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Purpose This intensified case finding study aimed to evaluate the prevalence of tuberculosis (TB) disease among people with HIV entering the largest prison in Malaysia. Design/methodology/approach The study was conducted in Kajang prison, starting in July 2013 in the men’s prison and June 2015 in the women’s prison. Individuals tested positive for HIV infection, during the mandatory HIV testing at the prison entry, were consecutively recruited over five months at each prison. Consented participants were interviewed using a structured questionnaire and asked to submit two sputum samples that were assessed using GeneXpert MTB/RIF (Xpert) and culture, irrespective of clinical presentation. Factors associated with active TB (defined as a positive result on either Xpert or culture) were assessed using regression analyses. Findings Overall, 214 incarcerated people with HIV were recruited. Most were men (84.6%), Malaysians (84.1%) and people who inject drugs (67.8%). The mean age was 37.5 (SD 8.2) years, and median CD4 lymphocyte count was 376 cells/mL (IQR 232–526). Overall, 27 (12.6%) TB cases were identified, which was independently associated with scores of five or more on the World Health Organization clinical scoring system for prisons (ARR 2.90 [95% CI 1.48–5.68]). Originality/value Limited data exists about the prevalence of TB disease at prison entry, globally and none from Malaysia. The reported high prevalence of TB disease in the study adds an important and highly needed information to design comprehensive TB control programmes in prisons.

Children with acute infectious diseases may not present to health facilities, particularly in low-income countries. We investigated healthcare seeking using a cross-sectional community survey, health facility-based exit interviews, and interviews with customers of private pharmacies in 2014 in Upper River Region (URR) The Gambia, within the Basse Health & Demographic Surveillance System. We estimated access to care using surveillance data from 2008 to 2017 calculating disease incidence versus distance to the nearest health facility. In the facility-based survey, children and adult patients sought care initially at a pharmacy (27.9% and 16.7% respectively), from a relative (23.1% and 28.6%), at a local shop or market (13.5% and 16.7%), and on less than 5% of occasions with a community-based health worker, private clinic, or traditional healer. In the community survey, recent symptoms of pneumonia or sepsis (15% and 1.5%) or malaria (10% and 4.6%) were common in children and adults. Rates of reported healthcare-seeking were high with families of children favoring health facilities and adults favoring pharmacies. In the pharmacy survey, 47.2% of children and 30.4% of adults had sought care from health facilities before visiting the pharmacy. Incidence of childhood disease declined with increasing distance of the household from the nearest health facility with access to care ratios of 0.75 for outpatient pneumonia, 0.82 for hospitalized pneumonia, 0.87 for bacterial sepsis, and 0.92 for bacterial meningitis. In rural Gambia, patients frequently seek initial care at pharmacies and informal drug-sellers rather than community-based health workers. Surveillance underestimates disease incidence by 8–25%.

ObjectiveContemporary data on the attainment of optimal diabetes treatment goals and the burden of diabetes complications in adult populations with type 2 diabetes in Africa are lacking. We aimed to document the current status of attainment of three key indicators of optimal diabetes care and the prevalence of five diabetes complications in adult African populations with type 2 diabetes.MethodsWe systematically searched Embase, PubMed and the Cochrane library for published studies from January 2000 to December 2020. Included studies reported any information on the proportion of attainment of optimal glycated haemoglobin (HbA1c), blood pressure (BP) and low-density lipoprotein cholesterol (LDLC) goals and/or prevalence of five diabetes complications (diabetic peripheral neuropathy, retinopathy, nephropathy, foot ulcers and peripheral arterial disease). Random effect model meta-analysis was performed to determine the pooled proportion of attainment of the three treatment goals and the prevalence of five diabetes complications.ResultsIn total, 109 studies with a total of 63 890 participants (53.3% being females) were included in the meta-analysis. Most of the studies were conducted in Eastern African countries (n=44, 40.4%). The pooled proportion of attainment of an optimal HbA1c, BP and LDLC goal was 27% (95% CI 24 to 30, I2=94.7%), 38% (95% CI 30 to 46, I2=98.7%) and 42% (95% CI 32 to 52, I2=97.4%), respectively. The pooled prevalence of diabetic peripheral neuropathy, retinopathy, diabetic nephropathy, peripheral arterial disease and foot ulcers was 38% (95% CI 31 to 45, I2=98.2%), 32% (95% CI 28 to 36, I2=98%), 31% (95% CI 22 to 41, I2=99.3%), 19% (95% CI 12 to 25, I2=98.1%) and 11% (95% CI 9 to 14, I2=97.4%), respectively.ConclusionAttainment of optimal diabetes treatment goals, especially HbA1c, in adult patients with type 2 diabetes in Africa remains a challenge. Diabetes complications, especially diabetic peripheral neuropathy and retinopathy, are highly prevalent in adult populations with type 2 diabetes in Africa.

Like most other industrial activities that affect the subsurface, hydraulic fracturing carries a risk of reactivating pre-existing faults and thereby causing induced seismicity. In some regions, regulators have responded to this risk by imposing Traffic Light Scheme-type regulations, where fracture stimulation programs must be amended or shut down if events larger than a given magnitude are induced. Some sites may be monitored with downhole arrays and/or dense near-surface arrays, capable of detecting very small microseismic events. However, such monitoring arrangements will not be logistically or economically feasible at all sites. Instead, operators are using small, sparse arrays of surface seismometers to meet their monitoring obligations. The challenge we address in this paper is to maximise the detection thresholds of such small, sparse, surface arrays, so that they are capable of robustly identifying small-magnitude events, whose signal-to-noise ratios may be close to 1. To do so we develop a beam-forming-and-stacking approach, computing running short-term/long-term average functions for each component of each recorded trace (P, SH and SV), time-shifting these functions by the expected travel-times for a given location, and performing a stack. We assess the effectiveness of this approach with a case study, using data from a small surface array that recorded a multi-well, multi-stage hydraulic fracture stimulation in Oklahoma over a period of 8 days. As a comparison, we initially used a conventional event-detection algorithm to identify events, finding a total of 17 events. In contrast, the beam-forming-and-stacking approach identified a total of 155 events during this period (including the 17 events detected by the conventional method). The events that were not detected by the conventional algorithm had low signal-to-noise ratios, to the extent that in some cases they would be unlikely to be identified even by manual analysis of the seismograms. We conclude that this approach is capable of improving the detection thresholds of small, sparse arrays, and so can be used to maximise the information generated when deployed to monitor industrial sites.

There’s a Schizo in our roadWith one in a hundredIt was bound to beThere’s a Schizo in our roadWe look for the contradictionsThat’s the way they say it isBut if you’re the Schizo in our roadHow do ...

Rationale: Contacts of patients with tuberculosis (TB) constitute an important target population for preventive measures because they are at high risk of infection with Mycobacterium tuberculosis and progression to disease. Objectives: We investigated bio-signatures with predictive ability for incident TB. Methods: In a case-control study nested within the Grand Challenges 6-74 longitudinal HIV-negative African cohort of exposed household contacts, we employed RNA sequencing, PCR, and the pair ratio algorithm in a training/test set approach. Overall, 79 progressors who developed TB between 3 and 24 months after diagnosis of index case and 328 matched nonprogressors who remained healthy during 24 months of follow-up were investigated. Measurements and Main Results: A four-transcript signature derived from samples in a South African and Gambian training set predicted progression up to two years before onset of disease in blinded test set samples from South Africa, the Gambia, and Ethiopia with little population-associated variability, and it was also validated in an external cohort of South African adolescents with latent M. tuberculosis infection. By contrast, published diagnostic or prognostic TB signatures were predicted in samples from some but not all three countries, indicating site-specific variability. Post hoc meta-analysis identified a single gene pair, C1QC/TRAV27 (complement C1q C-chain / T-cell receptor-a variable gene 27) that would consistently predict TB progression in household contacts from multiple African sites but not in infected adolescents without known recent exposure events. Conclusions: Collectively, we developed a simple whole blood-based PCR test to predict TB in recently exposed household contacts from diverse African populations. This test has potential for implementation in national TB contact investigation programs.

This study assesses the effectiveness of hyperspectral airborne imagery to map the intertidal vegetation at Roberts Bank, a large salt marsh and tidal flat complex in the Fraser River delta, British Columbia, Canada. This ecosystem is an important habitat for migratory and resident birds and fish and is part of the largest single salmon-producing stream in the world, the Fraser River. Imagery acquired by the compact airborne spectrographic imager (CASI) was radiometrically and geometrically corrected and mosaicked. A simple maximum likelihood classifier was used to classify intertidal vegetation cover. Training and test sites were collected using field observations and oblique aerial photographs. Seven vegetation-substrate classes were accurately (92.3%) classified, ranging from muddy sediments in the regularly inundated tidal flat and low marsh areas, to higher marsh communities of cattails, grasses, sedges, and rushes. This study showed that both the hyperspectral and hyperspatial characteristics of the...

The mitochondrial cytochrome b missense mutation, G167E, has been reported in a patient with cardiomyopathy. The residue G167 is located in an extramembranous helix close to the hinge region of the iron–sulfur protein. In order to characterize the effects of the mutation on the structure and function of the bc1 complex, we introduced G167E into the highly similar yeast cytochrome b. The mutation had a severe effect on the respiratory function, with the activity of the bc1 complex decreased to a few per cent of the wild type. Analysis of the enzyme activity indicated that the mutation affected its stability, which could be the result of an altered binding of the iron–sulfur protein on the complex. G167E had no major effect on the interaction between the iron– sulfur protein headgroup and the quinol oxidation site, as judged by the electron paramagnetic resonance signal, and only a minor effect on the rate of cytochrome b reduction, but it severely reduced the rate of cytochrome c1 reduction. This suggested that the mutation G167E could hinder the movement of the iron–sulfur protein, probably by distorting the structure of the hinge region. The function of bc1 was partially restored by mutations (W164L and W166L) located close to the primary change, which reduced the steric hindrance caused by G167E. Taken together, these observations suggest that the protein–protein interaction between the n-sulfur protein hinge region and the cytochrome b extramembranous cd2 helix is important for maintaining the structure of the hinge region and, by consequence, the movement of the headgroup and the integrity of the enzyme.

Cardiomyopathy Secondary to RVOT VT. Introduction: Several reports describe development of cardiomyopathics secondary to supraventricular tachycardia. Few reports have described cardiomyopathies secondary to ventricular tachycardia. Methods and Results: We describe a patient who presented with dilated cardiomyopathy and repetitive nonsustained monomorphic ventricular tachycardia. Cardiac cathcterization showed hemodynamically insignificant coronary artery disease. Radiofrequency ablation of a right ventricular outflow tract ventricular tachycardia resulted in improvement of the left ventricular systolic function and resolution of heart failure symptoms. Conclusions: This report suggests that right ventricular outflow tract ventricular tachycardia may cause reversible tachycardia-induced cardiomyopathy.

Atovaquone is a new anti-malarial agent that specifically targets the cytochrome bc1 complex and inhibits parasite respiration. A growing number of failures of this drug in the treatment of malaria have been genetically linked to point mutations in the mitochondrial cytochrome b gene. To better understand the molecular basis of atovaquone resistance in malaria, we introduced five of these mutations, including the most prevalent variant found in Plasmodium falciparum (Y268S), into the cytochrome b gene of the budding yeast Saccharomyces cerevisiae and thus obtained cytochrome bc1 complexes resistant to inhibition by atovaquone. By modeling the variations in cytochrome b structure and atovaquone binding with the mutated bc1 complexes, we obtained the first quantitative explanation for the molecular basis of atovaquone resistance in malaria parasites.

The mitochondrial cytochrome b missense mutation, G167E, has been reported in a patient with cardiomyopathy. The residue G167 is located in an extramembranous helix close to the hinge region of the iron-sulfur protein. In order to characterize the effects of the mutation on the structure and function of the bc(1) complex, we introduced G167E into the highly similar yeast cytochrome b. The mutation had a severe effect on the respiratory function, with the activity of the bc(1) complex decreased to a few per cent of the wild type. Analysis of the enzyme activity indicated that the mutation affected its stability, which could be the result of an altered binding of the iron-sulfur protein on the complex. G167E had no major effect on the interaction between the iron-sulfur protein headgroup and the quinol oxidation site, as judged by the electron paramagnetic resonance signal, and only a minor effect on the rate of cytochrome b reduction, but it severely reduced the rate of cytochrome c(1) reduction. This suggested that the mutation G167E could hinder the movement of the iron-sulfur protein, probably by distorting the structure of the hinge region. The function of bc(1) was partially restored by mutations (W164L and W166L) located close to the primary change, which reduced the steric hindrance caused by G167E. Taken together, these observations suggest that the protein-protein interaction between the n-sulfur protein hinge region and the cytochrome b extramembranous cd2 helix is important for maintaining the structure of the hinge region and, by consequence, the movement of the headgroup and the integrity of the enzyme.

The French research minister, Elisabeth Dufourcq, has called for a return to big technology projects in Eureka, the programme that encourages collaboration between European companies developing advanced technologies for civilian applications. Big projects are needed, she says, to "open up high growth markets and better equip European companies for the competition of the 21st century." She was speaking at a meeting held to celebrate 10 years of Eureka. The initiative currently involves 24 countries.

Atovaquone is a substituted hydroxynaphthoquinone that is widely used to prevent and clear Plasmodium falciparum malaria and Pneumocystis jirovecii pneumonia. Atovaquone inhibits respiration in target organisms by specifically binding to the ubiquinol oxidation site at center P of the cytochrome bc1 complex. The failure of atovaquone treatment and mortality of patients with malaria and P. jirovecii pneumonia has been linked to the appearance of mutations in the cytochrome b gene. To better understand the molecular basis of atovaquone resistance, we have introduced seven of the mutations from atovaquone-resistant P. jirovecii into the cytochrome b gene of Saccharomyces cerevisiae and thus obtained cytochrome bc1 complexes resistant to inhibition by atovaquone. In these enzymes, the IC50 for atovaquone increases from 25 nm for the enzyme from wild-type yeast to >500 nm for some of the mutated enzymes. Modeling of the changes in cytochrome b structure and atovaquone binding with the mutated bc1 complexes provides the first quantitative explanation for the molecular basis of atovaquone resistance.

Pneumocystis jiroveci (human-derived P. carinii ) is an opportunistic pathogenic fungus which causes pneumonia and is life-threatening in immunocompromised individuals. Spontaneously acquired resistance to atovaquone, a hydroxynaphthoquinone that is used to treat P. jiroveci infections, was linked to mutations in the mitochondrially encoded cytochrome b gene. Because P. jiroveci cannot be easily cultivated, we have developed Saccharomyces cerevisiae as an alternative system to study atovaquone resistance mutations. In this work, we introduced seven mutations linked with atovaquone resistance in P. jiroveci into the S. cerevisiae cytochrome b gene. The effects of the mutations on the respiratory function and on the sensitivity to the inhibitor were then characterized. Six of the reported mutations lowered the sensitivity of the S. cerevisiae bc 1 complex to atovaquone, while one mutation had no effect on the drug resistance. These results were confirmed by monitoring the in vivo resistance of S. cerevisiae mutants which carried both the cytochrome b mutations and a deletion of the ABC transporter genes, allowing the drug to bypass the weakened efflux pump system. S. cerevisiae thus provides an easy-to-use system to characterize in vivo and in vitro cytochrome b mutations reported in pathogens and to assess their role in drug resistance.

Atovaquone is a substituted 2-hydroxynaphthoquinone that is used therapeutically to treat Plasmodium falciparum malaria, Pneumocystis carinii pneumonia, and Toxoplasma gondii toxoplasmosis. It is thought to act on these organisms by inhibiting the cytochrome bc1 complex. We have examined the interaction of atovaquone with the bc1 complex isolated from Saccharomyces cerevisiae, a surrogate, nonpathogenic fungus. Atovaquone inhibits the bc1 complex competitively with apparent Ki = 9 nm, raises the midpoint potential of the Rieske iron-sulfur protein from 285 to 385 mV, and shifts the g values in the EPR spectrum of the Rieske center. These results indicate that atovaquone binds to the ubiquinol oxidation pocket of the bc1 complex, where it interacts with the Rieske iron-sulfur protein. A computed energy-minimized structure for atovaquone liganded to the yeast bc1 complex suggests that a phenylalanine at position 275 of cytochrome b in the bovine bc1 complex, as opposed to leucine at the equivalent position in the yeast enzyme, is responsible for the decreased sensitivity of the bovine bc1 complex (Ki = 80 nm) to atovaquone. When a L275F mutation was introduced into the yeast cytochrome b, the sensitivity of the yeast enzyme to atovaquone decreased (Ki = 100 nm) with no loss in activity, confirming that the L275F exchange contributes to the differential sensitivity of these two species to atovaquone. These results provide the first molecular description of how atovaquone binds to the bc1 complex and explain the differential inhibition of the fungal versus mammalian enzymes.

The French government has given the green light to a programme to install the infrastructure for information superhighways to cover the whole of the country by the year 2015. This follows recent recommendations by Gerard Thery, former chief executive of France Telecom (Physics World September p6).

France should should commit itself to constructing nationwide information superhighways, according to a report commissioned by France's prime minister Edouard Baladur. Its author, Gerard Thery, former chief executive of France Telecom, estimates that the total cost of equipping every home in France with infrastructure plus the associated software will be FE 600bn (about £72bn) spread over 15 years.

This paper examines the use made by management of market research data in the evaluation of new product development (NPD) projects. Stressing the need for a systematic approach to NPD the paper sets out four brief case histories, the products being Crocodillo, Paul Masson wine, the Prudential's Holburn UK Unit Trusts, and Golden Wonder's Preludes. These case histories illustrate both the value of a systematic approach to NPD by building up a market research programme and also the limitations of market research data which cannot alone be any guarantee of success.

Pseudomonas pseudomallei is the causative agent of melioidosis, a disease being increasingly recognized as an important cause of morbidity and mortality in many regions of the world. An intriguing observation regarding melioidosis is that a significant percentage of patients who develop the disease have preexisting diabetes mellitus. In this regard, we have tested the hypothesis that insulin may modulate the growth of P. pseudomallei. We have demonstrated that insulin markedly inhibits the growth of P. pseudomallei in vitro and in vivo. The growth rate of P. pseudomallei in minimal medium containing human recombinant insulin was significantly lower than that of control cultures containing no insulin. P. pseudomallei grew at an increased rate in serum samples obtained from diabetic rats compared with that in serum samples obtained from control animals. When the insulin level was restored by the addition of human recombinant insulin, the growth rate was reduced to a level similar to that seen in control serum. P. pseudomallei also grew significantly better in insulin-depleted human serum than control human serum. 125I-insulin binding studies demonstrated that P. pseudomallei possesses a specific, high-affinity binding site for human insulin. In in vivo studies, rats made diabetic by streptozotocin injection (80 mg/kg of body weight, intraperitoneally) were significantly more susceptible to P. pseudomallei septicemia than control rats. Thus, it appears that serum insulin levels may play a significant role in modulating the pathogenesis of P. pseudomallei septicemic infections.

SummaryUpon the isolated hearts of cats perfused with Ringer-Locke solution renin produced no significant effect. Angiotonin on the other hand brought about decrease in coronary flow and increase in amplitude of beat, but no consistent effect upon heart rate.