A census of baryons in the Universe from localized fast radio bursts.

More than three-quarters of the baryonic content of the Universe resides in a highly diffuse state that is difficult to detect, with only a small fraction directly observed in galaxies and galaxy clusters1,2. Censuses of the nearby Universe have used absorption line spectroscopy3,4 to observe the 'invisible' baryons, but these measurements rely on large and uncertain corrections and are insensitive to most of the Universe's volume and probably most of its mass. In particular, quasar spectroscopy is sensitive either to the very small amounts of hydrogen that exist in the atomic state, or to highly ionized and enriched gas4-6 in denser regions near galaxies7. Other techniques to observe these invisible baryons also have limitations; Sunyaev-Zel'dovich analyses8,9 can provide evidence from gas within filamentary structures, and studies of X-ray emission are most sensitive to gas near galaxy clusters9,10. Here we report a measurement of the baryon content of the Universe using the dispersion of a sample of localized fast radio bursts; this technique determines the electron column density along each line of sight and accounts for every ionized baryon11-13. We augment the sample of reported arcsecond-localized14-18 fast radio bursts with four new localizations in host galaxies that have measured redshifts of 0.291, 0.118, 0.378 and 0.522. This completes a sample sufficiently large to account for dispersion variations along the lines of sight and in the host-galaxy environments11, and we derive a cosmic baryon density of [Formula: see text] (95 per cent confidence; h70 = H0/(70 km s-1 Mpc-1) and H0 is Hubble's constant). This independent measurement is consistent with values derived from the cosmic microwave background and from Big Bang nucleosynthesis19,20.

An ecological and epidemiological single-season survey of Anaplasma and Ehrlichia positive ticks in Victoria Falls National Park, Zimbabwe.

There is an urgent need for continued research on the ecology of tick-borne diseases in Africa. Our objective was to provide a preliminary description of the ecology and epidemiology of tick species, tick-borne pathogens, and animal hosts in Zimbabwe, focusing efforts at Victoria Falls National Park, for a single season. We tested the hypothesis that tick surveillance and pathogen screening data can be used to model associations among ticks, hosts, and pathogens. We collected ticks from domesticated animals and wildlife in Zimbabwe and screened the ticks for the presence of Anaplasma and Ehrlichia bacteria. Nearly 30% of the screened ticks were PCR-positive; 89% of tick species were PCR-positive, and 88% of animal species carried at least one PCR-positive tick. We sequenced a subset of amplicons that were similar to three Anaplasma species and three Ehrlichia species. The odds of a tick being PCR-positive increased when many ticks were collected from the host or the tick was collected from a cow (domesticated animal). Tick species shared host species more often than expected. We demonstrate that ticks in northwestern Zimbabwe present a One Health problem for nearby wildlife and humans.

The impact of COVID-19 public health measures on attendance and overdose at supervised injecting facilities in Australia.

OBJECTIVES: The COVID-19 pandemic disrupted service provision of harm reduction and drug treatment services for people who inject drugs in many countries. The two supervised injecting facilities (SIFs) in Sydney and Melbourne were differentially impacted by the pandemic, requiring local procedural changes in each service. We aimed to examine the impact of pandemic responses (including restrictions on movement, known as 'lockdowns') on service use and key parameters such as client reports of drug injected and recorded overdose rates. STUDY DESIGN: Time series analysis of weekly client visits and monthly overdoses occurring at each service. METHODS: Administrative client data from the two SIFs (Sydney data from 1 January 2018 to 30 April 2022; Melbourne data from 1 July 2018 to 30 April 2022) were examined using interrupted time series analyses with lockdown dates in each state entered as interruption terms. We analysed weekly SIF visits overall and by drug type, and monthly rates of opioid overdose at each service. RESULTS: Lockdowns resulted in decreased visits to both services. The number of weekly client visits decreased during the first national lockdown for both the Sydney (trend change = -57.9; 95% CI [-109.4, -6.4]) and Melbourne SIF (near sig trend change = -54.8 [-110.8, 1.05]). Trends in visit numbers increased after lockdowns were lifted in each city; however, visits in Sydney have not returned to the numbers recorded prior to the pandemic. Visits to the Melbourne SIF related to heroin use declined at each lockdown (trend 1 = -42.7 [-81.5, -3.9]; trend 2 = -56.1 [-94.6, -17.7]; trend 3 = -33.8 [-67.4, -0.2]); heroin visits to the Sydney SIF declined during the first lockdown and remained low (trend = -55.6 [-82.8, -28.3]). Methamphetamine visits to the Sydney SIF fluctuated, surpassing heroin visits at several timepoints. Rates of monthly opioid overdoses at both services declined immediately following the start of the first lockdown (Sydney = -16.6 [-26.1, -6.8]; Melbourne = -6.4 [-8.7, -4.1]), with increasing trends recorded at the end of the final lockdown in each jurisdiction (Sydney = 2.8 [0.6, 5.0]; Melbourne = 1.3 [0.72, 3.2]). CONCLUSIONS: Public health restrictions related to the COVID-19 pandemic were associated with reduced client visits to, and overdoses in, Australian SIFs. Variations were noted in the drugs injected, likely reflecting changes in local drug markets. Shifts to other drugs during these periods were evident: methamphetamine in Sydney; co-injection of heroin and diphenhydramine in Melbourne.

Community efforts to monitor and manage Aedes mosquitoes (Diptera: Culicidae) with ovitraps and litter reduction in east Tennessee.

BACKGROUND: East Tennessee (USA) is burdened by mosquito-borne La Crosse virus disease, but minimal resources for mosquito surveillance, management, or related community education exist in the region. To address these needs, we developed a program to train middle and high school educators in basic medical entomology. The educators then used their skills in the classroom to teach students about La Crosse virus disease and conduct mosquito collection experiments. As a case study of a potential application of classroom-collected data, we also partnered with a local non-profit organization to assess the potential for a volunteer litter cleanup to reduce mosquito populations in a Tennessee neighborhood. METHODS: Our first objective was to investigate the ability for educators and their students (schools) to collect high-quality mosquito surveillance data. In 2019 and 2020, we collected Aedes (Diptera: Culicidae) eggs during the same study period as schools and assessed whether data collected by schools reflected the same findings as our own data. Our second objective was to investigate the impact of a volunteer litter cleanup event on Aedes mosquito abundance. In 2021, we collected Aedes eggs before and after a neighborhood trash cleanup while schools conducted their own mosquito egg collections. Using the school collections as non-treatment sites, we used a Before-After-Control-Impact analysis to determine if there was a significant decline in egg abundance after the cleanup. RESULTS: In 2019, mosquito abundance trends were similar between our data and school data but differed significantly during some weeks. After refining our protocols in 2020, school data was highly similar to our data, indicating that schools consistently collected high-quality surveillance data in the program's second year. In 2021, we found a significant decline in Aedes egg abundance after the litter cleanup event in comparison to the schools, but the number of adults reared from those eggs did not differ between sites after the cleanup. CONCLUSION: The results of our work demonstrate the potential for community-driven programs to monitor mosquito abundance trends and for volunteer-based cleanup events to reduce the burden of Aedes mosquitoes. In the absence of infrastructure and resources, academic-community partnerships like the ones evaluated here, provide opportunities to help resource limited areas.

Biological subtype, treatment response and outcomes in inflammatory breast cancer using data from the National Cancer Database.

BACKGROUND: Although inflammatory breast cancer (IBC) is postulated to be a distinct biological entity, practice guidelines and previous data suggest that treatment and outcomes are influenced by standard approximated biological subtype. The aim of this study was validation in a large recent National Cancer Database (NCDB) patient cohort. METHODS: Patients with non-metastatic IBC treated in 2010-2015 with neoadjuvant systemic therapy and surgery were identified from the NCDB. Approximated biological subtypes were categorized as oestrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-), ER-/HER2- and HER2+. Total pathological complete response (pCR) was defined as ypT0/ypTis, ypN0. χ2 tests were used to compare pCR rates, and Kaplan-Meier curves and Cox proportional hazards regression to analyse overall survival. RESULTS: Among 4068 patients with IBC (median age 56 years), the approximated biological subtype was ER+/HER2- in 1575 (38·7 per cent), HER2+ in 1323 (32·5 per cent) and ER-/HER2- in 1170 (28·8 per cent). A total of 3351 patients (84·0 per cent) were cN+ at presentation, with no differences across subtypes. Total pCR rates varied significantly by subtype: ER+/HER2- (6·2 per cent), HER2+ (38·8 per cent), ER-/HER2- (19·1 per cent) (P < 0·001), as did breast pCR rates (10·4, 44·5 and 25·2 per cent respectively) and nodal pCR rates (16·9, 56·9 and 33·1 per cent). The 5-year overall survival rate varied significantly across subtypes (ER+/HER2- 64·9 per cent, HER2+ 74·0 per cent, ER-/HER2- 44·0 per cent; P < 0·001) and by pCR within subtypes (all P < 0·001). In multivariable analysis, ER-/HER2- subtype (hazard ratio 2·89 versus HER2+ as reference; P < 0·001) and absence of total pCR (hazard ratio 3·23; P < 0·001) predicted worse survival. CONCLUSION: Both treatment response and survival in patients with IBC varied with approximated biological subtype, as among other invasive breast cancers. These data support continued tailoring of systemic treatment to approximated biological subtype and highlight the recent improved outcomes in patients with HER2+ disease.

ANTECEDENTES: En tanto que el cáncer inflamatorio de mama (inflammatory breast cancer, IBC) se ha postulado como una entidad biológica distinta, las guías de práctica clínica y datos previos sugieren que el tratamiento y los resultados están influenciados por aproximación al subtipo biológico estándar. El objetivo de este estudio fue la validación en una cohorte reciente de pacientes incluidas en una extensa Base de Datos Nacional de Cáncer (National Cancer Database, NCDB). MÉTODOS: A partir de la NCDB, se identificaron las pacientes con IBC no metastásico tratadas en con neoadyuvancia sistémica y cirugía durante el periodo 2010-2015. El subtipo biológico aproximado se categorizó como ER+/HER2-, ER-/HER2- y HER2+. La respuesta patológica completa total (pathologic complete response, pCR) se definió como ypT0/ypTis, ypN0. Se utilizaron pruebas de ji al cuadrado para comparar las tasas de pCR y las curvas de Kaplan-Meier y la regresión de riesgos proporcionales de Cox para analizar la supervivencia global (overall survival, OS). RESULTADOS: En las 4.068 pacientes con IBC (mediana de edad 56 años), el subtipo biológico aproximado fue ER+/HER2- en 1.575 (39%), HER2+ en 1.323 (33%) y ER-/HER2- en 1.170 (29%). Un total de 3.351 pacientes (84%) eran cN+ en el momento de la presentación, sin diferencias entre los subtipos. Las tasas totales de pCR variaron significativamente en función del subtipo: ER+/HER2- (6%), HER2+ (39%), ER-/HER2- (19%), P < 0,001, así como las tasas de pCR de la mama (10%, 45%, 25%) y las tasas de pCR de los ganglios linfáticos (17%, 57%, 33%). La OS a los 5 años varió significativamente según los subtipos (ER+/HER2- 65%, HER2+ 74%, ER-/HER2- 44%, P < 0,001) y según la pCR en cada uno de los subtipo (en cada uno P < 0,01). En el análisis multivariable, el subtipo ER-/HER2- (cociente de riesgos instantáneos, hazard ratio, HR 2,9, P < 0,001 versus HER2+) y la ausencia de pCR total (HR 3,2, P < 0,001) predijeron una peor supervivencia. CONCLUSIÓN: Tanto la respuesta al tratamiento del IBC y como la supervivencia variaron en función del subtipo biológico aproximado, tal como sucede en otros cánceres de mama invasivos. Estos datos apoyan la importancia de continuar ajustando el tratamiento sistémico al subtipo biológico aproximado y resaltan la mejoría reciente de los resultados en las pacientes HER2+.

Quantifying the hygroscopic properties of cyclodextrin containing aerosol for drug delivery to the lungs.

Aerosol dynamics is important to quantify in drug delivery to the lungs with the aim of delivering therapeutics to a target location and optimising drug efficacy. The macrocycle (2-hydroxypropyl)-ß-cyclodextrin (2-HP-ß-CD) is thought to alleviate symptoms associated with neurodegenerative diseases when inhaled but the hygroscopic response is not well understood. Here we measure the hygroscopic growth of individual aqueous aerosol containing 2-HP-ß-CD in optical tweezers through analysis of morphology-dependent resonances arising in Raman spectra. Droplets are analysed in the size range of 3-5 µm in radius. The evolving radius and refractive index of each droplet are measured in response to change in relative humidity from 98-20% to determine mass and radius based hygroscopic growth factors, and compared with dynamic vapour sorption measurements. Bulk solution refractive index and density measurements were used in accordance with the self-consistent Lorenz-Lorentz rule to determine melt solute and droplet properties. The refractive index of 2-HP-ß-CD was determined to be 1.520 ± 0.002 with a density of 1.389 ± 0.005 g cm-3. To our knowledge, we show the first aerosol measurements of 2-HP-ß-CD and determine hygroscopicity. By quantifying the hygroscopic growth and physicochemical properties of 2-HP-ß-CD, the impact of aerosol dynamics can be accounted for in tailoring drug formulations and informing models used to predict drug deposition patterns within the respiratory system.

Detection of N-glycolylneuraminic acid biomarkers in sera from patients with ovarian cancer using an engineered N-glycolylneuraminic acid-specific lectin SubB2M.

N-glycolylneuraminic acid (Neu5Gc)-containing glycans are a prominent form of aberrant glycosylation found in human tumor cells and have been proposed as cancer biomarkers. The B subunit of the subtilase cytotoxin (SubB) produced by Shiga toxigenic Escherichia coli recognises Neu5Gc containing glycans. We have previously engineered this lectin, SubB2M, for greater specificity and enhanced recognition of Neu5Gc-containing glycans. Here we further explore the utility of SubB2M to detect Neu5Gc tumor biomarkers in sera from patients with ovarian cancer. Using surface plasmon resonance (SPR) we show that SubB2M can detect the established ovarian cancer biomarker, CA125, in a highly sensitive and specific fashion in the context of human serum. These studies established conditions for screening serum samples from patients with ovarian cancer for Neu5Gc glycans. We found that serum from patients with all stages of ovarian cancer had significantly elevated mean levels of Neu5Gc glycans compared to normal controls. Serum from patients with late stage disease (stages IIIC, IV) had uniformly elevated levels of Neu5Gc glycans. Detection of Neu5Gc-glycans using SubB2M has the potential to be used as a diagnostic ovarian cancer biomarker, as well as a tool for monitoring treatment and disease progression in late stage disease.

ß-Catenin overexpression causes an increase in inflammatory cytokines and NF-κB activation in cardiomyocytes.

ß-Catenin has been implicated in various developmental and physiological processes. Defective Wnt signaling can result in different cardiac and vascular abnormalities and is activated under pathological conditions such as inflammation and obesity. In this study, roles of ß-catenin in inflammation in cardiomyocytes were investigated. 10 samples from hearts of patients with acute infarction and 10 from normal ones were collected in order to access roles of ß-catenin in cardiomyocytes. H9c2 cardiomyoblasts and primary neonatal rat cardiomyocytes were transfected with porcine cytomegalovirus (pCMV)-ß-catenin plasmid in order to overexpress ß-catenin. Protein level of ß-catenin protein was increased in human acute infarction tissues compared to ones from normal patients. The transcription factor had increased nuclear localization in cardiomyocytes of the Wistar rats with cardiac hypertension. Furthermore, expression of fibrosis protein markers increased. Protein expression of ß-catenin was increased in human acute infarction inflammatory heart tissues and in hearts of inflammatory obesity rats. After pCMV-ß-catenin plasmid was transfected in a dose-dependent manner, inflammation protein markers, TNF-α and IL-8, were upregulated in hypertensive neonatal rat cardiomyocytes and H9c2 cardiomyoblasts. In addition, overexpression of ß-catenin induced activation and nuclear localization of NF-κB. Therefore, ß-catenin is a potential molecular target for treatment of inflammation and fibrosis in cardiomyocytes.

Effect of treatment willingness on specialist assessment and treatment uptake for hepatitis C virus infection among people who use drugs: the ETHOS study.

Among people who inject drugs (PWID) with chronic HCV, the association between HCV treatment willingness and intent, and HCV specialist assessment and treatment were evaluated. The Enhancing Treatment for Hepatitis C in Opioid Substitution Settings (ETHOS) is a prospective observational cohort. Recruitment was through six opioid substitution treatment clinics, two community health centres and one Aboriginal community controlled health organisation in Australia. Analyses were performed using logistic regression. Among 415 participants (mean age 41 years, 71% male), 67% were 'definitely willing' to receive HCV treatment and 70% reported plans to initiate therapy 12 months postenrolment. Those definitely willing to receive HCV treatment were more likely to undergo specialist assessment (64% vs 32%, P < 0.001) and initiate therapy (36% vs 9%, P < 0.001), compared to those with lower treatment willingness. Those with early HCV treatment plans were more likely to undergo specialist assessment (65% vs 27%, P < 0.001) and initiate therapy (36% vs 5%, P < 0.001), compared to those without early plans. In adjusted analyses, HCV treatment willingness independently predicted specialist assessment (aOR 3.06, 95% CI 1.90, 4.94) and treatment uptake (aOR 4.33, 95% CI 2.14, 8.76). In adjusted analysis, having early HCV treatment plans independently predicted specialist assessment (aOR 4.38, 95% CI 2.63, 7.29) and treatment uptake (aOR 9.79, 95% CI 3.70, 25.93). HCV treatment willingness was high and predicted specialist assessment and treatment. Strategies for enhanced HCV care should be developed with an initial focus on people willing to receive treatment and to increase treatment willingness among those less willing.

From parent to 'peer facilitator': a qualitative study of a peer-led parenting programme.

BACKGROUND: Peer-led interventions are increasingly common in community health settings. Although peer-led approaches have proven benefits for service users, relatively little is known about the process and outcomes of participation for peer leaders. This study investigated experiences of parents who had participated as 'peer facilitators' in Empowering Parents, Empowering Communities (EPEC), a peer-led programme designed to improve access to evidence-based parenting support in socially disadvantaged communities. METHOD: A qualitative cross-sectional design was used. Semi-structured interviews were conducted with 14 peer facilitators and scrutinized using thematic analysis. RESULTS: Peer facilitators developed their knowledge and skills through personal experience of receiving parenting support, participation in formal training and supervised practice, access to an intervention manual, and peer modelling. Peer facilitators described positive changes in their own families, confidence and social status. Transformative personal gains reinforced peer facilitators' role commitment and contributed to a cohesive 'family' identity among EPEC staff and service users. Peer facilitators' enthusiasm, openness and mutual identification with families were seen as critical to EPEC's effectiveness and sustainability. Peer facilitators also found the training emotionally and intellectually demanding. There were particular difficulties around logistical issues (e.g. finding convenient supervision times), managing psychosocial complexity and child safeguarding. CONCLUSIONS: The successful delivery and sustained implementation of peer-led interventions requires careful attention to the personal qualities and support of peer leaders. Based on the findings of this study, support should include training, access to intervention manuals, regular and responsive supervision, and logistical/administrative assistance. Further research is required to elaborate and extend these findings to other peer-led programmes.

Distinct T-cell responses when BCG vaccination is delayed from birth to 6 weeks of age in Ugandan infants.

BACKGROUND: In Uganda, the tuberculosis vaccine BCG is administered on the first day of life. Infants delivered at home receive BCG vaccine at their first healthcare facility visit at 6 weeks of age. Our aim was to determine the effect of this delay in BCG vaccination on the induced immune response. METHODS: We assessed CD4(+) and CD8(+) T-cell responses with a 12-hour whole-blood intracellular cytokine/cytotoxic marker assay, and with a 6-day proliferation assay. RESULTS: We enrolled 92 infants: 50 had received BCG vaccine at birth and 42 at 6 weeks of age. Birth vaccination was associated with (1) greater induction of CD4(+) and CD8(+) T cells expressing either interferon γ (IFN-γ) alone or IFN-γ together with perforin and (2) induction of proliferating cells that had greater capacity to produce IFN-γ, tumor necrosis factor α (TNF-α), and interleukin 2 together, compared with delayed vaccination. CONCLUSIONS: Distinct patterns of T-cell induction occurred when BCG vaccine was given at birth and at 6 weeks of age. We propose that this diversity might impact protection against tuberculosis. Our results differ from those of studies of delayed BCG vaccination in South Africa and the Gambia, suggesting that geographical and population heterogeneity may affect the BCG vaccine-induced T-cell response.

Carriage of the PNPLA3 rs738409 C >G polymorphism confers an increased risk of non-alcoholic fatty liver disease associated hepatocellular carcinoma.

BACKGROUND & AIMS: Subtle inter-patient genetic variation and environmental factors combine to determine disease progression in non-alcoholic fatty liver disease (NAFLD). Carriage of the PNPLA3 rs738409 c.444C >G minor allele (encoding the I148M variant) has been robustly associated with advanced NAFLD. Although most hepatocellular carcinoma (HCC) is related to chronic viral hepatitis or alcoholic liver disease, the incidence of NAFLD-related HCC is increasing. We examined whether rs738409 C >G was associated with HCC-risk in patients with NAFLD. METHODS: PNPLA3 rs738409 genotype was determined by allelic discrimination in 100 European Caucasians with NAFLD-related HCC and 275 controls with histologically characterised NAFLD. RESULTS: Genotype frequencies were significantly different between NAFLD-HCC cases (CC=28, CG=43, GG=29) and NAFLD-controls (CC=125, CG=117, GG=33) (p=0.0001). In multivariate analysis adjusted for age, gender, diabetes, BMI, and presence of cirrhosis, carriage of each copy of the rs738409 minor (G) allele conferred an additive risk for HCC (adjusted OR 2.26 [95% CI 1.23-4.14], p=0.0082), with GG homozygotes exhibiting a 5-fold [1.47-17.29], p=0.01 increased risk over CC. When compared to the UK general population (1958 British Birth Cohort, n=1476), the risk-effect was more pronounced (GC vs. CC: unadjusted OR 2.52 [1.55-4.10], p=0.0002; GG vs. CC: OR 12.19 [6.89-21.58], p<0.0001). CONCLUSIONS: Carriage of the PNPLA3 rs738409 C >G polymorphism is not only associated with greater risk of progressive steatohepatitis and fibrosis but also of HCC. If validated, these findings suggest that PNPLA3 genotyping has the potential to contribute to multi-factorial patient-risk stratification, identifying those to whom HCC surveillance may be targeted.

A naturalistic, randomized, controlled trial combining cognitive remediation with cognitive-behavioural therapy after first-episode non-affective psychosis.

BACKGROUND: Cognitive remediation (CR) preceding cognitive-behavioural therapy for psychosis (CBTp) was trialled within routine clinical services, with the hypothesis that following first-episode non-affective psychosis CR would enhance CBTp efficacy by improving neuropsychological performance. METHOD: A total of 61 patients with DSM-IV non-affective psychoses waiting for routine CBTp were randomized to computerized CR over 12 weeks, supported by a trained support worker, or time-matched social contact (SC). Primary outcome was the blind-rated Psychotic Symptoms Rating Scale (PSYRATS). Secondary outcomes included measures of CBTp progress, cognition, symptoms, insight and self-esteem: all at baseline, after CR (12 weeks) and after CBTp (42 weeks). PSYRATS and global neuropsychological efficacy were tested using mixed-effects models with a group × time interaction term. Measures of CBTp progress and some neuropsychological measures were modelled by regression. RESULTS: There was no significant difference between the CR and SC groups in PSYRATS (group × time coefficient 0.3, 95% confidence interval -0.4 to 1.1, p = 0.39). However, after CR CBTp was shorter [median 7 sessions, interquartile range (IQR) 2-12 after CR; median 13, IQR 4-18 after SC; model p = 0.011] and linked to better insight (p = 0.02). Global cognition did not improve significantly more after CR (p = 0.20) but executive function did (Wisconsin Card Sort, p = 0.012). CONCLUSIONS: CBTp courses preceded by CR were far shorter but achieved the same outcome as CBTp preceded by an active control, consistent with neuropsychological improvement enhancing CBTp. CR was delivered by staff with minimal training, offering the potential to reduce the costs of CBTp considerably.

Twenty-year trends in benzodiazepine dispensing in the Australian population.

AIM: Considerable concern has been expressed about overprescribing of benzodiazepines and related harms. Past analyses have relied on World Health Organization-defined daily doses (DDD) which are sometimes out of keeping with clinical usage. This study examines 20-year (1992-2011) trends of benzodiazepine dispensing in Australia using both DDD and Ashton equivalent dose. METHODS: Data from the Drug Utilisation Sub-Committee and the Pharmaceutical Benefits Scheme (PBS) website were analysed. Trends in number of prescriptions, DDD/1000 people/day and DDD/prescription were examined over time, and between states/territories. RESULTS: In the 20-year period, 174 080 904 scripts were recorded, with temazepam the most dispensed benzodiazepine (35% of scripts), followed by diazepam (23%). Overall recorded utilisation fell from 27.7 DDD/1000 people/day in 1992 to 20.8 in 2011 (24.9% decrease). There were striking changes in use of individual benzodiazepines over time, with reductions in oxazepam and flunitrazepam and dramatic increases in alprazolam. Since 1998, there has been a steady increase, albeit modest, in per script DDD. The DDD/1000 people/day for items dispensed through PBS/Repatriaton-PBS was highest in Tasmania and lowest in Northern Territory. CONCLUSION: Despite a modest overall decline in the amount of benzodiazepine dispensed, the level of use is still likely to reflect relative over-prescribing given the paucity of accepted indications for long-term use. Since 1998, there was a polynomial increase in quantity dispensed per script. The WHO-defined DDD for clonazepam seems inappropriate and could impede monitoring of its abuse. Other problems include lack of national data for medications not subsidised on PBS/Repatriation PBS. A broad policy approach is required, not one which targets only one particular benzodiazepine.

The effects of different orthodontic appliances upon microbial communities.

OBJECTIVES: Orthodontic appliances can promote accumulation of dental plaque, with associated enamel decalcification or gingival inflammation. The aim of this study was to examine longer-term microbiological changes during orthodontic treatment with fixed appliances. MATERIALS AND METHODS: Twenty-four orthodontic patients aged 11-14 years undergoing fixed appliance therapy were recruited into the study. Each was randomized for cross-mouth assignment of molar bands and bonded molar tubes to contralateral quadrants of the mouth. All patients received self-ligating brackets, but again using randomization, one upper lateral incisor bracket (left or right) also received an elastomeric ligature. Plaque samples from the molars and upper lateral incisors were obtained at intervals during treatment and up to 1 year after appliance removal. Denaturing gradient gel electrophoresis and 16S rDNA microarray were used to compare plaque microbial fingerprints. RESULTS: Plaque populations changed within 3 months of commencing treatment at all sites. The greatest differences in plaque composition were seen with self-ligating brackets with an elastomeric ligature. Post-treatment plaque associated with both types of molar attachment contained increased levels of periodontal pathogens Porphyromonas gingivalis, Tannerella forsythia, and Eubacterium nodatum, while Campylobacter rectus, Parvimonas micra, and Actinomyces odontolyticus were also elevated with bonds. CONCLUSIONS: The results suggest that orthodontic treatment may cause sustained changes in plaque microbiotas and that molar bond-associated plaque may have raised disease potential.

General health of opioid substitution therapy clients.

Five common medical conditions among opioid substitution therapy (OST) clients were assessed during a health promotion event held at a tertiary hospital-based OST clinic in Sydney, Australia. Data were collected anthropometrically (body mass index and waist circumference), using spirometry, electrocardiogram, Pap test histories, Fibroscan and medical record review. Assessments were undertaken by specialised hospital staff. Abnormal results were found for 17% of those who underwent an electrocardiogram, 60% were anti-hepatitis C virus positive (40% were viraemic), fibrosis was detected in one-third (7% severe fibrosis and 18% cirrhosis), chronic obstructive pulmonary disease was detected among 30% of participants with 7% at Global Initiative for Chronic Obstructive Lung Disease stage II and 2% at stage III. Forty-seven percent of the female respondents reported that they had not had a Pap test in the previous 2 years. Findings indicate that OST clients suffer several health problems that OST clinics are well placed to identify and provide support for referrals.

Acute angioedema in Cape Town emergency centres and a suggested algorithm to simplify and improve management.

BACKGROUND: Angioedema is the most common acute allergic presentation to emergency centres (EC), with hospitalisation rates increasing in high-income countries. Angioedema can complicate with life-threatening laryngeal obstruction. There are no local data; therefore, we aimed to characterise acute angioedema cases presenting to ECs and develop a simple management algorithm. OBJECTIVE: To characterise the clinical presentation, management and outcomes of acute angioedema cases presenting to ECs. Based on these findings, we developed a management algorithm for acute angioedema to improve the care of acute angioedema in South Africa (SA). METHODS: We conducted a retrospective folder review of all patients admitted to Groote Schuur Hospital (tertiary) and Mitchells Plain District Hospital (secondary) ECs from 1  June 2018 to 31  June 2020. Using ICD-10 coding, folders of adults ≥18 years with possible angioedema presenting to the ECs were screened. An allergist extracted demographics, medical history, management and outcome data for each angioedema event. RESULTS: A total of 142 acute angioedema episodes were included, with a median (interquartile range) age of 42 (28 - 58) years, and 62% of patients were female. The majority (124/142, 87%) of acute angioedema EC presentations involved swelling above the shoulders, with airway involvement in 20 (14%) patients, with two patients requiring intubation. Nineteen (13%) patients required admission, with five (26%) admitted to high care/intensive care. Drug-induced angioedema was the most common cause, with 64/142 (45%) linked to a known offending drug, 42/64 (65.6%) being angiotensin-converting enzyme inhibitor (ACE-I). Critical information to guide angioedema management, including past personal/family allergy history, and duration of angioedema prior to EC visit, was not recorded in 64.7% and 37.8% of EC records, respectively. Unnecessary treatment with corticosteroids or antihistamines occurred in 19/53 (36%) and 16/53 (30%) cases with bradykinin-mediated angioedema ACE-I angioedema and hereditary angioedema). Overall, only 36/142 (25%) of angioedema patients were connected to allergy care. CONCLUSION: Angioedema is the most common allergy presentation to two ECs in Cape Town, SA. Bradykinin-mediated angioedema secondary to ACE-I therapy is the single most common offender, and was not appropriately managed in more than a third of cases. Based on these findings, we have developed a management algorithm that easily stratifies patients into bradykinin or mast cell-mediated angioedema with a step-by-step management approach that is applicable to the SA context. Ongoing awareness and education on allergy emergencies are required to ensure accurate diagnosis of less common causes of angioedema (particularly bradykinin-mediated angioedema) and linkage to allergy specialist care.

Self-reported beta-lactam allergy in government and private hospitals in Cape Town, South Africa.

BACKGROUND: Up to a quarter of inpatients in high-income countries (HICs) self-report beta-lactam allergy (BLA), which if incorrect,increases the use of alternative antibiotics, worsening individual health outcomes and driving bacterial resistance. In HICs, up to 95% ofself-reported BLAs are incorrect. The epidemiology of BLA in low- and middle-income African countries is unknown. OBJECTIVES: To describe the epidemiology and de-labelling outcomes of self-reported BLA in hospitalised South African (SA) patients. METHODS: Point-prevalence surveys were conducted at seven hospitals (adult, paediatric, government and privately funded, district andtertiary level) in Cape Town, SA, between April 2019 and June 2021. Ward prescription records and in-person interviews were conductedto identify and risk-stratify BLA patients using the validated PEN-FAST tool. De-labelling was attempted at the tertiary allergy clinic atGroote Schuur Hospital. RESULTS: A total of 1 486 hospital inpatients were surveyed (1 166 adults and 320 children). Only 48 patients (3.2%) self-reported a BLA,with a higher rate in private than in government-funded hospitals (6.3% v. 2.8%; p=0.014). Using the PEN-FAST tool, only 10.4% (n=5/48)of self-reported BLA patients were classified as high risk for true penicillin hypersensitivity. Antibiotics were prescribed to 70.8% (n=34/48)of self-reported BLA patients, with 64.7% (n=22/34) receiving a beta-lactam. Despite three attempts to contact patients for de-labelling atthe allergy clinic, only 3/36 underwent in vivo testing, with no positive results, and 1 patient proceeded to a negative oral challenge. CONCLUSION: Unlike HICs, self-reported BLA is low among inpatients in SA. The majority of those who self-reported BLA were low risk fortype 1 hypersensitivity, but outpatient de-labelling efforts were largely unsuccessful.

A lipid to treat non-alcoholic fatty liver disease - the dawn of 'lipo-rehabilitation'?

Nuclear hormone receptors regulate diverse metabolic pathways and the orphan nuclear receptor LRH-1 (also known as NR5A2) regulates bile acid biosynthesis. Structural studies have identified phospholipids as potential LRH-1 ligands, but their functional relevance is unclear. Here we show that an unusual phosphatidylcholine species with two saturated 12 carbon fatty acid acyl sidechains (dilauroyl phosphatidylcholine (DLPC)) is an LRH-1 agonist ligand in vitro. DLPC treatment induces bile acid biosynthetic enzymes in mouse liver, increases bile acid levels, and lowers hepatictriglycerides and serum glucose. DLPC treatment also decreases hepatic steatosis and improves glucose homeostasis in two mouse models of insulin resistance. Both the antidiabetic and lipotropic effects are lost in liver-specific Lrh-1 knockouts. These findings identify an LRH-1 dependent phosphatidylcholine signalling pathway that regulates bile acid metabolism and glucose homeostasis.