Regulation of cell proliferation in the retinal pigment epithelium: differential regulation of the death associated protein like-1 DAPL1 by alternative MITF splice forms

Summary

Vertebrate eye development and homoeostasis critically depend on the regulation of proliferation of cells forming the retinal pigment epithelium (RPE). Previous results indicated that the death associated protein like-1 DAPL1 cell-autonomously suppresses RPE proliferation in vivo and in vitro. Here we show in human RPE cell lines that the pigment cell transcription factor MITF regulates RPE cell proliferation by upregulating DAPL1 expression. DAPL1 regulation by MITF is, however, mediated predominantly by (-) MITF, one of two alternative splice isoforms of MITF that lacks six residues located upstream of the DNA binding basic domain. Furthermore, we find that the regulation of DAPL1 by MITF is indirect in that (-) MITF stimulates the transcription of Musashi-homolog-2 (MSI2), which negatively regulates the processing of the anti-DAPL1 microRNA miR-7. Our results provide molecular insights into the regulation of RPE cell proliferation and quiescence and may help us understand the mechanisms of normal RPE maintenance and of eye diseases associated with either RPE hyperproliferation or the lack of regenerative proliferation.

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Metastasis-specific patterns of response and progression with anti-PD-1 treatment in metastatic melanoma

Summary

This study evaluated patterns of response as discerned by comprehensive metastasis-specific analysis in metastatic melanoma patients receiving anti-PD-1 antibodies. Bi-dimensional measurements of every metastasis in patients enrolled in the KEYNOTE-001 trial at a single institution were obtained at baseline and throughout treatment. Twenty-seven evaluable patients had 399 baseline metastases measurable on CT imaging. Complete response (CR) which occurred in 52.6% of metastases was smaller (mean 223mm² vs. 760mm², p < 0.01) and occurred more frequently in the lungs (65% vs 39.4%, p < 0.01). Response was heterogenous (new/progressing metastases alongside CR metastases) at first assessment in 4/14 patients with objective response (OR) as opposed to 7/13 patients with non-OR. CR of individual metastases is common and influenced by site and size. Most patients with OR demonstrate homogenous regression in all metastases at the first assessment. In contrast, patients with early heterogeneity had a poor outcome.

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Acid hydrolysis reveals a low but constant level of pheomelanin in human black to brown hair

Summary

We previously reported a constant ratio of the benzothiazole-pheomelanin marker thiazole-2,4,5-tricarboxylic acid (TTCA) to the eumelanin marker pyrrole-2,3,5-tricaboxylic acid (PTCA) in eumelanic, black human hair. A constant level (20-25%) of benzothiazole-type pheomelanin was recently demonstrated in human skin with varying concentrations of melanin. Therefore, in this study, we aimed to investigate the origin of pheomelanin markers in black to brown human hair by developing a method to remove protein components from hair by heating with 6 M HCl at 110°C for 16 h. For comparison, synthetic melanins were prepared by oxidizing mixtures of varying ratios of dopa and cysteine with tyrosinase. Hair melanins and synthetic melanins were subjected to acid hydrolysis followed by alkaline H₂O₂ oxidation. The results show that the hydrolysis leads to decarboxylation of the 5,6-dihydroxyindole-2-carboxylic acid moiety in eumelanin and the benzothiazole moiety in pheomelanin and that eumelanic human hair contains 11 to 17% benzothiazole-type pheomelanin.

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Issue Information

Photodermatology and Photomedicine: Meeting Calendar

ESPD Photodermatology Day, Program and Abstracts

Oral keratinocytes synthesize CTACK: a new insight into the pathophysiology of the oral mucosa

Abstract

The skin-associated chemokine CTACK plays a key role in many inflammatory conditions and could be instrumental in the pathophysiology of tissue-specific immunological diseases such as oral lichen planus (OLP). In the present study, we investigated by RT-PCR, ELISA, chemotaxis assays, and fluorescence-activated cell sorting (FACS) the production of CTACK in oral keratinocytes, its expression in tissues from normal and OLP patients, and its role in T cell recruitment. CTACK was produced by the oral epithelium and it affects chemotaxis of memory CLA+ cells to the oral epithelium. CTACK mRNA was expressed constitutively in primary oral epithelium and was increased during pro-inflammatory IFN-γ treatment. We found a constitutive production of CTACK at a protein level in oral primary cells that increased after IFN-γ treatment. Moreover, we confirmed that CTACK attracts memory T cells and those T cells that express CLA above the level of basal migration.

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On the Validity of Beer-Lambert Law and its Significance for Sunscreens

Abstract

The sun protection factor (SPF) is the most important quantity to characterize the performance of sunscreens. As the standard method for its determination is based on clinical trials involving irradiation of human volunteers, calculations of sunscreen performance have become quite popular in order to reduce the number of in vivo studies. Such simulations imply the calculation of UV-transmittance of the sunscreen film using the amounts and spectroscopic properties of the UV-absorbers employed, and presuppose the validity of the Beer-Lambert law. As sunscreen films on human skin can contain considerable concentrations of UV-absorbers, it is questioned whether the Beer-Lambert law is still valid for these systems. The results of this work show, that the validity of the Beer-Lambert law is still given at the high concentrations at which of UV-absorbers occur in sunscreen films on human skin.

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Evaluation of three experimental in vitro models for the assessment of the mechanical cleansing efficacy of wound irrigation solutions

Abstract

The aim of this study was to compare different wound-rinsing solutions to determine differences in the efficiency and to evaluate three different in vitro models for wound cleansing. Different wound-rinsing solutions (physiological saline solution, ringer lactate solution for wound irrigation, water and a solution containing polihexanide and the surfactant undecylenamidopropyl-betain) were applied on standardised test models (one- and three-chamber model, flow-cell method and a biofilm model), each challenged with three different standardised wound test soils. In the one-chamber model saline showed a better effect on decontaminating proteins than the ringer lactate solution. In the flow-cell method, water performed better than physiological saline solution, whereas ringer lactate solution demonstrated the lowest cleansing effect. No obvious superiority between the two electrolyte-containing solutions was detectable in the biofilm model. Unfortunately, it was not possible to assess the protein decontamination qualities of the surfactant-containing solution because of the interference with the protein measurement. The flow-cell method was able to detect differences between different rinse solutions because it works at constant flow mechanics, imitating a wound-rinsing procedure. The three-chamber and the less-pronounced modified one-chamber method as well as the biofilm model had generated inhomogeneous results.

Unilateral pectoralis major muscle flap for the treatment of sternal wounds due to Ludwig's angina

Abstract

Necrotising descending mediastinitis may rarely originate from Ludwig's angina, which is an infection of the submandibular space. The use of the bilateral pectoralis major muscle flap for the treatment of sternal wound dehiscence is common, but reports of the unilateral application of this flap are scarce. This study aims to report the use of the unilateral pectoralis major muscle flap for the treatment of sternotomy dehiscence in a patient with mediastinitis due to Ludwig's angina. A 21-year-old male patient underwent an exploratory cervicotomy and median sternotomy for drainage of a submandibular infection that extended to the anterior, retropharyngeal and mediastinal cervical spaces. The patient had dehiscence of the sternal wound, and the unilateral pectoralis major muscle flap was used for reconstruction of the defect. This flap was able to completely cover the area of dehiscence of the sternotomy, and the patient presented a good postoperative evolution, without complications. The reconstruction technique using the unilateral pectoralis major muscle flap was considered a good option for the treatment of sternotomy dehiscence. It is an adjuvant method in the treatment of infections such as mediastinitis and osteomyelitis of the sternum secondary to Ludwig's angina, allowing a stable coverage of the sternum.

Mechanical effects of negative pressure wound therapy on abdominal wounds – effects of different pressures and wound fillers

Abstract

The mechanical deformation of the wound edge resulting from negative pressure wound therapy (NPWT) at the standard setting of around −120 mmHg has positive effects in promoting wound healing. However, it may cause pain to the patient during treatment. It is therefore important to study the mechanical effects of the wound edges using lower pressure and different wound fillers. Abdominal wounds were created on eight pigs. The wounds were sealed for NPWT using foam or gauze. Negative pressures between −20 and −160 mmHg were applied, and the decrease in wound diameter and the force with which the edges of the wound were drawn together (wound edge force) were measured. Increasing levels of negative pressure resulted in a gradual decrease in wound diameter and increase in wound edge force and reached a maximum at −120 mmHg, which is the pressure commonly used in clinical practice. Both the decrease in wound diameter and the increase in wound edge force was greater with foam than with gauze. A pressure of −80 mmHg has only 15% less effect than −120 mmHg, while a lower pressure (−40 mmHg) diminished the effects on diameter and force markedly. The NPWT-induced decrease in wound diameter and increase in wound edge force are greater at higher levels of negative pressure and when using foam than when using gauze as a wound filler. It may be possible to tailor the type of wound filler and level of negative pressure to obtain the best balance between wound healing and patient comfort.

Negative pressure wound therapy in complex cranio-maxillofacial and cervical wounds

Abstract

The care and the management of the healing of difficult wounds at the level of the skull-facial face many problems related to patient compliance and the need to perform multiple dressings, with long periods of healing and, occasionally, a very long hospitalisation period. The introduction and evolution of negative pressure wound therapy (NPWT) in the treatment of difficult wounds has resulted in better healing, with a drastic reduction in terms of time and biological costs to the patient and cost to the health care system. The main aim of this study is to describe and discuss, using out our experience, the usefulness of NPWT in the cranial-facial-cervical region. We studied 16 patients with complex wounds of the cranial-facial-cervical region treated with NPWT. We divided clinical cases in four groups: cervicofacial infectious disease, healing complications in oncological-reconstructive surgery, healing complications of injury with exposure of bone and/or internal fixations and healing complications in traumatic injury with loss of substance. We evaluated complete or incomplete wound healing; application time, related also to hospitalisation time; days of intensive care unit (ICU) stay; management of the upper airways; timing of medication renewal; and patient comfort and compliance (on a scale of 1–5). Depression values were always between −75 and −125 mmHg in a continuous aspiration pattern. For every patient, we used the ActiVAC Therapy Unit, derived from the vacuum-assisted closure system (Kinetic Concepts Inc., San Antonio, TX). Medication renewals were performed every 48–72 hours. The NPWT application time ranged from 4 to 22 days (mean of 11·57 day). Therapy was effective to gain a complete restitutio ad integrum in every patient included in the group of cervicofacial infectious disease. Therapy has, however, been well tolerated in our series; this is probably due to the decreased number of applications, the ease of use and the comfort of the system relative to traditional dressing. Results were satisfactory for most of cases treated; faster and more effective wound healing was achieved. The lower number of NPWT applications, relating to standard dressings, led to an increase in patient comfort and compliance and a decrease in the use of medical, and in some cases economic, resources according to international literature.

In vitro determination of Mexican Mestizo hair shaft diameter using optical coherence tomography

Abstract

Background

Mexican mestizo population has a pluriethnic mixture of Amerindian, European and African ancestry, predominant in most Latin American countries. Until now, there are no reports about hair characteristics in this population, necessary to define normal values, for hair diseases evaluation and comparison among other ethnic groups.

Methods

The VivoSight^® swept-source multibeam optical coherence tomography system was used to evaluate hair diameter and shape in 30 females. Three hair samples from each volunteer were measured transversely along three distances, generating nine cross-sectional images, two measurements per image and 18 measurements per patient for a total of 540 diameter measurements.

Results

Minimum hair diameter (n = 540) was 0.06 mm while maximum was 0.14 mm. Mean diameter was 0.10 ± 0.01 mm as compared with Asian hair, which ranges from 0.08 mm to 0.12 mm. On morphological analysis, Mexican Mestizo hair tends to have a round shape with homogenous diameters, resembling Caucasian and Asian hair.

Conclusion

Mexican hair is similar to Asian hair in diameter and shape and can be classified as 'thick' hair, which make it more resistant and with more volume. Cosmetic products intended to improve hair care in this population must to consider this characteristic.

Concerns about a New Preterm MR Imaging Scoring System [LETTERS]

Reply: [LETTERS]

The Role of Hemodynamics in Intracranial Bifurcation Arteries after Aneurysm Treatment with Flow-Diverter Stents [INTERVENTIONAL]

BACKGROUND AND PURPOSE:

Treatment of intracranial bifurcation aneurysms with flow-diverter stents can lead to caliber changes of the distal vessels in a subacute phase. This study aims to evaluate whether local anatomy and flow disruption induced by flow-diverter stents are associated with vessel caliber changes in intracranial bifurcations.

MATERIALS AND METHODS:

Radiologic images and demographic data were acquired for 25 patients with bifurcation aneurysms treated with flow-diverter stents. Whisker plots and Mann-Whitney rank sum tests were used to evaluate if anatomic data and caliber changes could be linked. Symmetry/asymmetry were defined as diameter ratio 1 = symmetric and diameter ratio <1 = asymmetric. Computational fluid dynamics was performed on idealized and patient-specific anatomies to evaluate flow changes induced by flow-diverter stents in the jailed vessel.

RESULTS:

Statistical analysis identified a marked correspondence between asymmetric bifurcation and caliber change. Symmetry ratios were lower for cases showing narrowing or subacute occlusion (medium daughter vessel diameter ratio = 0.59) compared with cases with posttreatment caliber conservation (medium daughter vessel diameter ratio = 0.95). Computational fluid dynamics analysis in idealized and patient-specific anatomies showed that wall shear stress in the jailed vessel was more affected when flow-diverter stents were deployed in asymmetric bifurcations (diameter ratio <0.65) and less affected when deployed in symmetric anatomies (diameter ratio ~1.00).

CONCLUSIONS:

Anatomic data analysis showed statistically significant correspondence between caliber changes and bifurcation asymmetry characterized by diameter ratio <0.7 (P < .001). Similarly, computational fluid dynamics results showed the highest impact on hemodynamics when flow-diverter stents are deployed in asymmetric bifurcations (diameter ratio <0.65) with noticeable changes on wall sheer stress fields. Further research and clinical validation are necessary to identify all elements involved in vessel caliber changes after flow-diverter stent procedures.

Temporal Lobe Malformations in Achondroplasia: Expanding the Brain Imaging Phenotype Associated with FGFR3-Related Skeletal Dysplasias [PEDIATRICS]

SUMMARY:

Thanatophoric dysplasia, achondroplasia, and hypochondroplasia belong to the fibroblast growth factor receptor 3 (FGFR3) group of genetic skeletal disorders. Temporal lobe abnormalities have been documented in thanatophoric dysplasia and hypochondroplasia, and in 1 case of achondroplasia. We retrospectively identified 13 children with achondroplasia who underwent MR imaging of the brain between 2002 and 2015. All children demonstrated a deep transverse temporal sulcus on MR imaging. Further common neuroimaging findings were incomplete hippocampal rotation (12 children), oversulcation of the mesial temporal lobe (11 children), loss of gray-white matter differentiation of the mesial temporal lobe (5 children), and a triangular shape of the temporal horn (6 children). These appearances are very similar to those described in hypochondroplasia, strengthening the association of temporal lobe malformations in FGFR3-associated skeletal dysplasias.

Feasibility of Brain Atrophy Measurement in Clinical Routine without Prior Standardization of the MRI Protocol: Results from MS-MRIUS, a Longitudinal Observational, Multicenter Real-World Outcome Study in Patients with Relapsing-Remitting MS [ADULT BRAIN]

BACKGROUND AND PURPOSE:

Feasibility of brain atrophy measurement in patients with MS in clinical routine, without prior standardization of the MRI protocol, is unknown. Our aim was to investigate the feasibility of brain atrophy measurement in patients with MS in clinical routine.

MATERIALS AND METHODS:

Multiple Sclerosis and Clinical Outcome and MR Imaging in the United States (MS-MRIUS) is a multicenter (33 sites), retrospective study that included patients with relapsing-remitting MS who began treatment with fingolimod. Brain MR imaging examinations previously acquired at the baseline and follow-up periods on 1.5T or 3T scanners with no prior standardization were used, to resemble a real-world situation. Brain atrophy outcomes included the percentage brain volume change measured by structural image evaluation with normalization of atrophy on 2D-T1-weighted imaging and 3D-T1WI and the percentage lateral ventricle volume change, measured by VIENA on 2D-T1WI and 3D-T1WI and NeuroSTREAM on T2-fluid-attenuated inversion recovery examinations.

RESULTS:

A total of 590 patients, followed for 16 months, were included. There were 585 (99.2%) T2-FLAIR, 425 (72%) 2D-T1WI, and 166 (28.2%) 3D-T1WI longitudinal pairs of examinations available. Excluding MR imaging examinations with scanner changes, the analyses were available on 388 (65.8%) patients on T2-FLAIR for the percentage lateral ventricle volume change, 259 and 257 (43.9% and 43.6%, respectively) on 2D-T1WI for the percentage brain volume change and the percentage lateral ventricle volume change, and 110 (18.6%) on 3D-T1WI for the percentage brain volume change and percentage lateral ventricle volume change. The median annualized percentage brain volume change was –0.31% on 2D-T1WI and –0.38% on 3D-T1WI. The median annualized percentage lateral ventricle volume change was 0.95% on 2D-T1WI, 1.47% on 3D-T1WI, and 0.90% on T2-FLAIR.

CONCLUSIONS:

Brain atrophy was more readily assessed by estimating the percentage lateral ventricle volume change on T2-FLAIR compared with the percentage brain volume change or percentage lateral ventricle volume change using 2D- or 3D-T1WI in this observational retrospective study. Although measurement of the percentage brain volume change on 3D-T1WI remains the criterion standard and should be encouraged in future prospective studies, T2-FLAIR–derived percentage lateral ventricle volume change may be a more feasible surrogate when historical or other practical constraints limit the availability of percentage brain volume change on 3D-T1WI.

Vertebroplasty and Kyphoplasty for Osteoporotic Vertebral Fractures: What Are the Latest Data? [REVIEW ARTICLE]

SUMMARY:

Osteoporotic vertebral compression fractures frequently result in significant morbidity and health care resource use. For patients with severe and disabling pain, vertebral augmentation (vertebroplasty and kyphoplasty) is often considered. Although vertebroplasty was introduced >30 years ago, there are conflicting opinions regarding the role of these procedures in the treatment of osteoporotic vertebral compression fractures. This review article updates clinicians on the published prospective randomized controlled data, including the most recent positive trials that followed initial negative trials in 2009. Analysis of multiple national claim datasets has also provided further insight into the utility of these procedures. Finally, we considered the recent recommendations of national organizations and medical societies that advise on the use of vertebral augmentation procedures for osteoporotic vertebral compression fractures.

Optimization of Quantitative Dynamic Postgadolinium MRI Technique Using Normalized Ratios for the Evaluation of Temporomandibular Joint Synovitis in Patients with Juvenile Idiopathic Arthritis [HEAD & NECK]

BACKGROUND AND PURPOSE:

MR imaging has been shown to be useful in the diagnosis of juvenile idiopathic arthritis of the temporomandibular joint. Prior MR imaging approaches have relied mainly on the subjective interpretation of synovial enhancement as a marker for synovial inflammation. Although, more recently, several attempts have been made to quantify synovial enhancement, these methods have not taken into account the dynamic enhancement characteristics of the temporomandibular joint and the effect of sampling time. Our aim was to develop a clinically feasible, reproducible, dynamic, contrast-enhanced MR imaging technique for the quantitative assessment of temporomandibular joint synovitis in patients with juvenile idiopathic arthritis and to study the effect of sampling time on the evaluation of synovitis.

MATERIALS AND METHODS:

This was a retrospective study of all patients who had dynamic, contrast-enhanced coronal T1 3T MR imaging through the temporomandibular joint at our institution between January 1, 2015, and July 8, 2016. Patients in this cohort included those with a history of juvenile idiopathic arthritis and control patients who underwent MR imaging for other routine, clinical purposes. Synovial enhancement was calculated for each temporomandibular joint using 3 different types of equations termed normalization ratios. The enhancement profiles generated by each equation were studied to determine which provided the best discrimination between affected and unaffected joints, was the least susceptible to sampling errors, and was the most clinically feasible.

RESULTS:

A ratio of synovial enhancement (defined as the difference between the postgadolinium and the pregadolinium T1 signal of the synovium) to the postgadolinium signal of the longus capitis provided the best discrimination between affected and unaffected joints, the least susceptibility to sampling error, and was thought to be the most clinically feasible method of quantification of synovial inflammation. Additional synovial enhancement ratios studied did not provide the same level rates of discrimination between the affected and unaffected joints and were thought to be too temporally variable to provide reliable clinical use.

CONCLUSIONS:

We provide a robust, reproducible, dynamic gadolinium-enhanced MR imaging technique for the quantitative assessment of temporomandibular joint synovitis in patients with juvenile idiopathic arthritis.

Leukoaraiosis Attenuates Diagnostic Accuracy of Large-Vessel Occlusion Scales [INTERVENTIONAL]

BACKGROUND AND PURPOSE:

Prehospital stroke scales may help identify patients likely to have large-vessel occlusion to facilitate rapid triage to thrombectomy-capable stroke centers. Scale misclassification may result in inaccurate decisions and possible harm. Pre-existing leukoaraiosis has been shown to attenuate the association between deficit type and stroke severity. We sought to determine whether leukoaraiosis affects the predictive ability of 5 commonly used large-vessel occlusion scales.

MATERIALS AND METHODS:

We retrospectively analyzed 274 consecutive patients with stroke with available brain MR imaging and vessel imaging. We used the following large-vessel occlusion scales: the 3-Item Stroke Scale; Field Assessment Stroke Triage for Emergency Destination; Rapid Arterial Occlusion Evaluation; Vision, Aphasia, Neglect score; and Cincinnati Prehospital Stroke Severity Scale. For diagnostic scale accuracy, we assessed sensitivity, specificity, positive predictive value, negative predictive value, and . Multivariable logistic regression was used to determine the predictive ability of the scales after adjustment for leukoaraiosis and potential confounders.

RESULTS:

In unadjusted analyses, all scales predicted the presence of large-vessel occlusion (n = 46, P < .01 each), though diagnostic accuracy was attenuated among patients with moderate-to-severe leukoaraiosis. After adjustment, the Field Assessment Stroke Triage for Emergency Destination (OR = 3.2; 95% CI, 1.1–9.5; P = .033) and Rapid Arterial Occlusion Evaluation (OR = 3.7; 95% CI, 1.3–10.8; P = .015), but not the 3-Item Stroke Scale (OR = 5.4; 95% CI, 0.86–33.9; P = .073), Vision, Aphasia, Neglect score (OR = 2.5; 95% CI, 0.8–7.2), and Cincinnati Prehospital Stroke Severity Scale (OR = 2.8; 95% CI, 1.0–8.0), predicted large-vessel occlusion.

CONCLUSIONS:

The diagnostic accuracy of the tested large-vessel occlusion scales was attenuated in the presence of moderate-to-severe leukoaraiosis. This information that may aid the design of future studies that require large-vessel occlusion scale screening of patients who are likely to have concomitant leukoaraiosis.

Posttreatment Infarct Volumes when Compared with 24-Hour and 90-Day Clinical Outcomes: Insights from the REVASCAT Randomized Controlled Trial [INTERVENTIONAL]

BACKGROUND AND PURPOSE:

Endovascular therapy has become the standard of care for patients with disabling anterior circulation ischemic stroke due to proximal intracranial thrombi. Our aim was to determine whether the beneficial effect of endovascular treatment on functional outcome could be explained by a reduction in posttreatment infarct volume in the Endovascular Revascularization With Solitaire Device Versus Best Medical Therapy in Anterior Circulation Stroke Within 8 Hours (REVASCAT) trial.

MATERIALS AND METHODS:

The REVASCAT trial was a multicenter randomized open-label trial with blinded outcome evaluation. Among 206 enrolled subjects (endovascular treatment, n = 103; control, n = 103), posttreatment infarct volume was measured in 204 subjects. Posttreatment infarct volumes were compared with treatment assignment and recanalization status. Appropriate statistical models were used to assess the relationship among baseline clinical and imaging variables, posttreatment infarct volume, the 24-hour NIHSS score, and functional status with the 90-day modified Rankin Scale score.

RESULTS:

The median posttreatment infarct volume in all subjects was 23.7 mL (interquartile range = 68.9 mL) and 16.3 mL (interquartile range = 50.2 mL) in the endovascular treatment arm and 38.6 mL (interquartile range = 74.9 mL) in the control arm (P = .02 for endovascular treatment versus control subjects). Baseline NIHSS (P < .01), site of occlusion (P < .03), baseline NCCT ASPECTS (P < .01), and recanalization status (P = .02) were independently associated with posttreatment infarct volume. Baseline NIHSS (P < .01), time from symptom onset to randomization (P = .02), treatment type (P = .04), and recanalization status (P < .01) were independently associated with the 24-hour NIHSS scores. The 24-hour NIHSS score strongly mediated the relationship between treatment type and 90-day mRS (P < .01 for indirect effect when adjusted for age), while posttreatment infarct volume did not (P = .26).

CONCLUSIONS:

Endovascular treatment saves brain and improves 90-day clinical outcomes primarily through a beneficial effect on the 24-hour stroke severity.

Perivascular Spaces in Old Age: Assessment, Distribution, and Correlation with White Matter Hyperintensities [ADULT BRAIN]

BACKGROUND AND PURPOSE:

The visual rating scales for perivascular spaces vary considerably. We sought to develop a new scale for visual assessment of perivascular spaces and to further describe their distribution and association with white matter hyperintensities in old age.

MATERIALS AND METHODS:

This population-based study included 530 individuals who did not have dementia and were not institutionalized (age, ≥60 years or older; mean age, 70.7 years; 58.9% women) who were living in central Stockholm, Sweden. A semiquantitative visual rating scale was developed to score the number and size of visible perivascular spaces in 7 brain regions in each hemisphere. A modified Scheltens visual rating scale was used to assess white matter hyperintensities.

RESULTS:

The global scores for perivascular spaces ranged from 4–32 for number, 3–22 for size, and 7–54 for the combination of number and size. The weighted statistics for the intra- and interrater reliability both were 0.77. The global score for the number of perivascular spaces increased with advancing age (P < .001). The scores for the number of perivascular spaces in the basal ganglia and subinsular regions were significantly correlated with the load of white matter hyperintensities, especially in lobar and deep white matter regions (partial correlation coefficients, >0.223; P < .01).

CONCLUSIONS:

The new visual rating scale for perivascular spaces shows excellent intra- and interrater reliability. The number of perivascular spaces globally and, especially, in the basal ganglia, is correlated with the load of lobar and deep white matter hyperintensities, supporting the view that perivascular spaces are a marker for cerebral small-vessel disease.

An exploratory open-label, investigator-initiated study to evaluate the efficacy and safety of combination sonidegib and buparlisib for advanced basal cell carcinomas

Climate mitigation, low-carbon society, and dynamism of educational institutes in a low-income country

Abstract

This paper aims to investigate carbon footprints of faculty members of University of Agriculture Faisalabad (UAF) associated with income and education in pursuance of a low-carbon society. For the study, 140 UAF faculty members (professors, associate professors, assistant professors, and lecturers) were selected using stratified random sampling technique, and a representative questionnaire was used to record primary data. Moreover, the ordinary least square (OLS) method was used to explain the statistical relationship between income, education, and carbon footprints. It was found that carbon footprints of UAF faculty members were 10.06 metric tons (mt) per year per person on an average. Our results further indicated that carbon footprints of assistant professors, associate professors, and professors were 10.83, 11.95, and 10.96 mt per person per annum, respectively. OLS estimates showed that an increase in one Doctor of Philosophy (Ph.D.) faculty member increases the carbon footprint by 1.15 mt per annum. Male faculty members emit more carbon footprints than females. Faculty members of Tenure Track System (TTS) had a higher income than those of Basic Pay Scale (BPS). Therefore, emissions of TTS faculty members were higher. Hence, in order to reduce carbon footprints and corroborate UAF campus environment-friendly, the attitude towards this aspect should be changed and awareness should be created. Furthermore, reduced car usage can be another bottom-up policy suggestion. As witnessed in green campuses of international universities, UAF should also be a motor-free campus (cycling and pedestrian only).

Facts and Values in Pragmatism and Logical Empiricism: Addressing the Eclipse Narrative

Abstract

The story of the rise and fall of pragmatism is sometimes called the eclipse narrative. This paper addresses a specific version of this narrative that the logical empiricists arrived in North America in the 1930s and within 30 years had supplanted the pragmatists as the dominant philosophy there. Philosophers such as Alan Richardson and Cheryl Misak have challenged this view by emphasizing the similarities between these two movements. While both seem to admit that there is a distinction between the two when it comes to values, I point out that the issue of values feeds into all aspects of pragmatist thinking, and so despite what seems on the surface to be agreements between the two movements, they were still quite different in all areas of their thinking. I challenge the degree of similarities by arguing that there were some sharp distinctions between the two movements, with the most important being the fact-value distinction and its impact on how each conceived of the term "practical." I close by addressing how these distinctions should affect how we conceive of the eclipse narrative.

Chemometric and high-resolution mass spectrometry tools for the characterization and comparison of raw and treated wastewater samples of a pilot plant on the SIPIBEL site

Abstract

Due to its key role in the contamination of natural resources, the assessment of raw and treated wastewater effluents is a current major concern and urges comprehensive analytical methods capable of selectively capturing the chemodiversity of these samples. In this context, the overall objective of this work can be summarized as (i) the assessment of the performance of secondary and tertiary (advanced oxidation) wastewater treatments through multivariate analysis followed by (ii) the comprehensive characterization of wastewater samples based on their spectral fingerprints and a combination of suspect and non-target screening approaches. Several compounds, belonging to different sources of contamination were annotated and/or partially identified: pharmaceuticals, metabolites and transformation compounds, human activity markers, surfactants, and polyethoxy compounds. These results highlight the contribution of filtering and screening tools such as monoisotopic exact mass, mass defect, MS/MS data-dependent acquisitions, isotopic pattern and retention time to the selection, and the identification of environmental contaminants and their metabolites/degradation products. This paper completes the target study conducted in the SIPIBEL site and offers an alternative for the assessment of treatment processes by broadening the spectrum to a larger number of compounds and the correlations between them.

Recycling of wastes from fish beneficiation by composting: chemical characteristics of the compost and efficiency of their humic acids in stimulating the growth of lettuce

Abstract

Waste from the beneficiation of fish was composted with crushed grass aiming to characterize their chemical composition and investigate the possibility of the use of the final compost as source of humic acids (HA) able to stimulate the growth of lettuce. Compost presented pH value, C/N ratio, and electrical conductivity that allow its use as an organic fertilizer. The element content was present in the following order of abundance in the compost: P > Ca > N > Mg > K > Fe > Zn > Mn > Mo > Cu, and the humus composition was similar to that observed in others kind of organic residues composted. The high content of oxygen pointed out a high level of oxidation of HA, in line with the predominance of phenolic acidity in the functional groups. The ¹³C-NMR spectra showed marked resonances due to the presence of lipids and other materials resistant to degradation as methoxy substituent and N-alkyl groups. A concentration of 20 mg L⁻¹ HA increased significantly both dry and wet root matter in lettuce but the CO₂ assimilation, stomatal conductance, and number of lateral roots of the plants were not affected. However, increases of 64% in the water-use efficiency was observed due to the HA addition, probably related to the root morphology alteration which resulted in 1.6-fold increase of lateral root average length and due to the higher H⁺ extrusion activity. Reuse of residues from the fish beneficiation activity by composting may represent a safe tool to increase the value of recycled organic residues and generate HA with potential use as plant growth stimulants.

Unequal Exposure or Unequal Vulnerability? Contributions of Neighborhood Conditions and Cardiovascular Risk Factors to Socioeconomic Inequality in Incident Cardiovascular Disease in the Multi-Ethnic Study of Atherosclerosis

Abstract

Risk factors can drive socioeconomic inequalities in cardiovascular disease (CVD) through differential exposure and differential vulnerability. We show how econometric decomposition directly enables simultaneous, policy-oriented assessment of these two mechanisms. We specifically estimated contributions via these mechanisms of neighborhood environment and proximal risk factors to socioeconomic inequality in CVD incidence. We followed 5,608 participants in the Multi-Ethnic Study of Atherosclerosis (2000–2012) until the first CVD event (median follow-up 12.2 years). We used a summary measure of baseline socioeconomic position (SEP). Covariates included baseline demographics, neighborhood, psychosocial, behavioral, and biomedical risk factors. Using Poisson models, we decomposed the difference (inequality) in incidence rates between low- and high-SEP groups into contributions of 1) differences in covariate means (differential exposure), and 2) differences in CVD risk associated with covariates (differential vulnerability). Notwithstanding large uncertainty in neighborhood estimates, our analysis suggests that differential exposure to poorer neighborhood socioeconomic conditions, adverse social environment, diabetes, and hypertension accounts for most of inequality. Psychosocial and behavioral contributions were negligible. Further, neighborhood SEP, female gender, and White race were more strongly associated with CVD among low-SEP (vs. high-SEP) participants. These differentials in vulnerability also accounted for nontrivial portions of the inequality, and could have important implications for intervention.

Maternal and Neonatal Vitamin D Status are not Associated With Risk of Childhood Type 1 Diabetes: A Scandinavian Case-Cohort Study

Abstract

Studies on vitamin D status during pregnancy and risk of type 1 diabetes (T1D) lack consistency, and are limited by small sample sizes or single measures of 25-hydroxyvitamin D (25(OH)D). We investigated whether average maternal 25(OH)D plasma concentrations during pregnancy are associated with risk of childhood T1D. In a case-cohort design, we identified 459 children with T1D and a random sample (n = 1,561) from the Danish National Birth Cohort (n = 97,127) and Norwegian Mother and Child Cohort Study (n = 113,053). Participants were born between 1996 and 2009. The primary exposure was the estimated average 25(OH)D concentration based on serial samples from the first trimester until delivery, and umbilical cord plasma. We estimated hazard ratios using weighted Cox regression adjusting for multiple confounders. The adjusted hazard ratio for T1D per 10 nmol/L increase in the estimated average 25(OH)D concentration was 1.00 (95% confidence interval: 0.90, 1.10). Results were consistent in both cohorts, in multiple sensitivity analyses, and when we analyzed mid-pregnancy or cord blood separately. In conclusion, our large study demonstrated that normal variation in maternal or neonatal 25(OH)D is unlikely to have a clinically important effect on risk of childhood T1D.

Bacillus amyloliquefaciens ssp. plantarum F11 isolated from Algerian salty lake as a source of biosurfactants and bioactive lipopeptides

Abstract

In this study, we identified a new Bacillus strain isolated from an Algerian salty lake that produces metabolites that are active against Gram-positive and Gram-negative bacteria, as well as fungal pathogens. The draft genome sequence of the strain is presented herein. Genome sequence analysis identified the strain to be B. amyloliquefaciens subspecies plantarum F11, and showed that the strain carries the gene clusters for the production of a number of bioactive and surface-active compounds. These include the lipopeptides surfactin and fengycin, antibacterial polyketides macrolactin and bacillaene, and a putative novel lanthipeptide, among others. Through an activity-guided purification method using hydrophobic interaction chromatographic techniques, we confirmed the ability of the strain to produce fengycin lipopeptides. The identities of the isolated fengycin homologues were ascertained through tandem mass spectrometry.

OV21/PETROC: A randomized Gynecologic Cancer Intergroup phase II study of intraperitoneal versus intravenous chemotherapy following neoadjuvant chemotherapy and optimal debulking surgery in epithelial ovarian cancer

Abstract

Background

The purpose of this multistage, adaptively, designed randomized phase II study was to evaluate the role of intraperitoneal (IP) chemotherapy following neoadjuvant chemotherapy (NACT) and optimal debulking surgery in women with epithelial ovarian cancer (EOC).

Patients and Methods

We performed a multicentre, 2 stage, phase II trial. Eligible patients with stage IIB-IVA EOC treated with platinum-based intravenous (IV) NACT followed by optimal (<1cm) debulking surgery were randomized to one of 3 treatment arms: 1) IV carboplatin/paclitaxel; 2) IP cisplatin plus IV/IP paclitaxel, or 3) IP carboplatin plus IV/IP paclitaxel. The primary endpoint was 9 month progressive disease rate (PD9). Secondary endpoints included progression free survival (PFS), overall survival (OS), toxicity and quality of life (QOL).

Results

Between 2009 and 2015, 275 patients were randomized. IP cisplatin containing arm did not progress beyond the first stage of the study after failing to meet the pre-set superiority rule. The final analysis compared IV carboplatin/paclitaxel (n = 101) to IP carboplatin, IV/IP paclitaxel (n = 102). The intention to treat PD9 was lower in the IP carboplatin arm compared to the IV carboplatin arm: 24.5% (95% CI 16.2%-32.9%) vs. 38.6% (95% CI 29.1%- 48.1%) p = 0.065. The study was underpowered to detect differences in PFS: HR PFS 0.82 (95% CI 0.57 - 1.17); p = 0.27 and OS HR 0.80 (95% CI 0.47-1.35) p = 0.40. The IP carboplatin based regimen was well tolerated with no reduction in QOL or increase in toxicity compared to IV administration alone.

Conclusion

In women with stage IIIC or IVA EOC treated with NACT and optimal debulking surgery, IP carboplatin based chemotherapy is well tolerated and associated with an improved PD9 compared to IV carboplatin based chemotherapy.clinicaltrials.gov, NCT01622543

Prevalence and clinical association of gene mutations through Multiplex Mutation Testing in patients with NSCLC: Results from the ETOP Lungscape Project

Abstract

Background

Reported prevalence of driver gene mutations in non-small cell lung cancer (NSCLC) is highly variable and clinical correlations are emerging. Using NSCLC biomaterial and clinical data from the ETOP Lungscape iBiobank, we explore the epidemiology of mutations and association to clinicopathological features and patient outcome (relapse-free survival, time-to-relapse, overall survival).

Methods

Clinically-annotated, resected stage I-III NSCLC FFPE tissue was assessed for gene mutation using a microfluidics-based multiplex PCR platform. Mutant-allele detection sensitivity is > 1% for most of the ∼150 (13 genes) mutations covered in the multiplex test.

Results

Multiplex testing has been performed in 2063 (76.2%) of the 2709 Lungscape cases (median follow-up 4.8 years).FFPE samples mostly date from 2005-8, yet recently extracted DNA quality and quantity was generally good. Average DNA yield/case was 2.63µg; 38 cases (1.4%) failed QC and were excluded from study. 95.1% of included cases allowed the complete panel of mutations to be tested.Most common were KRAS, MET, EGFR and PIK3CA mutations with overall prevalence of 23.0%, 6.8%, 5.4% and 4.9% respectively.KRAS and EGFR mutations were significantly more frequent in adenocarcinomas: PIK3CA in squamous cell carcinomas. MET mutation prevalence did not differ between histology groups.EGFR mutations were found predominantly in never smokers; KRAS in current/former smokers.For all the above mutations, there was no difference in outcome between mutated and non-mutated cases.

Conclusion

Archival FFPE NSCLC material is adequate for multiplex mutation analysis. In this large, predominantly European, clinically-annotated stage I-III NSCLC cohort, none of the mutations characterized showed prognostic significance.

New antiemetics: facing the current challenge

Sampling of Wide Local Excision Specimens in Cutaneous Malignant Melanoma

Background

Wide local excisions (WLE) are frequently undertaken in the management of cutaneous melanoma; however there is considerable variability in their macroscopic sampling. The aim of our study was to establish evidence-based guidelines for the macroscopic handling of these specimens with a subsequent review of the impact on our service.

Methods

The study group of 128 cases with initial biopsy and subsequent WLE in our institution in 2010 were identified by a computer-generated search. From analysis of this group, guidelines for macroscopic sampling were derived with a repeat search performed in 2012.

Results

Residual melanoma was detected only in those cases in which the original specimen had clear margins of ≤1mm or with a pigmented lesion. A 32% increase in case numbers was noted over this period with a reduction of 6.2% in block numbers. Average block numbers per case were reduced by 2.3 (30.7%).

Conclusions

We have shown that for WLE specimens with no evidence of a macroscopic lesion and clear margins on original biopsy, little is to be gained from extensive sampling. In these cases we recommend a maximum of 3 blocks per case. Reduction in sampling based on this evidence would result in saving valuable laboratory resources.

Severe Respiratory Illness Associated with Rhinovirus during the EV-D68 Outbreak in the United States, August – November, 2014

Abstract

BACKGROUND

In 2014, a nationwide outbreak of severe respiratory illness occurred in the United States, primarily associated with enterovirus D-68 (EV-D68). A proportion of illness was associated with rhinoviruses and other enteroviruses, which we aimed to characterize further.

METHODS

Respiratory specimens from pediatric and adult patients with respiratory illness were submitted to CDC during August – November 2014. While initial laboratory testing focused on identification of EV-D68, the negative specimens were typed by molecular sequencing to identify additional enterovirus (EV) and rhinovirus (RV) types. Testing for other pathogens was not conducted. We compared available clinical and epidemiologic characteristics among patients with EV-D68 and RV species A-C identified.

RESULTS

Among 2629 typed specimens, 1012 were EV-D68 (39%) and 81 (3.1%) represented 24 other EV types; 968 were RVs (37%) covering 114 types and grouped into three human RV species (RV-A=446, RV-B=133, RV-C=389); and 568 (22%) had no RV or EV detected. EV-D68 was more frequently identified in patients presenting earlier in the investigation period. Among patients with EV-D68, RV-A, RV-B, or RV-C identified, the age distributions markedly differed. Clinical syndromes and ICU admissions by age were largely similar among those with EV-D68 and RV species.

CONCLUSIONS

RVs were commonly associated with severe respiratory illness, alongside EV-D68, during the nationwide outbreak. Clinical characteristics were largely similar among those with EV-D68, RV-A, RV-B, or RV-C. A better understanding of the epidemiology of RVs and EVs is needed to help inform development and use of diagnostic tests, therapeutics, and preventive measures.

Efficacy and Safety of Oseltamivir in Children: Systematic Review and Individual Patient Data Meta-analysis of Randomized Controlled Trials

Abstract

Background

Oseltamivir has been used to treat children with influenza for nearly two decades, with treatment currently approved for infants 2 weeks of age or older, but efficacy and safety remain controversial. Newer randomized placebo controlled trials (RCT), not included in previous meta-analyses, can add to the evidence base.

Methods

We conducted a systematic review to identify RCTs of oseltamivir therapy in children. We obtained individual patient data and examined protocol-defined outcomes. We then conducted a two-stage, random effects meta-analysis to determine the efficacy of treatment in reducing the duration of illness, estimated using differences in restricted mean survival time (RSMT) by treatment group. We also examined complications and safety.

Results

We identified 5 trials including 2561 patients in the intent to treat (ITT) and 1598 in the intent to treat infected (ITTI) population. Overall, oseltamivir treatment significantly reduced the duration of illness in the ITTI population (RMST difference -17.6 hours 95% CI: -34.7 to -0.62 hours). In trials that enrolled patients without asthma, the difference was larger (-29.9 hours 95% CI -53.9 to -5.8 hours). Risk of otitis media was 34% lower in the ITTI population. Vomiting was the only adverse event with a significantly higher risk in the treatment group.

Conclusion

Despite substantial heterogeneity in pediatric trials, we found that treatment with oseltamivir significantly reduced the duration of illness in those with influenza and lowered the risk of developing otitis media. Alternative endpoints may be required to evaluate the efficacy of oseltamivir in pediatric patients with asthma.

Cognitive function among antiretroviral treatment-naïve individuals infected with HIV-1 Subtype G versus CRF02_AG in Nigeria

Abstract

Background

HIV-1 subtype has been shown to be associated with disease progression. We compared cognitive function between individuals infected with HIV-1 subtype G and CRF02_AG in Nigeria.

Methods

For this cross-sectional study, samples were analyzed from 146 antiretroviral naïve participants. Genotypic analysis of plasma HIV RNA was performed by nested PCR of protease and reverse transcriptase genes, and sequences aligned with curated HIV-1 subtype references. Cognitive status was determined using demographically adjusted T scores and global deficit scores (GDS) obtained from a comprehensive neuropsychological test battery.

Results

A total of 76 (52.1%) participants were infected with CRF02_AG, 48 (32.8%) with subtype G, and 22 (15.1%) with other HIV-1 strains. In a multivariable linear regression adjusting for plasma HIV RNA, CD4 count and depression score, mean global T score was lower among subtype G as compared to CRF02_AG infected participants (Mean difference: -3.0 [95% CI: -5.2,-0.7]; P = .011). Also, T scores were significantly lower among subtype G than CRF02_AG infected participants for the speed of information processing, executive function, and verbal fluency ability domains. Adjusting for similar variables in a logistic regression, the odds of global cognitive impairment (GDS ≥ 0.5) were 2.2 times higher among subtype G as compared to CRF02_AG infected participants (OR: 2.2 [95% CI: 0.9, 5.4]; P = .078).

Conclusion

Cognitive performance was significantly worse among antiretroviral naïve individuals with HIV-1 subtype G versus CRF02_AG infection. Further studies are required to characterize the mechanistic basis for these differences.

A Roadmap to Implementing Antimicrobial Stewardship Principles in Long-Term Care Facilities (LTCFs): Collaboration Between an Acute-Care Hospital and LTCFs

Abstract

The Centers for Medicare and Medicaid Services (CMS) finalized a rule in October 2016 mandating long-term care facilities (LTCFs) to have antimicrobial stewardship programs (ASPs) in place by 2017. Although guidance exists for establishing ASPs in LTCFs, limited data exists on the "how". As comprehensive ASPs already exist in many acute-care hospitals (ACHs) and, with the known "sharing of patients" between both settings, extending ACH ASP expertise to LTCFs will not only aid LTCFs in complying with the CMS mandate, but will likely also facilitate in decreasing multi-drug resistant organisms and Clostridumdifficile infection rates in patients of both organizations. In this report, we provide a roadmap on how to implement ASPs in LTCFs, using examples from our own ACH's collaboration with local LTCFs to develop and sustain LTCF ASPs. We discuss critical elements to achieving successful LTCF ASPs, including the potential barriers and how to overcome them.

Limited evidence for need for region-specific, genotypic drug-susceptibility assays for Mycobacterium tuberculosis

Mycobacterium tuberculosisgenotypic drug-susceptibility assaysIndia

Imaging mass spectrometry for novel insights into contact allergy – a proof-of-concept study on nickel

Summary

Background

In spite of extensive regulation to limit exposure, nickel remains the main cause of contact allergy in the general population. More detailed knowledge on the skin uptake of haptens is required. So far, no method exists for the visualization of clinically relevant haptens and their distribution in the skin.

Objectives

To show, in terms of a proof of concept, that imaging mass spectrometry [time of flight secondary ion mass spectrometry (ToF-SIMS)] can be applied for investigation of the penetration and distribution of nickel in human skin.

Method

Full-thickness human skin obtained from breast reduction surgery was exposed to nickel sulfate (5% in deionized water) for 24 h in Franz-type diffusion cells. Biopsies were obtained from nickel-treated samples and control (deionized water). The tissue was sliced, and analysed with ToF-SIMS, generating high-resolution images of ion distribution in the epidermis and upper dermis.

Results

The skin layers could be discerned from the ToF-SIMS data, particularly on the basis of the collagen signal. Nickel ions were localized to the stratum corneum and upper epidermis.

Conclusions

This is the first time that ToF-SIMS has been applied to trace the distribution of a hapten in human skin. Proof of principle was shown for nickel, and the technique can, in the future, be expanded for investigation of the skin distribution of clinically relevant sensitizers in general.

Percutaneous bone anchored hearing system implant survival after 550 primary implant surgeries

Abstract

The Bone Anchored Hearing System (BAHS) has become an established option for rehabilitation of several type of hearing impairment such as conductive hearing loss, mixed hearing loss and single sided deafness ¹. Overall good outcomes have been reported. Nevertheless, complications such as inflammation of the skin around the percutaneous abutment, pain and implant loss are related to BAHS ².

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Postoperative efficacy analysis of patients with facial nerve palsy associated with cholesteatoma otitis media: Our experience with 32 patients

Abstract

Patients who underwent surgery within 4 weeks after facial palsy had better outcomes than those who had surgery later.

The results of partial and near-complete decompression were good, with no difference between the two methods.

Even if the symptom duration of facial paralysis was > 4 weeks, surgery still had an impact.

Unlike in surgery for facial paralysis due to other causes, the integrity of the sheath membrane should be preserved.

There is a lag in the electroneurography test results.

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