Time domain optical imaging device based on a commercial time-to-digital converter

Time-domain diffuse optical imaging is a noninvasive technique that uses pulsed near-infrared light as the interrogation source to produce quantitative images displaying the variation in blood volume and oxygenation in the human brain. Measuring the times of flights of photons provides information on the photon pathlengths in tissue, which enables absolute concentrations of the oxygenated and deoxygenated forms of hemoglobin to be estimated. Recent advances in silicon electronics have enabled the development of time-domain systems, which are lightweight and low cost, potentially enabling the imaging technique to be applied to a far greater cohort of subjects in a variety of environments. While such technology usually depends on customized circuits, in this article, we present a system assembled from commercially available components, including a low-cost time-to-digital converter and a silicon photomultiplier detector. The system is able to generate histograms of photon flight times at a rate of 81–90 kS/s and with a sampled bin width of 54 ps. The linearity and performance of the system are presented, and its potential as the basis for a modular multi-detector imaging system is explored

Data-driven approach to optimum wavelength selection for diffuse optical imaging

The production of accurate and independent images of the changes in concentration of oxyhemoglobin and deoxyhemoglobin by diffuse optical imaging is heavily dependent on which wavelengths of near-infrared light are chosen to interrogate the target tissue. Although wavelengths can be selected by theoretical methods, in practice the accuracy of reconstructed images will be affected by wavelength-specific and system-specific factors such as laser source power and detector sensitivity. We describe the application of a data-driven approach to optimum wavelength selection for the second generation of University College London's multichannel, time-domain optical tomography system (MONSTIR II). By performing a functional activation experiment using 12 different wavelengths between 690 and 870 nm, we were able to identify the combinations of 2, 3, and 4 wavelengths which most accurately reproduced the results obtained using all 12 wavelengths via an imaging approach. Our results show that the set of 2, 3, and 4 wavelengths which produce the most accurate images of functional activation are [770, 810], [770, 790, 850], and [730, 770, 810, 850] respectively, but also that the system is relatively robust to wavelength selection within certain limits. Although these results are specific to MONSTIR II, the approach we developed can be applied to other multispectral near-infrared spectroscopy and optical imaging systems

Infection prevention and control compliance in Tanzanian outpatient facilities: a cross-sectional study with implications for the control of COVID-19.

BACKGROUND: As coronavirus disease 2019 (COVID-19) spreads, weak health systems must not become a vehicle for transmission through poor infection prevention and control practices. We assessed the compliance of health workers with infection prevention and control practices relevant to COVID-19 in outpatient settings in Tanzania, before the pandemic. METHODS: This study was based on a secondary analysis of cross-sectional data collected as part of a randomised controlled trial in private for-profit dispensaries and health centres and in faith-based dispensaries, health centres, and hospitals, in 18 regions. We observed provider-patient interactions in outpatient consultation rooms, laboratories, and dressing rooms, and categorised infection prevention and control practices into four domains: hand hygiene, glove use, disinfection of reusable equipment, and waste management. We calculated compliance as the proportion of indications (infection risks) in which a health worker performed a correct action, and examined associations between compliance and health worker and facility characteristics using multilevel mixed-effects logistic regression models. FINDINGS: Between Feb 7 and April 5, 2018, we visited 228 health facilities, and observed at least one infection prevention and control indication in 220 facilities (118 [54%] dispensaries, 66 [30%] health centres, and 36 [16%] hospitals). 18 710 indications were observed across 734 health workers (49 [7%] medical doctors, 214 [29%] assistant medical officers or clinical officers, 106 [14%] nurses or midwives, 126 [17%] clinical assistants, and 238 [32%] laboratory technicians or assistants). Compliance was 6·9% for hand hygiene (n=8655 indications), 74·8% for glove use (n=4915), 4·8% for disinfection of reusable equipment (n=841), and 43·3% for waste management (n=4299). Facility location was not associated with compliance in any of the infection prevention and control domains. Facility level and ownership were also not significantly associated with compliance, except for waste management. For hand hygiene, nurses and midwives (odds ratio 5·80 [95% CI 3·91-8·61]) and nursing and medical assistants (2·65 [1·67-4·20]) significantly outperformed the reference category of assistant medical officers or clinical officers. For glove use, nurses and midwives (10·06 [6·68-15·13]) and nursing and medical assistants (5·93 [4·05-8·71]) also significantly outperformed the reference category. Laboratory technicians performed significantly better in glove use (11·95 [8·98-15·89]), but significantly worse in hand hygiene (0·27 [0·17-0·43]) and waste management (0·25 [0·14-0·44] than the reference category. Health worker age was negatively associated with correct glove use and female health workers were more likely to comply with hand hygiene. INTERPRETATION: Health worker infection prevention and control compliance, particularly for hand hygiene and disinfection, was inadequate in these outpatient settings. Improvements in provision of supplies and health worker behaviours are urgently needed in the face of the current pandemic. FUNDING: UK Medical Research Council, Economic and Social Research Council, Department for International Development, Global Challenges Research Fund, Wellcome Trust

Correlation between nucleotide composition and folding energy of coding sequences with special attention to wobble bases

Background: The secondary structure and complexity of mRNA influences its accessibility to regulatory molecules (proteins, micro-RNAs), its stability and its level of expression. The mobile elements of the RNA sequence, the wobble bases, are expected to regulate the formation of structures encompassing coding sequences. Results: The sequence/folding energy (FE) relationship was studied by statistical, bioinformatic methods in 90 CDS containing 26,370 codons. I found that the FE (dG) associated with coding sequences is significant and negative (407 kcal/1000 bases, mean +/- S.E.M.) indicating that these sequences are able to form structures. However, the FE has only a small free component, less than 10% of the total. The contribution of the 1st and 3rd codon bases to the FE is larger than the contribution of the 2nd (central) bases. It is possible to achieve a ~ 4-fold change in FE by altering the wobble bases in synonymous codons. The sequence/FE relationship can be described with a simple algorithm, and the total FE can be predicted solely from the sequence composition of the nucleic acid. The contributions of different synonymous codons to the FE are additive and one codon cannot replace another. The accumulated contributions of synonymous codons of an amino acid to the total folding energy of an mRNA is strongly correlated to the relative amount of that amino acid in the translated protein. Conclusion: Synonymous codons are not interchangable with regard to their role in determining the mRNA FE and the relative amounts of amino acids in the translated protein, even if they are indistinguishable in respect of amino acid coding.Comment: 14 pages including 6 figures and 1 tabl

Is remaining indoors an effective way of reducing exposure to fine particulate matter during biomass burning events?

Bushfires, prescribed burns, and residential wood burning are significant sources of fine particles (aerodynamic diameter 2.5) affecting the health and well-being of many communities. Despite the lack of evidence, a common public health recommendation is to remain indoors, assuming that the home provides a protective barrier against ambient PM2.5. The study aimed to assess to what extent houses provide protection against peak concentrations of outdoor PM2.5 and whether remaining indoors is an effective way of reducing exposure to PM2.5. The effectiveness of this strategy was evaluated by conducting simultaneous week-long indoor and outdoor measurements of PM2.5 at 21 residences in regional areas of Victoria, Australia. During smoke plume events, remaining indoors protected residents from peak outdoor PM2.5 concentrations, but the level of protection was highly variable, ranging from 12% to 76%. Housing stock (e.g., age of the house) and ventilation (e.g., having windows/doors open or closed) played a significant role in the infiltration of outdoor PM2.5 indoors. The results also showed that leaving windows and doors closed once the smoke plume abates trapped PM2.5 indoors and increased indoor exposure to PM2.5. Furthermore, for approximately 50% of households, indoor sources such as cooking activities, smoking, and burning candles or incense contributed significantly to indoor PM2.5. Implications: Smoke from biomass burning sources can significantly impact on communities. Remaining indoors with windows and doors closed is a common recommendation by health authorities to minimize exposures to peak concentrations of fine particles during smoke plume events. Findings from this study have shown that the protection from fine particles in biomass burning smoke is highly variable among houses, with information on housing age and ventilation status providing an approximate assessment on the protection of a house. Leaving windows closed once a smoke plume abates traps particles indoors and increases exposures

How much healthcare is wasted? A cross-sectional study of outpatient overprovision in private-for-profit and faith-based health facilities in Tanzania.

Overprovision-healthcare whose harm exceeds its benefit-is of increasing concern in low- and middle-income countries, where the growth of the private-for-profit sector may amplify incentives for providing unnecessary care, and achieving universal health coverage will require efficient resource use. Measurement of overprovision has conceptual and practical challenges. We present a framework to conceptualize and measure overprovision, comparing for-profit and not-for-profit private outpatient facilities across 18 of mainland Tanzania's 22 regions. We developed a novel conceptualization of three harms of overprovision: economic (waste of resources), public health (unnecessary use of antimicrobial agents risking development of resistant organisms) and clinical (high risk of harm to individual patients). Standardized patients (SPs) visited 227 health facilities (99 for-profit and 128 not-for-profit) between May 3 and June 12, 2018, completing 909 visits and presenting 4 cases: asthma, non-malarial febrile illness, tuberculosis and upper respiratory tract infection. Tests and treatments prescribed were categorized as necessary or unnecessary, and unnecessary care was classified by type of harm(s). Fifty-three percent of 1995 drugs prescribed and 43% of 891 tests ordered were unnecessary. At the patient-visit level, 81% of SPs received unnecessary care, 67% received care harmful to public health (prescription of unnecessary antibiotics or antimalarials) and 6% received clinically harmful care. Thirteen percent of SPs were prescribed an antibiotic defined by WHO as 'Watch' (high priority for antimicrobial stewardship). Although overprovision was common in all sectors and geographical regions, clinically harmful care was more likely in for-profit than faith-based facilities and less common in urban than rural areas. Overprovision was widespread in both for-profit and not-for-profit facilities, suggesting considerable waste in the private sector, not solely driven by profit. Unnecessary antibiotic or antimalarial prescriptions are of concern for the development of antimicrobial resistance. Option for policymakers to address overprovision includes the use of strategic purchasing arrangements, provider training and patient education

Daily life stress and the cortisol awakening response : testing the anticipation hypothesis

Acknowledgments We thank Paul Stewart for his contribution to data collection and Dr Matthew Jones for programming the handheld computers. Author Contributions Conceived and designed the experiments: WS DJP. Performed the experiments: DJP. Analyzed the data: WS. Wrote the paper: WS DJP.Peer reviewedPublisher PD

Estradiol and testosterone levels in patients undergoing partial hepatectomy - A possible signal for hepatic regeneration?

In five adult male patients undergoing a 40-60% partial hepatectomy, serum sex hormone levels before and after hepatic resection were determined. Blood was drawn immediately prior to each surgical procedure and at specified time points postoperatively. Compared to hormone levels found prior to surgery, following major hepatic resection, estradiol levels increase at 24 and 48 hr, while testosterone levels decline, being significantly reduced at 96 and 144 hr. These data demonstrate that adult males who undergo a 40-60% partial hepatectomy experience alterations in their sex hormone levels similar to those observed in male rats following a 70% hepatectomy. These changes in sex hormone levels have been associated in animals with an alteration of the sex hormone receptor status of the liver that is thought to participate in the initiation of the regenerative response. These studies suggest, but do not prove, that in man, as in the case of the rat, sex hormones may participate in the initiation of or at least modulate in part the regenerative response that occurs following a major hepatic resection. © 1989 Plenum Publishing Corporation

The pestivirus N terminal protease N(pro) redistributes to mitochondria and peroxisomes suggesting new sites for regulation of IRF3 by N(pro.)

The N-terminal protease of pestiviruses, N(pro) is a unique viral protein, both because it is a distinct autoprotease that cleaves itself from the following polyprotein chain, and also because it binds and inactivates IRF3, a central regulator of interferon production. An important question remains the role of N(pro) in the inhibition of apoptosis. In this study, apoptotic signals induced by staurosporine, interferon, double stranded RNA, sodium arsenate and hydrogen peroxide were inhibited by expression of wild type N(pro), but not by mutant protein N(pro) C112R, which we show is less efficient at promoting degradation of IRF3, and led to the conclusion that N(pro) inhibits the stress-induced intrinsic mitochondrial pathway through inhibition of IRF3-dependent Bax activation. Both expression of N(pro) and infection with Bovine Viral Diarrhea Virus (BVDV) prevented Bax redistribution and mitochondrial fragmentation. Given the role played by signaling platforms during IRF3 activation, we have studied the subcellular distribution of N(pro) and we show that, in common with many other viral proteins, N(pro) targets mitochondria to inhibit apoptosis in response to cell stress. N(pro) itself not only relocated to mitochondria but in addition, both N(pro) and IRF3 associated with peroxisomes, with over 85% of N(pro) puncta co-distributing with PMP70, a marker for peroxisomes. In addition, peroxisomes containing N(pro) and IRF3 associated with ubiquitin. IRF3 was degraded, whereas N(pro) accumulated in response to cell stress. These results implicate mitochondria and peroxisomes as new sites for IRF3 regulation by N(pro), and highlight the role of these organelles in the anti-viral pathway

Use of low-dose oral theophylline as an adjunct to inhaled corticosteroids in preventing exacerbations of chronic obstructive pulmonary disease: study protocol for a randomised controlled trial.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with high morbidity, mortality, and health-care costs. An incomplete response to the anti-inflammatory effects of inhaled corticosteroids is present in COPD. Preclinical work indicates that 'low dose' theophylline improves steroid responsiveness. The Theophylline With Inhaled Corticosteroids (TWICS) trial investigates whether the addition of 'low dose' theophylline to inhaled corticosteroids has clinical and cost-effective benefits in COPD. METHOD/DESIGN: TWICS is a randomised double-blind placebo-controlled trial conducted in primary and secondary care sites in the UK. The inclusion criteria are the following: an established predominant respiratory diagnosis of COPD (post-bronchodilator forced expiratory volume in first second/forced vital capacity [FEV1/FVC] of less than 0.7), age of at least 40 years, smoking history of at least 10 pack-years, current inhaled corticosteroid use, and history of at least two exacerbations requiring treatment with antibiotics or oral corticosteroids in the previous year. A computerised randomisation system will stratify 1424 participants by region and recruitment setting (primary and secondary) and then randomly assign with equal probability to intervention or control arms. Participants will receive either 'low dose' theophylline (Uniphyllin MR 200 mg tablets) or placebo for 52 weeks. Dosing is based on pharmacokinetic modelling to achieve a steady-state serum theophylline of 1-5 mg/l. A dose of theophylline MR 200 mg once daily (or placebo once daily) will be taken by participants who do not smoke or participants who smoke but have an ideal body weight (IBW) of not more than 60 kg. A dose of theophylline MR 200 mg twice daily (or placebo twice daily) will be taken by participants who smoke and have an IBW of more than 60 kg. Participants will be reviewed at recruitment and after 6 and 12 months. The primary outcome is the total number of participant-reported COPD exacerbations requiring oral corticosteroids or antibiotics during the 52-week treatment period. DISCUSSION: The demonstration that 'low dose' theophylline increases the efficacy of inhaled corticosteroids in COPD by reducing the incidence of exacerbations is relevant not only to patients and clinicians but also to health-care providers, both in the UK and globally. TRIAL REGISTRATION: Current Controlled Trials ISRCTN27066620 was registered on Sept. 19, 2013, and the first subject was randomly assigned on Feb. 6, 2014