Incidence, clinical spectrum, diagnostic features, treatment and predictors of paradoxical reactions during antibiotic treatment of Mycobacterium ulcerans infections

Background: Paradoxical reactions from antibiotic treatment of Mycobacterium ulcerans have recently been recognized. Data is lacking regarding their incidence, clinical and diagnostic features, treatment, outcomes and risk factors in an Australian population.

Methods: Data was collected prospectively on all confirmed cases of M. ulcerans infection managed at Barwon Health Services, Australia, from 1/1/1998-31/12/2011. Paradoxical reactions were defined on clinical and histological criteria and cases were determined by retrospectively reviewing the clinical history and histology of excised lesions. A Poisson regression model was used to examine associations with paradoxical reactions.

Results: Thirty-two of 156 (21%) patients developed paradoxical reactions a median 39 days (IQR 20-73 days) from antibiotic initiation. Forty-two paradoxical episodes occurred with 26 (81%) patients experiencing one and 6 (19%) multiple episodes. Thirty-two (76%) episodes occurred during antibiotic treatment and 10 (24%) episodes occurred a median 37 days after antibiotic treatment. The reaction site involved the original lesion (wound) in 23 (55%), was separate to but within 3 cm of the original lesion (local) in 11 (26%) and was more than 3 cm from the original lesion (distant) in 8 (19%) episodes. Mycobacterial cultures were negative in 33/33 (100%) paradoxical episodes. Post-February 2009 treatment involved more cases with no antibiotic modifications (12/15 compared with 11/27, OR 5.82, 95% CI 1.12-34.07, p = 0.02) and no further surgery (9/15 compared with 2/27, OR 18.75, 95% CI 2.62-172.73, p < 0.001). Six severe cases received prednisone with marked clinical improvement. On multivariable analysis, age ≥ 60 years (RR 2.84, 95% CI 1.12-7.17, p = 0.03), an oedematous lesion (RR 3.44, 95% CI 1.11-10.70, p=0.03) and use of amikacin in the initial antibiotic regimen (RR 6.33, 95% CI 2.09-19.18, p < 0.01) were associated with an increased incidence of paradoxical reactions.

Conclusions: Paradoxical reactions occur frequently during or after antibiotic treatment of M. ulcerans infections in an Australian population and may be increased in older adults, oedematous disease forms, and in those treated with amikacin. Recognition of paradoxical reactions led to changes in management with less surgery, fewer antibiotic modifications and use of prednisolone for severe reactions.

Randomized trial of a population-based, home-delivered intervention for preschool language delay

OBJECTIVE: 

Performance of the assessment of quality of life measure in people with hip and knee joint disease and implications for research and clinical use

Objective
To comprehensively evaluate the performance of the Assessment of Quality of Life (AQoL) instrument for measuring health-related quality of life (HRQOL) in people with hip and knee joint disease (arthritis or osteoarthritis).

Methods
Data from 237 individuals were available for analysis from a national cross-sectional, population-based study of hip and knee joint disease in Australia. AQoL-4D data were evaluated using Rasch analysis. A range of measurement properties was explored, including model and item fit, threshold ordering, differential item functioning, and targeting.

Results
Good overall fit of the AQoL with the Rasch model was demonstrated across a range of tests, supporting internal validity. Only 1 item (relating to hearing) showed evidence of misfit. Most AQoL items showed logical sequencing of response option categories, with threshold disordering evident for only 2 of the 12 items (items 4 and 9). Minor issues with potential clinical and research implications include limited options for reporting pain and some evidence of measurement bias between demographic subgroups (including age and sex). Participants' HRQOL was generally better than that represented by the AQoL items (mean ± SD for person abilities −2.15 ± 1.39, mean ± SD for item difficulties 0.00 ± 0.67), indicating ceiling effects that could impact the instrument's ability to detect HRQOL improvement in population-based studies.

Conclusion
The AQoL is a competent tool for assessing HRQOL in people with hip and knee joint disease, although researchers and clinicians should consider the caveats identified when selecting appropriate HRQOL measures for future outcome assessment involving this patient group.

The clinical effectiveness and cost-effectiveness of bariatric (weight loss) surgery for obesity: a systematic review and economic evaluation

To assess the clinical effectiveness and cost-effectiveness of bariatric surgery for obesity. Seventeen electronic databases were searched [MEDLINE; EMBASE; PreMedline In-Process & Other Non-Indexed Citations; The Cochrane Library including the Cochrane Systematic Reviews Database, Cochrane Controlled Trials Register, DARE, NHS EED and HTA databases; Web of Knowledge Science Citation Index (SCI); Web of Knowledge ISI Proceedings; PsycInfo; CRD databases; BIOSIS; and databases listing ongoing clinical trials] from inception to August 2008. Bibliographies of related papers were assessed and experts were contacted to identify additional published and unpublished references. Two reviewers independently screened titles and abstracts for eligibility. Inclusion criteria were applied to the full text using a standard form. Interventions investigated were open and laparoscopic bariatric surgical procedures in widespread current use compared with one another and with non-surgical interventions. Population comprised adult patients with body mass index (BMI) > or = 30 and young obese people. Main outcomes were at least one of the following after at least 12 months follow-up: measures of weight change; quality of life (QoL); perioperative and postoperative mortality and morbidity; change in obesity-related comorbidities; cost-effectiveness. Studies eligible for inclusion in the systematic review for comparisons of Surgery versus Surgery were RCTs. For comparisons of Surgery versus Non-surgical procedures eligible studies were RCTs, controlled clinical trials and prospective cohort studies (with a control cohort). Studies eligible for inclusion in the systematic review of cost-effectiveness were full cost-effectiveness analyses, cost-utility analyses, cost-benefit analyses and cost-consequence analyses. One reviewer performed data extraction, which was checked by two reviewers independently. Two reviewers independently applied quality assessment criteria and differences in opinion were resolved at each stage. Studies were synthesised through a narrative review with full tabulation of the results of all included studies. In the economic model the analysis was developed for three patient populations, those with BMI > or = 40; BMI > or = 30 and < 40 with Type 2 diabetes at baseline; and BMI > or = 30 and < 35. Models were applied with assumptions on costs and comorbidity.

The relationship between coping and subclinical psychotic experiences in adolescents from the general population - a longitudinal study

Subclinical psychotic experiences during adolescence may represent liability for developing psychotic disorder. Both coping style and the degree of persistence of psychotic experiences may play a role in the progression to clinical psychotic disorder, but little is known about the causal relationship between the two. Path modelling was used to examine longitudinal relationships between subclinical positive psychotic experiences and three styles of coping (task-, emotion- and avoidance-oriented) in an adolescent general population sample (n=813) assessed three times in 3 years. Distinct developmental trajectories of psychotic experiences, identified with growth mixture modelling, were compared on the use of these coping styles. Over time, emotion-oriented coping in general was bi-directionally related to psychotic experiences. No meaningful results were found for task- or avoidance-oriented coping. Females reported using a wider range of coping styles than males, but the paths between coping and psychotic experiences did not differ by gender. Persistence of psychotic experiences was associated with a greater use of emotion-oriented coping, whereas a decrease in experiences over time was associated with an increased use of task-orientated coping. Emotion-oriented coping is the most important coping style in relation to psychotic experiences, as it may contribute to a 'vicious cycle' and is associated with persistence of experiences. In addition, more task-oriented coping may result in a decrease in psychotic experiences. Results suggest that opportunities for intervention may already be present at the level of subclinical psychosis.

The impact of insight in a first-episode mania with psychosis population on outcome at 18 months

To explore whether poor initial insight during a first episode of mania with psychotic features was predictive of poor psychosocial and clinical outcomes at 18 months.

Disease burden evaluation of fall-related events in the elderly due to hypoglycemia and other diabetic complications: a clinical review

A hypoglycemia-induced fall is common in older persons with diabetes. The etiology of falls in this population is usually multifactorial, and includes microvascular and macrovascular complications and age-related comorbidities, with hypoglycemia being one of the major precipitating causes. In this review, we systematically searched the literature that was available up to March 31, 2014 from MEDLINE/PubMed, Embase, and Google Scholar using the following terms: hypoglycemia; insulin; diabetic complications; and falls in elderly. Hypoglycemia, defined as blood glucose <4.0 mmol/L (70 mg/dL) requiring external assistance, occurs in one-third of elderly diabetics on glucose-lowering therapies. It represents a major barrier to the treatment of diabetes, particularly in the elderly population. Patients who experience hypoglycemia are at a high risk for adverse outcomes, including falls leading to bone fracture, seizures, cognitive dysfunction, and prolonged hospital stays. An increase in mortality has been observed in patients who experience any one of these events. Paradoxically, rational insulin therapy, dosed according to a patient's clinical status and the results of home blood glucose monitoring, so as to achieve and maintain recommended glycemic goals, can be an effective method for the prevention of hypoglycemia and falls in the elderly. Contingencies, such as clinician-directed hypoglycemia treatment protocols that guide the immediate treatment of hypoglycemia, help to limit both the duration and severity of the event. Older diabetic patients with or without underlying renal insufficiency or other severe illnesses represent groups that are at high risk for hypoglycemia-induced falls and, therefore, require lower insulin dosages. In this review, the risk factors of falls associated with hypoglycemia in elderly diabetics were highlighted and management plans were suggested. A target hemoglobin A1c level between 7% and 8% seems to be more appropriate for this population. In addition, the first-choice drugs should have good safety profiles and have the lowest probability of causing hypoglycemia - such as metformin (in the absence of significant renal impairment) and incretin enhancers - while other therapies that may cause more frequent hypoglycemia should be avoided.

The prevalence of vitamin B12 deficiency in a random sample from the Australian population

 Objective: Vitamin B12 deficiency is common in older adults, and may increase the risk of cognitive impairment. The distribution of vitamin B12 insufficiency in younger age groups is less studied. This study aims to assess the prevalence of vitamin B12 deficiency (<156ρmol/L) and subclinical low-normal levels (156-250ρmol/L) in a large, random sample of the Australian population across the adult life span.
Methods: We examined serum vitamin B12 levels in a random sample of 1,085 men and 1,125 women aged 20-97 years between 1994 and 2006; in the Barwon Statistical Division, a regional area in south eastern Australia that is representative of the socioeconomic status of the Australian population.
Results: The age-standardised prevalence of vitamin B12 deficiency in this cohort of men and women was 3.6%. Subclinical low-normal vitamin B12 levels (156-250ρmol/L) were found in 26%. Serum vitamin B12 levels declined with age among men (p-value <0.001) and were lower in men than women (p-value <0.001). Vitamin B12 levels were higher among supplement users (8.0% of the cohort).
Conclusions: Vitamin B12 levels decline with age, and have been associated with neurodegenerative diseases and cognitive decline. Early intervention by diet education or supplement use to address this age-associated decline in vitamin levels may be an effective strategy to prevent decline in a significant segment of the population. Such intervention may need to start in mid-life (from 50-years of age) before the onset age-related decline in vitamin B12 levels.

The study protocol of: 'initiating end of life care in stroke: clinical decision- making around prognosis'

 Background: The initiation of end of life care in an acute stroke context should be focused on those patients and families with greatest need. This requires clinicians to synthesise information on prognosis, patterns (trajectories) of dying and patient and family preferences. Within acute stroke, prognostic models are available to identify risks of dying, but variability in dying trajectories makes it difficult for clinicians to know when to commence palliative interventions. This study aims to investigate clinicians’ use of different types of evidence in decisions to initiate end of life care within trajectories typical of the acute stroke population.
Methods/design: This two-phase, mixed methods study comprises investigation of dying trajectories in acute stroke (Phase 1), and the use of clinical scenarios to investigate clinical decision-making in the initiation of palliative care (Phase 2). It will be conducted in four acute stroke services in North Wales and North West England. Patient and public involvement is integral to this research, with service users involved at each stage.
Discussion: This study will be the first to examine whether patterns of dying reported in other diagnostic groups are transferable to acute stroke care. The strengths and limitations of the study will be considered. This research will produce comprehensive understanding of the nature of clinical decision-making around end of life care in an acute stroke context, which in turn will inform the development of interventions to further build staff knowledge, skills and confidence in this challenging aspect of acute stroke care.

Is demography destiny? Application of machine learning techniques to accurately predict population health outcomes from a minimal demographic dataset

For years, we have relied on population surveys to keep track of regional public health statistics, including the prevalence of non-communicable diseases. Because of the cost and limitations of such surveys, we often do not have the up-to-date data on health outcomes of a region. In this paper, we examined the feasibility of inferring regional health outcomes from socio-demographic data that are widely available and timely updated through national censuses and community surveys. Using data for 50 American states (excluding Washington DC) from 2007 to 2012, we constructed a machine-learning model to predict the prevalence of six non-communicable disease (NCD) outcomes (four NCDs and two major clinical risk factors), based on population socio-demographic characteristics from the American Community Survey. We found that regional prevalence estimates for non-communicable diseases can be reasonably predicted. The predictions were highly correlated with the observed data, in both the states included in the derivation model (median correlation 0.88) and those excluded from the development for use as a completely separated validation sample (median correlation 0.85), demonstrating that the model had sufficient external validity to make good predictions, based on demographics alone, for areas not included in the model development. This highlights both the utility of this sophisticated approach to model development, and the vital importance of simple socio-demographic characteristics as both indicators and determinants of chronic disease.

Excessive daytime sleepiness and falls among older men and women: cross-sectional examination of a population-based sample

Background: Excessive daytime sleepiness (EDS) has been associated with an increased risk for falls among clinical samples of older adults. However, there is little detailed information among population-representative samples. The current study aimed to assess the relationship between EDS and falls among a cohort of population-based older adults. Methods: This study assessed 367 women aged 60-93years (median 72, interquartile range 65-79) and 451 men aged 60-92years (median 73, interquartile range 66-80) who participated in the Geelong Osteoporosis Study between the years 2001 and 2008. Falls during the prior year were documented via self-report, and for men, falls risk score was obtained using an Elderly Fall Screening Test (EFST). Sleepiness was assessed using the Epworth Sleepiness Scale (ESS), and scores of≥10 indicated EDS. Differences among those with and without EDS in regard to falls were tested using logistic regression models. Results: Among women, 50 (13.6 %) individuals reported EDS. Women with EDS were more likely to report a fall, and were more likely to report the fall occurring outside. EDS was similarly associated with an increased risk of a fall following adjustment for use of a walking aid, cases of nocturia and antidepressant medication use (adjusted OR∈=∈2.54, 95 % CI 1.24-5.21). Multivariate modelling revealed antidepressant use (current) as an effect modifier (p∈<∈.001 for the interaction term). After stratifying the data by antidepressant medication use, the association between EDS and falls was sustained following adjustment for nocturia among antidepressant non-users (adjusted OR∈=∈2.63, 95 % CI 1.31-5.30). Among men, 72 (16.0 %) individuals reported EDS. No differences were detected for men with and without EDS in regard to reported falls, and a trend towards significance was noted between EDS and a high falls risk as assessed by the EFST (p∈=∈0.06), however, age explained this relationship (age adjusted OR∈=∈2.20, 95 % CI 1.03-1.10). Conclusions: For women, EDS is independently associated with at least one fall during the previous year, and this is more likely to occur whilst located outside. Amelioration of EDS may assist in improving functional outcomes among these individuals by reducing the risk for falls.

Using clinical trial data and linked administrative health data to reduce the risk of adverse events associated with the uptake of newly released drugs by older Australians: a model process

BACKGROUND: The study was undertaken to evaluate the contribution of a process which uses clinical trial data plus linked de-identified administrative health data to forecast potential risk of adverse events associated with the use of newly released drugs by older Australian patients. METHODS: The study uses publicly available data from the clinical trials of a newly released drug to ascertain which patient age groups, gender, comorbidities and co-medications were excluded in the trials. It then uses linked de-identified hospital morbidity and medications dispensing data to investigate the comorbidities and co-medications of patients who suffer from the target morbidity of the new drug and who are the likely target population for the drug. The clinical trial information and the linked morbidity and medication data are compared to assess which patient groups could potentially be at risk of an adverse event associated with use of the new drug. RESULTS: Applying the model in a retrospective real-world scenario identified that the majority of the sample group of Australian patients aged 65 years and over with the target morbidity of the newly released COX-2-selective NSAID rofecoxib also suffered from a major morbidity excluded in the trials of that drug, indicating a substantial potential risk of adverse events amongst those patients. This risk was borne out in post-release morbidity and mortality associated with use of that drug. CONCLUSIONS: Clinical trial data and linked administrative health data can together support a prospective assessment of patient groups who could be at risk of an adverse event if they are prescribed a newly released drug in the context of their age, gender, comorbidities and/or co-medications. Communication of this independent risk information to prescribers has the potential to reduce adverse events in the period after the release of the new drug, which is when the risk is greatest.Note: The terms 'adverse drug reaction' and 'adverse drug event' have come to be used interchangeably in the current literature. For consistency, the authors have chosen to use the wider term 'adverse drug event' (ADE).

Which infants with eczema are at risk of food allergy? Results from a population-based cohort

BACKGROUND: The relationship between early onset eczema and food allergy among infants has never been examined in a population-based sample using the gold standard for diagnosis, oral food challenge. OBJECTIVE: We characterised the risk of challenge-proven food allergy among infants with eczema in the general population. METHODS: One-year-old infants (n = 4453 meeting criteria for this analysis) were assessed for history of eczema, received a nurse-administered eczema examination and underwent skin prick testing to peanut, egg and sesame. Those with a detectable wheal to one of the test foods underwent an oral food challenge irrespective of wheal size. The risk of food allergy, stratified by eczema severity and age of onset, was estimated using multivariate logistic regression with population sampling weights. RESULTS: One in five infants with eczema were allergic to peanut, egg white or sesame, compared to one in twenty-five infants without eczema (OR 6.2, 95% CI 4.9, 7.9, P < 0.001). The prevalence of peanut allergy was low in the absence of eczema (0.7% 95% CI 0.4, 1.1). Infants with eczema were 11.0 times more likely to develop peanut allergy (95% CI 6.6, 18.6) and 5.8 times more likely to develop egg allergy (95% CI 4.6, 7.4) by 12 months than infants without eczema. 50.8% of infants (95% CI 42.8, 58.9) with early eczema onset (<3 months) who required doctor-prescribed topical corticosteroid treatment developed challenge-proven food allergy. CONCLUSION AND CLINICAL RELEVANCE: Eczema, across the clinical severity spectrum in infancy, is a strong risk factor for IgE-mediated food allergy. Infants with eczema were six times more likely to have egg allergy and 11 times more likely to have peanut allergy by 12 months than infants without eczema. Our data suggest that a heightened awareness of food allergy risk among healthcare practitioners treating infants with eczema, especially if early onset and severe, is warranted.

"Cancer 2015": a prospective, population-based cancer cohort-phase 1: feasibility of genomics-guided precision medicine in the clinic

"Cancer 2015" is a longitudinal and prospective cohort. It is a phased study whose aim was to pilot recruiting 1000 patients during phase 1 to establish the feasibility of providing a population-based genomics cohort. Newly diagnosed adult patients with solid cancers, with residual tumour material for molecular genomics testing, were recruited into the cohort for the collection of a dataset containing clinical, molecular pathology, health resource use and outcomes data. 1685 patients have been recruited over almost 3 years from five hospitals. Thirty-two percent are aged between 61-70 years old, with a median age of 63 years. Diagnostic tumour samples were obtained for 90% of these patients for multiple parallel sequencing. Patients identified with somatic mutations of potentially "actionable" variants represented almost 10% of those tumours sequenced, while 42% of the cohort had no mutations identified. These genomic data were annotated with information such as cancer site, stage, morphology, treatment and patient outcomes and health resource use and cost. This cohort has delivered its main objective of establishing an upscalable genomics cohort within a clinical setting and in phase 2 aims to develop a protocol for how genomics testing can be used in real-time clinical decision-making, providing evidence on the value of precision medicine to clinical practice.

Falls and depression in men: a population-based study

The link between falls and depression has been researched in the elderly; however, little information is available on this association in younger adults, particularly men. This study sought to investigate the link between major depressive disorder (MDD) and falls in a population-based sample of 952 men (24-97 years). MDD was diagnosed utilizing the Structured Clinical Interview for DSM-IV-TR Research Version, Non-Patient edition, and categorized as 12-month/past/never. Body mass index and gait were measured; falls, smoking status, psychotropic medication use, and alcohol intake were self-reported as part of the Geelong Osteoporosis Study 5-year follow-up assessment. Thirty-four (3.6%) men met criteria for 12-month MDD, and 110 (11.6%) for past MDD. Of the 952 men, 175 (18.4%) reported falling at least once during the past 12 months. Fallers were older (66 [interquartile range: 48-79] vs. 59 [45-72] years, p = .001) and more likely to have uneven gait (n = 16, 10% vs. n = 31, 4%, p = .003) than nonfallers. Participants with 12-month MDD had more than twice the odds of falling (age-adjusted odds ratio: 2.22, 95% confidence interval [1.03, 4.80]). The odds of falling were not associated with past depression (p = .4). Further adjustments for psychotropic drug use, gait, body mass index, smoking status, blood pressure, and alcohol did not explain these associations. Given the 2.2-fold greater likelihood of falling associated with depression was not explained by age or psychotropic drug use, further research is warranted.