hospital Episode Statistics (HES) and Office for National Statistics (ONS) cause of death information. A total of 10 477 patients aged 15 years and above, diagnosed with a FS during 2000-2014, were individually matched with up to 20 comparator patients without a history of having a FS. Prevalence ratios (PRs) were estimated to compare the FS and comparison cohorts on clinical characteristics. Adjusted hazard ratios (HRs) for subsequent adverse outcomes were estimated from stratified Cox regression models.
Among patients diagnosed with FSs, we found elevated baseline prevalence of: any psychiatric illness (PR 1.77; 95% CI 1.72-1.82), anxiety disorders (PR 1.92; 1.85-1.99), depression (PR 1.89; 1.83-1.96), psychotropic prescriptions (PR 1.68; 1.64-1.72) and comorbid physical illness (PR 1.28; 1.23-1.32). We found no significant differences in risks for: all-cause mortality (HR 0.99; 0.91-1.09), natural death (HR 0.99; 0.90-1.09), unnatural death (HR 1.00; 0.59-1.72) or suicide (HR 1.68; 0.78-3.63). We did, however, observe a significantly elevated non-fatal self-harm risk: HR 1.83; 1.56-2.15.
The absence of elevated premature mortality risk is reassuring. The raised prevalence of mental illness and increased non-fatal self-harm risk indicate a need for enhanced assessment and management of psychopathology associated with fatigue syndromes.
Recent events in the USA have highlighted a lack of resilience in the coastal population to coastal flooding, especially amongst disadvantaged and isolated communities. Some low-income countries, ...such as Cuba and Bangladesh, have made significant progress towards transformed societies that are more resilient to the impacts of cyclones and coastal flooding. To understand how this has come about, a systematic review of the peer-reviewed and grey literature related to resilience of communities to coastal flooding was undertaken in both countries. In both Cuba and Bangladesh the trust between national and local authorities, community leaders and civil society is high. As a consequence evacuation warnings are generally followed and communities are well prepared. As a result over the past 25 years in Bangladesh the number of deaths directly related to cyclones and coastal flooding has decreased, despite an increase of almost 50 % in the number of people exposed to these hazards. In Cuba, over the course of eight hurricanes between 2003 and 2011, the normalized number of deaths related to cyclones and coastal floods was an order of magnitude less than in the USA. In low-income countries, warning systems and effective shelter/evacuation systems, combined with high levels of disaster risk-reduction education and social cohesion, coupled with trust between government authorities and vulnerable communities can help to increase resilience to coastal hazards and tropical cyclones. In the USA, transferable lessons include improving communication and the awareness of the risk posed by coastal surges, mainstreaming disaster risk reduction into the education system and building trusted community networks to help isolated and disadvantaged communities, and improve community resilience.
ObjectiveDetermine the association of incident antibiotic prescribing levels for common infections with infection-related complications and hospitalisations by comparing high with low prescribing ...general practitioner practices.Design retrospective cohort studyRetrospective cohort study.Data sourceUK primary care records from the Clinical Practice Research Datalink (CPRD GOLD) and SAIL Databank (SAIL) linked with Hospital Episode Statistics (HES) data, including 546 CPRD, 346 CPRD-HES and 338 SAIL-HES practices.ExposuresInitial general practice visit for one of six common infections and the proportion of antibiotic prescribing in each practice.Main outcome measuresIncidence of infection-related complications (as recorded in general practice) or infection-related hospital admission within 30 days after consultation for a common infection.ResultsA practice with 10.4% higher antibiotic prescribing (the IQR) was associated with a 5.7% lower rate of infection-related hospital admissions (adjusted analysis, 95% CI 3.3% to 8.0%). The association varied by infection with larger associations in hospital admissions with lower respiratory tract infection (16.1%; 95% CI 12.4% to 19.7%) and urinary tract infection (14.7%; 95% CI 7.6% to 21.1%) and smaller association in hospital admissions for upper respiratory tract infection (6.5%; 95% CI 3.5% to 9.5%) The association of antibiotic prescribing levels and hospital admission was largest in patients aged 18–39 years (8.6%; 95% CI 4.0% to 13.0%) and smallest in the elderly aged 75+ years (0.3%; 95% CI −3.4% to 3.9%).ConclusionsThere is an association between lower levels of practice level antibiotic prescribing and higher infection-related hospital admissions. Indiscriminately reducing antibiotic prescribing may lead to harm. Greater focus is needed to optimise antibiotic use by reducing inappropriate antibiotic prescribing and better targeting antibiotics to patients at high risk of infection-related complications.
High levels of antibiotic prescribing are a major concern as they drive antimicrobial resistance. It is currently unknown whether practices that prescribe higher levels of antibiotics also prescribe ...more medicines in general.
To evaluate the relationship between antibiotic and general prescribing levels in primary care.
Cross-sectional study in 2014-2015 of 6517 general practices in England using NHS digital practice prescribing data (NHS-DPPD) for the main study, and of 587 general practices in the UK using the Clinical Practice Research Datalink for a replication study.
Linear regression to assess determinants of antibiotic prescribing.
NHS-DPPD practices prescribed an average of 576.1 antibiotics per 1000 patients per year (329.9 at the 5th percentile and 808.7 at the 95th percentile). The levels of prescribing of antibiotics and other medicines were strongly correlated. Practices with high levels of prescribing of other medicines (a rate of 27 159.8 at the 95th percentile) prescribed 80% more antibiotics than low-prescribing practices (rate of 8815.9 at the 5th percentile). After adjustment, NHS-DPPD practices with high prescribing of other medicines gave 60% more antibiotic prescriptions than low-prescribing practices (corresponding to higher prescribing of 276.3 antibiotics per 1000 patients per year). Prescribing of non-opioid painkillers and benzodiazepines were also strong indicators of the level of antibiotic prescribing. General prescribing levels were a much stronger driver for antibiotic prescribing than other risk factors, such as deprivation.
The propensity of GPs to prescribe medications generally is an important driver for antibiotic prescribing. Interventions that aim to optimise antibiotic prescribing will need to target general prescribing behaviours, in addition to specifically targeting antibiotics.
PDF
