Improving 3D edge detection for visual inspection of MRI coregistration and alignment.

BACKGROUND: Visualizing edges is critical for neuroimaging. For example, edge maps enable quality assurance for the automatic alignment of an image from one modality (or individual) to another. NEW METHOD: We suggest that using the second derivative (difference of Gaussian, or DoG) provides robust edge detection. This method is tuned by size (which is typically known in neuroimaging) rather than intensity (which is relative). RESULTS: We demonstrate that this method performs well across a broad range of imaging modalities. The edge contours produced consistently form closed surfaces, whereas alternative methods may generate disconnected lines, introducing potential ambiguity in contiguity. COMPARISON WITH EXISTING METHODS: Current methods for computing edges are based on either the first derivative of the image (FSL), or a variation of the Canny Edge detection method (AFNI). These methods suffer from two primary limitations. First, the crucial tuning parameter for each of these methods relates to the image intensity. Unfortunately, image intensity is relative for most neuroimaging modalities making the performance of these methods unreliable. Second, these existing approaches do not necessarily generate a closed edge/surface, which can reduce the ability to determine the correspondence between a represented edge and another image. CONCLUSION: The second derivative is well suited for neuroimaging edge detection. We include this method as part of both the AFNI and FSL software packages, standalone code and online.

Open Source Antibiotics: Simple Diarylimidazoles Are Potent against Methicillin-Resistant Staphylococcus aureus.

Antimicrobial resistance (AMR) is widely acknowledged as one of the most serious public health threats facing the world, yet the private sector finds it challenging to generate much-needed medicines. As an alternative discovery approach, a small array of diarylimidazoles was screened against the ESKAPE pathogens, and the results were made publicly available through the Open Source Antibiotics (OSA) consortium (https://github.com/opensourceantibiotics). Of the 18 compounds tested (at 32 µg/mL), 15 showed >90% growth inhibition activity against methicillin-resistant Staphylococcus aureus (MRSA) alone. In the subsequent hit-to-lead optimization of this chemotype, 147 new heterocyclic compounds containing the diarylimidazole and other core motifs were synthesized and tested against MRSA, and their structure-activity relationships were identified. While potent, these compounds have moderate to high intrinsic clearance and some associated toxicity. The best overall balance of parameters was found with OSA_975, a compound with good potency, good solubility, and reduced intrinsic clearance in rat hepatocytes. We have progressed toward the knowledge of the molecular target of these phenotypically active compounds, with proteomic techniques suggesting TGFBR1 is potentially involved in the mechanism of action. Further development of these compounds toward antimicrobial medicines is available to anyone under the licensing terms of the project.

Medical imaging for plantar heel pain: a systematic review and meta-analysis.

BACKGROUND: Medical imaging can be used to assist with the diagnosis of plantar heel pain. The aim of this study was to synthesise medical imaging features associated with plantar heel pain. METHODS: This systematic review and meta-analysis conducted searches in MEDLINE, CINAHL, SPORTDiscus, Embase and the Cochrane Library from inception to 12th February 2021. Peer-reviewed articles of cross-sectional observational studies written in English that compared medical imaging findings in adult participants with plantar heel pain to control participants without plantar heel pain were included. Study quality and risk of bias was assessed using the National Institutes of Health quality assessment tool for observational cohort and cross-sectional studies. Sensitivity analyses were conducted where appropriate to account for studies that used unblinded assessors. RESULTS: Forty-two studies (2928 participants) were identified and included in analyses. Only 21% of studies were rated 'good' on quality assessment. Imaging features associated with plantar heel pain included a thickened plantar fascia (on ultrasound and MRI), abnormalities of the plantar fascia (on ultrasound and MRI), abnormalities of adjacent tissue such as a thickened loaded plantar heel fat pad (on ultrasound), and a plantar calcaneal spur (on x-ray). In addition, there is some evidence from more than one study that there is increased hyperaemia within the fascia (on power Doppler ultrasound) and abnormalities of bone in the calcaneus (increased uptake on technetium-99 m bone scan and bone marrow oedema on MRI). CONCLUSIONS: People with plantar heel pain are more likely to have a thickened plantar fascia, abnormal plantar fascia tissue, a thicker loaded plantar heel fat pad, and a plantar calcaneal spur. In addition, there is some evidence of hyperaemia within the plantar fascia and abnormalities of the calcaneus. Whilst these medical imaging features may aid with diagnosis, additional high-quality studies investigating medical imaging findings for some of these imaging features would be worthwhile to improve the precision of these findings and determine their clinical relevance.

The prevalence and impact of self-reported foot and ankle pain in the over 55 age group: a secondary data analysis from a large community sample.

BACKGROUND: While the prevalence and impact of musculoskeletal problems are high, most attention has been directed towards the back, knee and hip disorders. Foot pain is known to be common in older adults and accounts for a significant burden on health services. The aim of this study was to assess the impact of foot and ankle joint pain, considering age, presence of co-morbidities and other site joint pain, in a large community sample. METHODS: In the North Yorkshire Health study, 16,222 people over 55 years participated in a detailed survey of the prevalence and impact of lower limb joint problems. Self-assessment of overall body pain and functional activities of daily living were assessed. Participants indicated the presence of joint pain, stiffness or swelling during the last 3 months which had lasted for more than 6 weeks on a manikin: data were captured on the foot and the ankle. RESULTS: The prevalence of self-reported foot and ankle joint pain was substantial: 184.33 per 1000, second only to knee problems. While foot pain was common, it was mostly associated with joint pain at other sites; only 1 in 11 of those with foot and ankle pain reported it only in the foot. Logistic regression modeling revealed while established factors such as co-morbidities, knee and hip problems contributed to functional impairment, foot and ankle problems contributed to an additional increased risk of having difficulty standing and walking by two fold (OR = 2.314, 95%CI 2.061-2.598), going up and down stairs by 71% (OR = 1.711, 95%CI 1.478-1.980) and getting up from a seated position by 44% (OR = 1.438, 95%CI 1.197-1.729). CONCLUSION: These results suggest that not only are foot problems in the over 55 age group extremely prevalent, they have a considerable impact on functional abilities.

Fully automated peptide radiolabeling from [18F]fluoride.

The biological properties of receptor-targeted peptides have made them popular diagnostic imaging and therapeutic agents. Typically, the synthesis of fluorine-18 radiolabeled receptor-targeted peptides for positron emission tomography (PET) imaging is a time consuming, complex, multi-step synthetic process that is highly variable based on the peptide. The complexity associated with the radiolabeling route and lack of robust automated protocols can hinder translation into the clinic. A fully automated batch production to radiolabel three peptides (YGGFL, cRGDyK, and Pyr-QKLGNQWAVGHLM) from fluorine-18 using the ELIXYS FLEX/CHEM® radiosynthesizer in a two-step process is described. First, the prosthetic group, 6-[18F]fluoronicotinyl-2,3,5,6-tetrafluorophenyl ester ([18F]FPy-TFP) was synthesized and subsequently attached to the peptide. The [18F]FPy-peptides were synthesized in 13-26% decay corrected yields from fluorine-18 with high molar activity 1-5 Ci µmol-1 and radiochemical purity of >99% in an overall synthesis time of 97 ± 3 minutes.

Psychosocial variables and presence, severity and prognosis of plantar heel pain: A systematic review of cross-sectional and prognostic associations.

OBJECTIVE: Plantar heel pain (PHP) is often disabling, and persistent symptoms are common. Psychosocial variables are known to affect pain and disability but the association of these factors with PHP has yet to be established. The purpose of the present systematic review was to determine if psychosocial variables are associated with the presence, severity and prognosis of PHP. METHODS: A systematic review of the literature and qualitative synthesis was carried out. Electronic searches of MEDLINE, CINAHL, SPORTDiscus, PsycINFO and EMBASE were undertaken from the inception of the respective databases up to November 2017. Any study design incorporating measurements of psychosocial variables with participants with plantar heel pain were included. The quality of included articles was appraised using the Newcastle Ottawa Scale. RESULTS: Five articles from four studies were included in the review, with a total of 422 participants. Moderate-level evidence suggested a clinically unimportant association with the incidence of PHP and depression, anxiety and stress, and limited evidence suggested a clinically unimportant association with job dissatisfaction. Moderate-level evidence suggested that there may also be an association between depression, anxiety, stress and catastrophization and PHP pain, and between depression, anxiety, stress, catastrophization and kinesiophobia and PHP function. We also found moderate-level evidence that a psychological disorder may be associated with a poorer outcome to shockwave therapy. CONCLUSION: In light of this review, the association of psychosocial variables and plantar heel pain cannot be ruled out. Given recommendations to adopt an individualized and stratified approach to other musculoskeletal conditions, clinicians should remain vigilant to their presence.

Further studies on the iodine concentration of conventional, organic and UHT semi-skimmed milk at retail in the UK.

Milk is the largest source of iodine in UK diets and earlier studies showed organic summer and winter milk to be significantly lower in iodine than conventional milk. One study also showed UHT milk to have lower iodine concentration. The study on winter and UHT milk was small and accordingly a new study is reported here involving conventional, organic and UHT semi-skimmed milk from four supermarkets over a six-month period in summer and winter in two regions of the UK. The results showed organic milk to be 44% lower in iodine than conventional milk (427 vs. 241µg/L, P<0.001) and UHT milk was 27% lower in iodine than conventional milk (427 vs. 314µg/L, P<0.001) although the differences tended to be less in the summer. The results indicate that replacement of conventional milk by organic or UHT milk will increase the risk of sub-optimal iodine status especially for pregnant/lactating women.

How Does Managed Care Improve the Quality of Breast Cancer Care Among Medicare-Insured Minority Women?

PURPOSE: The aim of this study is to investigate if evidence-based clinical guidelines are implemented equitability among ethnic minority breast cancer patients using Medicare Advantage and investigate if presumed advantages of managed care over fee-for-service are greater for minorities than for Whites. METHODS: Data from the Surveillance, Epidemiology, and End Results and Medicare were used to examine 70,755 women over age 65 diagnosed with early stage breast cancer between 2005 and 2009. Implementation of two clinical guidelines was assessed: receipt of radiation therapy after breast conserving surgery and estrogen receptor status documentation. Multilevel logistic regression and inverse propensity weighting controlled for confounding. RESULTS: African Americans are still less likely than Whites to receive radiation therapy after breast-conserving surgery, whether they use Medicare fee-for-service (OR 95 % CI) = 0.90 (0.83, 0.98) or managed care (OR 95 % CI) = 0.87 (0.76, 1.00). Differences between receipt of radiation therapy by insurance plan type was nonexistent. Relative to FFS, the use of managed care improved the odds of having estrogen receptor status documented by 44 % in African Americans, (OR 95 % CI) = 1.44 (1.15, 1.83) and by 42 % in Latina patients (OR 95 % CI) = 1.42 (1.17, 1.78). CONCLUSIONS: Compared to Medicare fee-for-service, ethnic and racial disparities among Medicare Advantage users were reduced. We observed fewer disparities, but not an elimination of disparities, among Medicare Advantage enrollees receiving breast cancer care with an organizational and patient component of care. This suggests managed care may still need to focus on minority patient empowerment and involvement in care.

Sodium Hydroxide Enhances Extractability and Analysis of Proanthocyanidins in Ensiled Sainfoin (Onobrychis viciifolia).

Little information exists on the effects of ensiling on condensed tannins or proanthocyanidins. The acetone-butanol-HCl assay is suitable for measuring proanthocyanidin contents in a wide range of samples, silages included, but provides limited information on proanthocyanidin composition, which is of interest for deciphering the relationships between tannins and their bioactivities in terms of animal nutrition or health. Degradation with benzyl mercaptan (thiolysis) provides information on proanthocyanidin composition, but proanthocyanidins in several sainfoin silages have proved resistant to thiolysis. We now report that a pretreatment step with sodium hydroxide prior to thiolysis was needed to enable their analysis. This alkaline treatment increased their extractability from ensiled sainfoin and facilitated especially the release of larger proanthocyanidins. Ensiling reduced assayable proanthocyanidins by 29%, but the composition of the remaining proanthocyanidins in silage resembled that of the fresh plants.

Effect of milk type and processing on iodine concentration of organic and conventional winter milk at retail: implications for nutrition.

Milk is the largest source of iodine in UK diets and an earlier study showed that organic summer milk had significantly lower iodine concentration than conventional milk. There are no comparable studies with winter milk or the effect of milk fat class or heat processing method. Two retail studies with winter milk are reported. Study 1 showed no effect of fat class but organic milk was 32.2% lower in iodine than conventional milk (404 vs. 595 µg/L; P<0.001). Study 2 found no difference between conventional and Channel Island milk but organic milk contained 35.5% less iodine than conventional milk (474 vs. 306 µg/L; P<0.001). UHT and branded organic milk also had lower iodine concentrations than conventional milk (331 µg/L; P<0.001 and 268 µg/L: P<0.0001 respectively). The results indicate that replacement of conventional milk by organic or UHT milk will increase the risk of sub-optimal iodine status especially for pregnant/lactating women.

Protein Precipitation Behavior of Condensed Tannins from Lotus pedunculatus and Trifolium repens with Different Mean Degrees of Polymerization.

The precipitation of bovine serum albumin (BSA), lysozyme (LYS), and alfalfa leaf protein (ALF) by two large- and two medium-sized condensed tannin (CT) fractions of similar flavan-3-ol subunit composition is described. CT fractions isolated from white clover flowers and big trefoil leaves exhibited high-purity profiles by 1D/2D NMR and purities >90% (determined by thiolysis). At pH 6.5, large CTs with a mean degree of polymerization (mDP) of ∼18 exhibited similar protein precipitation behaviors and were significantly more effective than medium CTs (mDP ∼9). Medium CTs exhibited similar capacities to precipitate ALF or BSA, but showed small but significant differences in their capacity to precipitate LYS. All CTs precipitated ALF more effectively than BSA or LYS. Aggregation of CT-protein complexes likely aided precipitation of ALF and BSA, but not LYS. This study, one of the first to use CTs of confirmed high purity, demonstrates that the mDP of CTs influences protein precipitation efficacy.

¹H-¹³C HSQC NMR spectroscopy for estimating procyanidin/prodelphinidin and cis/trans-flavan-3-ol ratios of condensed tannin samples: correlation with thiolysis.

Studies with a diverse array of 22 purified condensed tannin (CT) samples from nine plant species demonstrated that procyanidin/prodelphinidin (PC/PD) and cis/trans-flavan-3-ol ratios can be appraised by (1)H-(13)C HSQC NMR spectroscopy. The method was developed from samples containing 44-∼100% CT, PC/PD ratios ranging from 0/100 to 99/1, and cis/trans ratios ranging from 58/42 to 95/5 as determined by thiolysis with benzyl mercaptan. Integration of cross-peak contours of H/C-6' signals from PC and of H/C-2',6' signals from PD yielded nuclei-adjusted estimates that were highly correlated with PC/PD ratios obtained by thiolysis (R(2) = 0.99). cis/trans-Flavan-3-ol ratios, obtained by integration of the respective H/C-4 cross-peak contours, were also related to determinations made by thiolysis (R(2) = 0.89). Overall, (1)H-(13)C HSQC NMR spectroscopy appears to be a viable alternative to thiolysis for estimating PC/PD and cis/trans ratios of CT if precautions are taken to avoid integration of cross-peak contours of contaminants.

Functional fluorescently labeled bithiazole ΔF508-CFTR corrector imaged in whole body slices in mice.

We previously reported the identification and structure-activity analysis of bithiazole-based correctors of defective cellular processing of the cystic fibrosis-causing CFTR mutant, ΔF508-CFTR. Here, we report the synthesis and uptake of a functional, fluorescently labeled bithiazole corrector. Following synthesis and functional analysis of four bithiazole-fluorophore conjugates, we found that 5, a bithazole-based BODIPY conjugate, had low micromolar potency for correction of defective ΔF508-CFTR cellular misprocessing, with comparable efficacy to benchmark corrector corr-4a. Intravenous administration of 5 to mice established its stability in extrahepatic tissues for tens of minutes. By fluorescence imaging of whole-body frozen slices, fluorescent corrector 5 was visualized strongly in gastrointestinal organs, with less in lung and liver. Our results provide proof-of-concept for mapping the biodistribution of a ΔF508-CFTR corrector by fluorophore labeling and fluorescence imaging of whole-body slices.

Armodafinil in the treatment of sleep/wake disorders.

Excessive sleepiness (ES) is a major but underestimated public health concern associated with significant impairments in alertness/wakefulness and significant morbidity. The term ES has been used in the sleep medicine literature for years, but due to its nonspecific symptoms (ie tiredness or fatigue), it frequently goes unrecognized or is misdiagnosed in primary care. In some cases ES arises due to poor sleep habits or self-imposed sleep deprivation; however, ES is also a key component of a number of sleep/wake disorders and multiple medical and psychiatric disorders. Identification and treatment of ES is critical to improve the quality of life and well-being of patients and for the safety of the wider community. The inability of patients to recognize the nature, extent, and symptomatic profile of sleep/wake disorders requires vigilance on the part of healthcare professionals. Interventions to address ES and its associated impairments, treatment of the underlying sleep/wake disorder, and follow-up are a priority given the potential for serious consequences if left untreated. Wakefulness-promoting agents are available that treat ES associated with sleep/wake disorders. This review examines current approaches for managing this debilitating and potentially life-threatening condition, focusing on the place of armodafinil as a wakefulness-promoting agent.