The New Normal: Delayed Peak SARS-CoV-2 Viral Loads Relative to Symptom Onset and Implications for COVID-19 Testing Programs.

BACKGROUND: Early in the coronavirus disease 2019 (COVID-19) pandemic, peak viral loads coincided with symptom onset. We hypothesized that in a highly immune population, symptom onset might occur earlier in infection, coinciding with lower viral loads. METHODS: We assessed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza A viral loads relative to symptom duration in symptomatic adults (≥16 years) presenting for testing in Georgia (4/2022-4/2023; Omicron variant predominant). Participants provided symptom duration and recent testing history. Nasal swabs were tested by Xpert Xpress SARS-CoV-2/Flu/RSV assay and cycle threshold (Ct) values recorded. Nucleoprotein concentrations in SARS-CoV-2 polymerase chain reaction (PCR)-positive samples were measured by single molecule array. To estimate hypothetical antigen rapid diagnostic test (Ag RDT) sensitivity on each day after symptom onset, percentages of individuals with Ct value ≤30 or ≤25 were calculated. RESULTS: Of 348 newly-diagnosed SARS-CoV-2 PCR-positive individuals (65.5% women, median 39.2 years), 317/348 (91.1%) had a history of vaccination, natural infection, or both. By both Ct value and antigen concentration measurements, median viral loads rose from the day of symptom onset and peaked on the fourth/fifth day. Ag RDT sensitivity estimates were 30.0%-60.0% on the first day, 59.2%-74.8% on the third day, and 80.0%-93.3% on the fourth day of symptoms.In 74 influenza A PCR-positive individuals (55.4% women; median 35.0 years), median influenza viral loads peaked on the second day of symptoms. CONCLUSIONS: In a highly immune adult population, median SARS-CoV-2 viral loads peaked around the fourth day of symptoms. Influenza A viral loads peaked soon after symptom onset. These findings have implications for ongoing use of Ag RDTs for COVID-19 and influenza.

Alpha-synucleinopathy reduces NMNAT3 protein levels and neurite formation that can be rescued by targeting the NAD+ pathway.

Parkinson's disease is characterized by the deposition of α-synuclein, which leads to synaptic dysfunction, the loss of neuronal connections and ultimately progressive neurodegeneration. Despite extensive research into Parkinson's disease pathogenesis, the mechanisms underlying α-synuclein-mediated synaptopathy have remained elusive. Several lines of evidence suggest that altered nicotinamide adenine dinucleotide (NAD+) metabolism might be causally related to synucleinopathies, including Parkinson's disease. NAD+ metabolism is central to the maintenance of synaptic structure and function. Its synthesis is mediated by nicotinamide mononucleotide adenylyltransferases (NMNATs), but their role in Parkinson's disease is not known. Here we report significantly decreased levels of NMNAT3 protein in the caudate nucleus of patients who have died with Parkinson's disease, which inversely correlated with the amount of monomeric α-synuclein. The detected alterations were specific and significant as the expression levels of NMNAT1, NMNAT2 and sterile alpha and TIR motif containing 1 (SARM1) were not significantly different in Parkinson's disease patients compared to controls. To test the functional significance of these findings, we ectopically expressed wild-type α-synuclein in retinoic acid-differentiated dopaminergic SH-SY5Y cells that resulted in decreased levels of NMNAT3 protein plus a neurite pathology, which could be rescued by FK866, an inhibitor of nicotinamide phosphoribosyltransferase that acts as a key enzyme in the regulation of NAD+ synthesis. Our results establish, for the first time, NMNAT3 alterations in Parkinson's disease and demonstrate in human cells that this phenotype together with neurite pathology is causally related to α-synucleinopathy. These findings identify alterations in the NAD+ biosynthetic pathway as a pathogenic mechanism underlying α-synuclein-mediated synaptopathy.

Sensitivity of rapid antigen tests against SARS-CoV-2 Omicron and Delta variants.

Rapid antigen tests (RATs) have become an invaluable tool for combating the COVID-19 pandemic. However, concerns have been raised regarding the ability of existing RATs to effectively detect emerging SARS-CoV-2 variants. We compared the performance of 10 commercially available, emergency use authorized RATs against the Delta and Omicron SARS-CoV-2 variants using both individual patient and serially diluted pooled clinical samples. The RATs exhibited lower sensitivity for Omicron samples when using PCR cycle threshold (CT) value (a rough proxy for RNA concentration) as the comparator. Interestingly, however, they exhibited similar sensitivity for Omicron and Delta samples when using quantitative antigen concentration as the comparator. We further found that the Omicron samples had lower ratios of antigen to RNA, which offers a potential explanation for the apparent lower sensitivity of RATs for that variant when using C T value as a reference. Our findings underscore the complexity in assessing RAT performance against emerging variants and highlight the need for ongoing evaluation in the face of changing population immunity and virus evolution.

Prevalence of SARS-CoV-2 in hemoglobinopathies is modified by age and race.

Prior literature has established a positive association between sickle cell disease and risk of contracting SARS-CoV-2. Data from a cross-sectional study evaluating COVID-19 testing devices (n = 10,567) was used to examine the association between underlying health conditions and SARS-CoV-2 infection in an urban metropolis in the southern United States. Firth's logistic regression was used to fit the model predicting SARS-CoV-2 positivity using vaccine status and different medical conditions commonly associated with COVID-19. Another model using the same method was built using SARS-CoV-2 positivity as the outcome and hemoglobinopathy presence, age (<16 Years vs. ≥16 Years), race/ethnicity and comorbidities, including hemoglobinopathy, as the factors. Our first model showed a significant association between hemoglobinopathy and SARS-CoV-2 infection (OR: 2.28, 95 % CI: (1.17,4.35), P = 0.016). However, in the second model, this association was not maintained (OR: 1.35, 95 % CI: (0.72,2.50), P = 0.344). We conclude that the association between SARS-CoV-2 positivity and presence of hemoglobinopathies like sickle cell disease is confounded by race, age, and comorbidity status. Our results illuminate previous findings by identifying underlying clinical/demographic factors that confound the reported association between hemoglobinopathies and SARS-CoV-2. These findings demonstrate how social determinants of health may influence disease manifestations more than genetics alone.

Changes in quality of life over time in patients diagnosed with oral leukoplakia: A prospective longitudinal study.

BACKGROUND: Oral leukoplakia (OL) is one of the most prevalent oral potentially malignant disorders (OPMD). Although there is emerging evidence that quality of life (QoL) is impaired in subjects with OL; studies to date are based on single and heterogenous point-in-time assessments. The aim of this study was to ascertain if QoL scores change over time in individuals diagnosed with OL. METHODS: Forty-one individuals with OL were administered the Short Generic Health Questionnaire (SF-12) and the discipline-specific Oral Potentially Malignant Disorder Questionnaire (OPMDQ) at four points in time: at the time of clinical diagnosis, at the post-biopsy review (confirmed diagnosis), and at 3- and 6-month follow-up appointments. Responses were compared between the four time points. RESULTS: No significant differences were observed in the SF-12 questionnaire scores over time. However, a general improvement in the participants' life quality was evident over the 6-month period under investigation in the domains of psychological and social well-being (p = 0.0027) and effect of treatment on daily life (p = 0.0317) as well as in the total score (p = 0.0005) of the OPMDQ. Age, gender, medical status, tobacco/alcohol use, lesion site, size, the presence of dysplasia and treatment did not impact QoL scores over time. CONCLUSIONS: QoL scores of OL subjects may improve with time. Our results suggest that studies examining QoL in individuals with OL should be controlled for time at which the participants are surveyed.

Use of oral nutritional supplements in irradiated patients with head and neck cancer.

OBJECTIVES: Malnutrition is common among patients with head and neck cancer (HNC) and associated with poorer outcomes. Oral nutritional supplements (ONS) are often prescribed, with concerns raised about their cariogenicity. This study examined ONS use and caries experience in patients with HNC 12 months post-diagnosis. METHODS: Fifty-four patients with HNC referred for pre-radiotherapy dental assessment were recruited. Data collected included: age, gender, residential postcode, smoking, alcohol use, HNC characteristics, dental history, oral hygiene habits, dietary advice and ONS use. Data was collected at diagnosis, during radiotherapy and 6 weeks, three, six- and 12-months post-treatment completion. RESULTS: Fifty-one subjects completed the study. 76.5% of the participants used ONS for an average of 13.8 weeks. Caries developed in 22.9% of ONS users and 11.1% of non-users (p = 0.6585). The mean overall duration of ONS use was 18.7 weeks for the caries group and 8.5 weeks for the caries-free group (p = 0.1507). Lack of collaboration and disconnection was noted between dietary advice given by dieticians and dentists. CONCLUSIONS: ONS use is common among patients with HNC. Larger studies are needed to establish the reasons for caries development and impacts of ONS use on oral health. Importance of multidisciplinary management of malnutrition is highlighted.

Proton pump inhibitors are associated with incident type 2 diabetes mellitus in a prospective population-based cohort study.

AIM: To investigate the association between proton pump inhibitors (PPIs) and risk of incident diabetes in a follow-up study and to investigate its potential mechanisms. METHODS: A total of 9531 individuals without type 2 diabetes (T2DM) at baseline were included from the Rotterdam Study, a prospective population-based cohort of 14 926 individuals aged 45 years or older. During the study period (1 April 1997 to 1 January 2012) all incident cases of T2DM were enrolled. We used multivariable linear regression analysis to investigate the associations of baseline PPI use and various serum biomarkers (eg, serum magnesium, insulin-like growth factor 1) which might modify the association. Thereafter, we excluded prevalent PPI users and performed a Cox proportional hazard regression analysis to explore the time-varying effect of incident PPI use on T2DM during follow-up. RESULTS: Baseline use of a PPI was associated with increased serum levels of fasting insulin (0.091 pmoL/L, 95% confidence interval [CI] 0.049, 0.133), homeostasis model assessment-insulin resistance (0.100, 95% CI 0.056, 0.145) and C-reactive protein (0.29 mg/L, 95% CI 0.198, 0.384), but decreased levels of magnesium (-0.009 mmol/L, 95% CI -0.014, -0.004) and IGF-1 (-0.805 nmoL/L, 95% CI -1.015, -0.595). After adjustment for risk factors such as physical activity and body mass index/waist-to-hip ratio, current use of PPI was associated with an increased risk of incident T2DM (hazard ratio [HR] 1.69, 95% CI 1.36-2.10). The effect was dose-dependent with the highest risk (HR 1.88, 95% CI 1.29-2.75) in those on more than one defined daily dose. CONCLUSION: New users of PPIs during follow-up had a significantly higher dose-dependent risk of incident diabetes. We suggest vigilance regarding their potential adverse effect on glucose homeostasis.

Cross-sectional Census Survey of Patients With Cancer who Received a Pharmacist Consultation in a Pharmacist Led Anti-cancer Clinic.

Pharmacists have a critical consulting role in patients undergoing oral antineoplastic drug therapy to ensure harm minimisation. Studies exploring the benefits of pharmacists in this role are limited. This study evaluated patient perceptions, experiences and overall satisfaction with clinical pharmacist consultations in patients treated with oral antineoplastic drugs. Data on 160 patients initiated on oral antineoplastic drugs between January 2019 and February 2021 were collected retrospectively from an outpatient Comprehensive Cancer Centre of a quaternary hospital in Western Australia (demographics, cancer type, oral antineoplastic drugs prescribed). In addition, patients were mailed a hard copy questionnaire in March 2021 to assess their satisfaction with pharmacist consultations in the pharmacist clinic, using a 5-point Likert scale. The statements included perceptions of the patient's understanding, medication adherence, experiences and overall satisfaction with the clinical pharmacist consultation. There were 76 (47.5%) completed questionnaires returned (52.6% female; average age was 63.2 ± 13.9 years). The majority of patients were satisfied with the service offered by the clinical pharmacist (73/76; 96.1%), perceived that clinical pharmacists provided an important service in outpatient cancer care (71/76; 93.4%) and improved their understanding of the use of oral antineoplastic drugs and side-effect management (48/74; 64.9%). Patients' perceived understanding of their medication regimen and additional health services available improved after pharmacist counselling. The patients also reported overall satisfaction with the service provided by the clinical pharmacist and found it beneficial to their care. The study supports the expanding role of the clinical pharmacist in an outpatient cancer centre.

Construct validity, reliability, and responsiveness of the Wrist Position Sense Test for use in children with hemiplegic cerebral palsy.

INTRODUCTION: We investigate the construct validity, test re-test reliability, and responsiveness of the Wrist Position Sense Test (WPST) for children with hemiplegic cerebral palsy (CP). METHODS: Twenty-eight children with spastic hemiplegic CP [mean age 10.8 years; SD 2.4 years] and 39 typically developing (TD) children [mean age 11 years; SD 2.9 years] participated in a cross-sectional study to investigate construct validity and association with an upper limb activity measure, the Box and Block Test (BBT). Twenty-two TD children were tested at a second time-point to examine reliability. Test responsiveness was determined by random allocation of 17 children with CP to a treatment (n = 10) or control (n = 7) group with assessments completed at four time-points. RESULTS: Significantly greater differences were observed in mean error of indicated wrist position (p < 0.01) in children with CP at baseline (M = 21.6°, SD = 21.6°) than in TD children (M = 12.8°, SD = 11.0°). Larger WPST errors were associated with poorer performance on the BBT (p < 0.01) indicating a substantial association, and there were no consistent differences between time-points indicating test re-test reliability within a TD population. The WPST demonstrated responsiveness to intervention with a statistically significant reduction in mean error following treatment (p < 0.001), not seen in the control group (p = 0.28). CONCLUSION: The WPST demonstrated construct validity in this preliminary study. Scores were associated with an upper limb activity measure, and scores changed significantly following somatosensory training. These findings support further research and future psychometric investigation of the WPST in children with CP. KEY POINTS FOR OCCUPATIONAL THERAPY: This study provides psychometric knowledge about the WPST tool The WPST shows promise as a discriminative measure with preliminary evidence of responsiveness and intra-rater reliability Until further testing, the WPST can be used cautiously in future research studies to measure wrist position sense.

CircaCompare: a method to estimate and statistically support differences in mesor, amplitude and phase, between circadian rhythms.

MOTIVATION: A fundamental interest in chronobiology is to compare patterns between groups of rhythmic data. However, many existing methods are ill-equipped to derive statements concerning the statistical significance of differences between rhythms that may be visually apparent. This is attributed to both the form of data used (longitudinal versus cross-sectional) and the limitations of the statistical tests used to draw conclusions. RESULTS: To address this problem, we propose that a cosinusoidal curve with a particular parametrization be used to model and compare data of two sets of observations collected over a 24-h period. The novelty of our test is in the parametrization, which allows the explicit estimation of rhythmic parameters [mesor (the rhythm-adjusted mean level of a response variable around which a wave function oscillates), amplitude and phase], and simultaneously testing for statistical significance in all three parameters between two or more groups of datasets. A statistically significant difference between two groups, regarding each of these rhythmic parameters, is indicated by a P-value. The method is evaluated by applying the model to publicly available datasets, and is further exemplified by comparison to the currently recommended method, DODR. The results suggest that the method proposed may be highly sensitive to detect rhythmic differences between groups in phase, amplitude and mesor. AVAILABILITY AND IMPLEMENTATION: https://github.com/RWParsons/circacompare/.

Nicotinamide N-methyltransferase expression in SH-SY5Y human neuroblastoma cells decreases oxidative stress.

Nicotinamide N-methyltransferase (NNMT) plays a central role in cellular metabolism, regulating pathways including epigenetic regulation, cell signalling, and energy production. Our previous studies have shown that the expression of NNMT in the human neuroblastoma cell line SH-SY5Y increased complex I activity and subsequent ATP synthesis. This increase in ATP synthesis was lower than the increase in complex I activity, suggesting uncoupling of the mitochondrial respiratory chain. We, therefore, hypothesised that pathways that reduce oxidative stress are also increased in NNMT-expressing SH-Y5Y cells. The expression of uncoupling protein-2 messenger RNA and protein were significantly increased in NNMT-expressing cells (57% ± 5.2% and 20.1% ± 1.5%, respectively; P = .001 for both). Total GSH (22 ± 0.3 vs 35.6 ± 1.1 nmol/mg protein), free GSH (21.9 ± 0.2 vs 33.5 ± 1 nmol/mg protein), and GSSG (0.6 ± 0.02 vs 1 ± 0.05 nmol/mg protein; P = .001 for all) concentrations were significantly increased in NNMT-expressing cells, whereas the GSH:GSSG ratio was decreased (39.4 ± 1.8 vs 32.3 ± 2.5; P = .02). Finally, reactive oxygen species (ROS) content was decreased in NNMT-expressing cells (0.3 ± 0.08 vs 0.12 ± 0.03; P = .039), as was the concentration of 8-isoprostane F2α (200 ± 11.5 vs 45 ± 2.6 pg/mg protein; P = .0012). Taken together, these results suggest that NNMT expression reduced ROS generation and subsequent lipid peroxidation by uncoupling the mitochondrial membrane potential and increasing GSH buffering capacity, most likely to compensate for increased complex I activity and ATP production.

Chronic disease comorbidity in patients with oral leukoplakia: A matched case-control study.

OBJECTIVE: The purpose of this study was to investigate the presence of chronic diseases in patients with oral leukoplakia (OL) compared to controls matched for age group, gender, smoking and alcohol use. SUBJECTS AND METHODS: This case-control study examined the general demographics, medical and social histories of 105 OL cases and 391 controls matched for age group, gender, tobacco and alcohol use. All OL cases were diagnosed based on both clinical and histopathological findings. RESULTS: Chronic diseases were significantly associated with OL, namely dyslipidaemia (p < .0001), musculoskeletal diseases (p = .0101) and asthma (p = .0052). The use of ACE inhibitors (p = .0177), opioid analgesics (p = .0300), anticoagulants (p = .0055) and statins (p = .0010) was significantly associated with OL. Dyslipidaemia (p < .0001; odds ratio [95% CI]: 6.4 [3.5-11.6]) and asthma (p = .0110; odds ratio [95% CI]: 2.2 [1.2-4.0]) were identified as independent predictors of OL in multivariate analysis, both of which were significantly more common amongst cases than controls. CONCLUSIONS: Results from this first Australian study suggest that dyslipidaemia and asthma may constitute independent predictors for the presence of OL. However, longitudinal studies are needed to ascertain the temporal relationship between OL and chronic disease comorbidity and the mechanisms underlying these associations.

Research protocol of a multifaceted prospective mixed-method longitudinal study: Navigating Through Life - Western Australian study of transitions from out-of-home care.

BACKGROUND: Developing robust evidence is a challenge for researchers working with disadvantaged or vulnerable populations. For example, research shows that young people who have transitioned from out-of-home care (OOHC) to independent adulthood often experience poor long-term outcomes. However, evidence for the aetiology of those outcomes is weak due to methodological limitations such as small sample sizes and a lack of longitudinal data. This paper details the protocol for Navigating Through Life, a study that utilises novel research methods to better understand the pathways and outcomes of young people as they leave OOHC in Western Australia (WA). METHODS: Navigating Through Life is a longitudinal, mixed methods, population-based study. A prospective longitudinal study of young people aged 15-25 years will follow participants' experiences and outcomes over a two-year period. Quantitative and qualitative data is being collected from participants five times over 2 years, using standardised outcome measures and individual interviews. Outcome measures focus on key dimensions of young people's lives (e.g., social inclusion, well-being, resilience, self-determination). Interviews examine important influences and the variable contexts into which young people have transitioned from care. In addition, retrospective population-level data for young people transitioning from OOHC will be obtained from linked Western Australian government administrative records. Using a multitude of data sources, analysis will map pathways and outcomes of young people with care experience, and comparisons will be made with other population groups within WA. DISCUSSION: Navigating Through Life exemplifies a novel utilisation of multiple data sources to research outcomes for vulnerable and difficult to reach populations, and offers insights for other complex mixed-methods longitudinal studies. Results will provide new and more comprehensive data about specific pathways that may be influential to a range of post-care outcomes. Findings will extend evidence to inform better service-delivery models that improve outcomes and reduce disparities for vulnerable young people.

The epidemiology of heart failure in the general Australian community - study of heart failure in the Australian primary carE setting (SHAPE): methods.

BACKGROUND: There is a paucity of information on the epidemiology of heart failure (HF) in Australia. The Study of Heart failure in the Australian Primary carE setting (SHAPE) study aims to estimate the prevalence and annual incidence of HF in the general Australian community and to describe the demographic and key clinical profile of Australians with HF. METHODS: We undertook a retrospective cohort study based on analysis of non-identifiable medical records of adult patients cared for at 43 general practices between 1 July 2013 and 30 June 2018. Data were extracted from coded (diagnosis, pathology and prescription fields) and uncoded fields (clinical notes) in the medical records. The latter searches of free text looked for common synonyms relevant to HF. The population was stratified into three groups based on a hierarchy of selection criteria: (1) definite HF, (2) probable HF and (3) possible HF. The prevalence and annual incidence of HF were calculated, along with 95% confidence intervals. RESULTS: The practices provided care to 2.3 million individual patients over the five-year study period, of whom 1.93 million were adults and 1.12 million were regular patients. Of these patients 15,468 were classified as having 'definite HF', 4751 as having 'probable HF' and 33,556 as having 'possible HF'. A further 39,247 were identified as having an aetiological condition associated with HF. A formal HF diagnosis, HF terms recorded as text in the notes and HF-specific medication were the most common methods to identify 'definite' HF patients. Typical signs and symptoms in combination with a diuretic prescription was the most common method to identify 'probable HF' patients. The majority of 'possible' HF patients were identified by the presence of 2 or more of the typical signs or symptoms. Dyspnoea was the commonest recorded symptom and an elevated jugular venous pressure the commonest recorded sign. CONCLUSIONS: This novel approach to undertaking retrospective research of primary care data successfully analysed a combination of coded and uncoded data from the electronic medical records of patients routinely managed in the GP setting. SHAPE is the first real-world study of the epidemiology of HF in the general Australian community setting.

Neonatal Admission and Its Relationship to Maternal Pain: Pain Scores and Analgesia.

The aim of this study was to determine whether postnatal women whose babies required neonatal intensive care unit (NICU) admission self-reported lower pain scores and required less analgesia than women whose babies remained with them. A prospective matched audit comparing pain scores and analgesia requirements where every woman with a baby admitted to the NICU was matched to 2 women whose babies remained on the ward was undertaken. Matches were based on age, number of previous births, type of birth, episiotomy, and epidural or spinal analgesia use. Data were collected on pain scores and analgesia administered in the first 72 hours postbirth. A total of 150 women were recruited and matched from November 2015 to May 2017. No statistically significant differences were found between the 2 groups for opiate analgesia use (P = .91) or pain scores (P = .89). Regardless of NICU admission, significantly higher pain scores were reported in participants who had episiotomies (P = .03). Birth via cesarean birth resulted in significantly higher pain scores (P < .01) and greater opiate administration (P < .01). This study found no statistically significant difference between pain scores or analgesia use of mothers whose babies required NICU admission and mothers whose babies remained with them.

Medical status of patients presenting for treatment at an Australian dental institute: a cross-sectional study.

BACKGROUND: Individuals seeking dental treatment often present with medical conditions which may affect dental treatment provision. The purpose of this study was to determine the prevalence of medical conditions and medication use among individuals attending dental clinics at a Western Australian tertiary institution. METHODS: This observational study examined the general demographics, medical and social histories of 873 subjects presenting for a general dental examination at a Western Australian Tertiary Institution between March 2018 and February 2019. Individual recruited were those presenting to the clinics either as new patients to the Centre or returning patients after an extended period of absence. RESULTS: Presence of a medical condition was reported by 86% of the participants, with males more commonly affected (p = 0.0448). Medication use was noted by 80% of the participants. Cardiovascular disease (37.9%), allergy (32.3%), mental health disorders (29.4%), musculoskeletal (23.0%), endocrine (22.4%) and respiratory disease (17.8%) were the most common conditions identified. Women were significantly more likely to report allergy (p = 0.0002) or a mental health condition (p = 0.0368). CONCLUSION: Medical comorbidities are common among individuals presenting for student dental treatment in Western Australia, highlighting the importance of knowledge and teaching of internal medicine and its application to the dental setting.

A sequence symmetry analysis of the interrelationships between statins, diabetes and skin infections.

AIMS: To determine statins' impact on skin infection risk in view of conflicting literature: that statins may reduce infection risk, but are also associated with diabetes mellitus, a risk factor for skin and soft tissue infections (SSTIs). METHODS: Sequence symmetry analysis was performed on prescription claims (2001-2011) from the Australian Department of Veterans' Affairs to determine the interrelationships between: (i) statins and SSTIs; (ii) statins and diabetes; and (iii) diabetes and SSTIs; as well as whether statins increased the risk of SSTIs, independent of diabetes status. Chi-square tests were performed to detect differences in Index of Relative Socio-economic Advantage and Disadvantage scores of patients within each interrelationship. Prescriptions for statins, antidiabetic medication, and antistaphylococcal antibiotics were evaluated using nonidentifiable client numbers, prescription dates filled, residential electorates, and pharmaceutical codes. Adjusted sequence ratio and confidence interval were calculated at intervals of 91, 182 and 365 days for sequence symmetry analysis studies. RESULTS: Statins were associated with: (i) significant SSTI risk (adjusted sequence ratio > 1; confidence interval >1), (ii) significant diabetes risk, and (iii) diabetic patients had increased risk of SSTIs. Diabetic and nondiabetic statin users had significantly increased risks of SSTIs, while the influence from socioeconomic status was not significant for each of the 3 relationships. CONCLUSIONS: Statins are associated with increased risk of SSTIs via direct and indirect mechanisms, probably independent of diabetes or socioeconomic statuses. We believe that clinicians should be aware of the association between statins and SSTIs, and, where appropriate, monitor blood glucose levels of statin users.

A feedback loop between dipeptide-repeat protein, TDP-43 and karyopherin-α mediates C9orf72-related neurodegeneration.

Accumulation and aggregation of TDP-43 is a major pathological hallmark of amyotrophic lateral sclerosis and frontotemporal dementia. TDP-43 inclusions also characterize patients with GGGGCC (G4C2) hexanucleotide repeat expansion in C9orf72 that causes the most common genetic form of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). Functional studies in cell and animal models have identified pathogenic mechanisms including repeat-induced RNA toxicity and accumulation of G4C2-derived dipeptide-repeat proteins. The role of TDP-43 dysfunction in C9ALS/FTD, however, remains elusive. We found G4C2-derived dipeptide-repeat protein but not G4C2-RNA accumulation caused TDP-43 proteinopathy that triggered onset and progression of disease in Drosophila models of C9ALS/FTD. Timing and extent of TDP-43 dysfunction was dependent on levels and identity of dipeptide-repeat proteins produced, with poly-GR causing early and poly-GA/poly-GP causing late onset of disease. Accumulating cytosolic, but not insoluble aggregated TDP-43 caused karyopherin-α2/4 (KPNA2/4) pathology, increased levels of dipeptide-repeat proteins and enhanced G4C2-related toxicity. Comparable KPNA4 pathology was observed in both sporadic frontotemporal dementia and C9ALS/FTD patient brains characterized by its nuclear depletion and cytosolic accumulation, irrespective of TDP-43 or dipeptide-repeat protein aggregates. These findings identify a vicious feedback cycle for dipeptide-repeat protein-mediated TDP-43 and subsequent KPNA pathology, which becomes self-sufficient of the initiating trigger and causes C9-related neurodegeneration.

The cost-effectiveness of a telephone-based intervention to support caregivers of older people discharged from hospital.

BACKGROUND: A telephone intervention for caregivers of older people discharged from hospital was shown to improve preparedness to care, reduce caregiver strain and caregiver distress. No cost-effectiveness analysis has been published on this, or similar interventions. The study aims addressed here were to examine whether positive outcomes for caregivers resulting from the Further Enabling Care at Home (FECH) program changed the use and costs of health services by patients; and to assess cost-effectiveness. METHODS: A single-blind randomised controlled trial compared FECH to usual care. FECH involved a specially trained nurse addressing support needs of caregivers of older patients discharged from hospital. A minimum clinically important difference in preparedness to care was defined as an increase in Preparedness for Caregiving scale score of ≥ two points from baseline. Designated data collection was at: Time 1, within four days of discharge; Time 2, 15-21 days post-discharge; and Time 3, six weeks post-discharge. A last observation carried forward approach to loss to follow-up was used, with a sensitivity analysis including only those who completed all time points. Patient use of hospital, emergency department (ED) and ambulance services were captured for 12 weeks post-discharge using administrative data. Costs included nurse time supporting caregivers, resources used by the nurse, and time taken training the nurse to deliver FECH. Cost-effectiveness was assessed using decision trees for preparedness for caregiving. RESULTS: Sixty-two intervention dyads and 79 controls provided complete data. A significantly greater proportion of intervention group caregivers reported improved preparedness to care to Time 2 (36.4% v 20.9%, p = 0.029), though this was not sustained to Time 3. The intervention cost $AUD268.28 above usual care per caregiver. No significant differences were observed in health service use between groups. The incremental cost-effectiveness ratio for each additional caregiver reporting improved preparedness to care at Time 2 was $AUD1,730.84. CONCLUSIONS: To our knowledge this is the first work to calculate the cost-effectiveness of a telephone-delivered intervention designed to support caregivers of older people post-discharge, and will support decision-making regarding implementation. Further research should examine different settings, and assess impacts on health service use with larger samples and a longer follow-up. TRIAL REGISTRATION: Australian and New Zealand Clinical Trial Registry: ACTRN12614001174673 . Registered 07/11/2014.