Short-duration stimulation of the supplementary eye fields perturbs anti-saccade performance while potentiating contralateral head orienting.
Many forms of brain stimulation utilize the notion of state dependency, whereby greater influences are observed when a given area is more engaged at the time of stimulation. Here, by delivering intracortical microstimulation (ICMS) to the supplementary eye fields (SEF) of monkeys performing interleaved pro- and anti-saccades, we show a surprising diversity of state-dependent effects of ICMS-SEF. Short-duration ICMS-SEF passed around cue presentation selectively disrupted anti-saccades by increasing reaction times and error rates bilaterally, and also recruited neck muscles, favoring contralateral head turning to a greater degree on anti-saccade trials. These results are consistent with the functional relevance of the SEF for anti-saccades. The multiplicity of stimulation-evoked effects, with ICMS-SEF simultaneously disrupting anti-saccade performance and facilitating contralateral head orienting, probably reflects both the diversity of cortical and subcortical targets of SEF projections, and the response of this oculomotor network to stimulation. We speculate that the bilateral disruption of anti-saccades arises via feedback loops that may include the thalamus, whereas neck muscle recruitment arises via feedforward polysynaptic pathways to the motor periphery. Consideration of both sets of results reveals a more complete picture of the highly complex and multiphasic response to ICMS-SEF that can play out differently in different effector systems.


Deformation of cholesteric elastomers by uniaxial stress along the helix axis.
The deformation of cholesteric elastomers by mechanical stress applied parallel to the helix axis is studied by calculation of the free-energy density. The Frank-elasticity contribution is taken into account. A chiral solvent, present at cross-linking time, is in general considered to be replaced after cross-linking by a solvent with different chirality. Two special cases considered are zero and unchanged solvent chirality, the first known as that of imprinted cholesteric elastomers, the latter equivalent to intrinsic cholesteric elastomers with chemically attached chiral groups. Depending on material parameters and imposed strain, the director can show a tilt towards the helix axis up to the maximum tilt, corresponding to a nematic state. In case of intrinsic elastomers with low conformation anisotropy, direct transitions from untilted to nematic states can be induced by straining. The helix structure of the director field is coarsened with an average wave number different to that of the information inscribed in the network at cross-linking time, if this lowers the average free-energy density. Switching between different states can be achieved with electric fields of reasonable values applied parallel to the helix axis. Spectra of the reflection of polarized light are calculated.


Suvorexant for Primary Insomnia: A Systematic Review and Meta-Analysis of Randomized Placebo-Controlled Trials.
We performed a systematic review and meta-analysis of double-blind, randomized, placebo-controlled trials evaluating suvorexant for primary insomnia. Relevant studies were identified through searches of PubMed, databases of the Cochrane Library, and PsycINFO citations through June 27, 2015. We performed a systematic review and meta-analysis of suvorexant trial efficacy and safety outcomes. The primary efficacy outcomes were either subjective total sleep time (sTST) or subjective time-to-sleep onset (sTSO) at 1 month. The secondary outcomes were other efficacy outcomes, discontinuation rate, and individual adverse events. The risk ratio, number-needed-to-treat/harm, and weighted mean difference (WMD) and 95% confidence intervals (CI) based on a random effects model were calculated. The computerized literature database search initially yielded 48 results, from which 37 articles were excluded following a review of titles and abstracts and another eight review articles after full-text review. Thus, we identified 4 trials that included a total of 3,076 patients. Suvorexant was superior to placebo with regard to the two primary efficacy outcomes (sTST: WMD = -20.16, 95% CI = -25.01 to -15.30, 1889 patients, 3 trials, sTSO: WMD = -7.62, 95% CI = -11.03 to -4.21, 1889 patients, 3 trials) and was not different from placebo in trial discontinuations. Suvorexant caused a higher incidence than placebo of at least one side effects, abnormal dreams, somnolence, excessive daytime sleepiness/sedation, fatigue, dry mouth, and rebound insomnia. Our analysis of published trial results suggests that suvorexant is effective in treating primary insomnia and is well-tolerated.


Protection of human left ventricular myocardium from cutting injury with 2,3-butanedione monoxime.
To prevent dissection injury when cutting strip preparations from human left ventricular papillary muscle tissue, dissections were carried out with 2,3-butanedione monoxime (30 mM) added to Krebs-Ringer solution and followed by washout with normal solution. Eleven muscle strip preparations were dissected from left ventricular papillary muscle tissue of five patients undergoing mitral valve replacement surgery. The average muscle strip length was 6.8 +/- 1.4 mm, and cross-section area was 0.49 +/- 0.16 mm2. Peak twitch tension was 2.02 +/- 1.33 g/mm2 and ranged from 0.67 to 5.5 g/mm2 at an extracellular calcium concentration of 2.5 mM (21 degrees C, 0.16 Hz). In one muscle strip, which was stored in Krebs-Ringer plus 2,3-butanedione monoxime solution for 20 hours, peak twitch tension in normal Krebs-Ringer solution was 1.85 g/mm2. When temperature was increased from 21 degrees C, there was a continuous increase in peak twitch tension (by 38%) up to about 28 degrees C; then peak twitch tension decreased so that at 37 degrees C (n = 3) average peak twitch tension was lower than at 21 degrees C by 47%. The force-frequency relation exhibited a broad force plateau between 40 and 120 beats/min at 37 degrees C. The plateau was markedly narrowed at 30 degrees C and 24 degrees C. Thermopile heat measurements revealed appropriate waveform characteristics in high-resolution single-beat heat records indicating minimal surface cell damage. Thus, cardioplegia with 2,3-butanedione monoxime protects human left ventricular myocardium from dissection injury facilitating dissection and preservation of strip preparations with extraordinarily low cross-sectional areas and high peak twitch tensions. These preparations are suitable for myothermal and mechanical measurements.


The fractional quantum Hall effect.
Recent research has uncovered a fascinating quantum liquid made up solely of electrons confined to a plane surface. Found only at temperatures near absolute zero and in extremely strong magnetic fields, this liquid can flow without friction. The excited states of this liquid consist of peculiar particle-like objects that carry an exact fraction of an electron charge. Called quasiparticles, these excitations can themselves condense into new liquid states. Each such liquid is characterized by a fractional quantum number that is directly observable in a simple electrical measurement. This article attempts to convey the qualitative essence of this still unfolding phenomenon, known as the fractional quantum Hall effect.


Protein phosphatase 2B (PP2B, calcineurin) in Paramecium: partial characterization reveals that two members of the unusually large catalytic subunit family have distinct roles in calcium-dependent processes.
We characterized the calcineurin (CaN) gene family, including the subunits CaNA and CaNB, based upon sequence information obtained from the Paramecium genome project. Paramecium tetraurelia has seven subfamilies of the catalytic CaNA subunit and one subfamily of the regulatory CaNB subunit, with each subfamily having two members of considerable identity on the amino acid level (>or=55% between subfamilies, >or=94% within CaNA subfamilies, and full identity in the CaNB subfamily). Within CaNA subfamily members, the catalytic domain and the CaNB binding region are highly conserved and molecular modeling revealed a three-dimensional structure almost identical to a human ortholog. At 14 members, the size of the CaNA family is unprecedented, and we hypothesized that the different CaNA subfamily members were not strictly redundant and that at least some fulfill different roles in the cell. This was tested by selecting two phylogenetically distinct members of this large family for posttranscriptional silencing by RNA interference. The two targets resulted in differing effects in exocytosis, calcium dynamics, and backward swimming behavior that supported our hypothesis that the large, highly conserved CaNA family members are not strictly redundant and that at least two members have evolved diverse but overlapping functions. In sum, the occurrence of CaN in Paramecium spp., although disputed in the past, has been established on a molecular level. Its role in exocytosis and ciliary beat regulation in a protozoan, as well as in more complex organisms, suggests that these roles for CaN were acquired early in the evolution of this protein family.


Automatic MR volume registration and its evaluation for the pelvis and prostate.
A three-dimensional (3D) mutual information registration method was created and used to register MRI volumes of the pelvis and prostate. It had special features to improve robustness. First, it used a multi-resolution approach and performed registration from low to high resolution. Second, it used two similarity measures, correlation coefficient at lower resolutions and mutual information at full resolution, because of their particular advantages. Third, we created a method to avoid local minima by restarting the registration with randomly perturbed parameters. The criterion for restarting was a correlation coefficient below an empirically determined threshold. Experiments determined the accuracy of registration under conditions found in potential applications in prostate cancer diagnosis, staging, treatment and interventional MRI (iMRI) guided therapies. Images were acquired in the diagnostic (supine) and treatment position (supine with legs raised). Images were also acquired as a function of bladder filling and the time interval between imaging sessions. Overall studies on three patients and three healthy volunteers, when both volumes in a pair were obtained in the diagnostic position under comparable conditions, bony landmarks and prostate 3D centroids were aligned within 1.6 +/- 0.2 mm and 1.4 +/- 0.2 mm, respectively, values only slightly larger than a voxel. Analysis suggests that actual errors are smaller because of the uncertainty in landmark localization and prostate segmentation. Between the diagnostic and treatment positions, bony landmarks continued to register well, but prostate centroids moved towards the posterior 2.8-3.4 mm. Manual cropping to remove voxels in the legs was necessary to register these images. In conclusion, automatic, rigid body registration is probably sufficiently accurate for many applications in prostate cancer. For potential iMRI-guided treatments, the small prostate displacement between the diagnostic and treatment positions can probably be avoided by acquiring volumes in similar positions and by reducing bladder and rectal volumes.


Cystatin C-Based eGFR Changes during Gender-Affirming Hormone Therapy in Transgender Individuals.
Men with CKD tend to experience a faster eGFR decline than women, potentially because of sex hormones. Limited research exists regarding the effect of gender-affirming hormone therapy (GAHT) on kidney function. Furthermore, monitoring kidney function during GAHT is challenging because serum creatinine is confounded by body composition. To investigate the relationship between sex hormones and kidney function, we studied the changes of serum creatinine and serum cystatin C, a filtration marker less affected by sex, during 1 year of GAHT. As part of the European Network for the Investigation of Gender Incongruence study, we measured serum creatinine and serum cystatin C in 260 transgender women and 285 transgender men before and 12 months after initiating GAHT. Transgender women received estradiol plus cyproterone acetate, while transgender men received testosterone. Cystatin C-based eGFR was calculated using the full-age-spectrum equation. In transgender women, cystatin C decreased by 0.069 mg/L (95% confidence interval [CI], 0.049 to 0.089), corresponding with a 7 ml/min per 1.73 m 2 increase in eGFR. In transgender men, cystatin C increased by 0.052 mg/L (95% CI, 0.031 to 0.072), corresponding with a 6 ml/min per 1.73 m 2 decrease in eGFR. Creatinine concentrations decreased (-0.065 mg/dl; 95% CI, -0.076 to -0.054) in transgender women and increased (+0.131 mg/dl; 95% CI, 0.119 to 0.142) in transgender men. Changes in creatinine-based eGFR varied substantially depending on the sex used in the equation. In this cohort of transgender individuals, cystatin C-based eGFR increased with estradiol and antiandrogen therapy and decreased with testosterone therapy.


Association between Serum Phospholipid Fatty Acids and Intraprostatic Inflammation in the Placebo Arm of the Prostate Cancer Prevention Trial.
Inflammation may play an etiologic role in prostate cancer. Several dietary factors influence inflammation; studies have shown that long-chain n-3 polyunsaturated fatty acids are anti-inflammatory, whereas n-6 and trans fatty acids are proinflammatory. We evaluated whether serum phospholipid n-3, n-6, and trans fatty acids were associated with intraprostatic inflammation, separately in 191 prostate cancer cases and 247 controls from the placebo arm of the Prostate Cancer Prevention Trial (PCPT). Men without a prostate cancer diagnosis underwent prostate biopsy at trial end, and benign prostate tissue inflammation was evaluated in approximately three biopsy cores per man; this was expressed as no, some, or all cores with inflammation. In controls, serum eicosapentaenoic acid [OR of all cores with inflammation versus none (95% CI), 0.35 (0.14-0.89)] and docosahexaenoic acid [OR (95% CI), 0.42 (0.17-1.02)] were inversely associated with, whereas linoleic acid [OR (95% CI), 3.85 (1.41-10.55)] was positively associated with intraprostatic inflammation. Serum trans fatty acids were not associated with intraprostatic inflammation. No significant associations were observed in cases; however, we could not rule out a positive association with linoleic acid and an inverse association with arachidonic acid. Thus, in the PCPT, we found that serum n-3 fatty acids were inversely, n-6 fatty acids were positively, and trans fatty acids were not associated with intraprostatic inflammation in controls. Although, in theory, inflammation could mediate associations of serum fatty acids with prostate cancer risk, our findings cannot explain the epidemiologic associations observed with n-3 and n-6 fatty acids.


A comparison of cardiovascular and autonomic adjustments to three types of cold stimulation tasks.
Two types of 'cold pressor' tasks are used frequently in research settings: immersing the hand or foot in ice water, and applying an icebag to the forehead. Both tasks have commonly been selected as 'alpha-adrenergic' tasks due to expected increases in blood pressure and peripheral resistance. However, the forehead cooling task has been used by others to produce increased vagal tone due to the elicitation of the 'diving reflex' and subsequent bradycardia. This differs from the prototypical increase in heart rate during hand immersion. The present study directly compared the cardiovascular adjustments of hand immersion and forehead stimulation. As stimulation of the trigeminal nerve is thought to increase vagal activity during forehead cooling, a third condition in which most of the face was covered with an icebag was included to ostensibly stimulate more of the trigeminal. 18 males had counterbalanced exposures to hand immersion, forehead cooling, and facial cooling for 90 s each. Cardiovascular variables derived from impedance cardiography and the ECG were measured. Respiration was paced at 14 breaths/min to facilitate comparisons of respiratory sinus arrhythmia across conditions. No differences among baseline or tasks were found for respiratory rate or cardiac output. The pattern of results for hand immersion was that of increased heart rate with moderate blood pressure increases. In contrast, the forehead and facial cooling tasks elicited small heart rate decreases with little change in blood pressure. Facial cooling elicited significantly more vagal activation than hand cooling as indexed by respiratory sinus arrhythmia. The patterns of response for facial and forehead cooling were almost identical. Probable reasons for the lack of significant blood pressure responses during the facial and forehead cooling are discussed.


Immunohistochemical study of beta- and kappa-casein in the human breast and breast carcinomas, using monoclonal antibodies.
The immunohistochemical analysis of human beta- and kappa-caseins in the human breast, benign breast disease, and breast carcinomas is reported. The monoclonal antibodies LICR-LON-32.2 and LICR-LON-14.1 which react with human beta- and kappa-casein, respectively (Earl, H. M., and McIlhinney, R. A. J. Mol. Immunol., 22: 981-991, 1985) were used for these studies. Human beta- and kappa-caseins were detected in lactating human breast tissue, lactational foci in the resting breast, and heterogeneously in the 16th-week pregnant breast, but not in normal breast tissue. In benign breast disease occasional epithelial cells were demonstrated to synthesize beta- and kappa-caseins, but this finding did not appear to correlate with the hormonal status or previous obstetric histories of the patients. However, similar studies in 45 breast carcinomas with a wide range of estrogen receptor content, demonstrated no detectable beta- or kappa-casein. These results demonstrate that the caseins, which are biochemical markers of mammary gland differentiated function, and have been previously put forward as markers of breast cancer, were not synthesized in the 45 human breast carcinomas studied here, even in tumors with high levels of estrogen receptor protein.


Stabilizing supply of artemisinin and artemisinin-based combination therapy in an era of wide-spread scale-up.
The global demand for artemisinin-based combination therapy (ACT) has grown sharply since its recommendation by the World Health Organization in 2002. However, a combination of financing and programmatic uncertainties, limited suppliers of finished products, information opacity across the different tiers in the supply chain, and widespread fluctuations in raw material prices have together contributed to a market fraught with demand and supply uncertainties and price volatility. Various short-term solutions have been deployed to alleviate supply shortages caused by these challenges; however, new mechanisms are required to build resilience into the supply chain. This review concludes that a mix of strategies is required to stabilize the artemisinin and ACT market. First, better and more effective pooling of demand and supply risks and better contracting to allow risk sharing among the stakeholders are needed. Physical and financial buffer stocks will enable better matching of demand and supply in the short and medium term. Secondly, physical buffers will allow stable supplies when there are procurement and supply management challenges while financial buffer funds will address issues around funding disruptions. Finally, in the medium to long term, significant investments in country level system strengthening will be required to minimize national level demand uncertainties. In addition a voluntary standard for extractors to ensure appropriate purchasing and sales practices as well as minimum quality and ethical standards could help stabilize the artemisinin market in the long term.


Metal backed fixed-bearing unicondylar knee arthroplasties using minimal invasive surgery: a promising outcome analysis of 132 cases.
Unicondylar knee arthroplasty (UKA) is a well-established treatment for isolated osteoarthritis (OA) of the medial knee compartment. Aim of this retrospective study was to evaluate the early clinical and radiological outcomes of a consecutive series of patients treated with medial metal backed fixed-bearing UKA. Furthermore, the influence of the component orientation on the outcome was analyzed. From 09/2006 to 11/2010 106 patients (132 knees; 69 ± 9 years) were treated using a metal backed fixed-bearing UKA with a MIS approach. All patients underwent a standardized clinical and radiological follow-up at 6 weeks, 1, 2 and 5 years. Mean follow-up was 3.4 ± 1.0 years. Two patients (three UKAs) deceased and two patients (two UKAs) were lost to follow-up. Three different survival analyses were performed using three different endpoints defining failure: (a) revision with exchange of any UKA component (b) aseptic loosening and (c), a worst case scenario, where it was assumed that all progressive radiolucencies would lead to aseptic loosening and thus these were additionally counted. Clinical outcome was assessed using the American knee society score (AKS) and the Oxford knee score (OKS). Radiographic analysis was done according to the American Knee Society Evaluation and Scoring System adapted for UKA and correlated with the AKS and OKS. Five UKAs (3.8 %) were revised to total knee arthroplasties (TKAs) after a median of 25 (10-33) months. Five year survival was 95.2, 97.5 and 87.7% for the aforementioned endpoints. At final follow-up the median AKS knee score was 99 (50-100) points and the median AKS function score was 100 (60-100) points. The median OKS was 43 (8-48) points. Clinical outcome was independent of the component orientation. Fixed-bearing UKA showed excellent clinical and radiological results at up to 5 years follow-up. Outcome was independent of component orientation.


Incidence of metachronous contralateral breast cancer in Denmark 1978-2009.
Incidence of contralateral breast cancer (CBC) is much less studied than primary breast cancer. We aimed to assess incidence rates of CBC in relation to age, calendar period and time since first breast cancer. Using the nationwide Danish Cancer Registry, we identified 85 863 women with a first primary invasive breast cancer without distant metastases in Denmark during 1978-2009. Among these, 3120 women developed metachronous CBC. Crude incidence rates for CBC were calculated by age and calendar period at first breast cancer as well as time since first breast cancer. Mutual adjustments were made by use of Poisson regression models. The incidence of CBC decreased with increasing age at first breast cancer. Before 1998, incidence rates of CBC showed little variation. The rates decreased by period of first primary from 546 per 10(5) person-years in 1993-97 to 328 per 10(5) person-years in 2003-09. After adjustment for age and calendar period, no clear trend was observed in the overall incidence according to time since first breast cancer. Occurrence of cancer in the contralateral breast seems to be rather independent of time passed since the first primary. The finding of a decreasing incidence of CBC after 1997 is likely to be due to more women receiving systemic adjuvant therapy such as tamoxifen and longer duration of this treatment as well as the introduction of aromatase inhibitors.


The role of informal carers in the diagnostic process of heart failure: a secondary qualitative analysis.
Heart failure (HF) is a common clinical syndrome, particularly in older people, and symptoms can develop gradually. The aim of this study was to explore the role of informal carers in the HF diagnostic process. Secondary analysis of qualitative interviews with 16 participants with a new diagnosis of HF. Original interviews were conducted in the participant's home, with carers present in some cases. Interview transcripts were re-analysed using the Framework Method for themes pertaining to informal carers and how they were involved in the diagnostic process. Informal carers often noticed symptoms, such as breathlessness, before participants. In some cases, carers colluded with participants in normalising symptoms but over time, when symptoms failed to resolve or got worse, they encouraged participants to seek medical help. Adult children of participants commonly initiated help-seeking behaviour. During the diagnostic process, carers coordinated participants' healthcare through advocacy and organisation. Carers were keen to be informed about the diagnosis, but both participants and carers struggled to understand some aspects of the term 'heart failure'. Carers play a crucial role in HF diagnosis, particularly in initiating contact with healthcare services, and should be empowered to encourage people with HF symptoms to seek medical help. Improving public awareness of HF could mean informal carers are more likely to notice symptoms. The important role of carers in supporting the patient's route to diagnosis should be incorporated into future care pathways and explored in further research.


Awareness and Attitudes of Student Dietitians in Lebanon, UK and USA towards Food Safety.
Allied health professionals such as dietitians can play a critical role in providing food safety advice to vulnerable consumers. To maximize food-related health and wellbeing, food needs to be safe and nutritious; consequently, food safety is referred to in international curricula for the training of dietitians. The purpose of this study was to explore the awareness and attitudes of student dietitians from three international institutions towards food safety. A total of 207 student dietitians participated in the study from Columbus, OH, USA (n = 99), Cardiff, Wales, UK (n = 78) and Beirut, Lebanon (n = 30). Completion of the study established that the students in three dietetic training programs lacked awareness of key food safety concepts. Close to half (43%) were not familiar with Campylobacter, with the USA students being significantly less knowledgeable (p < 0.001) with 58% being unaware of the pathogen. Understanding of safe handling of leftovers was the lowest for the students in all institutions; only 46% described appropriate reheating practices, with significantly lower (p < 0.001) understanding in Lebanon (28%). The students reported a good understanding of vulnerable populations and perceived food safety to be important for these groups. However, the knowledge of certain high-risk foods was lacking. For instance, 69% of students thought that fresh squeezed juices and smoothies made with raw fruits and vegetables were safe for vulnerable patients, with the UK students being the least familiar with this risk (16%). This is the first study of its kind to take an international perspective of student dietitian food safety awareness and attitudes; the findings are important to dietetic food safety educators and recommendations are made to further explore the interpretation of food safety requirements in international dietetic curricula. Future studies should extend student dietetic research to address attitudes, self-efficacy and the overall readiness to deliver food safety advice to the patients and the community.


Evidence of retinal vascular narrowing in glaucomatous eyes in an Asian population.
To examine the relationship between retinal vascular caliber and glaucoma in an Asian population. A population-based, cross-sectional study of 3019 persons of Asian Malay ethnicity aged 40 to 80 years residing in Singapore. All participants had dilated digital retinal photographs taken of both eyes. From these, retinal vascular caliber was measured with a computer-based technique according to a standardized protocol. Glaucoma was diagnosed based on the International Society of Geographic and Epidemiologic Ophthalmology classification and included people with glaucomatous optic neuropathy and compatible visual field loss. There were 127 (4.2%) participants with glaucoma. Mean retinal arteriolar and venular calibers were significantly narrower in persons with than in those without glaucoma (136.4 microm vs. 139.7 microm, P = 0.02 and 209.2 microm vs. 219.7 microm, P < 0.001, respectively). After adjusting for age, sex, smoking, IOP, and other vascular risk factors, persons with narrower retinal arteriolar and venular caliber were more likely to have glaucoma (odds ratio [OR], 1.29; 95% confidence interval [CI], 1.07-1.56 and OR, 1.49; 95% CI, 1.24-1.79, for each SD reduction in arteriolar and venular caliber, respectively) and a vertical cup-to-disc ratio >or= 0.7 (OR, 1.35; 95% CI, 1.12-1.63 and OR, 1.65; 95% CI, 1.38-1.98, respectively). Retinal vascular caliber was not associated with intraocular pressure. These findings support an association of narrower retinal arteriolar and venular caliber changes with glaucomatous optic neuropathy, independent of intraocular pressure.


Microlens characterization by digital holographic microscopy with physical spherical phase compensation.
Microlenses have been characterized by a digital holographic microscopy system, which is immune to the inherent wavefront aberration. The digital holographic microscopy system takes advantage of fiber optics and uses the light emitted directly from a single-mode fiber as the recording reference wave. By using such a reference beam, which is quasi-identical to the object beam, the inherent wavefront aberration of the digital holographic microscope is removed. The alignment of the optical setup can be optimized with the help of numerical reconstruction software to give the system phase with the off-axis tilt removed. There is one, and only one, reference fiber point position to give a reference wavefront that is quasi-identical to the object wavefront where the system is free of wavefront aberration and directly gives the quantitative phase of the test object without the need for complicated numerical compensation.


Operculoinsular cortex encodes pain intensity at the earliest stages of cortical processing as indicated by amplitude of laser-evoked potentials in humans.
Converging evidence from different functional imaging studies indicates that the intensity of activation of different nociceptive areas (including the operculoinsular cortex, the primary somatosensory cortex, and the anterior cingulate gyrus) correlates with perceived pain intensity in the human brain. Brief radiant laser pulses excite selectively Adelta and C nociceptors in the superficial skin layers, provide a purely nociceptive input, and evoke brain potentials (laser-evoked potentials, LEPs) that are commonly used to assess nociceptive pathways in physiological and clinical studies. Adelta-related LEPs are constituted of different components. The earliest is a lateralised, small negative component (N1) which could be generated by the operculoinsular cortex. The major negative component (N2) seems to be mainly the result of activation in the bilateral operculoinsular cortices and contralateral primary somatosensory cortex, and it is followed by a positive component (P2) probably generated by the cingulate gyrus. Currently, early and late LEP components are considered to be differentially sensitive to the subjective variability of pain perception: the late N2-P2 complex strongly correlates with perceived pain, whereas the early N1 component is thought to be a pre-perceptual sensory response. To obtain physiological information on the roles of the pain-related brain areas in healthy humans, we examined the relationship between perceived pain intensity and latency and amplitude of the early (N1) and late (N2, P2) LEP components. We found that the amplitude of the N1 component correlated significantly with the subjective pain ratings, both within and between subjects. Furthermore, we showed that the N2 and P2 late LEP components are differentially sensitive to the perceived sensation, and demonstrated that the N2 component mainly explains the previously described correlation between perceived pain and the amplitude of the N2-P2 vertex complex of LEPs. Our findings confirm the notion that pain intensity processing is distributed over several brain areas, and suggest that the intensity coding of a noxious stimulus occurs already at the earliest stage of perception processing, in the operculoinsular region and, possibly, the primary somatosensory area.


Effects of a high-salt diet on TRPV-1-dependent renal nerve activity in Dahl salt-sensitive rats.
To test the hypothesis that transient receptor potential vanilloid type 1 channel (TRPV1)-mediated increases in afferent renal nerve activity (ARNA) and release of substance P (SP) and calcitonin gene-related peptide (CGRP) from the renal pelvis are suppressed in Dahl salt-sensitive (DS), but not -resistant (DR), rats fed a high-salt (HS) diet. Male DS and DR rats were given a HS or low-salt (LS) diet for 3 weeks. Perfusion of capsaicin (CAP, 10(-6)M), a selective TRPV1 agonist, into the left renal pelvis increased ipsilateral ARNA in all groups, but with a smaller magnitude in DS-HS compared to other groups. CAP increased contralateral urine flow in all groups except DS-HS rats. CAP-induced release of SP and CGRP from the renal pelvis was less in DS-HS compared to other groups. Western blot showed that TRPV1 expression in the kidney decreased while expression of neurokinin 1 receptors increased in DS-HS compared to other groups. TRPV1-mediated increases in ARNA and release of SP and CGRP in the renal pelvis are impaired in DS rats fed a HS diet, which can likely be attributed to suppressed TRPV1 expression in the kidney and contributes to increased salt sensitivity.


Environment-insensitive and gate-controllable photocurrent enabled by bandgap engineering of MoS2 junctions.
Two-dimensional (2D) materials are composed of atomically thin crystals with an enormous surface-to-volume ratio, and their physical properties can be easily subjected to the change of the chemical environment. Encapsulation with other layered materials, such as hexagonal boron nitride, is a common practice; however, this approach often requires inextricable fabrication processes. Alternatively, it is intriguing to explore methods to control transport properties in the circumstance of no encapsulated layer. This is very challenging because of the ubiquitous presence of adsorbents, which can lead to charged-impurity scattering sites, charge traps, and recombination centers. Here, we show that the short-circuit photocurrent originated from the built-in electric field at the MoS2 junction is surprisingly insensitive to the gaseous environment over the range from a vacuum of 1 × 10-6 Torr to ambient condition. The environmental insensitivity of the short-circuit photocurrent is attributed to the characteristic of the diffusion current that is associated with the gradient of carrier density. Conversely, the photocurrent with bias exhibits typical persistent photoconductivity and greatly depends on the gaseous environment. The observation of environment-insensitive short-circuit photocurrent demonstrates an alternative method to design device structure for 2D-material-based optoelectronic applications.


Driven to distraction: a prospective controlled study of a simulated ward round experience to improve patient safety teaching for medical students.
Distraction and interruption are endemic in the clinical environment and contribute to error. This study assesses whether simulation-based training with targeted feedback can improve undergraduate management of distractions and interruptions to reduce error-making. A prospective non-randomised controlled study. 28 final year medical students undertook a simulated baseline ward round. 14 students formed an intervention group and received immediate feedback on distractor management and error. 14 students in a control group received no feedback. After 4 weeks, students participated in a post-intervention ward round of comparable rigour. Changes in medical error and distractor management between simulations were assessed with Mann-Whitney U tests using SPSS V.21. At baseline, error rates were high. The intervention group committed 72 total baseline errors (mean of 5.1 errors/student; median 5; range 3-7). The control group exhibited a comparable number of errors-with a total of 76 observed (mean of 5.4 errors/student; median 6; range 4-7). Many of these errors were life-threatening. At baseline distractions and interruptions were poorly managed by both groups. All forms of simulation training reduced error-making. In the intervention group the total number of errors post-intervention fell from 72 to 17 (mean 1.2 errors/student; median 1; range 0-3), representing a 76.4% fall (p<0.0001). In the control group the total number of errors also fell-from 76 to 44 (mean of 3.1 errors/student; median 3; range 1-5), representing a 42.1% reduction (p=0.0003). Medical students are not inherently equipped to manage common ward-based distractions to mitigate error. These skills can be taught-with simulation and feedback conferring the greatest benefit. Curricular integration of simulated ward round experiences is recommended.


Clinical and molecular investigation of a canine distemper outbreak and vector-borne infections in a group of rescue dogs imported from Hungary to Switzerland.
Canine distemper virus (CDV) is a major pathogen of dogs and wild carnivores worldwide. In Switzerland, distemper in domestic dogs is rarely reported. In recent years, the import of dogs from Eastern Europe to Switzerland has steadily increased. In the present study, we describe a distemper outbreak in 15 rescue dogs that were imported from Hungary to Switzerland by an animal welfare organisation. The data on vaccination and medical history were recorded (14 dogs), and the samples were collected to investigate CDV and vector-borne infections (13 dogs) and canine parvovirus infection (12 dogs). The dogs were monitored for six months. One dog was euthanised directly after import. Thirteen dogs showed clinical signs after arrival, i.e., diarrhoea (57 %), coughing (43 %) and nasal and/or ocular discharge (21 %); radiographic findings that were compatible with bronchopneumonia were present in four dogs. CDV infection was diagnosed in 11 dogs (85 %); 10 dogs (91 %) tested PCR-positive in conjunctival swabs. Vector-borne infections (Babesia spp., Leishmania infantum, Dirofilaria immitis) were found in 4 dogs (31 %). Three dogs were hospitalized, and six dogs received ambulatory therapy for up to two months until recovery. None of the dogs developed neurological disease. CDV shedding was detected for a period of up to four months. Because dogs were put under strict quarantine until CDV shedding ceased, CDV did not spread to any other dogs. The CDV isolates showed 99 % sequence identity in the HA gene among each other and belonged to the Arctic-like lineage of CDV. The present study highlights the imminent risks of spreading contagious viral and vector-borne infections through the non-selective import of sick dogs and dogs with incomplete vaccination from Eastern Europe. CDV shedding was detected for several months after the cessation of clinical signs, which emphasised the roles of asymptomatic carriers in CDV epidemiology. A long-term follow-up using sensitive PCR and strict quarantine measures is of upmost importance in preventing the spread of infection. Dog owners and animal welfare organisations should be educated regarding the importance of complete vaccinations and the impact of dog imports on the spread of viral and vector-borne pathogens.


A Hybrid III stepped wedge cluster randomized trial testing an implementation strategy to facilitate the use of an evidence-based practice in VA Homeless Primary Care Treatment Programs.
Homeless veterans often have multiple health care and psychosocial needs, including assistance with access to housing and health care, as well as support for ongoing treatment engagement. The Department of Veterans Affairs (VA) developed specialized Homeless Patient Alignment Care Teams (HPACT) with the goal of offering an integrated, "one-stop program" to address housing and health care needs of homeless veterans. However, while 70% of HPACT's veteran enrollees have co-occurring mental health and substance use disorders, HPACT does not have a uniform, embedded treatment protocol for this subpopulation. One wraparound intervention designed to address the needs of homeless veterans with co-occurring mental health and substance use disorders which is suitable to be integrated into HPACT clinic sites is the evidence-based practice called Maintaining Independence and Sobriety through Systems Integration, Outreach, and Networking-Veterans Edition, or MISSION-Vet. Despite the promise of MISSION-Vet within HPACT clinics, implementation of an evidence-based intervention within a busy program like HPACT can be difficult. The current study is being undertaken to identify an appropriate implementation strategy for MISSION-Vet within HPACT. The study will test the implementation platform called Facilitation and compared to implementation as usual (IU). The aims of this study are as follows: (1) Compare the extent to which IU or Facilitation strategies achieve fidelity to the MISSION-Vet intervention as delivered by HPACT homeless provider staff. (2) Compare the effects of Facilitation and IU strategies on the National HPACT Performance Measures. (3) Compare the effects of IU and Facilitation on the permanent housing status. (4) Identify and describe key stakeholders' (patients, providers, staff) experiences with, and perspectives on, the barriers to, and facilitators of implementing MISSION. Type III Hybrid modified stepped wedge implementation comparing IU to Facilitation across seven HPACT teams in three sites in the greater Los Angeles VA system. This is a cluster randomized trial. Integrating MISSION-Vet within HPACT has the potential to improve the health of thousands of veterans, but it is crucial to implement the intervention appropriately in order for it to succeed. The lessons learned in this protocol could assist with a larger roll-out of MISSION within HPACT. This protocol is registered with clinicaltrials.gov and was assigned the number NCT 02942979.


Errors in the 2017 APA Clinical Practice Guideline for the Treatment of PTSD: What the Data Actually Says.
The American Psychological Association (APA) Practice Guidelines for the Treatment of Posttraumatic Stress Disorder (PTSD) concluded that there was strong evidence for cognitive behavioral therapy (CBT), cognitive processing therapy (CPT), cognitive therapy (CT), and exposure therapy yet weak evidence for eye movement desensitization and reprocessing (EMDR). This is despite the findings from an associated systematic review which concluded that EMDR leads to loss of PTSD diagnosis and symptom reduction. Depression symptoms were also found to improve more with EMDR than control conditions. In that review, EMDR was marked down on strength of evidence (SOE) for symptom reduction for PTSD. However, there were several problems with the conclusions of that review. Firstly, in assessing the evidence in one of the studies, the reviewers chose an incorrect measure that skewed the data. We recalculated a meta-analysis with a more appropriate measure and found the SOE improved. The resulting effect size for EMDR on PTSD symptom reduction compared to a control condition was large for studies that meet the APA inclusion criteria (SMD = 1.28) and the heterogeneity was low (I2= 43%). Secondly, even if the original measure was chosen, we highlight inconsistencies with the way SOE was assessed for EMDR, CT, and CPT. Thirdly, we highlight two papers that were omitted from the analysis. One of these was omitted without any apparent reason. It found EMDR superior to a placebo control. The other study was published in 2015 and should have been part of APA guidelines since they were published in 2017. The inclusion of either study would have resulted in an improvement in SOE. Including both studies results in standard mean difference and confidence intervals that were better for EMDR than for CPT or CT. Therefore, the SOE should have been rated as moderate and EMDR assessed as at least equivalent to these CBT approaches in the APA guidelines. This would bring the APA guidelines in line with other recent practice guidelines from other countries. Less critical but also important, were several inaccuracies in assessing the risk of bias and the failure to consider studies supporting strong gains of EMDR at follow-up.


Which vascular lesions are of importance in vascular dementia?
Most necropsy surveys of dementia have found that vascular disease is second only to Alzheimer's disease as a cause of dementia. Alzheimer's disease and cerebrovascular disease also often coexist. The purpose of the present study was to determine the nature of the cerebrovascular lesions that are most significant in producing dementia. These were analyzed in a group of cases of dementia in which only vascular pathology was present and, in particular, no more than trivial amounts of Alzheimer-type pathology were present. The cerebrovascular lesions in this group of cases were compared with those in a group of stroke cases who were nondemented and a group of elderly cases without stroke or dementia. Severe cribriform change and deep white/grey matter micro-infarcts were significantly more common in the test group than in either of the control groups, whereas single macroscopic infarcts were more common in the stroke control group than either of the other two groups. Thus, microvascular deep white and grey matter lesions, but not macroscopic infarction, were significant in vascular dementia. The results of this study will be discussed in relation to the view that microvascular lesions may also contribute to dementia in subjects with more extensive Alzheimer-type pathology and thus lower the threshold at which Alzheimer-type pathology becomes clinically manifest.


Nucleotide-induced stable complex formation by HIV-1 reverse transcriptase.
Nondenaturing gel electrophoresis was used to study the nucleotide substrate-induced conformational change in reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1). Dead-end complex was formed between HIV-1 RT, dideoxynucleotide chain-terminated primer, and DNA template in the presence of deoxynucleotide triphosphate (dNTP) complementary to the next position on the template. Complexes which form in the absence of the next complementary dNTP were disrupted by adding excess poly(rA)/oligo(dT) or heparin just prior to electrophoresis. Dead-end complex formation by noncomplementary dNTP's or ribonucleotides was at least 2000-fold less efficient than with the complementary nucleotide. When dA was the next nucleotide on the template, analogues of dTTP supported dead-end complex formation with increased apparent Kd (dTTP < dideoxy-TTP approximately alpha-thio-dTTP < dUTP < 3'-azidothymidine triphosphate). A similar relationship was observed for dGTP analogues across from dC on the template (dGTP < dideoxy-GTP < alpha-thio-dGTP << dITP < dideoxy-ITP). The optimal length of the primer/template duplex region for dead-end complex formation was between 20 and 32 base pairs. Primer-template with a mismatched primer terminus did not support dead-end complex formation, and primer terminated with 3'-azidothymidine formed dead-end complex with 25-fold elevated apparent Kd. By contrast, dead-end complex formation on primer terminated with dideoxy-IMP base paired with dC on the template was more efficient than on primer terminated with dideoxy-GMP. Implications for the mechanisms of discrimination between nucleotide analogues by HIV-1 RT are discussed.


Review of cytomegalovirus shedding in bodily fluids and relevance to congenital cytomegalovirus infection.
Congenital cytomegalovirus (CMV) infections are a leading cause of sensorineural hearing loss (SNHL) and neurological impairment. Congenital transmission of CMV can occur with maternal primary infection, reactivation, or reinfection during pregnancy. We reviewed studies of CMV shedding in bodily fluids (defined as CMV detected by culture or CMV DNA detected by polymerase chain reaction). Following diagnosis at birth, children with congenital CMV infection exhibited the highest prevalences of CMV shedding (median = 80%, number of sample population prevalences [N] = 6) and duration of shedding, with a steep decline by age five. Healthy children attending day care shed more frequently (median = 23%, N = 24) than healthy children not attending day care (median = 12%, N = 11). Peak shedding prevalences in children occurred at 1-2 years of age, confirming that young children are the key transmission risk for pregnant women. CMV shedding among children was more prevalent in urine specimens than in oral secretions (median prevalence difference = 11.5%, N = 12). Adults with risk factors such as STD clinic attendance had higher shedding prevalences (median = 22%, N = 20) than adults without risk factors (median = 7%, N = 44). In adults with risk factors, CMV was shed more frequently in urine; in adults without risk factors genital shedding was most common. The prevalence of CMV shedding in nine sample populations of pregnant women increased with advancing gestation. In seven sample populations of children with congenital CMV infection, higher viral load at birth was consistently associated with an elevated risk of SNHL. Higher CMV viral load at birth also consistently correlated with the presence of symptoms of congenital CMV at birth. Published 2011. This article is a US Government work and is in the public domain in the USA.


Current pharmacotherapy of bradykinin-mediated angioedema.
Bradykinin-mediated angioedema is characterized by subcutaneous and/or submucosal edema formation without wheals and pruritus. It is linked to bradykinin-enhanced vascular permeability and, therefore, it does not respond to conventional measures, but requires specific therapy. This summary briefly reviews the different types of bradykinin-mediated angioedema and its remedies. Therapy focuses on relieving edema, as well as on decreasing its incidence and severity. The modes of the actions of attenuated androgens and antifibrinolytics are not precisely known - these agents have been introduced on an empirical basis. Contemporary treatments, by contrast, have been purposely developed to inhibit bradykinin. Most experience pertains to angioedema resulting from C1-inhibitor deficiency, and the controlled studies have focused on the hereditary form of this disease type (HAE). The pathomechanisms of HAE with normal C1-inhibitor activity, as well as of angiotensin-converting enzyme inhibitor-releated, and of non-histaminergic idiopathic sporadic angioedemas are largely unknown. Appropriate laboratory methods for the diagnosis, or specific interventions for the therapy of these conditions are not available or only available off-label. In this case, diagnosis and management are challenging. The range of targeted therapeutic options has increased in recent years and includes measures to handle emergencies, prevent edematous episodes and manage additional types of bradykinin-mediated angioedema.


Relationship of the C242T p22phox gene polymorphism to angiographic coronary artery disease and endothelial function.
Patients with coronary artery disease (CAD) have impaired endothelial function in part due to an increase in vascular oxidant stress. p22phox, an essential component of the NADPH oxidase, is thought to play a critical role in the generation of superoxide anions in the vessel wall. The C242T polymorphism, located in the potential heme-binding site of the p22phox gene, has recently been reported to confer a protective effect on CAD risk in a Japanese study population. In a U.S. population of 252 patients (83% Caucasian) undergoing angiography for diagnosis of CAD, we investigated whether the C242T polymorphism was associated with the presence of CAD. In a subset of 142 patients, we studied whether the polymorphism manifests its potential protective effects through alteration of vascular endothelial function by measuring coronary epicardial and microvascular responses to intracoronary acetylcholine and sodium nitroprusside. Prevalence of the C242T allele was not different in 149 patients with CAD compared to 103 patients with angiographically normal coronary arteries (65.1% vs. 54.4%, P = 0.11). The C242T allele frequency in our population was nearly fourfold higher than reported previously in a Japanese population. There were also no significant differences in coronary epicardial or microvascular responses to acetylcholine or sodium nitroprusside between groups of patients with or without the C242T allele. In a U.S. population, the C242T polymorphism does not appear to confer protection from endothelial dysfunction or CAD. Am. J. Med. Genet. 86:57-61, 1999. Published 1999 Wiley-Liss, Inc.


Effect of animal facility construction on basal hypothalamic-pituitary-adrenal and renin-aldosterone activity in the rat.
Although loud noise and intense vibration are known to alter the behavior and phenotype of laboratory animals, little is known about the effects of nearby construction. We studied the effect of a nearby construction project on the classic stress hormones ACTH, corticosterone, renin, and aldosterone in rats residing in a barrier animal facility before, for the first 3 months of a construction project, and at 1 month after all construction was completed. During some of the construction, noise and vibrations were not obvious to investigators inside the animal rooms. Body weight matched for age was not altered by nearby construction. During nearby construction, plasma ACTH, corticosterone, and aldosterone were approximately doubled compared with those of pre- and postconstruction levels. Expression of CRH mRNA in the paraventricular nucleus of the hypothalamus, CRH receptor and POMC mRNA in the anterior pituitary, and most mRNAs for steroidogenic genes in the adrenal gland were not significantly changed during construction. We conclude that nearby construction can cause a stress response without long-term effects on hypothalamic-pituitary-adrenal axis gene expression and body weight.


Cell-specific expression of the carrot EP2 lipid transfer protein gene.
A cDNA corresponding to a 10-kD protein, designated extracellular protein 2 (EP2), that is secreted by embryogenic cell cultures of carrot was obtained by expression screening. The derived protein sequence and antisera against heterologous plant lipid transfer proteins identified the EP2 protein as a lipid transfer protein. Protein gel blot analysis showed that the EP2 protein is present in cell walls and conditioned medium of cell cultures. RNA gel blot analysis revealed that the EP2 gene is expressed in embryogenic cell cultures, the shoot apex of seedlings, developing flowers, and maturing seeds. In situ hybridization showed expression of the EP2 gene in protoderm cells of somatic and zygotic embryos and transient expression in epidermis cells of leaf primordia and all flower organs. In the shoot apical meristem, expression is found in the tunica and lateral zone. In maturing seeds, the EP2 gene is expressed in the outer epidermis of the integument, the seed coat, and the pericarp epidermis, as well as transiently in between both mericarps. Based on the extracellular location of the EP2 protein and the expression pattern of the encoding gene, we propose a role for plant lipid transfer proteins in the transport of cutin monomers through the extracellular matrix to sites of cutin synthesis.


Thermosensitive molecularly imprinted core-shell CdTe quantum dots as a ratiometric fluorescence nanosensor for phycocyanin recognition and detection in seawater.
Versatile molecular imprinted fluorescence sensors have been prepared for various species, but the imprinting based fluorescence detection of target proteins upon different external stimulation is rarely reported. Herein, a novel phycocyanin-imprinted ratiometric fluorescence nanosensor was developed for the temperature regulated sensing and detection of a phycocyanin target based on fluorescence resonance energy transfer (FRET). The nanosensor was fabricated via simple facile copolymerization, with amino/carboxyl modified quantum dots (QDs) as a fluorescent support, N-isopropylacrylamide as a thermo-responsive functional monomer, N,N-methylenebisacrylamide as a cross-linker and phycocyanin as a template. Under temperature control at 20 °C and 45 °C, the fluorescence intensities of the QDs and phycocyanin were regularly decreased and enhanced, respectively, to a different extent as the concentration of phycocyanin increased, and thereby the ratio of the two fluorescence peak emission intensities of QDs and phycocyanin was used to determine the concentration of phycocyanin. Good linearity was obtained within the range of 0-1.8 μM (r = 0.9900) with a low detection limit of 3.2 nM, and excellent recognition selectivity towards the phycocyanin target was achieved over other proteins. Moreover, satisfactory recoveries of 92.0-106.8% were obtained in spiked seawater samples. This study provides a facile, fast and intelligent way to conduct identification analysis of trace proteins in complex water matrices, and can push forward protein imprinting and stimuli-responsive imprinting related research.


Immunochemical localization of keratan sulfate proteoglycans in cornea, sclera, and limbus using a keratanase-generated neoepitope monoclonal antibody.
To evaluate the use of neoepitope monoclonal antibody BKS-1, which recognizes keratanase-generated keratan sulfate (KS) stubs on keratan sulfate proteoglycans in human cornea, limbus, and sclera. BKS-1 specifically recognizes a keratanase-generated neoepitope [N-acetyl-glucosamine-6-sulfate (GlcNAc-6-S)] at the nonreducing terminal of corneal and skeletal KS glycosaminoglycan chains. It was produced by using keratanase-digested KS peptides from bovine cartilage aggrecan as the immunizing antigen. BKS-1 was used in conjunction with 5D4 to analyze the KS distribution in human cornea, limbus, and sclera using Western blotting, immunohistochemistry, and electron microscopy. 5D4 Western blot analysis displayed a diffuse staining pattern, and it was difficult to distinguish differences among cornea, sclera, and limbus. However, BKS-1 showed differences in KS levels, with higher levels in the cornea and lower levels in the limbus and sclera. Ultrastructural studies showed that the monoclonal antibody (mAb) BKS-1 neoepitope was not observed in the epithelium or basement membrane; however, 5D4 was present in these layers. Large quantities of both antibodies were present in Bowman's layer, stroma, and Descemet's membrane, but the quantity of 5D4 was significantly higher (P < 0.001) than the quantity of BKS-1 in all these layers of the cornea. mAb 5D4 recognizes oversulfated structures within KS chains, whereas BKS-1 recognizes a single neoepitope on KS after keratanase digestion of monosulfated KS disaccharides. With the use of BKS-1, the authors identified a more clearly defined pattern for KS distribution in the cornea than was seen with 5D4. The presence of a large quantity of BKS-1 immunostaining in the cornea suggests that KS-substituted proteoglycans are more prevalent in the cornea than in the limbus or sclera.


Safety and efficacy of the mRNA BNT162b2 vaccine against SARS-CoV-2 in five groups of immunocompromised patients and healthy controls in a prospective open-label clinical trial.
Patients with immunocompromised disorders have mainly been excluded from clinical trials of vaccination against COVID-19. Thus, the aim of this prospective clinical trial was to investigate safety and efficacy of BNT162b2 mRNA vaccination in five selected groups of immunocompromised patients and healthy controls. 539 study subjects (449 patients and 90 controls) were included. The patients had either primary (n=90), or secondary immunodeficiency disorders due to human immunodeficiency virus infection (n=90), allogeneic hematopoietic stem cell transplantation/CAR T cell therapy (n=90), solid organ transplantation (SOT) (n=89), or chronic lymphocytic leukemia (CLL) (n=90). The primary endpoint was seroconversion rate two weeks after the second dose. The secondary endpoints were safety and documented SARS-CoV-2 infection. Adverse events were generally mild, but one case of fatal suspected unexpected serious adverse reaction occurred. 72.2% of the immunocompromised patients seroconverted compared to 100% of the controls (p=0.004). Lowest seroconversion rates were found in the SOT (43.4%) and CLL (63.3%) patient groups with observed negative impact of treatment with mycophenolate mofetil and ibrutinib, respectively. The results showed that the mRNA BNT162b2 vaccine was safe in immunocompromised patients. Rate of seroconversion was substantially lower than in healthy controls, with a wide range of rates and antibody titres among predefined patient groups and subgroups. This clinical trial highlights the need for additional vaccine doses in certain immunocompromised patient groups to improve immunity. Knut and Alice Wallenberg Foundation, the Swedish Research Council, Nordstjernan AB, Region Stockholm, Karolinska Institutet, and organizations for PID/CLL-patients in Sweden.


Evaluation of Bi-Lateral Co-Infections and Antibiotic Resistance Rates among COVID-19 Patients.
In addition to the pathogenesis of SARS-CoV-2, bacterial co-infection plays an essential role in the incidence and progression of SARS-CoV-2 infections by increasing the severity of infection, as well as increasing disease symptoms, death rate and antimicrobial resistance (AMR). The current study was conducted in a tertiary-care hospital in Lahore, Pakistan, among hospitalized COVID-19 patients to see the prevalence of bacterial co-infections and the AMR rates among different isolated bacteria. Clinical samples for the laboratory diagnosis were collected from 1165 hospitalized COVID-19 patients, of which 423 were found to be positive for various bacterial infections. Most of the isolated bacteria were Gram-negative rods (n = 366), followed by Gram-positive cocci (n = 57). A significant association (p < 0.05) was noted between the hospitalized COVID-19 patients and bacterial co-infections. Staphylococcus aureus (S. aureus) showed high resistance against tetracycline (61.7%), Streptococcus pyogenes against penicillin (100%), E. coli against Amp-clavulanic acid (88.72%), Klebsiella pneumoniae against ampicillin (100%), and Pseudomonas aeruginosa against ciprofloxacin (75.40%). Acinetobacter baumannii was 100% resistant to the majority of tested antibiotics. The prevalence of methicillin-resistant S. aureus (MRSA) was 14.7%. The topmost symptoms of >50% of COVID-19 patients were fever, fatigue, dyspnea and chest pain with a significant association (p < 0.05) in bacterial co-infected patients. The current study results showed a comparatively high prevalence of AMR, which may become a severe health-related issue in the future. Therefore, strict compliance of antibiotic usage and employment of antibiotic stewardship programs at every public or private institutional level are recommended.


The cortical basis of global motion detection in blindsight.
The importance of stimulus qualities such as orientation, motion and luminance in blindsight are well known but their cortical basis has been much less explored. We therefore studied the performance of two blindsighted hemianopic subjects (GY and MS), in a task in which the subject had to decide in which of two adjunctive intervals a pattern of global spots moved coherently, at a variety of speeds, in the hemianopic field. Their ability was compared with that of two control subjects with normal vision. Both hemianopes performed this simple discrimination well in their blind fields but their performance was impaired by repetitive transcranial magnetic stimulation (rTMS) applied over cortical area hV5/MT(+) although not, or only slightly, by stimulation over the region of V3 or the vertex. The result is a direct demonstration that area hV5/MT(+) is necessary for global motion detection in blindsight.


Flow cytometric analysis of peripheral blood lymphocytes in ulcerative colitis and Crohn's disease.
Using two colour immunofluorescence with fluorescein isothiocyanate and phycoerythrin labelled monoclonal antibodies, multi-parameter flow cytometry was used to examine the antigenic characteristics of peripheral blood lymphocytes in whole blood of patients with ulcerative colitis and Crohn's disease who were not taking immunosuppressive drugs. The numbers of CD4+ and CD8+ lymphocytes in patients with ulcerative colitis and Crohn's disease remained unchanged so that the CD4/CD8 ratio was the same as that of normal control subjects. In Crohn's disease there were many activated T cells (CD3+, CD25+). Although natural killer cells in active Crohn's disease were lower than in normal control subjects, cytotoxic T lymphocytes, as defined by CD3+, CD16+, did not differ in patients with inflammatory bowel disease compared with normal control subjects. For B cell subsets, there were differences in Leu-1+ B cells, Leu-8+ B cells, Fc epsilon R+B cells (Leu-16+, Leu-20+), and activated B cells (Leu-12+, Leu-21+) between patients with inflammatory bowel disease and normal control subjects. These differences are compatible with local activation of B cells in the inflamed colon.


Long-term effects of ionizing radiation on gene expression in a zebrafish model.
Understanding how initial radiation injury translates into long-term effects is an important problem in radiation biology. Here, we define a set of changes in the transcription profile that are associated with the long-term response to radiation exposure. The study was performed in vivo using zebrafish, an established radiobiological model organism. To study the long-term response, 24 hour post-fertilization embryos were exposed to 0.1 Gy (low dose) or 1.0 Gy (moderate dose) of whole-body gamma radiation and allowed to develop for 16 weeks. Liver mRNA profiles were then analyzed using the Affymetrix microarray platform, with validation by quantitative PCR. As a basis for comparison, 16-week old adults were exposed at the same doses and analyzed after 4 hours. Statistical analysis was performed in a way to minimize the effects of multiple comparisons. The responses to these two treatment regimes differed greatly: 360 probe sets were associated primarily with the long-term response, whereas a different 2062 probe sets were associated primarily with the response when adults of the same age were irradiated 4 hours before exposure. Surprisingly, a ten-fold difference in radiation dose (0.1 versus 1.0 Gy) had little effect. Analysis at the gene and pathway level indicated that the long-term response includes the induction of cytokine and inflammatory regulators and transcription and growth factors. The acute response includes the induction of p53 target genes and modulation of the hypoxia-induced transcription factor-C/EBP axis. Results help define genes and pathways affected in the long-term, low and moderate dose radiation response and differentiate them from those affected in an acute response in the same tissue.


Aggression and Psychological Distress in Male and Female Anabolic-Androgenic Steroid Users: A Multigroup Latent Class Analysis.
The relationship between anabolic-androgenic steroid (AAS) use and aggression and psychological distress requires further elucidation. No previous study has examined whether the latent patterns of aggression and psychological distress are the same in male and female AAS users. Multigroup latent class analysis (MLCA) can be used to classify individuals into groups based on their responses on a set of variables, and to investigate measurement invariance across subgroups. We therefore conducted a MLCA to identify discrete subgroups of aggression and psychological distress in AAS users, and used measurement invariance to examine whether the identified subgroups can be applied to both sexes. We also examined the relationship between sex and subgroup belongingness. The sample comprised 206 AAS users (females = 58.30%) aged 14-56 (mean = 26.86, SD = 7.12) years. They completed questionnaires assessing demographics, AAS use, aggression, and psychological distress. Based on the MLCA, five subgroups were identified: high aggression moderate distress users (HAMoD: 07.63%), moderate aggression distress users (18.64%), moderate direct aggression-mild indirect aggression moderate distress users (22.95%), mild direct aggression-moderate indirect aggression-distress users (11.71%), and low aggression mild distress users (LAMiD: 39.06%). Although a homogenous five-class solution was the best model for both sexes, sex was significantly associated with the probability of subgroup membership. In particular, members of the HAMoD subgroup were more likely to be male whereas members of the LAMiD subgroup were more likely to be female. Our study provides novel empirical evidence of the idiosyncratic patterns of aggression and psychological distress among male and female AAS users.


A phase III, multicentre, randomised, double-blind, active-controlled, parallel-group trial comparing safety and efficacy of HD203, with innovator etanercept, in combination with methotrexate, in patients with rheumatoid arthritis: the HERA study.
To evaluate equivalence in efficacy for rheumatoid arthritis (RA) and compare the safety of the biosimilar HD203 with innovator etanercept (ETN) plus methotrexate (MTX) (ClinicalTrials.gov NCT01270997). Patients with active RA received 25 mg HD203 or ETN subcutaneously twice-weekly with MTX for 48 weeks in a phase III, multicentre, randomised, double-blind, parallel-group design. The primary end point was the proportion of patients achieving the American College of Rheumatology 20% response (ACR20) at week 24 for per-protocol study completer set (PPS). Secondary end points included ACR response criteria, ACRn, European League against Rheumatism (EULAR) response, change in Disease Activity Score 28 (DAS28), patient-reported outcomes, safety and immunogenicity. Of the 294 randomised patients (HD203, n=147; ETN, n=147), 233 comprised the 24-week PPS (n=115 and 118, respectively). ACR20 at week 24 was achieved by 83.48% and 81.36% of PPS patients, respectively, demonstrating equivalent efficacy within predefined margins of ±20% (treatment difference 2.12%, 95% CI -7.65% to 11.89%). Outcomes for secondary end points were consistent with the primary efficacy findings. Groups were comparable for overall incidences of treatment-emergent (all-causality) adverse events (AEs) (HD203 113 (76.9%) vs ETN 114 (78.1%) (p=0.804)), adverse drug reactions, serious AEs and discontinuations due to AEs. Few patients (HD203, n=8; ETN, n=3) tested positive for anti-drug antibodies. The study met the primary objective of demonstrating equivalent efficacy of HD203 and ETN. HD203 was well tolerated, with safety comparable with ETN in this population of patients with RA. NCT01270997; Results.


Luteococcus peritonei sp. nov., isolated from the human peritoneum.
An unusual catalase-positive pleomorphic Gram-positive rod isolated from a human clinical specimen was subjected to a polyphasic taxonomic analysis. Comparative 16S rRNA gene sequence analysis revealed the unknown bacterium was a member of the high G+C branch of the Gram-positive bacteria (Actinobacteria), and was phylogenetically a member of the family Propionibacteriaceae, with Luteococcus japonicus as its nearest relative. Based on both phenotypic and phylogenetic evidence, it is proposed that the unknown bacterium be classified in the genus Luteococcus, as Luteococcus peritonei sp. nov. The type strain of Luteococcus peritonei is CCUG 38120T.


Disclosing the diagnosis of dementia: the performance of Flemish general practitioners.
This issue of whether or not, how and when patients should be told of the diagnosis of dementia remains a matter for discussion. Recent data confirm that the patient is told of the diagnosis in only 40 to 55% of cases. We therefore studied the performance of Flemish general practitioners (GPs) in this area. A postal questionnaire, based on that prepared by Johnson et al., was sent to a random sample of 1000 Flemish GPs, out of a total of 7000. A total of 647 answers were returned, of which 521 were eligible for analysis (response rate 60%). Thirty-six percent of these 521 GPs always or usually disclose the diagnosis, while 37% provide information about the prognosis. Most doctors (75%) see benefits in disclosure, particularly as regards planning care, providing treatment and encouraging a good doctor-patient relationship. Only 61% of respondents present an appropriate differential diagnosis. The results obtained from the Flemish GPs are similar to those of other known studies. A detailed analysis of the reasons for and the benefits of disclosing the diagnosis reveal a less reluctant attitude than could be inferred from the rough data. GPs pay a great deal of attention to the patient's feelings, experiences and ability to cope and to the proper timing of their information. However, intensive educational projects have to be set up in order to stimulate a more etiologically-oriented diagnosis and to improve the quality of the process of disclosing the diagnosis of dementia.


Modern and ancient red fox (Vulpes vulpes) in Europe show an unusual lack of geographical and temporal structuring, and differing responses within the carnivores to historical climatic change.
Despite phylogeographical patterns being well characterised in a large number of species, and generalised patterns emerging, the carnivores do not all appear to show consistent trends. While some species tend to fit with standard theoretical phylogeographic expectations (e.g. bears), others show little obvious modern phylogeographic structure (e.g. wolves). In this study we briefly review these studies, and present a new phylogeographical study of the red fox (Vulpes vulpes) throughout Europe, using a combination of ancient DNA sequences obtained from museum specimens, and modern sequences collated from GenBank. We used cytochrome b (250 bp) and the mitochondrial control region (268 bp) to elucidate both current and historical phylogeographical patterning. We found evidence for slight isolation by distance in modern populations, as well as differentiation associated with time, both of which can likely be attributed to random genetic drift. Despite high sequence diversity (11.2% cytochrome b, 16.4% control region), no evidence for spatial structure (from Bayesian trees) is found either in modern samples or ancient samples for either gene, and Bayesian skyline plots suggested little change in the effective population size over the past 40,000 years. It is probable that the high dispersal ability and adaptability of the red fox has contributed to the lack of observable differentiation, which appears to have remained consistent over tens of thousands of years. Generalised patterns of how animals are thought to have responded to historical climatic change are not necessarily valid for all species, and so understanding the differences between species will be critical for predicting how species will be affected by future climatic change.


PDMS polymerized high internal phase emulsions (polyHIPEs) with closed-cell, aqueous-filled microcavities.
Emulsion templates can produce a wide range of unique microstructures via solidification of the continuous phase. Some of these structures result in unique, fluid-filled composites reminiscent of biological tissue when the templating droplets develop into closed-cell structures. However, the state-of-the-art falls short in replicating the mechanical and functional response of biological structures due to stiff, fragile, and bio-incompatible materials while lacking systematic processing parameters. This article describes the synthesis of high internal phase, closed-cell, polydimethylsiloxane (PDMS) elastomeric foams which simultaneously achieve biocompatibility, mechanical robustness, flexibility, and selective permeability. Water-in-oil high internal phase emulsions (HIPEs) stabilized by silica nano-particles (SNPs) provide the microstructural template, resulting in a >74% by volume aqueous phase (up to 82%). To overcome the prohibitive barrier to HIPE formation when using a mechanically-superior, but highly viscous commercial PDMS kit, we produce HIPE templates via centrifugation of low internal phase emulsions (LIPEs, <30% by volume dispersed phase). This oil phase crosslinks into an aqueous-filled (water + glycerol + NaCl) elastomeric composite. The composite's microstructural dependence on viscosity ratio, mixing speed, emulsifier concentration, and centrifugal force are systematically characterized. The resulting microstructured, fluid-filled elastomer composites exhibit mechanically robust and highly flexible behavior due to the excellent properties of the PDMS continuous phase.


Preparation of purified GPCRs for structural studies.
Since the publication of the first X-ray structure of a GPCR (G-protein couple receptor) in 2000, the rate at which subsequent ones have appeared has steadily increased. This has required the development of new methodology to overcome the challenges presented by instability of isolated GPCRs, combined with a systematic optimization of existing approaches for protein expression, purification and crystallization. In addition, quality control measures that are predictive of successful outcomes have been identified. Repeated attempts at solving the structures of GPCRs have highlighted experimental approaches that are most likely to lead to success, and have allowed definition of a first-pass protocol for new receptors.


Sexal reproductive cycle of Monascus in submerged shaken culture.
A strain of Monascus was grown in submerged, shaken culture using a glucose-salts mediumn. The formation of ascospores was studied by microscopic examination of samples taken at regular intervals for 6 days. All the stages of sexual reproduction previously described for Monascus were observed. The unusual feature of the strain studied was that it produced sexual structures and cliestothecia of greatly varying sizes.


Bipolar disorder among adolescents and young adults: results from an epidemiological sample.
Over the past decade, the clinical recognition and treatment of bipolar disorder (BD) in youth have increased significantly; however, little is known about prevalence of and service use for this disorder at a population level. The objective of this study was to measure the lifetime prevalence of BD, and to describe the socio-demographics, comorbidities, and use of mental health services among 15-24-year-olds with BD. Data were extracted from the Canadian Community Health Survey: Mental Health and Well-being (CCHS 1.2), a representative population-based survey of 36,984 people age 15 and older. Among subjects age 15-18 and 19-24 (N=5673), we calculated lifetime prevalence rates of BD and report the demographic and clinical characteristics and rates of service use of this sample. The weighted lifetime prevalence of BD was 3.0% among 15-24-year-olds (N=191): 2.1% among 15-18-year-olds, and 3.8% among 19-24-year-olds. Rates of psychiatric comorbidity were high, with anxiety disorders, problematic substance use, and suicidality present among nearly half of the sample. Mental health services were accessed in the previous 12 months by 56.1% of youth with BD. The questionnaire used in CCHS 1.2 relied on self-report, limiting its applicability to this younger sample. BD is particularly common among young adults and there are specific factors associated with BD in youth. Nearly half of all youth with BD have never used mental health services, suggesting that clinicians should be more vigilant about the signs and symptoms of BD in young people.


Role of PSIP1/LEDGF/p75 in lentiviral infectivity and integration targeting.
To replicate, lentiviruses such as HIV must integrate DNA copies of their RNA genomes into host cell chromosomes. Lentiviral integration is favored in active transcription units, which allows efficient viral gene expression after integration, but the mechanisms directing integration targeting are incompletely understood. A cellular protein, PSIP1/LEDGF/p75, binds tightly to the lentiviral-encoded integrase protein (IN), and has been reported to be important for HIV infectivity and integration targeting. Here we report studies of lentiviral integration targeting in 1) human cells with intensified RNAi knockdowns of PSIP1/LEDGF/p75, and 2) murine cells with homozygous gene trap mutations in the PSIP1/LEDGF/p75 locus. Infections with vectors derived from equine infections anemia virus (EIAV) and HIV were compared. Integration acceptor sites were analyzed by DNA bar coding and pyrosequencing. In both PSIP1/LEDGF/p75-depleted cell lines, reductions were seen in lentiviral infectivity compared to controls. For the human cells, integration was reduced in transcription units in the knockdowns, and this reduction was greater than in our previous studies of human cells less completely depleted for PSIP1/LEDGF/p75. For the homozygous mutant mouse cells, similar reductions in integration in transcription units were seen, paralleling a previous study of a different mutant mouse line. Integration did not become random, however-integration in transcription units in both cell types was still favored, though to a reduced degree. New trends also appeared, including favored integration near CpG islands. In addition, we carried out a bioinformatic study of 15 HIV integration site data sets in different cell types, which showed that the frequency of integration in transcription units was correlated with the cell-type specific levels of PSIP1/LEDGF/p75 expression.


Characterisation of a recombinant β-xylosidase (xylA) from Aspergillus oryzae expressed in Pichia pastoris.
β-xylosidases catalyse the hydrolysis of short chain xylooligosaccharides from their non-reducing ends into xylose. In this study we report the heterologous expression of Aspergillus oryzae β-xylosidase (XylA) in Pichia pastoris under the control of the glyceraldehyde-3-phosphate dehydrogenase promoter. The recombinant enzyme was optimally active at 55°C and pH 4.5 with Km and Vmax values of 1.0 mM and 250 μmol min(-1) mg(-1) respectively against 4-nitrophenyl β-xylopyranoside. Xylose was a competitive inhibitor with a Ki of 2.72 mM, whereas fructose was an uncompetitive inhibitor reducing substrate binding affinity (Km) and conversion efficiency (Vmax). The enzyme was characterised to be an exo-cutting enzyme releasing xylose from the non-reducing ends of β-1,4 linked xylooligosaccharides (X2, X3 and X4). Catalytic conversion of X2, X3 and X4 decreased (Vmax and kcat) with increasing chain length.


Differences in vertebrate microRNA expression.
MicroRNAs (miRNAs) attenuate gene expression by means of translational inhibition and mRNA degradation. They are abundant, highly conserved, and predicted to regulate a large number of transcripts. Several hundred miRNA classes are known, and many are associated with cell proliferation and differentiation. Many exhibit tissue-specific expression, which aids in evaluating their functions, and it has been assumed that their high level of sequence conservation implies a high level of expression conservation. A limited amount of data supports this, although discrepancies do exist. By comparing the expression of approximately 100 miRNAs in medaka and chicken with existing data for zebrafish and mouse, we conclude that the timing and location of miRNA expression is not strictly conserved. In some instances, differences in expression are associated with changes in miRNA copy number, genomic context, or both between species. Variation in miRNA expression is more pronounced the greater the differences in physiology, and it is enticing to speculate that changes in miRNA expression may play a role in shaping the physiological differences produced during animal development.


Paroxysmal anal hyperkinesis: a characteristic feature of proctalgia fugax.
Proctalgia fugax is a common problem, yet its pathophysiology is poorly understood. The objective was to characterise colorectal disturbances in a paraplegic patient with a 10 year history of proctalgia fugax that began two years after an attack of transverse myelitis. Standard anorectal manometry and prolonged 33 hour ambulatory colonic manometry at six sites in the colon were performed together with myoelectrical recording of the anus. Provocative tests designed to simulate psychological and physical stress and two types of meals were included. Anorectal manometry showed normal internal sphincter tone and normal rectoanal inhibitory reflex but an inability to squeeze or to bear down or to expel a simulated stool. Rectal sensation (up to 360 ml inflation) was absent. Pudendal nerve latency was prolonged (4.5 ms (normal < 2.2 ms). During colonic manometry, the patient reported 27 episodes of pain, of which 23 (85%) were associated with bursts (1-60 min) of a high amplitude (0.5 to > 3.2 mv), high frequency (5-50/min) anal myoelectrical activity, particularly after stress tests, meals, and at night. The myoelectrical disturbance only occurred with proctalgia. Intermittently, 16 bursts of 3 cycles/ min phasic rectal contractions were seen, but only six were associated with proctalgia. Colonic motility was reduced compared with normal subjects. The temporal association between a high amplitude, high frequency myoelectrical activity of the anal sphincter, and the occurrence of proctalgia suggests that paroxysmal hyperkinesis of the anus may cause proctalgia fugax.


Strong optical interaction of two adjacent rectangular nanoholes in a gold film.
The strong near-field optical interaction between two adjacent nanoholes milled in a gold film is investigated. A single nanohole is modeled as a magnetic dipole described by the simple relation between the magnetic- and electric-polarization in electromagnetic theory. To elucidate the role of the electric and magnetic fields in near-field characteristics of a nanohole illuminated by an optical plane-wave, the normalized electric and magnetic power amplitudes are accordingly introduced. This is extended to model the strong optical interaction of the two adjacent nanoholes in the near-field regime, leading to the magnetic coupled-dipole approximation (MCDA). It is shown that the optical transmission spectrum of the nanostructure may exhibit hybridized resonant peaks, depending on the configuration or the polarization. Compared to the known effects in the optical properties of a pair of metal nanoparticles for which the electric-field of the incident light is crucial, here it is illustrated that the magnetic-field of the incident light plays the dominant role in defining the optical properties of the complement structure. Thus, the strength of the interaction of the two adjacent nanoholes and the resulting hybridized plasmon resonances are strongly depends on the magnetic-field orientation in respect to the pair axis as well as on the separating distance of the nanoholes. The theoretical findings are supported by the electromagnetic computations.


Consensus and conflict among ecological forecasts of Zika virus outbreaks in the United States.
Ecologists are increasingly involved in the pandemic prediction process. In the course of the Zika outbreak in the Americas, several ecological models were developed to forecast the potential global distribution of the disease. Conflicting results produced by alternative methods are unresolved, hindering the development of appropriate public health forecasts. We compare ecological niche models and experimentally-driven mechanistic forecasts for Zika transmission in the continental United States. We use generic and uninformed stochastic county-level simulations to demonstrate the downstream epidemiological consequences of conflict among ecological models, and show how assumptions and parameterization in the ecological and epidemiological models propagate uncertainty and produce downstream model conflict. We conclude by proposing a basic consensus method that could resolve conflicting models of potential outbreak geography and seasonality. Our results illustrate the usually-undocumented margin of uncertainty that could emerge from using any one of these predictions without reservation or qualification. In the short term, ecologists face the task of developing better post hoc consensus that accurately forecasts spatial patterns of Zika virus outbreaks. Ultimately, methods are needed that bridge the gap between ecological and epidemiological approaches to predicting transmission and realistically capture both outbreak size and geography.


Host Factors Affecting Generation of Immunity Against Porcine Epidemic Diarrhea Virus in Pregnant and Lactating Swine and Passive Protection of Neonates.
Porcine epidemic diarrhea virus (PEDV) is a highly virulent re-emerging enteric coronavirus that causes acute diarrhea, dehydration, and up to 100% mortality in neonatal suckling piglets. Despite this, a safe and effective PEDV vaccine against highly virulent strains is unavailable, making PEDV prevention and control challenging. Lactogenic immunity induced via the gut-mammary gland-secretory IgA (sIgA) axis, remains the most promising and effective way to protect suckling piglets from PEDV. Therefore, a successful PEDV vaccine must induce protective maternal IgA antibodies that passively transfer into colostrum and milk. Identifying variables that influence lymphocyte migration and IgA secretion during gestation and lactation is imperative for designing maternal immunization strategies that generate the highest amount of lactogenic immune protection against PEDV in suckling piglets. Because pregnancy-associated immune alterations influence viral pathogenesis and adaptive immune responses in many different species, a better understanding of host immune responses to PEDV in pregnant swine may translate into improved maternal immunization strategies against enteric pathogens for multiple species. In this review, we discuss the role of host factors during pregnancy on antiviral immunity and their implications for generating protective lactogenic immunity in suckling neonates.


Resveratrol Improves Survival and Prolongs Life Following Hemorrhagic Shock.
Resveratrol has been shown to potentiate mitochondrial function and extend longevity; however, there is no evidence to support whether resveratrol can improve survival or prolong life following hemorrhagic shock. We sought to determine whether (a) resveratrol can improve survival following hemorrhage and resuscitation and (b) prolong life in the absence of resuscitation. Using a hemorrhagic injury (HI) model in the rat, we describe for the first time that the naturally occurring small molecule, resveratrol, may be an effective adjunct to resuscitation fluid. In a series of three sets of experiments we show that resveratrol administration during resuscitation improves survival following HI (p < 0.05), resveratrol and its synthetic mimic SRT1720 can significantly prolong life in the absence of resuscitation fluid (<30 min versus up to 4 h; p < 0.05), and resveratrol as well as SRT1720 restores left ventricular function following HI. We also found significant changes in the expression level of mitochondria-related transcription factors Ppar-α and Tfam, as well as Pgc-1α in the left ventricular tissues of rats subjected to HI and treated with resveratrol. The results indicate that resveratrol is a strong candidate adjunct to resuscitation following severe hemorrhage.


Metabolic Impacts of Confinement during the COVID-19 Pandemic Due to Modified Diet and Physical Activity Habits.
While the detrimental effects of a chronic positive energy balance due to a sedentary lifestyle have been well established, the impacts of a short period of abruptly reduced physical activity and overeating arising from strict confinement due to the COVID-19 pandemic will soon start to emerge. To reasonably anticipate major consequences according to the available evidence, we hereby review the literature for studies that have explored the health impacts of several weeks of a reduction in physical activity and daily step-count combined with modified eating habits. These studies identify as main metabolic consequences increases in insulin resistance, total body fat, abdominal fat and inflammatory cytokines. All these factors have been strongly associated with the development of metabolic syndrome, which in turn increases the risk of multiple chronic diseases. A plausible mechanism involved in these impacts could be a positive energy balance promoted by maintaining usual dietary intake while reducing energy expenditure. This means that just as calorie intake restriction could help mitigate the deleterious impacts of a bout of physical inactivity, overeating under conditions of home confinement is very likely to exacerbate these consequences. Moreover, hypertension, diabetes, and cardiovascular disease have been identified as potential risk factors for more severely ill patients with COVID-19. Thus, adequate control of metabolic disorders could be important to reduce the risk of severe COVID-19.


Endogenous generation and presentation of the ovalbumin peptide/Kb complex to T cells.
Peptide fragments are displayed on the APC surface by MHC class I molecules as ligands for appropriate TCR. Sequence analysis of MHC-bound peptide mixtures has suggested that naturally processed peptides are defined by their length and by the presence of MHC allele-defined consensus motifs. To define the minimal OVA peptide presented by Kb MHC, and the requirements for generation of endogenous OVA/Kb complex, APC were transfected with OVA cDNA constructs. We show that optimal stimulation of OVA/Kb-specific B3Z T cell hybrid by Kb-APC requires the OVA257-264 peptide (SIINFEKL, SL8) whether added exogenously, or when synthesized endogenously as precursor polypeptides. Thus, all information necessary for expression of the OVA/Kb complex is contained within the Kb octapeptide motif shared by SL8. Unexpectedly, the SL8/Kb or the influenza NP/Db complexes were also generated in APC even when the peptide coding sequences were placed in incorrect translational reading frames. By contrast, identical manipulations of the translational reading frame of the lacZ reporter gene reduced protein synthesis to undetectable levels demonstrating the remarkable efficiency with which endogenous peptide/MHC are generated in and presented by APC to T cells. These characteristics of the endogenous presentation may explain how large numbers of distinct peptide/MHC complexes are displayed on the cell surface and surveyed by TCR.


Perinatal Dietary Polyunsaturated Fatty Acids in Brain Development, Role in Neurodevelopmental Disorders.
n-3 and n-6 polyunsaturated fatty acids (PUFAs) are essential fatty acids that are provided by dietary intake. Growing evidence suggests that n-3 and n-6 PUFAs are paramount for brain functions. They constitute crucial elements of cellular membranes, especially in the brain. They are the precursors of several metabolites with different effects on inflammation and neuron outgrowth. Overall, long-chain PUFAs accumulate in the offspring brain during the embryonic and post-natal periods. In this review, we discuss how they accumulate in the developing brain, considering the maternal dietary supply, the polymorphisms of genes involved in their metabolism, and the differences linked to gender. We also report the mechanisms linking their bioavailability in the developing brain, their transfer from the mother to the embryo through the placenta, and their role in brain development. In addition, data on the potential role of altered bioavailability of long-chain n-3 PUFAs in the etiologies of neurodevelopmental diseases, such as autism, attention deficit and hyperactivity disorder, and schizophrenia, are reviewed.


Use of a "composite" vascular access graft in a young child on hemodialysis.
Although arterio-venous fistulae (AVF) are currently considered to be the first choice of permanent vascular access for hemodialysis, there are some patients who are not candidates for fistulae and synthetic grafts provide other options. The Thoratec (Vectra) polyurethane vascular access graft is a new prosthetic graft that may be cannulated within days of insertion due to "self-sealing" properties. However, a tendency for kinking at the suture site due to the strong elasticity of this graft, leading to undesirable complications such as thrombosis, have been reported. We describe a surgical modification of the anastomosis by interposing a segment of expanded polytetrafluoroethylene graft (ePTFE, Venaflo) between the native vessels and the polyurethane graft sections in a pediatric patient. This modification may overcome the kinking complication associated with use of the polyurethane graft and the resulting thrombosis.


Is it possible to feel at home in a patient room in an intensive care unit? Reflections on environmental aspects in technology-dense environments.
This paper focuses on the patient's perspective and the philosophical underpinnings that support what might be considered optimal for the future design of the intensive care unit (ICU) patient room. It also addresses the question of whether the aspects that support at-homeness are applicable to ICU patient rooms. The concept of "at-homeness" in ICUs is strongly related to privacy and control of space and territory. This study investigates whether the sense of at-homeness can be created in an ICU, when one or more patients share a room. From an interdisciplinary perspective, we critically reflect on various aspects associated with conflicts surrounding the use of ICU patient rooms. Thus, from an architectural and a caring perspective, the significance of space and personal territory in ICU patient rooms is emphasized. Recommendations for further research are suggested. In conclusion, privacy and control are deemed to be essential factors in the stimulation of recovery processes and the promotion of well-being in situations involving severe illness or life-threatening conditions.