Consumer Feedback following Participation in a Family-Based Intervention for Youth Mental Health.
Background. This paper presents findings derived from consumer feedback, following a multicentre randomised controlled trial for adolescent mental health problems and substance misuse. The paper focuses on the implementation of a family-based intervention, including fidelity of delivery, family members' experiences, and their suggestions for program improvements. Methods. Qualitative and quantitative data (n = 21) were drawn from the Deakin Family Options trial consumer focus groups, which occurred six months after the completion of the trial. Consumer focus groups were held in both metropolitan and regional locations in Victoria, Australia. Findings. Overall reductions in parental isolation, increases in parental self-care, and increased separation/individuation were the key therapeutic features of the intervention. Sharing family experiences with other parents was a key supportive factor, which improved parenting confidence and efficacy and potentially reduced family conflict. Consumer feedback also led to further development of the intervention, with a greater focus on aiding parents to engage adolescents in services and addressing family factors related to adolescent's mood and anxiety symptoms. Conclusions. Participant feedback provides valuable qualitative data, to monitor the fidelity of treatment implementation within a trial, to confirm predictions about the effective mechanisms of an intervention, and to inform the development of new interventions.


Automated segmentation and quantification of white matter hyperintensities in acute ischemic stroke patients with cerebral infarction.
White matter hyperintensities (WMHs) of presumed vascular origin are common in ageing population, especially in patients with acute cerebral infarction and the volume has been reported to be associated with mental impairment and the risk of hemorrhage from antithrombotic agents. WMHs delineation can be computerized to minimize human bias. However, the presence of cerebral infarcts greatly degrades the accuracy of WMHs detection and thus limits the application of computerized delineation to patients with acute cerebral infarction. We propose a computer-assisted segmentation method to depict WMHs in the presence of cerebral infarcts in combined T1-weighted, fluid attenuation inversion recovery, and diffusion-weighted magnetic resonance imaging (MRI). The proposed method detects WMHs by empirical threshold and atlas information, with subtraction of white matter voxels affected by acute infarction. The method was derived using MRI from 25 hemispheres with WMHs only and 13 hemispheres with both WMHs and cerebral infarcts. Similarity index (SI) and correlation were utilized to assess the agreement between the new automated method and a gold standard visually guided semi-automated method done by an expert rater. The proposed WMHs segmentation approach produced average SI, sensitivity and specificity of 83.142±11.742, 84.154±16.086 and 99.988±0.029% with WMHs only and of 68.826±14.036, 74.381±18.473 and 99.956±0.054% with both WMHs and cerebral infarcts in the derivation cohort. The performance of the proposed method with an external validation cohort was also highly consistent with that of the experienced rater.


Combining clinical and magnetic resonance imaging markers enhances prediction of 12-year employment status in multiple sclerosis patients.
Multiple sclerosis (MS) is frequently diagnosed in the most productive years of adulthood and is often associated with worsening employment status. However, reliable predictors of employment status change are lacking. To identify early clinical and brain magnetic resonance imaging (MRI) markers of employment status worsening in MS patients at 12-year follow-up. A total of 145 patients with early relapsing-remitting MS from the original Avonex-Steroids-Azathioprine (ASA) study were included in this prospective, longitudinal, observational cohort study. Cox models were conducted to identify MRI and clinical predictors (at baseline and during the first 12 months) of worsening employment status (patients either (1) working full-time or part-time with no limitations due to MS and retaining this status during the course of the study, or (2) patients working full-time or part-time with no limitations due to MS and switching to being unemployed or working part-time due to MS). In univariate analysis, brain parenchymal fraction, T1 and T2 lesion volume were the best MRI predictors of worsening employment status over the 12-year follow-up period. MS duration at baseline (hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.03-1.18; p = 0.040) was the only significant clinical predictor. Having one extra milliliter of T1 lesion volume was associated with a 53% greater risk of worsening employment status (HR = 1.53, 95% CI 1.16-2.02; p = 0.018). A brain parenchymal fraction decrease of 1% increased the risk of worsening employment status by 22% (HR = 0.78, 95% CI 0.65-0.95; p = 0.034). Brain atrophy and lesion load were significant predictors of worsening employment status in MS patients. Using a combination of clinical and MRI markers may improve the early prediction of an employment status change over long-term follow-up.


Piezofluorochromic Metal-Organic Framework: A Microscissor Lift.
We have successfully constructed a metal-organic framework, denoted as PCN-128W, starting from chromophoric linker and zirconium salt. PCN-128W exhibits interesting piezofluorochromic behavior, the color reversibly changes from white to yellow and so does the emission maximum from 470 to 538 nm. The stepwise fluorescence change was monitored by fluorospectroscopy which demonstrated gradual shift of the emission maximum when sequential compression was exerted. In order to gain deep insights into the piezofluorochromic mechanism, both the white and yellow phases are structurally characterized.


Immediate dilation in esophageal food impaction is safe and effective but performed infrequently: observations from a large Midwest US cohort.
This study aimed to determine the rate and safety of immediate esophageal dilation for esophageal food bolus impaction (EFBI) and evaluate its impact on early recurrence (i.e. prior to interval esophageal dilation) from a large Midwest US cohort. We also report practice patterns among community and academic gastroenterologists practicing in similar settings. We identified adult patients with a primary discharge diagnosis for EFBI from January 2012 to June 2018 using our institutional database. Pregnant patients, incarcerated patients, and patients with esophageal neoplasm were excluded. The primary outcome measured was rate of complications with immediate esophageal dilation after disimpaction of EFBI. Secondary outcomes were recurrence of food bolus impaction prior to scheduled interval endoscopy for dilation, practice patterns between academic and private gastroenterologists, and adherence to follow-up endoscopy. Two-hundred and fifty-six patients met our inclusion criteria. Esophageal dilation was performed in 46 patients (18%) at the time of disimpaction. A total of 45 gastroenterologists performed endoscopies for EFBI in our cohort. Twenty-five (62%) did not perform immediate esophageal dilation, and only 5 (11%) performed immediate dilation on greater than 50% of cases. Academic gastroenterologists performed disimpaction of EFBI for 102 patients, immediate dilation as performed in 20 patients and interval dilation was recommended in 82 patients. Of these 82, only 31 patients (38%) did not return for interval dilation. Four patients who did not undergo immediate dilation, presented with recurrent EFBI prior to interval dilation, within 3 months. None of the patients had complications. Complications with immediate esophageal dilation after disimpaction of EFBI are infrequent but are rarely performed. Failure of immediate dilation increases the risk of EFBI recurrence. Given poor patient adherence to interval dilation, immediate dilation is recommended.


Preparation of goat and rabbit anti-camel immunoglobulin G whole molecule labeled with horseradish peroxidase.
As the labeled anti-camel immunoglobulins (Igs) with enzymes for enzyme-linked immunosorbent assay (ELISA) are unavailable in the Egyptian market, the present investigation was directed for developing local labeled anti-camel IgG with horseradish peroxidase (HRP) to save hard curacy. For purification of camel IgG whole molecule, camel sera was preliminary precipitated with 50% saturated ammonium sulfate and dialyzed against 15 mM phosphate-buffered saline pH 7.2 then concentrated. This preparation was further purified by protein A sepharose affinity column chromatography. The purity of the eluted camel IgG was tested by sodium dodecyl sulfate polyacrylamide gel electrophoresi. Anti-camel IgG was prepared by immunization of goats and rabbits separately, with purified camel IgG. The anti-camel IgG was purified by protein A sepharose affinity column chromatography. Whole molecule anti-camel IgG was conjugated with HRP using glutraldehyde based assay. Sensitivity and specificity of prepared conjugated secondary antibodies were detected using positive and negative camel serum samples reacted with different antigens in ELISA, respectively. The potency of prepared conjugated antibodies was evaluated compared with protein A HRP. The stability of the conjugate at -20°C during 1 year was assessed by ELISA. The electrophoretic profile of camel IgG showed four bands of molecular weight 63, 52, 40 and 33 kDa. The recorded sensitivity and specificity of the product are 100%. Its potency is also 100% compared to 58-75% of commercial protein A HRP. The conjugates are stable for 1 year at -20°C as proved by ELISA. Collectively, this study introduces goat and rabbit anti-camel IgG whole molecules with simple, inexpensive method, with 100% sensitivity, 100% specificity and stability up to 1 year at -20°C. The important facet of the current study is saving hard curacy. Future investigations are necessary for preparation of IgG subclasses.


Assessing the comparative feasibility, acceptability and equivalence of videoconference interviews and face-to-face interviews using the time trade-off technique.
This study examines the comparative equivalence, feasibility and acceptability of video and in-person interviews in generating time trade-off (TTO) values. Sample participants in England were recruited using a blended approach of different methods and sampled based on age, gender, ethnicity, and index of multiple deprivation. Participants were randomly allocated to be interviewed either via video or in-person. Participants completed TTO tasks for the same block of 10 EQ-5D-5L health states using the EQ-VTv2 software. Feasibility, acceptability and equivalence was assessed across mode using: sample representativeness; participant understanding, engagement and feedback; participant preferred mode of interview; data quality; mean utility and distribution of values for each health state; and regression analyses assessing the impact of mode whilst controlling for participant characteristics. The video and in-person samples had statistically significant differences in ethnicity and income but were otherwise broadly similar. Video interviews generated marginally lower quality data across some criteria. Participant understanding and feedback was positive and similar across modes. TTO values were similar across modes; whilst mean in-person TTO values were lower for the more severe states, mode was insignificant in most regression analyses. There was no clear preference of mode across all participants, though the characteristics of participants preferring to be interviewed in-person or by video differs. Video and in-person TTO interviews were feasible, acceptable and generated good-quality data, though video interviews had lower quality data across some criteria. Whilst TTO values differed across modes for the more severe states, mode does not appear to be the cause. The study found that the characteristics of people preferring each mode differed, and this should be taken into account in future valuation studies since sample representativeness for some characteristics, and therefore potentially TTO values, could be affected by the choice of mode.


A central role for amyloid fibrin microclots in long COVID/PASC: origins and therapeutic implications.
Post-acute sequelae of COVID (PASC), usually referred to as 'Long COVID' (a phenotype of COVID-19), is a relatively frequent consequence of SARS-CoV-2 infection, in which symptoms such as breathlessness, fatigue, 'brain fog', tissue damage, inflammation, and coagulopathies (dysfunctions of the blood coagulation system) persist long after the initial infection. It bears similarities to other post-viral syndromes, and to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Many regulatory health bodies still do not recognize this syndrome as a separate disease entity, and refer to it under the broad terminology of 'COVID', although its demographics are quite different from those of acute COVID-19. A few years ago, we discovered that fibrinogen in blood can clot into an anomalous 'amyloid' form of fibrin that (like other β-rich amyloids and prions) is relatively resistant to proteolysis (fibrinolysis). The result, as is strongly manifested in platelet-poor plasma (PPP) of individuals with Long COVID, is extensive fibrin amyloid microclots that can persist, can entrap other proteins, and that may lead to the production of various autoantibodies. These microclots are more-or-less easily measured in PPP with the stain thioflavin T and a simple fluorescence microscope. Although the symptoms of Long COVID are multifarious, we here argue that the ability of these fibrin amyloid microclots (fibrinaloids) to block up capillaries, and thus to limit the passage of red blood cells and hence O2 exchange, can actually underpin the majority of these symptoms. Consistent with this, in a preliminary report, it has been shown that suitable and closely monitored 'triple' anticoagulant therapy that leads to the removal of the microclots also removes the other symptoms. Fibrin amyloid microclots represent a novel and potentially important target for both the understanding and treatment of Long COVID and related disorders.


Possible health effects of caffeinated coffee consumption on Alzheimer's disease and cardiovascular disease.
Coffee has been known to have both beneficial and harmful effects upon health. Coffee is one of the most widely consumed beverages, worldwide. Dementia/Alzheimer's disease (AD) and cardiovascular disease (CVD) are public health problems that are rapidly increasing in the aging population. Due to the high consumption of coffee, even small effects on an individual's health could have a large effect on public health.The aim of this review article is to provide an overview of previously published studies of coffee consumption on health. Herein, we focus on epidemiological and experimental findings to investigate whether coffee-drinking habits, and/or the quantity of coffee consumption, have any relationship to CVD, dementia/AD, and other chronic diseases. Although the underlying mechanisms are not fully understood, when comparing coffee drinkers with non-drinkers, moderate doses of caffeine showed protective effects against CVD and AD. We hypothesized that caffeine may be a novel therapy to treat CVD and dementia/AD.


Native point defects in CuIn(1-x)Ga(x)Se2: hybrid density functional calculations predict the origin of p- and n-type conductivity.
We have performed a first-principles study of the p- and n-type conductivity in CuIn(1-x)Ga(x)Se2 due to native point defects, based on the HSE06 hybrid functional. Band alignment shows that the band gap becomes larger with x due to the increasing conduction band minimum, rendering it hard to establish n-type conductivity in CuGaSe2. From the defect formation energies, we find that In/GaCu is a shallow donor, while V(Cu), V(In/Ga) and Cu(In/Ga) act as shallow acceptors. Using the total charge neutrality of ionized defects and intrinsic charge carriers to determine the Fermi level, we show that under In-rich growth conditions InCu causes strongly n-type conductivity in CuInSe2. Under increasingly In-poor growth conditions, the conductivity type in CuInSe2 alters to p-type and compensation of the acceptors by In(Cu) reduces, as also observed in photoluminescence experiments. In CuGaSe2, the native acceptors pin the Fermi level far away from the conduction band minimum, thus inhibiting n-type conductivity. On the other hand, CuGaSe2 shows strong p-type conductivity under a wide range of Ga-poor growth conditions. Maximal p-type conductivity in CuIn(1-x)Ga(x)Se2 is reached under In/Ga-poor growth conditions, in agreement with charge concentration measurements on samples with In/Ga-poor stoichiometry, and is primarily due to the dominant acceptor Cu(In/Ga).


A study of performance of delayed intentions in multiple sclerosis.
The ability to remember and perform delayed intentions was investigated in a sample of 40 participants with Multiple Sclerosis (MS) and compared to a group of 36 healthy, neurologically intact, control participants. Using a model of task division, performance on both the prospective memory (PM) component (a failure to remember to do something at a specific time) and the retrospective memory (RM) component (a failure to remember the content of the intention) of two "naturalistic" delayed intention experimental tasks were examined. Significantly poorer performance of the MS group in completing one of the delayed intention tasks successfully appeared to be primarily attributable to retrospective memory deficits rather than prospective memory deficits. This proposition was further supported by group differences on RAVLT measures of retrospective memory. By utilising a paradigm that enables the nature of failure in performing delayed intention tasks to be identified, specific strategies for the clinical management of MS cognitive deficits can be developed.


Exercise tolerance in children with juvenile idiopathic arthritis after autologous SCT.
Children with juvenile idiopathic arthritis (JIA) often have significant physical impairment. A minority is unresponsive to combinations of medications, and a possible treatment of resistant JIA is intense immunosuppression followed by autologous hematopoietic SCT (ASCT). Children resistant to conventional therapy have a poor prognosis with regard to long-term outcome of joint function, exercise tolerance and quality of life. It has previously been shown that ASCT can induce long-term remissions in such children. The long-term effects of this treatment are still largely unknown. This retrospective study investigates the exercise tolerance and functional ability in children with JIA who have undergone ASCT compared to healthy subjects. Ten children with JIA who received ASCT between 1997 and 2003 participated in this study. Patients were tested during their regular clinical follow-up. Exercise tolerance was determined using a maximal exercise test. Functional ability was measured using the Childhood Health Assessment Questionnaire and joint status. The study group showed significantly reduced exercise tolerance compared to healthy subjects. Functional ability and joint status were also decreased in patients after ASCT. Children with JIA postASCT have impaired exercise tolerance even 9 years postASCT.


Ceftriaxone-induced hemolytic anemia in a child successfully managed with intravenous immunoglobulin.
Drug-induced hemolytic anemia is an immune-mediated phenomenon that leads to the destruction of red blood cells. Here, we present a case of life-threatening ceftriaxone-induced hemolytic anemia (CIHA) in a previously healthy 3-year-old girl. We also reviewed the literature to summarize the clinical features and treatment of hemolytic anemia. Acute hemolysis is a rare side effect of ceftriaxone therapy associated with high mortality. Our patient had a sudden loss of consciousness with macroscopic hematuria and her hemoglobin dropped from 10.2 to 2.2 g/dl over 4 hours, indicating that the patient had life-threatening hemolysis after an intravascular dose of ceftriaxone who had previously been treated with ceftriaxone in intramuscular form for six days. CIHA is associated with a positive direct antiglobulin test, revealing the presence of IgG in all cases and C3d in most cases. Our patient's direct antiglobulin test was positive for IgG (3+) and for C3d (4+). The case was managed successfully with supportive measures and intravenous immunoglobulin therapy. Ceftriaxone is used very frequently in children; an early diagnosis and proper treatment of hemolytic anemia are essential to improve the patient outcome. The pathophysiological mechanism is the same as for non-drug autoimmune hemolytic anemia. However, there is still no consensus treatment for CIHA. Intravenous immunoglobulin can be used in clinical emergencies, such as our case, or in refractory cases.


Hypertriglyceridemia-Induced Pancreatitis With Rapid Response to Insulin Therapy.
Acute pancreatitis (AP) is one of the most common gastrointestinal-related causes of hospitalization in the USA, accounting for more than 200,000 admissions annually. Although mild and moderate cases usually improve within a week, severe AP conditions could lead to life-threatening pancreatic necrosis, multiple-organ dysfunction, and be fatal in some cases. Excessive alcohol use and gallstones are the two leading causes, nonetheless other systemic complication could also lead to AP. Hypertriglyceridemia is an important, yet uncommon, cause/risk factor of AP, especially when associated with heavy alcohol use. Additionally, the level of triglycerides (TGs) was found to be an important factor of determining the method and duration of treatment. Here we present a case of 38-year-old obese and active smoker male with hypertension and alcohol use disorder presented with a chief complaint of 2 weeks of progressive sharp epigastric pain. His medical history was significant of opioid use disorder that is maintained on methadone therapy. Computed tomography (CT) scan of the abdomen and pelvis revealed infiltration of the fat along the pancreatic tail and distal body with focus of decreased enhancement in the very distal pancreatic tail, which could represent a small infarct or phlegmon. In addition, laboratory data was significant of elevated lipase level (> 1,000 mg/dL), which together with the CT result confirmed the diagnosis of AP. Additional laboratory workup revealed extremely high level of TGs of > 2,000 mg/dL. The patient was subsequently transferred to the intensive care unit for management of hypertriglyceridemia. He was started on insulin therapy along with supportive treatment for the management of pancreatitis. Hypertriglyceridemia and pancreatitis rapidly improved over the course of hospitalization period and no additional intervention was needed. He was successfully discharged on fenofibrate.


Image reversal reactive immersion lithography improves the detection limit of focal molography.
Focal molography is a label-free optical biosensing method that relies on a coherent pattern of binding sites for biomolecular interaction analysis. Reactive immersion lithography (RIL) is central to the patterning of molographic chips but has potential for improvements. Here, we show that applying the idea of image reversal to RIL enables the fabrication of coherent binding patterns of increased quality (i.e., higher analyte efficiency). Thereby the detection limit of focal molography in biological assays can be improved.


An Easy and Flexible Inoculation Method for Accurately Assessing Powdery Mildew-Infection Phenotypes of Arabidopsis and Other Plants.
Reducing crop losses due to fungal diseases requires improved understanding of the mechanisms governing plant immunity and fungal pathogenesis, which in turn requires accurate determination of disease phenotypes of plants upon infection with a particular fungal pathogen. However, accurate disease phenotyping with unculturable biotrophic fungal pathogens such as powdery mildew is not easy to achieve and can be a rate-limiting step of a research project. Here, we have developed a safe, efficient, and easy-to-operate disease phenotyping system using the Arabidopsis-powdery mildew interaction as an example. This system mainly consists of three components: (i) a wooden inoculation box fitted with a removable lid mounted with a stainless steel or nylon mesh of ~50 µm pores for inoculating a flat of plants with fungal spores, (ii) a transparent plastic chamber with a small front opening for minimizing spore escape while conducting inoculation inside, and (iii) a spore-dislodging and distribution method for even and effective inoculation. The protocols described here include the steps and parameters for making the inoculation box and the plastic chamber at a low cost, and a video demonstration of how to use the system to enable even inoculation with powdery mildew spores, thereby improving accuracy and reproducibility of disease phenotyping.


Donor and recipient IL28B polymorphisms in HCV-infected patients undergoing antiviral therapy before and after liver transplantation.
IL28B gene polymorphisms are associated with the response to antiviral therapy in hepatitis C patients. We investigated the influence of IL28B polymorphisms on the response to therapy before and after liver transplantation (LT). Genotyping of SNPs rs8099917 and rs12979860 was performed in 128 HCV-infected liver transplant recipients and in their donors; all patients underwent antiviral treatment after LT. The prevalence of genotypes rs12979860CC and rs8099917TT was higher in donors than in recipients (50% vs.19%, p < 0.001 and 67% vs. 38%, p < 0.001, respectively). Response to antiviral therapy was significantly higher for recipient genotype rs12979860CC as compared to rs12979860CT/TT both before (100% vs. 48% p = 0.013) and after LT (59% vs. 25% p = 0.002). The figures were almost identical for SNP rs8099917. Sustained virological response after LT was particularly high in patients with favorable recipient and donor genotypes (p < 0.01 for both SNPs). In a subgroup of 34 patients treated while awaiting LT, a favorable donor IL28B genotype was associated with an improved virological response after LT. Our results support a major role of recipient IL28B genotype in the response to antiviral treatment for hepatitis C recurrence. Interestingly, donor genotype also seems to influence the response pattern, especially in recipients who have a favorable IL28B genotype.


Genome-wide methylomic analysis of monozygotic twins discordant for adolescent depression.
Adolescent depression is a common neuropsychiatric disorder that often continues into adulthood and is associated with a wide range of poor outcomes including suicide. Although numerous studies have looked at genetic markers associated with depression, the role of epigenetic variation remains relatively unexplored. Monozygotic (MZ) twins were selected from an adolescent twin study designed to investigate the interplay of genetic and environmental factors in the development of emotional and behavioral difficulties. There were 18 pairs of MZ twins identified in which one member scored consistently higher (group mean within the clinically significant range) on self-rated depression than the other. We assessed genome-wide patterns of DNA methylation in twin buccal cell DNA using the Infinium HumanMethylation450 BeadChip from Illumina. Quality control and data preprocessing was undertaken using the wateRmelon package. Differentially methylated probes (DMPs) were identified using an analysis strategy taking into account both the significance and the magnitude of DNA methylation differences. The top differentially methylated DMP was successfully validated by bisulfite-pyrosequencing, and identified DMPs were tested in postmortem brain samples obtained from patients with major depressive disorder (n = 14) and matched control subjects (n = 15). Two reproducible depression-associated DMPs were identified, including the top-ranked DMP that was located within STK32C, which encodes a serine/threonine kinase, of unknown function. Our data indicate that DNA methylation differences are apparent in MZ twins discordant for adolescent depression and that some of the disease-associated variation observed in buccal cell DNA is mirrored in adult brain tissue obtained from individuals with clinical depression.


Insights into the Microstructures and Energy Levels of Pr3+-Doped YAlO3 Scintillating Crystals.
Trivalent praseodymium (Pr3+)-doped materials have been extensively used in high-resolution laser spectroscopy, owing to their outstanding conversion efficiencies of plentiful transitions in the visible laser region. However, to clarify the microstructure and energy transfer mechanism of Pr3+-doped host crystals is a challenging topic. In this work, the stable structures of Pr3+-doped yttrium orthoaluminate (YAlO3) have been widely searched based on the CALYPSO method. A novel monoclinic structure with the Pm group symmetry is successfully identified. The Pr3+ impurity can precisely occupy the Y3+ position and get incorporated into the YAlO3 (YAP) host crystal with a Pr3+ concentration of 6.25%. The result of the electronic band structure reveals a 3.62 eV band gap, which suggests a semiconductor character of YAP:Pr. Using our developed well-established parametrization matrix diagonalization (WEPMD) method, we have systematically analyzed the energy level scheme and proposed a set of newly improved parameters. Additionally, the energy transfer mechanism of YAP:Pr is clarified by deciphering the numerical electric dipole and magnetic dipole transitions. The popular red emission at 653 nm is assigned to the transition 3P0 → 3F2, while the transition 3P0 → 3H4 with a large branching ratio is predicted to be a good laser channel. Many promising emission lines for laser actions are also obtained in the visible light region. Our results not only provide important insights into the energy transfer mechanisms of rare-earth ion-doped materials but also pave the way for the implementation of new types of laser devices.


Random Subspace Ensemble Learning for Functional Near-Infrared Spectroscopy Brain-Computer Interfaces.
The feasibility of the random subspace ensemble learning method was explored to improve the performance of functional near-infrared spectroscopy-based brain-computer interfaces (fNIRS-BCIs). Feature vectors have been constructed using the temporal characteristics of concentration changes in fNIRS chromophores such as mean, slope, and variance to implement fNIRS-BCIs systems. The mean and slope, which are the most popular features in fNIRS-BCIs, were adopted. Linear support vector machine and linear discriminant analysis were employed, respectively, as a single strong learner and multiple weak learners. All features in every channel and available time window were employed to train the strong learner, and the feature subsets were selected at random to train multiple weak learners. It was determined that random subspace ensemble learning is beneficial to enhance the performance of fNIRS-BCIs.


Sex-related growth differences are present but not enhanced in in vitro fertilization pregnancies.
To determine whether IVF modifies the effect of fetal sex on growth. Retrospective cohort study. Tertiary care center and related facilities. Singleton live births without fetal/maternal comorbidities from fertile women who conceived without the use of assisted reproductive technologies and infertile women who conceived with IVF. None. The primary outcome was birth weight (BW). Secondary outcomes were fetal crown-rump length (CRL) in the first trimester, biparietal diameter (BPD), and estimated fetal weight (EFW) in the second trimester. There were no differences in baseline characteristics between women carrying male fetuses and those carrying female fetuses in either mode of conception. In unadjusted analyses, the male-female differentials in fetal BPD and BW were more pronounced in the IVF cohort than in the unassisted cohort. In multivariable regression analysis, male BPD exceeded female BPD by 0.12 cm, male EFW exceeded female EFW by 12 g, and male BW exceeded female BW by 172 g. IVF did not have a significant effect on BPD but was associated with a 52 g increase in EFW in the midgestation. IVF was associated with an 81-g reduction in BW. IVF did not modify the magnitude of size differences between the sexes in the midgestation or at birth. Comparable sex-dependent differential growth occurs in unassisted and IVF pregnancies.


Changes in prescription pattern, pharmaceutical expenditure and quality of care after introduction of reimbursement restriction in diabetes in Korea.
To ensure effective prescription practices and reduce diabetes-related pharmaceutical expenditures, Korea adopted a clinical practice guideline for the reimbursement system. Health care providers cannot receive reimbursement from National Health Insurance(NHI) unless it is for an appropriate prescription under the predefined clinical condition. The aim of this study was to evaluate prescription patterns in oral hypoglycemic agents, costs and effects on patient care since the introduction of the diabetes reimbursement restriction. We used claim data from 2008 to 2013, which included 26 315 diabetes patients and 9907 hospitals. An interrupted time series study design using generalized estimating equations was used to evaluate changes in patterns of single and combination therapy, brand name drug prescriptions, cost and hospital admission following the reimbursement restriction. Following reimbursement restriction initiation, we found a statistically significant decrease in the average prescription rate of brand name drugs (-6.2%), whereas single therapy prescription increased (9.9%). There was also a reduction in trend change in the monthly prescription rate for combination therapy (-1.7%) and brand name drugs (-0.8%). For single therapy, the trend change in prescription rate increased after the intervention (0.8%). A reduction of trend change in pharmaceutical costs (-0.3%) was observed. However, we did not find a significant change in hospital admission for diabetes. Reimbursement restriction affects both pharmaceutical costs and physicians' decisions to prescribe oral hypoglycemic agents. We did not observe a significant reduction in quality of care following the intervention. Collectively, these findings indicate that reimbursement restriction has improved effective drug utilization and decreased health expenditures.


Building mental health workforce capacity through training and retention of psychiatrists in Zimbabwe.
Despite the need to improve the quantity and quality of psychiatry training in sub-Saharan Africa (SSA), very little is known about the experiences of psychiatric trainees in the region. This is the first study examining psychiatric trainees in a low-income country in SSA. It was carried out as part of the needs assessment for a unique Medical Education Partnership Initiative (MEPI) programme to find African solutions for medical shortages in Africa. We approached all doctors who had trained in post-graduate psychiatry in Zimbabwe in 2010 and conducted in-depth qualitative interviews with all except one (n = 6). We analysed the data using constant comparison and thematic analysis. Trainees described the apprenticeship model as the programme's primary strength, through providing clinical exposure and role models. Programme weaknesses included shortages in information sources, trainee salaries, trainers, public health education, and in the mental health service. Most respondents were, however, eager to continue practising psychiatry in Zimbabwe, motivated by family ties, national commitment and helping vulnerable, stigmatized individuals. Respondents called for sub-speciality training and for infrastructure and training to do research. Resources need to be made available for psychiatric trainees in more SSA settings to develop public health competencies. However, investment in psychiatry training programmes must balance service provision with trainees' educational needs. Directing investment towards needs identified by trainees may be a cost-effective, context-sensitive way to increase retention and learning outcomes.


Correspondence between food consistency and suprahyoid muscle activity, tongue pressure, and bolus transit times during the oropharyngeal phase of swallowing.
This study aimed to evaluate the effects of food texture and viscosity on the swallowing function by measuring tongue pressure and performing a videofluorographic (VF) examination. Eleven normal adults were recruited for this study. Test foods with different consistencies and liquid contents, i.e., a half-solid nutrient made of 0.8 and 1.5% agar powder, syrup, and a liquid containing 40 wt/vol% barium sulfate, were swallowed, and the anterior (AT) and posterior tongue pressures (PT) and electromyographic (EMG) activity of the suprahyoid muscles were recorded, together with VF images. The timing of each event obtained from EMG, tongue pressure, and VF recordings was measured and then compared. We found that the AT and PT activity patterns were similar and showed a single peak. The peak, area, and time duration of all of the variables for AT and PT and EMG burst increased with increasing hardness of the bolus. The onset of the EMG burst always preceded those of the AT and PT activities, while there were no significant differences in peak and offset times among EMG burst, AT, and PT. Total swallowing time and oral ejection time were significantly longer during the swallowing of 1.5% agar than any other boluses, while pharyngeal transit time and clearance time were significantly longer during the swallowing of syrup, which was as hard as the liquid, but showed a higher viscosity than the liquid. The results suggested that the major effects of food hardness were to delay oral ejection time, which strongly delays total swallowing time. In addition, pharyngeal bolus transit is not dependent on the hardness of food but on its viscosity.


Neuromedin B and gastrin-releasing peptide mRNAs are differentially distributed in the rat nervous system.
The bombesin-like peptides are a family of structurally related amidated peptide ligands that are known to have a variety of potent pharmacological actions on various cells, including neurons in the rat brain. Two mammalian representatives of the bombesin family of peptides have been identified, gastrin-releasing peptide (GRP) and neuromedin B (NMB). Previously, we cloned the rat preproGRP gene and determined the locations of neurons expressing this gene using in situ hybridization. In this study, we describe the structure and sequence of the rat preproNMB gene, and the first detailed cellular localization of preproNMB mRNA in rat brain using in situ hybridization. Nucleotide sequence analysis of cDNA and genomic clones reveals a 117 amino acid precursor whose overall structure is similar to that described for human preproNMB. Sequence similarity between the rat NMB and GRP genes is observed only over a limited 10 amino acid sequence encoding the carboxy termini of the GRP and NMB peptides, the region shown to be necessary and sufficient for high-affinity receptor binding. In situ hybridization studies performed with cRNA probes specific for NMB or GRP mRNA show that the distribution of cells expressing either mRNA in brain is very distinct. NMB mRNA is found most prominently in the olfactory bulb, dentate gyrus, and dorsal root ganglion. In contrast, the highest levels of GRP mRNA are observed in the forebrain (isocortex and hippocampal formation). This heterogeneity of mRNA distribution for these peptides suggests that these 2 structurally related peptides may have very distinct functions as neuropeptides in the rat nervous system.


Biological response to prosthetic debris.
Joint arthroplasty had revolutionized the outcome of orthopaedic surgery. Extensive and collaborative work of many innovator surgeons had led to the development of durable bearing surfaces, yet no single material is considered absolutely perfect. Generation of wear debris from any part of the prosthesis is unavoidable. Implant loosening secondary to osteolysis is the most common mode of failure of arthroplasty. Osteolysis is the resultant of complex contribution of the generated wear debris and the mechanical instability of the prosthetic components. Roughly speaking, all orthopedic biomaterials may induce a universal biologic host response to generated wear débris with little specific characteristics for each material; but some debris has been shown to be more cytotoxic than others. Prosthetic wear debris induces an extensive biological cascade of adverse cellular responses, where macrophages are the main cellular type involved in this hostile inflammatory process. Macrophages cause osteolysis indirectly by releasing numerous chemotactic inflammatory mediators, and directly by resorbing bone with their membrane microstructures. The bio-reactivity of wear particles depends on two major elements: particle characteristics (size, concentration and composition) and host characteristics. While any particle type may enhance hostile cellular reaction, cytological examination demonstrated that more than 70% of the debris burden is constituted of polyethylene particles. Comprehensive understanding of the intricate process of osteolysis is of utmost importance for future development of therapeutic modalities that may delay or prevent the disease progression.


Web-based versus paper administration of common ophthalmic questionnaires: comparison of subscale scores.
To compare participants' responses to Web-based and paper-and-pencil versions of an ophthalmic, patient-reported outcome (PRO) questionnaire. Questionnaire development. Matched subjects with ocular surface disease (OSD) (n = 68) and without OSD (controls, n = 50). Subjects completed a standard, paper-and-pencil and a Web-based version of the same questionnaire in randomized order. The administered questionnaire included several ophthalmic PRO subscales: the National Eye Institute's (NEI's) Refractive Error Quality of Life Instrument's Clarity of Vision, Near Vision, Far Vision, Glare, Symptoms, Worry, and Satisfaction with Correction subscales; the Ocular Surface Disease Index's (OSDI's) Symptoms subscale; and the NEI's Visual Function Questionnaire's Driving subscale. Possible scores for each subscale ranged from 0 (no difficulty) to 100 (most difficulty). Agreement of subscale scores between modes of administration was assessed using the Bland-Altman approach and multivariable logistic regression. Subscale scores and an unweighted average total score for each mode of administration. Mean differences in scores between modes of administration ranged from -2.1 to +2.3 units. Although no differences were found to be statistically significant, the Worry and Satisfaction with Correction subscales approached statistical significance (P = 0.07 and 0.08, respectively). Although most subscale mean differences in score did not differ significantly by gender, age (≥40 vs. <40 years), disease status (OSD vs. control), order of administration, or time between completion of the questionnaires, women had slightly greater score differences than men for the Driving (P = 0.04) and Clarity of Vision (P = 0.03) subscales; those with OSD had greater score differences for Clarity of Vision than did controls (P = 0.0006); and those aged ≥40 years had slightly greater differences in OSDI Symptoms subscale than those aged <40 years (P = 0.04). To our knowledge, this Food and Drug Administration and NEI collaboration is the first study to evaluate the equivalence of Web-based and paper versions of ophthalmic PRO questionnaires. We found no evidence of clinically significant differences between scores obtained by the 2 modes for any of the examined subscales. A Web-based instrument should yield scores equivalent to those obtained by standard methods, providing a useful tool that may facilitate ophthalmic innovation. The author(s) have no proprietary or commercial interest in any materials discussed in this article.


Three dimensional single molecule localization using a phase retrieved pupil function.
Localization-based superresolution imaging is dependent on finding the positions of individual fluorophores in a sample by fitting the observed single-molecule intensity pattern to the microscope point spread function (PSF). For three-dimensional imaging, system-specific aberrations of the optical system can lead to inaccurate localizations when the PSF model does not account for these aberrations. Here we describe the use of phase-retrieved pupil functions to generate a more accurate PSF and therefore more accurate 3D localizations. The complex-valued pupil function contains information about the system-specific aberrations and can thus be used to generate the PSF for arbitrary defocus. Further, it can be modified to include depth dependent aberrations. We describe the phase retrieval process, the method for including depth dependent aberrations, and a fast fitting algorithm using graphics processing units. The superior localization accuracy of the pupil function generated PSF is demonstrated with dual focal plane 3D superresolution imaging of biological structures.


Atomic inner-shell X-ray laser at 1.46 nanometres pumped by an X-ray free-electron laser.
Since the invention of the laser more than 50 years ago, scientists have striven to achieve amplification on atomic transitions of increasingly shorter wavelength. The introduction of X-ray free-electron lasers makes it possible to pump new atomic X-ray lasers with ultrashort pulse duration, extreme spectral brightness and full temporal coherence. Here we describe the implementation of an X-ray laser in the kiloelectronvolt energy regime, based on atomic population inversion and driven by rapid K-shell photo-ionization using pulses from an X-ray free-electron laser. We established a population inversion of the Kα transition in singly ionized neon at 1.46 nanometres (corresponding to a photon energy of 849 electronvolts) in an elongated plasma column created by irradiation of a gas medium. We observed strong amplified spontaneous emission from the end of the excited plasma. This resulted in femtosecond-duration, high-intensity X-ray pulses of much shorter wavelength and greater brilliance than achieved with previous atomic X-ray lasers. Moreover, this scheme provides greatly increased wavelength stability, monochromaticity and improved temporal coherence by comparison with present-day X-ray free-electron lasers. The atomic X-ray lasers realized here may be useful for high-resolution spectroscopy and nonlinear X-ray studies.


Human birth seasonality: latitudinal gradient and interplay with childhood disease dynamics.
More than a century of ecological studies have demonstrated the importance of demography in shaping spatial and temporal variation in population dynamics. Surprisingly, the impact of seasonal recruitment on infectious disease systems has received much less attention. Here, we present data encompassing 78 years of monthly natality in the USA, and reveal pronounced seasonality in birth rates, with geographical and temporal variation in both the peak birth timing and amplitude. The timing of annual birth pulses followed a latitudinal gradient, with northern states exhibiting spring/summer peaks and southern states exhibiting autumn peaks, a pattern we also observed throughout the Northern Hemisphere. Additionally, the amplitude of United States birth seasonality was more than twofold greater in southern states versus those in the north. Next, we examined the dynamical impact of birth seasonality on childhood disease incidence, using a mechanistic model of measles. Birth seasonality was found to have the potential to alter the magnitude and periodicity of epidemics, with the effect dependent on both birth peak timing and amplitude. In a simulation study, we fitted an susceptible-exposed-infected-recovered model to simulated data, and demonstrated that ignoring birth seasonality can bias the estimation of critical epidemiological parameters. Finally, we carried out statistical inference using historical measles incidence data from New York City. Our analyses did not identify the predicted systematic biases in parameter estimates. This may be owing to the well-known frequency-locking between measles epidemics and seasonal transmission rates, or may arise from substantial uncertainty in multiple model parameters and estimation stochasticity.


Effect of a 2-week interruption in methotrexate treatment versus continued treatment on COVID-19 booster vaccine immunity in adults with inflammatory conditions (VROOM study): a randomised, open label, superiority trial.
Immunosuppressive treatments inhibit vaccine-induced immunity against SARS-CoV-2. We evaluated whether a 2-week interruption of methotrexate treatment immediately after the COVID-19 vaccine booster improved antibody responses against the S1 receptor-binding domain (S1-RBD) of the SARS-CoV-2 spike protein compared with uninterrupted treatment in patients with immune-mediated inflammatory diseases. We did an open-label, prospective, two-arm, parallel-group, multicentre, randomised, controlled, superiority trial in 26 hospitals in the UK. We recruited adults from rheumatology and dermatology clinics who had been diagnosed with an immune-mediated inflammatory disease (eg, rheumatoid arthritis, psoriasis with or without arthritis, axial spondyloarthritis, atopic dermatitis, polymyalgia rheumatica, and systemic lupus erythematosus) and who were taking low-dose weekly methotrexate (≤25 mg per week) for at least 3 months. Participants also had to have received two primary vaccine doses from the UK COVID-19 vaccination programme. We randomly assigned the participants (1:1), using a centralised validated computer randomisation program, to suspend methotrexate treatment for 2 weeks immediately after their COVID-19 booster (suspend methotrexate group) or to continue treatment as usual (continue methotrexate group). Participants, investigators, clinical research staff, and data analysts were unmasked, while researchers doing the laboratory analyses were masked to group assignment. The primary outcome was S1-RBD antibody titres 4 weeks after receiving the COVID-19 booster vaccine dose, assessed in the intention-to-treat population. This trial is registered with ISRCT, ISRCTN11442263; following the pre-planned interim analysis, recruitment was stopped early. Between Sept 30, 2021 and March 3, 2022, we recruited 340 participants, of whom 254 were included in the interim analysis and had been randomly assigned to one of the two groups: 127 in the continue methotrexate group and 127 in the suspend methotrexate group. Their mean age was 59·1 years, 155 (61%) were female, 130 (51%) had rheumatoid arthritis, and 86 (34%) had psoriasis with or without arthritis. After 4 weeks, the geometric mean S1-RBD antibody titre was 22 750 U/mL (95% CI 19 314-26 796) in the suspend methotrexate group and 10 798 U/mL (8970-12 997) in the continue methotrexate group, with a geometric mean ratio (GMR) of 2·19 (95% CI 1·57-3·04; p<0·0001; mixed-effects model). The increased antibody response in the suspend methotrexate group was consistent across methotrexate dose, administration route, type of immune-mediated inflammatory disease, age, primary vaccination platform, and history of SARS-CoV-2 infection. There were no intervention-related serious adverse events. A 2-week interruption of methotrexate treatment for people with immune-mediated inflammatory diseases resulted in enhanced boosting of antibody responses after COVID-19 vaccination. This intervention is simple, low-cost, and easy to implement, and could potentially translate to increased vaccine efficacy and duration of protection for susceptible groups. National Institute for Health and Care Research.


Serum tocopherol levels and vitamin E intake are associated with lung function in the normative aging study.
The results of studies assessing relationships between vitamin E intake and status and lung function are conflicting. This study aimed to evaluate the effect of vitamin E intake and serum levels of tocopherol isoforms on lung function in a cross-sectional sample of 580 men from the Normative Aging Study, a longitudinal aging study. Regression models were used to look at associations of serum tocopherol isoform levels and vitamin E intake with lung function parameters after adjustment for confounders. Vitamin E intake was measured using a food frequency questionnaire and serum levels of γ, α, and δ-tocopherol levels were measured using high-performance liquid chromatography. After adjustment for potential confounders, serum γ-tocopherol had a significant inverse association with forced vital capacity (β = -0.10, p = 0.05). Alpha and δ-tocopherol were not associated with any lung function parameter. After classifying COPD status according to Global Initiative for Obstructive Lung Disease (GOLD) stage criteria, serum levels of δ-tocopherol were lower in participants with more severe COPD (p = 0.01). Serum levels of δ-tocopherol were also lower in participants with greater levels of smoking (p = 0.02). Both vitamin E intake (β = 0.03, p = 0.02; β = 0.03, p = 0.01) and use of vitamin E supplements (β = 0.05, p = 0.03; β = 0.06. p = 0.02) were positively associated with FEV1 and FVC, after adjusting for confounders. Subjects who took vitamin E supplements had significantly higher α-tocopherol levels (p < 0.0001) and lower γ-tocopherol levels (p < 0.0001) than non-users. In this study, there is a positive association between dietary vitamin E intake and lung function, and evidence of an inverse relationship between serum levels of γ-tocopherol and lung function.


DNA replication-independent silencing in S. cerevisiae.
In Saccharomyces cerevisiae, the silent mating loci are repressed by their assembly into heterochromatin. The formation of this heterochromatin requires a cell cycle event that occurs between early S phase and G(2)/M phase, which has been widely assumed to be DNA replication. To determine whether DNA replication through a silent mating-type locus, HMRa, is required for silencing to be established, we monitored heterochromatin formation at HMRa on a chromosome and on a nonreplicating extrachromosomal cassette as cells passed through S phase. Cells that passed through S phase established silencing at both the chromosomal HMRa locus and the extrachromosomal HMRa locus with equal efficiency. Thus, in contrast to the prevailing view, the establishment of silencing occurred in the absence of passage of the DNA replication fork through or near the HMR locus, but retained a cell cycle dependence.


A screening-level assessment of lead, cadmium, and zinc in fish and crayfish from Northeastern Oklahoma, USA.
The objective of this study was to evaluate potential human and ecological risks associated with metals in fish and crayfish from mining in the Tri-States Mining District (TSMD). Crayfish (Orconectes spp.) and fish of six frequently consumed species (common carp, Cyprinus carpio; channel catfish, Ictalurus punctatus; flathead catfish, Pylodictis olivaris; largemouth bass, Micropterus salmoides; spotted bass, M. punctulatus; and white crappie, Pomoxis annularis) were collected in 2001--2002 from the Oklahoma waters of the Spring River (SR) and Neosho River (NR), which drain the TSMD. Samples from a mining-contaminated site in eastern Missouri and from reference sites were also analyzed. Individual fish were prepared for human consumption in the manner used locally by Native Americans (headed, eviscerated, and scaled) and analyzed for lead, cadmium, and zinc. Whole crayfish were analyzed as composite samples of 5--60 animals. Metals concentrations were typically higher in samples from sites most heavily affected by mining and lowest in reference samples. Within the TSMD, most metals concentrations were higher at sites on the SR than on the NR and were typically highest in common carp and crayfish than in other taxa. Higher concentrations and greater risk were associated with fish and crayfish from heavily contaminated SR tributaries than the SR or NR mainstems. Based on the results of this and previous studies, the human consumption of carp and crayfish could be restricted based on current criteria for lead, cadmium, and zinc, and the consumption of channel catfish could be restricted due to lead. Metals concentrations were uniformly low in Micropterus spp. and crappie and would not warrant restriction, however. Some risk to carnivorous avian wildlife from lead and zinc in TSMD fish and invertebrates was also indicated, as was risk to the fish themselves. Overall, the wildlife assessment is consistent with previously reported biological effects attributed to metals from the TSMD. The results demonstrate the potential for adverse effects in fish, wildlife, and humans and indicate that further investigation of human health and ecological risks, to include additional exposure pathways and endpoints, is warranted.


Processed meat: the real villain?
Meat is a food rich in protein, minerals such as iron and zinc as well as a variety of vitamins, in particular B vitamins. However, the content of cholesterol and saturated fat is higher than in some other food groups. Processed meat is defined as products usually made of red meat that are cured, salted or smoked (e.g. ham or bacon) in order to improve the durability of the food and/or to improve colour and taste, and often contain a high amount of minced fatty tissue (e.g. sausages). Hence, high consumption of processed foods may lead to an increased intake of saturated fats, cholesterol, salt, nitrite, haem iron, polycyclic aromatic hydrocarbons, and, depending upon the chosen food preparation method, also heterocyclic amines. Several large cohort studies have shown that a high consumption of processed (red) meat is related to increased overall and cause-specific mortality. A meta-analysis of nine cohort studies observed a higher mortality among high consumers of processed red meat (relative risk (RR) = 1·23; 95 % CI 1·17, 1·28, top v. bottom consumption category), but not unprocessed red meat (RR = 1·10; 95 % CI 0·98, 1·22). Similar associations were reported in a second meta-analysis. All studies argue that plausible mechanisms are available linking processed meat consumption and risk of chronic diseases such as CVD, diabetes mellitus or some types of cancer. However, the results of meta-analyses do show some degree of heterogeneity between studies, and it has to be taken into account that individuals with low red or processed meat consumption tend to have a healthier lifestyle in general. Hence, substantial residual confounding cannot be excluded. Information from other types of studies in man is needed to support a causal role of processed meat in the aetiology of chronic diseases, e.g. studies using the Mendelian randomisation approach.


Circulating CD4 and CD8 T cells have little impact on host defense against experimental vaginal candidiasis.
The etiology of recurrent vulvovaginal candidiasis in otherwise healthy women of child-bearing age remains an enigma. To date, results from both clinical studies and a murine model of vaginal candidiasis indicate that Candida vaginitis can occur in the presence of Candida-specific Th1-type cell-mediated immunity expressed in the peripheral circulation. The present study was designed to determine the role of circulating CD4 and CD8 cells in primary and secondary vaginal infections with Candida albicans. Vaginal fungal burden, Candida-specific delayed-type hypersensitivity (DTH), and lymph node cell Th1/Th2 cytokine production were monitored in CD4 and/or CD8 cell-depleted mice during persistent primary vaginal infections and secondary vaginal infections against which partial protection was observed. Treatment of mice with anti-CD4 or anti-CD8 antibodies resulted in 90% or greater depletion of the respective cell populations. Mice depleted of CD4 cells had significantly reduced Candida-specific DTH and lymph node cell Th1-type cytokine production during a primary vaginal infection, as well as reduced anamnestic DTH during a secondary vaginal infection. In contrast, mice depleted of CD8 cells showed only reduced gamma interferon production during a primary infection; no alterations in DTH were observed. Despite reductions in DTH and cytokine production, however, CD4 and/or CD8 cell depletion had no effect on vaginal C. albicans burden in mice after a primary or secondary vaginal inoculation. Taken together, these results suggest that while circulating CD4 and CD8 cells contribute to systemic Candida-specific cell-mediated immunity in vaginally infected mice, neither CD4 nor CD8 circulating T cells appear to provide significant host defenses against C. albicans at the vaginal mucosa.


Transition-State Analogues of Phenylethanolamine N-Methyltransferase.
Phenylethanolamine N-methyltransferase (PNMT) is a critical enzyme in catecholamine synthesis. It transfers the methyl group of S-adenosylmethionine (SAM) to catalyze the synthesis of epinephrine from norepinephrine. Epinephrine has been associated with diverse human processes, including the regulation of blood pressure and respiration, as well as neurodegeneration found in Alzheimer's disease. Human PNMT (hPNMT) proceeds through an SN2 transition state (TS) in which the transfer of the methyl group is rate limiting. TS analogue enzyme inhibitors are specific for their target and bind orders of magnitude more tightly than their substrates. Molecules resembling the TS of hPNMT were designed, synthesized, and kinetically characterized. This new inhibitory scaffold was designed to mimic the geometry and electronic properties of the hPNMT TS. Synthetic efforts resulted in a tight-binding inhibitor with a Ki value of 12.0 nM. This is among the first of the TS analogue inhibitors of methyltransferase enzymes to show an affinity in the nanomolar range. Isothermal titration calorimetry (ITC) measurements indicated negative cooperative binding of inhibitor to the dimeric protein, driven by favorable entropic contributions. Structural analysis revealed that inhibitor 3 binds to hPNMT by filling the catalytic binding pockets for the cofactor (SAM) and the substrate (norepinephrine) binding sites.


Oxygen regulatory mechanisms of nitrogen fixation in rhizobia.
Rhizobia are α- and β-proteobacteria that form a symbiotic partnership with legumes, fixing atmospheric dinitrogen to ammonia and providing it to the plant. Oxygen regulation is key in this symbiosis. Fixation is performed by an oxygen-intolerant nitrogenase enzyme but requires respiration to meet its high energy demands. To satisfy these opposing constraints the symbiotic partners cooperate intimately, employing a variety of mechanisms to regulate and respond to oxygen concentration. During symbiosis rhizobia undergo significant changes in gene expression to differentiate into nitrogen-fixing bacteroids. Legumes host these bacteroids in specialized root organs called nodules. These generate a near-anoxic environment using an oxygen diffusion barrier, oxygen-binding leghemoglobin and control of mitochondria localization. Rhizobia sense oxygen using multiple interconnected systems which enable a finely-tuned response to the wide range of oxygen concentrations they experience when transitioning from soil to nodules. The oxygen-sensing FixL-FixJ and hybrid FixL-FxkR two-component systems activate at relatively high oxygen concentration and regulate fixK transcription. FixK activates the fixNOQP and fixGHIS operons producing a high-affinity terminal oxidase required for bacterial respiration in the microaerobic nodule. Additionally or alternatively, some rhizobia regulate expression of these operons by FnrN, an FNR-like oxygen-sensing protein. The final stage of symbiotic establishment is activated by the NifA protein, regulated by oxygen at both the transcriptional and protein level. A cross-species comparison of these systems highlights differences in their roles and interconnections but reveals common regulatory patterns and themes. Future work is needed to establish the complete regulon of these systems and identify other regulatory signals.


The impact of dietary Black Soldier Fly larvae oil and meal on laying hen performance and egg quality.
Recently, the US FDA and Association of American Feed Control Officials approved Black Soldier Fly larvae (BSFL) as a feed ingredient for poultry. The objectives of this work were 1) to evaluate the nutritional profile of BSFL oil and meal in laying hens, and 2) measure the impact of the BSFL treatments on hen performance and egg quality. In 2 experiments, BSFL oil and meal were fed to replicate hens from 43 to 47 wk and from 51 to 55 wk of age. The hens were fed isocaloric, isonitrogenous diets with 3 treatment levels of BSFL oil (1.5, 3, and 4.5%, Exp. 1) or BSFL meal (8, 16 and 24%, Exp. 2). Data were analyzed by one-factor ANOVA for the main effect of diet and Tukey's multiple comparison for mean separation when significant. Exp. 1 results suggest BSFL oil could readily substituted for soybean oil with commercial hens at inclusion levels up to 4.5%. ADFI, BW, egg production, FCR, and egg weight were not impacted by the oil treatments (P > 0.05). Yolk color among hens fed the BSFL oil was greater averaging 7.88 compared to 7.37 from Control hen eggs (P = 0.0001). Exp. 2 diet formulation replaced soybean oil and meal with BSFL meal, and some additional corn was used in the higher BSFL diets. Diet amino acid balance at the highest level of inclusion (24% BSFL meal) indicates arginine and tryptophan are limiting and ADFI, BW and egg production were reduced (P < 0.05). Egg production averaged 85.14% for the Control, 8 and 16% BSFL meal hens and was significantly greater than hens fed 24% meal at 77.01%. However, 8 and 16% BSFL meal levels had no negative impact on performance and were not significantly different than the Controls. Yolk color was again higher among the meal treatments compared to the control (P = 0.0351). These experiments indicate that BSFL oil and meal can be used as dietary energy, protein and amino acids for hen maintenance, egg production and yolk coloration, although there may be upper limits of dietary inclusion.


Vanadium(iv and v) complexes of pyrazolone based ligands: Synthesis, structural characterization and catalytic applications.
The ONO donor ligands obtained from the condensation of 4-benzoyl-3-methyl-1-phenyl-2-pyrazoline-5-one (Hbp) with benzoylhydrazide (H2bp-bhz I), furoylhydrazide (H2bp-fah II), nicotinoylhydrazide (H2bp-nah III) and isonicotinoylhydrazide (H2bp-inh IV), upon treatment with [VIVO(acac)2], lead to the formation of [VIVO(bp-bhz)(H2O)] 1, [VIVO(bp-fah)(H2O)] 2, [VIVO(bp-nah)(H2O)] 3 and [VIVO(bp-inh)(H2O)] 4, respectively. At neutral pH the in situ generated aqueous K[H2VVO4] reacts with ligands I and II, forming potassium salts, K(H2O)2[VVO2(bp-bhz)] 5 and K(H2O)2[VVO2(bp-fah)] 6, while ligands III and IV give neutral complexes, [VVO2(Hbp-nah)] 9 and [VVO2(Hbp-inh)] 10, respectively. Acidification of aqueous solutions of 5 and 6 with HCl also gives neutral complexes [VVO2(Hbp-bhz)] 7 and [VVO2(Hbp-fah)] 8, respectively. Complexes 1-4, upon slow aerial oxidation in methanol, convert into monooxidovanadium(v) complexes, [VVO(bp-bhz)(OMe)] 11, [VVO(bp-fah)(OMe)] 12, [VVO(bp-nah)(OMe)] 13 and [VVO(bp-inh)(OMe)] 14, respectively. All complexes were characterized by various spectroscopic techniques like FT-IR, UV-visible, EPR (for complexes 1-4) and NMR (1H, 13C and 51V), elemental analysis, thermogravimetry and single crystal X-ray diffraction (for complexes 5-10 and 12). In the solid state, all complexes characterized by X-ray diffraction show the metal ion 5-coordinated in a distorted square pyramidal geometry. Complexes 11-14 were tested as catalysts for the one-pot three-component (ethylacetoacetate, benzaldehyde and ammonium acetate) dynamic covalent assembly, via Hantzsch reaction, using hydrogen peroxide as oxidant in solution and under solvent-free conditions. The complexes are also active catalysts for the oxidation of tetralin to tetralone with H2O2 as oxidant. The influence of the amounts of catalyst and oxidant, and solvent, temperature and time on the catalyzed reactions was investigated.


Cellular homologs of the double jelly-roll major capsid proteins clarify the origins of an ancient virus kingdom.
Viruses are a distinct type of replicators that encode structural proteins encasing virus genomes in virions. For some of the widespread virus capsid proteins and other major components of virions, likely ancestors encoded by cellular life forms are identifiable. In particular, one of the most common capsid proteins, with the single jelly-roll (SJR) fold, appears to have evolved from a particular family of cellular carbohydrate-binding proteins. However, the double jelly-roll major capsid protein (DJR-MCP), the hallmark of the enormously diverse viruses of the kingdom Bamfordvirae within the realm Varidnaviria, which includes bacterial and archaeal icosahedral viruses as well as eukaryotic giant viruses, has been perceived as a virus innovation that evolved by duplication and fusion of the SJR capsid proteins. Here we employ protein structure comparison to show that the DJR fold is represented in several widespread families of cellular proteins, including several groups of carbohydrate-active enzymes. We show that DJR-MCPs share a common ancestry with a distinct family of bacterial DJR proteins (DUF2961) involved in carbohydrate metabolism. Based on this finding, we propose a scenario in which bamfordviruses evolved from nonviral replicators, in particular plasmids, by recruiting a host protein for capsid formation. This sequence of events appears to be the general route of virus origin. The results of this work indicate that virus kingdoms Bamfordvirae, with the DJR-MCPs, and Helvetiavirae that possess two SJR-MCPs, have distinct origins, suggesting a reappraisal of the realm Varidnaviria.


Cell polarity and PIN protein positioning in Arabidopsis require STEROL METHYLTRANSFERASE1 function.
Plants have many polarized cell types, but relatively little is known about the mechanisms that establish polarity. The orc mutant was identified originally by defects in root patterning, and positional cloning revealed that the affected gene encodes STEROL METHYLTRANSFERASE1, which is required for the appropriate synthesis and composition of major membrane sterols. smt1(orc) mutants displayed several conspicuous cell polarity defects. Columella root cap cells revealed perturbed polar positioning of different organelles, and in the smt1(orc) root epidermis, polar initiation of root hairs was more randomized. Polar auxin transport and expression of the auxin reporter DR5-beta-glucuronidase were aberrant in smt1(orc). Patterning defects in smt1(orc) resembled those observed in mutants of the PIN gene family of putative auxin efflux transporters. Consistently, the membrane localization of the PIN1 and PIN3 proteins was disturbed in smt1(orc), whereas polar positioning of the influx carrier AUX1 appeared normal. Our results suggest that balanced sterol composition is a major requirement for cell polarity and auxin efflux in Arabidopsis.


Not Your Mother's Suburb: Remaking Communities for a More Diverse Population.
The United States is a suburban nation with a majority of Americans living and working in this landscape. But the suburb is more than a physical location; it is also a social production. Built upon a middle class, white, nuclear family ideal, the suburb is now diversifying demographically and economically, yet zoning ordinances and the built environment continue to reflect this outdated ideal. Today's suburb is not your mother's suburb. We argue that these demographic changes create both a point of rupture that challenges traditional land use regulations and actual uses of space, and an opening for communities to embrace and plan for new residents. In order to respond to the needs of a diversifying suburban population, communities need to challenge the underlying assumptions of traditional zoning ordinances - the separation of uses and preference for single-family housing. We present an agenda for the future that includes planning responses that rethink the zoning hierarchy, promote new forms of densification, move beyond restrictive family definitions, and experiment with new forms of service delivery.


Zellweger spectrum disorder: A cross-sectional study of symptom prevalence using input from family caregivers.
Zellweger spectrum disorders (ZSD) are rare, debilitating genetic diseases of peroxisome biogenesis that affect multiple organ systems and present with broad clinical heterogeneity. Although many case studies have characterized the multitude of signs and symptoms associated with ZSD, there are few reports on the prevalence of symptoms to help inform the development of meaningful endpoints for future clinical trials in ZSD. In the present study, we used an online survey tool completed by family caregivers to study the occurrence, frequency and severity of symptoms in individuals diagnosed with ZSD. Responses from caregivers representing 54 living and 25 deceased individuals with ZSD were collected over an 8-month period. Both perception of disease severity and prevalence of various symptoms were greater in responses from family caregivers of deceased individuals compared to those of living individuals with ZSD. Compared with previous reports for ZSD, the combined prevalence of seizures (53%) and adrenal insufficiency (45%) were nearly twice as high. Overall, this community-engaged approach to rare disease data collection is the largest study reporting on the prevalence of symptoms in ZSD, and our findings suggest that previous reports may be underreporting the true prevalence of several symptoms in ZSD. Studies such as this used in conjunction with clinician- led reports may be useful for informing the design of future clinical trials addressing ZSD.


Clinical association between teeth malocclusions, wrong posture and ocular convergence disorders: an epidemiological investigation on primary school children.
As the various systems in the body are inter-connected to form a single structural unit, a pathological condition in one area can also affect other areas. There are many known correlations between the visual and motor system. The importance of visual function, particularly the paracentral peripheral field of view, in motor coordination, ambulation and the maintenance of balance has been amply demonstrated.In line with current medical principles, which are moving towards a more holistic view of the human body, this study aims to investigate, in an interdisciplinary manner, the incidence of dental malocclusions together with posture and eye convergence disorders. Six hundred and five children attending at the 3rd, 4th and 5th years of seven Genoa primary schools were examined. Each child underwent the following examinations: (i) dental/occlusal; (ii) orthoptic; and (iii) postural. Occlusal data concerned the presence of cross-bite, midline deviation with a mandibular shift, bad habits and deep or open bite.Postural assessment involved frontal and lateral inspection, investigation during trunk flexion and ambulation, and note of any asymmetry in the lower limbs. The recorded orthoptic data included those pertaining to ocular dominance, a cover test, convergence and the Brock string test. A prevalence of cases with an unphysiological gait was found in patients with overjet (14.70%) or overbite (14.87%), while the percentage of patients with normal occlusion that showed an unphysiological gait was 13.08%. Also, about 93.8%-94.2% of children showed normal legs without dysmetry, with no difference in respect to the type of occlusion. Subjects with an open bite or deep bite showed a slightly different distribution of right or left dominant eyes. About 13% of children showed a pathological gait and, among them, vertical anomalies of occlusion (deep bite or open bite) were prevalent with respect to the other occlusal defects. The vertical dimension of occlusion revealed a slight relationship with the proper dominant eye. Postural, orthoptic, osteopathic and occlusal variables were often clinically associated, and therefore these disorders appear to request a multidisciplinary medical approach for their treatment.


Initial outcomes of provider-initiated routine HIV testing and counseling during outpatient care at a rural Ugandan hospital: risky sexual behavior, partner HIV testing, disclosure, and HIV care seeking.
Provider-initiated routine HIV testing is being scaled up throughout the world, however, little is known about the outcomes of routine HIV testing on subsequent behavior. This study examined the initial outcomes of provider-initiated routine HIV testing at a rural Ugandan hospital regarding partner HIV testing, sexual risk behavior, disclosure, and HIV care seeking. In a prospective cohort study, 245 outpatients receiving routine HIV testing completed baseline and 3-month follow-up interviews. After receiving routine HIV testing the percentage of participants engaging in risky sex decreased from 70.1% to 50.3% among HIV-negative and from 75.0% to 53.5% among HIV-positive participants, the percentage knowing their partner(s)' HIV status increased from 18.7% to 34.3% of HIV-negative and from 14.3% to 35.7% of HIV-positive participants. Among those reporting risky sex at baseline, HIV-positive participants were more likely to eliminate risky sex in general and specifically to become abstinent at follow-up than were HIV-negative participants. Similarly, unmarried participants who were risky at baseline were more likely to become safe in general, become abstinent, and start 100% condom use than were married/cohabitating participants. Rates of disclosure were high. Over 85% of those who tested HIV positive enrolled in care. Routine HIV testing in this setting may promote earlier HIV diagnosis and access to care but leads to only modest reductions in risky sexual behavior. To fully realize the potential HIV prevention benefits of routine HIV testing an emphasis on tailored risk-reduction counseling may be necessary.


Postoperative Haematocrit and Outcome in Critically Ill Surgical Patients.
Haematocrit has been studied as an outcome predictor. The aim of this study was to evaluate the correlation between low haematocrit at surgical intensive care unit admission and high disease scoring system score and early outcomes. This retrospective study included 4398 patients admitted to the surgical intensive care unit between January 2006 and July 2013. Acute physiology and chronic health evaluation and simplified acute physiology score II values were calculated and all variables entered as parameters were evaluated independently. Patients were classified as haematocrit if they had a haematocrit < 30% at surgical intensive care unit admission. The correlation between admission haematocrit and outcome was evaluated by univariate analysis and linear regression. A total of 1126 (25.6%) patients had haematocrit. These patients had higher rates of major cardiac events (4% vs 1.9%, p < 0.001), acute renal failure (11.5% vs 4.7%, p < 0.001), and mortality during surgical intensive care unit stay (3% vs 0.8%, p < 0.001) and hospital stay (12% vs 5.9%, p < 0.001). A haematocrit level < 30% at surgical intensive care unit admission was frequent and appears to be a predictor for poorer outcome in critical surgical patients. Patients with haematocrit had longer surgical intensive care unit and hospital stay lengths, more postoperative complications, and higher surgical intensive care unit and hospital mortality rates.


Performance of the dynamic single photon emission computed tomography (dSPECT) method for decreasing or increasing activity changes.
Radionuclide imaging is now widely used whenever functional information is required. We present a new approach to dynamic SPECT imaging (dSPECT method) that uses a single slow rotation of a conventional camera and allows us to reconstruct a series of 3D images corresponding to the radiotracer distribution in the body at various times. Using simulations of various camera configurations and acquisition protocols, we have shown that this method is able to reconstruct washout half-lives with an accuracy greater than 90% when used with triple-head SPECT cameras. Accuracy decreases when using fewer camera heads, but dual-head geometries still give an accuracy greater than 80% for short and 90% for long half-lives and about 50-75% for single-head systems. Dynamic phantom experiments have yielded similar results. Presence of attenuation and background activity does not affect the accuracy of the dSPECT reconstructions. In all situations investigated satisfactory dynamic images were produced. A preliminary normal volunteer study measuring renal function was performed. The reconstructed dynamic images may be presented as a three-dimensional movie showing movement of the tracer through the kidneys and the measurement of the regional renal function can be performed. The time-activity curves determined from this dSPECT data are very similar to those obtained from dynamic planar scans.


Cost-effectiveness of antibiotic-impregnated bone cement used in primary total hip arthroplasty.
Antibiotic-impregnated bone cement is infrequently used in the United States for primary total hip arthroplasty because of concerns about cost, performance, and the possible development of antibiotic resistance and because it has been approved only for use in revision arthroplasty after infection. The purpose of this study was to model the use of antibiotic-impregnated bone cement in primary total hip arthroplasty for the treatment of osteoarthritis to determine whether use of the cement is cost-effective when compared with the use of cement without antibiotics. To evaluate the cost-effectiveness of each strategy, we used a Markov decision model to tabulate costs and quality-adjusted life years (QALYs) accumulated by each patient. Rates of revision due to infection and aseptic loosening were estimated from data in the Norwegian Arthroplasty Register and were used to determine the probability of undergoing a revision arthroplasty because of either infection or aseptic loosening. The primary outcome measure was either all revisions or revision due to infection. Perioperative mortality rates, utilities, and disutilities were estimated from data in the arthroplasty literature. Costs for primary arthroplasty were estimated from data on in-hospital resource use in the literature. The additional cost of using antibiotic-impregnated bone cement ($600) was then added to the average cost of the initial procedure ($21,654). When all revisions were considered to be the primary outcome measure, the use of antibiotic-impregnated bone cement was found to result in a decrease in overall cost of $200 per patient. When revision due to infection was considered to be the primary outcome measure, the use of the cement was found to have an incremental cost-effectiveness ratio of $37,355 per QALY compared with cement without antibiotics; this cost-effectiveness compares favorably with that of accepted medical procedures. When only revision due to infection was considered, it was found that the additional cost of the antibiotic-impregnated bone cement would need to exceed $650 or the average patient age would need to be greater than seventy-one years before its cost would exceed $50,000 per QALY gained. When revision due to either infection or aseptic loosening is considered to be the primary outcome, the use of antibiotic-impregnated bone cement results in an overall cost decrease. When only revision due to infection is considered, the model is strongly influenced by the cost of the cement and the average age of the patients. With few patients less than seventy years of age undergoing total hip arthroplasty with cement in the United States, the use of antibiotic-impregnated bone cement in primary total hip arthroplasty may be of limited value unless its cost is substantially reduced.


Accumulation of sequence-specific RNA-binding proteins in the cytosol of activated T cells undergoing RNA degradation and apoptosis.
Engagement of the T cell antigen receptor (TCR) causes transformed T cell hybridomas to produce lymphokines and then die by an apoptotic mechanism. Here we show that these functional effects of TCR-mediated signaling are associated with the accumulation of several cytosolic mRNA-binding proteins including the previously described AU-A, -B, and -C proteins as well as a novel 70-kDa protein. The results indicate that the 70-kDa protein derived from a 90-kDa precursor present in unactivated T cells and that both proteins bound to two independent sites at the 3'-end of the interleukin-2 mRNA, one in the coding region and the other in an AU-rich segment of the 3'-untranslated region. Glucocorticoids, TCR engagement by monoclonal antibodies, pharmacologic mimics of TCR signaling, or high concentrations of protein or RNA synthesis inhibitors all induced apoptosis, the cytosolic appearance of the RNA-binding proteins, and an increased rate of RNA turnover. Moreover, drugs that interfere with TCR-mediated signals, such as cyclosporin A and staurosporin, prevented both apoptosis and the appearance of the RNA-binding factors. The fact that the accumulation of these factors occurred in the presence of inhibitors of transcription and translation suggested that these proteins are present in an inactive form in unstimulated T cells and are activated when apoptosis is induced.


Ca2+ regulatory mechanisms of exercise protection against coronary artery disease in metabolic syndrome and diabetes.
Chronic exercise attenuates coronary artery disease (CAD) in humans largely independent of reductions in risk factors; thus major protective mechanisms of exercise are directly within the coronary vasculature. Further, tight control of diabetes, e.g., blood glucose, can be detrimental. Accordingly, knowledge of mechanisms by which exercise attenuates diabetic CAD could catalyze development of molecular therapies. Exercise attenuates CAD (atherosclerosis) and restenosis in miniature swine models, which enable precise control of exercise parameters (intensity, duration, and frequency) and characterization of the metabolic syndrome (MetS) and diabetic milieu. Intracellular Ca(2+) is a pivotal second messenger for coronary smooth muscle (CSM) excitation-contraction and excitation-transcription coupling that modulates CSM proliferation, migration, and calcification. CSM of diabetic dyslipidemic Yucatan swine have impaired Ca(2+) extrusion via the plasmalemma Ca(2+) ATPase (PMCA), downregulation of L-type voltage-gated Ca(2+) channels (VGCC), increased Ca(2+) sequestration by the sarcoplasmic reticulum (SR) Ca(2+) ATPase (SERCA), increased nuclear Ca(2+) localization, and greater activation of K channels by Ca(2+) release from the SR. Endurance exercise training prevents Ca(2+) transport changes with virtually no effect on the diabetic milieu (glucose, lipids). In MetS Ossabaw swine transient receptor potential canonical (TRPC) channels are upregulated and exercise training reverses expression and TRPC-mediated Ca(2+) influx with almost no change in the MetS milieu. Overall, exercise effects on Ca(2+) signaling modulate CSM phenotype. Future studies should 1) selectively target key Ca(2+) transporters to determine definitively their causal role in atherosclerosis and 2) combine mechanistic studies with clinical outcomes, e.g., reduction of myocardial infarction.


Digital health Systems in Kenyan Public Hospitals: a mixed-methods survey.
As healthcare facilities in Low- and Middle-Income Countries adopt digital health systems to improve hospital administration and patient care, it is important to understand the adoption process and assess the systems' capabilities. This survey aimed to provide decision-makers with information on the digital health systems landscape and to support the rapidly developing digital health community in Kenya and the region by sharing knowledge. We conducted a survey of County Health Records Information Officers (CHRIOs) to determine the extent to which digital health systems in public hospitals that serve as internship training centres in Kenya are adopted. We conducted site visits and interviewed hospital administrators and end users who were at the facility on the day of the visit. We also interviewed digital health system vendors to understand the adoption process from their perspective. Semi-structured interview guides adapted from the literature were used. We identified emergent themes using a thematic analysis from the data. We obtained information from 39 CHRIOs, 58 hospital managers and system users, and 9 digital health system vendors through semi-structured interviews and completed questionnaires. From the survey, all facilities mentioned purchased a digital health system primarily for administrative purposes. Radiology and laboratory management systems were commonly standalone systems and there were varying levels of interoperability within facilities that had multiple systems. We only saw one in-patient clinical module in use. Users reported on issues such as system usability, inadequate training, infrastructure and system support. Vendors reported the availability of a wide range of modules, but implementation was constrained by funding, prioritisation of services, users' lack of confidence in new technologies and lack of appropriate data sharing policies. Public hospitals in Kenya are increasingly purchasing systems to support administrative functions and this study highlights challenges faced by hospital users and vendors. Significant work is required to ensure interoperability of systems within hospitals and with other government services. Additional studies on clinical usability and the workflow fit of digital health systems are required to ensure efficient system implementation. However, this requires support from key stakeholders including the government, international donors and regional health informatics organisations.


A Multimodal Pancreas Phantom for Computer-Assisted Surgery Training.
Training of surgical residents and the establishment of innovative surgical techniques require training phantoms that realistically mimic human anatomy. Because animal models have their limitations due to ethical aspects, costs, and the required efforts to set up such training, artificial phantoms are a promising alternative. In the field of image-guided surgery, the challenge lies in developing phantoms that are accurate both anatomically and in terms of imaging properties, while taking the cost factor into account. With respect to the pancreas, animal models are less suitable because their anatomy differs significantly from human anatomy and tissue properties rapidly degrade in the case of ex vivo models. Nevertheless, progress with artificial phantoms has been sparse, although the need for innovative, minimally invasive therapies that require adequate training is steadily increasing. Methods: In the course of this project, an artificial pancreas phantom that is compatible with basic electrosurgical techniques was developed with realistic anatomic and haptic properties, computed tomography, and ultrasound imaging capabilities. This article contains step-by-step instructions for the fabrication of a low-cost pancreatic phantom. The molds are also available for download in a 3D file format. Results: The phantom was successfully validated with regard to its computed tomography and ultrasound properties. As a result, the phantom could be used in combination with a state-of-the-art computer-assisted navigation system. The resection capabilities were positively evaluated in a preclinical study evaluating endoscopic resections using the navigation system. Finally, the durability of the phantom material was tested in a study with multiple needle insertions. Conclusion: The developed phantom represents an open-access and low-cost durable alternative to conventional animal models in the continuous process of surgical training and development of new techniques.


[Self harm in adolescents in Flanders].
Deliberate self harm is an important precursor to suicide. Little is known about the epidemiology and circumstances of self harm behaviour that cannot be treated with medication. To use international data in order to obtain insight into the prevalence, the circumstances and possible ways of presenting self harm in adolescents in the general population in Flanders. With the frameworks of the Child and Adolescent Self Harm in Europe (case)- study 4500 Flemish adolescents were asked to complete an anonymous self-report questionnaire. results 10.4% of the adolescents questioned admitted to having engaged in self harm on one or more occasions during their life. 7% (males 4.1%, females 10.1%) reported they had engaged in self harm during the past year. Self harm seemed to be strongly associated with a family history of self harm, physical ill-treatment and sexual abuse. Adolescents seldom sought help from adults and hardly ever from professional care workers. Deliberate self harm is more common in Flanders than in other countries participating in the case-study. Flanders needs to set up a school-based prevention campaign and should take steps to lower the barriers that currently stop adolescents from seeking professional help.


Height in relation to dementia death: individual participant meta-analysis of 18 UK prospective cohort studies.
That risk factors measured in middle age may not fully explain future dementia risk implicates exposures acting earlier in life. Height may capture early-life illness, adversity, nutrition and psychosocial stress. To investigate the little-explored association between height and dementia death. Method Individual participant meta-analysis using 18 prospective general population cohort studies with identical methodologies (1994-2008; n = 181 800). Mean follow-up of 9.8 years gave rise to 426 and 667 dementia deaths in men and women respectively. The mean heights were 174.4 cm (s.d. = 7.3) for men and 161.0 cm (s.d. = 6.8) for women. In analyses taking into account multiple covariates, increasing height was related to lower rates of death from dementia in a dose-response pattern (P ⩽ 0.01 for trend). There was evidence of a differential effect by gender (P = 0.016 for interaction). Thus, the association observed in men (hazard ratio per s.d. decrease in height 1.24, 95% CI 1.11-1.39) was markedly stronger than that apparent in women (HR = 1.13, 95% CI 1.03-1.24). Early-life circumstances, indexed by adult height, may influence later dementia risk.


Physical educators' beliefs and self-reported behaviors toward including students with autism spectrum disorder.
With an increase in the presence of students with autism spectrum disorder (ASD) in the general physical education (GPE) classroom, understanding the current state of GPE teachers' beliefs and behaviors for including these students is warranted. The current study aimed to examine the beliefs and self-reported behaviors of GPE teachers' inclusion of students with ASD. In addition, the study examined potential factors affecting their inclusion behaviors. Using a national stratified random sample, participants were 142 current GPE teachers who submitted surveys anonymously online. Results from a regression analysis indicate that teachers' experience, graduate coursework in adapted physical education (APE), and perceptions of strength in undergraduate training in APE significantly predicted their self-reported behavior for including students with ASD. Although the participant response rate is considerably low, this study provides some support toward the importance of teacher education programs for inclusion training.


mRNA degradation by miRNAs and GW182 requires both CCR4:NOT deadenylase and DCP1:DCP2 decapping complexes.
MicroRNAs (miRNAs) silence the expression of target genes post-transcriptionally. Their function is mediated by the Argonaute proteins (AGOs), which colocalize to P-bodies with mRNA degradation enzymes. Mammalian P-bodies are also marked by the GW182 protein, which interacts with the AGOs and is required for miRNA function. We show that depletion of GW182 leads to changes in mRNA expression profiles strikingly similar to those observed in cells depleted of the essential Drosophila miRNA effector AGO1, indicating that GW182 functions in the miRNA pathway. When GW182 is bound to a reporter transcript, it silences its expression, bypassing the requirement for AGO1. Silencing by GW182 is effected by changes in protein expression and mRNA stability. Similarly, miRNAs silence gene expression by repressing protein expression and/or by promoting mRNA decay, and both mechanisms require GW182. mRNA degradation, but not translational repression, by GW182 or miRNAs is inhibited in cells depleted of CAF1, NOT1, or the decapping DCP1:DCP2 complex. We further show that the N-terminal GW repeats of GW182 interact with the PIWI domain of AGO1. Our findings indicate that GW182 links the miRNA pathway to mRNA degradation by interacting with AGO1 and promoting decay of at least a subset of miRNA targets.