Cell turnover in the "resting" human breast: influence of parity, contraceptive pill, age and laterality.
Morphological identification of cell multiplication (mitosis) and cell deletion (apoptosis) within the lobules of the "resting" human breast is used to assess the response of the breast parenchyma to the menstrual cycle. The responses are shown to have a biorhythm in phase with the menstrual cycle, with a 3-day separation of the mitotic and apoptotic peaks. The study fails to demonstrate significant differences in the responses between groups defined according to parity, contraceptive-pill use or presence of fibroadenoma. However, significant differences are found in the apoptotic response according to age and laterality. The results highlight the complexity of modulating influences on breast parenchymal turnover in the "resting" state, and prompt the investigation of other factors as well as steroid hormones and prolactin in the promotion of mitosis. The factors promoting apoptosis in the breast are still not clear.


Raman spectroscopy in microsurgery: impact of operating microscope illumination sources on data quality and tissue classification.
Ambient light artifacts can confound Raman spectroscopy measurements performed in a clinical setting such as during open surgery. However, requiring light sources to be turned off during intraoperative spectral acquisition can be impractical because it can slow down the procedure by requiring surgeons to acquire data under light conditions different from the routine clinical practice. Here a filter system is introduced allowing in vivo Raman spectroscopy measurements to be performed with the light source of a neurosurgical microscope turned on, without interfering with the standard procedure. Ex vivo and in vivo results on calf and human brain, respectively, show that when the new filter system is used there is no significant difference between Raman spectra acquired under pitch dark conditions or with the microscope light source turned on. This is important for the clinical translation of Raman spectroscopy because of the resulting decrease in total imaging time for each measurement and because the surgeon can now acquire spectroscopic data with no disruption of the surgical workflow.


How to Make or Break Implicit Bias Instruction: Implications for Curriculum Development.
To analyze faculty experiences regarding facilitating discussions as part of the institution's curriculum on racial and ethnic implicit bias recognition and management. Between July 2014 and September 2016, the authors conducted 21 in-depth interviews with faculty who had experience teaching in implicit bias instruction or were interested in facilitating discussions related to implicit bias and the Implicit Association Test. Grounded theory methodology was used to analyze interview transcripts. Participants identified challenges that affect their ability to facilitate instruction in implicit bias. Faculty described the influence of their own background and identities as well as the influence of institutional values on their ability to facilitate implicit bias discussions. They noted the impact of resistant learners and faculty during discussions and made suggestions for institutional measures including the need for implementation of formalized longitudinal implicit bias curricula and faculty development. Faculty facilitating sessions on implicit bias must attend faculty development sessions to be equipped to deal with some of the challenges they may face. Buy-in from institutional leadership is essential for successful implementation of implicit bias teaching, and medical educators need to consider formalized longitudinal curricula addressing the recognition and management of implicit biases.


A comparison of the effectiveness of two types of deceit detection training methods in older adults.
In general, people are poor at detecting deception. Older adults are even worse than young adults at detecting deceit, which might make them uniquely vulnerable to certain types of financial fraud. One reason for poor deceit detection abilities is that lay theories of cues to deception are not valid. This study compared the effectiveness of two training methods to improve deceit detection among older adults: valid facial cues versus valid verbal cues to deception. Approximately 150 older adults were randomly assigned to facial training, verbal training, or a control condition. Participants completed a pre-test deceit detection task, their assigned training, and a post-test deceit detection task. Both training groups significantly improved at recognizing their respectively trained cues after training. However, the facial cue training group were less accurate at detecting deception post-test compared to pre-test and the control group exhibited improved accuracy of deceit detection from pre-test to post-test. These results are consistent with the body of literature on deception suggesting people hover around chance accuracy, even after training. Older adults' facial and verbal cue recognition can be improved with training, but these improvements did not translate into more accurate deceit detection, and actually hampered performance in the facial condition. Older adults showed the most benefit from sheer practice at detecting deception (in the control condition), perhaps because this condition encouraged implicit rather than explicit judgments of deception.


Lower Extremity Compartment Syndrome From Prolonged Limb Compression and Immobilization During an Airborne Operation.
Acute compartment syndrome (ACS) involving the leg can occur in association with various traumatic and nontraumatic conditions, and it can have serious longterm consequences when unrecognized or untreated. Nontraumatic causes of ACS, such as those associated with cases of prolonged immobilization and/or extremity compression, can be easily overlooked, and several cases of ACS occurring with prolonged surgical positioning can be found in the literature. We present the case of a 19-year-old Army paratrooper who developed acute anterior and lateral compartment syndrome of the lower extremity after being immobilized in an aircraft for hours with several hundred pounds of equipment compressing his lower extremities. To our knowledge, this is the first documented case of ACS occurring as a result of prejump conditions. It demonstrates a potentially serious complication that could result in medical separation and/or permanent disability of the service member. ACS of the extremity should be considered in any Soldier who is required to bear heavy loads, is immobilized for several hours at a time, and complains of symptoms such as extremity pain, numbness, and weakness.


Association between birthweight and later body mass index: an individual-based pooled analysis of 27 twin cohorts participating in the CODATwins project.
There is evidence that birthweight is positively associated with body mass index (BMI) in later life, but it remains unclear whether this is explained by genetic factors or the intrauterine environment. We analysed the association between birthweight and BMI from infancy to adulthood within twin pairs, which provides insights into the role of genetic and environmental individual-specific factors. This study is based on the data from 27 twin cohorts in 17 countries. The pooled data included 78 642 twin individuals (20 635 monozygotic and 18 686 same-sex dizygotic twin pairs) with information on birthweight and a total of 214 930 BMI measurements at ages ranging from 1 to 49 years. The association between birthweight and BMI was analysed at both the individual and within-pair levels using linear regression analyses. At the individual level, a 1-kg increase in birthweight was linearly associated with up to 0.9 kg/m2 higher BMI (P < 0.001). Within twin pairs, regression coefficients were generally greater (up to 1.2 kg/m2 per kg birthweight, P < 0.001) than those from the individual-level analyses. Intra-pair associations between birthweight and later BMI were similar in both zygosity groups and sexes and were lower in adulthood. These findings indicate that environmental factors unique to each individual have an important role in the positive association between birthweight and later BMI, at least until young adulthood.


Embedding flexible fibers into responsive gels to create composites with controllable dexterity.
Using computational modeling, we design a composite that encompasses a thermo-responsive gel and photo-responsive fibers that extend from the surface of the gel. By simulating the effect of light and heat on the sample, we isolate scenarios where cooperative interactions within the system allow the gel to actuate the "finger-like" motion of the embedded fibers. To achieve this distinctive behavior, we consider a gel formed from poly(N-isopropylacrylamide) (PNIPAAm), which shrinks when heated above the lower critical solution temperature (LCST). The fibers are functionalized with spirobenzopyran (SP) chromophores that extend a finite region into the polymer network. The application of heat causes the entire gel to shrink, while the application of light causes the regions around the functionalized fibers to collapse. With the fibers arranged in a square or circular pattern in the center of the gel, heating the non-illuminated samples drives the fibers to move apart as they bend outward (away from the center). With the application of light, the tips of fibers come together as the fibers bend inward. In this configuration, the fibers could act as grippers that bind objects in the presence of light. With the illumination turned off, the grippers could controllably release the objects. By placing the fibers closer to the edge of the sample, the combination of heat and light could be harnessed to bind and release larger objects. We also show that by illuminating the fibers separately, we can manipulate the motion of the individual finger-like objects, and thus, potentially expand the utility of the system. Overall, our findings provide guidelines for controllably reconfiguring the shape of soft materials and thus, tailoring the material to display different functionalities in different environments.


Marmara University Medical Students' Perception on Sexual Violence against Women and Induced Abortion in Turkey.
Historically, sexual assault is a common issue in Turkey. As doctors are one of the steps to help sexually assaulted women, medical students should have basic knowledge of and sensitivity regarding this subject. Another common women's public health issue is induced abortion. In countries where access to abortion is restricted, there is a tendency towards unhealthy abortion. The aims of this study are: (1) to determine the attitudes and opinions of Marmara University Medical Faculty students about sexual assault against women and induced abortion and (2) to propose an educational program for medical students about sexual assault and abortion. Cross-sectional study. The questionnaires were self-administered and the data were analyzed using SPSS v.15.0. First, the descriptive statistics were analyzed, followed by Chi-square for contingency tests assessing differences in attitudes toward sexual assault and induced abortion by factors such as gender and educational term. Differences were considered statistically significant at p<0.05. About 89.6% of the participants (n=266) reported that they had never been sexually assaulted and about 11.5% of the women (n=19) had been sexually assaulted. There was no significant relationship between previous sexual assault and gender (p>0.05). Although there was no significant difference regarding the extent of punishment by victim's status as a virgin, 21.3% (n=63) agreed that punishment should be more severe when the victim was a virgin. About 40.7% (n=120) agreed that the legal period of abortion in Turkey (10 weeks) should be longer. The majority (86.1%, n=255) agreed that legally prohibiting abortions causes an increase in unhealthy abortions. An educational program on these issues should be developed for medical students.


Profile of upper limb recovery and development of secondary impairments in patients after stroke with a disabled upper limb: An observational study.
Purpose: To investigate, in patients after stroke with a very weak upper limb, the profile of recovery for upper limb activity over the first 12 weeks, and whether early secondary impairments predict later upper limb activity. Method: Forty patients within 2 weeks of stroke with a very weak upper limb (<4/6 Item 6 of Motor Assessment Scale) were observed longitudinally. Upper limb activity (Items 6, 7, and 8 of Motor Assessment Scale), shoulder subluxation (vertical distance), shoulder pain (visual analogue scale), and upper limb range of motion were measured at 2, 6, and 12 weeks poststroke. Results: By Week 12, upper limb activity was 1.0/18 (IQR 3.0). Shoulder subluxation was 42 mm (SD 8), 7 mm > the intact side at 2 weeks. Pain at rest was 0.1/10 (IQR 1.1), and pain during movement was 2.6/10 (IQR 4.5). Passive shoulder external rotation was 23° (SD 34), 30% of the intact side at 2 weeks. Shoulder pain during movement at 2 weeks predicted shoulder pain during movement at 6 and 12 weeks after stroke (p = 0.05). Conclusion: Most patients with a disabled upper limb after stroke have little recovery of activity in the first 12 weeks. Shoulder pain on movement at 2 weeks should be flagged as a predictor of future pain.


Eye examinations for VA patients with diabetes: standardizing performance measures.
To demonstrate the potential of the Health Plan Employer Data and Information Set (HEDIS) for the calculation of a performance measure for eye exams in the diabetic population using Veterans Health Administration (VA) administrative data. We calculated a 1-year HEDIS-defined patient denominator and three alternative denominators that considered coding factors in identifying a VA patient as diabetic. We calculated the HEDIS-defined numerator, along with alternative specifications that captured other types of eye exams. Finally, we supplemented national data with VA pharmacy and Medicare claims data to identify all VA diabetic patients at 14 selected VA facilities and to establish a more accurate picture of non-VA health care utilization. The national average annual HEDIS-defined eye exam rate in the VA was 26% in fiscal 1997 compared with 39% for managed care organizations. Medicare utilization raised this by 15 percentage points at 14 northeastern VA hospitals. Over 2 years, at least two-thirds of diabetic VA patients had some type of eye exam through VA or Medicare. A HEDIS measure of eye exams for VA patients with diabetes can be calculated using VA administrative data only. However, the question remains to what extent the denominator and numerator accurately and completely identify all diabetic patients using VA services and all appropriate eye exams. We recommend caution in interpreting the results of performance measurement across different health care sectors based on what we currently know are data system limitations.


Role of oxidative stress in the clinical outcome of patients with multiple blunt trauma.
This prospective study evaluated serum total oxidant status (TOS), total antioxidant status (TAS) and oxidative stress index (OSI), along with the Revised Trauma Score (RTS) and Injury Severity Score (ISS), as predictors of clinical outcome in the early post-traumatic period in patients with multiple blunt trauma (MBT). The study included 52 patients admitted to the emergency department with MBT and 40 age- and sex-matched healthy control subjects. The overall MBT patient mortality was 32.7% (17/52). There was no significant association between age and mortality in MBT patients, but there was a negative correlation between mortality and RTS, and a positive correlation between mortality and ISS. TOS levels were significantly higher in nonsurvivors compared with survivors. There was no correlation between TAS or OSI and survival. ISS and RTS showed positive and negative correlations with TOS level, respectively, but neither was significantly related to TAS or OSI. These findings suggest that TOS, as an early oxidative stress biomarker, may be an objective alternative criterion to the ISS and RTS for managing patients with MBT during the early period following traumatic injury.


Consequences of interaction of a lipophilic endotoxin antagonist with plasma lipoproteins.
E5531, a novel synthetic lipid A analogue, antagonizes the toxic effects of lipopolysaccharide, making it a potential intravenously administered therapeutic agent for the treatment of sepsis. This report describes the distribution of E5531 in human blood and its activity when it is associated with different lipoprotein subclasses. After in vitro incubation of [(14)C]E5531 with blood, the great majority (>92%) of material was found in the plasma fraction. Analysis by size-exclusion and affinity chromatographies and density gradient centrifugation indicates that [(14)C]E5531 binds to lipoproteins, primarily high-density lipoproteins (HDLs), with distribution into low-density lipoproteins (LDLs) and very low density lipoproteins (VLDLs) being dependent on the plasma LDL or VLDL cholesterol concentration. Similar results were also seen in a limited study of [(14)C]E5531 administration to human volunteers. The potency of E5531 in freshly drawn human blood directly correlates to increasing LDL cholesterol levels. Finally, preincubation of E5531 with plasma or purified lipoproteins indicated that binding to HDL resulted in a time-dependent loss of drug activity. This loss in activity was not observed with drug binding to LDLs or to VLDLs or chylomicrons. Taken together, these results indicate that E5531 binds to plasma lipoproteins, making its long-term antagonistic potency dependent on the plasma lipoprotein composition.


Pediatric sleep pharmacology.
This article reviews the most common pharmacologic options in the treatment of sleep disorders in children. Despite the high prevalence of sleep disorders in children, there is a paucity of education and information available on the pharmacologic management of sleep disorders in children. The principles of sleep physiology and pathophysiology that help provide more rational pharmacologic management are discussed. Medications are typically not Food and Drug Administration (FDA) approved for the pediatric age range or for the specific sleep disorder. Medications have a role for insomnia, narcolepsy, parasomnias, and sleep-related movement disorders. The available choices of hypnotics are reviewed. Medications to increase alertness of narcoleptics and decrease cataplexy are discussed. The use of dopaminergic agents for Restless Legs Syndrome is reviewed. The potential use of medication in sleep apnea is also reviewed. Pharmacologic guidelines need to be developed specifically for sleep disorders in children. Ideally, these guidelines should be FDA approved for the specific sleep disorder and for the pediatric age range. The development of easy to swallow, chewable or liquid forms of these medications are needed. Training programs should play the lead role in enhancing pediatricians' knowledge of the pharmacologic treatment of sleep disorders in children.


Correlation between the intima-media thickness of the carotid artery and aortic pulse-wave velocity in patients with type 2 diabetes. Vessel wall properties in type 2 diabetes.
The aim of this study was to assess the relationship between atherotic (structural) and sclerotic (functional) changes in patients with type 2 diabetes. Aortic distensibility and carotid intimal-media thickness (IMT) were evaluated using carotid-femoral aortic pulse-wave velocity (a-PWV) and high-resolution B-mode ultrasonography in 271 patients with type 2 diabetes and 285 age-matched control subjects. a-PWV and carotid IMT were significantly higher in the patients than in the control subjects in all age-groups (P < 0.0001, respectively). The carotid IMT and a-PWV were significantly correlated with age in both the patients with type 2 diabetes and control subjects. There was a significant positive relationship between the carotid IMT and a-PWV in both the patients (r = 0.482, P < 0.0001) and control subjects (r = 0.424, P < 0.0001). The slope of the regression line for the carotid IMT to the a-PWV was significantly steeper in the diabetic patients than in the control subjects (P < 0.05). Multiple regression analysis in all subjects showed that age, diabetic state, and cigarette smoking were independently common risk factors for the increase in carotid IMT and a-PWV. In the diabetic patients, the independent risk factors associated with the carotid IMT were age, hyperlipidemia, and duration of diabetes (R2 = 0.232, P < 0.0001), while those associated with a-PWV were age and duration of diabetes (R2 = 0.334, P < 0.0001). The results indicated that diabetic patients showed more advanced changes in atherosis than that in sclerosis as compared with age- and sex-matched control subjects. Such atherotic changes in diabetic patients may be associated with hyperlipidemia.


WFUMB guidelines and recommendations for clinical use of ultrasound elastography: Part 3: liver.
The World Federation for Ultrasound in Medicine and Biology (WFUMB) has produced these guidelines for the use of elastography techniques in liver disease. For each available technique, the reproducibility, results, and limitations are analyzed, and recommendations are given. Finally, recommendations based on the international literature and the findings of the WFUMB expert group are established as answers to common questions. The document has a clinical perspective and is aimed at assessing the usefulness of elastography in the management of liver diseases.


Genetic correlations between meat quality traits and growth and carcass traits in Merino sheep1.
Genetic correlations between 16 meat quality and nutritional value traits and live weight at various ages, live ultrasound fat and muscle depth, carcass measures, and carcass dissection traits were estimated for Merino sheep in the Information Nucleus (IN). Genetic correlations between live weight at various ages and the carcass traits are also reported. The IN comprised 8 genetically linked flocks managed across a range of Australian sheep environments. Meat quality traits included between 1,200 and 1,300 records for progeny from over 170 sires for intramuscular fat (IMF), lean meat yield (LMY), shear force (SF5), pH, meat color, and meat nutritional value traits including iron and zinc levels and long-chain omega-3 and omega-6 polyunsaturated fatty acid levels. The genetic correlations indicated that selection of Merino sheep to either reduce fat or increase muscle using ultrasound assessments will result in little change in IMF and SF5. Myoglobin levels would tend to be reduced following selection for reduced ultrasound fat depth (0.35 ± 0.21, 0.43 ± 0.14), whereas increases in myoglobin levels would occur due to selection for increased ultrasound muscle depth (0.25 ± 0.24, 0.38 ± 0.15). Selection for increased live weight will result in favorable correlated responses in hot carcass weight (0.76 to 0.97), dressing percentage (0.13 to 0.47), and carcass muscle (0.37 to 0.95), but unfavorable responses of increases in carcass fatness (0.13 to 0.65) and possible small reductions in muscle oxidative activity (-0.13 ± 0.14 to -0.73 ± 0.33) and iron content (-0.14 ± 0.15 to -0.38 ± 0.16), and a possible deterioration of shear force from selection at later ages (0.15 ± 0.26, 0.27 ± 0.24). Negligible changes are generally expected for LMY and meat color traits following selection for increased live weight (most genetic correlations less than 0.20 in size). Selection for increased LMY would tend to result in unfavorable changes in several aspects of meat quality, including reduced IMF (-0.27 ± 0.18), meat tenderness (0.53 ± 0.26), and meat redness (-0.69 ± 0.40), as well as reduced iron levels (-0.25 ± 0.22). These genetic correlations are a first step in assisting the development of breeding values for new traits to be incorporated into genetic evaluation programs to improve meat production from Merino sheep and other dual-purpose sheep breeds.


P2X receptors as targets for the treatment of status epilepticus.
Prolonged seizures are amongst the most common neurological emergencies. Status epilepticus is a state of continuous seizures that is life-threatening and prompt termination of status epilepticus is critical to protect the brain from permanent damage. Frontline treatment comprises parenteral administration of anticonvulsants such as lorazepam that facilitate γ-amino butyric acid (GABA) transmission. Because status epilepticus can become refractory to anticonvulsants in a significant proportion of patients, drugs which act on different neurotransmitter systems may represent potential adjunctive treatments. P2X receptors are a class of ligand-gated ion channel activated by ATP that contributes to neuro- and glio-transmission. P2X receptors are expressed by both neurons and glia in various brain regions, including the hippocampus. Electrophysiology, pharmacology and genetic studies suggest certain P2X receptors are activated during pathologic brain activity. Expression of several members of the family including P2X2, P2X4, and P2X7 receptors has been reported to be altered in the hippocampus following status epilepticus. Recent studies have shown that ligands of the P2X7 receptor can have potent effects on seizure severity during status epilepticus and mice lacking this receptor display altered seizures in response to chemoconvulsants. Antagonists of the P2X7 receptor also modulate neuronal death, microglial responses and neuroinflammatory signaling. Recent work also found altered neuronal injury and inflammation after status epilepticus in mice lacking the P2X4 receptor. In summary, members of the P2X receptor family may serve important roles in the pathophysiology of status epilepticus and represent novel targets for seizure control and neuroprotection.


Effective use of mesenchymal stem cells in human skin substitutes generated by tissue engineering.
Mesenchymal stem cells (MSCs) can differentiate toward epithelial cells and may be used as an alternative source for generation of heterotypical artificial human skin substitutes, thus, enhancing their development and translation potential to the clinic. The present study aimed at comparing four types of heterotypical human bioengineered skin generated using MSCs as an alternative epithelial cell source. Adipose-tissue-derived stem cells (ADSCs), dental pulp stem cells (DPSCs), Wharton's jelly stem cells (WJSCs) and bone marrow stem cells (BMSCs) were used for epidermal regeneration on top of dermal skin substitutes. Heterotypic human skin substitutes were evaluated before and after implantation in immune-deficient athymic mice for 30 d. Histological and genetic studies were performed to evaluate extracellular matrix synthesis, epidermal differentiation and human leukocyte antigen (HLA) molecule expression. The four cell types differentiated into keratinocytes, as shown by the expression of cytokeratin 10 and filaggrin 30 d post-grafting; also, they induced dermal fibroblasts responsible for the synthesis of extracellular fibrillar and non-fibrillar components, in a similar way among each other. WJSCs and BMSCs showed higher expression of cytokeratin 10 and filaggrin, suggesting these cells were more prone to epidermal regeneration. The absence of HLA molecules, even when the epithelial layer was differentiated, supports the future clinical use of these substitutes - especially ADSCs, DPSCs and WJSCs - with low rejection risk. MSCs allowed the generation of bioengineered human skin substitutes with potential clinical usefulness. According to their epidermal differentiation potential and lack of HLA antigens, WJSCs should preferentially be used.


Fabrication and characterisation of the graphene ring micro electrode (GRiME) with an integrated, concentric Ag/AgCl reference electrode.
We report the fabrication and characterisation of the first graphene ring micro electrodes with the addition of a miniature concentric Ag/AgCl reference electrode. The graphene ring electrode is formed by dip coating fibre optics with graphene produced by a modified Hummers method. The reference electrode is formed using an established photocatalytically initiated electroless deposition (PIED) plating method. The performance of the so-formed graphene ring micro electrodes (GRiMEs) and associated reference electrode is studied using the probe redox system ferricyanide and electrode thicknesses assessed using established electrochemical methods. Using 220 µm diameter fibre optics, a ~15 nm thick graphene ring electrode is obtained corresponding to an inner to outer radius ratio of >0.999, so allowing for use of extant analytical descriptions of very thin ring microelectrodes in data analysis. GRiMEs are highly reliable (current response invariant over >3,000 scans), with the concentric reference electrode showing comparable stability (current response invariant over >300 scans). Furthermore the micro-ring design allows for efficient use of electrochemically active graphene edge sites and the associated nA scale currents obtained neatly obviate issues relating to the high resistivity of undoped graphene. Thus, the use of graphene in ring microelectrodes improves the reliability of existing micro-electrode designs and expands the range of use of graphene-based electrochemical devices.


Atomically resolved calcium phosphate coating on a gold substrate.
Some articles have revealed that the electrodeposition of calcium phosphate (CaP) coatings entails a precursor phase, similarly to biomineralization in vivo. The chemical composition of the initial layer and its thickness are, however, still arguable, to the best of our knowledge. Moreover, while CaP and electrodeposition of metal coatings have been studied utilizing atom-probe tomography (APT), the electrodeposition of CaP ceramics has not been heretofore studied. Herein, we present an investigation of the CaP deposition on a gold substrate. Using APT and transmission electron microscopy (TEM) it is found that a mixture of phases, which could serve as transient precursor phases to hydroxyapatite (HAp), can be detected. The thickness of these phases is tens of nanometers, and they consist of amorphous CaP (ACP), dibasic calcium phosphate dihydrate (DCPD), and octacalcium phosphate (OCP). This demonstrates the value of using atomic-resolved characterization techniques for identifying the precursor phases. It also indicates that the kinetics of their transformation into the more stable HAp is not too fast to enable their observation. The coating gradually displays higher Ca/P atomic ratios, a porous nature, and concomitantly a change in its density.


Description of a new species of Calliostoma (Gastropoda, Calliostomatidae) from Southeastern Brazil.
Calliostoma tupinamba isa new species from Southeastern Brazil, ranging from southern Rio de Janeiro to northern São Paulo, and found only on coastal islands, on rocks and sessile invertebrates at 3 to 5 meters of depth. Shell and soft part morphology is described here in detail. Calliostoma tupinamba is mainly characterized by a depressed trochoid shell; eight slightly convex whorls; a sharply suprasutural carina starting on the third whorl and forming a peripheral rounded keel; and a whitish, funnel-shaped and deep umbilicus, measuring about 5%-10% of maximum shell width. Calliostoma tupinamba resembles Calliostoma bullisi Clench & Turner, 1960 in shape, but differs from it in being taller and wider, having a smaller umbilicus and lacking a strong and large innermost spiral cord at its base. Finally, an identification key of Brazilian Calliostoma species is presented.


Visualization of two-dimensional phase gradients by subtraction of a reference periodic pattern.
We describe a simple method for visualization of phase objects. The phase object is placed between a printed two-dimensional periodic pattern and a CCD camera. The ray deflection that is due to the phase object distorts the image of the pattern. This image is subtracted from a reference image and then, by squaring and low-pass filtering, a measurement of the two-dimensional refractive-index changes is obtained. Because the optical system does not require special alignment or illumination, the method presented has potential application for detection of gas leaks in industrial environments.


Effects of green tea polyphenol on preservation of human saphenous vein.
The potential role of green tea polyphenol (GtPP) in preserving the human saphenous vein was investigated under physiological conditions. The vein segments were incubated for 1, 3, 5, 7 and 14 days, either after 4h of treatment with 1.0mg/ml GtPP or in the presence of GtPP at the same concentration. After incubation, the endothelial cell viability, endothelial nitric oxide synthase (eNOS) expression and the vein histology were evaluated. When the veins were not treated with GtPP, the viability of the endothelial cells was significantly reduced with the progress in the culture time, and none of the cells expressed eNOS after 5 days. Furthermore, severe histological changes and structural damage were observed in the non-treated veins. In contrast, incubating the veins after 4h of GtPP treatment significantly prevented these phenomena. The cellular viability of the GtPP-treated vein was approximately 64% after 7 days, and eNOS expression was maintained up to 40%, compared to that of the fresh vein. The histological observations showed that the vasculature was quite similar to that of the fresh vein. When incubated with GtPP, the vein could also be preserved for 1 week under physiological conditions retaining both its cellular viability (61%) and eNOS expression level (45%) and maintaining its venous structure without any morphological changes. These results demonstrate that GtPP treatment may be a useful method for preserving the HSV.


BAG-1 p50 isoform interacts with the vitamin D receptor and its cellular overexpression inhibits the vitamin D pathway.
Human BAG-1 is an anti-apoptotic protein with four protein isoforms (BAG-1 p50, p46, p33, and p29). BAG-1 p46 was originally isolated in a screen for proteins binding to the glucocorticoid receptor; it binds and modulates the action of several members of the nuclear steroid hormone receptor superfamily. The vitamin D receptor (VDR) is another member of this superfamily, and the vitamin D pathway is important for prevention and therapy of osteoporosis, renal failure, cancer, and psoriasis. Therefore, we investigated the effect of the recently isolated BAG-1 p50 on the vitamin D pathway. By use of Far Western blot analysis and glutathione S-transferase BAG-1 p50 binding assays, BAG-1 p50 was demonstrated to interact with the VDR, and the BAG-1 p50 N-terminus was required. In U87 cells that were stably transfected with BAG-1 p50, binding of the VDR to its response element in electrophoretic mobility shift assays was blocked, enhancement of transcriptional activation was inhibited, cell growth rate was enhanced, cell growth inhibition induced by 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] was blocked, and 1,25(OH)2D3-mediated VDR induction was inhibited. These results suggest that BAG-1 p50 is a novel regulator of the vitamin D signaling pathway, and its overexpression may lead to cellular resistance to 1,25(OH)2D3 therapy.


Ultrasound-guided tunneled lower extremity peripherally inserted central catheter placement in infants.
Tunneled lower extremity peripherally inserted central catheters (PICCs) are placed in infants under combined ultrasound and fluoroscopic guidance in the interventional radiology suite. In infants requiring a bedside procedure, image guidance is limited, often using portable radiographs during the procedure. This report demonstrates feasibility of placing tunneled lower extremity PICCs using ultrasound as the sole imaging modality for vascular access, intravascular length measurement, and final confirmation of catheter tip position in a case series of 15 critically ill infants. The technique negates the need for added imaging confirmation methods that use ionizing radiation and can be performed at the bedside.


Response to Comment on "The hologenomic basis of speciation: gut bacteria cause hybrid lethality in the genus Nasonia".
Chandler and Turelli postulate that intrinsic hybrid dysfunction underscores hybrid lethality in Nasonia. Although it is a suitable conception for examining hybrid incompatibilities, their account of the evidence is factually inaccurate and leaves out the evolutionary process for why lethality became conditional on nuclear-microbe interactions. Hybrid incompatibilities in the context of phylosymbiosis are resolved by hologenomic principles and exemplify this emerging postmodern synthesis.


Beyond self-monitored plasma glucose and HbA1c: the role of non-traditional glycaemic markers in gestational diabetes mellitus.
Strict glycaemic management is the cornerstone of metabolic control in gestational diabetes mellitus (GDM). Current monitoring standards involve self-monitoring plasma glucose (SMBG) and haemoglobin A1c (HbA1c). However, both have important limitations. SMBG only reflects instantaneous blood glucose and the inconvenience of self-collecting blood frequently results in poor compliance. HbA1c provides information on blood glucose levels from the previous 2 to 3 months and it is influenced by iron-deficient states, common during pregnancy. There is an urgent need for new shorter-term glycaemic markers, as glycated albumin, fructosamine or 1,5-anhydroglucitol. Glycated albumin seems especially interesting as it provides information on blood glucose levels over the foregoing 2-3 weeks and it is not influenced by iron deficiency or the dilutional anaemia of pregnancy. Fructosamine has a precise and inexpensive measurement and it is not affected by haemoglobin characteristics. This review further discusses the potential value of these non-traditional indicators of glycaemic control in patients with GDM, outlining their possible future applications.


Low-protein vegetarian diet does not have a short-term effect on blood acid-base status but raises oxygen consumption during submaximal cycling.
Acid-base balance refers to the equilibrium between acids and bases in the human body. Nutrition may affect acid-base balance and further physical performance. With the help of PRAL (potential renal acid load), a low-protein vegetarian diet (LPVD) was designed to enhance the production of bases in body. The aim of this study was to investigate if LPVD has an effect on blood acid-base status and performance during submaximal and maximal aerobic cycling. Nine healthy, recreationally active men (age 23.5 ± 3.4 yr) participated in the study and were randomly divided into two groups in a cross-over study design. Group 1 followed LPVD for 4 days and group 2 ate normally (ND) before performing a cycle ergometer test. The test included three 10-min stages at 40, 60 and 80% of VO2max. The fourth stage was performed at 100% of VO2max until exhaustion. After 10-16 days, the groups started a second 4-day diet, and at the end performed the similar ergometer test. Venous blood samples were collected at the beginning and at the end of both diet periods and after every stage cycled. Diet caused no significant difference in venous blood pH, strong ion difference (SID), total concentration of weak acids (Atot), partial pressure of CO2 (pCO2) or HCO3- at rest or during cycling between LPVD and ND. In the LPVD group, at rest SID significantly increased over the diet period (38.6 ± 1.8 vs. 39.8 ± 0.9, p=0.009). Diet had no significant effect on exercise time to exhaustion, but VO2 was significantly higher at 40, 60 and 80% of VO2max after LPVD compared to ND (2.03 ± 0.25 vs. 1.82 ± 0.21 l/min, p=0.035; 2.86 ± 0.36 vs. 2.52 ± 0.33 l/min, p<0.001 and 4.03 ± 0.50 vs. 3.54 ± 0.58 l/min, p<0.001; respectively). There was no difference in venous blood acid-base status between a 4-day LPVD and ND. VO2 was increased during submaximal cycling after LPVD suggesting that the exercise economy was poorer. This had no further effect on maximal aerobic performance. More studies are needed to define how nutrition affects acid-base balance and performance.


School-based vaccinations delivered by general practice in rural north Queensland: an evaluation of a new human papilloma virus vaccination program.
A local general practice was contracted to provide the school-based immunisation program over two years in Mount Isa, Queensland. The schedule was for female Year 10, 11 and 12 students to receive three doses of human papilloma virus (HPV) vaccination (Gardasil). This was provided as part of the broader immunisation program that involved providing Year 8 students with two doses of hepatitis B vaccination and one dose of varicella-zoster, and Year 10 students with one dose of diphtheria-tetanus-pertussis (DTPa). Data were collected on the number of consent forms returned and how many declined vaccination, how many students were vaccinated and those requiring catch-up vaccinations, as well as the total number completing the full course of immunisations. Adverse events were also recorded. The total cohort of girls eligible for HPV vaccination was 304 (consented to vaccination--275 (90%), declined vaccination--13 (4%), coverage for first HPV dose--89%, coverage for second HPV dose--88%, coverage for third HPV dose--79%). When compared with other adolescent vaccinations given concurrently as part of the broader vaccination program, HPV coverage was higher. There were only three significant adverse events. Three girls fainted at the time of immunisation but recovered immediately. The HPV immunisation had a good uptake and was well tolerated. Integrating school immunisation provision with general practice provides continuity with preschool immunisations and provides a convenient location for parents to bring children who have missed out on immunisations or would like to discuss the immunisation program


Functional characterization of novel loss-of-function mutations in the vasopressin type 2 receptor gene causing nephrogenic diabetes insipidus.
X-linked nephrogenic diabetes insipidus (NDI) is a rare polyuric disorder caused by inactivating mutations in the arginine vasopressin receptor Type 2 (AVPR2) gene. NDI patients from six unrelated families were subjected to mutational analysis of the AVPR2 gene. In-depth in vitro characterization of novel AVPR2 mutants by a combination of functional and immunological techniques provided further insight into molecular mechanisms causing receptor dysfunction. Mutational analysis revealed four novel (A89P, G107R, Q174R, W208X) and three recurrent (V277A, R337X, ΔR247-G250) mutations within the AVPR2 gene. One family carried the missense mutation R337X and a 12-bp deletion (ΔR247-G250), corresponding to a fragment in the third intracellular loop (ICL3), which was not genetically linked to R337X. The functionally tested missense mutations A89P, G107R and Q174R led to reduced receptor cell surface expression in transfected COS-7 cells, most probably due to misfolding and intracellular retention, and consequently to reduction or loss of agonist-mediated cyclic adenosine monophosphate formation. Deletion of R247-G250 had no effect on receptor function in vitro. Comparison with other mammalian AVPR2 orthologs showed that this part of the ICL3 is structurally not conserved and, therefore, less relevant for receptor function. In contrast, all missense mutations (A89P, G107R, Q174R, V277A) affect receptor positions that were fully preserved during mammalian evolution. Our results provide valuable information about residues critical for AVPR2 folding, trafficking and function and proof that these mutations are responsible for causing NDI in the affected subjects.


Elective repeat caesarean section versus induction of labour for women with a previous caesarean birth.
When a woman has had a previous caesarean birth and requires induction of labour in a subsequent pregnancy there are two options for her care, an elective repeat caesarean or planned induction of labour. While there are risks and benefits for both elective repeat caesarean birth and planned induction of labour, current sources of information are limited to non-randomised cohort studies. Studies designed in this way have significant potential for bias and consequently any conclusions based on these results are limited in their reliability and should be interpreted with caution. To assess, using the best available evidence, the benefits and harms of elective repeat caesarean section and planned induction of labour for women with a previous caesarean birth, who require induction of labour in a subsequent pregnancy. We searched the Cochrane Pregnancy and Childbirth Group Trials Register (31 October 2014). Randomised controlled trials with reported data that compared outcomes in mothers and babies for women who planned an elective repeat caesarean section with outcomes in women who planned induction of labour, where a previous birth had been by caesarean. There was no data extraction performed. There were no randomised controlled trials identified. Both planned elective repeat caesarean section and planned induction of labour for women with a prior caesarean birth are associated with benefits and harms. Evidence for these care practices is drawn from non-randomised studies that are associated with potential bias. Any results and conclusions must therefore be interpreted with caution. Randomised controlled trials are required to provide the most reliable evidence regarding the benefits and harms of both planned elective repeat caesarean section and planned induction of labour for women with a previous caesarean birth.


Early primary care follow-up after ED and hospital discharge - does it affect readmissions?
After hospitalization, timely discharge follow-up has been linked to reduced readmissions in the heart failure population, but data from general inpatients has been mixed. The objective of this study was to determine if there was an association between completed follow-up appointments within 14 days of hospital discharge and 30-day readmission amongst primary care patients at an urban academic medical center. Index discharges included both inpatient and emergency room settings. A secondary objective was to identify patient factors associated with completed follow-up appointments within 14 days. We conducted a retrospective review of primary care patients at an urban academic medical center who were discharged from either the emergency department (ED) or inpatient services at the Weill Cornell Medical Center/New York Presbyterian Hospital from 1 January 2014-31 December 2014. Cox proportional hazard models were used to identify the relationship between follow-up in primary care within 14 days and readmission within 30 days. Logistic regression was used to evaluate the association of patient factors with 14-day follow-up. Among 9,662 inpatient and ED discharges, multivariable analysis (adjusting for age, gender, race/ethnicity, insurance, number of diagnoses on problem list, length of stay, and discharge service) showed that follow-up with primary care within 14 days was not associated with a lower hazard of readmission within 30 days (HR = 0.78; 95% CI 0.56-1.09). A higher number of diagnoses on the problem list was associated with greater odds of follow-up for both inpatient and emergency department discharges (inpatient: HR = 1.03, 95% CI 1.02-1.04; ED: HR = 1.02, 95% CI 1.00-1.04). For inpatient discharges, each additional day in length of stay was associated with 3% lower odds of follow-up (HR = 0.97, 95% CI 0.96-0.99). Early follow-up within 14 days after discharge from general inpatient services was associated with a trend toward lower hazard of 30-day readmission though this finding was not significant. Future studies should focus on identifying additional cohorts of patients in which readmission is reduced by early follow-up, so that access to primary care appointments is not compromised.


Basic and supplementary sensory feedback in handwriting.
The mastering of handwriting is so essential in our society that it is important to try to find new methods for facilitating its learning and rehabilitation. The ability to control the graphic movements clearly impacts on the quality of the writing. This control allows both the programming of letter formation before movement execution and the online adjustments during execution, thanks to diverse sensory feedback (FB). New technologies improve existing techniques or enable new methods to supply the writer with real-time computer-assisted FB. The possibilities are numerous and various. Therefore, two main questions arise: (1) What aspect of the movement is concerned and (2) How can we best inform the writer to help them correct their handwriting? In a first step, we report studies on FB naturally used by the writer. The purpose is to determine which information is carried by each sensory modality, how it is used in handwriting control and how this control changes with practice and learning. In a second step, we report studies on supplementary FB provided to the writer to help them to better control and learn how to write. We suggest that, depending on their contents, certain sensory modalities will be more appropriate than others to assist handwriting motor control. We emphasize particularly the relevance of auditory modality as online supplementary FB on handwriting movements. Using real-time supplementary FB to assist in the handwriting process is probably destined for a brilliant future with the growing availability and rapid development of tablets.


Correlates and moderators of change in subjective memory and memory performance: findings from the health and retirement study.
Aging researchers have long been interested in understanding individuals' subjective perceptions of their own memory functioning. Previous research has shown that subjective memory ratings are partly based on memory performance but also reflect the influence of other factors, such as depressive symptoms. The aim of the present study was to examine (1) longitudinal associations between trajectories of subjective memory and memory performance, (2) variables that predict levels of and changes in subjective memory and memory performance, and (3) variables that moderate associations between these constructs. We applied a latent growth curve model to four occasions of data from 15,824 participants of the Health and Retirement Study (HRS; mean age at baseline=64.27 years, SD=9.90; 58% women). Results revealed that latent changes in subjective memory were correlated with latent changes in memory performance (φ=0.49), indicating that participants who reported steeper declines of subjective memory indeed showed steeper declines of memory performance over time. Three major patterns of associations emerged with respect to predictors of subjective memory and subjective memory change. First, the level of memory performance showed stronger associations with age, gender, and education, whereas subjective memory was more strongly associated with subjective age and personality traits. For example, women performed better than men on the episodic memory test, but there were no gender differences in subjective memory. Also, older age was associated with steeper declines of memory performance but with less decline of subjective memory. Second, personality traits that predicted subjective memory intercepts did not predict subjective memory slopes. Third, the strength of associations between levels and slopes of subjective memory and memory performance varied as a function of gender, education, depressive symptoms, and personality traits. Conscientiousness moderated the relationship of the level of subjective memory to the level of memory performance, consistent with the hypothesis that persons high in conscientiousness more accurately monitor memory successes and failures. The results reinforce the importance of depressive symptoms as a predictor of subjective memory but also indicate that a broader perspective on the reasons why memory complaints have modest correlations with memory itself is needed.


Effects of Internet-based guided self-help problem-solving therapy for adolescents with depression and anxiety: a randomized controlled trial.
Symptoms of depression and anxiety are highly prevalent in adolescence and they are the cause of considerable suffering. Even so, adolescents are not inclined to seek professional help for emotional problems. Internet-based preventive interventions have been suggested as a feasible method of providing appropriate care to adolescents with internalizing symptoms. The objective of this study was to evaluate the effects of preventive Internet-based (guided) self-help problem-solving therapy (PST) for adolescents reporting mild to moderate symptoms of depression and/or anxiety as compared to a waiting list control group (WL). A total of 45 participants were randomized to the 2 conditions. PST consisted of 5 weekly lessons. Participants were supported by e-mail. Self-report measures of depression and anxiety were filled in at baseline and after 3 weeks, 5 weeks, and 4 months. Of the 45 participants, 28 (62.2%) completed questionnaires after 3 weeks, 28 (62.2%) after 5 weeks, and 27 (60%) after 4 months. Hierarchical linear modeling analyses revealed overall improvement over time for both groups on depressive and anxiety symptoms. However, no significant group x time interactions were found. No differences were found between completers and non-completers. Results show that depressive and anxiety symptoms declined in both groups. No support was found, however, for the assumption that Internet-based PST was efficacious in reducing depression and anxiety in comparison to the waiting list control group. This finding could represent lack of power. Netherlands Trial Register NTR1322.


Monocytes from HIV-infected individuals show impaired cholesterol efflux and increased foam cell formation after transendothelial migration.
HIV-infected (HIV+) individuals have an increased risk of atherosclerosis and cardiovascular disease which is independent of antiretroviral therapy and traditional risk factors. Monocytes play a central role in the development of atherosclerosis, and HIV-related chronic inflammation and monocyte activation may contribute to increased atherosclerosis, but the mechanisms are unknown. Using an in-vitro model of atherosclerotic plaque formation, we measured the transendothelial migration of purified monocytes from age-matched HIV+ and uninfected donors and examined their differentiation into foam cells. Cholesterol efflux and the expression of cholesterol metabolism genes were also assessed. Monocytes from HIV+ individuals showed increased foam cell formation compared with controls (18.9 vs. 0%, respectively, P = 0.004) and serum from virologically suppressed HIV+ individuals potentiated foam cell formation by monocytes from both uninfected and HIV+ donors. Plasma tumour necrosis factor (TNF) levels were increased in HIV+ vs. control donors (5.9 vs. 3.5 pg/ml, P = 0.02) and foam cell formation was inhibited by blocking antibodies to TNF receptors, suggesting a direct effect on monocyte differentiation to foam cells. Monocytes from virologically suppressed HIV+ donors showed impaired cholesterol efflux and decreased expression of key genes regulating cholesterol metabolism, including the cholesterol transporter ABCA1 (P = 0.02). Monocytes from HIV+ individuals show impaired cholesterol efflux and are primed for foam cell formation following transendothelial migration. Factors present in HIV+ serum, including elevated TNF levels, further enhance foam cell formation. The proatherogenic phenotype of monocytes persists in virologically suppressed HIV+ individuals and may contribute mechanistically to increased atherosclerosis in this population.


Genetic and environmental factors shape infant sleep patterns: a study of 18-month-old twins.
Between 25% and 30% of children and adolescents experience sleep disorders. These disorders are complex phenotypes that are regulated by many genes, the environment, and gene-environment interactions. The objective of this study was to evaluate the contribution of genetic and environmental factors to sleep behaviors in early childhood and to contribute to the knowledge on appropriate therapeutic approaches, using a twin design. Data on sleeping behavior were collected from 314 18-month-old twin pairs (127 monozygotic and 187 dizygotic)using a parent-rated questionnaire. We used structural equation modeling to estimate genetic and environmental variance components for different sleep behaviors (cosleeping, sleep duration, and night awakenings). Shared environment explained almost all (98.3%) of the total variance in cosleeping. Sleep duration was substantially influenced by shared environmental factors (64.1% nocturnal sleep and 61.2% diurnal sleep), with a moderate contribution of additive genetic effects (30.8% and 36.3% for nocturnal and diurnal sleep, respectively). For nocturnal waking episodes, we found a shared environmental contribution of 63.2% and a heritability estimate of 35.3%. Most sleep disturbances during early childhood are explained by common shared environmental factors, and behavioral interventions adopted by parents and focused on modifying sleep behavior could contribute to solving sleep disturbances in this age group. However, the influence of genetic factors should not be underestimated, and research in this area could clarify the physiologic architecture of sleeping and contribute to selecting appropriate personalized therapeutic approaches.


Edge Functionalized Graphene Layers for (Ultra) High Exfoliation in Carbon Papers and Aerogels in the Presence of Chitosan.
Ultra-high exfoliation in water of a nanosized graphite (HSAG) was obtained thanks to the synergy between a graphene layer edge functionalized with hydroxy groups and a polymer such as chitosan (CS). The edge functionalization of graphene layers was performed with a serinol derivative containing a pyrrole ring, serinol pyrrole (SP). The adduct between CS and HSAG functionalized with SP was formed simply with a mortar and pestle, then preparing water dispersions stable for months in the presence of acetic acid. Simple casting of such dispersions on a glass support led to carbon papers. Aerogels were prepared through the freeze-dry procedure. Exfoliation was observed in both these families of composites and ultra-high exfoliation was documented in aerogels swollen in water. Carbon papers and aerogels were stable for months in solvents in a wide range of solubility parameter and in a pretty wide range of pH. By considering that a moderately functionalized nanographite was straightforwardly exfoliated in water in the presence of one of the most abundant biobased polymers, the obtained results pave the way for the simple and sustainable preparation of graphene-based nanocomposites. HSAG-SP/CS adducts were characterized by wide angle X-ray diffraction (WAXD), scanning and transmission electron microscopy (SEM, TEM and HRTEM), Fourier transform infrared spectroscopy (FT-IR), X-ray photoelectron spectroscopy (XPS) and Raman spectroscopy. Thermal stability of the composites was studied by thermogravimetric analysis (TGA) and their direct electrical conductivity with the four-point probe method.


Scalemic Caged Xanthones Isolated from the Stem Bark Extract of Garcinia propinqua.
Seven new caged xanthones, doitunggarcinones E-K (1-7), all as scalemic mixtures and 10 known compounds (8-17), were isolated from the stem bark extract of Garcinia propinqua. The structures were elucidated on the basis of spectroscopic methods. The separation of the enantiomers of 1-6 was achieved by semipreparative chiral HPLC. The absolute configuration of compound (+)-1 was determined by single-crystal X-ray crystallographic analysis using Cu Kα radiation. The absolute configurations of the other related compounds were determined from comparisons of their ECD spectra with that of compound (+)-1. Compounds (-)-6 and 7 showed cytotoxicity against a colon cancer cell line with IC50 values of 14.23 and 23.95 μM, respectively.


Novel Models of Genetic Education and Testing for Pancreatic Cancer Interception: Preliminary Results from the GENERATE Study.
Up to 10% of patients with pancreatic ductal adenocarcinoma (PDAC) carry underlying germline pathogenic variants in cancer susceptibility genes. The GENetic Education Risk Assessment and TEsting (GENERATE) study aimed to evaluate novel methods of genetic education and testing in relatives of patients with PDAC. Eligible individuals had a family history of PDAC and a relative with a germline pathogenic variant in APC, ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PALB2, PMS2, STK11, or TP53 genes. Participants were recruited at six academic cancer centers and through social media campaigns and patient advocacy efforts. Enrollment occurred via the study website (https://GENERATEstudy.org) and all participation, including collecting a saliva sample for genetic testing, could be done from home. Participants were randomized to one of two remote methods that delivered genetic education about the risks of inherited PDAC and strategies for surveillance. The primary outcome of the study was uptake of genetic testing. From 5/8/2019 to 5/6/2020, 49 participants were randomized to each of the intervention arms. Overall, 90 of 98 (92%) of randomized participants completed genetic testing. The most frequently detected pathogenic variants included those in BRCA2 (N = 15, 17%), ATM (N = 11, 12%), and CDKN2A (N = 4, 4%). Participation in the study remained steady throughout the onset of the Coronavirus disease (COVID-19) pandemic. Preliminary data from the GENERATE study indicate success of remote alternatives to traditional cascade testing, with genetic testing rates over 90% and a high rate of identification of germline pathogenic variant carriers who would be ideal candidates for PDAC interception approaches. PREVENTION RELEVANCE: Preliminary data from the GENERATE study indicate success of remote alternatives for pancreatic cancer genetic testing and education, with genetic testing uptake rates over 90% and a high rate of identification of germline pathogenic variant carriers who would be ideal candidates for pancreatic cancer interception.


Dynamic models of Fabry-Perot interferometers.
Long-baseline, high-finesse Fabry-Perot interferometers can be used to make distance measurements that are precise enough to detect gravity waves. This level of sensitivity is achieved in part when the interferometer mirrors are isolated dynamically, with pendulum mounts and high-bandwidth cavity length control servos to reduce the effects of seismic noise. We present dynamical models of the cavity fields and signals of Fabry-Perot interferometers for use in the design and evaluation of length control systems for gravity-wave detectors. Models are described and compared with experimental data.


Skin disorders associated with obesity in children and adolescents: a population-based study.
Obesity in children is a major public health concern in the United States. The objectives of the current study were to determine the prevalence of various groups of cutaneous disorders in obese children and adolescents and to compare the use of dermatology services in obese subjects with that those with a normal body mass index (BMI). This was a retrospective, population-based study at the Kaiser Permanente Northern California Managed Healthcare System. The main outcome measures were the relative risk of cutaneous disorders associated with insulin resistance, androgen excess, bacterial infection, fungal infection, viral infection, inflammation, mechanical changes, and other skin conditions (hidradenitis, hyperhidrosis) in three weight groups (normal, overweight, obese) and the number of dermatology visits. A total of 248,775 subjects were included. Bivariate analyses showed a higher proportion of insulin resistance disorders, bacterial infection, fungal infection, inflammatory disorders, mechanical changes, and other skin conditions in obese subjects than in subjects with a normal BMI (p < 0.001). Disorders of androgen excess and viral infection were significantly less common in obese subjects (p < 0.001). Obese subjects had significantly lower odds of having at least one dermatology encounter than subjects with a normal BMI (odds ratio = 0.92, 95% confidence interval 0.88, 0.96, p = 0.003). Early onset obesity is associated with cutaneous disorders characterized by hyperproliferation, inflammation, bacterial and fungal infection, and mechanical changes but lower rates of disorders of androgen excess and viral infection. The use of dermatology services was not greater in obese patients. Heightened recognition and further analysis of adipose tissue as an endocrine organ that is capable of affecting the skin is warranted.


In vitro activity of antimicrobial agents against the endosymbiont Wolbachia pipientis.
Arthropod-transmitted (filarial) nematodes are important causes of disease in humans in tropical countries, yet no safe drug appropriate for mass delivery kills the adult worms. However, most filarial nematodes contain rickettsia-like bacteria of the genus Wolbachia, and related bacteria also occur in insects. There is increasing evidence that these bacteria have significant functions in the biology of filarial nematodes. They are thus important targets in the search for antifilarial drugs and experiments in animals and humans have suggested that antibiotic therapy has potential in treating filarial infections. To optimize future clinical trials there is a need for a fast and simple in vitro drug screen to compare drug efficacies against Wolbachia. In the absence of Wolbachia-infected nematode cell lines, we have utilized an Aedes albopictus insect cell line, naturally infected with Wolbachia, to test the activity of antimicrobial agents. Of the five antibiotics tested, doxycycline, oxytetracycline and rifampicin showed good activity (MICs of 0.0625, 4 and 0.0625 mg/L, respectively) whereas ciprofloxacin and penicillin were shown to have no effect.


Mitochondrial uncoupling prodrug improves tissue sparing, cognitive outcome, and mitochondrial bioenergetics after traumatic brain injury in male mice.
Traumatic brain injury (TBI) results in cognitive impairment, which can be long-lasting after moderate to severe TBI. Currently, there are no FDA-approved therapeutics to treat the devastating consequences of TBI and improve recovery. This study utilizes a prodrug of 2,4-dinitrophenol, MP201, a mitochondrial uncoupler with extended elimination time, that was administered after TBI to target mitochondrial dysfunction, a hallmark of TBI. Using a model of cortical impact in male C57/BL6 mice, MP201 (80 mg/kg) was provided via oral gavage 2-hr post-injury and daily afterwards. At 25-hr post-injury, mice were euthanized and the acute rescue of mitochondrial bioenergetics was assessed demonstrating a significant improvement in both the ipsilateral cortex and ipsilateral hippocampus after treatment with MP201. Additionally, oxidative markers, 4-hydroxyneneal and protein carbonyls, were reduced compared to vehicle animals after MP201 administration. At 2-weeks post-injury, mice treated with MP201 post-injury (80 mg/kg; q.d.) displayed significantly increased cortical sparing (p = .0059; 38% lesion spared) and improved cognitive outcome (p = .0133) compared to vehicle-treated mice. Additionally, vehicle-treated mice had significantly lower (p = .0019) CA3 neuron count compared to sham while MP201-treated mice were not significantly different from sham levels. These results suggest that acute mitochondrial dysfunction can be targeted to impart neuroprotection from reactive oxygen species, but chronic administration may have an added benefit in recovery. This study highlights the potential for safe, effective therapy by MP201 to alleviate negative outcomes of TBI.


Comparative visual function in four piscivorous fishes inhabiting Chesapeake Bay.
Maintaining optimal visual performance is a difficult task in photodynamic coastal and estuarine waters because of the unavoidable tradeoffs between luminous sensitivity and spatial and temporal resolution, yet the visual systems of coastal piscivores remain understudied despite differences in their ecomorphology and microhabitat use. We therefore used electroretinographic techniques to describe the light sensitivities, temporal properties and spectral sensitivities of the visual systems of four piscivorous fishes common to coastal and estuarine waters of the western North Atlantic: striped bass (Morone saxatilis), bluefish (Pomatomus saltatrix), summer flounder (Paralichthys dentatus) and cobia (Rachycentron canadum). Benthic summer flounder exhibited higher luminous sensitivity and broader dynamic range than the three pelagic foragers. The former were at the more sensitive end of an emerging continuum for coastal fishes. By contrast, pelagic species were comparatively less sensitive, but showed larger day-night differences, consistent with their use of diel light-variant photic habitats. Flicker fusion frequency experiments revealed significant interspecific differences at maximum intensities that correlated with lifestyle and habitat. Spectral responses of most species spanned 400-610 nm, with significant day-night differences in striped bass and bluefish. Anadromous striped bass additionally responded to longer wavelengths, similar to many freshwater fishes. Collectively, these results suggest that pelagic piscivores are well adapted to bright photoclimates, which may be at odds with the modern state of eutrified coastal and estuarine waters that they utilize. Recent anthropogenic degradation of water quality in coastal environments, at a pace faster than the evolution of visual systems, may impede visually foraging piscivores, change selected prey, and eventually restructure ecosystems.


Neuron-to-neuron transmission of neurodegenerative pathology.
One of the hallmarks of neurodegenerative dementia diseases is the progressive loss of mental functions and the ability to manage activities of daily life. This progression is caused by the spread of the disease to more and more brain areas via anatomical connections. The pathophysiological process responsible for this spread of disease has long been sought after. There has been an increased understanding that the driving force of these neurodegenerative diseases could be the small, soluble intraneuronal accumulations of neurodegenerative proteins rather than the large, extracellular accumulations. Recently we have shown that the mechanism of spread of Alzheimer's disease most likely depends on the neuron-to-neuron spread of such soluble intraneuronal accumulations of β-amyloid through neuritic connections. Similar transmissions have been shown for several other neurodegenerative proteins but little is known about the cellular mechanisms and about any potential strategies that might stop this spread. Resolving these questions requires good cellular models. We have established a unique model of synaptic transmission between human neuronal-like cells, something that has previously been difficult to target. This opens the possibility of developing potential inhibitors of progression of these devastating diseases.


Community engagement and its impact on child health disparities: building blocks, examples, and resources.
National attention to racial and ethnic health disparities has increased over the last decades, but marked improvements in minority health, especially among children, have been slow to emerge. A life-course perspective with sustained community engagement takes into account root causes of poor health in minority and low-income communities. This perspective involves a variety of primary care, public health, and academic stakeholders. A life-course perspective holds great promise for having a positive impact on health inequities. In this article we provide background information on available tools and resources for engaging with communities. We also offer examples of community-primary care provider interventions that have had a positive impact on racial and ethnic health disparities. Common elements of these projects are described; additional local and national resources are listed; and future research needs, specifically in communities around issues that are relevant to children, are articulated. Examples throughout the history of pediatrics show the potential to eliminate racial and ethnic health disparities not only for children but also for all populations across the life course.


Does gender moderate the relationship between childhood maltreatment and adult depression?
Although considerable evidence demonstrates that adults who report childhood maltreatment are at increased risk of depression in adulthood, little is known about whether gender moderates risk. In a sample of 5,673 adult Health Maintenance Organization (HMO) patients, the authors employed the Patient Health Questionnaire-8 (PHQ-8) to assess major depressive disorder (MDD) and the Childhood Trauma Questionnaire (CTQ) to assess five different types of childhood maltreatment: emotional, physical, and sexual abuse, as well as emotional and physical neglect. Logistic regression models tested the main and interactive effects of gender and childhood maltreatment. Consistent with previous studies, men and women with histories of each type of childhood adversity were significantly more likely to meet criteria for MDD. However, the authors found no evidence that gender moderates the risk of depression. These findings suggest that men and women reporting history of childhood maltreatment are equally likely to suffer major depression in adulthood.


Redefining disease? The nosologic implications of molecular genetic knowledge.
How will developments in genetic knowledge affect the classification of disease? Leaders in genetics have suggested that knowledge of the role of genes in disease can determine nosology. Diseases might be defined by genotype, thus avoiding the limitations of more empirical approaches to categorization. Other commentators caution against disease definitions that are detached from the look and feel of disease, and argue for an interplay between genotypic and phenotypic information. Still others attribute nosologic change to social processes. We draw on an analysis of the scientific literature, our conversations with genetics clinicians, and reviews of patient organization Web sites to offer a revised interpretation of the nosologic implications of molecular genetic knowledge. We review the recent histories of three diseases--hemophilia, Rett syndrome, and cystic fibrosis--to argue that nosologic change cannot be explained by either biologic theories of disease etiology or sociologic theories of social tendencies. Although new genetic information challenges disease classifications and is highly influential in their redesign, genetic information can be used in diverse ways to reconstruct disease categories and is not the only influence in these revisions. Ironically, genetic information is likely to play a central role in producing a new, but still empirical, classification scheme.


Sleep and developmental disabilities: assessment, treatment, and outcome measures.
People with developmental disabilities sleep less and experience higher incidence of clinical sleep disorders than the general population. Exploring the neurophysiology linking sleep with daytime performance in patients with developmental disabilities is now possible using minimally sufficient sleep and sleep-sensitive behavioral assays. Although frequent sampling represents the primary difficulty, it is required to untangle coincident effects of sleep quality amidst circadian variation. Recent evidence finds high quality sleep promotes brain plasticity, improves health measures, and enriches quality of life. Sleep treatments for apnea, insomnia, restless limbs, and conditioned sleep-aversion are available, although not readily provided, for people with developmental disabilities. This population would gain both clinical and behavioral benefits as improved sleep-monitoring, behavioral testing, and sleep-treatment technology is adapted to their needs.


Insights into an Extensively Fragmented Eukaryotic Genome: De Novo Genome Sequencing of the Multinuclear Ciliate Uroleptopsis citrina.
Ciliated protists are a large group of single-celled eukaryotes with separate germline and somatic nuclei in each cell. The somatic genome is developed from the zygotic nucleus through a series of chromosomal rearrangements, including fragmentation, DNA elimination, de novo telomere addition, and DNA amplification. This unique feature makes them perfect models for research in genome biology and evolution. However, genomic research of ciliates has been limited to a few species, owing to problems with DNA contamination and obstacles in cultivation. Here, we introduce a method combining telomere-primer PCR amplification and high-throughput sequencing, which can reduce DNA contamination and obtain genomic data efficiently. Based on this method, we report a draft somatic genome of a multimacronuclear ciliate, Uroleptopsis citrina. 1) The telomeric sequence in U. citrina is confirmed to be C4A4C4A4C4 by directly blunt-end cloning. 2) Genomic analysis of the resulting chromosomes shows a "one-gene one-chromosome" pattern, with a small number of multiple-gene chromosomes. 3) Amino acid usage is analyzed, and reassignment of stop codons is confirmed. 4) Chromosomal analysis shows an obvious asymmetrical GC skew and high bias between A and T in the subtelomeric regions of the sense-strand, with the detection of an 11-bp high AT motif region in the 3' subtelomeric region. 5) The subtelomeric sequence also has an obvious 40 nt strand oscillation of nucleotide ratio. 6) In the 5' subtelomeric region of the coding strand, the distribution of potential TATA-box regions is illustrated, which accumulate between 30 and 50 nt. This work provides a valuable reference for genomic research and furthers our understanding of the dynamic nature of unicellular eukaryotic genomes.


Perceived oral health in patients with Crohn's disease.
The aim of the present study was to investigate perceived oral health in patients with Crohn's disease (CD) in comparison with a control group without CD. The study population comprised 1943 patients with CD recruited from the Swedish National Patients Organisation of inflammatory bowel disease and 1000 randomly selected controls. All participants received a questionnaire with questions concerning socioeconomic variables, education, civil status, income, dental care habits, oral health and tobacco use. Eighty-eight per cent of the patients and 75% of the controls answered the questionnaire. Patients with CD perceived their oral health to be worse than controls. The odds ratio (OR) for the patients to estimate their oral health as much worse than others in the same age group was 9.7 (95% CI, 5.8 to 16.4) after adjustment for age, smoking habit, gender and education. The patients also reported a significantly greater need for dental treatment than the controls, with an OR of 5.7 (95% CI, 4.2 to 7.9) after taking into account the age, smoking habit, gender and education. Furthermore, the patients with CD reported significantly more mouth-related problems than controls (OR 3.2), such as significantly more caries and more gingival bleeding. Of note, there were significantly more smokers in the patient group. The results of the present study show that patients with CD perceived their oral health to be worse and have a greater need for dental treatment compared with the control group.


Engineering Requirements of a Herpes Simplex Virus Patient Registry: Discovery Phase of a Real-World Evidence Platform to Advance Pharmacogenomics and Personalized Medicine.
Comprehensive pharmacogenomic understanding requires both robust genomic and demographic data. Patient registries present an opportunity to collect large amounts of robust, patient-level data. Pharmacogenomic advancement in the treatment of infectious diseases is yet to be fully realised. Herpes simplex virus (HSV) is one disease for which pharmacogenomic understanding is wanting. This paper aims to understand the key factors that impact data collection quality for medical registries and suggest potential design features of an HSV medical registry to overcome current constraints and allow for this data to be used as a complement to genomic and clinical data to further the treatment of HSV. This paper outlines the discovery phase for the development of an HSV registry with the aim of learning about the users and their contexts, the technological constraints and the potential improvements that can be made. The design requirements and user stories for the HSV registry have been identified for further alpha phase development. The current landscape of HSV research and patient registry development were discussed. Through the analysis of the current state of the art and thematic user analysis, potential design features were elucidated to facilitate the collection of high-quality, robust patient-level data which could contribute to advances in pharmacogenomic understanding and personalised medicine in HSV. The user requirements specification for the development of an HSV registry has been summarised and implementation strategies for the alpha phase discussed.


Nanotheranostic Interface Based on Antibiotic-Loaded Conducting Polymer Nanoparticles for Real-Time Monitoring of Bacterial Growth Inhibition.
Conducting polymers have been increasingly used as biologically interfacing electrodes for biomedical applications due to their excellent and fast electrochemical response, reversible doping-dedoping characteristics, high stability, easy processability, and biocompatibility. These advantageous properties can be used for the rapid detection and eradication of infections associated to bacterial growth since these are a tremendous burden for individual patients as well as the global healthcare system. Herein, a smart nanotheranostic electroresponsive platform, which consists of chloramphenicol (CAM)-loaded in poly(3,4-ethylendioxythiophene) nanoparticles (PEDOT/CAM NPs) for concurrent release of the antibiotic and real-time monitoring of bacterial growth is presented. PEDOT/CAM NPs, with an antibiotic loading content of 11.9 ± 1.3% w/w, are proved to inhibit the growth of Escherichia coli and Streptococcus sanguinis due to the antibiotic release by cyclic voltammetry. Furthermore, in situ monitoring of bacterial activity is achieved through the electrochemical detection of β-nicotinamide adenine dinucleotide, a redox active specie produced by the microbial metabolism that diffuse to the extracellular medium. According to these results, the proposed nanotheranostic platform has great potential for real-time monitoring of the response of bacteria to the released antibiotic, contributing to the evolution of the personalized medicine.


Microfluidic formation of proteinosomes.
Herein we describe a novel microfluidic method for the generation of proteinosome micro-droplets, based on bovine serum albumin and glucose oxidase conjugated to PNIPAAm chains. The size of such water-in-oil droplets is regulated via control of the input reagent flow rate, with generated proteinosome populations exhibiting narrower size distributions than those observed when using standard bulk methodologies. Importantly, proteinosomes transferred from an oil to an aqueous-environment remain intact, become fully hydrated and exhibit an increase in average size. Moreover, functional proteinosomes prepared via microfluidics exhibit lower Km values and higher enzymatic activities than proteinosomes produced by bulk methodologies.


CD45+ Cells Present Within Mesenchymal Stem Cell Populations Affect Network Formation of Blood-Derived Endothelial Outgrowth Cells.
Mesenchymal stem cells (MSCs) and endothelial progenitor cells (EPCs) represent promising cell sources for angiogenic therapies. There are, however, conflicting reports regarding the ability of MSCs to support network formation of endothelial cells. The goal of this study was to assess the ability of human bone marrow-derived MSCs to support network formation of endothelial outgrowth cells (EOCs) derived from umbilical cord blood EPCs. We hypothesized that upon in vitro coculture, MSCs and EOCs promote a microenvironment conducive for EOC network formation without the addition of angiogenic growth supplements. EOC networks formed by coculture with MSCs underwent regression and cell loss by day 10 with a near 4-fold and 2-fold reduction in branch points and mean segment length, respectively, in comparison with networks formed by coculture vascular smooth muscle cell (SMC) cocultures. EOC network regression in MSC cocultures was not caused by lack of vascular endothelial growth factor (VEGF)-A or changes in TGF-β1 or Ang-2 supernatant concentrations in comparison with SMC cocultures. Removal of CD45+ cells from MSCs improved EOC network formation through a 2-fold increase in total segment length and number of branch points in comparison to unsorted MSCs by day 6. These improvements, however, were not sustained by day 10. CD45 expression in MSC cocultures correlated with EOC network regression with a 5-fold increase between day 6 and day 10 of culture. The addition of supplemental growth factors VEGF, fibroblastic growth factor-2, EGF, hydrocortisone, insulin growth factor-1, ascorbic acid, and heparin to MSC cocultures promoted stable EOC network formation over 2 weeks in vitro, without affecting CD45 expression, as evidenced by a lack of significant differences in total segment length (p=0.96). These findings demonstrate the ability of MSCs to support EOC network formation correlates with removal of CD45+ cells and improves upon the addition of soluble growth factors.


Musculoskeletal disorders among construction workers: a one-year follow-up study.
Work-related musculoskeletal disorders (MSDs) are an important cause of functional impairments and disability among construction workers. An improved understanding of MSDs in different construction occupations is likely to be of value for selecting preventive measures. This study aimed to survey the prevalence of symptoms of MSDs, the work-relatedness of the symptoms and the problems experienced during work among two construction occupations: bricklayers and supervisors. We randomly selected 750 bricklayers and 750 supervisors resident in the Netherlands in December 2009. This sample was surveyed by means of a baseline questionnaire and a follow-up questionnaire one year later. The participants were asked about complaints of the musculoskeletal system during the last six months, the perceived work-relatedness of the symptoms, the problems that occurred during work and the occupational tasks that were perceived as causes or aggravating factors of the MSD. Baseline response rate was 37%, follow-up response was 80%. The prevalence of MSDs among 267 bricklayers and 232 supervisors was 67% and 57%, respectively. Complaints of the back, knee and shoulder/upper arm were the most prevalent among both occupations. Irrespective of the body region, most of the bricklayers and supervisors reported that their complaints were work-related. Complaints of the back and elbow were the most often reported among the bricklayers during work, whereas lower arm/wrist and upper leg complaints were the most often reported among the supervisors. In both occupations, a majority of the participants perceived several occupational physical tasks and activities as causes or aggravating factors for their MSD. Recurrent complaints at follow-up were reported by both bricklayers (47% of the complaints) and supervisors (31% of the complaints). Participants in both occupations report that mainly back and knee complaints result in additional problems during work, at the time of follow-up. A substantial number of the bricklayers and the supervisors report musculoskeletal disorders, mainly back, knee and shoulder/upper arm complaints. The majority of the bricklayers and half of the supervisors believe that their complaints are work-related. Irrespective of occupation, participants with MSDs report substantial problems during work. Workplace intervention measures aimed at occupational physical tasks and activities seem justified for both occupations.


Memantine protects rats treated with intrathecal methotrexate from developing spatial memory deficits.
To test whether memantine can prevent methotrexate-induced cognitive deficits in a preclinical model. After noting that methotrexate exposure induces prolonged elevations of the glutamate analog homocysteic acid (HCA) within cerebrospinal fluid, we tested whether intrathecal injection of HCA would produce memory deficits similar to those observed after intrathecal methotrexate. We then tested whether memantine, an antagonist of the N-methyl-d-aspartate (NMDA) subclass of glutamate receptors, could protect animals treated with clinically relevant doses of intrathecal methotrexate against developing memory deficits. Finally, we asked whether memantine affected this pathway beyond inhibiting the NMDA receptor by altering expression of the NMDA receptor or affecting concentrations of HCA or glutamate within the central nervous system. Four intrathecal doses of methotrexate induced deficits in spatial memory, persisting at least one month following the final injection. Intrathecal HCA was sufficient to reproduce this deficit. Concurrent administration of memantine during the period of methotrexate exposure was protective, decreasing the incidence of methotrexate-induced spatial memory deficits from 56% to 20% (P < 0.05). Memantine neither altered expression of NMDA receptors within the hippocampus nor blunted the methotrexate-induced increases in glutamate or HCA. Excitotoxic glutamate analogs including HCA contribute to cognitive deficits observed after intrathecal methotrexate. Memantine, an NMDA receptor antagonist, reduces the incidence of cognitive deficits in rats treated with intrathecal methotrexate, and may therefore benefit patients with cancer receiving similar treatment.


Relationship between decrease of erythrocyte count and progression of periodontal disease in a rural Japanese population.
Limited research has been reported on the relationship between periodontal status and erythrocyte parameters. In the present study, longitudinal data from health checkups are used to clarify the relationship between periodontal disease progression and changes in parameters of erythrocytes. In this prospective study, a total of 120 subjects (35 men and 85 women; age range: 30 to 63 years) participated in a comprehensive health screening and dental checkup in 2006 and 2007. Medical examinations, including anthropometric and manometric measurements, blood-chemistry tests, and oral examinations, were performed. Subjects with periodontal disease progression (i.e., the progression group) were defined based on the presence of ≥1 tooth demonstrating a longitudinal loss of periodontal attachment ≥3 mm or tooth loss during the study period. The Wilcoxon signed-rank, χ(2), Fisher exact, and Mann-Whitney U tests and stepwise logistic regression analysis were used for statistical analyses. The progression group comprised 30 subjects. A significant difference between the progression and non-progression groups was observed in changes of erythrocyte counts but not those of the body mass index, systolic and diastolic blood pressure, creatinine, fasting blood glucose, hemoglobin, hematocrit, triglycerides, high- and low-density lipoprotein cholesterol, total cholesterol, aspartate and alanine aminotransferase, and γ-glutamyl transpeptidase. Stepwise logistic regression analysis showed that the progression of periodontal disease was associated with a change (year 2007 minus year 2006) of erythrocyte counts (adjusted odds ratio = 0.970; P = 0.009) after adjusting for age at baseline. Within the limitations of this study, the progression of periodontal disease is associated with a decrease in erythrocyte counts in a rural Japanese population.


Effects on Engagement and Health Literacy Outcomes of Web-Based Materials Promoting Physical Activity in People With Diabetes: An International Randomized Trial.
Developing accessible Web-based materials to support diabetes self-management in people with lower levels of health literacy is a continuing challenge. The objective of this international study was to develop a Web-based intervention promoting physical activity among people with type 2 diabetes to determine whether audiovisual presentation and interactivity (quizzes, planners, tailoring) could help to overcome the digital divide by making digital interventions accessible and effective for people with all levels of health literacy. This study also aimed to determine whether these materials can improve health literacy outcomes for people with lower levels of health literacy and also be effective for people with higher levels of health literacy. To assess the impact of interactivity and audiovisual features on usage, engagement, and health literacy outcomes, we designed two versions of a Web-based intervention (one interactive and one plain-text version of the same content) to promote physical activity in people with type 2 diabetes. We randomly assigned participants from the United Kingdom, Austria, Germany, Ireland, and Taiwan to either an interactive or plain-text version of the intervention in English, German, or Mandarin. Intervention usage was objectively recorded by the intervention software. Self-report measures were taken at baseline and follow-up (immediately after participants viewed the intervention) and included measures of health literacy, engagement (website satisfaction and willingness to recommend the intervention to others), and health literacy outcomes (diabetes knowledge, enablement, attitude, perceived behavioral control, and intention to undertake physical activity). In total, 1041 people took part in this study. Of the 1005 who completed health literacy information, 268 (26.67%) had intermediate or low levels of health literacy. The interactive intervention overall did not produce better outcomes than did the plain-text version. Participants in the plain-text intervention group looked at significantly more sections of the intervention (mean difference -0.47, 95% CI -0.64 to -0.30, P<.001), but this did not lead to better outcomes. Health literacy outcomes, including attitudes and intentions to engage in physical activity, significantly improved following the intervention for participants in both intervention groups. These improvements were similar across higher and lower health literacy levels and in all countries. Participants in the interactive intervention group had acquired more diabetes knowledge (mean difference 0.80, 95% CI 0.65-0.94, P<.001). Participants from both groups reported high levels of website satisfaction and would recommend the website to others. Following established practice for simple, clear design and presentation and using a person-based approach to intervention development, with in-depth iterative feedback from users, may be more important than interactivity and audiovisual presentations when developing accessible digital health interventions to improve health literacy outcomes. International Standard Randomized Controlled Trial Number (ISRCTN): 43587048; http://www.isrctn.com/ISRCTN43587048. (Archived by WebCite at http://www.webcitation.org/6nGhaP9bv).


Collaborative Care for patients with severe borderline and NOS personality disorders: a comparative multiple case study on processes and outcomes.
Structured psychotherapy is recommended as the preferred treatment of personality disorders. A substantial group of patients, however, has no access to these therapies or does not benefit. For those patients who have no (longer) access to psychotherapy a Collaborative Care Program (CCP) is developed. Collaborative Care originated in somatic health care to increase shared decision making and to enhance self management skills of chronic patients. Nurses have a prominent position in CCP's as they are responsible for optimal continuity and coordination of care. The aim of the CCP is to improve quality of life and self management skills, and reduce destructive behaviour and other manifestations of the personality disorder. Quantitative and qualitative data are combined in a comparative multiple case study. This makes it possible to test the feasibility of the CCP, and also provides insight into the preliminary outcomes of CCP. Two treatment conditions will be compared, one in which the CCP is provided, the other in which Care as Usual is offered. In both conditions 16 patients will be included. The perspectives of patients, their informal carers and nurses are integrated in this study. Data (questionnaires, documents, and interviews) will be collected among these three groups of participants. The process of treatment and care within both research conditions is described with qualitative research methods. Additional quantitative data provide insight in the preliminary results of the CCP compared to CAU. With a stepped analysis plan the 'black box' of the application of the program will be revealed in order to understand which characteristics and influencing factors are indicative for positive or negative outcomes. The present study is, as to the best of our knowledge, the first to examine Collaborative Care for patients with severe personality disorders receiving outpatient mental health care. With the chosen design we want to examine how and which elements of the CC Program could contribute to a better quality of life for the patients. Netherlands Trial Register (NTR): NTR2763.