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Backgrounds. Africa comprises 54 countries with varying degrees of economic development. As with other healthcare systems, rare diseases such as adrenal insufficiency are neglected and poorly documented. Objectives. We wished to explore primary adrenal insufficiency (PAI) in Africa, its prevalence, aetiology, genetics, presentation, diagnosis, and treatment and to determine the unmet needs in clinical care, education, and research. Materials and Methods. A narrative nonsystematic review of the literature was undertaken. We searched two online databases (PubMed and Google scholar) using the search terms “Addison’s disease/PAI, primary adrenal insufficiency coupled with “Africa,” “country names,” and “genetic disorders.” A total of 184 PAI records were reviewed. The exclusion of abstracts, conference proceedings, single case reports, and duplicate studies covering the same subject matter yielded 124 articles, of which 97 informed the final manuscript. Results. A wide range of aetiology of PAI was encountered, but their true prevalence is unknown. Aetiology varied with region and age of presentation as reflected by predominantly TB, HIV, and infective causes occurring in sub-Saharan Africa and more congenital forms described in North Africa associated with consanguinity. In Africa, the diagnostic criteria for PAI do not universally accord with conventional criteria, and there is a heavy reliance on clinical suspicion and biochemistry, including random cortisol of

There is a lack of affordable and acceptable sanitation solutions for dense, low-income urban settlements. One option that has been proposed is container-based sanitation, where a sealed cartridge installed in a free-standing toilet is regularly changed and adequately separates users from their excreta. Though container-based toilets are considered a safely managed sanitation solution that meets the Sustainable Development Goal for sanitation, little is known about user experiences to inform how such a solution should be viewed by governments. We conducted a longitudinal prospective cohort study of changes in objective and subjective measures of sanitation quality due to the Clean Team Ghana (CTG) container- based toilet service in Kumasi, Ghana from June to December 2019. We collected data immediately prior to installation of a toilet and 10 weeks afterwards for 292 customers. Most initially used public toilets with good structural quality, but sometimes had poor cleanliness, a lack of handwashing facilities, and required a 14.3 minute mean round trip time to use. The evaluation found that CTG delivers a high-quality service that positively impacts the quality of life of CTG customers, as well as saving them money, reducing gender gaps in quality of life, and addressing the needs of those with physical disabilities. Satisfaction with CTG toilet and service characteristics was high, with the largest increases for satisfaction with smell, comfort, disgust, and privacy. Women in particular were positively impacted both for explicitly gendered indicators like the ability to practice menstrual hygiene management, and other indicators where women scored lower than men at baseline, including ease of access, ease of use, and cleanliness. Use of the service also benefitted those who had been unable to use a toilet for physical or social reasons beforehand. Problems with the CTG service, such as leaking, filling, smelling, or not being replaced as scheduled, were reported by fewer than 10% of customers. While one product or service does not fit the needs of all customers, this evaluation supports the growing body of evidence that container-based sanitation provides a service valued by users and acceptable to policymakers in dense urban settlements.

Background Hormone therapy in transgender individuals may impact processes that lead to changes in biochemical analytes, and therefore reference intervals. Currently, few reference interval studies are available for the transgender population. We determined biochemical reference intervals for transgender individuals receiving hormone therapy. Methods Our retrospective, laboratory-based, observational study included healthy transgender males ( N = 24) and transgender females ( N = 84) on hormone therapy. Various biochemical reference intervals were established for each cohort and compared to their cisgender counterparts. Results We detected significant differences in reference intervals for sodium, 139–142 mmol/L vs. 136–145 mmol/L when comparing transgender males (TM) with cisgender males (CM). The following significant changes in upper reference limits (URL) for TM versus CM were detected, ALP (URL: 96 U/L vs. 128 U/L), GGT (URL: 27 U/L vs. 67 U/L) and testosterone (URL: 46.7 nmol/L vs. 29.0 nmol/L), respectively. Moreover, when comparing transgender female (TF) to cisgender female (CF), significant differences in creatinine (URL: 117 μmol/L vs. 90 μmol/L), albumin (lower reference limit: 41 g/L, vs. 35 g/L), AST (URL: 50 U/L vs. 35 U/L), ALP (URL: 118 U/L vs. 98 U/L) and oestradiol (URL: 934 pmol/L vs. 213 pmol/L) were noted, respectively. Significantly higher LDL-C was observed for TM on hormone treatment, compared to baseline (2.9 mmol/L vs. 2.2 mmol/L, p Conclusions Biochemical results for TM and TF receiving hormone therapy can be evaluated against our transgender-specific reference intervals for some analytes, while others can be compared to their identified gender reference intervals.

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.

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.

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 P P P 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.

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 SO42- 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 SO42- impurities in technical PM approach the reported SO42- 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.

IntroductionDomestic hand hygiene could prevent over 500,000 attributable deaths per year, but 6 in 10 people in least developed countries (LDCs) do not have a handwashing facility with soap and water available at home. We estimated the economic costs of universal access to basic hand hygiene services in household settings in 46 LDCs. MethodsOur model combines quantities of households with no handwashing facility (HWF) and prices of promotion campaigns, HWFs, soap, and water. For quantities, we used estimates from the WHO/UNICEF Joint Monitoring Programme. For prices, we collated data from recent impact evaluations and electronic searches. Accounting for inflation and purchasing power, we calculated costs over 2021-2030, and estimated total cost probabilistically using Monte Carlo simulation. ResultsAn estimated US$ 12.2 - 15.3 billion over 10 years is needed for universal hand hygiene in household settings in 46 LDCs. The average annual cost of hand hygiene promotion is $334 million (24% of annual total), with a further $233 million for top-up promotion (17%). Together, these promotion costs represent $0.47 annually per head of LDC population. The annual cost of HWFs, a purpose-built drum with tap and stand, is $174 million (13%). The annual cost of soap is $497 million (36%), and water $127 million (9%). ConclusionThe annual cost of behaviour change promotion to those with no handwashing facility represents 4.7% of median government health expenditure in LDCs, and 1% of their annual aid receipts. These costs could be covered by mobilising resources from across government and partners, and could be reduced by harnessing economies of scale and integrating hand hygiene with other behaviour change campaigns where appropriate. Innovation is required to make soap more affordable and available for the poorest households. Summary boxO_ST_ABSWhat is already known?C_ST_ABSO_LIUnderstanding resource requirements is important for planning, but data on the costs of improving domestic hand hygiene are scarce. C_LIO_LIWhile a 2016 study estimated the global cost of drinking water, sanitation and hygiene, it did not report hygiene-specific estimates of recurrent or total cost, nor did it describe the assumed promotion intervention and handwashing facility or consider alternatives to them. C_LI What are the new findings?O_LIThe total economic cost over 10 years is US$ 12.2 - 15.3 billion, of which $4.9 - 6.6 billion (42%) is for behaviour change promotion interventions. C_LIO_LIThe remainder is for facilities and supplies, with soap the biggest cost category (36%) followed by handwashing facilities (13%) and water (9%). C_LIO_LIThe facility and supply costs per household comprise an initial investment in a handwashing facility (lasting 5 years) at a median of US$ 17, accompanied by an annual cost of $17 for soap and $5 for water (Figure 1). C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=86 SRC="FIGDIR/small/21262011v1_fig1.gif" ALT="Figure 1"> View larger version (12K): org.highwire.dtl.DTLVardef@1c02d4org.highwire.dtl.DTLVardef@fde3bforg.highwire.dtl.DTLVardef@73228borg.highwire.dtl.DTLVardef@e0f9dc_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure 1:C_FLOATNO Distribution of key input price variables in international dollars (I$) * The base case promotion intervention includes one-to-one activities, group activities and mass media. The alternative case excludes one-to-one activities. This figure presents results in I$ - the median US$ prices per household after converting to local purchasing power are $33.9 for base case promotion, $16.6 for HWF, $17.1 for soap expenditure, and $17.2 for alternative case promotion. Median annual expenditure per household on water for handwashing was $5.7 in rural areas and $4.0 in urban areas. The US$ median for the home-made HWF considered under sensitivity analysis was $1.2. C_FIG What do the new findings imply?O_LIThe annual cost of behaviour change promotion to those with no handwashing facility represents 4.7% of median government health expenditure in LDCs. C_LIO_LIOn top of this, investments in infrastructure and supplies are required. Soap in particular is a substantial and recurrent cost, which may be unaffordable for the poorest households. C_LIO_LIPromotion costs could be covered by mobilising resources from across government and partners, and could be reduced by harnessing economies of scale and integrating hand hygiene with other behaviour change campaigns where appropriate. C_LI

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 [Cmax], and 0–24 h area under the concentration-time curve [AUC0–24] 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 [p = 0.048]. The concentration-time profiles in pericardial fluid versus plasma exhibited system hysteresis. The pericardial fluid-to-plasma Cmax peak concentration ratio was 0.28 (p = 0.032), while the AUC0–24 ratio was 0.793. The concentration-time profiles in saliva had a similar shape to those in plasma, but the saliva-to-plasma Cmax was 0.59 [p = 0.032]. Conclusion The prednisolone AUC0–24 achieved in pericardial fluid approximates that in plasma, but the Cmax is low due to delayed absorption. Saliva can be used as surrogate sampling site for pericardial fluid prednisolone.

Microalgae-based bulk production, especially for biofuel, is not yet economically feasible. One way to improve financial performance of such systems is to maximise value through a biorefinery approach (e.g. co-production streams, waste minimisation). This can be implemented via extraction of valuable intracellular compounds upon cell disruption; however both low-cost, energy efficient, and scalable cell disruption techniques, and green chemicals are required. Waste heat is a readily available resource in most production plants, and can be used to power a hydrothermal pre-treatment (HTP) step to disrupt the cells. In this study, we use HTP (120–180 °C, 5–30 min) to disrupt Chlorella sp. cell walls. We perform a subsequent water-miscible solvent and/or urea extraction (UX) to solubilise and recover proteins. The maximum extraction efficiency of 62% was achieved after HTP at 180 °C for 10 min. Regardless of the reaction time, 120 °C was found to be ineffective for protein extraction. The efficiency can be further increased to 84% if a filter-washing step with acetone and urea is implemented. Most of the recovered proteins are between 8 to 14 kDa across all temperature ranges, suggesting that extraction efficiency depended both on partial protein hydrolysis and on accessibility to solvent (i.e. cell wall degradation, solid dispersion, membrane solubilisation). The most significant amino acid losses on a per mole basis were lysine (22%) and arginine (14%). The production of flexible and high-value protein-based products via HTP-UX may enable a circular and sustainable production step for microalgal biorefineries, while improving the downstream fuel processes through nitrogen heteroatom reduction.

This paper presents results of research that has developed a set of diagnostic and decision-support tools for assessing sanitation services city-wide. It highlights features of the tools and illustrates key results from their validation through application in five cities worldwide. Collective use of these tools reveals and explains the complexities of the enabling environment and political economy within which sanitation services are delivered. Results present not only the status quo of services but also reasons for them being so. The tools have proven effective in guiding the collection, analysis and discussion of evidence, as a precursor to detailed feasibility studies, necessary to ultimately plan appropriate city-wide sanitation interventions.

ObjectivesCortisol plays a key role in initiating and maintaining different sleep stages. Patients with Addison’s disease (AD) frequently report disrupted sleep, and their hydrocortisone medication regimes do not restore the natural diurnal rhythm of cortisol. However, few studies have investigated relations between sleep quality, especially as measured by polysomnographic equipment, and night-time cortisol concentrations in patients with AD.MethodsWe used sleep-adapted EEG to monitor a full night of sleep in seven patients with AD and seven healthy controls. We sampled salivary cortisol before bedtime, at midnight, upon awakening and at 30 min post waking.ResultsControls had lower cortisol concentrations than patients before bedtime and at midnight. During the second half of the night, patient cortisol concentrations declined steeply, while control concentrations increased steadily. Whereas most controls experienced a positive cortisol awakening response, all patients experienced a decrease in cortisol concentrations from waking to 30 min post waking (P = 0.003). Patients experienced significantly lower proportions of slow-wave sleep (SWS;P = 0.001), which was associated with elevated night-time cortisol concentrations.ConclusionOverall, these results suggest that patients with AD demonstrate different patterns of night-time cortisol concentrations to healthy controls and that relatively elevated concentrations are associated with a reduction of SWS. These hormonal and sleep architectural aberrations may disrupt the routine sleep-dependent processes of memory consolidation, and hence, may explain, at least partially, the memory impairments often experienced by patients with AD.

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.

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%); pppp = 0.500], genetic including adrenoleukodystrophy (ALD) [5 (0.7%) vs 16 (12.0%); pp = 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%); pp = 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%); pp = 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.

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&rsquo, 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&ndash, cost ratio was 3.7 (95% CI: 1.9&ndash, 5.4) and the net present value was Int&rsquo, l $1,193,786 (95% CI: 406,017&ndash, 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).

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.

Background: Pericardial disorders are a common cause of heart disease, and the most common cause of pericarditis in developing countries is tuberculous (TB) pericarditis. It has been shown that prednisolone added to standard anti-TB therapy leads to a lower rate of constrictive pericarditis. We conducted a pilot study to evaluate the effect of adjunctive prednisolone treatment on the concentration of inflammatory markers in pericardial tuberculosis, in order to inform immunological mechanisms at the disease site. Methods: Pericardial fluid, plasma and saliva samples were collected from fourteen patients with pericardial tuberculosis, at multiple time points. Inflammatory markers were measured using multiplex luminex analysis and ELISA. Results: In samples from 14 patients we confirmed a strongly compartmentalized immune response at the disease site and found that prednisolone significantly reduced IL-6 concentrations in plasma by 8 hours of treatment, IL-1beta concentrations in saliva, as well as IL-8 concentrations in both pericardial fluid and saliva by 24 hours. Conclusion: Monitoring the early effect of adjunctive immunotherapy in plasma or saliva is a possibility in pericarditis. Keywords: Tuberculosis, HIV, Pericarditis, Steroids, Treatment monitoring

Oxygenic photosynthetic organisms use solar energy to split water into protons, electrons, and oxygen. Unicellular green algae like Chlamydomonas reinhardtii have evolved the additional ability to reduce protons to produce hydrogen (H2) via chloroplast hydrogenases (HYDA1 and HYDA2) under light-driven anaerobic conditions. In wild type cells, H2 production is limited by proton and electron supply to HYDA; most electrons are diverted to ferredoxin-NADP+-reductase. To enhance electron supply to HYDA and improve H2 production, variant ferredoxins with reduced ferredoxin-NADP+-reductase affinity have been demonstrated in vitro. Ferredoxin-hydrogenase fusions have also been tested, but achieving robust expression in vivo has been challenging. To improve efficiency, we here combine (1) a ferredoxin-HYDA fusion containing (2) a mutant FDX1 ferredoxin (D19A, D58A) with lowered affinity for ferredoxin-NADP+-reductase, utilising (3) a strongly inducible lhcbm9 promoter for controllable expression, and (4) a transgene construct containing introns for higher nuclear expression levels. Fusion constructs with 15 (pDK6-15) or 25 (pDK6-25) amino acid linkers were expressed in the nucleus of a HYDA1/HYDA2 knockout strain. Under illuminated, sulfur-deprived conditions, the variant ferredoxin-HYDA fusion strains yielded 3.0 and 4.6-fold more H2 than the wild type background strain over a 6-day period (typical purity range attained; 92–97%), confirming that the variant ferredoxin fused to HYDA is functional in vivo, strongly inducible, expresses at a similar level to the native HYDA gene, and significantly increases light-driven H2 production over wild type levels, likely by reducing losses to other electron acceptors such as ferredoxin-NADP+-reductase.

Context: Patients with Addison's disease (AD) have increased cardiovascular mortality. Objective: To study visceral fat and conventional and exploratory cardiovascular risk factors in patients with AD. Subjects: Patients (n = 76; n = 51 women) with AD and 76 healthy control subjects were matched for sex, age, body mass index (BMI), and smoking habits. Main outcome measures: The primary outcome variable was visceral abdominal adipose tissue (VAT) measured using computed tomography. Secondary outcome variables were prevalence of metabolic syndrome (MetS) and 92 biomarkers of cardiovascular disease. Results: The mean 6 standard deviation age of all subjects was 53 6 14 years; mean BMI, 25 6 4 kg/ m2; and mean duration of AD, 17 6 12 years. The median (range) daily hydrocortisone dose was 30 mg (10 to 50 mg). Median (interquartile range) 24-hour urinary free cortisol excretion was increased in patients vs controls [359 nmol (193 to 601 nmol) vs 175 nmol (140 to 244 nmol); P, 0.001]. VAT did not differ between groups. After correction for multiple testing, 17 of the 92 studied biomarkers differed significantly between patients and control subjects. Inflammatory, proinflammatory, and proatherogenic risk biomarkers were increased in patients [fold change (FC),.1] and vasodilatory protective marker was decreased (FC, < 1). Twenty-six patients (34%) vs 12 control subjects (16%) fulfilled the criteria for MetS (P = 0.01). Conclusion: Despite higher cortisol exposure, VAT was not increased in patients with AD. The prevalence of MetS was increased and several biomarkers of cardiovascular disease were adversely affected in patients with AD.

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., Highlights • Different sanitation interventions might improve quality of life to varying degrees. • We explored attributes of sanitation-related quality of life as capabilities. • We identified five core attributes: health, disgust, shame, safety, and privacy. • Results aligned with studies framed in terms of insecurity, stress and motives. • Conversion factors moderate how sanitation (e.g. a toilet) supports capabilities.

BACKGROUND: Hydrogen is a clean, versatile fuel and energy carrier which can be produced by a range of renewable technologies for combustion, use in fuel cells, or as a manufacturing feedstock. Despite its attraction and significant technological innovation, commercial feasibility of photobiological hydrogen processes is far from demonstrated.OBJECTIVE: This review examines direct photobiological biohydrogen systems, with a particular focus on the main obstacles that must be overcome to deliver commercially viable, net energy positive systems. As part of this process the interactions between future photobiological biohydrogen systems and other parts of a renewable energy economy are examined to analyse potential technology integration paths.RESULTS: The primary driver for renewably produced hydrogen is the potential for CO2 emissions reductions. Renewable hydrogen is largely solar driven, either directly (e.g. natural photosynthesis, or bio-inspired devices) or indirectly (e.g. fermentation, electrical hydrolysis). A significant market for hydrogen already exists and is supported by extensive infrastructure providing significant opportunities for emerging renewable hydrogen streams. Several key physiological obstacles to efficient photobiohydrogen production have already been overcome, with oxygen tolerance as the most significant remaining problem.CONCLUSIONS: A much deeper understanding of photosynthetic biology is required before existing knowledge can be integrated with real world systems. Cross-fertilisation between engineering and biology represents the best path forward for implementation as a robust biotechnology.

Efficient photosynthetic biomass production in a high rate pond (HRP) or a photobioreactor (PBR) represents the first step of microalgae platforms for the production of renewable fuels, animal feeds and a diverse range of high value products. This study analyses the interplay between solar energy input, ambient temperature and system surface area to volume (SA:V) ratio in terms of photosynthetic performance (yield, areal and volumetric productivity, photon conversion efficiency). Ten pilot scale trials were conducted under subtropical conditions using 2 microalgae strains (Chlorella sorokiniana and Chlorella sp.) in 5 different cultivation system geometries: HRPs, flat panel PBRs (0.75 m and 1.5 m high) and tubular PBRs (0.74 m and 1.49 m high). The evaluation of culture temperature and biomass productivity response to solar irradiance in the five production systems suggests that the optimal SA:V ratio range lies between 43–73 m2 m− 3 for C. sorokiniana in non-cooled systems regardless of system geometry under the conditions tested. The overall photosynthetic performance at higher SA:V ratios was improved for Chlorella sp. using temperature regulation. The highest observed daily photon conversion efficiency (PCE) was 4.44% (based on illuminated PBR surface area and total solar spectrum) in the high flat panel PBR using C. sorokiniana (40.8 g m− 2 d− 1, 0.23 g L− 1 d− 1). The highest achieved mean PCE (based on illuminated PBR surface area and total solar spectrum) was 2.5% in the low tubular PBR with Chlorella sp. (24.9 g m− 2 d− 1, 0.43 g L− 1 d− 1). The trial data provides important design principles to help fast track systems optimisation for near optimal sub-tropical conditions.

Microalgae offer a promising route to the production of high-value products, foods, animal feeds, and biofuels. Efficient algal dewatering strategies are therefore important for minimising energy and costs. Bio-flocculation is a potentially low-cost, low-energy harvesting strategy which can be facilitated by the microbial production of extracellular polymeric substances (EPS), but must be inducible since productive algal culture generally requires cells to be in suspension. Here we show that algal bio-flocculation can be controllably induced using the protozoan Tetrahymena. As little as 1:400 starved Tetrahymena to algal cells can be used to initiate rapid bio-flocculation. We demonstrate that stimulators of ryanodine receptors (caffeine and p-chlorocresol) trigger exocytosis in Tetrahymena and that inexpensive physicochemical stimuli (ammonium ions, shifts in pH and salinity) can also be effective. We suggest that triggered EPS secretion by protozoans in the starved state may explain apparently spontaneous bioflocculation of algae in both natural and artificial systems.

Outdoor microalgae systems are a promising platform for fuels and chemicals, but are currently limited by relatively low productivities. This study investigated the effects of photoacclimation on the productivity of Chlamydomonas reinhardtii grown under fluctuating light regimes which simulate well-mixed cultures in outdoor reactors. Simulations represented cells cycling between high light and dark zones in high-density ( HD Fluc , light fraction (LF) = 0.5) and low-density ( LD Fluc , LF = 0.9) cultures. Each fluctuating treatment was controlled by cultures grown under non-fluctuating light of the same hourly average irradiance ( HD Avg and LD Avg ) to differentiate between light dosage and regime. The large dark fraction of HD Fluc resulted in a low-light acclimated phenotype displaying up-regulation of light harvesting pigments and low NPQ caused by reduced levels of the dissipative protein LHCSR3. All other treatments led to high-light acclimation phenotypes. HD Fluc showed an estimated three-fold lower biomass yield relative to light absorbed and significant reductions in the quantum yield of PSII compared to HD Avg . This suggests that during high light periods of fluctuating cycles, higher absorption and an inability to safely dissipate excess light, resulted in greater photodamage and respiration required for repair. A framework for including these findings in predictive modelling of mass cultures is presented.

Many rural point-water sources in developing countries consist of wells or boreholes equipped with handpumps. Various estimates have been made of the functionality of such water points, and functionality is now routinely monitored in national and local surveys of service performance. We argue, however, that a single binary (functional/non-functional) indicator is crude and insufficient to provide much information about service sustainability. We set out a categorization of functionality which includes three sub-categories of functional water points and five non-functional sub-categories, with well/handpump water points in mind. We use a simple model to demonstrate that reduction of high rates of early post-construction abandonment and reduction of total downtimes would greatly improve service performance. We show that functionality levels for multi-age populations of wells or boreholes equipped with handpumps would not normally be expected to exceed about 85 per cent. We recommend going beyond functionality monitoring via the collection of quantitative data on rates of abandonment, frequency and duration of breakdown, combined with descriptive narratives of actions to manage and repair water points, in order to generate more nuanced understanding of service performance.

Pericardial tuberculosis (TB) is associated with high therapy failure and high mortality rates. Antibiotics have to penetrate to site of infection at sufficient non-protein bound concentrations, and then enter bacteria to inhibit intracellular biochemical processes. The antibiotic concentrations achieved in pericardial fluid in TB pericarditis have never been measured before. We recruited two cohorts of patients with TB pericarditis, and left a pigtail catheter in-situ for serial drug concentration measurements over 24 h. Altogether, 704 drug concentrations were comodeled for pharmacokinetic analyses. The drug concentrations achieved in pericardial fluid were compared to the minimum inhibitory concentrations (MICs) of clinical Mycobacterium tuberculosis isolates. The total rifampicin concentration pericardial-to-serum ratios in 16 paired samples were 0.19 ± 0.33. The protein concentrations of the pericardial fluid in TB pericarditis were observed to be as high as in plasma. The non-protein bound rifampicin concentrations in pericardial fluid were 4-fold lower than rifampicin MICs in the pilot study, and the peak concentration was 0.125 versus 0.208 mg/L in the second (p = 0.001). The rifampicin clearance from pericardial fluid was 9.45 L/h versus 7.82 L/h in plasma (p = 0.002). Ethambutol peak concentrations had a pericardial-to-plasma ratio of 0.55 ± 0.22; free ethambutol peak concentrations were 2.30-lower than MICs (p, Highlights • The amounts of antibiotics such as rifampicin, ethambutol, pyrazinamide and isoniazid used to treat TB pericarditis that enter pericardial fluid have up to now been unknown • The study found that the pH in pericardial fluid was alkaline, which would mean that pyrazinamide effect would be compromised. • The protein content in pericardial fluid was high, which would lead to low non-protein bound rifampicin and ethambutol concentrations • The concentrations of rifampicin, ethambutol and pyrazinamide in pericardial were dramatically low and below the MICs of Mycobacterium tuberculosis

Microalgae provide a powerful solar driven biotechnology platform for the production of the increasing quantity of food, fuel, high value products, fine chemicals and clean water required to supply our expanding global population. Light capture fuels all photosynthetically driven microalgae processes and consequently, maximizing light capture efficiency at minimal cost is central to process design. Raceway-style and paddle wheel operated open ponds, also known as high rate ponds (HRP0), are widely used, easy to operate and offer low-cost evaporative cooling compared to energy intensive closed systems. Here, the concept of delivering light from the surface into greater depths of the algae solution was tested at pilot-scale, by fitting a standard HRP0 with light transmitting guides designed to allow the capture of sunlight between ~10:00 am and ~3:00 pm to improve light distribution throughout the depth of the solution (HRP+). This prototype (HRP+) was analyzed to compare light distribution and biomass production efficiency against two control systems in two separate experiments such as: 1) a standard High Rate Pond (HRP0), and 2) a standard HRP0 fitted with no light transmitting dummy guides (HRP-) to maintain comparable fluid dynamics system characteristics. Under semi-continuous cultivation, HRP+ showed a significantly improved light distribution within the culture compared to the HRP- when operated at moderate to high densities. An increased proportion of the culture in the HRP+ was kept within the desired optimal photosynthetic zones while dark zones (unfit for photosynthesis and causing biomass loss) were drastically reduced compared to the HRP-. The HRP+ system exhibited a 3.9-fold higher maximum areal productivity of 49.2 ± 8.3 g·m−2·d−1 compared to HRP- (March–April 2018). Overall, this study establishes proof-of-concept of the functionality of light guides to improve light distribution and productivities in microalgae cultivation systems compared to the control systems run at the same incident light levels.

Photosynthetic linear electron flow (LEF) produces ATP and NADPH, while cyclic electron flow (CEF) exclusively drives photophosphorylation to supply extra ATP. The fine-tuning of linear and cyclic electron transport levels allows photosynthetic organisms to balance light energy absorption with cellular energy requirements under constantly changing light conditions. As LEF and CEF share many electron transfer components, a key question is how the same individual structural units contribute to these two different functional modes. Here, we report the structural identification of a photosystem I (PSI)–light harvesting complex I (LHCI)–cytochrome (cyt) b(6)f supercomplex isolated from the unicellular alga Chlamydomonas reinhardtii under anaerobic conditions, which induces CEF. This provides strong evidence for the model that enhanced CEF is induced by the formation of CEF supercomplexes, when stromal electron carriers are reduced, to generate additional ATP. The additional identification of PSI–LHCI–LHCII complexes is consistent with recent findings that both CEF enhancement and state transitions are triggered by similar conditions, but can occur independently from each other. Single molecule fluorescence correlation spectroscopy indicates a physical association between cyt b(6)f and fluorescent chlorophyll containing PSI–LHCI supercomplexes. Single particle analysis identified top-view projections of the corresponding PSI–LHCI–cyt b(6)f supercomplex. Based on molecular modeling and mass spectrometry analyses, we propose a model in which dissociation of LHCA2 and LHCA9 from PSI supports the formation of this CEF supercomplex. This is supported by the finding that a Δlhca2 knockout mutant has constitutively enhanced CEF.

Microalgae provide a powerful biotechnology platform for the production of renewable fuels, animal-feeds and high-value products. Here, a newhigh-throughput nutrient optimisation screen was used to maximise photoautotrophic growth rates for 100 newly bio-prospectedmicroalgae isolates. The multidimensional statistical design enabled the optimisation of 12 critical nutrients (N, P, Ca, Mg, Fe, Cu, Mn, Zn, B, Se, V and Si) and identified the highest specific-growth rates, elemental main-effects (Ca, Mg and Zn accounted for 71% of all main effects under photoautotrophic conditions) and pair-wise nutrient interactions (e.g. Ca-Mg, Mg-Zn, B-Zn, B-Se, Mn-Zn and Zn-Si) for each of the 100 strains tested (25,100 trials, over 2000-fold data-compression compared to a full factorial design) as well as their ability to use different carbon sources. Photoautotrophic growth rates reaching 0.067 h(-1) (0.289 h(-1) at microwell plate scale) and 2.78 g L-1 (batch cultivation in flasks) are amongst the highest reported, promoting the capacity for a high-throughput optimisation of microalgae production processes using established and newly bio-prospected strains. Crown Copyright (C) 2015 Published by Elsevier B.V. All rights reserved.

Light-harvesting complex (LHC) proteins are among the most abundant proteins on Earth and play critical roles in photosynthesis, both in light capture and in photoprotective mechanisms. The Chlamydomonas reinhardtii nucleic acid-binding protein 1 (NAB1) is a negative regulator of LHC protein translation. Its N-terminal cold-shock domain (CSD) binds to a 13-nt element [CSD consensus sequence (CSDCS)] found in the mRNA of specific LHC proteins associated with Photosystem II (PSII), an interaction which regulates LHC expression and, consequently, PSII-associated antenna size, structure and function. In the present study, we elucidated the solution structure of the NAB1 CSD as determined by heteronuclear NMR. The CSD adopts a characteristic five-stranded anti parallel β-barrel fold. Upon addition of CSDCS RNA, a large number of NMR chemical shift perturbations were observed, corresponding primarily to surface-exposed residues within the highly conserved β2- and β3-strands in the canonical RNA-binding region, but also to residues on β-strand 5 extending the positive surface patch and the overall RNA-binding site. Additional chemical shift perturbations that accompanied RNA binding involved buried residues, suggesting that transcript recognition is accompanied by conformational change. Our results indicate that NAB1 associates with RNA transcripts through a mechanism involving its CSD that is conserved with mechanisms of sequence-specific nucleic acid recognition employed by ancestrally related bacterial cold-shock proteins (CSPs).

Intermittent water supply (IWS) is prevalent throughout low and middle-income countries. IWS is associated with increased microbial contamination and potentially elevated risk of waterborne illness. We used existing data sets to estimate the population exposed to IWS, assess the probability of infection using quantitative microbial risk assessment, and calculate the subsequent burden of diarrheal disease attributable to consuming fecally contaminated tap water from an IWS. We used reference pathogens Campylobacter, Cryptosporidium, and rotavirus as conservative risk proxies for infections via bacteria, protozoa, and viruses, respectively. Results indicate that the median daily risk of infection is an estimated 1 in 23 500 for Campylobacter, 1 in 5 050 000 for Cryptosporidium, and 1 in 118 000 for rotavirus. Based on these risks, IWS may account for 17.2 million infections causing 4.52 million cases of diarrhea, 109 000 diarrheal DALYs, and 1560 deaths each year. The burden of diarrheal disease associated with IWS likely exceeds the WHO health-based normative guideline for drinking water of 10-6 DALYs per person per year. Our results underscore the importance water safety management in water supplies and the potential benefits of point-of-use treatment to mitigate risks.

The surface of our planet receives ∼3020 ZJ per year of solar energy annually, which is >5000 times the energy required to power our entire global economy (∼0.6 ZJ per year). Of this energy, ∼43% is photosynthetic active light radiation (PAR) that can be used to drive microalgal biotechnologies for the production of food, fuels, high value products, carbon sequestration, and bioremediation. The first step of all light-driven microalgal processes is light capture. A diverse array of highly efficient, self-assembling, light-responsive “solar interfaces,” the thylakoid membranes, have evolved to tap into this abundant, but constantly changing, energy resource to power the biosphere. The photosynthetic machinery within the thylakoids is intricately arranged in a complex 3D architecture and designed to adapt dynamically (i.e., 4D: representing changes in 3D structures over time) to constantly changing environmental conditions, to maximize solar to chemical energy conversion. The ATP and NADPH generated are used to produce the complex set of biomolecules that collectively form biomass. Here, we review the structural organization of these amazing photosynthetic interfaces in the model organism Chlamydomonas reinhardtii and summarize recent advances in structural biology, which underpin the development of next-generation atomic resolution dynamic simulations of these systems. Revealing such a 4D atlas of 3D structures in atomic resolution detail is of fundamental importance to enable structure-guided design of natural photosynthetic systems for biotechnological application and to provide a blueprint for the design of nanoscale components, which are the building blocks for the development of next-generation artificial solar fuel systems.

In this mini review, the embryological and functional development of the adrenal glands is presented from a molecular perspective. While acknowledging that this is a highly complex series of events, the processes are described in simple and broad strokes in a single text for the reader who is interested in this field but is not an active researcher. The origin of the adrenal glands is in the mesodermal ridge as early as the fourth week of gestation. Between the eighth and ninth weeks of gestation, the adrenal glands are encapsulated and this results in the presence of a distinct organ. There have been great strides in deciphering the very complicated molecular aspects of adrenal gland development in which multiple transcription factors have been identified, directing the adrenogonadal primordium into the adrenal cortex, kidney, or bipotential gonad. Adrenocorticotrophic hormone is critical for early development of the hypothalamic-pituitary adrenal axis. Several mutations in transcription factors, responsible for normal adrenal gland development have been found to induce the familial syndrome of congenital adrenal hypoplasia or neoplasia.

Patients with Addison's disease frequently self-report memory and attention difficulties, even when on standard replacement therapy. However, few published studies examine, using objective measures and assessing across multiple domains, the cognitive functioning of Addison's disease patients relative to healthy controls. The primary aim of this study was to investigate whether the previously reported subjective cognitive deficits in Addison's disease are confirmed by objective measures. Conducting comprehensive neuropsychological assessments of patients with relatively rare clinical disorders, such as Addison's disease, is challenging because access to those patients is often limited, and because their medical condition might prevent extended testing sessions. Brief telephonic cognitive assessments are a useful tool in such circumstances. Hence, we administered the Brief Test of Adult Cognition by Telephone to 27 Addison's disease patients and 27 matched healthy controls. The instrument provides objective assessment of episodic memory, working memory, executive functioning, reasoning, and speed of processing. Statistical analyses confirmed that, as expected, patients performed significantly more poorly than controls on the episodic memory subtest. There were, however, no significant between-group differences on the attention, executive functioning, reasoning, and speed of processing subtests. Furthermore, patients with a longer duration of illness performed more poorly across all domains of cognition. We conclude that, for Addison's disease patients, previously reported subjective cognitive deficits are matched by objective impairment, but only in the domain of episodic memory. Future research might investigate (a) whether these memory deficits are material-specific (i.e., whether non-verbal memory is also affected), and (b) the neurobiological mechanisms underlying these deficits.

Danger signals activate Toll-like receptors (TLRs), thereby initiating inflammatory responses. Canonical TLR signalling, via Toll/Interleukin-1 receptor domain (TIR)-containing adaptors and proinflammatory transcription factors such as NF-κB, occurs in many cell types; however, additional mechanisms are required for specificity of inflammatory responses in innate immune cells. Here we show that SCIMP, an immune-restricted, transmembrane adaptor protein (TRAP), promotes selective proinflammatory cytokine responses by direct modulation of TLR4. SCIMP is a non-TIR-containing adaptor, binding directly to the TLR4-TIR domain in response to lipopolysaccharide. In macrophages, SCIMP is constitutively associated with the Lyn tyrosine kinase, is required for tyrosine phosphorylation of TLR4, and facilitates TLR-inducible production of the proinflammatory cytokines IL-6 and IL-12p40. Point mutations in SCIMP abrogating TLR4 binding also prevent SCIMP-mediated cytokine production. SCIMP is, therefore, an immune-specific TLR adaptor that shapes host defence and inflammation., Toll-like receptors engage TIR domain-containing adaptors to control proinflammatory gene expression in response to pathogens and tissue damage. Here the authors show that the non-TIR domain-containing transmembrane protein SCIMP is a previously unrecognized TLR adaptor expressed by macrophages.

Protein aggregation is a hallmark of many neurodegenerative diseases, notably Alzheimer’s and Parkinson’s disease. Parkinson’s disease is characterized by the presence of Lewy bodies, abnormal aggregates mainly composed of α-synuclein. Moreover, cases of familial Parkinson’s disease have been linked to mutations in α-synuclein. In this study, we compared the behavior of wild-type (WT) α-synuclein and five of its pathological mutants (A30P, E46K, H50Q, G51D and A53T). To this end, single-molecule fluorescence detection was coupled to cell-free protein expression to measure precisely the oligomerization of proteins without purification, denaturation or labelling steps. In these conditions, we could detect the formation of oligomeric and pre-fibrillar species at very short time scale and low micromolar concentrations. The pathogenic mutants surprisingly segregated into two classes: one group forming large aggregates and fibrils while the other tending to form mostly oligomers. Strikingly, co-expression experiments reveal that members from the different groups do not generally interact with each other, both at the fibril and monomer levels. Together, this data paints a completely different picture of α-synuclein aggregation, with two possible pathways leading to the development of fibrils.