Osteopathic Manipulative Therapy in Patients With Chronic Tension-Type Headache: A Pilot Study.
Nonpharmacologic treatment, such as osteopathic manipulative therapy (OMTh; manipulative care provided by foreign-trained osteopaths) may be a beneficial complementary treatment for tension-type headache. However, to the authors' knowledge, the benefit of OMTh in the management of tension-type headache has not been explored, especially chronic tension-type headache (CTTH). To investigate the effectiveness of OMTh compared with traditional treatment in reducing pain intensity, frequency, and duration of CTTH, and to evaluate the objective postural measurement of the forward head posture (FHP) as an integral parameter in the assessment of the effects of OMTh and traditional management of CTTH. Patients with CTTH were registered at the Headache Centre of Trieste in Italy. At the time of the study, none of the patients had been taking any headache prophylaxis in the past 3 months. A 3-month baseline period was recorded by all patients with an ad hoc diary. Patients were randomly placed in the test or control group using a simple randomization program in Excel (Microsoft). Patients in the OMTh group underwent a 3-month period of OMTh, and patients in the control group were treated with amitriptyline. Pain intensity, frequency, and duration of headaches, as well as FHP were analyzed. The study enrolled 10 patients (mean [SD] age, 42.6 [15.2] years) in the OMTh group and 10 patients (51.4 [17.3] years) in the control group. The final assessment of OMTh patients showed statistically significant changes in all headache parameters: pain intensity decreased from a mean (SD) score of 4.9 (1.4) to 3.1 (1.1) (P=.002); frequency decreased from 19.8 (6) to 8.3 (6.2) days per month (P=.002); and the duration of headaches decreased from 10 (4.2) to 6 (3) hours (P=.01). Significant improvement of all parameters was found in the control group as well: pain intensity decreased from a mean (SD) score of 5.9 (0.7) to 4.2 (1.75) (P=.03); frequency decreased from 23.4 (7.2) to 7.4 (8.7) days per month (P=.003); and duration decreased from 7.8 (2.9) to 3.6 (2.1) hours (P=.002). Forward head posture significantly improved in OMTh patients (P=.003). Our data suggested that OMTh may be an effective treatment to improve headaches in patients with CTTH. Our results also suggest that OMTh may reduce FHP.


High-Yield Methods for Accurate Two-Alternative Visual Psychophysics in Head-Fixed Mice.
Research in neuroscience increasingly relies on the mouse, a mammalian species that affords unparalleled genetic tractability and brain atlases. Here, we introduce high-yield methods for probing mouse visual decisions. Mice are head-fixed, facilitating repeatable visual stimulation, eye tracking, and brain access. They turn a steering wheel to make two alternative choices, forced or unforced. Learning is rapid thanks to intuitive coupling of stimuli to wheel position. The mouse decisions deliver high-quality psychometric curves for detection and discrimination and conform to the predictions of a simple probabilistic observer model. The task is readily paired with two-photon imaging of cortical activity. Optogenetic inactivation reveals that the task requires mice to use their visual cortex. Mice are motivated to perform the task by fluid reward or optogenetic stimulation of dopamine neurons. This stimulation elicits a larger number of trials and faster learning. These methods provide a platform to accurately probe mouse vision and its neural basis.


Emerging role of intensity-modulated radiation therapy in anorectal cancer.
Although radiation therapy has an established role to play in the management of rectal and anal tumors, there are often treatment-related morbidities that negatively impact on patients. There is a long-standing interest in radiation oncology on maximizing treatment efficacy while minimizing treatment-related toxicities, which can be pronounced in the treatment of pelvic malignancies. Intensity-modulated radiation therapy is a recently introduced technology that has the potential to increase the efficacy:toxicity ratio. It has been implemented in the treatment of prostate and head and neck tumors with success. This article reviews the rationale for its use in treating anorectal tumors and discusses early clinical data supporting its continued investigation.


Tsp36, a tapeworm small heat-shock protein with a duplicated alpha-crystallin domain, forms dimers and tetramers with good chaperone-like activity.
Small heat shock proteins (sHSPs), which range in monomer size between 12 and 42 kDa, are characterized by a conserved C-terminal alpha-crystallin domain of 80-100 residues. They generally form large homo- or heteromeric complexes, and typically have in vitro chaperone-like activity, keeping unfolding proteins in solution. A special type of sHSP, with a duplicated alpha-crystallin domain, is present in parasitic flatworms (Platyhelminthes). Considering that an alpha-crystallin domain is essential for the oligomerization and chaperone-like properties of sHSPs, we characterized Tsp36 from the tapeworm Taenia saginata. Both wild-type Tsp36 and a mutant (Tsp36C-->R) in which the single cysteine has been replaced by arginine were expressed and purified. Far-UV CD measurements of Tsp36 were in agreement with secondary structure predictions, which indicated alpha-helical structure in the N-terminal region and the expected beta-sandwich structure for the two alpha-crystallin domains. Gel permeation chromatography and nano-ESI-MS showed that wild type Tsp36 forms dimers in a reducing environment, and tetramers in a non-reducing environment. The tetramers are stabilized by disulfide bridges involving a large proportion of the Tsp36 monomers. Tsp36C-->R exclusively occurs as dimers according to gel permeation chromatography, while the nondisulfide bonded fraction of wild type Tsp36 dissociates from tetramers into dimers under nonreducing conditions at increased temperature (43 degrees C). The tetrameric form of Tsp36 has a greater chaperone-like activity than the dimeric form.


A cross-sectional analytical study of geophagia practices and blood metal concentrations in pregnant women in Johannesburg, South Africa.
Geophagia, a form of pica, has been shown to be widely practised in sub-Saharan Africa, especially among pregnant women. To assess the prevalence of geophagia and examine exposure to selected metals and associated risk factors in women attending an antenatal clinic at Rahima Moosa Mother and Child Hospital, Johannesburg, South Africa, during June and July 2010. We conducted a cross-sectional study on a convenience sample of 307 pregnant women, ranging in age from 18 to 46 years. Structured interviews were conducted to understand geophagia practices. Blood samples were collected to determine haemoglobin values and concentrations of arsenic, cadmium, mercury and lead. Statistical analyses using the χ2 test, Wilcoxon's rank-sum test and logistic regression analyses were performed as appropriate. Mean parity was 1.4 and the mean (standard deviation) gestational age 30.3 (6.0) weeks. Geophagia was reported by 60 women (19.5%), and the majority purchased soil from street vendors (83.3%). The prevalence of anaemia in the study sample was 16.9% (95% confidence interval 13.1 - 21.6%). Geophagic women had significantly higher blood lead levels than non-geophagic women (2.1 v. 1.4 µg/dl; p<0.001). Anaemia, the use of African traditional medicines and craving of non-nutritive substances in a previous pregnancy were associated with geophagia. Geophagia is practised by a considerable proportion of pregnant women in Johannesburg, especially migrant women. Greater vigilance in respect of pica, especially geophagia, may be needed as part of antenatal care programmes to avoid potentially detrimental health effects of the practice.


Nationwide inventory of mosquito biodiversity (Diptera: Culicidae) in Belgium, Europe.
To advance our restricted knowledge on mosquito biodiversity and distribution in Belgium, a national inventory started in 2007 (MODIRISK) based on a random selection of 936 collection points in three main environmental types: urban, rural and natural areas. Additionally, 64 sites were selected because of the risk of importing a vector or pathogen in these sites. Each site was sampled once between May and October 2007 and once in 2008 using Mosquito Magnet Liberty Plus traps. Diversity in pre-defined habitat types was calculated using three indices. The association between species and environmental types was assessed using a correspondence analysis. Twenty-three mosquito species belonging to traditionally recognized genera were found, including 21 indigenous and two exotic species. Highest species diversity (Simpson 0.765) and species richness (20 species) was observed in natural areas, although urban sites scored also well (Simpson 0.476, 16 species). Four clusters could be distinguished based on the correspondence analysis. The first one is related to human modified landscapes (such as urban, rural and industrial sites). A second is composed of species not associated with a specific habitat type, including the now widely distributed Anopheles plumbeus. A third group includes species commonly found in restored natural or bird migration areas, and a fourth cluster is composed of forest species. Outcomes of this study demonstrate the effectiveness of the designed sampling scheme and support the choice of the trap type. Obtained results of this first country-wide inventory of the Culicidae in Belgium may serve as a basis for risk assessment of emerging mosquito-borne diseases.


Becoming posthuman: hepatitis C, the race to elimination and the politics of remaking the subject.
Hepatitis C has long been a public health problem in Australia. 'Revolutionary' new drugs with the potential to cure hepatitis C have now emerged. The Australian government has invested heavily in them, and has an ambitious goal to eliminate hepatitis C by 2030. Numerous shifts in policy and practice are required if the elimination agenda is to be realised. This paper explores the significance of these shifts. We ask: what is the race to elimination doing with the subject? We argue that the race to elimination can be understood, simultaneously, as a product of posthuman forces, capable of being analysed using the theoretical tools made available via the posthuman turn; producing an intervention in what it means to be human; and generating a dilemma for people who use (or used) drugs, people with hepatitis C, and posthuman scholarship. In drawing out these issues, we aim to: trace the significant developments underway in hepatitis C medicine and raise awareness of them; encourage reflection on the consequences of these developments; and invite reflections on what might be lost when the human is remade by hepatitis C medicine.


Origami-based cellular metamaterial with auxetic, bistable, and self-locking properties.
We present a novel cellular metamaterial constructed from Origami building blocks based on Miura-ori fold. The proposed cellular metamaterial exhibits unusual properties some of which stemming from the inherent properties of its Origami building blocks, and others manifesting due to its unique geometrical construction and architecture. These properties include foldability with two fully-folded configurations, auxeticity (i.e., negative Poisson's ratio), bistability, and self-locking of Origami building blocks to construct load-bearing cellular metamaterials. The kinematics and force response of the cellular metamaterial during folding were studied to investigate the underlying mechanisms resulting in its unique properties using analytical modeling and experiments.


Phosphorylation mechanism of nucleoside diphosphate kinase: 31P-nuclear magnetic resonance studies.
The phosphorylation mechanism of Dictyostelium discoideum nucleoside diphosphate (NDP) kinase was investigated by NMR. 31P chemical shifts were measured on both native and denatured enzyme. In the enzymatically phosphorylated enzyme denatured by 9 M urea or 7 M guanidine hydrochloride, the NDP kinase phosphohistidine signal appeared between the signals of N delta and N epsilon free monophosphohistidines used as reference compounds and added to the sample. A signal with the same intermediate position was also observed in the pronase digest of the alkaline-denatured phosphorylated enzyme. However, when phosphohistidines of the phosphorylated synthetic peptide pGlu-His-Gly were taken as references, the NDP kinase and the N delta peptide phosphohistidine signals were shown to be identical, providing evidence that phosphorylation occurs on the N delta of the active site histidine residue. Moreover, the rate of hydrolysis of the histidine-bound phosphate is in agreement with a modification at the N delta position. Phosphorylation of the NDP kinase by phosphoramidate provided a result similar to that of the enzymatic phosphorylation. In both cases, phosphorylation could not be detected on any amino acid other than histidine. Particularly, no phosphoserine residue was observed.


MicroED: a versatile cryoEM method for structure determination.
Micro-electron diffraction, or MicroED, is a structure determination method that uses a cryo-transmission electron microscope to collect electron diffraction data from nanocrystals. This technique has been successfully used to determine the high-resolution structures of many targets from crystals orders of magnitude smaller than what is needed for X-ray diffraction experiments. In this review, we will describe the MicroED method and recent structures that have been determined. Additionally, applications of electron diffraction to the fields of small molecule crystallography and materials science will be discussed.


Effects of adult exposure to bisphenol a on genes involved in the physiopathology of rat prefrontal cortex.
Several neurological and behavioral dysfunctions have been reported in animals exposed to bisphenol A (BPA). However, little is known about the impact of adult exposure to BPA on brain physiopathology. Here, we focused on prefrontal cortex (PFC) of rats, because it is an important area for cognitive control, complex behaviors and is altered in many psychopathologies. Gamma-aminobutyric acid (GABA) and serotonin (5-HT) systems are essential for PFC function. Therefore, we examined the effects of adult exposure to BPA on 5α-Reductase (5α-R) and cytochrome P450 aromatase (P450arom), enzymes that synthesize GABAA receptor modulators, and tryptophan hydroxylase (Tph), the rate-limiting enzyme in 5-HT biosynthesis. To gain better understanding of BPA's action in the adult PFC, 84 genes involved in neurotoxicity were also analysed. Adult male and female rats were subcutaneously injected for 4 days with 50 µg/kg/day, the current reference safe dose for BPA. mRNA and protein levels of 5α-R, P450arom and Tph were quantified by real-time RT-PCR and Western blot. Genes linked to neurotoxicity were analyzed by PCR-Array technology. Adult exposure to BPA increased both P450arom and Tph2 expression in PFC of male and female, but decreased 5α-R1 expression in female. Moreover, we identified 17 genes related to PFC functions such as synaptic plasticity and memory, as potential targets of BPA. Our results provided new insights on the molecular mechanisms underlying BPA action in the physiopathology of PFC, but also raise the question about the safety of short-term exposure to it in the adulthood.


Sexual assault survivors' perspectives on clinical follow-up in the Eden District, South Africa: A qualitative study.
Although effective follow-up of sexual assault survivors is linked to optimal recovery, attendance at follow-up consultations is poor. It is therefore essential that health care providers maximise the benefit of follow-up care for every sexual assault survivor. This study explored the personal experiences of sexual assault survivors to better understand the enablers of, and barriers to, attendance at follow-up consultations. This phenomenological qualitative study was conducted at the three hospitals which manage most sexual assault survivors within the Eden District. Using purposive sampling, 10 participants were selected. Consenting participants shared their experiencesduring semi-structured interviews with the researcher. Authoritative, client-held documentation was a powerful enabler to accessing follow-up care. Individualised, patient-centred care further enhanced participants' access to, and utilisation of, health care services. The failure of health care providers to integrate follow-up care for sexual assault survivors into established chronic care services was a missedopportunity in the continuum of care. Negative perceptions, based on others' or personal prior experience of police, judicial and health care systems, were further barriers to follow-up care. This study highlights the need of survivors of sexual assault for integrated,patient-centred care, encompassing principles of good communication. Committed actions of all stakeholders are necessary to tackle negative perceptions that create barriers to follow-upcare. A simple practical strategy, the provision of a scheduled appointment on official stationery, is easy to effect at facility level. As a powerful enabler to follow-up care, this should be implemented as a priority intervention.


Withering Minds: towards a unified embodied mind theory of personal identity for understanding dementia.
A prominent view on personal identity over time, Jeff McMahan's 'Embodied Mind Account' (2002) holds that we cease to exist only once our brains can no longer sustain the basic capacity to uphold consciousness. One of the many implications of this view on identity persistence is that we continue to exist throughout even the most severe cases of dementia, until our consciousness irreversibly shuts down. In this paper, I argue that, while the most convincing of prominent accounts of personal identity over time, McMahan's account faces serious challenges in explanatory power of dementias and related neurodegenerative conditions. Particularly, this becomes visible in the face of emerging methods for neural tissue regeneration, and the possibility of 're-emerging patients'. I argue that medical professionals' neglecting qualitative aspects of identity risks resulting in grave misunderstandings in decision-making processes, and ethically objectionable outcomes in future practices. Finally, I propose revisions which could potentially salvage the great benefits that Embodied Mind Theory still can bring to the field of dementia care in terms of understanding life, death, and identity across the lifespan.


Biological effects of 6-formylindolo[3,2-b]carbazole (FICZ) in vivo are enhanced by loss of CYP1A function in an Ahr2-dependent manner.
6-Formylindolo[3,2-b]carbazole (FICZ) is a potent aryl hydrocarbon receptor (AHR) agonist that is efficiently metabolized by AHR-regulated cytochrome P4501 enzymes. FICZ is a proposed physiological AHR ligand that induces its own degradation as part of a regulatory negative feedback loop. In vitro studies in cells show that CYP1 inhibition in the presence of FICZ results in enhanced AHR activation, suggesting that FICZ accumulates in the cell when its metabolism is blocked. We used zebrafish (Danio rerio) embryos to investigate the in vivo effects of FICZ when CYP1A is knocked down or inhibited. Embryos were injected with morpholino antisense oligonucleotides targeting CYP1A (CYP1A-MO), Ahr2, or a combination of both. FICZ exposure of non-injected embryos or embryos injected with control morpholino had little effect. In CYP1A-MO-injected embryos, however, FICZ dramatically increased mortality, incidence and severity of pericardial edema and circulation failure, reduced hatching frequency, blocked swim bladder inflation, and strongly potentiated expression of Ahr2-regulated genes. These effects were substantially reduced in embryos with a combined knockdown of Ahr2 and CYP1A, indicating that the toxicity was mediated at least partly by Ahr2. Co-exposure to the CYP1 inhibitor alpha-naphthoflavone (αNF) and FICZ had similar effects as the combination of CYP1A-MO and FICZ. HPLC analysis of FICZ-exposed embryos showed increased levels of FICZ after concomitant CYP1A-MO injection or αNF co-exposure. Together, these results show that a functioning CYP1/AHR feedback loop is crucial for regulation of AHR signaling by a potential physiological ligand in vivo and further highlights the role of CYP1 enzymes in regulating biological effects of FICZ.


Concerted Electronic and Nuclear Fluxes During Coherent Tunnelling in Asymmetric Double-Well Potentials.
The quantum theory of concerted electronic and nuclear fluxes (CENFs) during coherent periodic tunnelling from reactants (R) to products (P) and back to R in molecules with asymmetric double-well potentials is developed. The results are deduced from the solution of the time-dependent Schrödinger equation as a coherent superposition of two eigenstates; here, these are the two states of the lowest tunnelling doublet. This allows the periodic time evolutions of the resulting electronic and nuclear probability densities (EPDs and NPDs) as well as the CENFs to be expressed in terms of simple sinusodial functions. These analytical results reveal various phenomena during coherent tunnelling in asymmetric double-well potentials, e.g., all EPDs and NPDs as well as all CENFs are synchronous. Distortion of the symmetric reference to a system with an asymmetric double-well potential breaks the spatial symmetry of the EPDs and NPDs, but, surprisingly, the symmetry of the CENFs is conserved. Exemplary application to the Cope rearrangement of semibullvalene shows that tunnelling of the ideal symmetric system can be suppressed by asymmetries induced by rather small external electric fields. The amplitude for the half tunnelling, half nontunnelling border is as low as 0.218 × 10(-8) V/cm. At the same time, the delocalized eigenstates of the symmetric reference, which can be regarded as Schrödinger's cat-type states representing R and P with equal probabilities, get localized at one or the other minima of the asymmetric double-well potential, representing either R or P.


Serial Analysis of Gene Expression in Plasmodium berghei salivary gland sporozoites.
The invasion of Anopheles salivary glands by Plasmodium sporozoites is an essential step for transmission of the parasite to the vertebrate host. Salivary gland sporozoites undergo a developmental programme to express genes required for their journey from the site of the mosquito bite to the liver and subsequent invasion of, and development within, hepatocytes. A Serial Analysis of Gene Expression was performed on Anopheles gambiae salivary glands infected or not with Plasmodium berghei and we report here the analysis of the Plasmodium sporozoite transcriptome. Annotation of 530 tag sequences homologous to Plasmodium berghei genomic sequences identified 123 genes expressed in salivary gland sporozoites and these genes were classified according to their transcript abundance. A subset of these genes was further studied by quantitative PCR to determine their expression profiles. This revealed that sporozoites modulate their RNA amounts not only between the midgut and salivary glands, but also during their storage within the latter. Among the 123 genes, the expression of 66 is described for the first time in sporozoites of rodent Plasmodium species. These novel sporozoite expressed genes, especially those expressed at high levels in salivary gland sporozoites, are likely to play a role in Plasmodium infectivity in the mammalian host.


Design of an enantioselective artificial metallo-hydratase enzyme containing an unnatural metal-binding amino acid.
The design of artificial metalloenzymes is a challenging, yet ultimately highly rewarding objective because of the potential for accessing new-to-nature reactions. One of the main challenges is identifying catalytically active substrate-metal cofactor-host geometries. The advent of expanded genetic code methods for the in vivo incorporation of non-canonical metal-binding amino acids into proteins allow to address an important aspect of this challenge: the creation of a stable, well-defined metal-binding site. Here, we report a designed artificial metallohydratase, based on the transcriptional repressor lactococcal multidrug resistance regulator (LmrR), in which the non-canonical amino acid (2,2'-bipyridin-5yl)alanine is used to bind the catalytic Cu(ii) ion. Starting from a set of empirical pre-conditions, a combination of cluster model calculations (QM), protein-ligand docking and molecular dynamics simulations was used to propose metallohydratase variants, that were experimentally verified. The agreement observed between the computationally predicted and experimentally observed catalysis results demonstrates the power of the artificial metalloenzyme design approach presented here.


A letter of consequence: referral letters from general practitioners to secondary mental health services.
The referral letter is a key instrument in moving patients from primary to secondary care services. Consequently, the circumstances in which a referral should be made and its contents have been the subject of clinical guidelines. This article is based on a project that demonstrated that physicians do not adhere to clinical guidelines when referring patients to secondary mental health services. This research supports earlier findings into noncompliance with guidelines by general practitioners (GPs). The authors briefly note possible reasons, which have been the subject of some debate. They also present a content analysis of referral letters to demonstrate the important ways in which they differ from guideline criteria. However, their central argument is that the role of the referral letter in relation to the GP's repertoire of treatments has not been understood fully. Such understanding implies the need for a reexamination of the support available for GPs.


Assessing gene-environment interaction effects of FTO, MC4R and lifestyle factors on obesity using an extreme phenotype sampling design: Results from the HUNT study.
Our aim was to assess the influence of age, gender and lifestyle factors on the effect of the obesity-promoting alleles of FTO and MCR4. The HUNT study comprises health information on the population of Nord-Trøndelag county, Norway. Extreme phenotype participants (gender-wise lower and upper quartiles of waist-hip-ratio and BMI ≥ 35 kg/m2) in the third survey, HUNT3 (2006-08), were genotyped for the single-nucleotide polymorphisms rs9939609 (FTO) and rs17782313 (MC4R); 25686 participants were successfully genotyped. Extreme sampling was chosen to increase power to detect genetic and gene-environment effects on waist-hip-ratio and BMI. Statistical inference was based on linear regression models and a missing-covariate likelihood approach for the extreme phenotype sampling design. Environmental factors were physical activity, diet (artificially sweetened beverages) and smoking. Longitudinal analysis was performed using material from HUNT2 (1995-97). Cross-sectional and longitudinal genetic effects indicated stronger genetic associations with obesity in young than in old, as well as differences between women and men. We observed larger genetic effects among physically inactive compared to active individuals. This interaction was age-dependent and seen mainly in 20-40 year olds. We observed a greater FTO effect among men with a regular intake of artificially sweetened beverages, compared to non-drinkers. Interaction analysis of smoking was mainly inconclusive. In a large all-adult and area-based population survey the effects of obesity-promoting minor-alleles of FTO and MCR4, and interactions with life style factors are age- and gender-related. These findings appear relevant when designing individualized treatment for and prophylaxis against obesity.


Novel Pressure-Sensing Smart Insole System Used for the Prevention of Pressure Ulceration in the Insensate Foot.
Wounds of the foot challenge reconstructive surgeons to manage multiple factors: sensibility, stability, and durability. In this article, we focus on the insensate foot, which poses challenges to wound prevention with its propensity to develop pressure ulceration. The authors present the innovative use of a pressure-sensing smart insole system (SurroSense Rx, Orpyx Medical Technologies Inc., Calgary, Canada) in the management of the insensate foot in a patient following foot reconstruction. The pressure-sensing smart insole system provided unique feedback to both patient and provider in ways that contributed to the prevention of pressure ulcer recurrence, as well as highlight the importance of prescribed footwear in both the affected and unaffected foot. Wearable real-time monitoring and feedback faces the challenge of patient adherence. Future studies are indicated to examine the specific behaviors that are associated with favorable outcomes and long-term behavior changes.


Intimate Partner Violence and Risk for Mortality and Incident Dementia in Older Women.
The aim of this study was to assess the long-term risk for mortality and incident dementia associated with exposure to intimate partner violence (IPV) at any time over the life course. Data were taken from the Australian Longitudinal Study of Women's Health, a population-based cohort study initiated in 1996. Analysis is based on 12,085 community-dwelling women aged 70 to 75 years at baseline from all states and territories. Self-reported exposure to violence was separated into historical (any time before baseline), current (past 12 months), or both. Date of death was obtained from the National Death Index, and dementia status was self-reported or obtained from administrative data. We modeled mortality risk using Cox regression, and risk for incident dementia using Fine-Gray proportional hazards modeling with death as a competing risk. Follow up continued to December 2017. At baseline, 728 women (6.0%) reported historical IPV, 121 (1.0%) reported current violence, and 38 reported both (0.3%). Historical IPV increased 20-year mortality risk after controlling for demographic, socioeconomic, and lifestyle variables (hazard ratio 1.10, 95% confidence interval = [1.00, 1.20]). There was no relationship between current violence and mortality (hazard ratio 1.04, 95% confidence interval = [0.85, 1.29]). There was also no association between IPV and risk for incident dementia (hazard ratio 1.02, 95% confidence interval = [0.89, 1.17]). Older women who self-report exposure to IPV over the lifespan die significantly earlier than women who do not. Further research that considers the mediating role of psychological trauma is needed to examine the relationship between IPV and dementia.


The impact of living arrangements and deinstitutionalisation in the health status of persons with intellectual disability in Europe.
Despite progress in the process of deinstitutionalisation, very little is known about the health conditions of people with intellectual disability (PWID) who live in large institutions and PWID living in small residential services, family homes or independent living within the community. Furthermore, there are no international comparison studies at European level of the health status and health risk factors of PWID living in fully staffed residential services with formal support and care compared with those living in unstaffed family homes or independent houses with no formal support. A total of 1269 persons with ID and/or their proxy respondents were recruited and face-to-face interviewed in 14 EU countries with the P15, a multinational assessment battery for collecting data on health indicators relevant to PWID. Participants were grouped according to their living arrangements, availability of formal support and stage of deinstitutionalisation. Obesity and sedentary lifestyle along with a number of illnesses such as epilepsy, mental disorders, allergies or constipation were highly prevalent among PWID. A significantly higher presence of myocardial infarctions, chronic bronchitis, osteoporosis and gastric or duodenal ulcers was found among participants in countries considered to be at the early stage of deinstitutionalisation. Regardless of deinstitutionalisation stage, important deficits in variables related to such medical health promotion measures as vaccinations, cancer screenings and medical checks were found in family homes and independent living arrangements. Age, number of people living in the same home or number of places in residential services, presence of affective symptoms and obesity require further attention as they seem to be related to an increase in the number of illnesses suffered by PWID. Particular illnesses were found to be highly prevalent in PWID. There were important differences between different living arrangements depending on the level of formal support available and the stage of deinstitutionalisation. PWID are in need of tailored primary health programs that guarantee their access to quality health and health promotion and the preventative health actions of vaccination programs, systematic health checks, specific screenings and nutritional controls. Extensive national health surveys and epidemiological studies of PWID in the EC member states are urgently needed in order to reduce increased morbidity rates among this population.


Cardiovascular reflex responses in Bangladeshi and European subjects.
1. Cardiovascular responses to three different interventions, namely the Valsalva manoeuvre, deep breathing and a cold stimulus on the face, were studied in two ethnic groups (European and Bangladeshi) that have been shown to differ in the prevalence of hypertensive-vascular disease. The data obtained consisted of systolic blood pressure, diastolic blood pressure, mean blood pressure, heart rate measured by using a beat-by-beat non-invasive blood pressure monitor (the Finapres), forearm blood flow determined by venous occlusion plethysmography, and calculated forearm vascular resistance. 2. The resting haemodynamic status was similar in European and Bangladeshi subjects. However, Bangladeshi subjects showed a greater increase in heart rate, but only after 20 s into the Valsalva manoeuvre, and greater overshoots in mean blood pressure after the manoeuvre than the European subjects. Furthermore, after cold face stimulation the fall in forearm vascular resistance to baseline levels was delayed in Bangladeshi subjects relative to that in the European subjects. 3. There were no inter-group differences in the reflex bradycardia relative to mean blood pressure or in the cardiac baroreflex sensitivity estimated from systolic blood pressure and pulse interval after the Valsalva manoeuvre. In addition, values for the mean difference between maximum and minimum pulse intervals during deep breathing did not differ in Bangladeshi and European subjects. 4. These findings together suggest that, although cardiac vagal reflex responses appear similar in the two groups, sympatho-adrenal influences on the heart and vasculature may be greater in Bangladeshi subjects than in European subjects.


Mutation analysis of a cohort of US patients with hemophilia B.
Hemophilia B (HB) is a disorder resulting from genetic mutations in the Factor 9 gene (F9). Genotyping of HB patients is important for genetic counseling and patient management. Here we report a study of mutations identified in a large sample of HB patients in the US. Patients were enrolled through an inhibitor surveillance study at 17 hemophilia treatment centers. A total of 87 unique mutations were identified from 225 of the 226 patients, including deletions, insertions, and point mutations. Point mutations were distributed throughout the F9 gene and were found in 86% of the patients. Of these mutations, 24 were recurrent in the population, and 3 of them (c.316G>A, c.1025C>T, and c.1328T>A) accounted for 84 patients (37.1%). Haplotype analysis revealed that the high recurrence arose from a founder effect. The severity of HB was found to correlate with the type of mutation. Inhibitors developed only in severe cases with large deletions and nonsense mutations. None of the mild or moderate patients developed inhibitors. Our results provide a resource describing F9 mutations in US HB patients and confirm previous findings that patients bearing large deletions and nonsense mutations are at high risk of developing inhibitors.


Activated Protein C Drives the Hyperfibrinolysis of Acute Traumatic Coagulopathy.
Major trauma is a leading cause of morbidity and mortality worldwide with hemorrhage accounting for 40% of deaths. Acute traumatic coagulopathy exacerbates bleeding, but controversy remains over the degree to which inhibition of procoagulant pathways (anticoagulation), fibrinogen loss, and fibrinolysis drive the pathologic process. Through a combination of experimental study in a murine model of trauma hemorrhage and human observation, the authors' objective was to determine the predominant pathophysiology of acute traumatic coagulopathy. First, a prospective cohort study of 300 trauma patients admitted to a single level 1 trauma center with blood samples collected on arrival was performed. Second, a murine model of acute traumatic coagulopathy with suppressed protein C activation via genetic mutation of thrombomodulin was used. In both studies, analysis for coagulation screen, activated protein C levels, and rotational thromboelastometry (ROTEM) was performed. In patients with acute traumatic coagulopathy, the authors have demonstrated elevated activated protein C levels with profound fibrinolytic activity and early depletion of fibrinogen. Procoagulant pathways were only minimally inhibited with preservation of capacity to generate thrombin. Compared to factors V and VIII, proteases that do not undergo activated protein C-mediated cleavage were reduced but maintained within normal levels. In transgenic mice with reduced capacity to activate protein C, both fibrinolysis and fibrinogen depletion were significantly attenuated. Other recognized drivers of coagulopathy were associated with less significant perturbations of coagulation. Activated protein C-associated fibrinolysis and fibrinogenolysis, rather than inhibition of procoagulant pathways, predominate in acute traumatic coagulopathy. In combination, these findings suggest a central role for the protein C pathway in acute traumatic coagulopathy and provide new translational opportunities for management of major trauma hemorrhage.


National Cancer Institute's Cancer Disparities Research Partnership Program: Experience and Lessons Learned.
To increase access of underserved/health disparities communities to National Cancer Institute (NCI) clinical trials, the Radiation Research Program piloted a unique model - the Cancer Disparities Research Partnership (CDRP) program. CDRP targeted community hospitals with a limited past NCI funding history and provided funding to establish the infrastructure for their clinical research program. Initially, 5-year planning phase funding was awarded to six CDRP institutions through a cooperative agreement (U56). Five were subsequently eligible to compete for 5-year implementation phase (U54) funding and three received a second award. Additionally, the NCI Center to Reduce Cancer Health Disparities supported their U56 patient navigation programs. Community-based hospitals with little or no clinical trials experience required at least a year to develop the infrastructure and establish community outreach/education and patient navigation programs before accrual to clinical trials could begin. Once established, CDRP sites increased their yearly patient accrual mainly to NCI-sponsored cooperative group trials (~60%) and Principal Investigator/mentor-initiated trials (~30%). The total number of patients accrued on all types of trials was 2,371, while 5,147 patients received navigation services. Despite a historical gap in participation in clinical cancer research, underserved communities are willing/eager to participate. Since a limited number of cooperative group trials address locally advanced diseases seen in health disparities populations; this shortcoming needs to be rectified. Sustainability for these programs remains a challenge. Addressing these gaps through research and public health mechanisms may have an important impact on their health, scientific progress, and efforts to increase diversity in NCI clinical trials.


High-temperature behavior of natural ferrierite: In-situ synchrotron X-ray powder diffraction study.
In this paper, we report the results of the first study focused on the thermal stability and dehydration dynamics of the natural zeolite mineral ferrierite. A sample from Monastir, Sardinia [(Na0.56K1.19Mg2.02Ca0.52Sr0.14) (Al6.89Si29.04)O72·17.86H2O; a = 19.2241(3) Å; b = 14.1563(2) Å; c = 7.5106(1) Å, V = 2043.95(7) Å3] was investigated by thermogravimetric analysis and in-situ synchrotron X-ray powder diffraction. Thermogravimetric data show that H2O release begins already in the range 50-100 °C and is complete at ~600 °C. The results of the structure refinements performed in Immm space group by Rietveld analysis with data collected up to 670 °C show that ferrierite belongs to the group of zeolites that do not undergo phase transitions. Upon heating to 670 °C, ferrierite behaves as a non-collapsible structure displaying only a slight contraction of the unit-cell volume (ΔV = -3%). The unit-cell parameter reductions are anisotropic, more pronounced for a than for b and c (Δa = -1.6%; Δb = -0.76%; Δc = -0.70%). This anisotropic response to a temperature increase is interpreted as due to the presence in the ferrierite framework of five-membered ring chains of SiO4 tetrahedra, which impart a higher structural rigidity along b and c. Upon dehydration we observe: (1) the gradual H2O loss, beginning with the molecules hosted in the 10MR channel, is almost complete at 670 °C, in good agreement with the TG data; (2) as a consequence of the decreased H2O content, Mg and K migrate from their original positions, moving from the center of the 10MR channel toward the walls to coordinate the framework oxygen atoms. The observation of transmission electron microscopy selected-area electron diffraction patterns revealed defective crystals with an occasional and moderate structural disorder. Beyond providing information on the thermal stability and behavior of natural ferrierite, the results of this work have significant implications for possible technological applications. These data allow for comparison with the dehydration kinetics/mechanisms of the corresponding synthetic phases, clarifying the role played by framework and extra-framework species on the high-temperature behavior of porous materials with ferrierite topology. Moreover, the information on the thermal behavior of natural ferrierite can be used to predict the energetic performances of analogous synthetic Si-pure counterparts, namely "zeosil-electrolyte" systems, under non-ambient conditions. Specifically, the very high thermal stability of ferrierite determined in this study, coupled with the baric behavior determined in other investigations, suggests that the "Si-FER-electrolyte" system may be an excellent candidate for use as an energy reservoir. Indeed, ferrierite exhibits the so-called "spring behavior," i.e., upon compression in water or in an electrolyte solution, it converts the mechanical energy into interfacial energy, and-when pressure is released-it can completely restore the supplied mechanical energy accumulated during the compression step.


Clinical profile of childhood-onset psoriasis and prevalence of HLA-Cw6: a hospital-based study from India.
Childhood-onset psoriasis (COP), a distinct clinical entity, may be associated with HLA-Cw6 positivity and metabolic and cardiovascular complications. There is some evidence that HLA-Cw6 positivity is associated with more extensive or severe disease and that positivity is lower in Asian patients than in Caucasians. We describe the clinical profile, prevalence of the HLA-Cw6 allele, metabolic syndrome (MetS) and vitamin D deficiency in Indian patients with COP. In this cross-sectional hospital-based study over 15 months (June 2010-August 2011), 108 consecutive patients with disease onset ≤16 years were enrolled. Demographic, clinical and laboratory data were collected. Patients were categorised as children with COP (CCOP; n=69) or adults with COP (ACOP; n=39). Disease severity was assessed using body surface area (BSA) involved and Psoriasis Area and Severity Index (PASI) score. The most common morphological type was chronic plaque psoriasis; follicular psoriasis was seen only in children. Adults with disease onset in childhood, when compared with CCOP, had later disease onset (11.0±4.0 vs 6.9±3.8 (mean±SD) years; p<0.0001) of greater severity (p=0.021) based on BSA involved. PASI scores were, however, similar in ACOP and CCOP. Body mass index was not associated with disease severity. Of the 83 who underwent HLA-C typing, 46 (55.4%) were positive; positivity was associated with guttate lesions (p=0.031), scalp involvement (p=0.004), greater BSA involvement (p=0.002) and higher PASI scores (p=0.013). Vitamin D deficiency, obesity and MetS were present in 77.4%, 10.7% and 14.5% of patients, respectively. Among Indian patients, CCOP have earlier disease onset than ACOP. HLA-Cw6 was associated with guttate psoriasis, scalp involvement and disease severity. Vitamin D deficiency was common.


Detection of O6-carboxymethyl-2'-deoxyguanosine in DNA following reaction of nitric oxide with glycine and in human blood DNA using a quantitative immunoslot blot assay.
Previous research has shown that a range of nitrosated glycine derivatives react with DNA to form O6-carboxymethylguanine and O6-methylguanine DNA adducts [Harrison et al. (1999) Chem. Res. Toxicol. 12, 106-111). Nitrosated glycine derivatives may be formed in the gastrointestinal tract from the reaction of dietary glycine with nitrosating agents. The aim of this study was to further investigate the role of dietary glycine in the formation of O6-guanine adducts at physiologically relevant concentrations. In vitro studies were performed by reacting 10 microM to 50 mM glycine with nitric oxide in the presence of oxygen. An HPLC assay was developed to measure the resulting nitrosated glycine derivative, diazoacetate anion. The amount of nitrosating agent present in the reaction mixture was determined by colorimetric measurement of nitrite, the hydrolysis product of N2O3. Diazoacetate anion formation depended linearly on glycine concentration. Solutions of nitrosated glycine reacted with 2'-deoxyguanosine and calf thymus DNA to give O6-carboxymethyl-2'-deoxyguanosine and, at high concentrations of glycine and nitric oxide, O6-methyl-2'-deoxyguanosine. At physiological concentrations of glycine and nitric oxide, diazoacetate anion was not detectable. Studies with synthetic diazoacetate anion showed that concentrations < 14 microM did not give detectable O6-carboxyethylguanine in DNA, even when a sensitive immunoslot blot assay was used. However, O6-carboxymethylguanine was detected in human blood DNA samples obtained from three volunteers consuming a standardized high meat diet, using the immunoslot blot assay. O6-Carboxymethylguanine levels ranged from 35 to 80 (detection limit = 15) O6-carboxymethylguanine per 10(8) bases. These studies provide further evidence that nitrosated amino acids may be risk factors for gastrointestinal tract cancers.


Preliminary evidence differentiating ADHD using brain SPECT imaging in older patients.
The objective of this study was to differentiate ADHD patients from a healthy comparison group using high resolution brain SPECT imaging in older patients. Using extensive chart reviews of structured interviews, DSM-IV criteria, and psychiatrist-given diagnoses, we identified 27 patients over age 50 with ADHD, either combined or inattentive types. Patients were compared to an age-matched group of healthy subjects with brain SPECT imaging at rest and during concentration using semiquantitative visual readings. Significantly lower cortical activity is noted in the ADHD group, particularly in the prefrontal poles, orbits, and parietal lobes. Older ADHD patients can be discerned from healthy subjects using brain SPECT. The results support the executive dysfunction model of ADHD.


Steric effects on multivalent ligand-receptor binding: exclusion of ligand sites by bound cell surface receptors.
Steric effects can influence the binding of a cell surface receptor to a multivalent ligand. To account for steric effects arising from the size of a receptor and from the spacing of binding sites on a ligand, we extend a standard mathematical model for ligand-receptor interactions by introducing a steric hindrance factor. This factor gives the fraction of unbound ligand sites that are accessible to receptors, and thus available for binding, as a function of ligand site occupancy. We derive expressions for the steric hindrance factor for various cases in which the receptor covers a compact region on the ligand surface and the ligand expresses sites that are distributed regularly or randomly in one or two dimensions. These expressions are relevant for ligands such as linear polymers, proteins, and viruses. We also present numerical algorithms that can be used to calculate steric hindrance factors for other cases. These theoretical results allow us to quantify the effects of steric hindrance on ligand-receptor kinetics and equilibria.


Mitochondrial Ca2+ and Reactive Oxygen Species in Trypanosomatids.
Significance: Millions of people are infected with trypanosomatids and new therapeutic approaches are needed. Trypanosomatids possess one mitochondrion per cell and its study has led to discoveries of general biological interest. These mitochondria, as in their animal counterparts, generate reactive oxygen species (ROS) and have evolved enzymatic and nonenzymatic defenses against them. Mitochondrial calcium ion (Ca2+) overload leads to generation of ROS and its study could lead to relevant information on the biology of trypanosomatids and to novel drug targets. Recent Advances: Mitochondrial Ca2+ is normally involved in maintaining the bioenergetics of trypanosomes, but when Ca2+ overload occurs, it is associated with cell death. Trypanosomes lack key players in the mechanism of cell death described in mammalian cells, although mitochondrial Ca2+ overload results in collapse of their membrane potential, production of ROS, and cytochrome c release. They are also very resistant to mitochondrial permeability transition, and cell death after mitochondrial Ca2+ overload depends on generation of ROS. Critical Issues: In this review, we consider the mechanisms of mitochondrial oxidant generation and removal and the involvement of Ca2+ in trypanosome cell death. Future Directions: More studies are required to determine the reactions involved in generation of ROS by the mitochondria of trypanosomatids, their enzymatic and nonenzymatic defenses against ROS, and the occurrence and composition of a mitochondrial permeability transition pore. Antioxid. Redox Signal. 36, 969-983.


Preventing intrusive memories after trauma via a brief intervention involving Tetris computer game play in the emergency department: a proof-of-concept randomized controlled trial.
After psychological trauma, recurrent intrusive visual memories may be distressing and disruptive. Preventive interventions post trauma are lacking. Here we test a behavioural intervention after real-life trauma derived from cognitive neuroscience. We hypothesized that intrusive memories would be significantly reduced in number by an intervention involving a computer game with high visuospatial demands (Tetris), via disrupting consolidation of sensory elements of trauma memory. The Tetris-based intervention (trauma memory reminder cue plus c. 20 min game play) vs attention-placebo control (written activity log for same duration) were both delivered in an emergency department within 6 h of a motor vehicle accident. The randomized controlled trial compared the impact on the number of intrusive trauma memories in the subsequent week (primary outcome). Results vindicated the efficacy of the Tetris-based intervention compared with the control condition: there were fewer intrusive memories overall, and time-series analyses showed that intrusion incidence declined more quickly. There were convergent findings on a measure of clinical post-trauma intrusion symptoms at 1 week, but not on other symptom clusters or at 1 month. Results of this proof-of-concept study suggest that a larger trial, powered to detect differences at 1 month, is warranted. Participants found the intervention easy, helpful and minimally distressing. By translating emerging neuroscientific insights and experimental research into the real world, we offer a promising new low-intensity psychiatric intervention that could prevent debilitating intrusive memories following trauma.


SU-E-I-111: Evaluation of the Analytical Scattering Models of 1) Lynch-Dahl 2) Highland and 3) Rossi for Proton Beams and Comparison with GEANT4 Monte Carlo Simulations as a Prerequisite for Proton Radiography Applications for Patients.
To evaluate the approximate 1) Lynch-Dahl 2) Highland and 3) Rossi scattering models for proton beams with GEANT4 Monte Carlo. This is a prerequisite for proton radiography applications for patients. A Matlab program developed in-house at MGH was used to obtain a semianalytical generalized Fermi-Eyges theory estimation of the spatial and angular spreads of a 230 MeV zero-spread incident proton beam as a function of depth. The constants of 1) Lynch-Dahl 2) Highland and 3) Rossi were used respectively for each model. MC simulations will determine which approximation provides the best prediction for different media configurations. Further, the calculated spreads were used to inform proton radiography imaging by calculating two limiting angles, a positional Acut and a directional Ccut. Acut is defined as the viewing angle of a point of incidence observer at which they see a point displaced by one positional standard deviation. Ccut is defined as the direction cosine of one angular standard deviation momenta. Both the angular and spatial spreads as well as their respective model differences rose monotonically with depth in water. At 30 cm depth the angular spread reached values around 3 degrees with about 0.32 degrees model difference, translating to Ccut differences in the first or second significant digit. At the same depth the spatial spread reached values around 1.2 cm with about 0.7 mm model difference, translating to Acut differences in the first or second significant digit. Preliminary MC data (not shown) indicate that the signals obtained due to the influence of inhomogeneities are small and the model differences may be relevant. We observed non-negligible differences between the models using MC. Further analysis is required to understand, which model provides most accurate scattering predictions for protons penetrating different media configurations.


[Treatment of sight-threatening diabetic retinopathy].
In diabetic retinopathy, treatment is indicated for sight-threatening complications like proliferative diabetic retinopathy (PDR) and diabetic macular oedema (DME). For decades, treatment has been with panretinal laser for PDR and focal/grid laser for DME. In recent years, intravitreal therapy with vascular endothelial growth factor (VEGF) inhibition or steroids has replaced laser treatment in centre-involving DME. Intravitreal VEGF-inhibition has also demonstrated effectiveness in PDR, but long-term studies are needed to address the concern of a potential continuous treatment burden.


Differences between non-suicidal self injury and suicide attempt in Chinese adolescents.
Self-harm behaviors are predominant health risks among adolescents. This study aimed to elucidate the lifetime prevalence and differences in social psychological factors between non-suicidal self-injury (NSSI) and suicide attempt (SA) among Chinese adolescents. Data were collected from 2131 middle school students with a mean age of 13.92 (SD 1.63) years (49.1% girls). Participants were asked to self-report NSSI and SA over their lifetime. Post hoc tests pairwise comparisons and multinomial logistic regression analyses were conducted to investigate differences and similarities between subjects with NSSI and attempted suicide. The prevalence of lifetime NSSI and SA endorsed by the participants were 23.2% and 3.2%, respectively, and the co-occurrence of these two behaviors (NSSI+SA) was reported to 2.3%. Boys were comparable with girls in the prevalence rate of NSSI, but not in the rate of SA. It revealed that single-child was not the risk factor for self-harm behavior in Mainland China, but lower higher family cohesion and adaptability. Factors that distinguished the NSSI+SA group from the NSSI only group were female gender, lower grade, impulsivity, health risk behaviors and family cohesion. Being female gender, single-parent family, depressive symptoms and impulsivity were factors differentiating attempted suicide from NSSI. Our findings suggest that Chinese adolescents engaging both in NSSI and SA had severe suicidal attempts and were different from those who engaged in NSSI alone.


Predictors of diagnostic conversion from major depression to bipolar disorder: a Swedish national longitudinal study.
It is clinically important to predict the conversion of major depression (MD) to bipolar disorder (BD). Therefore, we sought to identify related conversion rates and risk factors. This cohort study included the Swedish population born from 1941 onward. Data were collected from Swedish population-based registers. Potential risk factors, including family genetic risk scores (FGRS), which were calculated based on the phenotypes of relatives in the extended family and not molecular data, and demographic/clinical characteristics from these registers were retrieved. Those with first MD registrations from 2006 were followed up until 2018. The conversion rate to BD and related risk factors were analyzed using Cox proportional hazards models. Additional analyses were performed for late converters and with stratification by sex. The cumulative incidence of conversion was 5.84% [95% confidence interval (95% CI) 5.72-5.96] for 13 years. In the multivariable analysis, the strongest risk factors for conversion were high FGRS of BD [hazard ratio (HR) = 2.73, 95% CI 2.43-3.08], inpatient treatment settings (HR = 2.64, 95% CI 2.44-2.84), and psychotic depression (HR = 2.58, 95% CI 2.14-3.11). For late converters, the first registration of MD during the teenage years was a stronger risk factor when compared with the baseline model. When the interactions between risk factors and sex were significant, stratification by sex revealed that they were more predictive in females. Family history of BD, inpatient treatment, and psychotic symptoms were the strongest predictors of conversion from MD to BD.


Representation of health conditions on Facebook: content analysis and evaluation of user engagement.
A sizable majority of adult Internet users report looking for health information online. Social networking sites (SNS) like Facebook represent a common place to seek information, but very little is known about the representation and use of health content on SNS. Our goal in this study was to understand the role of SNS in health information seeking. More specifically, we aimed to describe how health conditions are represented on Facebook Pages and how users interact with these different conditions. We used Google Insights to identify the 20 most searched for health conditions on Google and then searched each of the resulting terms on Facebook. We compiled a list of the first 50 Facebook "Pages" results for each health condition. After filtering results to identify pages relevant to our research, we categorized pages into one of seven categories based on the page's primary purpose. We then measured user engagement by evaluating the number of "Likes" for different conditions and types of pages. The search returned 50 pages for 18 of the health conditions, but only 48 pages were found for "anemia" and 5 pages were found for "flu symptoms", yielding a total of 953 pages. A large number of pages (29.4%, 280/953) were irrelevant to the health condition searched. Of the 673 relevant pages, 151 were not in English or originated outside the United States, leaving 522 pages to be coded for content. The most common type of page was marketing/promotion (32.2%, 168/522) followed by information/awareness (20.7%, 108/522), Wikipedia-type pages (15.5%, 81/522), patient support (9.4%, 49/522), and general support (3.6%, 19/522). Health conditions varied greatly by the primary page type. All health conditions had some marketing/promotion pages and this made up 76% (29/38) of pages on acquired immunodeficiency syndrome (AIDS). The largest percentage of general support pages were cancer (19%, 6/32) and stomach (16%, 4/25). For patient support, stroke (67%, 4/6), lupus (33%, 10/30), breast cancer (19%, 6/31), arthritis (16%, 6/36), and diabetes (16%, 6/37) ranked the highest. Six health conditions were not represented by any type of support pages (ie, human papillomavirus, diarrhea, flu symptoms, pneumonia, spine, human immunodeficiency virus). Marketing/promotion pages accounted for 46.73% (10,371,169/22,191,633) of all Likes, followed by support pages (40.66%, 9,023,234/22,191,633). Cancer and breast cancer accounted for 86.90% (19,284,066/22,191,633) of all page Likes. This research represents the first attempts to comprehensively describe publicly available health content and user engagement with health conditions on Facebook pages. Public health interventions using Facebook will need to be designed to ensure relevant information is easy to find and with an understanding that stigma associated with some health conditions may limit the users' engagement with Facebook pages. This line of research merits further investigation as Facebook and other SNS continue to evolve over the coming years.


Human papillomavirus and diseases of the upper airway: head and neck cancer and respiratory papillomatosis.
Human papillomavirus (HPV) infection is causally associated with benign and malignant diseases of the upper airway, including respiratory papillomatosis and oropharyngeal cancer. Low-risk HPV types 6 and 11 are the predominant cause of papillomatosis, whereas only HPV16 definitively satisfies both molecular and epidemiological causal criteria as a carcinogenic or high-risk type in the upper airway. HPV16 E6/E7 mRNA expression and integration are observed predominantly among oropharyngeal cancers, and experimental models have shown E6/E7 expression to be necessary for the initiation and maintenance of the malignant phenotype of these cancers. From an epidemiological perspective, a strong and consistent association between markers of HPV16 exposure and oropharyngeal cancer has been demonstrated in numerous case-control studies. HPV-positive oropharyngeal cancers have also been shown to be distinct from HPV-negative head and neck squamous cell cancers with regard to risk-factor profiles, molecular genetic alterations, population-level incidence trends over time, and prognosis. Tumor HPV status (as determined by certain HPV16 in situ hybridization assays or certain p16 immunohistochemistry assays) is the strongest determinant of survival for patients with local-regionally advanced oropharyngeal cancer: patients with HPV-positive cancer have at least a 50% improvement in overall survival at 5 years, which is equivalent to an approximate 30% difference in absolute survival. Thus, HPV status determination is now part of the routine diagnostic evaluation for prognostication. Preliminary evidence indicates that a small proportion of head and neck cancers may be caused by additional HPV types (e.g., 18, 31, 33, 35) and that HPV-caused cancers may rarely arise from non-oropharyngeal sites (e.g., the oral cavity, nasopharynx, and larynx). Whether or not HPV vaccination has the potential to prevent oral HPV infections that lead to cancer or papillomatosis in the upper airway is currently unknown, as is the potential for secondary prevention with HPV detection. This article forms part of a special supplement entitled "Comprehensive Control of HPV Infections and Related Diseases" Vaccine Volume 30, Supplement 5, 2012.


Effects of preventive cognitive self-instruction training on adolescent attitudes, experiences, and state anxiety.
The effects of teacher-directed cognitive self-instruction (TI) were compared with an instructions-only component control condition (IO) in order to examine the former's efficacy as a primary prevention strategy. In a quasi-experimental design. two intact high school psychology classes were randomly assigned to either TI or IO. Each condition lasted for eight 45-minute class periods, and each group was given an in vivo homework assignment. Pretreatment equivalence and demand analyses yielded no evidence of differences. Results of a posttreatment measure of attitude toward treatments and a pre- and posttreatment measure of state anxiety suggested that trainerdirected cognitive self-instruction may be a promising primary prevention strategy.


Protist tubulins: new arrivals, evolutionary relationships and insights to cytoskeletal function.
The protists exhibit probably the most extravagant expression of microtubule-containing structures found in any organism. These structures--flagella, cilia, axostyles, spindles and a veritable constellation of microtubule bundles and cortical arrays--provide shape, form, motility, anchorage and apparatuses for feeding. The cytoskeletal structures have a precise order (i.e. size, position and number) that must be replicated and segregated with fidelity at each division, some components being inherited conservatively and others semi-conservatively. Intriguingly, it is now apparent that much of the high-order organisation, which was recognised and described by light and electron microscopy during the last century, is a reflection of molecular polarities set by assembly of constituent proteins. Tubulins and microtubules lie at the heart of this morphogenetic pattern.


Photorefractive processing for large adaptive phased arrays.
An adaptive null-steering phased-array optical processor that utilizes a photorefractive crystal to time integrate the adaptive weights and null out correlated jammers is described. This is a beam-steering processor in which the temporal waveform of the desired signal is known but the look direction is not. The processor computes the angle(s) of arrival of the desired signal and steers the array to look in that direction while rotating the nulls of the antenna pattern toward any narrow-band jammers that may be present. We have experimentally demonstrated a simplified version of this adaptive phased-array-radar processor that nulls out the narrow-band jammers by using feedback-correlation detection. In this processor it is assumed that we know a priori only that the signal is broadband and the jammers are narrow band. These are examples of a class of optical processors that use the angular selectivity of volume holograms to form the nulls and look directions in an adaptive phased-array-radar pattern and thereby to harness the computational abilities of three-dimensional parallelism in the volume of photorefractive crystals. The development of this processing in volume holographic system has led to a new algorithm for phased-array-radar processing that uses fewer tapped-delay lines than does the classic time-domain beam former. The optical implementation of the new algorithm has the further advantage of utilization of a single photorefractive crystal to implement as many as a million adaptive weights, allowing the radar system to scale to large size with no increase in processing hardware.


Beyond the Affordable Care Act: achieving real improvements in Americans' health.
Improved access to health care is essential if we are to fill the striking gaps between how healthy Americans are and how healthy they could be. But access alone is not enough. Health and longevity are also profoundly influenced by where and how Americans live, learn, work, and play. Recognizing this, the Robert Wood Johnson Foundation's Commission to Build a Healthier America has identified concrete, feasible actions outside of medical care that constitute an urgent agenda for improving America's health. These recommendations require action at all levels of society to promote development and health in childhood, good nutrition, and communities conducive to good health.


Early Warning Score Communication Bundle: A Pilot Study.
Unplanned admissions of patients to intensive care units from medical-surgical units often result from failure to recognize clinical deterioration. The early warning score is a clinical decision support tool for nurse surveillance but must be communicated to nurses and implemented appropriately. A communication process including collaboration with experienced intensive care unit nurses may reduce unplanned transfers. To determine the impact of an early warning score communication bundle on medical-surgical transfers to the intensive care unit, rapid response team calls, and morbidity of patients upon intensive care unit transfer. After an early warning score was electronically embedded into medical records, a communication bundle including notification of and telephone collaboration between medical-surgical and intensive care unit nurses was implemented. Data were collected 3 months before and 21 months after implementation. Rapid response team calls increased nonsignificantly during the study period (from 6.47 to 8.29 per 1000 patient-days). Rapid response team calls for patients with early warning scores greater than 4 declined (from 2.04 to 1.77 per 1000 patient-days). Intensive care unit admissions of patients after rapid response team calls significantly declined (P = .03), as did admissions of patients with early warning scores greater than 4 (P = .01), suggesting that earlier intervention for patient deterioration occurred. Documented reassessment response time declined significantly to 28 minutes (P = .002). Electronic surveillance and collaboration with experienced intensive care unit nurses may improve care, control costs, and save lives. Critical care nurses have a role in coaching and guiding less experienced nurses.


Predicting conversion to wet age-related macular degeneration using deep learning.
Progression to exudative 'wet' age-related macular degeneration (exAMD) is a major cause of visual deterioration. In patients diagnosed with exAMD in one eye, we introduce an artificial intelligence (AI) system to predict progression to exAMD in the second eye. By combining models based on three-dimensional (3D) optical coherence tomography images and corresponding automatic tissue maps, our system predicts conversion to exAMD within a clinically actionable 6-month time window, achieving a per-volumetric-scan sensitivity of 80% at 55% specificity, and 34% sensitivity at 90% specificity. This level of performance corresponds to true positives in 78% and 41% of individual eyes, and false positives in 56% and 17% of individual eyes at the high sensitivity and high specificity points, respectively. Moreover, we show that automatic tissue segmentation can identify anatomical changes before conversion and high-risk subgroups. This AI system overcomes substantial interobserver variability in expert predictions, performing better than five out of six experts, and demonstrates the potential of using AI to predict disease progression.


Altered Amygdala Excitation and CB1 Receptor Modulation of Aggressive Behavior in the Neuroligin-3R451C Mouse Model of Autism.
Understanding neuronal mechanisms underlying aggression in patients with autism spectrum disorder (ASD) could lead to better treatments and prognosis. The Neuroligin-3 (NL3)R451C mouse model of ASD has a heightened aggressive phenotype, however the biological mechanisms underlying this behavior are unknown. It is well established that NL3R451C mice have imbalanced excitatory and inhibitory synaptic activity in the hippocampus and somatosensory cortex. The amygdala plays a role in modulating aggressive behavior, however potential changes in synaptic activity in this region have not previously been assessed in this model. We investigated whether aggressive behavior is robustly present in mice expressing the R451C mutation, following back-crossing onto a congenic background strain. Endocannabinoids influence social interaction and aggressive behavior, therefore we also studied the effects of cannabinoid receptor 1 (CB1) agonist on NL3R451C mice. We report that NL3R451C mice have increased amplitude of miniature excitatory postsynaptic currents (EPSCs) with a concomitant decrease in the amplitude of inhibitory postsynaptic currents (IPSCs) in the basolateral amygdala. Importantly, we demonstrated that NL3R451C mice bred on a C57Bl/6 background strain exhibit an aggressive phenotype. Following non-sedating doses (0.3 and 1.0 mg/kg) of the CB1 receptor agonist WIN55,212-2 (WIN), we observed a significant reduction in aggressive behavior in NL3R451C mice. These findings demonstrate altered synaptic activity in the basolateral amygdala and suggest that the NL3R451C mouse model is a useful preclinical tool to understand the role of CB1 receptor function in aggressive behavior.


Pyruvate Dehydrogenase Phosphatase Regulatory Gene Expression Correlates with Exercise Training Insulin Sensitivity Changes.
Whole body insulin sensitivity (Si) typically improves after aerobic exercise training; however, individual responses can be highly variable. The purpose of this study was to use global gene expression to identify skeletal muscle genes that correlate with exercise-induced Si changes. Longitudinal cohorts from the Studies of Targeted Risk Reduction Intervention through Defined Exercise were used as Discovery (Affymetrix) and Confirmation (Illumina) of vastus lateralis gene expression profiles. Discovery (n = 39; 21 men) and Confirmation (n = 42; 19 men) cohorts were matched for age (52 ± 8 vs 51 ± 10 yr), body mass index (30.4 ± 2.8 vs 29.7 ± 2.8 kg·m), and V˙O2max (30.4 ± 2.8 vs 29.7 ± 2.8 mL·kg·min). Si was determined via intravenous glucose tolerance test pretraining and posttraining. Pearson product-moment correlation coefficients determined relationships between a) baseline and b) training-induced changes in gene expression and %ΔSi after training. Expression of 2454 (Discovery) and 1778 genes (Confirmation) at baseline were significantly (P < 0.05) correlated to %ΔSi; 112 genes overlapped. Pathway analyses identified Ca signaling-related transcripts in this 112-gene list. Expression changes of 1384 (Discovery) and 1288 genes (Confirmation) after training were significantly (P < 0.05) correlated to %ΔSi; 33 genes overlapped, representing contractile apparatus of skeletal and smooth muscle genes. Pyruvate dehydrogenase phosphatase regulatory subunit expression at baseline (P = 0.01, r = 0.41) and posttraining (P = 0.01, r = 0.43) were both correlated with %ΔSi. Exercise-induced adaptations in skeletal muscle Si are related to baseline levels of Ca-regulating transcripts, which may prime the muscle for adaptation. Relationships between %ΔSi and pyruvate dehydrogenase phosphatase regulatory, a regulatory subunit of the pyruvate dehydrogenase complex, indicate that the Si response is strongly related to key steps in metabolic regulation.


A founder mutation of the BRCA1 gene in Western Sweden associated with a high incidence of breast and ovarian cancer.
The aim of this study was to describe and characterise a founder mutation of the BRCA1 gene in western Sweden. Of 62 families screened for BRCA mutations, 24 had BRCA1 mutations and two had BRCA2 mutations. Tumours that occurred in family members were histologically reviewed and mutational status was analysed using archival paraffin-embedded tissues. The same BRCA1 mutation, 3171ins5, was found in 16 families who were clustered along the western coast of Sweden. Mutation analysis revealed a maternal linkage in 13 families and a paternal linkage in 3. There was complete agreement between mutation analysis results obtained from blood and archival tissues. The penetrance of breast or ovarian cancer by age 70 years was estimated to be between 59 and 93%. There were no differences in survivals between breast or ovarian cancer patients with the mutation and age-matched controls. Thus, a predominant BRCA1 gene founder mutation associated with a high risk of breast and ovarian cancer has been identified and found to occur in a restricted geographical area, thereby allowing timely and cost-effective mutation screening using blood samples or archival histological material.


Active Surveillance versus Spontaneous Reporting for First-Line Antiretroviral Medicines in Namibia: A Cost-Utility Analysis.
Active surveillance pharmacovigilance is a systematic approach to medicine safety assessment and health systems strengthening, but has not been widely implemented in low- and middle-income countries. This study aimed to assess the cost effectiveness of a national active surveillance pharmacovigilance system for highly active antiretroviral therapy (HAART) compared with the existing spontaneous reporting system in Namibia. A cost-utility analysis from a governmental perspective compared active surveillance pharmacovigilance to spontaneous reporting. Data from a sentinel site active surveillance program in Namibia from August 2012 to April 2013 was projected to all HIV-infected adults initiating HAART in Namibia. Costs (pharmacovigilance program, HAART, adverse event [AE] treatment), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs, dollars/QALY) were evaluated. Analysis was completed for (i) cohort analysis: a single cohort beginning HAART in 1 year in Namibia followed over their remaining lifetime, and (ii) population analysis: patients continued to enter and leave care and treatment over 10 years. For the cohort analysis, totals were US$21,267,902 (2015 US dollars) and 116,224 QALYs for care and treatment under active surveillance pharmacovigilance versus US$15,257,381 and 116,122 QALYs for care and treatment under spontaneous reporting pharmacovigilance, resulting in an ICER of US$58,867/QALY for active surveillance compared with spontaneous reporting pharmacovigilance. The population analysis ICER was US$4989/QALY. Results were sensitive to quality of life associated with AEs. Active surveillance pharmacovigilance was projected to be highly cost effective to improve treatment for HIV in Namibia. Active surveillance pharmacovigilance may be valuable to improve lives of HIV patients and more efficiently allocate health resources in Namibia.


Stem and progenitor cell dysfunction in human trisomies.
Trisomy 21, the commonest constitutional aneuploidy in humans, causes profound perturbation of stem and progenitor cell growth, which is both cell context dependent and developmental stage specific and mediated by complex genetic mechanisms beyond increased Hsa21 gene dosage. While proliferation of fetal hematopoietic and testicular stem/progenitors is increased and may underlie increased susceptibility to childhood leukemia and testicular cancer, fetal stem/progenitor proliferation in other tissues is markedly impaired leading to the characteristic craniofacial, neurocognitive and cardiac features in individuals with Down syndrome. After birth, trisomy 21-mediated premature aging of stem/progenitor cells may contribute to the progressive multi-system deterioration, including development of Alzheimer's disease.


Industry-Sponsored Research Payments in Neurosurgery-Analysis of the Open Payments Database From 2014 to 2018.
The Open Payments Database (OPD) started in 2013 to combat financial conflicts of interest between physicians and medical industry. To evaluate the first 5 yr of the OPD regarding industry-sponsored research funding (ISRF) in neurosurgery. The Open Payments Research Payments dataset was examined from 2014 to 2018 for payments where the clinical primary investigator identified their specialty as neurosurgery. Between 2014 and 2018, a $106.77 million in ISRF was made to 731 neurosurgeons. Fewer than 11% of neurosurgeons received ISRF yearly. The average received $140 000 in total but the median received $30,000. This was because the highest paid neurosurgeon received $3.56 million. A greater proportion ISRF was made to neurosurgeons affiliated with teaching institutions when compared to other specialties (26.74% vs 20.89%, P = .0021). The proportion of the total value of ISRF distributed to neurosurgery declined from 0.43% of payments to all specialties in 2014 to 0.37% in 2018 (P < .001), but no steady decline was observed from year to year. ISRF to neurosurgeons comprises a small percentage of research payments made to medical research by industry sponsors. Although a greater percentage of payments are made to neurosurgeons in teaching institutions compared to other specialties, the majority is given to neurosurgeons not affiliated with a teaching institution. A significant percentage of ISRF is given to a small percentage of neurosurgeons. There may be opportunities for more neurosurgeons to engage in industry-sponsored research to advance our field as long as full and complete disclosures can always be made.


Analyzing global trends of biomarker use in drug interventional clinical studies.
The trend of biomarker use in drug interventional clinical studies was analyzed using ClinicalTrials.gov to provide an overview of how biomarkers are used to streamline clinical studies and to examine regional differences. A total of 3,383 clinical study data was analyzed according to phase, region, sponsor, and therapeutic class. The number of clinical studies using biomarkers has been increasing constantly and is dependent on the number of Phase I and II studies. The majority of studies (58.5%) were sponsored by the United States, with the studies being conducted mainly in the sponsor's home region (80.3%). The use of biomarkers was prominent in the oncology area (37.1%). Although current data indicates some bias in the clinical use of biomarkers, it is expected that their use will increase in later phase studies or other therapeutic areas as biomarker development proceeds. In addition, limited regional use of biomarkers may lead to differences in biomarker use in drug development and in combination with political support may result in differences in competitiveness of drug development. Biomarkers would be a powerful tool against deteriorating research and development productivity when used more in appropriate clinical study conditions.


Monitoring patients on chronic treatment with antidepressants between 2003 and 2011: analysis of factors associated with compliance.
Clinical practice guidelines consider the use of antidepressants as one of the standard treatments for anxiety disorders, due to the significant improvements obtained in quality of life and functional disability. In addition, in patients who have not achieved a favorable response after 3 months of psychotherapy, antidepressants are recommended as part of a combined treatment approach. This combination with psychotropic drugs and psychotherapy appears to be indicated from baseline in patients with moderate, severe or recurrent depression. In the last decade, antidepressant prescription rates in general practice have increased between 4 and 10 times. Depression presents high rates of relapse and recurrence. Treatment is often interrupted prematurely, leading to increases in both relapse rates and health care costs. Few studies have analysed the chronic use of antidepressant drugs and long-term adherence. To evaluate compliance with antidepressant treatment between 2003 and 2011 and to explore the associated factors. Retrospective cohort study of antidepressant dispensing. Health Region of Lleida between 2003 and 2011. Patients with chronic prescription of antidepressants (ATC code NO6A) during 2003 were followed up until December 2011. The sample comprised 3684 subjects. The compliance rate was calculated on the basis of the number of units withdrawn from the pharmacy and the theoretical number of units required according to the scheduled duration of treatment: compliance was defined in cases with scores greater than or equal to 80%. 12.5% of patients received chronic antidepressant treatment for at least 4 years. Mean age was 54 years, and 73.2% of patients were female. Almost a third (32.4%) presented anxiety disorders and 26.5% mood disorders. The overall compliance rate was 22% (28% in patients with depression, and 21% in patients with anxiety). According to gender, compliance rates were 21.4% for males and 22.4% for females. Compliance was more likely in patients with polypharmacy. One in 4 patients complied with treatment. Factors associated with better compliance were polypharmacy and diagnosis of depressive or mixed anxiety-depressive disorder.


Effects of dermatan sulfate and heparin on inhibition of thrombus growth in vivo.
The effects of dermatan sulfate and heparin on inhibition of fibrin accretion onto existing thrombi as related to their ex vivo anticoagulant activity and abilities to inhibit increased prothrombin clearance induced by thrombi were investigated. Our results indicate that for equivalent anti-thrombin activities, dermatan sulfate is a more effective inhibitor of fibrin accretion onto existing thrombi than is heparin. These observations raise the possibility that in some clinical conditions dermatan sulfate, rather than heparin, may be a better antithrombotic agent of choice. This beneficial effect of dermatan sulfate appears to be unrelated to anti-factor Xa activity either endogenous to dermatan sulfate itself (which is unlikely since it does not catalyze factor Xa inhibition) or to anti-factor Xa activity associated with other glycosaminoglycans released into the circulation following dermatan sulfate administration since this activity is less than that associated with heparin treatment. It is more likely that dermatan sulfate mediates this beneficial effect by more effectively inhibiting thrombin within a thrombus than can heparin. This possibility is supported by the ability of dermatan sulfate to normalize prothrombin consumption in animals with existing thrombi.


Monoclonal antibody M195: a diagnostic marker for acute myelogenous leukemia.
Monoclonal antibody (mAb) M195 is a mouse IgG2a reactive with a myelomonocytic differentiation antigen found on early myeloid cells and monocytes. The reactivity of M195 with fresh hematopoietic neoplasms in the blood or bone marrow from 227 patients at Memorial Hospital was determined by flow cytometry. M195 was positive on 67% of 61 myeloblastic leukemias. Seventy percent of Tdt-negative ANLL and 30% of Tdt-positive ANLL were positive; 100% of CMMOL and 100% of CML in myeloblastic crisis or accelerated phase were positive. In contrast, M195 was positive on only 8% of 51 lymphoblastic leukemias and 1% of 70 other nonmyeloid samples. M195 binding did not correlate well with FAB classification of ANLL. The pattern of reactivity of M195 was similar but not identical to that of MY9 (CD33) on the same cases (83% concordance). Cross-blocking of M195 binding by MY9 and L4F3 (CD33) was demonstrated. M195 may bind to a different epitope on the same protein antigen. The presence of both MY9 and M195 positivity on a leukemia sample had a 98% specificity of diagnosing ANLL, which was greater than MY9 alone (88%) or M195 alone (92%). Assays of granulocytic-monocytic and erythroid colony-forming units showed M195 to be present on these hematopoietic progenitors. This pattern of reactivity of M195, together with its lack of reactivity with mature granulocytic elements or with adult tissues, make it a candidate for therapy of ANLL in vivo.


The 5' and 3' splice sites come together via a three dimensional diffusion mechanism.
We present evidence that the splice sites in mammalian pre-mRNAs are brought together via a three dimensional diffusion mechanism. We tested two mechanisms for splice site pairing: a lateral diffusion ('scanning') model and the currently favored three dimensional diffusion ('jumping') model. Two lines of evidence that distinguish between these two models are presented. The first utilized bipartite splicing substrates tethered by double-stranded RNA stems predicted to provide either a moderate or severe block to splice site pairing via a scanning mechanism. Splice site pairing via a jumping mechanism was expected to be unaffected or affected minimally. The second approach utilized a flexible poly(ethylene glycol) moiety within the intron. This insertion was predicted to reduce scanning efficiency but not the efficiency of a three dimensional diffusion mechanism. The best explanation for the data with the bipartite RNAs is that splice site pairing occurs through three dimensional diffusion. Kinetic analysis of the poly(ethylene glycol) containing substrate showed that neither the lag phase nor the initial rates of mRNA production and spliceosome assembly were affected by this insertion. Therefore, both experimental approaches supported the three dimensional diffusion model of splice site pairing.


Effectiveness of glyceryl trinitrate for enhancing digital submural perfusion in horses.
To evaluate the clinical efficacy of topically administered glyceryl trinitrate (GTN) for inducing digital submural vasodilation in clinically normal horses. 7 adult horses without foot abnormalities. A concurrent-control crossover design was used to determine whether topical application of GTN ointment for prevention or treatment of laminitis would result in a detectable increase in digital perfusion. Heat-acclimated horses instumented for detection of wall surface temperature (HWST), mean systemic pressure, and heart rate were used. Horses were exposed to cold to induce digital vasoconstriction and treated with GTN in an attempt to induce digital vasodilation. Application of GTN failed to induce an increase in digital submural perfusion but did induce a mild decrease in mean systemic pressure. Topical application of 60 mg of GTN as a 2% ointment on the skin over the major vasculature in the region of the proximal interphalangeal joint (pastern) of horses was not effective in significantly increasing digital perfusion. A decrease in mean systemic pressure following treatment was observed, implying that the drug was absorbed. Use of GTN may result in a decrease in digital submural perfusion secondary to induction of peripheral constriction or a decrease in digital perfusion pressure.


How do peers promote social inclusion of children with disabilities?A mixed-methods systematic review.
Purpose: This mixed-methods systematic review synthesized findings from studies published between January 1, 2006 and July 31, 2018 on the social inclusion experiences of children with and without disabilities, as viewed from their own perspective, with a focus on how typically developing peers promote social inclusion.Method: Forty-five studies met the inclusion criteria. Data from included studies were synthesized by means of content analysis.Results: The findings detail the inner social inclusion experiences (e.g., feeling included, different) of children with disabilities and provide information regarding the influence of disability type (e.g., physical, social, affective) on typically developing peers' responses (e.g., acceptance vs. rejection), peers' explanations for social inclusion/exclusion, and peers' relationships with children with disabilities. Barriers to social inclusion, supports, as well as strategies used to promote social inclusion, as perceived by peers and children with disabilities, are also reported.Conclusion: The findings of this review provide evidence that despite society's efforts to promote social inclusion, children with disabilities continue to report feeling lonely and excluded, having limited contact socially outside of home, and encountering systemic barriers (e.g., bullying, discrimination). More research on the social inclusion experiences of children with disabilities beyond educational settings is needed, such as in the contexts of recreation and leisure, community, and employment.Implications for rehabilitationThe perspectives of children with and without disabilities need to be integrated in activities and programs aimed at promoting social inclusion.Teaching social inclusion strategies to children with and without disabilities is needed to help them deal with barriers.In addition to educational settings, rehabilitation clinicians need to promote social inclusion strategies in other contexts such as recreation and leisure, community, and employment contexts.


Targeted disruption of BMP signaling through type IA receptor (BMPR1A) in osteocyte suppresses SOST and RANKL, leading to dramatic increase in bone mass, bone mineral density and mechanical strength.
Recent studies suggest a critical role of osteocytes in controlling skeletal development and bone remodeling although the molecular mechanism is largely unknown. This study investigated BMP signaling in osteocytes by disrupting Bmpr1a under the Dmp1-promoter. The conditional knockout (cKO) mice displayed a striking osteosclerotic phenotype with increased trabecular bone volume, thickness, number, and mineral density as assessed by X-ray and micro-CT. The bone histomorphometry, H&E, and TRAP staining revealed a dramatic increase in trabecular and cortical bone masses but a sharp reduction in osteoclast number. Moreover, there was an increase in BrdU positive osteocytes (2-5-fold) and osteoid volume (~4-fold) but a decrease in the bone formation rate (~85%) in the cKO bones, indicating a defective mineralization. The SEM analysis revealed poorly formed osteocytes: a sharp increase in cell numbers, a great reduction in cell dendrites, and a remarkable change in the cell distribution pattern. Molecular studies demonstrated a significant decrease in the Sost mRNA levels in bone (>95%), and the SOST protein levels in serum (~85%) and bone matrices. There was a significant increase in the β-catenin (>3-fold) mRNA levels as well as its target genes Tcf1 (>6-fold) and Tcf3 (~2-fold) in the cKO bones. We also showed a significant decrease in the RANKL levels of serum proteins (~65%) and bone mRNA (~57%), and a significant increase in the Opg mRNA levels (>20-fold) together with a significant reduction in the Rankl/Opg ratio (>95%), which are responsible for a sharp reduction in the cKO osteoclasts. The values of mechanical strength were higher in cKO femora (i.e. max force, displacement, and work failure). These results suggest that loss of BMP signaling specifically in osteocytes dramatically increases bone mass presumably through simultaneous inhibition of RANKL and SOST, leading to osteoclast inhibition and Wnt activation together. Finally, a working hypothesis is proposed to explain how BMPR1A controls bone remodeling by inhibiting cell proliferation and stimulating differentiation. It is reported that RANKL and SOST are abundantly expressed by osteocytes. Thus, BMP signaling through BMPR1A plays important roles in osteocytes.


Congenital adrenal hyperplasia cases identified by newborn screening in one- and two-screen states.
There is no clear consensus among state newborn screening programs on whether routine second screening of newborns identifies clinically relevant cases of congenital adrenal hyperplasia. This retrospective study evaluated laboratory practices, along with biochemical and medical characteristics of congenital adrenal hyperplasia (CAH) cases (1) detected on the first newborn screen in one-screen compared to two-screen states, and (2) detected on the first versus the second screen in the two-screen states, to determine the effectiveness of a second screen. A total of 374 confirmed cases of CAH from 2 one-screen states and 5 two-screen states were included in this study. Demographic data and diagnostic information on each reported case were collected and analyzed. Additionally, laboratory data, including screening methodologies and algorithms, were evaluated. The one-screen states reported 99 cases of CAH out of 1,740,586 (1 in 17,500) newborns screened: 88 (89%) identified on the first screen and 5 (5%) identified on the targeted second screen. The two-screen states reported 275 cases of CAH out of 2,629,627 (1 in 9500) newborns screened: 165 (60%) identified on the first screen and 99 (36%) identified on the second screen. Using a multivariate model, the only significant predictor of whether a case was identified on the first or the second screen in the two-screen states was the type of CAH. Compared with classical salt-wasting CAH, classical simple virilizing and non-classical CAH cases were less likely to be detected on the first versus the second screen. The routine second newborn screen is important for identifying children with CAH, particularly simple virilizing and non-classical forms, which might otherwise not be captured through a single screen.