Publications by authors named "David Lawrence"

660 Publications

Novel Beings: Moral Status and Regulation.

Camb Q Healthc Ethics 2021 Jul;30(3):415-419

Newcastle Law School, Newcastle University, Newcastle Upon TyneNE1 7RU, United Kingdom.

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http://dx.doi.org/10.1017/S0963180120000961DOI Listing
July 2021

Regulating the Tyrell Corporation: the Emergence of Novel Beings.

Camb Q Healthc Ethics 2021 Jul;30(3):421-434

Newcastle Law School, Newcastle University, Newcastle Upon TyneNE1 7RU, United Kingdom.

Emerging biotechnologies and advances in computer science promise the arrival of novel beings possessed of some degree of moral status, even potentially sentient or sapient life. Such a manifestation will constitute an epochal change, and perhaps threaten Homo sapiens' status as the only being generally considered worthy of personhood and its contingent protections; as well as being the root of any number of social and legal issues. The law as it stands is not likely to be capable of managing or adapting to this challenge. This paper highlights the likely societal ramifications of novel beings and the gaps in the legislation which is likely to be relied upon to respond to these. In so doing, the authors make a case for the development of new regulatory structures to manage the moral issues surrounding this new technological upheaval.
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http://dx.doi.org/10.1017/S0963180120000973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610962PMC
July 2021

Colorectal cancer Outcomes in people with Severe Mental Illness Cohort (COSMIC): a protocol for an Australian retrospective cohort using linked administrative data.

BMJ Open 2021 06 8;11(6):e044737. Epub 2021 Jun 8.

School of Clinical Medicine, The University of Queensland, Brisbane, Queensland, Australia

Introduction: Colorectal cancer (CRC) mortality is significantly higher in those with severe mental illness (SMI) compared with the general population, despite similar incidence rates, suggesting that barriers to optimal screening and cancer care may contribute to disparities in CRC mortality in those with SMI. This study aims to compare participation in Australia's National Bowel Cancer Screening Programme (NBCSP) in those with SMI and those in the general population. We will also investigate treatment pathways after diagnosis to determine whether treatment variations could explain differences in CRC mortality.

Methods And Analysis: We will undertake a retrospective cohort study of Australians using linked administrative data to assess differences in screening and cancer care between those with and without SMI, aged 50-74 years on or after 1 January 2006. People with SMI will be defined using antipsychotic medication prescription data. The comparison group will be people enrolled in Medicare (Australia's universal healthcare system) who have not been prescribed antipsychotic medication. Data on outcomes (NBCSP participation, follow-up colonoscopy, CRC incidence and CRC-cause and all-cause mortality) and confounders will be obtained from national-based and state-based administrative health datasets. All people in New South Wales, aged 50-74 with a new diagnosis of CRC on or after 1 January 2006, will be ascertained to examine stage at diagnosis and cancer treatment in those with and without SMI. Poisson regression will be used to calculate incidence rates and rate ratios for each outcome.

Ethics And Dissemination: Ethics approval has been obtained from the University of Queensland Human Research Ethics Committee, the Australian Institute of Health and Welfare Ethics Committee and data custodians from every Australian State/Territory. Findings will be disseminated via publications in peer-reviewed journals and presented at appropriate conferences.

Trial Registration Number: ACTRN12620000781943.
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http://dx.doi.org/10.1136/bmjopen-2020-044737DOI Listing
June 2021

Equity in clinical trials for HIV-associated cryptococcal meningitis: A systematic review of global representation and inclusion of patients and researchers.

PLoS Negl Trop Dis 2021 May 27;15(5):e0009376. Epub 2021 May 27.

Botswana Harvard AIDS Institute Partnership, Gaborone, Botswana.

Background: It is essential that clinical trial participants are representative of the population under investigation. Using HIV-associated cryptococcal meningitis (CM) as a case study, we conducted a systematic review of clinical trials to determine how inclusive and representative they were both in terms of the affected population and the involvement of local investigators.

Methods: We searched Medline, EMBASE, Cochrane, Africa-Wide, CINAHL Plus, and Web of Science. Data were extracted for 5 domains: study location and design, screening, participants, researchers, and funders. Data were summarised and compared over 3 time periods: pre-antiretroviral therapy (ART) (pre-2000), early ART (2000 to 2009), and established ART (post-2010) using chi-squared and chi-squared for trend. Comparisons were made with global disease burden estimates and a composite reference derived from observational studies.

Results: Thirty-nine trials published between 1990 and 2019 were included. Earlier studies were predominantly conducted in high-income countries (HICs) and recent studies in low- and middle-income countries (LMICs). Most recent studies occurred in high CM incidence countries, but some highly affected countries have not hosted trials. The sex and ART status of participants matched those of the general CM population. Patients with reduced consciousness and those suffering a CM relapse were underrepresented. Authorship had poor representation of women (29% of all authors), particularly as first and final authors. Compared to trials conducted in HICs, trials conducted in LMICs were more likely to include female authors (32% versus 20% p = 0.014) but less likely to have authors resident in (75% versus 100%, p < 0.001) or nationals (61% versus 93%, p < 0.001) of the trial location.

Conclusions: There has been a marked shift in CM trials over the course of the HIV epidemic. Trials are primarily performed in locations and populations that reflect the burden of disease, but severe and relapse cases are underrepresented. Most CM trials now take place in LMICs, but the research is primarily funded and led by individuals and institutions from HICs.
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http://dx.doi.org/10.1371/journal.pntd.0009376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8158913PMC
May 2021

Ten-Word List Performance in Healthy Athletes and Athletes at 3-to-5 Days Following Concussion.

Clin J Sport Med 2021 May 21. Epub 2021 May 21.

Faculty of Kinesiology & Physical Education, University of Toronto, Toronto, ON, Canada; David L. MacIntosh Sport Medicine Clinic, Faculty of Kinesiology & Physical Education, University of Toronto, Toronto, ON, Canada; and Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, ON, Canada.

Objective: Although the word recall component of the Sport Concussion Assessment Tool (SCAT) was updated from 5-to-10 words, its clinical utility across athletic populations remains unknown. The purpose of this study was to provide normative data on the SCAT-5 10-word test and examine its discriminative ability between healthy university level athletes and those with sport-related concussion (SRC).

Design: Cross-sectional.

Setting: University.

Participants: Three hundred sixty-three (363, M = 220, F = 153) healthy athletes and 49 (M = 30, F = 19) athletes following SRC.

Independent Variable: Healthy athletes measured preseason were compared with athletes following an SRC (median = 4.0 days postinjury).

Main Outcome Measure: Ten-word list performance from the SCAT-5.

Results: There were no significant differences in either immediate (P = 0.228, Cohen's D = 0.18) or delayed (P = 0.908, Cohen's D = 0.02) recall tests between athletes with SRC and healthy athletes; the null findings extended to both the male and female subset comparisons. Among healthy athletes, females outperformed males on both immediate (mean difference = 1.0, P < 0.001) and delayed (mean difference = 0.5, P = 0.006) recall tasks.

Conclusion: Concussion does not seem to impact immediate or delayed recall of the 10-word list in the subacute period following injury. Practitioners should be mindful of sex differences and the time point of administration following injury.
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http://dx.doi.org/10.1097/JSM.0000000000000941DOI Listing
May 2021

Genotypic and Phenotypic Diversity among Human Isolates of Akkermansia muciniphila.

mBio 2021 May 18;12(3). Epub 2021 May 18.

Department of Molecular Genetics and Microbiology, Duke University, Durham, North Carolina, USA

The mucophilic anaerobic bacterium is a prominent member of the gastrointestinal (GI) microbiota and the only known species of the phylum in the mammalian gut. A high prevalence of in adult humans is associated with leanness and a lower risk for the development of obesity and diabetes. Four distinct phylogenetic groups have been described, but little is known about their relative abundance in humans or how they impact human metabolic health. In this study, we isolated and characterized 71 new strains from a cohort of children and adolescents undergoing treatment for obesity. Based on genomic and phenotypic analysis of these strains, we found several phylogroup-specific phenotypes that may impact the colonization of the GI tract or modulate host functions, such as oxygen tolerance, adherence to epithelial cells, iron and sulfur metabolism, and bacterial aggregation. In antibiotic-treated mice, phylogroups AmIV and AmII outcompeted AmI strains. In children and adolescents, AmI strains were most prominent, but we observed high variance in abundance and single phylogroup dominance, with phylogroup switching occurring in a small subset of patients. Overall, these results highlight that the ecological principles determining which phylogroup predominates in humans are complex and that strain genetic and phenotypic diversity may represent an important variable that should be taken into account when making inferences as to this microbe's impact on its host's health. The abundance of in the gastrointestinal (GI) tract is linked to multiple positive health outcomes. There are four known phylogroups, yet the prevalence of these phylogroups and how they vary in their ability to influence human health is largely unknown. In this study, we performed a genomic and phenotypic analysis of 71 strains and identified phylogroup-specific traits such as oxygen tolerance, adherence, and sulfur acquisition that likely influence colonization of the GI tract and differentially impact metabolic and immunological health. In humans, we observed that single phylogroups predominate at a given time but that the phylotype can switch in an individual. This collection of strains provides the foundation for the functional characterization of phylogroup-specific effects on the multitude of host outcomes associated with colonization, including protection from obesity, diabetes, colitis, and neurological diseases, as well as enhanced responses to cancer immunotherapies.
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http://dx.doi.org/10.1128/mBio.00478-21DOI Listing
May 2021

Challenges of Diagnosing and Managing Designer Benzodiazepine Dependence and Withdrawal: A Case Report.

J Addict Med 2021 May 17. Epub 2021 May 17.

Department of Medicine, Division of General Internal Medicine and Geriatrics, Section of Addiction Medicine, Oregon Health & Science University, Portland, OR (LP, DL, XAL); Hooper Detoxification and Stabilization Center, Central City Concern, Portland, OR (DL).

Background: Over the last 10 years, an increasing number of unregulated novel psychoactive substances, including "designer benzodiazepines" (DBZDs), have emerged on the recreational drug market. Despite the rapidly increasing usage of DBZDs, there is a significant lack of information regarding clinical management. Here we present a case illustrating the difficulties of diagnosing and managing DBZD related sedative-hypnotic use disorder.

Case Presentation: Our patient is a 30-year-old man with severe opioid and sedative-hypnotic use disorders. He had a 10-year history of using heroin, clonazolam, and alprazolam. He stopped using heroin when on methadone maintenance therapy but continued using clonazolam and nonprescribed alprazolam. His opioid treatment program discontinued methadone due to benzodiazepine intoxication, and he returned to heroin use. He then presented for residential withdrawal management where he underwent successful buprenorphine induction and benzodiazepine withdrawal management. During a 3-month period of benzodiazepine abstinence, he struggled with ongoing cravings and post-acute withdrawal syndrome, ultimately leading to return to DBZD use.

Discussion: Despite the increasing prevalence of DBZD use, the usage of DBZDs is likely under-recognized because these compounds are generally not included on standard in-office urine drug immunoassay tests. Initial studies suggest that DBZDs have high potencies, shorter half-lives, are more addictive, and can result in more severe withdrawal symptoms compared to known benzodiazepines. However, there remains a lack of information about the pharmacokinetics and pharmacodynamics of DBZDs, making clinical management for DBZD related sedative-hypnotic use disorders challenging to treat.
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http://dx.doi.org/10.1097/ADM.0000000000000869DOI Listing
May 2021

Australian adolescent population norms for the child health utility index 9D-results from the young minds matter survey.

Qual Life Res 2021 May 17. Epub 2021 May 17.

Deakin Health Economics, Faculty of Health, Institute for Health Transformation, School of Health and Social Development, Deakin University, Geelong, Australia.

Objective: Patient-reported outcomes of health-related quality-of-life (HRQoL) are important descriptors of population health. A recent Australian adolescent population survey provided a unique opportunity to derive preference-based HRQoL.

Methods: Data from 2967 adolescents aged 11-17 years were analysed. An interviewer-led parent/carer questionnaire was administered for demographic variables and mental disorders of adolescents during previous 12 months using the Diagnostic Interview Schedule for Children. A self-report survey was administered to derive HRQoL using the child health utility nine-dimensions instrument (CHU-9D). Weighted HRQoL was derived for several demographic groups, mental disorder diagnosis, and youth risk behaviours.

Results: The total population had a mean utility of 0.78 [standard deviation (SD): 0.20]. Males had a significantly higher mean utility (0.81, SD 0.18) than females (0.76, SD: 0.21) (Cohen's d = 0.23, p < 0.001), and utility decreased with age for both males and females (p < 0.001). Family type and some parent/carer variables were associated with significant lower HRQoL scores with small effect size. Youth risk behaviours were associated with reduced HRQoL with moderate effect sizes. Adolescents who self-harmed, had suicidal ideation, or had a mental disorder had significantly lower utilities scores with moderate to large effect sizes compared to those who did not have such conditions.

Conclusions: This study has provided contemporary Australian population norms for HRQoL in adolescents that may be used as cross comparison between studies as well as indicators allowing estimation of population health (e.g. estimation of the burden of disease) and can be used to populate future economic models.
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http://dx.doi.org/10.1007/s11136-021-02864-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126511PMC
May 2021

Efficacy and safety of fevipiprant in patients with uncontrolled asthma: Two replicate, phase 3, randomised, double-blind, placebo-controlled trials (ZEAL-1 and ZEAL-2).

EClinicalMedicine 2021 May 25;35:100847. Epub 2021 Apr 25.

Allergy and Respiratory Research Unit, Fundación CIDEA, Buenos Aires, Argentina.

Background: These studies assessed the efficacy and safety of fevipiprant, an oral antagonist of the prostaglandin D (PGD) receptor (DP), compared with placebo when added to standard-of-care (SoC) asthma therapy in patients with uncontrolled asthma.

Methods: ZEAL-1 (NCT03215758) and ZEAL-2 (NCT03226392) are two replicate, phase 3, multicentre, randomised, double-blind, placebo-controlled, parallel-group studies in which fevipiprant 150 mg once daily (o.d.) or placebo was added to SoC asthma therapy in patients aged ≥12 years with uncontrolled asthma. Primary endpoint: change from baseline in pre-dose forced expiratory volume in 1 s (FEV) after 12 weeks' treatment. Key secondary endpoints: daytime asthma symptom score, short-acting β-agonist (SABA) use and Asthma Quality-of-Life Questionnaire (AQLQ+12) score after 12-weeks treatment.

Findings: 662 patients in ZEAL-1 and 685 patients in ZEAL-2 completed the treatment period. In ZEAL-1, the least squares (LS) mean change from baseline in pre-dose FEV was 112 mL in fevipiprant vs 71 mL in placebo group (difference [∆]:41 mL; 95% CI: -6, 88; adjusted p-value 0·088). In ZEAL-2, the LS mean change in pre-dose FEV was 126 mL and 157 mL in the fevipiprant and placebo groups, respectively (∆:-31 mL; 95% CI: -80, 18; adjusted p-value 0·214). For both studies, there were no statistically significant differences in the key secondary objectives between the treatment groups.

Interpretation: The ZEAL studies did not demonstrate significant improvement in lung function or other clinical outcomes. These results suggest that DP receptor inhibition with fevipiprant is not effective in the studied patient population.
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http://dx.doi.org/10.1016/j.eclinm.2021.100847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099656PMC
May 2021

The Australian Child Maltreatment Study (ACMS): protocol for a national survey of the prevalence of child abuse and neglect, associated mental disorders and physical health problems, and burden of disease.

BMJ Open 2021 05 11;11(5):e047074. Epub 2021 May 11.

Graduate School of Education, University of Western Australia, Perth, Western Australia, Australia.

Introduction: Child maltreatment (physical abuse, sexual abuse, emotional abuse, neglect and exposure to domestic violence) is widely understood to be associated with multiple mental health disorders, physical health problems and health risk behaviours throughout life. However, Australia lacks fundamental evidence about the prevalence and characteristics of child maltreatment, its associations with mental disorders and physical health, and the associated burden of disease. These evidence gaps impede the development of public health strategies to better prevent and respond to child maltreatment. The aims of this research are to generate the first comprehensive population-based national data on the prevalence of child maltreatment in Australia, identify associations with mental disorders and physical health conditions and other adverse consequences, estimate attributable burden of disease and indicate targeted areas for future optimal public health prevention strategies.

Methods And Analysis: The Australian Child Maltreatment Study (ACMS) is a nationwide, cross-sectional study of Australia's population aged 16 years and over. A survey of approximately 10 000 Australians will capture retrospective self-reported data on the experience in childhood of all five types of maltreatment (physical abuse, sexual abuse, emotional abuse, neglect and exposure to domestic violence). A customised, multimodule survey instrument has been designed to obtain information including: the prevalence and characteristics of these experiences; diagnostic screening of common mental health disorders; physical health; health risk behaviours and health service utilisation. The survey will be administered in March-November 2021 to a random sample of the nationwide population, recruited through mobile phone numbers. Participants will be surveyed using computer-assisted telephone interviews, conducted by trained interviewers from the Social Research Centre, an agency with extensive experience in studies of health and adversity. Rigorous protocols protect the safety of both participants and interviewers, and comply with all ethical and legal requirements. Analysis will include descriptive statistics reporting the prevalence of individual and multitype child maltreatment, multiple logistic and linear regression analyses to determine associations with mental disorders and physical health problems. We will calculate the population attributable fractions of these putative outcomes to enable an estimation of the disease burden attributable to child maltreatment.

Ethics And Dissemination: The study has been approved by the Queensland University of Technology Human Research Ethics Committee (#1900000477, 16 August 2019). Results will be published to the scientific community in peer-reviewed journals, scientific meetings and through targeted networks. Findings and recommendations will be shared with government policymakers and community and organisational stakeholders through diverse engagement activities, a dedicated Advisory Board and a systematic knowledge translation strategy. Results will be communicated to the public through an organised media strategy and the ACMS website.
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http://dx.doi.org/10.1136/bmjopen-2020-047074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8118019PMC
May 2021

Unacceptably high: an audit of Kimberley self-harm data 2014-2018.

Australas Psychiatry 2021 May 5:10398562211010790. Epub 2021 May 5.

School of Indigenous Studies, University of Western Australia, The University of Western Australia, Perth, WA, Australia.

Objective: To explore the rates and characteristics of self-harm across the Kimberley region of Western Australia.

Method: Retrospective, cross-sectional audit. We obtained and descriptively analysed routinely collected self-harm data from the Kimberley District of the Western Australia Police Force (2014-2018) and the Emergency Department Data Collection (June 2017-December 2018). Variables included age, sex, Indigenous status, time of incident, and alcohol and drug use.

Results: The rate of emergency department attendance for self-harm was three times higher in the Kimberley than the rest of Western Australia. Both emergency department and police data showed a disproportionately high percentage of incidents involving Aboriginal people, with highest rates in the 15-19 and 20-24 year age groups. Almost 80% of self-harm events recorded by police involving individuals aged 25-50 years involved alcohol. Many self-harm incidents occurred in the evening and at night.

Conclusions: The rates of self-harm across the Kimberley region from 2014-2018 are unacceptably high. Increased funding and alignment of services to meet regional need are required as part of a holistic effort to reduce regional rates of self-harm.
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http://dx.doi.org/10.1177/10398562211010790DOI Listing
May 2021

Concordance between adolescents and parents on the Strengths and Difficulties Questionnaire: Analysis of an Australian nationally representative sample.

Aust N Z J Psychiatry 2021 Apr 30:48674211009610. Epub 2021 Apr 30.

QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.

Objective: Differences between adolescent self-reported and parent-reported emotional and behavioural difficulties may influence psychiatric epidemiological research. This study examined concordance between adolescents and their parents about mental health symptoms using the Strengths and Difficulties Questionnaire.

Methods: The study comprised a randomly selected, nationally representative sample of adolescents aged 11-17 years who participated in the Second Australian Child and Adolescent Survey of Mental Health and Wellbeing ( = 2967). Matched adolescent and parent responses across the five Strengths and Difficulties Questionnaire subscales (emotional problems, hyperactivity, peer problems, conduct problems and prosocial behaviour), as well as total difficulties and total impact scores were examined to estimate concordance. Concordance patterns were analysed by sex, after stratifying the sample by age group (younger adolescents: 11-14 years; older adolescents: 15-17 years).

Results: Concordance was 86.7% for total difficulties, 77.5% for total impact and ranged from 82.4% to 94.3% across the five Strengths and Difficulties Questionnaire subscales. There were no differences in concordance between sexes on the total difficulties score. Older females were more likely to disagree with their parents about emotional problems compared to males of the same age. Younger males were more likely to disagree with their parents compared to same-aged females about peer problems, hyperactivity, conduct problems and prosocial skills, as well as the impact of their problems. Older males were more likely to disagree with their parents about their prosocial skills compared to older females.

Conclusion: Overall, concordance between adolescents and parents on the Strengths and Difficulties Questionnaire was largely driven by the high proportion of respondents who reported having no problems. Discordance on a subscale increased as the prevalence of problems in a sex and age demographic subgroup increased. These findings highlight the need for a multi-informant approach to detect emotional and behavioural difficulties in adolescents, particularly when assessing the impact of symptoms, as this subscale had the lowest concordance.
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http://dx.doi.org/10.1177/00048674211009610DOI Listing
April 2021

Lung Decortication With Argon Plasma Energy for the Treatment of Chronic Pleural Empyema.

Innovations (Phila) 2021 Apr 29:15569845211011163. Epub 2021 Apr 29.

8964 Department of Thoracic Surgery, University College London Hospitals NHS Foundation Trust, London, UK.

Lung decortication for the treatment of chronic pleural empyema remains a technically challenging procedure that is associated with bleeding and air leak. The recent advent of pure argon plasma has provided thoracic surgeons with an electrically neutral energy source for dissection and coagulation of pulmonary tissue with minimal depth of necrosis. In this article, we describe the technique of lung decortication with argon plasma energy (PlasmaJet, Plasma Surgical, Roswell, GA, USA) for the treatment of chronic pleural empyema. With appropriate application, the PlasmaJet can facilitate the removal of fibrous cortex with satisfactory hemostasis and aerostasis. Argon plasma energy can potentially be a useful adjunct in lung decortication. Controlled trials are needed to determine its role in the surgical management of advanced pleural empyema.
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http://dx.doi.org/10.1177/15569845211011163DOI Listing
April 2021

Tobacco smoking and mental disorders in Australian adolescents.

Aust N Z J Psychiatry 2021 Apr 28:48674211009617. Epub 2021 Apr 28.

School of Psychology and Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia.

Objectives: This study aimed to (1) examine the strength of the association between mental disorders/mental health problems, risk behaviours and tobacco smoking among Australian adolescents, (2) compare rates of tobacco smoking among Australian adolescents with major depressive disorder, attention-deficit/hyperactivity disorder and/or conduct disorder in 2013/14 vs 1998, and (3) identify the extent to which an association between tobacco smoking and mental health problems among adolescents can be attributed to non-mental health risk factors.

Methods: The study utilised data from the first (1998) and second (2013/14) child and adolescent components of the National Surveys of Mental Health and Wellbeing. Both surveys identified nationally representative samples of Australian young people aged 4-17 years, living in private dwellings. Information was collected from parents and 13- to 17-year-olds about mental disorders, mental health problems, risk behaviours and tobacco smoking.

Results: In the 2013/14 survey, the rate of current tobacco smoking among those with a mental disorder was 20% compared to 5% in those without a mental disorder. Rates were highest for young people with conduct disorder (50%), major depressive disorder (24%) and anxiety disorders (19%). In 2013/14, 38% of current tobacco smokers had a mental disorder and 32% reported self-harm and/or suicidal ideation vs 10% and 5%, respectively, among adolescents who had never smoked. Females with mental disorders or reporting self-harm or suicidal ideation had higher rates of current smoking than males. Other significant factors associated with current smoking included school-related problems, binge eating and having had more than one sexual partner.

Conclusion: While smoking rates in 13- to 17-year-olds with mental disorders had declined since 1998, the strength of the association between mental disorders and smoking had increased, especially among females. Our findings highlight the need to address the tobacco smoking among adolescents with mental disorders, particularly females.
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http://dx.doi.org/10.1177/00048674211009617DOI Listing
April 2021

Estimation of risk of neuropsychiatric adverse events from varenicline, bupropion and nicotine patch versus placebo: secondary analysis of results from the EAGLES trial using Bayes factors.

Addiction 2021 Apr 22. Epub 2021 Apr 22.

Research Department of Behavioural Science and Health, University College London, London, UK.

Background And Aims: Analysed using classical frequentist hypothesis testing with alpha set to 0.05, the Evaluating Adverse Events in a Global Smoking Cessation Study (EAGLES) did not find enough evidence to reject the hypothesis of no difference in neuropsychiatric adverse events (NPSAEs) attributable to varenicline, bupropion, or nicotine patch compared with placebo. This might be because the null hypothesis was true or because the data were insensitive. The present study aimed to test the hypothesis more directly using Bayes factors.

Design: EAGLES was a randomised, double-blind, triple-dummy, controlled trial.

Setting: Global (16 countries across five continents), between November 2011 and January 2015.

Participants: Participants were smokers with (n = 4116) and without (n = 4028) psychiatric disorders.

Interventions: Varenicline (1 mg twice daily), bupropion (150 mg twice daily), nicotine patch (21 mg once daily with taper) and matched placebos.

Measurements: The outcomes included: (i) a composite measure of moderate/severe NPSAEs; and (ii) a composite measure of severe NPSAEs. The relative evidence for there being no difference in NPSAEs versus data insensitivity for the medications was calculated in the full and sub-samples using Bayes factors and corresponding robustness regions.

Findings: For all but two comparisons, Bayes factors were <1/3, indicating moderate to strong evidence for no difference in risk of NPSAEs between active medications and placebo (Bayes factor = 0.02-0.23). In the psychiatric cohort versus placebo, the data were suggestive, but not conclusive of no increase in NPSAEs with varenicline (Bayes factor = 0.52) and bupropion (Bayes factor = 0.71). Here, the robustness regions ruled out a ≥7% and ≥8% risk increase with varenicline and bupropion, respectively.

Conclusions: Secondary analysis of the Evaluating Adverse Events in a Global Smoking Cessation Study trial using Bayes factors provides moderate to strong evidence that use of varenicline, bupropion or nicotine patches for smoking cessation does not increase the risk of neuropsychiatric adverse events relative to use of placebo in smokers without a history of psychiatric disorder. For smokers with a history of psychiatric disorder the evidence also points to no increased risk but with less confidence.
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http://dx.doi.org/10.1111/add.15440DOI Listing
April 2021

The cost of Medicare-funded medical and pharmaceutical services for mental disorders in children and adolescents in Australia.

PLoS One 2021 9;16(4):e0249902. Epub 2021 Apr 9.

School of Health and Social Development, Deakin University, Geelong, Australia.

Objective: To examine the health care costs associated with mental disorders and subthreshold mental disorders within a nationally representative sample of children and adolescents in Australia.

Method: Data were derived from the Young Minds Matter Survey (N = 6,310). Mental disorders were classified using the Diagnostic Interview Schedule for Children Version IV. Participant data were linked to administrative data on health care costs. Adjusted generalized linear regression models and two-part models were used to estimate mean differences in costs between those with a mental disorder or subthreshold disorder and those without.

Results: Costs associated with health care attendances and medications were higher for children and adolescents with mental disorders and subthreshold mental disorders compared to those without a mental disorder. The additional population health care costs due to mental disorders amounted to AUD$234 million annually in children and adolescents, of which approximately 16% was attributed to out-of-pocket costs. Findings showed that those with subthreshold mental disorders or comorbid mental disorders have substantial additional costs of Medicare-funded medical and pharmaceutical services.

Conclusion And Implication: Mental disorders in children and adolescents are associated with significant health care costs. Further research is needed to ensure that this population is receiving effective and efficient care.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0249902PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034743PMC
April 2021

Conception by fertility treatment and offspring deoxyribonucleic acid methylation.

Fertil Steril 2021 Apr 3. Epub 2021 Apr 3.

Department of Epidemiology and Biostatistics, University at Albany School of Public Health, Albany, New York.

Objective: To investigate whether deoxyribonucleic acid (DNA) methylation at birth and in childhood differ by conception using assisted reproductive technologies (ART) or ovulation induction compared with those in children conceived without fertility treatment.

Design: Upstate KIDS is a matched exposure cohort which oversampled on newborns conceived by treatment.

Setting: New York State (excluding New York City).

Patient(s): This analysis included 855 newborns and 152 children at approximately 9 years of age.

Intervention(s): None.

Main Outcome Measure(s): DNA methylation levels were measured using the Illumina EPIC platform. Single CpG and regional analyses at imprinting genes were conducted.

Result(s): Compared to no fertility treatment, ART was associated with lower mean DNA methylation levels at birth in 11 CpGs (located in/near SYCE1, SPRN, KIAA2013, MYO1D, GET1/WRB-SH4BGR, IGF1R, SORD, NECAB3/ACTL10, and GET1) and higher mean methylation level in 1 CpG (KLK4; all false discovery rate P<.05). The strongest association (cg17676129) was located at SYCE1, which codes for a synaptonemal complex that plays a role in meiosis and therefore infertility. This CpG remained associated with newborn hypomethylation when the analysis was limited to those conceived with ICSI, but this may be because of underlying male infertility. In addition, nine regions in maternally imprinted genes (IGF1R, PPIEL, SVOPL GNAS, L3MBTL, BLCAP, HYMAI/PLAGL1, SNU13, and MEST) were observed to have decreased mean DNA methylation levels among newborns conceived by ART. In childhood, hypomethylation of the maternally imprinted gene, GNAS, persisted. No CpGs or regions were associated with ovulation induction.

Conclusion(s): ART but not ovulation induction was associated with hypomethylation at birth, but only one difference at an imprinting region appeared to persist in childhood.
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http://dx.doi.org/10.1016/j.fertnstert.2021.03.011DOI Listing
April 2021

The Lived Experience Of Participants in an African RandomiseD trial (LEOPARD): protocol for an in-depth qualitative study within a multisite randomised controlled trial for HIV-associated cryptococcal meningitis.

BMJ Open 2021 04 5;11(4):e039191. Epub 2021 Apr 5.

Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, UK.

Introduction: Individuals recruited into clinical trials for life-threatening illnesses are particularly vulnerable. This is especially true in low-income settings. The decision to enrol may be influenced by existing inequalities, poor healthcare infrastructure and fear of death. Where patients are confused or unconscious the responsibility for this decision falls to relatives. This qualitative study is nested in the ongoing AMBIsome Therapy Induction OptimisatioN (AMBITION) Trial. AMBITION is recruiting participants from five countries in sub-Saharan Africa and is trialling a novel treatment approach for HIV-associated cryptococcal meningitis, an infection known to affect brain function. We aim to learn from the experiences of participants, relatives and researchers involved in AMBITION.

Methods And Analysis: We will collect data through in-depth interviews with trial participants and the next of kin of participants who were confused at enrolment and therefore provided surrogate consent. Data will be collected in Gaborone, Botswana; Kampala, Uganda and Harare, Zimbabwe. Interviews will follow a narrative approach including participatory drawing of participation timelines. This will be supplemented by direct observation of the research process at each of the three recruiting hospitals. Interviews will also take place with researchers from the African and European institutions that form the partnership through which the trial is administered. Interviews will be transcribed verbatim, translated (if necessary) and organised thematically for narrative analysis.

Ethics And Dissemination: This study has been approved by the Health Research Development Committee, Gaborone (Reference: HPDME:13/18/1); Makerere School of Health Sciences Institutional Review Board, Kampala (Reference: 2019-061); University of Zimbabwe Joint Research Ethics Committee, Harare (Reference: 219/19), and the London School of Hygiene and Tropical Medicine (Reference: 17957). Study findings will be shared with research participants from the sites, key stakeholders at each research institution and ministries of health to help inform the development and implementation of future trials. The findings of this study will be published in journals and presented at academic meetings.

Trial Registration: Registered at www.clinicaltrials.gov:NCT04296292.
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http://dx.doi.org/10.1136/bmjopen-2020-039191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8030472PMC
April 2021

Sexual orientation and prevalence of mental health difficulties among emergency services employees.

J Affect Disord 2021 05 26;287:240-246. Epub 2021 Feb 26.

Graduate School of Education, The University of Western Australia, Australia.

Background: LGBQ+ people (Lesbian, Gay, Bisexual, Queer) are at-risk of discrimination and developing mental health issues within general populations. Limited research has assessed their mental health in emergency services occupations, a population which are known to experience poorer mental health. The current study explores the extent to which sexual orientation is associated with higher rates of mental health issues among emergency personnel.

Methods: A stratified random sample of employees from twenty-nine police (N = 8,088), ambulance (N = 3,473), and fire and rescue (N = 2,975) agencies from around Australia participated in a cross-sectional mental health survey (N = 14,536, male = 64.2%, 42.7% over 45 years of age, heterosexual = 92.7%).

Results: Employees with a bisexual/pansexual orientation or those who were not sure about their sexual orientation were significantly more likely to report suicidal thoughts, suicide plans, psychological distress, and illicit drug use when compared with heterosexual employees. LGBQ+ employees reported significantly higher rates of lifetime suicide plans and attempts. Specifically, LGBQ+ fire and rescue personnel were roughly six times more likely to report lifetime suicide attempts, and approximately five times more likely to use illicit drugs weekly than their heterosexual colleagues in the fire and rescue sector. Female LGBQ+ personnel were significantly less likely to consume illicit drugs weekly and monthly than male LGBQ+ personnel.

Conclusions: Emergency services personnel are already at-risk of developing pervasive mental health difficulties. It is important that organisations foster positive working environments, particularly for LGBQ+ people who may be more marginalized within organisations.
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http://dx.doi.org/10.1016/j.jad.2021.02.032DOI Listing
May 2021

Psychiatric co-morbidity and multi-morbidity in the EAGLES trial: Descriptive correlates and associations with neuropsychiatric adverse events, treatment adherence, and smoking cessation.

Nicotine Tob Res 2021 Mar 31. Epub 2021 Mar 31.

Department of Psychiatry, University of California - San Diego, 9500 Gilman Drive, La Jolla, CA.

Introduction: Psychiatric and substance use disorders represent barriers to smoking cessation. We sought to identify correlates of psychiatric co-morbidity (2 diagnoses) and multi-morbidity (3+ diagnoses) among smokers attempting to quit and to evaluate whether these conditions predicted neuropsychiatric adverse events (NPSAEs), treatment adherence, or cessation efficacy (CE).

Method: Data were collected from November 2011 to January 2015 across sixteen countries and reflect the psychiatric cohort of the EAGLES trial. Participants were randomly assigned to receive varenicline, bupropion, nicotine replacement therapy, or placebo for 12 weeks and were followed for an additional 12 weeks post-treatment. NPSAE outcomes reflected sixteen moderate-to-severe neuropsychiatric symptom categories, and CE outcomes included continuous abstinence at weeks 9-12 and weeks 9-24.

Results: Of the 4103 participants included, 36.2% were diagnosed with multiple psychiatric conditions (20.9% co-morbidity, 15.3% multi-morbidity). Psychiatric co- and multi-morbidity were associated with several baseline factors, including male gender, non-white race/ethnicity, more previous quit attempts, and more severe mental health symptoms. The incidence of moderate-to-severe NPSAEs was significantly higher (p<0.01) in participants with multi-morbidity (11.9%) than those with co-morbidity (5.1%) or primary diagnosis only (4.6%). There were no significant (ps>0.05) main effects or interactions with treatment condition for diagnostic grouping on treatment adherence or CE outcomes.

Conclusions: While having multiple psychiatric diagnoses increased risk of developing moderate-to-severe NPSAEs during a quit attempt, neither co- nor multi-morbidity were associated with treatment adherence or odds of quitting. These findings reassure providers to advise smokers with multiple stable psychiatric conditions to consider using FDA-approved medications when trying to quit.
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http://dx.doi.org/10.1093/ntr/ntab056DOI Listing
March 2021

Exposure, health effects, sensing, and remediation of the emerging PFAS contaminants - Scientific challenges and potential research directions.

Sci Total Environ 2021 Aug 17;780:146399. Epub 2021 Mar 17.

Department of Chemical and Biomolecular Engineering, University of Connecticut, Storrs, CT 06269, USA.

Per- and polyfluoroalkyl substances (PFAS) make up a large group of persistent anthropogenic chemicals which are difficult to degrade and/or destroy. PFAS are an emerging class of contaminants, but little is known about the long-term health effects related to exposure. In addition, technologies to identify levels of contamination in the environment and to remediate contaminated sites are currently inadequate. In this opinion-type discussion paper, a team of researchers from the University of Connecticut and the University at Albany discuss the scientific challenges in their specific but intertwined PFAS research areas, including rapid and low-cost detection, energy-saving remediation, the role of T helper cells in immunotoxicity, and the biochemical and molecular effects of PFAS among community residents with measurable PFAS concentrations. Potential research directions that may be employed to address those challenges and improve the understanding of sensing, remediation, exposure to, and health effects of PFAS are then presented. We hope our account of emerging problems related to PFAS contamination will encourage a broad range of scientific experts to bring these research initiatives addressing PFAS into play on a national scale.
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http://dx.doi.org/10.1016/j.scitotenv.2021.146399DOI Listing
August 2021

Efficacy and Safety of Ertugliflozin in Patients with Type 2 Diabetes Inadequately Controlled by Metformin and Sulfonylurea: A Sub-Study of VERTIS CV.

Diabetes Ther 2021 May 15;12(5):1279-1297. Epub 2021 Mar 15.

Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy.

Introduction: VERTIS CV is the cardiovascular outcome trial for the sodium-glucose cotransporter 2 (SGLT2) inhibitor ertugliflozin. A sub-study was conducted to assess the efficacy and safety of ertugliflozin in patients with type 2 diabetes mellitus (T2DM) inadequately glycemic-controlled on metformin and a sulfonylurea (SU).

Methods: Patients with T2DM, established atherosclerotic cardiovascular disease (ASCVD), and an HbA1c of 7.0-10.5% on stable metformin (≥ 1500 mg/day) and moderate to high SU doses were randomly assigned to once-daily ertugliflozin (5 or 15 mg) or placebo. The primary sub-study objectives were to assess the effect of ertugliflozin on HbA1c compared with placebo and to evaluate safety following 18 weeks of treatment. Key secondary endpoints included changes in fasting plasma glucose (FPG), body weight (BW), blood pressure (BP), and the proportion of patients achieving HbA1c < 7%.

Results: Of the 8246 patients enrolled in VERTIS CV, 330 were eligible for this sub-study (ertugliflozin 5 mg, n = 100; ertugliflozin 15 mg, n = 113; placebo, n = 117). This subgroup had a mean (SD) age of 63.2 (8.4) years and T2DM duration of 11.4 (7.4) years. At week 18, ertugliflozin 5 mg and 15 mg were each associated with significantly greater least squares (LS) mean reductions from baseline in HbA1c relative to placebo (placebo-adjusted LS mean [95% CI] - 0.66% [- 0.89, - 0.43] and - 0.75% [- 0.98, - 0.53], respectively, p < 0.001 for each dose vs placebo). Ertugliflozin significantly reduced FPG and BW compared with placebo (p < 0.001), but not systolic BP. Adverse events were reported in 48.0%, 54.9%, and 47.0% of patients in the ertugliflozin 5 mg and 15 mg, and placebo groups. The incidences of symptomatic hypoglycemia were 11.0% (5 mg), 12.4% (15 mg), and 7.7% (placebo), and of severe hypoglycemia 2.0% (5 mg), 1.8% (15 mg), and 0.9% (placebo).

Conclusions: In patients with T2DM and ASCVD, ertugliflozin added to metformin and SU improved glycemic control, reduced BW, and was generally well tolerated.

Trial Registration: VERTIS CV ClinicalTrials.gov identifier, NCT01986881.
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http://dx.doi.org/10.1007/s13300-021-01033-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099972PMC
May 2021

Surgical excision of a rare cardiac tumor: Cardiac hibernoma.

J Card Surg 2021 Jun 8;36(6):2140-2142. Epub 2021 Mar 8.

Department of Cardiothoracic Surgery, St. Bartholomew's Hospital, London, UK.

Background And Aim: Cardiac hibernoma is a very rare benign cardiac tumour. We report a case of its surgical management.

Methods: A case study with retrospective review of prospective patient data.

Results: A 60 year old male who presented with acute shortness of breath was found to have SVC compression on cardiac imaging. At operation the tumour was in the right atrial wall invading the intra-atrial groove and extending over superior vena cava (SVC), causing significant symptoms of SVC obstruction and tamponade. This was resected and the right atrium was reconstructed with Bovine pericardial patch. He was discharged home well.

Conclusions: Cardiac hibernoma is a rare tumour which can be successfully treated by surgical excision.
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http://dx.doi.org/10.1111/jocs.15460DOI Listing
June 2021

An alternative and safe technique to tie down a biological aortic valve in small aortic roots.

Ann Thorac Surg 2021 Mar 2. Epub 2021 Mar 2.

Department of Cardiac Surgery, St Bartholomew's Hospital, London. Electronic address:

Biological aortic valves are constructed with three stents corresponding to the commissures, which will sit in the aortic root. When implanted using interrupted sutures, these stents may make the valve difficult to tie down safely in patients with small, calcified aortic root. We present an easily reproducible technique to make this valve tie down safer.
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http://dx.doi.org/10.1016/j.athoracsur.2020.12.091DOI Listing
March 2021

Mental health and wellbeing of Australian police and emergency services employees.

Arch Environ Occup Health 2021 Mar 3:1-11. Epub 2021 Mar 3.

Graduate School of Education, The University of Western Australia, Perth, Western Australia, Australia.

, the Australian National Police and Emergency Services Mental Health and Wellbeing Study, surveyed 14,868 Australian ambulance, fire and rescue, police, and state emergency service employees. Emergency services personnel had lower rates of mental wellbeing and higher rates of psychological distress and probable PTSD than the general adult population. Overall 30% had low wellbeing, 21% had high and 9% had very high psychological distress, and 10% had probable PTSD. An estimated 5% had suicidal ideation and 2% had a suicide plan in the past 12 months, while 16% binge drink at least weekly. Only one in five of those with very high psychological distress or probable PTSD felt they received adequate support for their condition. These findings highlight the risk of mental health conditions associated with work in the emergency services sector.
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http://dx.doi.org/10.1080/19338244.2021.1893631DOI Listing
March 2021

The Pediatric Obesity Microbiome and Metabolism Study (POMMS): Methods, Baseline Data, and Early Insights.

Obesity (Silver Spring) 2021 03;29(3):569-578

Department of Pediatrics, Duke University, Durham, North Carolina, USA.

Objective: The purpose of this study was to establish a biorepository of clinical, metabolomic, and microbiome samples from adolescents with obesity as they undergo lifestyle modification.

Methods: A total of 223 adolescents aged 10 to 18 years with BMI ≥95th percentile were enrolled, along with 71 healthy weight participants. Clinical data, fasting serum, and fecal samples were collected at repeated intervals over 6 months. Herein, the study design, data collection methods, and interim analysis-including targeted serum metabolite measurements and fecal 16S ribosomal RNA gene amplicon sequencing among adolescents with obesity (n = 27) and healthy weight controls (n = 27)-are presented.

Results: Adolescents with obesity have higher serum alanine aminotransferase, C-reactive protein, and glycated hemoglobin, and they have lower high-density lipoprotein cholesterol when compared with healthy weight controls. Metabolomics revealed differences in branched-chain amino acid-related metabolites. Also observed was a differential abundance of specific microbial taxa and lower species diversity among adolescents with obesity when compared with the healthy weight group.

Conclusions: The Pediatric Metabolism and Microbiome Study (POMMS) biorepository is available as a shared resource. Early findings suggest evidence of a metabolic signature of obesity unique to adolescents, along with confirmation of previously reported findings that describe metabolic and microbiome markers of obesity.
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http://dx.doi.org/10.1002/oby.23081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927749PMC
March 2021

Recurrent angina from spontaneous left atrial dissection.

Eur Heart J Cardiovasc Imaging 2021 Feb 17. Epub 2021 Feb 17.

Department of Cardiology, Royal Berkshire Hospital NHS Foundation Trust, London Road, Reading, UK.

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http://dx.doi.org/10.1093/ehjci/jeab024DOI Listing
February 2021

The prevalence of laboratory-confirmed Pneumocystis jirovecii in HIV-infected adults in Africa: A systematic review and meta-analysis.

Med Mycol 2021 Feb 12. Epub 2021 Feb 12.

Department of Clinical Research, Faculty of infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, WC1E 7HT, UK.

Background: The epidemiology of Pneumocystis jirovecii, known to colonize the respiratory tract and cause a life-threatening HIV-associated pneumonia (PCP), is poorly described in Africa. We conducted a systematic review to evaluate P. jirovecii prevalence in African HIV-positive adults with or without respiratory symptoms.

Methods: We searched Medline, Embase, Cochrane library, Africa-Wide, and Web of Science for studies employing PCR and/or microscopy for P. jirovecii detection in respiratory samples from HIV-positive adults in Africa between 1995 and 2020. Prevalence with respiratory symptoms was pooled using random-effect meta-analysis, and stratified by laboratory method, sample tested, study setting, CD4 count, and trimethoprim/sulfamethoxazole prophylaxis. Colonization prevalence in asymptomatic adults and in adults with non-PCP respiratory disease was described, and quantitative PCR (qPCR) thresholds to distinguish colonization from microscopy-confirmed PCP reviewed.

Results: Thirty-two studies were included, with 27 studies (87%) at high risk of selection bias. P. jirovecii was detected in 19% [95% confidence interval (CI): 12-27%] of 3583 symptomatic and in 9% [95% CI: 0-45%] of 140 asymptomatic adults. Among symptomatic adults, prevalence was 22% [95% CI: 12-35%] by PCR and 15% [95% CI: 9-23%] by microscopy. Seven percent of 435 symptomatic adults had PCR-detected Pneumocystis colonization without evidence of PCP [95% CI: 5-10%, four studies]. One study established a qPCR cutoff of 78 copies/5μl of DNA in 305 induced sputum samples to distinguish Pneumocystis colonization from microscopy-confirmed PCP.

Conclusion: Despite widened access to HIV services, P. jirovecii remains common in Africa. Prevalence estimates and qPCR-based definitions of colonization are limited, and overall quality of studies is low.
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http://dx.doi.org/10.1093/mmy/myab002DOI Listing
February 2021

Using a dual antibody point-of-care test with visual and digital reads to diagnose syphilis among people living with HIV in Botswana.

Int J STD AIDS 2021 Apr 11;32(5):453-461. Epub 2021 Feb 11.

292006Botswana Harvard AIDS Institute Partnership, Gaborone, Botswana.

Syphilis data from low- and middle-income countries are lacking due to limited testing. Point-of-care tests (POCTs) have been promoted to expand testing but previously only included treponemal tests, which cannot distinguish active from past infection. We aimed to assess the feasibility of using a combined treponemal and non-treponemal POCT in HIV clinic patients in Gaborone, Botswana, and estimate syphilis prevalence in our clinic sample using this approach. We recruited 390 non-pregnant patients. Participants underwent a combined treponemal and non-treponemal POCT (Dual Path Platform (DPP®) Syphilis Screen and Confirm Assay (Chembio Diagnostic Systems)) on finger-prick blood sample and a questionnaire. Median age 45 years, 30% men, median CD4 count 565 cells/μL, and 91% had an HIV viral load <400 copies/mL. Five participants had active syphilis (1.3%, 95% CI 0.5-3.0%) and 64 had previous syphilis (16.4%, 95% CI 13.0-20.4%) using the DPP POCT. There was a reasonable level of agreement between digital and visual reading of the POCT (kappa statistic of 0.81); however, visual reading missed three active infections (60%). The level of active syphilis was similar to local antenatal data. The DPP POCT led to five participants with active syphilis being diagnosed and starting same-day treatment. The digital reader should be used.
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http://dx.doi.org/10.1177/0956462420975639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008391PMC
April 2021

Health disparities: Intracellular consequences of social determinants of health.

Toxicol Appl Pharmacol 2021 04 5;416:115444. Epub 2021 Feb 5.

University at Albany School of Public Health, Rensselaer, NY, USA; Wadsworth Center, New York State Department of Health, Albany, NY, USA. Electronic address:

Health disparities exist dependent on socioeconomic status, living conditions, race/ethnicity, diet, and exposures to environmental pollutants. Herein, the various exposures contributing to a person's exposome are collectively considered social determinants of health (SDOH), and the SDOH-exposome impacts health more than health care. This review discusses the extent of evidence of the physiologic consequences of these exposures at the intracellular level. We consider how the SDOH-exposome, which captures how individuals live, work and age, induces cell processes that modulate a conceptual "redox rheostat." Like an electrical resistor, the SDOH-exposome, along with genetic predisposition and age, regulate reductive and oxidative (redox) stress circuits and thereby stimulate inflammation. Regardless of the source of the SDOH-exposome that induces chronic inflammation and immunosenescence, the outcome influences cardiometabolic diseases, cancers, infections, sepsis, neurodegeneration and autoimmune diseases. The endogenous redox rheostat is connected with regulatory molecules such as NAD/NADH and SIRT1 that drive redox pathways. In addition to these intracellular and mitochondrial processes, we discuss how the SDOH-exposome can influence the balance between metabolism and regulation of immune responsiveness involving the two main molecular drivers of inflammation, the NLRP3 inflammasome and NF-κB induction. Mitochondrial and inflammasome activities play key roles in mediating defenses against pathogens and controlling inflammation before diverse cell death pathways are induced. Specifically, pyroptosis, cell death by inflammation, is intimately associated with common disease outcomes that are influenced by the SDOH-exposome. Redox influences on immunometabolism including protein cysteines and ion fluxes are discussed regarding health outcomes. In summary, this review presents a translational research perspective, with evidence from in vitro and in vivo models as well as clinical and epidemiological studies, to outline the intracellular consequences of the SDOH-exposome that drive health disparities in patients and populations. The relevance of this conceptual and theoretical model considering the SARS-CoV-2 pandemic are highlighted. Finally, the case of asthma is presented as a chronic condition that is modified by adverse SDOH exposures and is manifested through the dysregulation of immune cell redox regulatory processes we highlight in this review.
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http://dx.doi.org/10.1016/j.taap.2021.115444DOI Listing
April 2021