Ubiquitin-specific protease 11 structure in complex with an engineered substrate mimetic reveals a molecular feature for deubiquitination selectivity.

Ubiquitin-specific proteases (USPs) are crucial for controlling cellular proteostasis and signaling pathways but how deubiquitination is selective remains poorly understood, in particular between paralogues. Here, we developed a fusion tag method by mining the Protein Data Bank and trapped USP11, a key regulator of DNA double-strand break repair, in complex with a novel engineered substrate mimetic. Together, this enabled structure determination of USP11 as a Michaelis-like complex that revealed key S1 and S1' binding site interactions with a substrate. Combined mutational, enzymatic, and binding experiments identified Met77 in linear diubiquitin as a significant residue that leads to substrate discrimination. We identified an aspartate "gatekeeper" residue in the S1' site of USP11 as a contributing feature for discriminating against linear diubiquitin. When mutated to a glycine, the corresponding residue in paralog USP15, USP11 acquired elevated activity toward linear diubiquitin in-gel shift assays, but not controls. The reverse mutation in USP15 confirmed that this position confers paralog-specific differences impacting diubiquitin cleavage rates. The results advance our understanding of the molecular basis for the higher selectivity of USP11 compared to USP15 and may aid targeted inhibitor development. Moreover, the reported carrier-based crystallization strategy may be applicable to other challenging targets.

National surveillance using a clinical quality indicator for prolonged antipsychotic use among older Australians with dementia who access aged care services.

OBJECTIVES: Dementia guidelines recommend antipsychotics are only used for behavioral and psychological symptoms when non-drug interventions fail, and to regularly review use. Population-level clinical quality indicators (CQIs) for dementia care in permanent residential aged care (PRAC) typically monitor prevalence of antipsychotic use but not prolonged use. This study aimed to develop a CQI for antipsychotic use >90 days and examine trends, associated factors, and variation in CQI incidence; and examine duration of the first episode of use among individuals with dementia accessing home care packages (HCPs) or PRAC. METHODS: Retrospective cohort study, including older individuals with dementia who accessed HCPs (n = 50,257) or PRAC (n = 250,196). Trends in annual CQI incidence (2011-12 to 2015-16) and associated factors were determined using Poisson regression. Funnel plots examined geographical and facility variation. Time to antipsychotic discontinuation was estimated among new antipsychotic users accessing HCP (n = 2367) and PRAC (n = 15,597) using the cumulative incidence function. RESULTS: Between 2011-12 and 2015-16, antipsychotic use for >90 days decreased in HCP recipients from 10.7% (95% CI 10.2-11.1) to 10.1% (95% CI 9.6-10.5, adjusted incidence rate ratio (aIRR) 0.97 (95% CI 0.95-0.98)), and in PRAC residents from 24.5% (95% CI 24.2-24.7) to 21.8% (95% CI 21.5-22.0, aIRR 0.97 (95% CI 0.96-0.98)). Prior antipsychotic use (both cohorts) and being male and greater socioeconomic disadvantage (PRAC cohort) were associated with higher CQI incidence. Little geographical/facility variation was observed. Median treatment duration in HCP and PRAC was 334 (interquartile range [IQR] 108-958) and 555 (IQR 197-1239) days, respectively. CONCLUSIONS: While small decreases in antipsychotic use >90 days were observed between 2011-12 and 2015-16, findings suggest antipsychotic use among aged care recipients with dementia can be further minimized.

Allergic Rhinitis: A Review.

Importance: Allergic rhinitis affects an estimated 15% of the US population (approximately 50 million individuals) and is associated with the presence of asthma, eczema, chronic or recurrent sinusitis, cough, and both tension and migraine headaches. Observations: Allergic rhinitis occurs when disruption of the epithelial barrier allows allergens to penetrate the mucosal epithelium of nasal passages, inducing a T-helper type 2 inflammatory response and production of allergen-specific IgE. Allergic rhinitis typically presents with symptoms of nasal congestion, rhinorrhea, postnasal drainage, sneezing, and itching of the eyes, nose, and throat. In an international study, the most common symptoms of allergic rhinitis were rhinorrhea (90.38%) and nasal congestion (94.23%). Patients with nonallergic rhinitis present primarily with nasal congestion and postnasal drainage frequently associated with sinus pressure, ear plugging, muffled sounds and pain, and eustachian tube dysfunction that is less responsive to nasal corticosteroids. Patients with seasonal allergic rhinitis typically have physical examination findings of edematous and pale turbinates. Patients with perennial allergic rhinitis typically have erythematous and inflamed turbinates with serous secretions that appear similar to other forms of chronic rhinitis at physical examination. Patients with nonallergic rhinitis have negative test results for specific IgE aeroallergens. Intermittent allergic rhinitis is defined as symptoms occurring less than 4 consecutive days/week or less than 4 consecutive weeks/year. Persistent allergic rhinitis is defined as symptoms occurring more often than 4 consecutive days/week and for more than 4 consecutive weeks/year. Patients with allergic rhinitis should avoid inciting allergens. In addition, first-line treatment for mild intermittent or mild persistent allergic rhinitis may include a second-generation H1 antihistamine (eg, cetirizine, fexofenadine, desloratadine, loratadine) or an intranasal antihistamine (eg, azelastine, olopatadine), whereas patients with persistent moderate to severe allergic rhinitis should be treated initially with an intranasal corticosteroid (eg, fluticasone, triamcinolone, budesonide, mometasone) either alone or in combination with an intranasal antihistamine. In contrast, first-line therapy for patients with nonallergic rhinitis consists of an intranasal antihistamine as monotherapy or in combination with an intranasal corticosteroid. Conclusions and Relevance: Allergic rhinitis is associated with symptoms of nasal congestion, sneezing, and itching of the eyes, nose, and throat. Patients with allergic rhinitis should be instructed to avoid inciting allergens. Therapies include second-generation H1 antihistamines (eg, cetirizine, fexofenadine, desloratadine, loratadine), intranasal antihistamines (eg, azelastine, olopatadine), and intranasal corticosteroids (eg, fluticasone, triamcinolone, budesonide, mometasone) and should be selected based on the severity and frequency of symptoms and patient preference.

The association between sex hormones and the change in brain-predicted age difference in older women.

OBJECTIVE: The role of circulating sex hormones on structural brain ageing is yet to be established. This study explored whether concentrations of circulating sex hormones in older women are associated with the baseline and longitudinal changes in structural brain ageing, defined by the brain-predicted age difference (brain-PAD). DESIGN: Prospective cohort study using data from NEURO and Sex Hormones in Older Women; substudies of the ASPirin in Reducing Events in the Elderly clinical trial. PATIENTS: Community-dwelling older women (aged 70+ years). MEASUREMENTS: Oestrone, testosterone, dehydroepiandrosterone (DHEA), and sex-hormone binding globulin (SHBG) were quantified from plasma samples collected at baseline. T1-weighted magnetic resonance imaging was performed at baseline, 1 and 3 years. Brain age was derived from whole brain volume using a validated algorithm. RESULTS: The sample comprised of 207 women not taking medications known to influence sex hormone concentrations. A statistically higher baseline brain-PAD (older brain age relative to chronological age) was seen for women in the highest DHEA tertile compared with the lowest in the unadjusted analysis (p = .04). This was not significant when adjusted for chronological age, and potential confounding health and behavioural factors. Oestrone, testosterone and SHBG were not associated with brain-PAD cross-sectionally, nor were any of the examined sex hormones or SHBG associated with brain-PAD longitudinally. CONCLUSION: No strong evidence of an association between circulating sex hormones and brain-PAD. Given there is prior evidence to suggests sex hormones may be important for brain ageing, further studies of circulating sex hormones and brain health in postmenopausal women are warranted.

Factors contributing to school food program acceptance: a Review of Canadian literature.

Diet quality and food security are a concern in school-aged children in Canada. In 2019, the Canadian federal government announced the intention to work towards a national school food program. Understanding the factors that impact school food program acceptability can inform planning to ensure that students are willing to participate. A scoping review of school food programs in Canada completed in 2019 identified 17 peer-reviewed and 18 grey literature publications. Of these, five peer-reviewed and nine grey literature publications included a discussion of factors that impact the acceptance of school food programs. These factors were thematically analyzed into categories: stigmatization, communication, food choice and cultural considerations, administration, location and timing, and social considerations. Considering these factors while planning can help to maximize program acceptability.

Diet quality and having sufficient food to eat are concerns in school-aged children in Canada. In 2019, the Canadian federal government announced the intention to work towards a national school food program. Providing food to children in schools can only address diet concerns if children participate. Understanding the factors that impact school food program acceptability can inform planning to contribute to program acceptance. Themes of factors contributing to school food program acceptance discussed in 14 publications were identified. Themes included stigmatization, communication, food choice and cultural considerations, administration, location and timing, and social considerations. Considering these factors while planning can help to maximize school food program acceptability.

Impact of economic factors, social health and stressful life events on physical health-related quality of life trajectories in older Australians.

PURPOSE: Physical health-related quality of life (HRQoL) is associated with adverse health outcomes, including hospitalizations and all-cause mortality. However, little is known about how physical HRQoL changes over time in older people and the predictors of this trajectory. This study (a) identified trajectories of physical HRQoL among older people and (b) explored whether economic factors, social health or stressful life events impact physical HRQoL trajectories. METHOD: A cohort of 12,506 relatively 'healthy' community-dwelling Australians aged ≥ 70 years (54.4% females), enrolled in the ASPREE Longitudinal Study of Older Persons (ALSOP) study and was followed for six years. Economic factors, social health and life events in the last 12 months were assessed through a questionnaire at baseline. Physical HRQoL was measured by using the 12-item short form at baseline and annual follow-ups. Growth mixture and structural equation modelling were used to identify physical HRQoL trajectories and their predictors. RESULTS: Four physical HRQoL trajectories were identified-stable low (7.1%), declining (9.0%), stable intermediate (17.9%) and stable high (66.0%). Living in more disadvantaged areas, having a lower household income, no paid work, no voluntary work, loneliness and stressful life events (i.e. spousal illness, friend/family illness, financial problem) were associated with a 10%-152% higher likelihood of being in the stable low or declining physical HRQoL trajectory than the stable high group. CONCLUSION: Specific stressful life events had a greater impact on adverse physical HRQoL trajectories in older people than other factors. Volunteering may prevent physical HRQoL decline and requires further investigation.

Sleep-disordered breathing was associated with lower health-related quality of life and cognitive function in a cross-sectional study of older adults.

BACKGROUND AND OBJECTIVE: The clinical significance of sleep-disordered breathing (SDB) in older age is uncertain. This study determined the prevalence and associations of SDB with mood, daytime sleepiness, quality of life (QOL) and cognition in a relatively healthy older Australian cohort. METHODS: A cross-sectional analysis was conducted from the Study of Neurocognitive Outcomes, Radiological and retinal Effects of Aspirin in Sleep Apnoea. Participants completed an unattended limited channel sleep study to measure the oxygen desaturation index (ODI) to define mild (ODI 5-15) and moderate/severe (ODI ≥ 15) SDB, the Centre for Epidemiological Studies Scale, the Epworth Sleepiness Scale, the 12-item Short-Form for QOL and neuropsychological tests. RESULTS: Of the 1399 participants (mean age 74.0 years), 36% (273 of 753) of men and 25% (164 of 646) of women had moderate/severe SDB. SDB was associated with lower physical health-related QOL (mild SDB: beta coefficient [ß] -2.5, 95% CI -3.6 to -1.3, p < 0.001; moderate/severe SDB: ß -1.8, 95% CI -3.0 to -0.6, p = 0.005) and with lower global composite cognition (mild SDB: ß -0.1, 95% CI -0.2 to 0.0, p = 0.022; moderate/severe SDB: ß -0.1, 95% CI -0.2 to 0.0, p = 0.032) compared to no SDB. SDB was not associated with daytime sleepiness nor depression. CONCLUSION: SDB was associated with lower physical health-related quality of life and cognitive function. Given the high prevalence of SDB in older age, assessing QOL and cognition may better delineate subgroups requiring further management, and provide useful treatment target measures for this age group.

Trajectories of beverage consumption during adolescence.

Beverages contribute substantially to daily energy and nutrient intakes. However, little is known about the co-development of beverage consumption throughout adolescence. This study aimed to investigate the presence of naturally occurring sub-groups of girls and boys following distinct trajectories of various types of beverage consumption (i.e. sugary beverages, tea and coffee, water, and milk) throughout adolescence. During the Monitoring Activities for Teenagers to Comprehend their Habits study, data were collected from 744 Canadian youths followed for six years (2013-2019). The participants were asked yearly (start-age 10-11 years old) to report how many times they consumed sugary beverages, tea and coffee, water, and milk in a week. Trajectories of beverage consumption were identified from age 11 to 18 using a person-centred approach, namely group-based multi-trajectory modelling. For girls, three different groups were identified: 'Water consumers' (62.7%), 'High beverage consumers' (20.9%), and 'Water and milk consumers' (16.4%). For boys, four different groups were identified: 'Water consumers' (39.1%), 'Water and milk consumers' (30.5%), 'Sugary drinks, coffee and tea consumers' (20.1%), and 'High beverage consumers' (10.4%). This study illustrates the complexity of beverage consumption patterns in adolescence. Various types of public health messaging and interventions may be required to promote healthier beverage consumption patterns among all adolescents.

Dispositional Optimism and All-Cause Mortality in Older Adults: A Cohort Study.

OBJECTIVE: Optimism is modifiable and may be associated with healthy aging. We aim to investigate whether dispositional optimism is associated with all-cause mortality in adults 70 years and older. METHODS: Between 2010 and 2014, older adults free of serious cardiovascular disease and dementia were recruited through primary care physicians and enrolled in the Aspirin Reducing Events in the Elderly (ASPREE) clinical trial. Australian ASPREE participants were invited to participate in the ASPREE Longitudinal Study of Older Persons (ALSOP) that was running in parallel to ASPREE. Optimism was assessed at baseline using the Life Orientation Test-Revised. The association between optimism, divided into quartiles, and all-cause mortality was assessed using Cox proportional hazards models. RESULTS: A total of 11,701 participants (mean [standard deviation] age = 75.1 [4.24] years; 46.6% men) returned the ALSOP Social questionnaire and completed the Life Orientation Test-Revised. During a median follow-up of 4.7 years, 469 deaths occurred. The fully adjusted model was not significant (hazard ratio = 0.78, 95% confidence interval = 0.58-1.06). There was evidence that age was an effect modifier of the association between optimism and longevity. Higher optimism was associated with lower mortality risk in the oldest individuals only (77+ years; hazard ratio = 0.61, 95% confidence interval = 0.39-0.96). CONCLUSIONS: We observed no independent relationship between optimism and all-cause mortality in the total sample, although optimism seemed to be associated with lower risk among the oldest old (adults 77 years and older).

A Cohort Study of Anticholinergic Medication Burden and Incident Dementia and Stroke in Older Adults.

BACKGROUND: Anticholinergic medications may increase risk of dementia and stroke, but prospective studies in healthy older people are lacking. OBJECTIVE: Compare risk of incident dementia and stroke by anticholinergic burden among initially healthy older people. DESIGN: Prospective cohort study. SETTING: Primary care (Australia and USA). PARTICIPANTS: 19,114 community-dwelling participants recruited for the ASPREE trial, aged 70+ years (65+ if US minorities) without major cardiovascular disease, dementia diagnosis, or Modified Mini-Mental State Examination score below 78/100. MEASUREMENTS: Baseline anticholinergic exposure was calculated using the Anticholinergic Cognitive Burden (ACB) score. Dementia was adjudicated using Diagnostic and Statistical Manual of Mental Disorders volume IV criteria, and stroke using the World Health Organization definition. RESULTS: At baseline, 15,000 participants (79%) had an ACB score of zero, 2930 (15%) a score of 1-2, and 1184 (6%) a score of ≥ 3 (indicating higher burden). After a median follow-up of 4.7 years and adjusting for baseline covariates, a baseline ACB score of ≥ 3 was associated with increased risk of ischemic stroke (adjusted HR 1.58, 95% CI 1.06, 2.35), or dementia (adjusted HR 1.36, 95% CI 1.01, 1.82), especially of mixed etiology (adjusted HR 1.53, 95% CI 1.06, 2.21). Results were similar for those exposed to moderate/highly anticholinergic medications. LIMITATIONS: Residual confounding and reverse causality are possible. Assessment of dose or duration was not possible. CONCLUSIONS: High anticholinergic burden in initially healthy older people was associated with increased risk of incident dementia and ischemic stroke. A vascular effect may underlie this association. These findings highlight the importance of minimizing anticholinergic exposure in healthy older people.

Withdrawal or continuation of cholinesterase inhibitors or memantine or both, in people with dementia.

BACKGROUND: Dementia is a progressive syndrome characterised by deterioration in memory, thinking and behaviour, and by impaired ability to perform daily activities. Two classes of drug - cholinesterase inhibitors (donepezil, galantamine and rivastigmine) and memantine - are widely licensed for dementia due to Alzheimer's disease, and rivastigmine is also licensed for Parkinson's disease dementia. These drugs are prescribed to alleviate symptoms and delay disease progression in these and sometimes in other forms of dementia. There are uncertainties about the benefits and adverse effects of these drugs in the long term and in severe dementia, about effects of withdrawal, and about the most appropriate time to discontinue treatment. OBJECTIVES: To evaluate the effects of withdrawal or continuation of cholinesterase inhibitors or memantine, or both, in people with dementia on: cognitive, neuropsychiatric and functional outcomes, rates of institutionalisation, adverse events, dropout from trials, mortality, quality of life and carer-related outcomes. SEARCH METHODS: We searched the Cochrane Dementia and Cognitive Improvement Group's Specialised Register up to 17 October 2020 using terms appropriate for the retrieval of studies of cholinesterase inhibitors or memantine. The Specialised Register contains records of clinical trials identified from monthly searches of a number of major healthcare databases, numerous trial registries and grey literature sources. SELECTION CRITERIA: We included all randomised, controlled clinical trials (RCTs) which compared withdrawal of cholinesterase inhibitors or memantine, or both, with continuation of the same drug or drugs. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed citations and full-text articles for inclusion, extracted data from included trials and assessed risk of bias using the Cochrane risk of bias tool. Where trials were sufficiently similar, we pooled data for outcomes in the short term (up to 2 months after randomisation), medium term (3-11 months) and long term (12 months or more). We assessed the overall certainty of the evidence for each outcome using GRADE methods. MAIN RESULTS: We included six trials investigating cholinesterase inhibitor withdrawal, and one trial investigating withdrawal of either donepezil or memantine. No trials assessed withdrawal of memantine only. Drugs were withdrawn abruptly in five trials and stepwise in two trials. All participants had dementia due to Alzheimer's disease, with severities ranging from mild to very severe, and were taking cholinesterase inhibitors without known adverse effects at baseline. The included trials randomised 759 participants to treatment groups relevant to this review. Study duration ranged from 6 weeks to 12 months. There were too few included studies to allow planned subgroup analyses. We considered some studies to be at unclear or high risk of selection, performance, detection, attrition or reporting bias. Compared to continuing cholinesterase inhibitors, discontinuing treatment may be associated with worse cognitive function in the short term (standardised mean difference (SMD) -0.42, 95% confidence interval (CI) -0.64 to -0.21; 4 studies; low certainty), but the effect in the medium term is very uncertain (SMD -0.40, 95% CI -0.87 to 0.07; 3 studies; very low certainty). In a sensitivity analysis omitting data from a study which only included participants who had shown a relatively poor prior response to donepezil, inconsistency was reduced and we found that cognitive function may be worse in the discontinuation group in the medium term (SMD -0.62; 95% CI -0.94 to -0.31). Data from one longer-term study suggest that discontinuing a cholinesterase inhibitor is probably associated with worse cognitive function at 12 months (mean difference (MD) -2.09 Standardised Mini-Mental State Examination (SMMSE) points, 95% CI -3.43 to -0.75; moderate certainty). Discontinuation may make little or no difference to functional status in the short term (SMD -0.25, 95% CI -0.54 to 0.04; 2 studies; low certainty), and its effect in the medium term is uncertain (SMD -0.38, 95% CI -0.74 to -0.01; 2 studies; very low certainty). After 12 months, discontinuing a cholinesterase inhibitor probably results in greater functional impairment than continuing treatment (MD -3.38 Bristol Activities of Daily Living Scale (BADLS) points, 95% CI -6.67 to -0.10; one study; moderate certainty). Discontinuation may be associated with a worsening of neuropsychiatric symptoms over the short term and medium term, although we cannot exclude a minimal effect (SMD - 0.48, 95% CI -0.82 to -0.13; 2 studies; low certainty; and SMD -0.27, 95% CI -0.47 to -0.08; 3 studies; low certainty, respectively). Data from one study suggest that discontinuing a cholinesterase inhibitor may result in little to no change in neuropsychiatric status at 12 months (MD -0.87 Neuropsychiatric Inventory (NPI) points; 95% CI -8.42 to 6.68; moderate certainty). We found no clear evidence of an effect of discontinuation on dropout due to lack of medication efficacy or deterioration in overall medical condition (odds ratio (OR) 1.53, 95% CI 0.84 to 2.76; 4 studies; low certainty), on number of adverse events (OR 0.85, 95% CI 0.57 to 1.27; 4 studies; low certainty) or serious adverse events (OR 0.80, 95% CI 0.46 to 1.39; 4 studies; low certainty), and on mortality (OR 0.75, 95% CI 0.36 to 1.55; 5 studies; low certainty). Institutionalisation was reported in one trial, but it was not possible to extract data for the groups relevant to this review. AUTHORS' CONCLUSIONS: This review suggests that discontinuing cholinesterase inhibitors may result in worse cognitive, neuropsychiatric and functional status than continuing treatment, although this is supported by limited evidence, almost all of low or very low certainty. As all participants had dementia due to Alzheimer's disease, our findings are not transferable to other dementia types. We were unable to determine whether the effects of discontinuing cholinesterase inhibitors differed with baseline dementia severity. There is currently no evidence to guide decisions about discontinuing memantine. There is a need for further well-designed RCTs, across a range of dementia severities and settings. We are aware of two ongoing registered trials. In making decisions about discontinuing these drugs, clinicians should exercise caution, considering the evidence from existing trials along with other factors important to patients and their carers.

Understanding diagnostic settings and carer experiences for dementia diagnosis in Australia.

BACKGROUND: Australian guidelines advocate referral to comprehensive memory services for dementia diagnosis, but many patients may be diagnosed elsewhere. AIMS: To determine common settings for dementia diagnosis in Australia and to compare patient and carer experience between settings. METHODS: Exploratory cross-sectional study of patients with dementia admitted to a Melbourne sub-acute hospital. Patients who had capacity to participate were included; carers were recruited for patients without capacity. Participants completed an interviewer-administered survey which asked them to recall the diagnostic setting, discussions about diagnosis and management (clinical care) and overall experience of diagnosis. Descriptive statistics were applied and open-ended questions were analysed using inductive and deductive coding approaches. RESULTS: From 81 eligible participants, 74 consented to participate (one patient, 74 carers). Participants reported dementia diagnosis occurred a median of 24 months before interview, in the following settings: hospitals (31.3%), private specialist clinics (29.7%), memory clinics (14.9%), general practice (13.5%), community health services (9.5%) and residential care (1.4%). Recall of discussions about dementia-modulating medications was higher in participants diagnosed in memory clinics and private specialist clinics (70%) compared to other settings (15%) (P < 0.001). Discussion about living circumstances was highest in hospitals (87% vs 40%) (P < 0.001). One third of participants reported dissatisfaction with their experience. Reported satisfaction was highest for memory clinics. CONCLUSION: Results suggest majority of people with dementia are diagnosed outside memory services. Significant variability exists in experiences between services, with a high proportion of participants expressing dissatisfaction with their experience with dementia diagnosis. Strategies to standardise diagnosis of dementia, measure and improve quality of care across all settings are required.

Optimising participation of persons with cognitive impairment in a national dementia registry: challenges and solutions.

Clinical quality registries are increasingly utilised to monitor and improve healthcare quality. Opt-out consent is recommended to maximise participation and ensure validity of data, however, presents specific considerations when including persons with impaired decision-making abilities. This paper describes the innovative Australian Dementia Network Registry recruitment framework designed to optimise inclusion of people with dementia and mild cognitive impairment.

Clinical testing for COVID-19.

As the novel coronavirus severe acute respiratory syndrome coronavirus 2 caused coronavirus disease 2019 cases in the United States, the initial test was developed and performed at the Centers for Disease Control and Prevention. As the number of cases increased, the demand for tests multiplied, leading the Centers for Disease Control and Prevention to use the Emergency Utilization Authorization to allow clinical and commercial laboratories to develop tests to detect the presence of the virus. Many nucleic acid tests based on RT-PCR were developed, each with different techniques, specifications, and turnaround time. As the illnesses turned into a pandemic, testing became more crucial. The test supply became inadequate to meet the need and so it had to be prioritized according to guidance. For surveillance, the need for serologic tests emerged. Here, we review the timeline of test development, the turnaround times, and the various approved tests, and compare them as regards the genes they detect. We concentrate on the point-of-care tests and discuss the basis for new serologic tests. We discuss the testing guidance for prioritization and their application in a hospital setting.

Evaluation of the Pain Impact Index for Community-Dwelling Older Adults Through the Application of Rasch Modelling.

OBJECTIVE: Evaluate the Pain Impact Index, a simple, brief, easy-to-use, and novel tool to assess the impact of chronic pain in community-dwelling older adults. METHODS: A Rasch modelling analysis was undertaken in Stata using a partial credit model suited to the Likert-type items that comprised the Index. The Index was evaluated for ordering of category thresholds, unidimensionality, overall fit to the Rasch model, measurement bias (Differential Item Functioning, DIF), targeting, and construct validity. RESULTS: The four-item Pain Impact Index was self-completed by 6454 community-dwelling Australians who were aged at least 70 years and experienced pain on most days. Two items showed evidence of threshold disordering, and this was resolved by collapsing response categories (from 5 to 3) for all items. The rescored Index conformed to the unidimensionality assumption and had satisfactory fit with the Rasch model (analyses conducted on a reduced sample size to mitigate the potential for overpowering: n = 377, P > 0.0125, power > 77%). When considering uniform DIF, the most frequent sources of measurement bias were age, knee pain, and upper back pain. When considering nonuniform DIF, the most frequent source of measurement bias was knee pain. The Index had good ability to differentiate between respondents with different levels of pain impact and had highest measurement precision for respondents located around the average level of pain impact in the study sample. Both convergent and discriminant validity of the Index were supported. CONCLUSION: The Pain Impact Index showed evidence of unidimensionality, was able to successfully differentiate between levels of pain impact, and had good evidence of construct validity.

Hypersensitivity to tetracyclines: Skin testing, graded challenge, and desensitization regimens.

BACKGROUND: Hypersensitivity reactions (HSRs) to tetracyclines and the related compound, tigecycline, can limit the use of these medications and compromise optimal patient care. Despite this, there is little discussion in the literature describing the presentation of these reactions or guiding clinicians on the management of these reactions in adult and pediatric patients. OBJECTIVE: To describe the clinical features, optimal diagnostic approach, and management of HSRs to tetracyclines. METHODS: Patients with reactions to tetracyclines at our institution from 2011 to 2019 were identified by retrospective chart review. Skin testing protocols were designed for each antibiotic. Graded challenge and desensitization procedures were devised based on medical history, skin testing results when available, and need for readministration. RESULTS: The HSRs to tetracyclines, their workup, and management are described for 10 patients, aged 7 to 68 years. Our skin testing protocols for doxycycline, minocycline, and tigecycline described herein had good negative predictive value. When skin testing was negative and the initial reaction was not severe, graded challenge to the culprit drug was performed. Using the included procedures, 3 patients were desensitized to oral doxycycline, 3 to oral minocycline, and 2 to intravenous tigecycline. All the desensitizations were successful. CONCLUSION: Once identified, HSRs to tetracyclines can be further evaluated with skin testing and graded challenge and managed in appropriate cases with desensitization. These procedures can facilitate first-line therapy for patients who require tetracyclines but developed hypersensitivity reactions.

Advances in pathophysiology and neuroimaging: Implications for sleep and dementia.

The burden of dementia is increasing globally. In the absence of curative treatment, preventive strategies to delay or reduce progression of dementia are crucial. This relies on the identification of modifiable risk factors. The effects of dementia on sleep are well recognized; however, there is now growing evidence suggesting a bidirectional relationship between sleep pathologies and dementia. SDB, poor quality sleep and extremes of sleep duration are commonly experienced by both middle-aged and older populations. All have been associated with increased risk of dementia and cognitive decline in a number of observational studies, albeit inconsistently. The mechanisms by which these sleep disorders may contribute to neurodegeneration are manifold, and include impacts of fragmented sleep on the clearance of neurotoxins, and in SDB by the additive effects of intermittent hypoxia on beta-amyloid production, hypoxic cell death, neuroinflammation and damage to cerebral vasculature. Untangling the mechanisms by which sleep pathologies may impact risk of dementia is a challenge. Many insights into the pathophysiology of these relationships have been derived from animal- and population-based studies. Neuroimaging modalities offer important opportunities to further understand the link between sleep pathologies and dementia risk in vivo, especially in the critical preclinical phase of AD. In this review, we canvas updates in dementia pathophysiology, the evidence linking sleep pathologies with dementia and outline the advances in determining this potential pathophysiological link that have eventuated from the application of neuroimaging.

The protocol of a clinical quality registry for dementia and mild cognitive impairment (MCI): the Australian dementia network (ADNeT) Registry.

BACKGROUND: Dementia was identified as a priority area for the development of a Clinical Quality Registry (CQR) in Australia in 2016. The Australian Dementia Network (ADNeT) Registry is being established as part of the ADNeT initiative, with the primary objective of collecting data to monitor and enhance the quality of care and patient outcomes for people diagnosed with either dementia or Mild Cognitive Impairment (MCI). A secondary aim is to facilitate the recruitment of participants into dementia research and trials. This paper describes the Registry protocol. METHODS: The ADNeT Registry is a prospective CQR of patients newly diagnosed with either dementia or MCI. Eligible patients will be identified initially from memory clinics and individual medical specialists (e.g., geriatricians, psychiatrists and neurologists) involved in the diagnosis of dementia. Participants will be recruited using either an opt-out approach or waiver of consent based on three key determinants (capacity, person responsible, and communication of diagnosis). Data will be collected from four sources: participating sites, registry participants, carers, and linkage with administrative datasets. It is anticipated that the Registry will recruit approximately 10,000 participants by the end of 2023. The ADNeT registry will be developed and implemented to comply with the national operating principles for CQRs and governed by the ADNeT Registry Steering Committee. DISCUSSION: The ADNeT Registry will provide important data on current clinical practice in the diagnosis, treatment and care of people with dementia and MCI in Australia as well as long-term outcomes among these people. These data will help to identify variations in clinical practice and patient outcomes and reasons underlying these variations, which in turn, will inform the development of interventions to improve care and outcomes for people with dementia and MCI.

Effectiveness of the Healthy Start-Départ Santé approach on physical activity, healthy eating and fundamental movement skills of preschoolers attending childcare centres: a randomized controlled trial.

BACKGROUND: Since young children spend approximately 30 h per week in early childcare centres (ECC), this setting is ideal to foster healthy behaviours. This study aimed to assess the effectiveness of the Healthy Start-Départ Santé (HSDS) randomized controlled trial in increasing physical activity (PA) levels and improving healthy eating and fundamental movement skills in preschoolers attending ECC. METHODS: Sixty-one ECC were randomly selected and allocated to either the usual practice (n = 30; n = 433 children) or intervention group (n = 31; n = 464 children). The HSDS intervention group was provided a 3-h on-site training for childcare educators which aimed to increase their knowledge and self-efficacy in promoting healthy eating, PA and development of fundamental movement skills in preschoolers. PA was measured during childcare hours for five consecutive days using the Actical accelerometer. Preschoolers' fundamental movement skills were assessed using the standard TGMD-II protocol and POMP scores. Food intake was evaluated using digital photography-assisted weighted plate waste at lunch, over two consecutive days. All data were collected prior to the HSDS intervention and again 9 months later. Mixed-effect models were used to analyse the effectiveness of the HSDS intervention on all outcome measures. RESULTS: Total number of children who provided valid data at baseline and endpoint for PA, food intake and fundamental movement skills were 259, 670 and 492, respectively. Children in the HSDS intervention group had, on average, a 3.33 greater point increase in their locomotor motor skills scores than children in the control group (ß = 3.33, p = 0.009). No significant differences in effects were observed for object control, PA and food intake. However, results demonstrated a marginal increase in portions of fruits and vegetables served in the intervention group compared to control group (ß = 0.06, p = 0.05). CONCLUSION: Of the 12 outcome variables investigated in this study, 10 were not different between the study groups and two of them (locomotor skills and vegetables and fruits servings) showed a significant improvement. This suggests that HSDS is an effective intervention for the promotion of some healthy behaviours among preschoolers attending ECC. TRIAL REGISTRATION: Clinical Trials NCT02375490. Registered on February 24, 2015; 77 retrospectively registered.

Dairy producers in the Southeast United States are concerned with cow care and welfare.

This research communication addresses the hypothesis that Southeast dairy producers' self-reported bulk tank somatic cell count (BTSCC) was associated with producers' response to three statements (1) 'a troublesome thing about mastitis is the worries it causes me,' (2) 'a troublesome thing about mastitis is that cows suffer,' and (3) 'my broad goals include taking good care of my cows and heifers.' Surveys were mailed to producers in Georgia, Kentucky, Mississippi, North Carolina, South Carolina, Tennessee, and Virginia (29% response rate, N = 596; final analysis N = 574), as part of a larger survey to assess Southeastern dairy producers' opinions related to BTSCC. Surveys contained 34 binomial (n = 9), Likert scale (n = 7), and descriptive (n = 18) statements targeted at producer self-assessment of herd records, management practices, and BTSCC. Statements 1 and 2 were assessed on a 5-point Likert scale from 'strongly disagree' to 'strongly agree.' Statement 3 was assessed on a 5-point Likert scale from 'very unimportant' to 'very important.' Reported mean BTSCC for all participants was 254 500 cells/ml. Separate univariable logistic regressions using generalized linear mixed models (SAS 9.4, Cary, NC, USA) with a random effect of farm, were performed to determine if BTSCC was associated with probability for a producer's response to statements. If BTSCC was significant, forward manual addition was performed until no additional variables were significant (P ≤ 0.05), but included BTSCC, regardless of significance. Bulk tank somatic cell count was associated with 'a troublesome thing about mastitis is the worries it causes me,' but not with Statements 2 or 3. This demonstrates that >75% of Southeastern dairy producers are concerned with animal care and cow suffering, regardless of BTSCC. Understanding Southeast producers' emphasis on cow care is necessary to create targeted management tools for herds with elevated BTSCC.