Publications by authors named "Ian Ross"

170 Publications

Sleep, Cognition and Cortisol in Addison's Disease: A Mechanistic Relationship.

Front Endocrinol (Lausanne) 2021 27;12:694046. Epub 2021 Aug 27.

Division of Endocrinology, Department of Medicine, University of Cape Town, Cape Town, South Africa.

Sleep is a critical biological process, essential for cognitive well-being. Neuroscientific literature suggests there are mechanistic relations between sleep disruption and memory deficits, and that varying concentrations of cortisol may play an important role in mediating those relations. Patients with Addison's disease (AD) experience consistent and predictable periods of sub- and supra-physiological cortisol concentrations due to lifelong glucocorticoid replacement therapy, and they frequently report disrupted sleep and impaired memory. These disruptions and impairments may be related to the failure of replacement regimens to restore a normal circadian rhythm of cortisol secretion. Available data provides support for existing theoretical frameworks which postulate that in AD and other neuroendocrine, neurological, or psychiatric disorders, disrupted sleep is an important biological mechanism that underlies, at least partially, the memory impairments that patients frequently report experiencing. Given the literature linking sleep disruption and cognitive impairment in AD, future initiatives should aim to improve patients' cognitive performance (and, indeed, their overall quality of life) by prioritizing and optimizing sleep. This review summarizes the literature on sleep and cognition in AD, and the role that cortisol concentrations play in the relationship between the two.
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http://dx.doi.org/10.3389/fendo.2021.694046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8429905PMC
August 2021

Single-neuron correlate of epilepsy-related cognitive deficits in visual recognition memory in right mesial temporal lobe.

Epilepsia 2021 Sep 21;62(9):2082-2093. Epub 2021 Jul 21.

Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Objective: Impaired memory is a common comorbidity of refractory temporal lobe epilepsy (TLE) and often perceived by patients as more problematic than the seizures themselves. The objective of this study is to understand what the relationship of these behavioral impairments is to the underlying pathophysiology, as there are currently no treatments for these deficits, and it remains unknown what circuits are affected.

Methods: We recorded single neurons in the medial temporal lobes (MTLs) of 62 patients (37 with refractory TLE) who performed a visual recognition memory task to characterize the relationship between behavior, tuning, and anatomical location of memory selective and visually selective neurons.

Results: Subjects with a seizure onset zone (SOZ) in the right but not left MTL demonstrated impaired ability to recollect as indicated by the degree of asymmetry of the receiver operating characteristic curve. Of the 1973 recorded neurons, 159 were memory selective (MS) and 366 were visually selective (VS) category cells. The responses of MS neurons located within right but not left MTL SOZs were impaired during high-confidence retrieval trials, mirroring the behavioral deficit seen both in our task and in standardized neuropsychological tests. In contrast, responses of VS neurons were unimpaired in both left and right MTL SOZs. Our findings show that neuronal dysfunction within SOZs in the MTL was specific to a functional cell type and behavior, whereas other cell types respond normally even within the SOZ. We show behavioral metrics that detect right MTL SOZ-related deficits and identify a neuronal correlate of this impairment.

Significance: Together, these findings show that single-cell responses can be used to assess the causal effects of local circuit disruption by an SOZ in the MTL, and establish a neural correlate of cognitive impairment due to epilepsy that can be used as a biomarker to assess the efficacy of novel treatments.
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http://dx.doi.org/10.1111/epi.17010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8403636PMC
September 2021

Using path analysis to test theory of change: a quantitative process evaluation of the MapSan trial.

BMC Public Health 2021 07 16;21(1):1411. Epub 2021 Jul 16.

Department of Disease Control, London School of Hygiene and Tropical Medicine, London, UK.

Background: Although theory-driven evaluations should have empirical components, few evaluations of public health interventions quantitatively test the causal model made explicit in the theory of change (ToC). In the context of a shared sanitation trial (MapSan) in Maputo, Mozambique, we report findings of a quantitative process evaluation assessing intervention implementation, participant response and impacts on hypothesised intermediary outcomes on the pathway to trial health outcomes. We examine the utility of path analysis in testing intervention theory using process indicators from the intervention's ToC.

Methods: Process data were collected through a cross-sectional survey of intervention and control compounds of the MapSan trial > 24-months post-intervention, sampling adult residents and compound leaders. Indicators of implementation fidelity (dose received, reach) and participant response (participant behaviours, intermediary outcomes) were compared between trial arms. The intervention's ToC (formalised post-intervention) was converted to an initial structural model with multiple alternative pathways. Path analysis was conducted through linear structural equation modelling (SEM) and generalised SEM (probit model), using a model trimming process and grouped analysis to identify parsimonious models that explained variation in outcomes, incorporating demographics of respondents and compounds.

Results: Among study compounds, the MapSan intervention was implemented with high fidelity, with a strong participant response in intervention compounds: improvements were made to intermediary outcomes related to sanitation 'quality' - latrine cleanliness, maintenance and privacy - but not to handwashing (presence of soap / soap residue). These outcomes varied by intervention type: single-cabin latrines or multiple-cabin blocks (designed for > 20 users). Path analysis suggested that changes in intermediary outcomes were likely driven by direct effects of intervention facilities, with little contribution from hygiene promotion activities nor core elements expected to mediate change: a compound sanitation committee and maintenance fund. A distinct structural model for two compound size subgroups (≤ 20 members vs. > 20 members) explained differences by intervention type, and other contextual factors influenced specific model parameters.

Conclusions: While process evaluation found that the MapSan intervention achieved sufficient fidelity and participant response, the path analysis approach applied to test the ToC added to understanding of possible 'mechanisms of change', and has value in disentangling complex intervention pathways.

Trial Registration: MapSan trial registration: NCT02362932 Feb-13-2015.
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http://dx.doi.org/10.1186/s12889-021-11364-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285873PMC
July 2021

Risk factors for COVID-19 hospitalisation and death in people living with diabetes: A virtual cohort study from the Western Cape Province, South Africa.

Diabetes Res Clin Pract 2021 Jul 21;177:108925. Epub 2021 Jun 21.

Department of Medicine, Groote Schuur Hospital and University of Cape Town, South Africa.

Background: COVID-19 outcomes and risk factors, including comorbidities and medication regimens, in people living with diabetes (PLWD) are poorly defined for low- and middle-income countries.

Methods: The Provincial Health Data Centre (Western Cape, South Africa) is a health information exchange collating patient-level routine health data for approximately 4 million public sector health care seekers. Data from COVID-19 patients diagnosed between March and July 2020, including PLWD, were analysed to describe risk factors, including dispensed diabetes medications and comorbidities, and their association with COVID-19 outcomes in this population.

Findings: There were 64,476 COVID-19 patients diagnosed. Of 9305 PLWD, 44.9% were hospitalised, 4.0% admitted to ICU, 0.6% received ventilation and 15.4% died. In contrast, proportions of COVID-19 patients without diabetes were: 12.2% hospitalised, 1.0% admitted, 0.1% ventilated and 4.6% died. PLWD were significantly more likely to be admitted (OR:3.73, 95 %CI: 3.53, 3.94) and to die (OR:3.01, 95 %CI: 2.76,3.28). Significant hospitalised risk factors included HIV infection, chronic kidney disease, current TB, male sex and increasing age. Significant risk factors for mortality were CKD, male sex, HIV infection, previous TB and increasing age. Pre-infection use of insulin was associated with a significant increased risk for hospitalisation (OR:1·39, 95 %CI:1·24,1·57) and mortality (OR1·49, 95 %CI:1·27; 1·74) and metformin was associated with a reduced risk for hospitalisation (OR:0·62,95 %CI:0·55, 0·71) and mortality (OR 0·77, 95 %CI:0·64; 0·92).

Interpretation: Using routine health data from this large virtual cohort, we have described the association of infectious and noncommunicable comorbidities as well as pre-infection diabetes medications with COVID-19 outcomes in PLWD in the Western Cape, South Africa.

Funding: This research was funded in part, by the Wellcome Trust 203135/Z/16/Z, through support of NT. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. The Wellcome Centre for Infectious Diseases Research in Africa is supported by core funding from the Wellcome Trust [203135/Z/16/Z]. NT receives funding from the CIDRI-Africa Wellcome Trust grant (203135/Z/16/Z), and NT and TT receive funding from the NIH H3ABioNET award (U24HG006941). NT receives funding from the UKRI/MRC (MC_PC_MR/T037733/1).
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http://dx.doi.org/10.1016/j.diabres.2021.108925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215881PMC
July 2021

The impact of improved water supply on cholera and diarrhoeal diseases in Uvira, Democratic Republic of the Congo: a protocol for a pragmatic stepped-wedge cluster randomised trial and economic evaluation.

Trials 2021 Jun 21;22(1):408. Epub 2021 Jun 21.

Department of Disease Control, London School of Hygiene and Tropical Medicine, London, UK.

Introduction: Diarrhoeal disease remains a leading cause of mortality and morbidity worldwide. Cholera alone is estimated to cause 95,000 deaths per year, most of which occur in endemic settings with inadequate water access. Whilst a global strategy to eliminate cholera by 2030 calls for investment in improved drinking water services, there is limited rigorous evidence for the impact of improved water supply on endemic cholera transmission in low-income urban settings. Our protocol is designed to deliver a pragmatic health impact evaluation of a large-scale water supply intervention in Uvira (Democratic Republic of the Congo), a cholera transmission hotspot.

Methods/design: A stepped-wedge cluster randomised trial (SW-CRT) was designed to evaluate the impact of a large-scale drinking water supply intervention on cholera incidence among the 280,000 inhabitants of Uvira. The city was divided into 16 clusters, where new community and household taps will be installed following a randomised sequence over a transition period of up to 8 weeks in each cluster. The primary trial outcomes are the monthly incidence of "confirmed" cholera cases (patients testing positive by rapid detection kit) and of "suspected" cholera cases (patients admitted to the cholera treatment centre). Concurrent process and economic evaluations will provide further information on the context, costs, and efficiency of the intervention.

Discussion: In this protocol, we describe a pragmatic approach to conducting rigorous research to assess the impacts of a complex water supply intervention on severe diarrhoeal disease and cholera in an unstable, low-resource setting representative of cholera-affected areas. In particular, we discuss a series of pre-identified risks and linked mitigation strategies as well as the value of combining different data collection methods and preparation of multiple analysis scenarios to account for possible deviations from the protocol. The study described here has the potential to provide robust evidence to support more effective cholera control in challenging, high-burden settings.

Trial Registration: This trial is registered on clinicaltrials.gov ( NCT02928341 , 10th October 2016) and has received ethics approval from the London School of Hygiene and Tropical Medicine (8913, 10603) and from the Ethics Committee from the School of Public Health, University of Kinshasa, Democratic Republic of the Congo (ESP/CE/088/2015).
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http://dx.doi.org/10.1186/s13063-021-05249-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215491PMC
June 2021

Microalgal nanocellulose - opportunities for a circular bioeconomy.

Trends Plant Sci 2021 Sep 15;26(9):924-939. Epub 2021 Jun 15.

Australian Institute for Bioengineering and Nanotechnology (AIBN), The University of Queensland, Brisbane, QLD 4072, Australia. Electronic address:

Over 3 billion years, photosynthetic algae have evolved complex uses for cellulose, the most abundant polymer worldwide. A major cell-wall component of lignocellulosic plants, seaweeds, microalgae, and bacteria, cellulose can be processed to nanocellulose, a promising nanomaterial with novel properties. The structural diversity of macro- and microalgal nanocelluloses opens opportunities to couple low-impact biomass production with novel, green-chemistry processing to yield valuable, sustainable nanomaterials for a multitude of applications ranging from novel wound dressings to organic solar cells. We review the origins of algal cellulose and the applications and uses of nanocellulose, and highlight the potential for microalgae as a nanocellulose source. Given the limited state of current knowledge, we identify research challenges and strategies to help to realise this potential.
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http://dx.doi.org/10.1016/j.tplants.2021.05.004DOI Listing
September 2021

Per- and poly-fluoroalkyl substance remediation from soil and sorbents: A review of adsorption behaviour and ultrasonic treatment.

Chemosphere 2021 Nov 28;282:131025. Epub 2021 May 28.

University of Surrey, Department of Chemical and Process Engineering, Surrey, England, GU2 7XH, UK. Electronic address:

Per- and poly-fluoroalkyl substances (PFAS) are xenobiotics, present at variable concentrations in soils and groundwater worldwide. Some of the current remediation techniques being researched or applied for PFAS-impacted soils involve solidification-stabilisation, soil washing, excavation and disposal to landfill, on site or in situ smouldering, thermal desorption, ball milling and incineration. Given the large volumes of soil requiring treatment, there is a need for a more environmentally friendly technique to remove and treat PFASs from soils. Sorbents such as granular/powdered activated carbon, ion exchange resins and silicas are used in water treatment to remove PFAS. In this work, PFAS adsorption mechanisms and the effect of pore size, pH and organic matter on adsorption efficacy are discussed. Then, adsorption of PFAS to soils and sorbents is considered when assessing the viability of remediation techniques. Sonication-aided treatment was predicted to be an effective removal technique for PFAS from a solid phase, and the effect of varying frequency, power and particle size on the effectiveness of the desorption process is discussed. Causes and mitigation strategies for possible cavitation-induced particle erosion during ultrasound washing are also identified. Following soil remediation, degrading the extracted PFAS using sonolysis in a water-organic solvent mixture is discussed. The implications for future soil remediation and sorbent regeneration based on the findings in this study are given.
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http://dx.doi.org/10.1016/j.chemosphere.2021.131025DOI Listing
November 2021

Through the Fog.

Authors:
Ian R Ross

N Engl J Med 2021 May 15;384(20):1882-1883. Epub 2021 May 15.

From the General Medicine Service, John Cochran Veterans Affairs Medical Center, St. Louis.

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http://dx.doi.org/10.1056/NEJMp2033891DOI Listing
May 2021

Case - Spontaneous thrombosis of varix in childhood.

Can Urol Assoc J 2021 Feb 12. Epub 2021 Feb 12.

Division of Urology, Department of Surgery, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.

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http://dx.doi.org/10.5489/cuaj.7016DOI Listing
February 2021

How does sanitation influence people's quality of life? Qualitative research in low-income areas of Maputo, Mozambique.

Soc Sci Med 2021 03 21;272:113709. Epub 2021 Jan 21.

Department of Global Health and Development, London School of Hygiene and Tropical Medicine, 15-17 Tavistock Place, London, WC1H 9SH, United Kingdom. Electronic address:

Preventing infectious disease has often been the primary rationale for public investment in sanitation. However, broader aspects of sanitation such as privacy and safety are important to users across settings, and have been linked to mental wellbeing. The aim of this study is to investigate what people most value about sanitation in low-income areas of Maputo, Mozambique, to inform a definition and conceptual model of sanitation-related quality of life. Our approach to qualitative research was rooted in economics and applied the capability approach, bringing a focus on what people had reason to value. We undertook 19 in-depth interviews and 8 focus group discussions. After eliciting attributes of "a good life" in general, we used them to structure discussion of what was valuable about sanitation. We applied framework analysis to identify core attributes of sanitation-related quality of life, and used pile-sorting and triad exercises to triangulate findings on attributes' relative importance. The five core attributes identified were health, disgust, shame, safety, and privacy. We present a conceptual model illustrating how sanitation interventions might improve quality of life via changes in these attributes, and how changes are likely to be moderated by conversion factors (e.g. individual and environmental characteristics). The five capability-based attributes are consistent with those identified in studies of sanitation-related insecurity, stress and motives in both rural and urban areas, which is supportive of theoretical generalisability. Since two people might experience the same toilet or level of sanitation service differently, quality of life effects of interventions may be heterogeneous. Future evaluations of sanitation interventions should consider how changes in quality of life might be captured.
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http://dx.doi.org/10.1016/j.socscimed.2021.113709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938219PMC
March 2021

Where Shared Sanitation is the Only Immediate Option: A Research Agenda for Shared Sanitation in Densely Populated Low-Income Urban Settings.

Am J Trop Med Hyg 2020 Nov 16. Epub 2020 Nov 16.

African Population and Health Research Center, Nairobi, Kenya.

Shared sanitation is not currently accepted within the international normative definitions of "basic" or "safely managed" sanitation. We argue that pro-poor government strategies and investment plans must include high-quality shared sanitation as an intermediate step in some densely populated urban areas. User experience must be considered in establishing the definition of high quality. We call for additional research on effective interventions to reach these quality standards and for the development of rigorous measures applicable to global monitoring.
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http://dx.doi.org/10.4269/ajtmh.20-0985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866357PMC
November 2020

Tiered healthcare in South Africa exposes deficiencies in management and more patients with infectious etiology of primary adrenal insufficiency.

PLoS One 2020 5;15(11):e0241845. Epub 2020 Nov 5.

Division of Endocrinology, Department of Medicine (University of Cape Town), Cape Town, South Africa.

Objective: We wished to determine the prevalence, etiology, presentation, and available management strategies for primary adrenal insufficiency (PAI) in South Africa (SA), hypothesizing a prevalence greater than the described 3.1 per million. There is great inequity in healthcare allocation, as two parallel healthcare systems exist, potentially modifying PAI patients' clinical profiles, private being better resourced than public healthcare.

Methods: An online survey of physicians' experience relating to PAI.

Results: The physicians were managing 811 patients, equal to a prevalence of 14.2 per million. Likely causes of PAI in public/ academic vs private settings included: AIDS-related [304 (44.8%) vs 5 (3.8%); p<0.001], tuberculosis [288 (42.5%) vs 8 (6.0%); p<0.001], autoimmune disease [50 (7.4%) vs 88 (66.2%); p<0.001], malignancy [27 (4.0%) vs 7 (5.3%); p = 0.500], genetic including adrenoleukodystrophy (ALD) [5 (0.7%) vs 16 (12.0%); p<0.001], respectively. Overall, more patients presented with nausea [101 (74.3%) and vomiting 89 (65.9%), than diarrhoea 76 (58.9%); p = 0.008 and 126 (15.5%) in adrenal crisis. Features suggestive of a crisis were hypoglycaemia [40 (78.4%) vs 42 (48.8%); p = 0.001], shock [36 (67.9%) vs 31(36.9%); p<0.001], and loss of consciousness [25 (52.1%) vs 27 (32.9%); p = 0.031]. Greater unavailability of antibody testing in the public vs. the private sector [32 (66.7%) vs 30 (32.1%); p = 0.001], [serum-ACTH 25 (52.1%) vs 16 (19.5%); p<0.001] and glucocorticoids were [26 (54.2%) vs 33 (40.2%); p = 0.015]. Many patients, 389(66.7%) were not using identification, indicating that they need steroids in an emergency.

Conclusion: A survey of South African physicians suggests a higher prevalence than previously reported. Patients presented with typical symptoms, and 15.5% presented in adrenal crisis. Significant disparities in the availability of physicians' expertise, diagnostic resources, and management options were noted in the public versus private settings. Greater awareness among health practitioners to timeously diagnose PAI is required to prevent a life-threatening outcome.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0241845PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644036PMC
January 2021

Benefits and Costs of a Community-Led Total Sanitation Intervention in Rural Ethiopia-A Trial-Based ex post Economic Evaluation.

Int J Environ Res Public Health 2020 07 14;17(14). Epub 2020 Jul 14.

Faculty of Infectious and Tropical Disease, London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT, UK.

We estimated the costs and benefits of a community-led total sanitation (CLTS) intervention using the empirical results from a cluster-randomized controlled trial in rural Ethiopia. We modelled benefits and costs of the intervention over 10 years, as compared to an existing local government program. Health benefits were estimated as the value of averted mortality due to diarrheal disease and the cost of illness arising from averted diarrheal morbidity. We also estimated the value of time savings from avoided open defecation and use of neighbours' latrines. Intervention delivery costs were estimated top-down based on financial records, while recurrent costs were estimated bottom-up from trial data. We explored methodological and parameter uncertainty using one-way and probabilistic sensitivity analyses. Avoided mortality accounted for 58% of total benefits, followed by time savings from increased access to household latrines. The base case benefit-cost ratio was 3.7 (95% CI: 1.9-5.4) and the net present value was Int'l $1,193,786 (95% CI: 406,017-1,977,960). The sources of the largest uncertainty in one-way sensitivity analyses were the effect of the CLTS intervention and the assumed lifespan of an improved latrine. Our results suggest that CLTS interventions can yield favourable economic returns, particularly if follow-up after the triggering is implemented intensively and uptake of improved latrines is achieved (as opposed to unimproved).
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http://dx.doi.org/10.3390/ijerph17145068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399893PMC
July 2020

POPS case: A 30-year-old Filipino woman with fevers, lymphadenopathy, painful scalp lesions, and a neck mass.

Allergy Asthma Proc 2020 07;41(4):305-308

Division of Hospital Medicine, Penn State Health Milton S. Hershey Medical Center, Hershey, Pennsylvania.

We described a case of a 30-year-old Filipino woman who presented with fevers, night sweats, left hip pain, painful scalp lesions, and a neck mass. Symptoms began 6 months earlier, with nasal drainage, fever, cough, and occasional hemoptysis, which did not resolve with outpatient antibiotics. A further workup revealed lymphadenopathy and several lytic bone lesions. Her hospital course was later further complicated by the development of a tracheoesophageal fistula secondary to an esophageal mass and, then later, aseptic meningitis. Extensive diagnostic workup and immunologic tests were performed and finally led to the diagnosis. Here, we discussed the diagnostic workup and pathophysiology of the underlying condition. This case illustrated the importance of appropriate immunologic workup to make the diagnosis of a rare condition that proves to be clinically significant and presents challenges in management.
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http://dx.doi.org/10.2500/aap.2020.41.200012DOI Listing
July 2020

Ultrasonic degradation of perfluorooctane sulfonic acid (PFOS) correlated with sonochemical and sonoluminescence characterisation.

Ultrason Sonochem 2020 Nov 13;68:105196. Epub 2020 Jun 13.

Department of Chemical and Process Engineering, University of Surrey, Guildford, Surrey GU2 7XH, United Kingdom. Electronic address:

Sonolysis has been proposed as a promising treatment technology to remove per- and polyfluoroalkyl substances (PFASs) from contaminated water. The mechanism of degradation is generally accepted to be high temperature pyrolysis at the bubble surface with dependency upon surface reaction site availability. However, the parametric effects of the ultrasonic system on PFAS degradation are poorly understood, making upscale challenging and leading to less than optimal use of ultrasonic energy. Hence, a thorough understanding of these parametric effects could lead to improved efficiency and commercial viability. Here, reactor characterisation was performed at 44, 400, 500, and 1000 kHz using potassium iodide (KI) dosimetry, sonochemiluminescence (SCL), and sonoluminescence (SL) in water and a solution of potassium salt of PFOS (hereafter, K-PFOS). Then the degradation of K-PFOS (10 mg L in 200 mL solution) was investigated at these four frequencies. At 44 kHz, no PFOS degradation was observed. At 400, 500, and 1000 kHz the amount of degradation was 96.9, 93.8, and 91.2%, respectively, over four hours and was accompanied by stoichiometric fluoride release, indicating mineralisation of the PFOS molecule. Close correlation of PFOS degradation trends with KI dosimetry and SCL intensity was observed, which suggested degradation occurred under similar conditions to these sonochemical processes. At 1000 kHz, where the overall intensity of collapse was significantly reduced (measured by SL), PFOS degradation was not similarly decreased. Discussion is presented that suggests a hydrated electron degradation mechanism for PFOS may occur in ultrasonic conditions. This mechanism is a novel hypothesis in the field of PFAS sonolysis.
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http://dx.doi.org/10.1016/j.ultsonch.2020.105196DOI Listing
November 2020

Value-Related Neuronal Responses in the Human Amygdala during Observational Learning.

J Neurosci 2020 06 6;40(24):4761-4772. Epub 2020 May 6.

Computation and Neural Systems, Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125.

The amygdala plays an important role in many aspects of social cognition and reward learning. Here, we aimed to determine whether human amygdala neurons are involved in the computations necessary to implement learning through observation. We performed single-neuron recordings from the amygdalae of human neurosurgical patients (male and female) while they learned about the value of stimuli through observing the outcomes experienced by another agent interacting with those stimuli. We used a detailed computational modeling approach to describe patients' behavior in the task. We found a significant proportion of amygdala neurons whose activity correlated with both expected rewards for oneself and others, and in tracking outcome values received by oneself or other agents. Additionally, a population decoding analysis suggests the presence of information for both observed and experiential outcomes in the amygdala. Encoding and decoding analyses suggested observational value coding in amygdala neurons occurred in a different subset of neurons than experiential value coding. Collectively, these findings support a key role for the human amygdala in the computations underlying the capacity for learning through observation. Single-neuron studies of the human brain provide a unique window into the computational mechanisms of cognition. In this study, epilepsy patients implanted intracranially with hybrid depth electrodes performed an observational learning (OL) task. We measured single-neuron activity in the amygdala and found a representation for observational rewards as well as observational expected reward values. Additionally, distinct subsets of amygdala neurons represented self-experienced and observational values. This study provides a rare glimpse into the role of human amygdala neurons in social cognition.
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http://dx.doi.org/10.1523/JNEUROSCI.2897-19.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294800PMC
June 2020

Significant barriers to diagnosis and management of adrenal insufficiency in Africa.

Endocr Connect 2020 May;9(5):445-456

Division of Endocrinology, Department of Medicine, University of Cape Town, Cape Town, South Africa.

Background: The burden and management of primary adrenal insufficiency (PAI) in Africa have not been well documented. We aimed to identify specific disease characteristics, patient demographics, and patterns of clinical management in established PAI in Africa.

Methods: An online survey of physicians' experience relating to PAI.

Results: There were 1334 responses received, 589 were complete, and 332 respondents reported managing patients with hypoadrenalism. The described responses were related to a calculated pool of 5787 patients with hypoadrenalism (2746 females, 3041 males), of whom 2302 had PAI. The likely causes of PAI in Sub-Saharan Africa (SSA) vs the Middle East and North Africa (MENA) regions included autoimmune disease (20% vs 60.3%; P < 0.001), tuberculosis (34% vs 4.1%; P < 0.001), AIDS (29.8% vs 1%; P < 0.001), malignancy, and genetic conditions. Sixteen percent of AD patients (376/2302) presented in an adrenal crisis. Medical emergency identification was not used by 1233 (83.6%) SSA vs 330 (40.4%) MENA patients (P < 0.001), respectively. Relative non-availability of diagnostic tests across both regions included adrenal antibodies 63% vs 69.6% (P = 0.328), s-cortisol 49.4 % vs 26.7% (P = 0.004), s-ACTH 55.7% vs 53.3% (P = 0.217), and adrenal CT scans 52.4% vs 31.8% (P = 0.017) in the SSA and MENA region, respectively. Across the entire cohort, the overall hydrocortisone use and extrapolated proportion of synacthen use were 59.4% and 50.7%, respectively.

Conclusions: Through the perception and practice of healthcare professionals, we identified significant challenges in the diagnosis and management of PAI which may herald high mortality. Differences between regions may reflect the allocation of healthcare resources.
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http://dx.doi.org/10.1530/EC-20-0129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274557PMC
May 2020

Detection and identification of dermatophyte fungi in clinical samples using a commercial multiplex tandem PCR assay.

Pathology 2020 Jun 16;52(4):473-477. Epub 2020 Apr 16.

National Mycology Reference Centre, Microbiology and Infectious Diseases, SA Pathology, Adelaide, SA, Australia. Electronic address:

We evaluated the performance of a commercial multiplex tandem polymerase chain reaction (PCR) for detection of dermatophytes and other fungi in skin and nail specimens by (1) testing a range of fungal and bacterial reference cultures, (2) retrospectively testing a set of skin and nail specimens with known microscopy and culture results, and (3) prospectively testing skin and nail specimens in parallel to microscopy and culture. The AusDiagnostics Dermatophytes and Other Fungi assay accurately detected and identified a range of common dermatophytes to species, species complex or genus level, as well as Candida, Aspergillus and Scopulariopsis spp. It was unable to detect uncommon dermatophytes such as Nannizzia fulva (previously Microsporum fulvum), and Paraphyton cookei (previously Microsporum cookei). PCR identified a dermatophyte in 25.9% of prospective specimens which were culture negative. Sensitivity, specificity, positive predictive value, and negative predictive value were highest where microscopy and PCR results were combined, versus microscopy and culture combined, which highlights the significant contribution of microscopy in the diagnostic pathway. This assay has the potential to reduce the workload and results turnaround time associated with culturing and identification of dermatophytes, although microscopy remains important.
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http://dx.doi.org/10.1016/j.pathol.2020.03.002DOI Listing
June 2020

Impact of an intervention to improve pit latrine emptying practices in low income urban neighborhoods of Maputo, Mozambique.

Int J Hyg Environ Health 2020 05 18;226:113480. Epub 2020 Feb 18.

Civil and Environmental Engineering, Georgia Institute of Technology, Atlanta, GA, USA. Electronic address:

Safe fecal sludge management (FSM) - the hygienic emptying, transport, and treatment for reuse or disposal of fecal sludge - is an essential part of safely managed sanitation, especially in towns and cities in low- and middle-income countries with limited sewer coverage. The need for safe and affordable FSM services has become more acute as cities grow and densify. Hygienic pit-emptying uses equipment that limits direct human exposure with fecal sludge and hygienic transport conveys fecal sludge offsite for treatment. We evaluated whether a program of on-site sanitation infrastructure upgrades and FSM capacity development in urban Maputo, Mozambique resulted in more hygienic pit-emptying and safe transportation of fecal sludge. We compared reported emptying practices among multi-household compounds receiving sanitation upgrades with control compounds, both from the Maputo Sanitation (MapSan) trial at 24-36 months after the intervention. Intervention compounds (comprising 1-40 households, median = 3) received a subsidized pour-flush latrine to septic tank system that replaced an existing shared latrine; control compounds continued using existing shared latrines. We surveyed compound residents and analyzed available municipal data on FSM in the city. Due to the recent construction of the intervention, emptying was more frequent in control compounds: 5.6% (15/270) of intervention compounds and 30% (74/247) of controls had emptied their on-site sanitation system in the previous year. Among those compounds which had emptied a sanitation facility in the previous year, intervention compounds were 3.8 (95% CI: 1.4, 10) times more likely to have to done so hygienically. Results suggest that the construction of subsidized pour-flush sanitation systems increased hygienic emptying of fecal sludge in this setting. Further gains in hygienic emptying in urban Maputo may be limited by affordability and physical accessibility.
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http://dx.doi.org/10.1016/j.ijheh.2020.113480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184672PMC
May 2020

Evaluating perfluorooctanesulfonate oxidation in permanganate systems.

Environ Sci Pollut Res Int 2020 Apr 8;27(12):13976-13984. Epub 2020 Feb 8.

Arcadis (UK) Limited, Arcadis House, 34 York Way, London, N1 9AB, UK.

Permanganate (PM) has shown to be able to oxidize a range of organic contaminants including perfluorooctane sulfonate (PFOS). However, mechanisms of PFOS removal by PM have been questioned. To provide clarity to what may be happening to PFOS in PM systems, here we evaluated the ability of PM on PFOS destruction by conducting studies similar to previous studies that reported PFOS destruction which included PM solutions and PM combined with persulfate (PS). We also evaluated if addition of various soluble catalysts could enhance PM's potential to breakdown PFOS. We observed no PFOS destruction by PM. We also show that the F and SO generation reported in a published study as evidence that PM was breaking bonds in PFOS were found below or not significantly higher than reported limits of quantitation and that SO impurities in technical PM approach the reported SO levels. For PM-PS systems, heterogeneous PFOS distribution was observed when subsampling reaction vessels at different depths and "salting-out" of PFOS was evident. In addition, subsequent sonication and filtering of the samples led to the apparent disappearance of most of the PFOS, which was an artifact arising from the behavior of PFOS aggregates or potential hemi-micelle formation. Given these findings, addition of salts may have application for collecting or concentrating PFOS and other PFAAs in a remediation or water treatment strategy.
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http://dx.doi.org/10.1007/s11356-020-07803-7DOI Listing
April 2020

Improving the use of intravenous antihypertensive medications in the hospital setting: a quality improvement initiative for patient safety.

BMJ Open Qual 2019 27;8(4):e000626. Epub 2019 Nov 27.

Pharmacy Department, Crittenton Hospital Medical Center, Rochester, Michigan, USA.

Intravenous (IV) hydralazine, enalapril and labetalol are oftentimes used without indication for the treatment of asymptomatic hypertension in the hospital setting and have been shown to have substantial adverse effects that are associated with increased morbidity and mortality, as well as longer length of stay. Their use is also associated with greater monetary costs. In this project, we studied the frequency of use and consequences of these medications before and after a series of education cycles which clarified when and when not to use intravenous antihypertensives (IVAHs). Our initial aim was to decrease the unindicated use of IVAH by at least 25% in the setting of asymptomatic hypertension in our community hospital within a 1-year period after introducing education on the topic. Multidisciplinary involvement throughout three Plan-Do-Study-Act (PDSA) cycles yielded favourable results. We focused on education towards a hospital-wide knowledge gap stemming from a lack of guidelines regarding the treatment of asymptomatic hypertension, as well as the guideline indications for IVAH. After three cycles of education targeting different groups, the unindicated use of IVAH fell by a total of 66%, decreasing patient exposure by approximately 248 cases over the total course of the study and ultimately, yielding a 52% increase in patient safety. Secondary outcome included a reduction in cost. It was noted that IV drugs cost more than their oral counterparts. The culture change in switching away from IVAH unless otherwise indicated was driven by repetitive education and group discussion to close the gap created by a lack of guidelines.
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http://dx.doi.org/10.1136/bmjoq-2019-000626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6887509PMC
July 2020

A Portrait of the Physician as a Young Man.

Authors:
Ian R Ross

Ann Intern Med 2019 11;171(10):769

Penn State College of Medicine, Hershey, Pennsylvania (I.R.R.).

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http://dx.doi.org/10.7326/M19-0892DOI Listing
November 2019

A localized sanitation status index as a proxy for fecal contamination in urban Maputo, Mozambique.

PLoS One 2019 25;14(10):e0224333. Epub 2019 Oct 25.

Civil and Environmental Engineering, Georgia Institute of Technology, Atlanta, Georgia, United States of America.

Sanitary surveys are used in low- and middle-income countries to assess water, sanitation, and hygiene conditions, but have rarely been compared with direct measures of environmental fecal contamination. We conducted a cross-sectional assessment of sanitary conditions and E. coli counts in soils and on surfaces of compounds (household clusters) in low-income neighborhoods of Maputo, Mozambique. We adapted the World Bank's Urban Sanitation Status Index to implement a sanitary survey tool specifically for compounds: a Localized Sanitation Status Index (LSSI) ranging from zero (poor sanitary conditions) to one (better sanitary conditions) calculated from 20 variables that characterized local sanitary conditions. We measured the variation in the LSSI with E. coli counts in soil (nine locations/compound) and surface swabs (seven locations/compound) in 80 compounds to assess reliability. Multivariable regression indicated that a ten-percentage point increase in LSSI was associated with 0.05 (95% CI: 0.00, 0.11) log10 fewer E. coli/dry gram in courtyard soil. Overall, the LSSI may be associated with fecal contamination in compound soil; however, the differences detected may not be meaningful in terms of public health hazards.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0224333PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814227PMC
March 2020

Automated Extraction and Visualization of Protein-Protein Interaction Networks and Beyond: A Text-Mining Protocol.

Methods Mol Biol 2020 ;2074:13-34

Regenerative Biology, Morgridge Institute for Research, Madison, WI, USA.

Proteins perform their functions by interacting with other proteins. Protein-protein interaction (PPI) is critical for understanding the functions of individual proteins, the mechanisms of biological processes, and the disease mechanisms. High-throughput experiments accumulated a huge number of PPIs in PubMed articles, and their extraction is possible only through automated approaches. The standard text-mining protocol includes four major tasks, namely, recognizing protein mentions, normalizing protein names and aliases to unique identifiers such as gene symbol, extracting PPIs, and visualizing the PPI network using Cytoscape or other visualization tools. Each task is challenging and has been revised over several years to improve the performance. We present a protocol based on our hybrid approaches and show the possibility of presenting each task as an independent web-based tool, NAGGNER for protein name recognition, ProNormz for protein name normalization, PPInterFinder for PPI extraction, and HPIminer for PPI network visualization. The protocol is specific to human but can be generalized to other organisms. We include KinderMiner, our most recent text-mining tool that predicts PPIs by retrieving significant co-occurring protein pairs. The algorithm is simple, easy to implement, and generalizable to other biological challenges.
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http://dx.doi.org/10.1007/978-1-4939-9873-9_2DOI Listing
January 2021

Machine Learning Assisted Discovery of Novel Predictive Lab Tests Using Electronic Health Record Data.

AMIA Jt Summits Transl Sci Proc 2019 6;2019:572-581. Epub 2019 May 6.

Carnegie Mellon University, Pittsburgh, PA.

Epidemiological studies identifying biological markers of disease state are valuable, but can be time-consuming, expensive, and require extensive intuition and expertise. Furthermore, not all hypothesized markers will be borne out in a study, suggesting that higher quality initial hypotheses are crucial. In this work, we propose a high-throughput pipeline to produce a ranked list of high-quality hypothesized marker laboratory tests for diagnoses. Our pipeline generates a large number of candidate lab-diagnosis hypotheses derived from machine learning models, filters and ranks them according to their potential novelty using text mining, and corroborate final hypotheses with logistic regression analysis. We test our approach on a large electronic health record dataset and the PubMed corpus, and find several promising candidate hypotheses.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6568080PMC
May 2019

Management of Intracranial Stenotic Disease in Cancer Patients Treated With Vasotoxic Agents.

J Stroke Cerebrovasc Dis 2019 Jul 8;28(7):1886-1890. Epub 2019 May 8.

Departments of Neurosurgery and Radiology, Huntington Memorial Hospital, Pasadena, CA. Electronic address:

Objective: To summarize the characteristics of and therapeutic options for cancer patients whose treatments may be vasotoxic and cause intracranial arterial stenotic disease and stroke.

Methods: We describe 3 patients with symptomatic cerebrovascular pathology that were being actively treated for cancer.

Results: Two of the patients were being treated with tyrosine kinase inhibitors (TKIs); and the third was being treated with 2 monoclonal antibodies, one of which was targeting an endothelial growth factor. These agents have been associated with vascular adverse events. Surgical revascularization was done in the first 2 patients, as they were suffering from cerebral ischemia. The third patient had suffered a significant brain hemorrhage, and therapeutic options were limited. In the first 2 patients, treatments also included antiplatelet agents and stopping/changing the TKI. In one of these patients we demonstrated regression of arterial stenosis after changing the TKI.

Conclusions: Possibilities for treatment in this population, beyond the usual medical and surgical administrations, may include stopping or changing cancer drugs that may be related to the development of arterial pathology. Collaboration with oncologists is essential in this subset of patients. While aware of the potential for vascular toxicity, oncologists are often not fully appreciative of the fact that their therapeutic agents can cause stroke.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2019.04.005DOI Listing
July 2019

Detectable prednisolone is delayed in pericardial fluid, compared with plasma of patients with tuberculous pericarditis: A pilot study.

Int J Cardiol Heart Vasc 2019 Mar 11;22:105-110. Epub 2019 Jan 11.

Department of Medicine, University of Cape Town, South Africa.

Background: In patients with tuberculous pericarditis [TBP] adjunctive prednisolone reduces the incidence of constrictive pericarditis. It is unknown whether prednisolone permeates adequately into pericardial fluid. Drug measurements in pericardial fluid require invasive procedures, and thus less invasive methods are needed to perform full pharmacokinetic characterization of prednisolone in large numbers of patients. We sought to evaluate the relationship between prednisolone concentrations in pericardial fluid, plasma, and saliva.

Methods: Plasma, pericardial fluid, and saliva samples were collected at 7 time points from TBP patients randomized to 120 mg prednisolone or placebo. Compartmental pharmacokinetic parameters, peak concentration [C], and 0-24 h area under the concentration-time curve [AUC] were identified in plasma, saliva and pericardial fluid.

Results: There were five patients each in the prednisolone and placebo groups. Prednisolone concentrations were best described using a one compartment model. The absorption half-life into plasma was 1 h, while that into pericardial fluid was 9.4 h, which led to a median time-to-maximum concentration in plasma of 2.0 h versus 5.0 h in pericardial fluid [ = 0.048]. The concentration-time profiles in pericardial fluid versus plasma exhibited system hysteresis. The pericardial fluid-to-plasma C peak concentration ratio was 0.28 ( = 0.032), while the AUC ratio was 0.793. The concentration-time profiles in saliva had a similar shape to those in plasma, but the saliva-to-plasma C was 0.59 [ = 0.032].

Conclusion: The prednisolone AUC achieved in pericardial fluid approximates that in plasma, but the C is low due to delayed absorption. Saliva can be used as surrogate sampling site for pericardial fluid prednisolone.
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http://dx.doi.org/10.1016/j.ijcha.2018.12.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6437290PMC
March 2019

Factors Associated with Water Service Continuity for the Rural Populations of Bangladesh, Pakistan, Ethiopia, and Mozambique.

Environ Sci Technol 2019 04 4;53(8):4355-4363. Epub 2019 Apr 4.

School of Civil and Environmental Engineering , Georgia Institute of Technology , Atlanta , Georgia 30308 , United States.

Access to continuous water supply is key for improving health and economic outcomes in rural areas of low- and middle-income countries, but the factors associated with continuous water access in these areas have not been well-characterized. We surveyed 4786 households for evidence of technical, financial, institutional, social, and environmental predictors of rural water service continuity (WSC), defined as the percentage of the year that water is available from a source. Multiple imputed fractional logistic regression models that account for the survey design were used to assess operational risks to WSC for piped supply, tube wells, boreholes, springs, dug wells, and surface water for the rural populations of Bangladesh, Pakistan, Ethiopia, and Mozambique. Multivariable regressions indicate that households using multiple water sources were associated with lower WSC in Bangladesh, Pakistan, and Mozambique. However, the possibility must be considered that households may use more than one water source because services are intermittent. Water scarcity and drought were largely unassociated with WSC, suggesting that service interruptions may not be primarily due to physical water resource constraints. Consistent findings across countries may have broader relevance for meeting established targets for service availability as well as human health.
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http://dx.doi.org/10.1021/acs.est.8b07173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6724210PMC
April 2019

Single-Neuron Correlates of Error Monitoring and Post-Error Adjustments in Human Medial Frontal Cortex.

Neuron 2019 01 4;101(1):165-177.e5. Epub 2018 Dec 4.

Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA; Computation and Neural Systems Program, California Institute of Technology, Pasadena, CA, USA; Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Center for Neural Science and Medicine, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Electronic address:

Humans can self-monitor errors without explicit feedback, resulting in behavioral adjustments on subsequent trials such as post-error slowing (PES). The error-related negativity (ERN) is a well-established macroscopic scalp EEG correlate of error self-monitoring, but its neural origins and relationship to PES remain unknown. We recorded in the frontal cortex of patients performing a Stroop task and found neurons that track self-monitored errors and error history in dorsal anterior cingulate cortex (dACC) and pre-supplementary motor area (pre-SMA). Both the intracranial ERN (iERN) and error neuron responses appeared first in pre-SMA, and ∼50 ms later in dACC. Error neuron responses were correlated with iERN amplitude on individual trials. In dACC, such error neuron-iERN synchrony and responses of error-history neurons predicted the magnitude of PES. These data reveal a human single-neuron correlate of the ERN and suggest that dACC synthesizes error information to recruit behavioral control through coordinated neural activity.
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http://dx.doi.org/10.1016/j.neuron.2018.11.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354767PMC
January 2019
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