Waterless bathing for inpatients with neurological issues and complex needs.
Waterless bathing techniques can enhance the care of patients with neurological difficulties. Traditional methods can be uncomfortable and time consuming. Hospital-acquired infections in the NHS are a significant concern because of both financial burdens and antibiotic resistance, and preventing them is paramount. ContiTM waterless bathing products help reduce infection risks, save time and improve the patient experience. Four case studies illustrate the application of these techniques in a specialist hospital for people with complex and serious neurological conditions, demonstrating their practicality and efficacy as well as improvements in patient care and infection control within healthcare facilities.


Employment rates among the disabled in Israel.
Seven hundred sixty two disabled individuals were interviewed. Of these, 220 were found to be working or to have done so in the past three years. The remaining 542 were unemployed and had been so for at least that long. Employment status was found to be related to a number of demographic and disability related variables: sex, with whom the subject lived, country of origin, father's country of origin, and SES. The employed were more likely to be male, to live in an upper middle or upper class neighborhood, to be Israeli born, have European or American born fathers, and to be living with someone else. They were also likely to be more educated, younger, have a lower disability degree, a less serious medical disability, and have more recent disabilities. The other variables studies, including place of residence, family status, year of immigration, number of children, and several specific disability related measures, were not related to employment status. The findings are in keeping with those of previous studies. Their implications for improving employment rates among the disabled are discussed.


Potential Effects of Nutraceuticals in Retinopathy of Prematurity.
Retinopathy of prematurity (ROP), the most common cause of childhood blindness, is a hypoxia-induced eye disease characterized by retinal neovascularization. In the normal retina, a well-organized vascular network provides oxygen and nutrients as energy sources to maintain a normal visual function; however, it is disrupted when pathological angiogenesis is induced in ROP patients. Under hypoxia, inadequate oxygen and energy supply lead to oxidative stress and stimulate neovasculature formation as well as affecting the function of photoreceptors. In order to meet the metabolic needs in the developing retina, protection against abnormal vascular formation is one way to manage ROP. Although current treatments provide beneficial effects in reducing the severity of ROP, these invasive therapies may also induce life-long consequences such as systemic structural and functional complications as well as neurodevelopment disruption in the developing infants. Nutritional supplements for the newborns are a novel concept for restoring energy supply by protecting the retinal vasculature and may lead to better ROP management. Nutraceuticals are provided in a non-invasive manner without the developmental side effects associated with current treatments. These nutraceuticals have been investigated through various in vitro and in vivo methods and are indicated to protect retinal vasculature. Here, we reviewed and discussed how the use of these nutraceuticals may be beneficial in ROP prevention and management.


Alcohol drinking patterns among high school students in Ethiopia: a cross-sectional study.
Alcohol use is an important risk factor for morbidity, mortality and social harm among adolescents. There is paucity of data on alcohol use among high school students in Ethiopia. This study aimed to determine the prevalence and factors associated with alcohol use among high school students in Ethiopia A cross-sectional study was conducted to assess the prevalence of alcohol use and its predictors among high school students in eastern Ethiopia in April 2010. A sample of students was taken from all schools based on their enrollment size. Prevalence estimates and their 95% confidence intervals were calculated. Logistic regression was performed to adjust and examine associations. A total of 1721 students participated in the study. The mean age of the study population was 16.4 (SD 1.6) years. A total of 372 (22.2%; 95% CI 20.2 - 24.2%) students drink alcohol. Of these, 118 (31.7%) were females and 254 (68.3) males. Multivariate analysis indicated that males (OR 2.09; 95% CI 1.45-3.00), older age (OR 1.16; 95% CI 1.01-1.34), having friends who used alcohol (OR 10.09; 95% CI 6.84-14.89) and living with people who use alcohol (OR 2.77; 95% CI 1.89-4.07) increased the odds of drinking among students. There is a high level of alcohol use among high school students in the study area. Involvement of parents, health workers and school authorities are necessary to avert the problem. Specifically, their involvement in awareness campaigns and peer education training are important to encourage students to avoid alcohol use.


Testing water-soluble carbohydrate QTL effects in perennial ryegrass (Lolium perenne L.) by marker selection.
Water-soluble carbohydrates (WSC) are an important factor determining the nutritional value of grass forage and development of genetic markers for selection of WSC traits in perennial ryegrass would benefit future breeding programmes. Quantitative trait loci (QTLs) for WSC have been published for an F(2) ryegrass mapping family. Markers showing significant associations with these QTLs were used to design narrow-based populations with homozygosity for target QTLs. Founders were selected from within the mapping family. The divergent populations produced were analysed for WSC content in the glasshouse and the field. There was evidence of complex interactions between WSC content and other factors and traits, including the scale of assessment, time/degree of sward establishment and other forage quality parameters. Differences between the divergent pairs of the various populations were small. However, differences observed between the founder selection groups were maintained and the roles of the QTL regions in regulating forage WSC content were confirmed. In general, the individual divergent populations exploited only a limited extent of the large phenotypic variation available within the mapping family. However, this study sets the scene for exploring the opportunities for marker-assisted breeding strategies for complex traits in obligate out-breeding species, and the challenges of doing this are discussed.


Unusual, high genetic diversity of Aleutian mink disease virus.
The genetic diversity of Aleutian mink disease virus (AMDV) was examined. Sequences obtained from 35 clinical samples were compared with five published sequences. An unusual, high genetic variability was revealed. Three phylogenetic subgroups of AMDV were identified, and the presence of more than one genotype at some farms was detected.


Comparing Cognitive Control Performance During Seated Rest and Self-Paced Cycling on a Desk Bike in Preadolescent Children.
Although active workstations, such as desk bikes, have proven to be beneficial for health, there is limited information regarding their effects on children's acute cognitive performance during self-paced exercise. This study used a within-subjects, fully counterbalanced design with a sample of 38 preadolescent children (mean age = 12.50 y, SD = 0.62; 43% male), who performed cognitive tests while being seated or while cycling for 45 minutes with a 7-day interval. Effects of using a desk bike were evaluated on cognitive control: verbal and visuospatial working memory capacities were tested, and inhibition was assessed using a modified flanker task. In addition, subjective task experience was explored using self-report measures. Cognitive control performance was not degraded but also not improved with the short-term use of desk bikes. Because of the null effects, there is no direction and magnitude of the outcomes to discuss. These findings suggest that schools can successfully implement desk bikes to increase physical activity and reduce sedentary time among children without compromising cognitive control processes necessary for academic achievement.


Subacromial impingement syndrome.
Subacromial impingement syndrome (SAIS) represents a spectrum of pathology ranging from subacromial bursitis to rotator cuff tendinopathy and full-thickness rotator cuff tears. The relationship between subacromial impingement and rotator cuff disease in the etiology of rotator cuff injury is a matter of debate. However, the etiology is multi-factorial, and it has been attributed to both extrinsic and intrinsic mechanisms. Management includes physical therapy, injections, and, for some patients, surgery. No high-quality randomized controlled trials are available so far to provide possible evidence for differences in outcome of different treatment strategies. There remains a need for high-quality clinical research on the diagnosis and treatment of SAIS.


Oxidative Stress Is a Central Target for Physical Exercise Neuroprotection Against Pathological Brain Aging.
Physical exercise is suggested for preventing or delaying senescence and Alzheimer's disease (AD). We have examined its therapeutic value in the advanced stage of AD-like pathology in 3xTg-AD female mice through voluntary wheel running from 12 to 15 months of age. Mice submitted to exercise showed improved body fitness, immunorejuvenation, improvement of behavior and cognition, and reduced amyloid and tau pathology. Brain tissue analysis of aged 3xTg-AD mice showed high levels of oxidative damage. However, this damage was decreased by physical exercise through regulation of redox homeostasis. Network analyses showed that oxidative stress was a central event, which correlated with AD-like pathology and the AD-related behaviors of anxiety, apathy, and cognitive loss. This study corroborates the importance of redox mechanisms in the neuroprotective effect of physical exercise, and supports the theory of the crucial role of oxidative stress in the switch from normal brain aging to pathological aging and AD.


The Relationship Between Surgeon Gender and Stress During the Covid-19 Pandemic.
To investigate the relationship between surgeon gender and stress during the Covid-19 pandemic. Although female surgeons face difficulties integrating work and home in the best of times, the Covid-19 pandemic has presented new challenges. The implications for the female surgical workforce are unknown. This cross-sectional, multi-center telephone survey study of surgeons was conducted across 5 academic institutions (May 15-June 5, 2020). The primary outcome was maximum stress level, measured using the validated Stress Numerical Rating Scale-11. Mixed-effects generalized linear models were used to estimate the relationship between surgeon stress level and gender. Of 529 surgeons contacted, 337 surgeons responded and 335 surveys were complete (response rate 63.7%). The majority of female respondents were housestaff (58.1%), and the majority of male respondents were faculty (56.8%) (P = 0.008). A greater proportion of male surgeons (50.3%) than female surgeons (36.8%) had children ≤18 years (P = 0.015). The mean maximum stress level for female surgeons was 7.51 (SD 1.49) and for male surgeons was 6.71 (SD 2.15) (P < 0.001). After adjusting for the presence of children and training status, female gender was associated with a significantly higher maximum stress level (P < 0.001). Our findings that women experienced more stress than men during the Covid-19 pandemic, regardless of parental status, suggest that there is more to the gendered differences in the stress experience of the pandemic than the added demands of childcare. Deliberate interventions are needed to promote and support the female surgical workforce during the pandemic.


Johne's disease in cattle: an in vitro model to study early response to infection of Mycobacterium avium subsp. paratuberculosis using RNA-seq.
Johne's disease is a chronic granulomatous enteritis caused by Mycobacterium avium subsp. paratubercolosis (MAP) which affects ruminants worldwide and has a significant economic impact. MAP has also been associated with human Crohn's disease, although this connection is not well established. MAP is highly adapted for survival within host macrophages and prevents macrophage activation, blocks phagosome acidification and maturation, and attenuates presentation of antigens to the immune system. The consequence is a very long silent infection before clinical signs are observed. The present work examined the transcriptome of bovine monocyte-derived macrophages (MDM) infected with the L1 strain of MAP at 2h, 6h and 24h post infection using RNA-seq. Pathway over-representation analysis of genes differentially expressed between infected vs. control MDM identified that immune related pathways were affected. Genes belonging to the cytokine-cytokine receptor interaction pathway and members of the JAK-STAT pathway, which is involved in the regulation of immune response, were up-regulated. However, in parallel inhibitors of immune functions were activated, including suppressor of cytokine signaling (SOCS) and cytokine-inducible SH2-containing protein (CISH), which most likely suppresses IFNγ and the JAK/STAT signaling cascade in infected MDM, which may favour MAP survival. After exposure, macrophages phagocytise pathogens, activate the complement cascade and the adaptive immune system through the antigen presentation process. However, data presented here suggest that genes related to phagocytosis and lysosome function are down regulated in MAP infected MDM. Genes of MHC class II and complement pathway were also down-regulated. This study therefore shows that MAP infection is associated with changes in expression of genes related to the host immune response that may affect its ability to survive and multiply inside the host cell.


Effect of pancreatic warm ischemia on islet yield and viability in dogs.
Defining tolerable warm ischemia (WI) is mandatory before nonheartbeating cadavers can be used to enlarge the donor pool. No studies to date have precisely evaluated the effect of pancreatic WI on islet yield and viability in a large animal model. We used mongrel dogs in our study at the University of Minnesota. Excised pancreases were left in situ for a designated period (0, 30, 45, and 60 min in groups 1 to 4, respectively) of WI. Then, they were digested by the automated collagenase digestion method of Ricordi, purified on Euro-Ficoll discontinuous gradients with the COBE cell processor, and autotransplanted into the liver via a mesenteric vein. We compared the four groups in terms of islet yield, expressed as islet equivalents (IE; diameter standardizing to 150 microm) per pancreas weight (IE/g pancreas), and viability, assessed by functional success (maintenance of normoglycemia for 2 weeks) after transplant. Mean islet yield (+/- SD) and the functional success rate after transplant were as follows: 6200+/-1800 IE/g pancreas and 4 of 4 (100%) in group 1; 6300+/-4400 and 4 of 4 (100%) in group 2; 3800+/-2600 and 2 of 4 (50%) in group 3; and 1400+/-1300 and 0 of 4 (0%) in group 4 (P=0.01 vs. group 1). With 30 min or less of WI, there are no deleterious effects on islet yield and viability. However, with periods of WI longer than 30 min, the loss in islet yield is severe, resulting in functional failure after autotransplantation. The limit of WI that is tolerable for islets is shorter than for a whole pancreas.


The effects of renal variation upon measurements of perfusion and leakage volume in breast tumours.
Dynamic contrast enhanced MRI (DCE-MRI) and pharmacokinetic models have been used to measure tumour permeability (K(trans)) and leakage volume (ve) in numerous studies. The construction of pharmacokinetic models describing such tissue properties relies on defining the blood plasma concentration of contrast agent with respect to time (Cp(t)). When direct measurement is not possible a bi-exponential decay has been applied using data from healthy volunteers. This work investigates, by simulation, the magnitude of errors resulting from this definition with respect to normal variation in renal function and for cases with renal impairment. Errors up to 23% in ve and 28% in K(trans) were found for the normal simulations, and 67% in ve and 61% in K(trans) for the impaired simulations. If this bi-exponential curve is used as an input function to the generalized kinetic model and used in oncology, estimates of tissue permeability and leakage volume will possess large errors due to variation in Cp(t) curves between subjects.


Fluorescent substrates for flow cytometric evaluation of efflux inhibition in ABCB1, ABCC1, and ABCG2 transporters.
ATP binding cassette (ABC) transmembrane efflux pumps such as P-glycoprotein (ABCB1), multidrug resistance protein 1 (ABCC1), and breast cancer resistance protein (ABCG2) play an important role in anticancer drug resistance. A large number of structurally and functionally diverse compounds act as substrates or modulators of these pumps. In vitro assessment of the affinity of drug candidates for multidrug resistance proteins is central to predict in vivo pharmacokinetics and drug-drug interactions. The objective of this study was to identify and characterize new substrates for these transporters. As part of a collaborative project with Life Technologies, 102 fluorescent probes were investigated in a flow cytometric screen of ABC transporters. The primary screen compared substrate efflux activity in parental cell lines with their corresponding highly expressing resistant counterparts. The fluorescent compound library included a range of excitation/emission profiles and required dual laser excitation as well as multiple fluorescence detection channels. A total of 31 substrates with active efflux in one or more pumps and practical fluorescence response ranges were identified and tested for interaction with eight known inhibitors. This screening approach provides an efficient tool for identification and characterization of new fluorescent substrates for ABCB1, ABCC1, and ABCG2.


Quantifying the sources of pollutants in the Great Barrier Reef catchments and the relative risk to reef ecosystems.
Development of the Great Barrier Reef (GBR) catchments in the last 150 years has increased the loads of suspended sediment, nutrients and pesticides ('pollutants') delivered to the GBR. The scale and type of development, the pollutants generated and the ecosystems offshore vary regionally. We analysed the relative risk of pollutants from agricultural land uses and identified the sources of these pollutants from different land uses for each region to develop priorities for management. The assessment showed the Wet Tropics and Mackay Whitsunday regions to be of relatively high risk dominated by sugarcane cultivation, contributing pesticide and dissolved inorganic nitrogen (DIN). The Burdekin and Fitzroy ranked medium-high risk dominated by grazing suspended sediment inputs for both, and additionally sugarcane DIN and pesticide inputs for the Burdekin. The Burnett Mary ranked medium risk, dominated by grazing and sugarcane. Cape York was not formally ranked but is considered to be low risk.


Longitudinal analysis of citrullinated protein/peptide antibodies (anti-CP) during 5 year follow up in early rheumatoid arthritis: anti-CP status predicts worse disease activity and greater radiological progression.
To study serum levels of citrullinated protein/peptide antibodies (anti-CP) during up to 5 years' follow up of patients with early rheumatoid arthritis (RA), and to relate serum levels to disease course and to treatments in clinical practice. 279 patients with early RA were followed up with clinical investigations, radiographs, and measurement of anti-CP at baseline and after 3 months, 1, 2, 3, and 5 years. 160/279 (57.3%) patients were anti-CP positive at the first visit (mean 5 months after first symptoms). During follow up only 11/279 (3.9%) of the patients changed their anti-CP status. Anti-CP levels fell significantly during the first year, and this drop correlated with the extent of sulfasalazine treatment but not with other drugs or clinical indices. Anti-CP positive and negative patients had similar disease activities at baseline, but during follow up the anti-CP positive patients had worse clinical disease and greater radiological progression, despite at least equally intensive antirheumatic treatment. Anti-CP are stable during the first 5 years of RA, suggesting that events before rather than after onset of clinical manifestations of disease determine this phenotype. The presence of anti-CP at diagnosis predicts a less favourable disease course and greater radiological progression despite antirheumatic treatment, but subsequent changes in antibody levels do not reflect changes in disease activity. Taken together, these observations suggest that anti-CP positive RA is a distinct clinical and pathophysiological entity.


Carrier gas triggered controlled biolistic delivery of DNA and protein therapeutics from metal-organic frameworks.
The efficacy and specificity of protein, DNA, and RNA-based drugs make them popular in the clinic; however, these drugs are often delivered via injection, requiring skilled medical personnel, and producing biohazardous waste. Here, we report an approach that allows for their controlled delivery, affording either a burst or slow release without altering the formulation. We show that when encapsulated within zeolitic-imidazolate framework eight (ZIF-8), the biomolecules are stable in powder formulations and can be inoculated with a low-cost, gas-powered "MOF-Jet" into living animal and plant tissues. Additionally, their release profiles can be modulated through judicious selection of the carrier gas used in the MOF-Jet. Our in vitro and in vivo studies reveal that when CO2 is used, it creates a transient and weakly acidic local environment that causes a near-instantaneous release of the biomolecules through an immediate dissolution of ZIF-8. Conversely, when air is used, ZIF-8 biodegrades slowly, releasing the biomolecules over a week. This is the first example of controlled-biolistic delivery of biomolecules using ZIF-8, which provides a powerful tool for fundamental and applied science research.


The importance of scatter correction for the assessment of lung shunting prior to yttrium-90 radioembolization therapy.
Treatment of inoperable hepatocellular carcinoma or secondary metastases by radioembolization using yttrium-90 (90Y) microspheres is a promising method for the treatment of unresectable liver metastases. A pretreatment scintigraphy planar scan using 99mTc-labelled macroaggregated albumin (99mTc-MAA) injected directly into the hepatic artery is carried out to assess the degree of portal shunting of blood between the liver and the lungs. The quantitative results of this scan are used to modulate the activity of therapeutic 90Y microspheres injected into the patient to limit the radiation dose received by the lungs. The presence of scattered events in the MAA lung shunt scan leads to an overestimation of the true shunting ratio, which in turn leads to the administered therapeutic activity being lowered unnecessarily to comply with the protocols of radiation protection. Overall, this may impact the efficacy of treatment. This study analyses the impact of a window-based analytical scatter-correction method on lung shunt analysis using an anthropomorphic torso phantom, and retrospectively analysed three patient case studies. Our results of scatter in the phantom show a marked decrease in the lung shunt percentage. Clinical analysis of patient data shows that the lung shunt percentage can be overestimated by up to 50% in clinical cases, and depending on the lung shunt percentage, the efficacy of treatment by therapeutic dose reduction may be compromised. Our results indicate that scatter correction should be used on 90Y pretreatment 99mTc-MAA scans in order to more accurately assess the lung shunting percentage before therapy.


Phylogenetic diversity of 200+ isolates of the ectomycorrhizal fungus Cenococcum geophilum associated with Populus trichocarpa soils in the Pacific Northwest, USA and comparison to globally distributed representatives.
The ectomycorrhizal fungal symbiont Cenococcum geophilum is of high interest as it is globally distributed, associates with many plant species, and has resistance to multiple environmental stressors. C. geophilum is only known from asexual states but is often considered a cryptic species complex, since extreme phylogenetic divergence is often observed within nearly morphologically identical strains. Alternatively, C. geophilum may represent a highly diverse single species, which would suggest cryptic but frequent recombination. Here we describe a new isolate collection of 229 C. geophilum isolates from soils under Populus trichocarpa at 123 collection sites spanning a ~283 mile north-south transect in Western Washington and Oregon, USA (PNW). To further understanding of the phylogenetic relationships within C. geophilum, we performed maximum likelihood and Bayesian phylogenetic analyses to assess divergence within the PNW isolate collection, as well as a global phylogenetic analysis of 789 isolates with publicly available data from the United States, Japan, and European countries. Phylogenetic analyses of the PNW isolates revealed three distinct phylogenetic groups, with 15 clades that strongly resolved at >80% bootstrap support based on a GAPDH phylogeny and one clade segregating strongly in two principle component analyses. The abundance and representation of PNW isolate clades varied greatly across the North-South range, including a monophyletic group of isolates that spanned nearly the entire gradient at ~250 miles. A direct comparison between the GAPDH and ITS rRNA gene region phylogenies, combined with additional analyses revealed stark incongruence between the ITS and GAPDH gene regions, consistent with intra-species recombination between PNW isolates. In the global isolate collection phylogeny, 34 clades were strongly resolved using Maximum Likelihood and Bayesian approaches (at >80% MLBS and >0.90 BPP respectively), with some clades having intra- and intercontinental distributions. Together these data are highly suggestive of divergence within multiple cryptic species, however additional analyses such as higher resolution genotype-by-sequencing approaches are needed to distinguish potential species boundaries and the mode and tempo of recombination patterns.


Considering Computational Mathematics IGHG3 as Malignant Melanoma Is Associated with Immune Infiltration of Malignant Melanoma.
Malignant melanoma is one of the most threatening cancers to human health. Only 14% of patients with malignant melanoma have a remaining life span of 5 years. At present, there have been some studies looking for potential prognostic indicators of esophageal cancer from the level of genes and infiltrating immune cells, but there are still some problems that need to be resolved urgently. This paper proposes IGHG3 as the immune infiltration of malignant melanoma, which takes into account the computational mathematics. It aims to deduce the characteristics of immune cell infiltration in malignant melanoma and study the relationship between different immune cell infiltration characteristics and prognosis. The method in this article is to establish a computational mathematical model for the immunotherapy of melanoma, then study the method of identification of the affinity of the IGHG3 reagent, and finally obtain the gene expression of immune infiltration. The functions of these methods are, respectively, to predict the dynamic behavior of T cells with two different specificities through mathematical models and to test the matching degree of different concentrations of IGHG3 reagent with the human body. Then use the ssGSEA algorithm to obtain immune infiltration related data and calculate the difference between the weighted empirical cumulative distribution function of all genes in the effect of IGHG3 on melanoma that was carried out. The experimental results showed the computational mathematical method genome and all the remaining genes. In this study, a computational mathematical method to detect the IGHG3 gene expression had a significant inhibitory effect on A375 cells in the experimental group, and the knockdown efficiency reached 85.6%.


Characterization of the chloroquine resistance transporter homologue in Toxoplasma gondii.
Mutations in the Plasmodium falciparum chloroquine resistance transporter (PfCRT) protein confer resistance to the antimalarial drug chloroquine. PfCRT localizes to the parasite digestive vacuole, the site of chloroquine action, where it mediates resistance by transporting chloroquine out of the digestive vacuole. PfCRT belongs to a family of transporter proteins called the chloroquine resistance transporter family. CRT family proteins are found throughout the Apicomplexa, in some protists, and in plants. Despite the importance of PfCRT in drug resistance, little is known about the evolution or native function of CRT proteins. The apicomplexan parasite Toxoplasma gondii contains one CRT family protein. We demonstrate that T. gondii CRT (TgCRT) colocalizes with markers for the vacuolar (VAC) compartment in these parasites. The TgCRT-containing VAC is a highly dynamic organelle, changing its morphology and protein composition between intracellular and extracellular forms of the parasite. Regulated knockdown of TgCRT expression resulted in modest reduction in parasite fitness and swelling of the VAC, indicating that TgCRT contributes to parasite growth and VAC physiology. Together, our findings provide new information on the role of CRT family proteins in apicomplexan parasites.


Quantitative analysis of levels of serum immunoglobulin G against botulinum neurotoxin type D and association with protection in natural outbreaks of cattle botulism.
The recent outbreaks of cattle botulism in vaccinated Israeli dairy cattle prompted us to determine vaccine efficacy and reasons for vaccine failure. Analysis of clinical signs, feeding practice, vaccination history, and epidemic curves enabled us to define a study population in two outbreaks, where high doses of Clostridium botulinum neurotoxin type D (BoNT/D) were evenly consumed by the affected animal groups. Attack rates among unvaccinated 6- to 24-month-old heifers were 96% (55/57) and 85% (53/62). The attack rates in vaccinated parity 1, 2, and >or=3 cows were 40.4% (21/52), 14.3% (4/28), and 5.6% (3/54), respectively. Vaccine efficacies for these cow groups were 52.5%, 83.2%, and 93.4%, respectively. In younger, unvaccinated 2- to 6-month-old calves, presumably protected by maternal antibodies, the attack rate was 24% (17/71). These differences correlated with significant differences in levels of specific anti-BoNT/D antibody in serum by an enzyme-linked immunosorbent assay (ELISA). The ELISA performance for predicting protection was analyzed by receiver operating characteristic analysis and was found to be highly significant, with an area under the curve of 0.941 (standard error, 0.034; 95% confidence interval, 0.875 to 1.008; P < 0.000). No animals with serum ELISA unit levels above 0.33 were affected in these exposed groups. At this cutoff level, the specificity of the ELISA was 100%, sensitivity was 67%, and accuracy was 92%. We concluded that botulinum toxoids can confer adequate protection against natural exposure to lethal doses of BoNT/D; however, the vaccination protocols should be optimized. Our in-house ELISA system will enable us to optimize vaccination protocols in the animal population.


The clinical significance of antiphospholipid antibodies.
The antiphospholipid syndrome is defined as the association between the presence of antiphospholipid antibodies, detected as anticardiolipin antibodies and/or lupus anticoagulant, and a history of either arterial or venous thrombosis and/or recurrent pregnancy loss. Because thrombosis may occur in virtually any organ system, diagnosing the antiphospholipid syndrome and taking appropriate anticoagulation measures are important considerations in all medical specialties. Antiphospholipid antibody-associated thrombosis tends to recur. Antithrombotic prophylaxis to prevent recurrences is therefore needed. Prophylaxis in individuals with circulating antiphospholipid antibodies who have no history of thrombosis is still controversial. Although direct evidence for a pathogenetic role of antiphospholipid antibodies in the development of thrombosis is still lacking, recent studies suggest that it is causative rather than coincidental. New insights on the possible mechanisms leading to thrombosis were provided by the discovery of the serum cofactor (beta2-GPI), a coagulation inhibitor which is required for binding of anticardiolipin antibodies to cardiolipin. More recently, patients with antiphospholipid antibodies were found to possess autoantibodies directed against other coagulation factors, including prothrombin, protein C and protein S. Future studies should clarify whether these different antigenic specificities are associated with particular clinical events and assess the risk of thrombosis associated with the presence of antiphospholipid antibodies in asymptomatic individuals.


A portable microfluidic Aptamer-Tethered Enzyme Capture (APTEC) biosensor for malaria diagnosis.
There is a critical need for better biosensors for the detection and diagnosis of malaria. We previously developed a DNA aptamer that recognises the Plasmodium falciparum lactate dehydrogenase (PfLDH) enzyme with high sensitivity and specificity. The aptamer was integrated into an Aptamer-Tethered Enzyme Capture (APTEC) assay as a laboratory-based diagnostic approach. However, a portable equipment-free point-of-care aptamer-mediated biosensor could have a significant impact on malaria diagnosis in endemic regions. Here, we present a new concept for a malaria biosensor whereby aptamers are coated onto magnetic microbeads for magnet-guided capture, wash and detection of the biomarker. A biosensor incorporating three separate microfluidic chambers was designed to enable such magnet-guided equipment-free colorimetric detection of PfLDH. A series of microfluidic biosensor prototypes were optimised to lower rates of inter-chamber diffusion, increase sensitivity, and provide a method for point-of-care sample testing. The biosensor showed high sensitivity and specificity when detecting PfLDH using both in vitro cultured parasite samples and using clinical samples from malaria patients. The high performance of the biosensor provides a proof-of-principle for a portable biosensor that could be adaptable for a variety of aptamer-mediated diagnostic scenarios.


Hepatitis Viruses B and D and Human Immunodeficiency Virus Infections in Hemodialysis Patients in the South of Iran: Prevalence and Genotypes.
Hepatitis B virus (HBV), hepatitis D virus (HDV), and human immunodeficiency virus (HIV) are transmitted by blood transfusion. Thus, hemodialysis (HD) patients are more prone to become the carriers of these infections due to their treatment demands. The aim of this study was to assess the prevalence of HBV and HIV infections among HD patients in Bandar Abbas, Iran, 2015. A total of 153 patients with chronic renal failure undergoing HD at Shahid Mohammadi hospital in Bandar Abbas were examined for hepatitis B surface antigen (HBsAg), anti- hepatitis C virus, and anti-HIV over a period of 2 months. Thereafter, all of the specimens were evaluated for HBV-DNA, HDV-RNA and HIV-RNA using polymerase chain reaction (PCR) and further techniques. All statistical analyses were carried out using SPSS version 12 for Windows with the t-test and chi-square (χ(2)) test. Both kinds of assay determined that nine (5.88%) patients were HBV positive (HBsAg-positive), whereas no HIV- and HDV-positive patients were diagnosed. All of the diagnosed HBV samples belonged to genotype D; the prevalence of HBV is associated with age, duration of HD, history of blood transfusion, and using shared HD devices. In conclusion, the prevalence of HBV infection was low in the south of Iran, but genotype D represented the major HBV genotype in this population. Among the variables, age, duration of HD, history of blood transfusion, and using shared HD devices influenced the prevalence of HBV among HD patients.


Son of sevenless binds to the SH3 domain of src-type tyrosine kinase.
To identify molecules which bind to the SH3 domains of p56lck, we screened a mouse T-cell lymphoma cDNA library using the yeast two-hybrid system. As a result, we obtained several positive clones including the Son of Sevenless gene which encodes a mammalian homolog of Drosophila Ras GDP/GTP exchange factor. In a subsequent analysis with the yeast two-hybrid system, Sos associated only with the constitutively active form of p56lck (F505) but not with wild type p56lck (Y505), indicating the requirement for an active conformation of p56lck for binding to Sos. Subsequently, we have demonstrated in vitro that the SH3 domain of p56lck as well as the proline-rich sequences of Sos are responsible for this association. In addition, the proline-rich domain of Sos also bound to the SH3 domains of other src-type tyrosine kinases, src and fyn, but not to that of PLC-gamma. More importantly, the p56lck SH3-Sos interaction was enhanced by serum stimulation, suggesting the possibility that the direct interaction between p56lck SH3 and Sos may contribute to the regulation of the Ras pathway.


Characterization of inflammatory bowel disease in elderly patients: A review of epidemiology, current practices and outcomes of current management strategies.
The authors review and summarize the current literature regarding the epidemiology, clinical presentation and management of inflammatory bowel disease (IBD) in elderly patients. Among elderly patients, the incidence of ulcerative colitis (UC) is higher than that of Crohn disease (CD). Elderly patients with a new diagnosis of UC are more likely to be male and have left-sided colitis. Elderly patients with a new diagnosis of CD are more likely to be female and have colonic disease. Conversely, increasing age at diagnosis has been associated with a lower likelihood of having any of a family history of IBD, perianal disease in CD and extraintestinal manifestations. Although response to drug therapies appears to be similar in elderly patients and younger individuals, the elderly are more likely to receive 5-aminosalicylic acid agents, and less likely to receive immunomodulators and biologics. Corticosteroid use in the elderly is comparable with use in younger individuals. The rates of surgical intervention appear to be lower for elderly CD patients but not elderly UC patients. Elderly individuals with UC are more likely to need urgent colectomy, which is associated with an increased mortality rate. Elective surgery is associated with similar outcomes among the elderly and young patients with IBD. Therefore, the use of immunomodulators and biologics, and earlier consideration of elective surgery for medically refractory disease in elderly patients with IBD, should be emphasized and further evaluated to prevent complications of chronic corticosteroid(s) use and to prevent emergency surgery.


The integration of multiple HIV/AIDS projects into a coordinated national programme in China.
External financial support from developed countries is a major resource for any developing country's national AIDS programme. The influence of donors on the content and implementation of these programmes is thus inevitable. China is a large developing country that has received considerable international support for its HIV/AIDS programme. In the early stage of the response, each large HIV/AIDS project independently implemented their activities according to their project framework. When internationally funded projects were few and the quantity of domestic support was minimal, their independent implementation did not pose a problem. When many HIV/AIDS projects were simultaneously implemented in the same locations, problems emerged such as inconsistency and overlap in data collection. China has thus coordinated and integrated all large international and domestic HIV/AIDS projects into one national programme. The process of integration began slowly and initially consisted of unified data collection. Integration is now complete and encompasses the processes of project planning, budgeting, implementation, monitoring and evaluation. The process was facilitated by having a single coordinating body, cooperation from international agencies and financial commitment from the government. Some problems were encountered during this process, such as initial reluctance from health-care staff to allocate additional time to coordinate projects. This paper describes that process of integrating domestic and foreign HIV/AIDS projects and may serve as a useful example for other developing countries for management of scarce resources.


Induction of monooxygenase and UDP-glucuronosyltransferase activities in primary cultures of rat hepatocytes.
The inducibility of two monooxygenase and UDP-glucuronosyltransferase (GT) forms was studied in primary cultures of adult rat hepatocytes. The following enzyme activities were determined: cytochrome P-448-dependent ethoxyresorufin O-deethylase (ERDE) and cytochrome P-450-dependent aldrin epoxidase (AE), and, furthermore, the GT form(s) metabolizing 3-hydroxybenzo(a)pyrene (GT1) and the GT form(s) metabolizing 4-hydroxybiphenyl (GT2). The results were as follows. The activity of AE and GT2 decreased markedly during the first days of culture, whereas ERDE and GT1 remained stable or even increased slightly. The maintenance of ERDE activity was dependent on the presence of dexamethasone. Pregnenolone-16 alpha-carbonitrile (PCN), phenobarbital (PB), and benz(a)anthracene (BA) induced the activity of ERDE in hepatocytes cultured in HM 84 medium by a factor of 4, 8, and 12, respectively. Similar factors of induction were obtained at the fifth day of culture using a modified Leibovitz L-15 medium. However, the time course of induction differed greatly in the two media. BA and PB had an additive effect on ERDE activity, suggesting different mechanisms of action for the two inducers. Monoclonal antibodies directed against cytochrome P-448 inhibited ERDE activities induced by BA and PB to a similar extent. Neither PB nor PCN significantly increased AE activity. However, these compounds induced GT2. BA did not affect GT2 but induced GT1. The present results show that the culture of adult rat hepatocytes changes the relative distribution of monooxygenase and GT forms. The response to inducers resembles only partially that observed in vivo.


Removal of methylene blue from aqueous solution using a polarizable nanolayered manganese oxide film.
A layered manganese oxide film grown electrochemically was applied to remove methylene blue (MB), a cationic dye, from an aqueous solution. A layered MnO(x) film intercalated with tetraethylammonium (Et(4)N) cations was deposited potentiostatically at +1.0 V (vs. Ag/AgCl) from an aqueous Mn(2+) solution containing Et(4)NCl. Et(4)N cations were sandwiched between negatively charged MnO(x) layers. When the Et(4)N/MnO(x) film was immersed in a solution containing MB alone, the intercalated Et(4)N cations were replaced with MB in a solution phase by an ion-exchange mechanism. The uptake capacity of the Et(4)N/MnO(x) film for MB was estimated to be 45.3 mg per 1.0 g of MnO(2). In the presence of KCl, the MB sorption was seriously restricted because the interlayer space was occupied by K(+) ions. However, the MnO(x) film anodized at +0.8 V can selectively take up MB molecules from the KCl solution. This can be ascribed to an increase in the interlayer space available to the sorption of MB due to the extraction of K(+) ions, where the MnO(x) surface probably has a specific affinity toward MB molecules.


Tooth loss--an assessment of dental health state utility values.
The study described aimed to measure the value placed on oral health, by measuring the utility of mouths in which teeth had been lost. A total of 102 subjects who had experienced tooth loss were interviewed and presented with 19 different scenarios of mouths with missing teeth. Each written description was accompanied by a verbal explanation and digital pictures of mouth models. Participants were asked to indicate on a standardized visual analogue scale how they would value the health of their mouth if they had lost the tooth/teeth described and the resulting space was left unrestored. With a utility value of 0.0 representing the worst possible health state for a mouth and 1.0 representing the best, the mouth with the upper central incisor missing attracted the lowest utility value (utility = 0.16), the one with a missing upper second molar and the missing lower second molar attracted the highest utility values (utility = 0.48, 0.47, respectively). With respect to shortened dental arch (SDA) scenarios, a mouth with a SDA with only the second molar teeth in all quadrants missing attracted the highest utility value (utility = 0.45). A mouth with an extreme SDA with both missing molar and premolar teeth attracted the lowest utility value (utility = 0.06). Both age and gender have a significant influence on how the dentition is valued. It is feasible and possible to derive measurements of the impact of various degrees of tooth loss on individuals. Further studies are required to examine whether past tooth loss or oral health status affects how tooth loss is viewed.


Cancer mortality in residents of the terrain-shielded area exposed to fallout from the Nagasaki atomic bombing.
The health effects of radiation exposure from the atomic bomb fallout remain unclear. The objective of the present study is to elucidate the association between low-dose radiation exposure from the atomic bomb fallout and cancer mortality among Nagasaki atomic bomb survivors. Of 77 884 members in the Nagasaki University Atomic Bomb Survivors Cohort, 610 residents in the terrain-shielded area with fallout were selected for this analysis; 1443 residents in the terrain-shielded area without fallout were selected as a control group; and 3194 residents in the direct exposure area were also selected for study. Fifty-two deaths due to cancer in the terrain-shielded fallout area were observed during the follow-up period from 1 January 1970 to 31 December 2012. The hazard ratio for cancer mortality in the terrain-shielded fallout area was 0.90 (95% confidence interval: 0.65-1.24). No increase in the risk of cancer mortality was observed, probably because the dose of the radiation exposure was low for residents in the terrain-shielded fallout areas of the Nagasaki atomic bomb, and also because the number of study subjects was small.


Understanding the implementation of the holiday activities and food programme in the North East of England using normalization process theory.
Following several pilot projects, in 2020, the Department for Education (DfE) in England committed funding of £220M p. a to its Holiday Activities and Food (HAF) programme to support all 153 upper-tier local authorities, comprising City Councils, County Councils and Metropolitan Borough Councils, to provide an activity and food programme for children who are in receipt of means-tested free school meals. In this study, qualitative interviews were conducted with representatives from three Local Authorities in the North East of England who were responsible for overseeing the implementation and delivery of HAF programmes in their Local Authority area to examine how the summer HAF programme was implemented during summer 2021. Interviews were conducted with eight participants prior to the implementation of the HAF programme, and four interviews were conducted after the programme had been delivered. Using a directed content analysis approach, an interpretative framework was co-developed, based on the four constructs (and selected sub-constructs) of Normalization Process Theory. This framework guided data coding. The analysis aimed to identify and understand the barriers and opportunities in relation to HAF implementation within local authorities. Participants did not perceive HAF as a totally new initiative as many had either commissioned or delivered holiday clubs in the past. However, the increased scale and scope of HAF was perceived as highly complex, involving multiple local authority departments and stakeholders. Nonetheless, HAF funding enabled local authorities to improve the quality and reach of their holiday programmes. Strong networks and good communication between all stakeholders supported successful delivery, despite tight delivery timescales. However, the rigidity of some of the DfE guidance was a barrier for some providers, particularly the recommended delivery model of 4 h a day, 4 days a week for 4 weeks, with many individual holiday clubs struggling to meet this level of delivery, and local authority leads interpreting the guidance at a club level rather than an individual child access level. Furthermore, participants considered the HAF eligibility criteria too restrictive. Many councils were developing long-term plans for HAF delivery, integrated into planning across several departments, and all local authorities were actively seeking ways to engage with and embed HAF within local communities.


Advances towards programmable droplet transport on solid surfaces and its applications.
Droplets moving on solid surfaces are at the heart of many phenomena of fundamental and applied interest in chemistry, physics and materials science. On the fundamental side, as they are often subject to evaporation, these droplets are a beautiful and complex example of non-equilibrium physical chemistry, whose explanation and understanding still capture the imagination of multiple researchers around the world. In technology, droplets on solid surfaces are of widespread use for handling small amounts of matter, for harvesting energy, for manufacturing materials and for sensing chemical and biological analytes. A key underlying factor of their widespread applicability is the degree of control that can be achieved over their transport on surfaces. This tutorial review provides an overview of recent progress towards the programmable transport of droplets on solid surfaces. We will first present the physical principles behind the main experimental strategies for droplet transport. We will then review the most inspiring applications where these strategies have been employed in chemistry, materials science and engineering. Finally, we will outline possible future research directions for the programmable transport of droplets. Beyond projecting the reader at the forefront of this exciting field of physical chemistry, we believe that this tutorial review will inspire diverse, multidisciplinary scientific communities to devise novel ways of manipulating the flow of matter, energy and information on solid surfaces using programmable droplets as vessels.


Reduced glutamate neurotransmission in patients with Alzheimer's disease -- an in vivo (13)C magnetic resonance spectroscopy study.
Cognitive impairment in Alzheimer's disease (AD) is not fully explained. PET indicates reduced cerebral metabolic rate for glucose. Since glutamate neurotransmission (GNT) consumes more than 80% of the ATP generated from metabolism, a pilot study was carried out to determine the neuronal tricarboxylic acid cycle (TCA) based on the hypothesis that reduced GNT could contribute to cognitive impairment in AD. Three AD patients with cognitive impairment (mini-mental state exam: 24 vs 30, P<0.05) and significant reduction in both N-acetyl aspartate (NAA)/Creatine (Cr) ( P<0.009) and NAA/myo-inositol (mI) ratio ( P<0.01), and three age-matched controls each received 0.014-0.016 g/kg/min 99%1-13C glucose IV. Quantitative (1)H and proton-decoupled (13)C MR brain spectra were acquired from combined posterior-parietal white matter and posterior-cingulate gray matter every 5 min for 140 min.(13)C magnetic resonance spectroscopy (MRS) measures of glucose oxidation and neuronal TCA rate, including prolonged time to (13)C enrichment of glutamate (Glu2) ( P<0.004) and bicarbonate (HCO(3)) ( P<0.03) as well as reduced relative enrichment of Glu(2)/Glu(4) between 60 and 100 min ( P<0.04), were significantly different in AD patients vs. controls. (13)C measures of GNT, glutamine (Gln)(2)/Glu(2) ( P<0.02) and rates of glutamate enrichment (Glu(2)/glucose: 0.34 vs 0.86, P=ns and Glu(4)/glucose 0.26 vs 0.83, P=ns), were also reduced.(13)C MRS measures of neuronal TCA cycle, glucose oxidation and GNT were significantly correlated with measures of neuronal integrity: NAA/Cr, [NAA] and mI/NAA as determined by (1)H MRS ( R(2)=0.73-0.95; P<0.05-0.01), suggesting that impairment of GNT may be a contributing factor in the cognitive impairment characteristic of AD.


Zuclopenthixol decanoate for schizophrenia and other serious mental illnesses.
There is a clear link between stopping antipsychotic medications and a relapse of psychotic symptoms. A series of long-acting intra-muscular preparations has been developed since the 1960s in the hope of reducing the frequency of relapse and, hence, overall disability. These depot preparations, active for weeks at a time, are frequently used for those who find taking oral medication on a regular basis difficult or unacceptable. It has, however, been a consistent concern that any reduction in relapse rate afforded by depot preparations may be offset by an increase in adverse effects such as drug-induced movement disorders. To compare zuclopenthixol decanoate to oral zuclopenthixol and other antipsychotic preparations for the treatment of schizophrenia and similar serious mental illness. Electronic searches of Biological Abstracts (1982-1998), CINAHL (1982-1998), The Cochrane Library (Issue 2, 1998), The Cochrane Schizophrenia Group's Register (April 1998), EMBASE (1980-1998), MEDLINE (1966-1998), and PsycLIT (1974-1998) were searched. References of all eligible studies were searched for further trials. The manufacturer of zuclopenthixol was contacted. Inclusion criteria were that the clinical study should be randomised, focus on people with schizophrenia or other serious mental illness with psychotic symptoms, and compare the use of zuclopenthixol decanoate to oral zuclopenthixol or other antipsychotic preparations. Data was extracted independently by two reviewers (EC, MF). Authors of trials were contacted for additional and missing data. Odds ratios (ORs) and 95% confidence intervals (CIs) of homogenous dichotomous data were calculated with the Peto method. Where possible the number needed to treat (NNT) and its 95% confidence interval was also calculated. Four studies relating to zuclopenthixol decanoate were included. All compared zuclopenthixol decanoate with other depot preparations. Zuclopenthixol decanoate prevented or postponed relapses when compared to other depots (NNT 8, CI 5-53). However, zuclopenthixol decanoate may induce more adverse effects (NNH 5, CI 3-31) although it decreases need for anticholinergic medication when compared to a group of other depot preparations (NNT 9, CI 5-38). For the risk of leaving the study early, there was also a trend for benefit to those allocated to zuclopenthixol decanoate. None of the studies reported outcomes on service utilisation, costs, or quality of life. Choice of which depot to use must always take into account clinical judgement and the preferences of the recipients of care and their carers. Limited trial data suggests, however, that there are real differences between zuclopenthixol decanoate and other depots and these differences largely favour the former. This review highlights the need for good controlled clinical trials to fully address the effects of zuclopenthixol decanoate for those with schizophrenia. Future studies should report service utilisation data, as well as satisfaction with care and economic outcomes. Duration of such trials should be of a longer duration than the included studies (12 months or more).


Three cycles of ABDV plus extended field radiotherapy in patients with poor prognosis early-intermediate stage Hodgkin's disease.
The aim of the study was to verify the possibility of treating patients with poor prognosis early-intermediate Hodgkin's disease with a combined modality therapy consisting of three cycles of ABVD followed by extended field irradiation (EFRT). No patient had bulky mediastinum or had previously been administered chemo- or radiotherapy. At pathological restaging, 40/44 (91%) evaluable patients achieved complete responses (CR). After a ten-year followup, freedom from progression (FFP), relapse-free survival (RFS) and overall survival (OS) were 80%, 83% and 81%, respectively. Of the prognostic factors, univariate analysis showed that only stage III negatively influenced RFS, but not OS. Toxicity was mild except for subclinical mediastinal fibrosis in 32.5% of CR patients. No patient reported reduced fertility. Two cases of second neoplasms were recorded: one ameboid glioma and one thymoma, both occurring within five years after discontinuing chemo-radiotherapy. Our data suggest that three cycles of ABVD preceeding EFRT is an effective treatment for poor prognosis early-intermediate stage Hodgkin's disease; nevertheless, stage III patients and some stage II patients with unfavorable prognostic factors should be treated with a more aggressive approach.


The nucleotide sequence of the rho gene of E. coli K-12.
We have determined the nucleotide sequence of the rho gene which encodes the E. coli K-12 transcription termination factor. The structural gene was located on a cloned 3.6 kilobase BglII-HindIII restriction fragment by the introduction of the insertion element gamma delta and analysis of the recombinant plasmids by restriction analysis and in maxicells. The coding region consists of 1260 nucleotides directing the synthesis of a polypeptide 419 amino acids in length with a calculated molecular weight of 46,094. The deduced amino acid composition, amino-terminal protein sequence and calculated molecular weight are consistent with the data from the analysis of purified rho protein (16). We have shown that the rho genes from E. coli K-12, B and C strains are located on PvuII-HindIII fragments of the same size by hybridization to the rho (K-12) coding sequences.


Population-based incidence rates and risk factors for type 2 diabetes in white individuals: the Bruneck study.
Incidence rates and risk factors for type 2 diabetes in low-risk populations are not well documented. We investigated these in white individuals who were aged 40-79 years and from the population of Bruneck, Italy. Of an age- and sex-stratified random sample of 1,000 individuals who were identified in 1990, 919 underwent an oral glucose tolerance test (OGTT) and an assessment of physiological risk factors for diabetes, including insulin resistance (homeostasis model assessment, HOMA-IR), and postchallenge insulin response (Sluiter's Index). Diabetes at baseline by fasting or 2-h OGTT plasma glucose (World Health Organization criteria, n = 82) was excluded, leaving 837 individuals who were followed for 10 years. Incident cases of diabetes were ascertained by confirmed diabetes treatment or a fasting glucose >or=7.0 mmol/l. At follow-up, 64 individuals had developed diabetes, corresponding to a population-standardized incidence rate of 7.6 per 1,000 person-years. Sex- and age-adjusted incidence rates were elevated 11-fold in individuals with impaired fasting glucose at baseline, 4-fold in those with impaired glucose tolerance, 3-fold in overweight individuals, 10-fold in obese individuals, and approximately 2-fold in individuals with dyslipidemia or hypertension. Incidence rates increased with increasing HOMA-IR and decreasing Sluiter's Index. As compared with normal insulin sensitivity and normal insulin response, individuals with low insulin sensitivity and low insulin response had a sevenfold higher risk of diabetes. Baseline impaired fasting glucose, BMI, HOMA-IR, and Sluiter's Index were the only independent predictors of incident diabetes in multivariate analyses. We conclude that approximately 1% of European white individuals aged 40-79 years develop type 2 diabetes annually and that "subdiabetic" hyperglycemia, obesity, insulin resistance, and impaired insulin response to glucose are independent predictors of diabetes.


Lack of effect of L-carnitine supplementation on weight gain in very preterm infants.
Carnitine transfer across the placenta occurs predominantly during the third trimester. Unless L-carnitine is provided, very preterm infants develop carnitine deficiency. Although breast milk and infant formulas contain L-carnitine, parenteral nutrition solutions do not routinely provide L-carnitine. We hypothesized that prolonged L-carnitine supplementation in very preterm infants would improve weight gain and shorten length of stay in the hospital. The study was a double-blind parallel placebo-controlled randomized clinical trial. Eligible patients were <29 weeks of gestation, <72 hours of age, and did not have a potentially life-threatening congenital malformation or hereditary metabolic disorder. Patients were stratified by gestational age (23 to 25(6/7) and 26 to 28(6/7) weeks), and randomized to receive, either L-carnitine at a dose of 50 mumol/kg/day, or placebo. Carnitine was provided intravenously until the infants tolerated 16 ml/day of feeds. The sample size was calculated to have 80% power to detect a 10% increase in weight gain from birth until 36 weeks of postmenstrual age or discharge from the hospital. Secondary outcome variables included food efficiency (defined as weight gain divided by caloric intake), weight gain at 4 weeks of age, time to regain birth weight and length of stay. Among the 63 infants enrolled in the trial, 32 were randomized to L-carnitine and 31 to placebo. L-Carnitine supplementation did not significantly affect average daily weight gain from birth until 36 weeks or hospital discharge, or any of the secondary outcome variables. Prolonged supplementation of L-carnitine did not improve long-term weight gain in very preterm infants.


A novel prophylactic Chinese parachute ankle brace.
The objective is to compare the effects of a self-designed and self-manufactured novel prophylactic ankle brace [Chinese parachute ankle brace (CPAB)] and two ordinary ankle braces on the ankle joint during a half-squat parachute landing (HSPL) via biomechanical assessment. Twenty elite paratroopers were in four different conditions: no brace, elastic brace, semi-rigid brace, and CPAB. Each participant was instructed to jump off a platform with three different heights, 40, 80, and 120 cm, and land on the force plate in a half-squat posture. The vertical ground reaction forces (vGRFs), joint angles, moments, powers, and works were calculated. After the experiment, every participant completed the questionnaires designed for this study. Increasing the dropping height increased all of the parameters significantly (P<0.01), except for time to peak vGRF (T-PvGRF). Applying three braces can all slightly increase vGRF (P=0.237) and reduce T-PvGRF by 6-10 ms, as well as decrease the joint angles, velocities, and moments on the sagittal and coronal planes. Wearing CPAB and a semi-rigid brace more efficiently restricted dorsiflexion and inversion (P<0.05), and they both significantly reduced ankle work (t=5.107, P<0.01; t=3.331, P<0.01) and peak power (t=7.237, P<0.01; t=6.711, P<0.01) at 120 cm. The total scores from low-to-high were semi-rigid brace (19.20±2.99), elastic brace (21.91±3.25), and CPAB (23.37±3.08). The CPAB was more effective at restricting ankle joint motion on the coronal and sagittal planes than the other two prophylactic ankle braces. Therefore, the CPAB had the advantages of a novel appearance, high efficiency, and superior comfort, providing a reliable choice for parachute jumping and training in China.


Interleukin-6 is necessary, but not sufficient, for induction of the humanC-reactive protein gene in vivo.
We have investigated the involvement of interleukin-6 (IL-6) in the induction of the gene encoding the acute-phase protein human C-reactive protein (hCRP). In transgenic mice the hCRP gene can be induced by lipopolysaccharide (LPS), but not by IL-6. In contrast, hCRP was inducible by IL-6 in primary human hepatocytes and in primary hepatocytes isolated from transgenic mice. To further evaluate the role of IL-6, we introduced the hCRP transgene into animals lacking endogenous IL-6 (IL-6-negative mice). Here, hCRP was not inducible by LPS, but was induced by a combination of LPS and IL-6. These results clearly demonstrate that IL-6 is necessary, but not sufficient, for the induction of hCRP expression. These animal models will allow further dissection of the cytokine network responsible for the regulation of the major human acute-phase reactant CRP.


Risk factors for maternal mortality in a Tertiary Hospital in Kenya: a case control study.
Maternal mortality is high in Africa, especially in Kenya where there is evidence of insufficient progress towards Millennium Development Goal (MDG) Five, which is to reduce the global maternal mortality rate by three quarters and provide universal access to reproductive health by 2015. This study aims to identify risk factors associated with maternal mortality in a tertiary level hospital in Kenya. A manual review of records for 150 maternal deaths (cases) and 300 controls was undertaken using a standard audit form. The sample included pregnant women aged 15-49 years admitted to the Obstetric and Gynaecological wards at the Moi Teaching and Referral Hospital (MTRH) in Kenya from January 2004 and March 2011. Logistic regression analysis was used to assess risk factors for maternal mortality. Factors significantly associated with maternal mortality included: having no education relative to secondary education (OR 3.3, 95% CI 1.1-10.4, p = 0.0284), history of underlying medical conditions (OR 3.9, 95% CI 1.7-9.2, p = 0.0016), doctor attendance at birth (OR 4.6, 95% CI 2.1-10.1, p = 0.0001), having no antenatal visits (OR 4.1, 95% CI 1.6-10.4, p = 0.0007), being admitted with eclampsia (OR 10.9, 95% CI 3.7-31.9, p < 0.0001), being admitted with comorbidities (OR 9.0, 95% CI 4.2-19.3, p < 0.0001), having an elevated pulse on admission (OR 10.7, 95% CI 2.7-43.4, p = 0.0002), and being referred to MTRH (OR 2.1, 95% CI 1.0-4.3, p = 0.0459). Antenatal care and maternal education are important risk factors for maternal mortality, even after adjusting for comorbidities and complications. Antenatal visits can provide opportunities for detecting risk factors for eclampsia, and other underlying illnesses but the visits need to be frequent and timely. Education enables access to information and helps empower women and their spouses to make appropriate decisions during pregnancy.


Mechanistic study of CBT-Cys click reaction and its application for identifying bioactive N-terminal cysteine peptides in amniotic fluid.
CBT-Cys click condensation reaction has a high second-order reaction rate constant and has found wide applicability in recent years. However, its reaction mechanism has not been experimentally validated and its application for identifying bioactive N-terminal Cys peptides in real clinical samples has not been reported. Herein, firstly, by employing induced nanoelectrospray ionization-mass spectrometry (InESI-MS) and a home-built micro-reactor, we successfully intercepted and structurally characterized the crucial intermediate in this click reaction for the first time. With the intermediate, the proposed mechanism of this reaction was corroborated. Moreover, we also applied this MS setup to monitor the reaction in real time and obtained the second-order reaction rate constants of this reaction at different pH values. After mechanistic study, we applied this click reaction for identifying bioactive N-terminal cysteine peptides in amniotic fluid (AF). Eight unique N-terminal Cys peptides in AF, three of which are located in the functional domain regions of their corresponding proteins, were identified with a false positive rate less than 1%. One of the three peptides was found able to inhibit the growth of uterine endometrial cancer HEC-1-B cells but not the endometrial normal cells via a typical apoptotic pathway. With its mechanism satisfactorily elucidated, the kinetic parameters obtained, as well as its application for fishing bioactive N-terminal Cys peptides from vast complex clinical samples, we anticipate that this CBT-Cys click reaction could be applied more widely for the facile isolation, site-specific identification, and quantification of N-terminal Cys-containing peptides in complex biological samples.


In vivo skin effects of a dimethylaminoethanol (DMAE) based formulation.
Dimethylaminoethanol (DMAE) has been used in anti-aging formulations but few scientifically based data address its efficacy. The aim of this study was to evaluate the effects of DMAE-based formulations on hairless mice and human skin. Formulations containing with or without DMAE were applied to the dorsum of hairless mice. Histopathological and histometric evaluations were carried out after seven days. Formulations were also applied to the ventral forearm and the lateral periocular area of human volunteers. Stratum corneum water content and skin mechanical properties were analyzed using Corneometer and Cutometer, before and after a single and repeated application. Histometric evaluations showed that formulations with or without DMAE increased the viable epidermis thickness, but only the DMAE-supplemented formulation led to increased dermal thickness. DMAE also induced increase in collagen fiber thickness, which was observed in the histopathological study. After the single and the 8-week period application on human skin, formulations with and without DMAE enhanced the stratum corneum water content in the forearm skin. Mechanical properties were not significantly modified. So, we can suggest that DMAE action is related to its effects on the dermis as observed in the histopathological and histometric studies and showed hydration effects on skin.


Substance P activates coincident NF-AT- and NF-kappa B-dependent adhesion molecule gene expression in microvascular endothelial cells through intracellular calcium mobilization.
Upon stimulation, cutaneous sensory nerves release neuropeptides such as substance P (SP), which modulate responses in the skin by activating a number of target cells via neurokinin receptors. We have demonstrated that SP preferentially binds to the NK-1R on human dermal microvascular cells, resulting in increased intracellular Ca2+ and induction of ICAM-1 and VCAM-1 expression. In the current studies, we identify specific elements in the regulatory regions of ICAM-1 and VCAM-1 genes as necessary and sufficient for SP-dependent transcriptional activation. SP treatment of human dermal microvascular endothelial cells leads to coincident activation and binding of the transcription factor NF-AT to the -191/-170 region of the ICAM-1 gene (a region bound by activated p65/p65 homodimers in response to TNF-alpha), and NF-kappa B (p65/p50) to tandem NF-kappa B binding sites at -76/-52 of the VCAM-1 gene. The SP-elicited intracellular Ca2+ signal was required for activation and subsequent binding of both NF-AT and NF-kappa B. The transacting factor induction by SP was specific, since a selective NK-1R antagonist blocked SP activation and subsequent NF-AT and NF-kappa B activation and binding. These data demonstrate coincident activation of NF-AT and NF-kappa B via SP-induced intracellular Ca2+ mobilization and indicate a crucial role for neuropeptides in modulating localized cutaneous inflammatory responses.


Atmospheric ions and germination of uredospores of Puccinia striiformis.
Atmospheric ions, identified by mobility characteristics, were associated with germination of lyophilized uredospores of Puccinia striiformis West. at Bozeman Montana. Ions of intermediate size were highest in concentration, and percentage germination of spores was lowest during periods conducive to air pollution. In duplicate experiments at an isolated site near Barrow. Alaska, essentially all atmospheric ions were small ions and the fungus spores were consistently germinated near maximum.


Radiation pattern of plasmonic nano-antennas in a homogeneous medium.
Radiation patterns from plasmonic nano-antennas formed on a glass substrate were investigated using index-matching oils. It was confirmed that the pattern from single nano-antennas for various cases of index-mismatching between the substrate and the oil is explained well by the patterns of infinitesimal electric dipoles. We found that for an angular resolution of 2°, the index mismatch must be smaller than 0.001 to realize isotropic radiation. By using the appropriate condition, the radiation patterns of nano Yagi-Uda antennas in a quasi-homogeneous medium were obtained experimentally.


[Current considerations around the search for extraterrestrial life].
In this paper, the current cosmological topics are considered: a) The fourth centenary celebration of Giordano Bruno's death at the Roman's inquisition stake. This eminent philosopher, based on the Coppernican Revolution, concibed the Cosmos as a infinite universe with innumerable inhabited worlds. He acted on reason to believe not only in extraterrestrial life but in extraterrestrial intelligent life. Here we write a few words in his memory and honour. b) The active project SETI@home in the framework of today's classic program "Search for Extra-Terrestrial Intelligence", by means of the reception of radioelectrical signals. c) Search for extrasolar planets.


Safety and pharmacokinetics of oral cannabidiol when administered concomitantly with intravenous fentanyl in humans.
Cannabidiol (CBD) is hypothesized as a potential treatment for opioid addiction, with safety studies an important first step for medication development. We determined CBD safety and pharmacokinetics when administered concomitantly with a high-potency opioid in healthy subjects. This double-blind, placebo-controlled cross-over study of CBD, coadministered with intravenous fentanyl, was conducted at the Clinical Research Center in Mount Sinai Hospital, a tertiary care medical center in New York City. Participants were healthy volunteers aged 21 to 65 years with prior opioid exposure, regardless of the route. Blood samples were obtained before and after 400 or 800 mg of CBD pretreatment, followed by a single 0.5 (session 1) or 1.0 μg/kg (session 2) of intravenous fentanyl dose. The primary outcome was the Systematic Assessment for Treatment Emergent Events (SAFTEE) to assess safety and adverse effects. CBD peak plasma concentrations, time to reach peak plasma concentrations (tmax), and area under the curve (AUC) were measured. SAFTEE data were similar between groups without respiratory depression or cardiovascular complications during any test session. After low-dose CBD, tmax occurred at 3 and 1.5 hours in sessions 1 and 2, respectively. After high-dose CBD, tmax occurred at 3 and 4 hours in sessions 1 and 2, respectively. There were no significant differences in plasma CBD or cortisol (AUC P = NS) between sessions. Cannabidiol does not exacerbate adverse effects associated with intravenous fentanyl administration. Coadministration of CBD and opioids was safe and well tolerated. These data provide the foundation for future studies examining CBD as a potential treatment for opioid abuse.


A novel approach using pulmonary artery catheter-directed rapid right ventricular pacing to facilitate precise deployment of endografts in the thoracic aorta.
Controlled hypotension is critical for precise deployment of endografts in the thoracic aorta and for safe balloon dilation after deployment. We describe a novel approach to rapid right ventricular pacing using a pulmonary artery catheter (PAC) that is placed during the procedure for hemodynamic monitoring. The study included 27 patients (20 men and seven women), with a mean age of 74 years, who underwent endograft placement in the thoracic aorta with PAC-directed rapid right ventricular pacing. Hemodynamic parameters, accuracy of deployment, complications related to rapid right ventricular pacing and PAC placement, presence of endoleaks, and postoperative complications were evaluated. PAC-directed rapid right ventricular pacing was performed during endograft deployment and balloon dilation after deployment without technical difficulty. Each patient underwent a median of two pacing episodes (range, 1-4). The length of each pacing episode was a mean of 11 seconds (range, 8-14 seconds). Mean pacing rate was 170 ± 15 beats/min, which achieved an average mean arterial pressure (MAP) of 42 ± 8 mm Hg. After pacing cessation, the recovery time of MAP to prepacing levels was <5 seconds (mean, 2 seconds) in all but one patient. All endografts were precisely deployed at a mean of 2 mm from the intended placement site, and there was no unintentional branch vessel coverage. One patient with severe valvular heart disease died. There were nine endoleaks, one postoperative stroke (4%), and one access wound hematoma (4%). PAC-directed rapid right ventricular pacing is an effective method of inducing hypotension, enabling precise thoracic endograft deployment and safe balloon dilation after deployment. However, despite these advantages, the technique may be contraindicated in patients with severe valvular or ischemic heart disease.


Pulpotomy reconsidered: application of an adhesive system to pulpotomized permanent primate pulps.
This study was undertaken to compare the healing response of permanent primate pulps to pulpotomy procedures following hemorrhage control and adhesive hybridization to their response after conventional treatments. Forty-two cavities were placed throughout the dentitions of 4 adult monkeys. In 24 teeth, following mechanical bur exposure and pulpotomy, hemorrhage was controlled with application of 3% sodium hypochlorite. The cavity was rinsed and the enamel-dentin-pulp surface was restored with an adhesive system for 6 and 7 months. Calcium hydroxide, formocresol, and resin-modified glass-ionomer cement were placed as conventional treatments in 18 teeth for 70 days and cavities were sealed with resin-modified glass-ionomer cement. Following perfusion fixation, tissues were demineralized, sectioned, stained, and histologically graded using defined criteria. Of 24 adhesive system pulps, 10 showed no or minimal pulpal response, 1 showed an acute response, 6 showed a chronic response, 2 showed a severe response, and 5 showed compartmentalized zones of localized necrosis. Only 8 adhesive system pulps showed stained bacteria associated with inflamed tissues. Thirteen adhesive system pulps showed dentin bridging directly at the adhesive system interface. Calcium hydroxide-treated specimens showed healing and dentin formation, while resin-modified glass-ionomer cement and formocresol treatments failed to result in any bridging. Apical tissues in all adhesive-treated specimens showed normal pulps and primary odontoblasts along their entire walls. Permanent pulps without periapical radiolucencies may survive pulpotomy, provided that hemorrhage is properly controlled and the pulp-restoration interface is hybridized to exclude all microleakage.


Challenges in access and satisfaction with reproductive, maternal, newborn and child health services in Nigeria during the COVID-19 pandemic: A cross-sectional survey.
The presence of COVID-19 has led to the disruption of health systems globally, including essential reproductive, maternal, newborn and child health (RMNCH) services. This study aimed to assess the challenges faced by women who used RMNCH services in Nigeria's epicentre, their satisfaction with care received during the COVID-19 pandemic and the factors associated with their satisfaction. This cross-sectional survey was conducted in Lagos, southwest Nigeria among 1,241 women of reproductive age who had just received RMNCH services at one of twenty-two health facilities across the primary, secondary and tertiary tiers of health care. The respondents were selected via multi-stage sampling and face to face exit interviews were conducted by trained interviewers. Client satisfaction was assessed across four sub-scales: health care delivery, health facility, interpersonal aspects of care and access to services. Bivariate and multivariate analyses were used to assess the relationship between personal characteristics and client satisfaction. About 43.51% of respondents had at least one challenge in accessing RMNCH services since the COVID-19 outbreak. Close to a third (31.91%) could not access service because they could not leave their houses during the lockdown and 18.13% could not access service because there was no transportation. The mean clients' satisfaction score among the respondents was 43.25 (SD: 6.28) out of a possible score of 57. Satisfaction scores for the interpersonal aspects of care were statistically significantly lower in the PHCs and general hospitals compared to teaching hospitals. Being over 30 years of age was significantly associated with an increased clients' satisfaction score (ß = 1.80, 95%CI: 1.10-2.50). The COVID-19 lockdown posed challenges to accessing RMNCH services for a significant proportion of women surveyed. Although overall satisfaction with care was fairly high, there is a need to provide tailored COVID-19 sensitive inter-personal care to clients at all levels of care.


Prevention of decompression sickness during a simulated space docking mission.
This study has shown that repetitive exchanges between the American Apollo space vehicle atmosphere of 100% oxygen at 5 psia (258 torr) and the Russian Soyuz spacecraft atmosphere of 30% oxygen-70% nitrogen at 10 psia (523 torr), as simulated in altitude chambers, will not likely result in any form of decompression sickness. This conclusion is based upon the absence of any form of bends in seven crewmen who participated in 11 tests distributed over three 24-h periods. During each period, three transfers from the 5 to the 10 psia environments were performed by simulating passage through a docking module which served as an airlock where astronauts and cosmonauts first adapted to each other's cabin gases and pressures before transfer. Biochemical tests, subjective fatigue scores, and the complete absence of any form of pain were also indicative that decompression sickness should not be expected if this spacecraft transfer schedule is followed.


Complement testing in the clinical laboratory.
The complement system is the human's first line of defense against microbial pathogens because of its important housekeeping and infection/inflammation roles. It is composed of a series of soluble and cell-bound proteins that are activated in a cascade effect, similar to the coagulation pathways. There are different pattern recognizing molecules that activate the complement system in response to stimuli or threats, acting through three initiation pathways: classical, lectin, and alternative. All three activation pathways converge at the C3 component and share the terminal pathway. The main outputs of the complement system action are lytic killing of microbes, the release of pro-inflammatory anaphylatoxins, and opsonization of targets. Laboratory testing is relevant in the setting of suspected complement deficiencies, as well as in the emerging number of diseases related to dysregulation (over-activation) of complement. Most common assays measure complement lytic activity and the different complement component concentrations. Specialized testing includes the evaluation of autoantibodies against complement components, activation fragments, and genetic studies. In this review, we cover laboratory testing for complement and the conditions with complement involvement, as well as current challenges in the field.


Dynamic brain structural changes after left hemisphere subcortical stroke.
This study aimed to quantify dynamic structural changes in the brain after subcortical stroke and identify brain areas that contribute to motor recovery of affected limbs. High-resolution structural MRI and neurological examinations were conducted at five consecutive time points during the year following stroke in 10 patients with left hemisphere subcortical infarctions involving motor pathways. Gray matter volume (GMV) was calculated using an optimized voxel-based morphometry technique, and dynamic changes in GMV were evaluated using a mixed-effects model. After stroke, GMV was decreased bilaterally in brain areas that directly or indirectly connected with lesions, which suggests the presence of regional damage in these "healthy" brain tissues in stroke patients. Moreover, the GMVs of these brain areas were not correlated with the Motricity Index (MI) scores when controlling for time intervals after stroke, which indicates that these structural changes may reflect an independent process (such as axonal degeneration) but cannot affect the improvement of motor function. In contrast, the GMV was increased in several brain areas associated with motor and cognitive functions after stroke. When controlling for time intervals after stroke, only the GMVs in the cognitive-related brain areas (hippocampus and precuneus) were positively correlated with MI scores, which suggests that the structural reorganization in cognitive-related brain areas may facilitate the recovery of motor function. However, considering the small sample size of this study, further studies are needed to clarify the exact relationships between structural changes and recovery of motor function in stroke patients.


Health Burden of Hansen's Disease in Central India: A 4-Year Retrospective Study.
Despite the implementation of multidrug therapy by WHO to treat Hansen's disease (HD), new case detection rates are still high indicating active transmission. To study the clinical profile of HD in central India along with its epidemiological characteristics. Medical records of clinically diagnosed Hansen's patients were recruited retrospectively during January 2015 to December 2018. Case records were evaluated with respect to demographic, clinical, histopathological, and bacteriological investigations, development of reaction, and deformities. Patients were classified based on Ridley Jopling classification and treated accordingly. Statistical analysis was done using proportion, mean, and percentage. A total of 400 new patients were enrolled and males outnumbered females. Maximum cases, 115 (28.75%), were in the age group of 31-40 years. Sixteen (4%) cases belonged to the pediatric age (less than 18 years) group. Most common clinical spectrum was borderline lepromatous (n = 156, 39%) followed by lepromatous HD (n = 120, 30%). Eleven patients had pure neuritic HD and nine had histoid HD. Grade 2 deformity was found in 52 and grade 1 deformity was found in 16 patients. Most common lepra reaction was type 2 lepra reaction (n = 112, 28%). Thirteen (3.25%) patients were of relapse of HD among which maximum eight were BL HD followed by LL HD three (0.75%) and TT HD two (0.5%). Early diagnosis is very important for timely and proper implementation of treatment which will prevent sequelae and physical disabilities that can have an impact on the individual's social and working life, which are responsible for stigma and prejudice regarding the disease. Detection of this huge number of cases signifies a high burden of HD in this area even in the post elimination era.


Binding of protoporphyrin IX and metal derivatives to the active site of wild-type mouse ferrochelatase at low porphyrin-to-protein ratios.
Resonance Raman (RR) spectroscopy is used to examine porphyrin substrate, product, and inhibitor interactions with the active site of murine ferrochelatase (EC 188.8.131.52), the terminal enzyme in the biosynthesis of heme. The enzyme catalyzes in vivo Fe(2+) chelation into protoporphyrin IX to give heme. The RR spectra of native ferrochelatase show that the protein, as isolated, contains varying amounts of endogenously bound high- or low-spin ferric heme, always at much less than 1 equiv. RR data on the binding of free-base protoporphyrin IX and its metalated complexes (Fe(III), Fe(II), and Ni(II)) to active wild-type protein were obtained at varying ratios of porphyrin to protein. The binding of ferric heme, a known inhibitor of the enzyme, leads to the formation of a low-spin six-coordinate adduct. Ferrous heme, the enzyme's natural product, binds in the ferrous high-spin five-coordinate state. Ni(II) protoporphyrin, a metalloporphyrin that has a low tendency toward axial ligation, becomes distorted when bound to ferrochelatase. Similarly for free-base protoporphyrin, the natural substrate of ferrochelatase, the RR spectra of porphyrin-protein complexes reveal a saddling distortion of the porphyrin. These results corroborate and extend our previous findings that porphyrin distortion, a crucial step of the catalytic mechanism, occurs even in the absence of bound metal substrate. Moreover, RR data reveal the presence of an amino acid residue in the active site of ferrochelatase which is capable of specific axial ligation to metals.


RENATA study-Latin American prospective experience: clinical outcome of patients treated with palbociclib in hormone receptor-positive metastatic breast cancer-real-world use.
In hormone receptor-positive, HER-2 negative (HR+/HER2-) advanced breast cancer (ABC) endocrine therapy (ET) plus cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in first and second line improved progression-free survival (PFS), overall response rate (ORR) and clinical benefit rate (CB) without deterioration in quality of life compared with ET alone. In addition, recent data showed improvement in overall survival (OS) for premenopausal women in first line setting and for different subgroups of patients in second line. Since 2015, in Argentina, the combination of ET with CDK4/6i is a standard of care in HR+/HER2- ABC. We carried out a prospective analysis of real-world use of palbociclib with ET in HR+/HER2- ABC patients who received treatment between October 2015 and August 2019 in two private institutes from Buenos Aires, Argentina. The aims of the study were to determine efficacy and safety of patients treated with ET and palbociclib, describe patient profile and treatment strategy beyond progression. One-hundred and twenty-eight patients were included in the final analysis. Main baseline characteristics include, median age 57 years, 20% were premenopausal women, 44% had visceral metastasis and 26% bone only disease. More than half of patients had two or more metastatic sites, 44.4% had performance status 1, and most of them (59.4%) were treated with palbociclib in first-line setting. Palbociclib was preferentially associated with aromatase inhibitors in 63.9% of patients, and with fulvestrant in the remaining. All premenopausal women received ovarian suppression or ovarian ablation (OS/OA). The median PFS was 36.7 months in first line and 24.2 months in second line. The ORR was 45.3% and 25.0% in first and second line, respectively. The median OS in the entire population was not reached. Half of patients did not require dose interruption and/or delay, dose reduction was required in 15% of patients and almost no patients required drug discontinuation (2.0%). With regard to safety, 55% of patients developed grade 3-4 adverse events, 20% neutropenia grade 3-4, and 7% febrile neutropenia. Infections were presented in one out of three patients, mostly uncomplicated. This is the first prospective evidence of real-world use of palbociclib in a Latin American population. We found similar outcomes to the PALOMA-2 and PALOMA-3 randomised trials and Real-World Data already published, with lower incidence of side effects and treatment discontinuation, but with higher incidence of febrile neutropenia.


Current treatment options for intracerebral hemorrhage.
Intracerebral hemorrhage (ICH) remains the least treatable form of stroke. Despite ongoing attempts to find effective interventions based on the physiopathologic understanding of this disease, evidence-based medical therapies for ICH are limited to recommendations on blood pressure (BP) reduction, intracranial pressure monitoring, osmotherapy with adequate fluid resuscitation, fever and glycemic control, and seizure prophylaxis. Although the value of surgical treatment remains in doubt because of the negative results of the International Surgical Trial in Intracerebral Haemorrhage (STICH), a subgroup analysis of this study suggested better outcomes among patients with superficial hematomas who underwent surgical evacuation, supporting the ongoing STICH-II trial. Other approaches currently under study include ultra-early hemostatic therapy and BP reduction, thrombolytic therapy for intraventricular hemorrhage, and minimally invasive surgical approaches.


Autism-Associated Vigilin Depletion Impairs DNA Damage Repair.
Vigilin (Vgl1) is essential for heterochromatin formation, chromosome segregation, and mRNA stability and is associated with autism spectrum disorders and cancer: vigilin, for example, can suppress proto-oncogene c-fms expression in breast cancer. Conserved from yeast to humans, vigilin is an RNA-binding protein with 14 tandemly arranged nonidentical hnRNP K-type homology (KH) domains. Here, we report that vigilin depletion increased cell sensitivity to cisplatin- or ionizing radiation (IR)-induced cell death and genomic instability due to defective DNA repair. Vigilin depletion delayed dephosphorylation of IR-induced γ-H2AX and elevated levels of residual 53BP1 and RIF1 foci, while reducing Rad51 and BRCA1 focus formation, DNA end resection, and double-strand break (DSB) repair. We show that vigilin interacts with the DNA damage response (DDR) proteins RAD51 and BRCA1, and vigilin depletion impairs their recruitment to DSB sites. Transient hydroxyurea (HU)-induced replicative stress in vigilin-depleted cells increased replication fork stalling and blocked restart of DNA synthesis. Furthermore, histone acetylation promoted vigilin recruitment to DSBs preferentially in the transcriptionally active genome. These findings uncover a novel vigilin role in DNA damage repair with implications for autism and cancer-related disorders.


Facial rehabilitation: a neuromuscular reeducation, patient-centered approach.
Individuals with facial paralysis and distorted facial expressions and movements secondary to a facial neuromotor disorder experience substantial physical, psychological, and social disability. Previously, facial rehabilitation has not been widely available or considered to be of much benefit. An emerging rehabilitation science of neuromuscular reeducation and evidence for the efficacy of facial neuromuscular reeducation, a process of facilitating the return of intended facial movement patterns and eliminating unwanted patterns of facial movement and expression, may provide patients with disorders of facial paralysis or facial movement control opportunity for the recovery of facial movement and function. We provide a brief overview of the scientific rationale for facial neuromuscular reeducation in the structure and function of the facial neuromotor system, the neuropsychology of facial expression, and relations among expressions, movement, and emotion. The primary purpose is to describe principles of neuromuscular reeducation, assessment and outcome measures, approach to treatment, the process, including surface-electromyographic biofeedback as an adjunct to reeducation, and the goal of enhancing the recovery of facial expression and function in a patient-centered approach to facial rehabilitation.


Evidence of vertical transmission of West Nile virus in field-collected mosquitoes.
Male and nulliparous female mosquitoes were surveyed for evidence of vertical WNV infection in East Baton Rouge Parish, Louisiana. Adult male mosquitoes collected by trapping and aspiration, and adult male and nulliparous female mosquitoes reared from field-collected larvae were tested. Adult male Culex spp., female Aedes albopictus (Skuse), and female Culex quinquifasciatus Say mosquitoes that were collected as larvae were test-positive for WNV RNA. Infectious WNV was detected using virus isolation in field-collected male Aedes triseriatus Say and Culex salinarius Coquillett; these data represent the first field evidence of vertical transmission of WNV in Ae. triseriatus and Cx. salinarius.


Structural neurodegeneration correlates with early diabetic retinopathy.
To examine differences in structural and functional neurodegenerative measurements between patients with no and early diabetic retinopathy (DR). In this cross-sectional study, we examined 103 patients with type 2 diabetes mellitus. In 7-field fundus photographs acquired with Topcon TRC-NW6S, a single, certified grader determined the presence of DR according to the Early Treatment Diabetic Retinopathy Study (ETDRS) scale. Retinal neurodegeneration was evaluated by Topcon 3D OCT-2000 spectral domain optical coherence tomography (OCT) and by a RETI-scan multifocal electroretinography (mf-ERG) system in rings 1-6. Median age and duration of diabetes were 63.6 and 10 years, respectively, and 46% were men. Median HbA1c was 50 mmol/mol (6.7%), and ETDRS levels were 10 (41.7%, n = 43), 20 (35.0%, n = 36), and 35 (23.3%, n = 24). The duration of diabetes increased with higher levels of DR (p = 0.04), but patients with different level of DR did not differ according to age, sex, blood pressure, HbA1c, and mf-ERG or OCT parameters. In a multiple logistic regression model, macular ganglion cell layer thickness was associated with the presence of DR (OR 1.73 per 5 μm increase, 95% CI 1.06-2.85, p = 0.03). Conversely, retinal nerve fibre layer thickness at optic disc was inversely related to DR (OR 0.69 per 5 μm increase, 95% CI 0.51-0.95, p = 0.02). There were no associations between DR and mf-ERG outcomes. In patients with type 2 diabetes, structural neurogenic characteristics were associated with DR. If confirmed by larger prospective studies, these results may indicate that a complex neurovascular interaction is an early event in the pathogenesis of DR.