The ARIC predictive model reliably predicted risk of type II diabetes in Asian populations.
Identification of high-risk individuals is crucial for effective implementation of type 2 diabetes mellitus prevention programs. Several studies have shown that multivariable predictive functions perform as well as the 2-hour post-challenge glucose in identifying these high-risk individuals. The performance of these functions in Asian populations, where the rise in prevalence of type 2 diabetes mellitus is expected to be the greatest in the next several decades, is relatively unknown. Using data from three Asian populations in Singapore, we compared the performance of three multivariate predictive models in terms of their discriminatory power and calibration quality: the San Antonio Health Study model, Atherosclerosis Risk in Communities model and the Framingham model. The San Antonio Health Study and Atherosclerosis Risk in Communities models had better discriminative powers than using only fasting plasma glucose or the 2-hour post-challenge glucose. However, the Framingham model did not perform significantly better than fasting glucose or the 2-hour post-challenge glucose. All published models suffered from poor calibration. After recalibration, the Atherosclerosis Risk in Communities model achieved good calibration, the San Antonio Health Study model showed a significant lack of fit in females and the Framingham model showed a significant lack of fit in both females and males. We conclude that adoption of the ARIC model for Asian populations is feasible and highly recommended when local prospective data is unavailable.


Induction of competence for natural transformation in Legionella pneumophila and exploitation for mutant construction.
Many Gram-positive and Gram-negative bacteria possess natural competence mechanisms for DNA -capture and internalization that play an important role in diversifying adaptation of bacteria through horizontal gene transfer. Natural transformation and other mechanisms of horizontal gene transfer are dependent on DNA recombination. Natural competence can be exploited both for studying adaptation and horizontal gene transfer as well as for genetic engineering of a strain. We report here different approaches to measure competence on solid and in liquid media by using a reporter plasmid where GFP is fused to the comEA gene or by inducing competence and measuring transformability induced by DNA-damaging stress. Finally we describe a method where competence is induced through a combined temperature and aeration shift, which may be exploited for the construction of mutants in Legionella pneumophila. This approach seems to be less prone to the appearance of secondary mutations during mutant construction as compared to procedures using electroporation.


Hepatic tristetraprolin promotes insulin resistance through RNA destabilization of FGF21.
The role of posttranscriptional metabolic gene regulatory programs in diabetes is not well understood. Here, we show that the RNA-binding protein tristetraprolin (TTP) is reduced in the livers of diabetic mice and humans and is transcriptionally induced in response to insulin treatment in murine livers in vitro and in vivo. Liver-specific Ttp-KO (lsTtp-KO) mice challenged with high-fat diet (HFD) have improved glucose tolerance and peripheral insulin sensitivity compared with littermate controls. Analysis of secreted hepatic factors demonstrated that fibroblast growth factor 21 (FGF21) is posttranscriptionally repressed by TTP. Consistent with increased FGF21, lsTtp-KO mice fed HFD have increased brown fat activation, peripheral tissue glucose uptake, and adiponectin production compared with littermate controls. Downregulation of hepatic Fgf21 via an adeno-associated virus-driven shRNA in mice fed HFD reverses the insulin-sensitizing effects of hepatic Ttp deletion. Thus, hepatic TTP posttranscriptionally regulates systemic insulin sensitivity in diabetes through liver-derived FGF21.


Elucidation of the Ebola virus VP24 cellular interactome and disruption of virus biology through targeted inhibition of host-cell protein function.
Viral pathogenesis in the infected cell is a balance between antiviral responses and subversion of host-cell processes. Many viral proteins specifically interact with host-cell proteins to promote virus biology. Understanding these interactions can lead to knowledge gains about infection and provide potential targets for antiviral therapy. One such virus is Ebola, which has profound consequences for human health and causes viral hemorrhagic fever where case fatality rates can approach 90%. The Ebola virus VP24 protein plays a critical role in the evasion of the host immune response and is likely to interact with multiple cellular proteins. To map these interactions and better understand the potential functions of VP24, label-free quantitative proteomics was used to identify cellular proteins that had a high probability of forming the VP24 cellular interactome. Several known interactions were confirmed, thus placing confidence in the technique, but new interactions were also discovered including one with ATP1A1, which is involved in osmoregulation and cell signaling. Disrupting the activity of ATP1A1 in Ebola-virus-infected cells with a small molecule inhibitor resulted in a decrease in progeny virus, thus illustrating how quantitative proteomics can be used to identify potential therapeutic targets.


Exposure to disease agents in the endangered Iberian lynx (Lynx pardinus).
The Iberian lynx (Lynx pardinus) is the most endangered felid species in the world. Lynx populations have decreased dramatically in size and distribution in the last four decades, thus becoming increasingly vulnerable to catastrophic events such as epizooties. From 1989 to 2000, serum samples were obtained from 48 free-ranging lynx captured in the Doñana National Park (DNP, n = 31) and mountains of Sierra Morena (SM, n = 17) in southern Spain. Samples were tested for antibodies against Toxoplasma gondii, feline herpesvirus 1 (FHV-1), feline calicivirus (FCV), feline/canine parvovirus (FPV/CPV), feline coronavirus, feline immunodeficiency virus (FIV), feline leukaemia virus and canine distemper virus (CDV) and for FeLV p27 antigen, to document baseline exposure levels. Antibodies against T. gondii were detected in 44% of lynx, with a significantly greater prevalence in DNP (61%) than in SM (12%). In DNP, prevalence was significantly higher in adult (81%) than in juvenile and sub-adult (41%) lynx, but no such difference was observed in SM. Low prevalences (≤11%) of minimally positive titres were found for FHV-1, FCV and FPV/CPV. This, combined with the lack of evidence for exposure to CDV, FIV and FeLV, suggests that these lynx populations are naïve and might be vulnerable to a disease outbreak in the future. Because of the reduced size of lynx populations, the documented low level of genetic variation (particularly in the DNP population) coupled with the recently documented state of immune depletion in a majority of necropsied lynx, it is important to better understand the threat and potential impact that disease agents might pose for the conservation of this endangered species. Future surveillance programs must include possible disease reservoir hosts such as domestic cats and dogs and other wild carnivores.


Infectious episodes before and after a marathon race.
The aim of this study was to investigate the incidence of self-reported infectious episodes (IE) during 3 weeks before (pre-IE) and 3 weeks after (post-IE) a marathon race and relate these figures to training status, running time, socioeconomic and demographic factors. Two questionnaires, including questions about important factors for IE incidence, were given to a representative cohort of 1694 runners (17% of all finishers) in the Stockholm Marathon 2000. Pre-IE incidence in the cohort was 17% with no difference between women and men. Post-IE incidence in the whole cohort was 19% with no significant (P>0.05) difference between women and men. The post-IE incidence in runners without a pre-IE was 16% (P>0.05 to pre-IE incidence). In the group of runners with pre-IE, 33% experienced an IE after the race also (P<0.05 to Pre-IE incidence). A logistic regression analysis showed that younger age and pre race health status and, for men only, experienced nausea during and after the race were depended factors explaining post-IE incidence. Younger runners were more prone to experience IE both before and after the race. There was no relation between training volume 6 months before the race, finishing time and socioeconomic and demographic factors and pre-IE or post-IE. This study does not support the theory of increased infection rate after exhaustive long-distance running ("The Open Window Theory") in recreational runners, but suggests that the sometimes experienced increased rate of infections among athletes can be caused by strenuous exercise too soon after an infection.


SMNDelta7, the major product of the centromeric survival motor neuron (SMN2) gene, extends survival in mice with spinal muscular atrophy and associates with full-length SMN.
Spinal muscular atrophy (SMA) is an autosomal recessive disorder in humans which results in the loss of motor neurons. It is caused by reduced levels of the survival motor neuron (SMN) protein as a result of loss or mutation of the SMN1 gene. SMN is encoded by two genes, SMN1 and SMN2, which essentially differ by a single nucleotide in exon 7. As a result, the majority of the transcript from SMN2 lacks exon 7 (SMNDelta7). SMNDelta7 may be toxic and detrimental in SMA, which, if true, could lead to adverse effects with drugs that stimulate expression of SMN2. To determine the role of SMNDelta7 in SMA, we created transgenic mice expressing SMNDelta7 and crossed them onto a severe SMA background. We found that the SMNDelta7 is not detrimental in that it extends survival of SMA mice from 5.2 to 13.3 days. Unlike mice with selective deletion of SMN exon 7 in muscle, these mice with a small amount of full-length SMN (FL-SMN) did not show a dystrophic phenotype. This indicates that low levels of FL-SMN as found in SMA patients and absence of FL-SMN in muscle tissue have different effects and raises the question of the importance of high SMN levels in muscle in the presentation of SMA. SMN and SMNDelta7 can associate with each other and we suggest that this association stabilizes SMNDelta7 protein turnover and ameliorates the SMA phenotype by increasing the amount of oligomeric SMN. The increased survival of the SMNDelta7 SMA mice we report will facilitate testing of therapies and indicates the importance of considering co-complexes of SMN and SMNDelta7 when analyzing SMN function.


PlanHab: the combined and separate effects of 16 days of bed rest and normobaric hypoxic confinement on circulating lipids and indices of insulin sensitivity in healthy men.
PlanHab is a planetary habitat simulation study. The atmosphere within future space habitats is anticipated to have reduced Po2, but information is scarce as to how physiological systems may respond to combined exposure to moderate hypoxia and reduced gravity. This study investigated, using a randomized-crossover design, how insulin sensitivity, glucose tolerance, and circulating lipids were affected by 16 days of horizontal bed rest in normobaric normoxia [NBR: FiO2 = 0.209; PiO2 = 133.1 (0.3) mmHg], horizontal bed rest in normobaric hypoxia [HBR: FiO2 = 0.141 (0.004); PiO2 = 90.0 (0.4) mmHg], and confinement in normobaric hypoxia combined with daily moderate intensity exercise (HAMB). A mixed-meal tolerance test, with arterialized-venous blood sampling, was performed in 11 healthy, nonobese men (25-45 yr) before (V1) and on the morning ofday 17of each intervention (V2). Postprandial glucose and c-peptide response were increased at V2 of both bed rest interventions (P< 0.05 in each case), with c-peptide:insulin ratio higher at V2 in HAMB and HBR, both in the fed and fasted state (P< 0.005 in each case). Fasting total cholesterol was reduced at V2 in HAMB [-0.47 (0.36) mmol/l;P< 0.005] and HBR [-0.55 (0.41) mmol/l;P< 0.005]. Fasting HDL was lower at V2 in all interventions, with the reduction observed in HBR [-0.30 (0.21) mmol/l] greater than that measured in HAMB [-0.13 (0.14) mmol/l;P< 0.005] and NBR [-0.17 (0.15) mmol/l;P< 0.05]. Hypoxia did not alter the adverse effects of bed rest on insulin sensitivity and glucose tolerance but appeared to increase insulin clearance. The negative effect of bed rest on HDL was compounded in hypoxia, which may have implications for long-term health of those living in future space habitats.


Acanthamoeba keratitis: the role of domestic tap water contamination in the United Kingdom.
The incidence of acanthamoeba keratitis (AK) in the UK is some 15 times that in the United States and seven times that in Holland. To investigate reasons for this higher frequency, a study of the role of domestic tap water as a potential source of AK was undertaken. Tap outlets from the homes of 27 patients with culture-proven AK were sampled and cultured for free-living amoebae (FLA). For all Acanthamoeba isolates, mitochondrial DNA (mtDNA) restriction fragment length polymorphisms (RFLPs) and cytochrome oxidase (cox 1/2) sequence typing was performed to determine the similarity between corneal and tap water isolates. FLA, including Acanthamoeba, were isolated from 24 (89%) of 27 homes, and the presence within the homes varied significantly with tap water temperature and location: 19 (76%) of 25 bathroom sink cold taps sampled compared with 6 (24%) of 25 hot and 9 (47%) of 19 kitchen cold taps compared with 3 (16%) of 19 of hot kitchen taps. Acanthamoeba were isolated from 8 (30%) of 27 homes (five bathroom sink cold taps, one cloakroom cold tap, one bath, and one bedroom sink mixer [hot/cold] taps). In six cases, identical Acanthamoeba mtDNA profiles were found for the clinical and home tap water isolates. In keeping with UK plumbing practice, 24 of 27 homes had internal roof water storage tanks to supply domestic taps, but the mains fed the kitchen cold tap. Water storage tanks promote colonization of domestic water with FLA, including Acanthamoeba, and hence increase the risk of AK. This accounts for the significantly greater incidence of AK in the UK and supports advice to avoid using tap water in contact lens care routines.


Enhancement of antibody responses to influenza vaccination in the elderly following a cognitive-behavioural stress management intervention.
Previous research has demonstrated that the psychological morbidity experienced by informal caregivers is associated with increased vulnerability to infectious diseases, in particular influenza. A pragmatic trial was conducted to examine whether a stress management intervention (SMI) could reduce psychological morbidity and enhance the antibody response to influenza vaccination in the elderly, and whether changes in immune response of SMI participants were associated with hypothalamic-pituitary-adrenal (HPA) axis activity. Forty-three elderly spousal carers of dementia patients and 27 non-carer controls were recruited. Sixteen carers were allocated to an 8-week SMI or a non-intervention condition (n = 27). The non-carers formed a no treatment, 'normal' comparison group. At the end of the SMI or its equivalent time period, all participants received an influenza vaccination. IgG antibody titres to the vaccine were measured 0, 2, 4 and 6 weeks post-vaccine. There was evidence of elevated distress in both carer groups compared with non-carer controls throughout the SMI period, but no between-group differences in salivary cortisol. Immune responses to the vaccine revealed that 50% of SMI carers, 7% of non-intervention carers and 29% of non-carer controls produced a four-fold increase in antibody titre. The immune response to influenza vaccination appears amenable to improvement through stress management, although the mechanisms underlying this effect remain unclear.


Contact and friction of nanoasperities: effects of adsorbed monolayers.
Molecular dynamics simulations are used to study contact between a rigid, nonadhesive, and spherical tip with radius of order 30 nm and a flat elastic substrate covered with a fluid monolayer of adsorbed chain molecules. Previous studies of bare surfaces showed that the atomic scale deviations from a sphere that are present on any tip constructed from discrete atoms lead to significant deviations from continuum theory and dramatic variability in friction forces. Introducing an adsorbed monolayer leads to larger deviations from continuum theory but decreases the variations between tips with different atomic structure. Although the film is fluid, it remains in the contact and behaves qualitatively like a thin elastic coating except for certain tips at high loads. Measures of the contact area based on the moments or outer limits of the pressure distribution and on counting contacting atoms are compared. The number of tip atoms making contact during a time interval Deltat grows as a power of Deltat when the film is present and as the logarithm of Deltat for bare surfaces. Friction is measured by displacing the tip at a constant velocity or pulling the tip with a spring. Both static and kinetic friction rise linearly with load at small loads. Transitions in the state of the film lead to nonlinear behavior at large loads. The friction is less clearly correlated with contact area than load.


Examination of thromboxane synthase as a prognostic factor and therapeutic target in non-small cell lung cancer.
Thromboxane synthase (TXS) metabolises prostaglandin H2 into thromboxanes, which are biologically active on cancer cells. TXS over-expression has been reported in a range of cancers, and associated with a poor prognosis. TXS inhibition induces cell death in-vitro, providing a rationale for therapeutic intervention. We aimed to determine the expression profile of TXS in NSCLC and if it is prognostic and/or a survival factor in the disease. TXS expression was examined in human NSCLC and matched controls by western analysis and IHC. TXS metabolite (TXB2) levels were measured by EIA. A 204-patient NSCLC TMA was stained for COX-2 and downstream TXS expression. TXS tissue expression was correlated with clinical parameters, including overall survival. Cell proliferation/survival and invasion was examined in NSCLC cells following both selective TXS inhibition and stable TXS over-expression. TXS was over-expressed in human NSCLC samples, relative to matched normal controls. TXS and TXB2 levels were increased in protein (p < 0.05) and plasma (p < 0.01) NSCLC samples respectively. TXS tissue expression was higher in adenocarcinoma (p < 0.001) and female patients (p < 0.05). No significant correlation with patient survival was observed. Selective TXS inhibition significantly reduced tumour cell growth and increased apoptosis, while TXS over-expression stimulated cell proliferation and invasiveness, and was protective against apoptosis. TXS is over-expressed in NSCLC, particularly in the adenocarcinoma subtype. Inhibition of this enzyme inhibits proliferation and induces apoptosis. Targeting thromboxane synthase alone, or in combination with conventional chemotherapy is a potential therapeutic strategy for NSCLC.


The design and conduct of a randomized clinical trial comparing emergency department initiation of sublingual versus a 7-day extended-release injection formulation of buprenorphine for opioid use disorder: Project ED Innovation.
ED-INNOVATION (Emergency Department-INitiated bupreNOrphine VAlidaTION) is a Hybrid Type-1 Implementation-Effectiveness multisite emergency department (ED) study funded through The Helping to End Addiction Long-termSM Initiative, or NIH HEAL InitiativeSM efforts to increase access to medications for opioid use disorder (OUD). We use components of Implementation Facilitation to enhance adoption of ED-initiated buprenorphine (BUP) at approximately 30 sites. Subsequently we compare the effectiveness of two BUP formulations, sublingual (SL-BUP) and 7-day extended-release injectable (CAM2038, XR-BUP) in a randomized clinical trial (RCT) of approximately 2000 patients with OUD on the primary outcome of engagement in formal addiction treatment at 7 days. Secondary outcomes assessed at 7 and 30 days include self-reported opioid use, craving and satisfaction, health service utilization, overdose events, and engagement in formal addiction treatment (30 days) and receipt of medications for OUD (at 7 and 30 days). A sample size of 1000 per group provides 90% power at the 2-sided significance level to detect a difference in the primary outcome of 8% and accommodates a 15% dropout rate. We will compare the cost effectiveness of the two treatments on the primary outcome using the incremental cost-effectiveness ratio. We will also conduct an ancillary study in approximately 75 patients experiencing minimal to no opioid withdrawal who will undergo XR-BUP initiation. If the ancillary study demonstrates safety, we will expand the eligibility criteria for the RCT to include individuals with minimal to no opioid withdrawal. The results of these studies will inform implementation of ED-initiated BUP in diverse EDs which has the potential to improve treatment access.


Analysis of GAD65 autoantibodies in Stiff-Person syndrome patients.
Autoantibodies to the 65-kDa isoform of glutamate decarboxylase GAD65 (GAD65Ab) are strong candidates for a pathological role in Stiff-Person syndrome (SPS). We have analyzed the binding specificity of the GAD65Ab in serum and cerebrospinal fluid (CSF) of 12 patients with SPS by competitive displacement studies with GAD65-specific rFab-derived from a number of human and mouse mAbs specific for different determinants on the Ag. We demonstrate considerable differences in the epitope specificity when comparing paired serum and CSF samples, suggesting local stimulation of B cells in the CSF compartment of these patients. Moreover, these autoantibodies strongly inhibit the enzymatic activity of GAD65, thus blocking the formation of the neurotransmitter gamma-aminobutyric acid. The capacity of the sera to inhibit the enzymatic activity of GAD65 correlated with their binding to a conformational C-terminal Ab epitope. Investigation of the inhibitory mechanism revealed that the inhibition could not be overcome by high concentrations of glutamate or the cofactor pyridoxal phosphate, suggesting a noncompetitive inhibitory mechanism. Finally, we identified a linear epitope on amino acids residues 4-22 of GAD65 that was recognized solely by autoantibodies from patients with SPS but not by serum from type 1 diabetes patients. A mAb (N-GAD65 mAb) recognizing this N-terminal epitope was successfully humanized to enhance its potential therapeutic value by reducing its overall immunogenicity.


Analysis of Postoperative Venous Thromboembolism in Patients With Chronic Ulcerative Colitis: Is It the Disease or the Operation?
Patients with IBD have a higher baseline risk of venous thromboembolism, which further increases with surgery. Therefore, extended venous thromboembolism chemoprophylaxis has been suggested in certain high-risk cohorts. The purpose of this study was to determine whether the underlying diagnosis, operative procedure, or both influence the incidence of postoperative venous thromboembolism. This was a retrospective review. The American College of Surgeons-National Surgical Quality Improvement Project database was analyzed. The NSQIP database was queried for patients with chronic ulcerative colitis and non-IBD undergoing colorectal resections using surgical Current Procedural Terminology codes modeled after the 3 stages used for the surgical management of chronic ulcerative colitis from 2005 to 2013. We measured 30-day postoperative venous thromboembolism risk in patients with chronic ulcerative colitis based on operative stage and risk factors for development of venous thromboembolism. A total of 18,833 patients met inclusion criteria, with an overall rate of venous thromboembolism of 3.8. Among procedure risk groups, venous thromboembolism rates were high risk, 4.4%; intermediate risk, 1.6%; and low risk, 0.7% (across risk groups, p < 0.01). Emergent case subjects exhibited a higher rate of venous thromboembolism than their elective counterparts (6.9% vs 3.1%). Factors significantly associated with venous thromboembolism on adjusted analysis included emergent risk case (adjusted OR = 7.85), high-risk elective case (adjusted OR = 5.07), intermediate-risk elective case (adjusted OR = 2.69), steroid use (adjusted OR = 1.54), and preoperative albumin <3.5 g/dL (adjusted OR = 1.45). Because of its retrospective nature, correlation between procedures and venous thromboembolism risk can be demonstrated, but causation cannot be proven. In addition, data on inpatient and extended venous thromboembolism prophylaxis use are not available. Emergent status and operative procedure are the 2 highest risk factors for postoperative venous thromboembolism. Extended venous thromboembolism prophylaxis might be appropriate for patients undergoing these high-risk procedures or any emergent colorectal procedures. See Video Abstract at http://links.lww.com/DCR/A339.


An N-rich metal-organic framework with an rht topology: high CO2 and C2 hydrocarbons uptake and selective capture from CH4.
We report the storage capacities and separation selectivity of an rht-type s-heptazine-based metal organic framework (MOF), [Cu3(TDPAH)(H2O)3]·13H2O·8DMA, 1, (where TDPAH is 2,5,8-tris(3,5-dicarboxylphenylamino)-s-heptazine and DMA is N,N-dimethylacetamide) for C2 hydrocarbons and CO2 over CH4. MOF 1 displays the highest C2H2/CH4 selectivity of 80.9 as well as record high C2H4 and C2H6 adsorption enthalpies. Theoretical calculations reveal that s-heptazine and NH groups within the framework have synergistic effects on CO2 binding.


Design of a data-driven predictive controller for start-up process of AMT vehicles.
In this paper, a data-driven predictive controller is designed for the start-up process of vehicles with automated manual transmissions (AMTs). It is obtained directly from the input-output data of a driveline simulation model constructed by the commercial software AMESim. In order to obtain offset-free control for the reference input, the predictor equation is gained with incremental inputs and outputs. Because of the physical characteristics, the input and output constraints are considered explicitly in the problem formulation. The contradictory requirements of less friction losses and less driveline shock are included in the objective function. The designed controller is tested under nominal conditions and changed conditions. The simulation results show that, during the start-up process, the AMT clutch with the proposed controller works very well, and the process meets the control objectives: fast clutch lockup time, small friction losses, and the preservation of driver comfort, i.e., smooth acceleration of the vehicle. At the same time, the closed-loop system has the ability to reject uncertainties, such as the vehicle mass and road grade.


A role for recombination in centromere function.
Centromeres are essential for chromosome segregation during both mitosis and meiosis. There are no obvious or conserved DNA sequence motif determinants for centromere function, but the complex centromeres found in the majority of eukaryotes studied to date consist of repetitive DNA sequences. A striking feature of these repeats is that they maintain a high level of inter-repeat sequence identity within the centromere. This observation is suggestive of a recombination mechanism that operates at centromeres. Here we postulate that inter-repeat homologous recombination plays an intrinsic role in centromere function by forming covalently closed DNA loops. Moreover, the model provides an explanation of why both inverted and direct repeats are maintained and how they contribute to centromere function.


Advancing psychiatry trainee wellbeing and safety: Building on RANZCP Position Statement 48.
The RANZCP recently released Position Statement 48 on the 'safety and wellbeing of psychiatrists and those in psychiatry training'. This article will examine the five key domains highlighted by this statement and provide suggestions on how this guidance might relate to trainees. The domains covered are (i) safe workplaces free from discrimination, bullying, harassment, and violence; (ii) positive team cultures; (iii) positive professional peer relationships; (iv) supportive supervision and mentorship; and (v) work-life balance. In the context of the significant and complex demands of psychiatry training, Position Statement 48 helps to provide a framework for trainees and the people and systems that support them to understand, anticipate, and successfully manage the potential risks to trainee wellbeing and safety.


Androgen Receptor CAG Repeat Length as a Risk Factor of Late-Onset Hypogonadism in a Korean Male Population.
Testosterone action is mediated through the androgen receptor (AR), whose sensitivity is influenced by the AR CAG repeat polymorphism. However, the relation between late-onset hypogonadism (LOH) and AR CAG repeat length is unclear and studies of Asian populations are limited. To investigate the relation between AR CAG repeat length and LOH in Korean men. 263 Korean men (mean age = 63.43 ± 10.9 years) were enrolled from 2014 to 2015. LOH diagnosis was based on a serum testosterone level lower than 3.5 ng/mL and positive androgen deficiency according to the Aging Males' Symptom Scale (AMS). Total testosterone levels and answers to the LOH-related questionnaire were analyzed. The relation between AR CAG repeat length and LOH was determined. Mean CAG repeat length was 22.1 ± 4.6 and mean serum testosterone levels were 2.6 ± 0.7 and 6.0 ± 2.0 ng/mL in men with and without LOH, respectively. Men with LOH showed significantly longer AR CAG repeat lengths than men without LOH (26.1 vs 21.6, P < .001). Longer CAG repeat lengths were correlated with higher AMS total scores (r = 0.454, P = .001) and AMS psychotic, somatic, and sexual sub-scores (r = 0.276, 0.246, and 0.571, P = .006, .007, .001, respectively) and significantly lower 5-item International Index of Erectile Function scores (r = -0.261, P = .001). Multivariate analysis showed that patient age and CAG repeat length were independently associated with LOH (odds ratio = 1.05 and 1.29, P = .041 and <.001, respectively). A longer CAG repeat length is associated with LOH symptoms and LOH. Associations between CAG repeats and LOH were verified in Korean patients. Moreover, a longer CAG repeat length was shown to be an independent risk factor for LOH. Limitations included the small number of LOH patients studied and that other sex hormone-associated factors were not measured. AR CAG repeat length was associated with LOH prevalence and clinical symptoms in this Korean male population. Thus, it is important to measure CAG repeat length for patients with LOH symptoms with normal testosterone levels. Kim JW, Bae YD, Ahn ST, et al. Androgen Receptor CAG Repeat Length as a Risk Factor of Late-Onset Hypogonadism in a Korean Male Population. Sex Med 2018;6:203-209.


Self-efficacy and pain behavior among subjects with fibromyalgia.
Given the lack of objective physical measures for assessing fibromyalgia syndrome (FS), the role of pain assessment is particularly important. The role of psychological factors is controversial among FS patients. This study was designed to better understand the relationship between pain behaviors and psychological variables. Specifically, this study (1) refined a pain behavior observation (PBO) methodology for use with FS patients, (2) determined whether stretching is a valid pain behavior, and (3) assessed whether psychological variables including self-efficacy and/or depression can predict pain behaviors after controlling for disease severity and age. The 73 FS subjects meeting the American College of Rheumatology classification system completed questionnaires measuring self-efficacy, depression, and pain. Trained physicians conducted tender-point examinations. Subjects were video-taped using a standardized procedure. Two trained raters independently coded all pain behaviors. Kappa coefficients and correlations among pain behaviors and self-reported pain indicated that the PBO method was both reliable and valid. However, the newly defined pain behavior 'stretching' was found to be negatively associated with self-reported pain. Hierarchical multiple regression (MR) analyses revealed that depression did not predict pain behavior over and above myalgic scores and age; however, in 3 separate MR analyses, self-efficacy for function, pain, and other symptoms each predicted pain behavior over and above myalgic scores and age. This study indicated that the original pain behavior scoring methodology is appropriate for use with the FS population and should not be modified to include the pain behavior 'stretching'. Self-efficacy was related to pain behavior while depression was not among this FS sample.


Pneumatic actuated robotic assistant system for aortic valve replacement under MRI guidance.
We present a pneumatic actuated robotic assistant system for transapical aortic valve replacement under MRI guidance in a beating heart. This is a minimally invasive procedure that is currently performed manually inside the MRI bore. A robotic assistance system that integrates an interactive real-time MRI system, a robotic arm with a newly developed robotic valve delivery module, as well as user interfaces for the physician to plan the procedure and manipulate the robot, would be advantageous for the procedure. An Innomotion arm with hands-on cooperative interface was used as a device holder. A compact MRI compatible robotic delivery module was developed for delivering both balloon-expandable and self-expanding prostheses. A compact fiducial that can be placed close to the volume of interest and requires a single image plane was used for image-based robot registration. The system provides different user interfaces at various stages of the procedure. We present the development and evaluation of the components and the system in ex-vivo experiments.


[Homozygous familial hypercholesterolaemia: Spanish adaptation of the position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society. Consensus document of the Spanish Society of Arteriosclerosis (SEA) and Familial Hypercholesterolaemia Foundation (FHF)].
Homozygous familial hypercholesterolaemia (HoFH) is a rare life-threatening disease characterized by markedly elevated circulating levels of low-density lipoprotein cholesterol (LDL-C) and accelerated, premature atherosclerotic cardiovascular disease (ACVD). The Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society (EAS) has recently published a clinical guide to diagnose and manage HoFH (Eur Heart J. 2014;35:2146-57). Both the Spanish Society of Atherosclerosis (SEA) and Familial Hypercholesterolaemia Foundation (FHF) consider this European Consensus document of great value and utility. However, there are particularities in our country which advise to have a Spanish adaptation of the European HoFH document in order to approximate this clinical guide to our environment. In Spain, chronic treatment with statins, ezetimibe and resins (colesevelam) has a reduced contribution in the National Health System (NHS) and is one of the few European countries where LDL apheresis is included in the Basic Service Portfolio coverage. This Spanish document also includes clinical experience in the management of these patients in our country. The Drafting Committee emphasizes the need for early identification of HoFH patients, prompt referral to specialized units, and an early and appropriate treatment. These recommendations will provide a guidance for HoFH patient management in Spain.


The economic burden of gluten-free products and gluten-free diet: a cost estimation analysis in Greece.
Adherence to a gluten-free diet (GFD) demonsrates various difficulties, including the high cost of the diet. The present study aimed to (i) compare the cost of gluten-free products (GFP) from supermarkets and pharmacies with the cost of their conventional counterparts and (ii) estimate the weekly economic burden of a GFD. The prices of all food products labelled as 'gluten-free' available at four supermarket chains in Athens, as well as the prices of all similar conventional food products, were recorded. The prices of the pharmacy GFP were recorded from the official list of the National Health Service Organisation. For every product, the price per 100 g was calculated. All products were classified into 24 categories, which consisted of three subcategories: conventional, supermarket GFP and pharmacy GFP. Three weekly menus were designed for children, adolescents and adults, selecting the upper levels of energy intake, to cover the majority of the patients. For all three weekly menus, the price difference between conventional and GFP, both from supermarkets and pharmacies, was calculated. Compared with conventional food products, all supermarket GFP, except for one, were more expensive by 22-334% (P < 0.05) and all pharmacy GFP were more expensive by 88-476% (P < 0.05). The weekly economic burden of a GFD ranged from €12 to €28 per week, depending on age and GFP place of purchase. The present study confirms the higher cost of GFP compared to their conventional equivalents in Greece, leading to a weekly economic burden for people on a gluten-free diet.


Nablus mask-like facial syndrome is caused by a microdeletion of 8q detected by array-based comparative genomic hybridization.
In 2000, Teebi reported on a 4-year-old boy with a distinctive pattern of malformation, which he termed the "Nablus mask-like facial syndrome" (OMIM# 608156). Characterization of this syndrome has been difficult because of the paucity of patients described in the medical literature and its unknown etiology and pathogenesis. We present two patients with Nablus mask-like facial syndrome who both display a microdeletion in the 8q21-8q22 region detected by array-based comparative genomic hybridization. Patient 1, a boy, has a distinct facial appearance characterized by severe blepharophimosis, tight-appearing glistening facial skin, sparse and unruly hair, a flat and broad nose, and distinctive ears that are triangular in shape with prominent antihelices. He also demonstrates camptodactyly, contractures, unusual dentition, cryptorchidism, mild developmental delay, and a happy demeanor. Patient 2, a girl with a strikingly similar phenotype, was previously described in a report by Salpietro et al. 2003. She has distinctive ears, dental anomalies, and developmental delay. The etiology of her pattern of malformation was not identified at that time. Although high-resolution chromosome and subtelomeric FISH analyses were normal, array-based comparative genomic hybridization revealed an approximately 4 Mb deletion involving the 8q21.3-8q22.1 region in both patients. This region encompasses a number of genes that may contribute to this unique phenotype. These results demonstrate a chromosomal microdeletion as the etiology of Nablus mask-like facial syndrome and emphasize the diagnostic utility of array-based comparative genomic hybridization in the evaluation of multiple malformation syndromes of previously unrecognized causation.


Genome Size Evolution Differs Between Drosophila Subgenera with Striking Differences in Male and Female Genome Size in Sophophora.
Genome size varies across the tree of life, with no clear correlation to organismal complexity or coding sequence, but with differences in non-coding regions. Phylogenetic methods have recently been incorporated to further disentangle this enigma, yet most of these studies have focused on widely diverged species. Few have compared patterns of genome size change in closely related species with known structural differences in the genome. As a consequence, the relationship between genome size and differences in chromosome number or inter-sexual differences attributed to XY systems are largely unstudied. We hypothesize that structural differences associated with chromosome number and X-Y chromosome differentiation, should result in differing rates and patterns of genome size change. In this study, we utilize the subgenera within the Drosophila to ask if patterns and rates of genome size change differ between closely related species with differences in chromosome numbers and states of the XY system. Genome sizes for males and females of 152 species are used to answer these questions (with 92 newly added or updated estimates). While we find no relationship between chromosome number and genome size or chromosome number and inter-sexual differences in genome size, we find evidence for differing patterns of genome size change between the subgenera, and increasing rates of change throughout time. Estimated shifts in rates of change in sex differences in genome size occur more often in Sophophora and correspond to known neo-sex events.


Knowledge and Perceptions Regarding Palliative Care Among Religious Leaders in Uasin Gishu County, Kenya: Survey and Focus Group Analysis.
Spirituality and religion are at the core of Kenyan life. Pastoral leaders play a key role in shaping the individual and community's response to living with chronic and life-threatening illnesses. Involvement of religious leaders would therefore be critical in advocacy and education efforts in palliative care (PC) to address the needs of this population. The goal of this study was to evaluate the knowledge and perceptions of religious leaders in Western Kenya regarding PC. This was a mixed-methods study with 86 religious leaders utilizing a 25-question survey followed by 5-person focus group discussions. Eighty-one percent of participants agreed that pastors should encourage members with life-threatening illnesses to talk about death and dying. However, almost a third of participants (29%) also agreed with the statement that full use of PC can hasten death. The pastors underscored challenges in end-of-life spiritual preparation as well as the importance of traditional beliefs in shaping cultural norms. Pastors supported the need for community-based PC education and additional training in PC for religious leaders. The results of this study confirm the dominant role of religion and spirituality in PC in Kenya. This dominant role in shaping PC is tied closely to Kenyan attitudes and norms surrounding death and dying.


Invasion of human deep nodular endometriotic lesions is associated with collective cell migration and nerve development.
To study the mechanisms of invasion and innervation of deep endometriosis in women. Morphologic and immunohistochemical analysis of human endometriotic lesions. Academic research unit. Seventeen biopsy samples of deep endometriotic lesions were collected from patients undergoing surgery for deep endometriosis. The endometriotic samples were divided into two parts: the front (the most invasive area of lesions, approaching rectal infiltration) and center (the area close to the posterior part of the cervix). To elucidate: gland morphology, proliferation, and expression of adhesion molecules (β-catenin, E-cadherin, and N-cadherin) to determine the possible role of collective cell migration (CCM) in the invasion process; and nerve growth factor (NGF) and nerve fiber density (NFD) values to shed further light on the mechanism of innervation. Glands from the front showed significantly reduced thickness, but significantly higher proliferation. β-Catenin expression was similar between the lesion center and front. E-cadherin levels were significantly lower and N-cadherin levels significantly higher in glands located at the front of the lesions. Expression of matrix metalloproteinase-9 was significantly higher in glands and stromal cells located at the invasion front. NFD and NGF expression were also significantly higher at the lesion front. Although some data in the literature point to features of epithelial to mesenchymal transition in human deep nodular endometriosis, our study suggests that gland invasion in these lesions is dominated by CCM. Innervation of deep nodular endometriotic lesions may be a consequence of nerve recruitment from surrounding organs.


Distributed hierarchical processing in the primate cerebral cortex.
In recent years, many new cortical areas have been identified in the macaque monkey. The number of identified connections between areas has increased even more dramatically. We report here on (1) a summary of the layout of cortical areas associated with vision and with other modalities, (2) a computerized database for storing and representing large amounts of information on connectivity patterns, and (3) the application of these data to the analysis of hierarchical organization of the cerebral cortex. Our analysis concentrates on the visual system, which includes 25 neocortical areas that are predominantly or exclusively visual in function, plus an additional 7 areas that we regard as visual-association areas on the basis of their extensive visual inputs. A total of 305 connections among these 32 visual and visual-association areas have been reported. This represents 31% of the possible number of pathways if each area were connected with all others. The actual degree of connectivity is likely to be closer to 40%. The great majority of pathways involve reciprocal connections between areas. There are also extensive connections with cortical areas outside the visual system proper, including the somatosensory cortex, as well as neocortical, transitional, and archicortical regions in the temporal and frontal lobes. In the somatosensory/motor system, there are 62 identified pathways linking 13 cortical areas, suggesting an overall connectivity of about 40%. Based on the laminar patterns of connections between areas, we propose a hierarchy of visual areas and of somatosensory/motor areas that is more comprehensive than those suggested in other recent studies. The current version of the visual hierarchy includes 10 levels of cortical processing. Altogether, it contains 14 levels if one includes the retina and lateral geniculate nucleus at the bottom as well as the entorhinal cortex and hippocampus at the top. Within this hierarchy, there are multiple, intertwined processing streams, which, at a low level, are related to the compartmental organization of areas V1 and V2 and, at a high level, are related to the distinction between processing centers in the temporal and parietal lobes. However, there are some pathways and relationships (about 10% of the total) whose descriptions do not fit cleanly into this hierarchical scheme for one reason or another. In most instances, though, it is unclear whether these represent genuine exceptions to a strict hierarchy rather than inaccuracies or uncertainities in the reported assignment.


Loss of alpha6 integrins in keratinocytes leads to an increase in TGFbeta and AP1 signaling and in expression of differentiation genes.
Mice lacking the alpha6 integrin chain die at birth with severe skin blistering. To further study the function of alpha6 integrin in skin, we generated conditionally immortalized cell lines from the epidermis of wild-type and alpha6 deficient mouse embryos. Mutant cells presented a decreased adhesion on laminin 5, the major component of the basement membrane in the skin, and on laminins 10/11 and 2. A DNA array analysis revealed alterations in the expression of extracellular matrix (ECM) components including laminin 5, cytoskeletal elements, but also membrane receptors like the hemidesmosomal components integrin beta4 and collagen XVII, or growth factors and signaling molecules of the TGFbeta, EGF, and Wnt pathways. Finally, an increase of several epidermal differentiation markers was observed in cells and tissue at the protein level. Further examination of the mutant tissue revealed alterations in the filaggrin signal. These differences may be linked to an upregulation of the TGFbeta and the Jun/Fos pathways in mutant keratinocytes. These results are in favor of a role for integrin alpha6beta4 in the maintenance of basal keratinocyte properties and epidermal homeostasis.


Limnohabitans australis sp. nov., isolated from a freshwater pond, and emended description of the genus Limnohabitans.
A chemo-organotrophic, aerobic, non-motile strain, MWH-BRAZ-DAM2D(T), isolated from a freshwater pond in Brazil, was characterized phenotypically, phylogenetically and chemotaxonomically. Phylogenetic analysis of 16S rRNA gene sequences indicated affiliation of the strain with the genus Limnohabitans (Comamonadaceae, Betaproteobacteria). 16S rRNA gene sequence similarities between the isolate and Limnohabitans curvus MWH-C5(T), representing the type species of the genus, and the type strains of Limnohabitans parvus and Limnohabitans planktonicus were 98.2, 96.5 and 97.0 %, respectively. DNA-DNA reassociation analyses with DNA of the type strains of all three previously described Limnohabitans species revealed similarity values in the range 26.2-44.6 %. The predominant fatty acids of the isolate were C(16 : 1)ω7c/ω6c, C(16 : 0), C(12 : 0) and C(8 : 0) 3-OH, the major quinone was ubiquinone Q-8 and the DNA G+C content was 55.8 mol%. The isolate could be discriminated from the type strains of the three Limnohabitans species by several phenotypic traits including differences in the utilization of several carbon sources. Based on the phylogeny of the isolate and its differences from the three most closely related species, the isolate represents a novel species for which the name Limnohabitans australis sp. nov. is proposed. The type strain is MWH-BRAZ-DAM2D(T) (=DSM 21646(T)=CCUG 56719(T)).


ordpy: A Python package for data analysis with permutation entropy and ordinal network methods.
Since Bandt and Pompe's seminal work, permutation entropy has been used in several applications and is now an essential tool for time series analysis. Beyond becoming a popular and successful technique, permutation entropy inspired a framework for mapping time series into symbolic sequences that triggered the development of many other tools, including an approach for creating networks from time series known as ordinal networks. Despite increasing popularity, the computational development of these methods is fragmented, and there were still no efforts focusing on creating a unified software package. Here, we present ordpy (http://github.com/arthurpessa/ordpy), a simple and open-source Python module that implements permutation entropy and several of the principal methods related to Bandt and Pompe's framework to analyze time series and two-dimensional data. In particular, ordpy implements permutation entropy, Tsallis and Rényi permutation entropies, complexity-entropy plane, complexity-entropy curves, missing ordinal patterns, ordinal networks, and missing ordinal transitions for one-dimensional (time series) and two-dimensional (images) data as well as their multiscale generalizations. We review some theoretical aspects of these tools and illustrate the use of ordpy by replicating several literature results.


Predicting coin flips: using resampling and hierarchical models to help untangle the NHL's shoot-out.
Roughly 14% of regular season National Hockey League games since the 2005-06 season have been decided by a shoot-out, and the resulting allocation of points has impacted play-off races each season. But despite interest from fans, players and league officials, there is little in the way of published research on team or individual shoot-out performance. This manuscript attempts to fill that void. We present both generalised linear mixed model and Bayesian hierarchical model frameworks to model shoot-out outcomes, with results suggesting that there are (i) small but statistically significant talent gaps between shooters, (ii) marginal differences in performance among netminders and (iii) few, if any, predictors of player success after accounting for individual talent. We also provide a resampling strategy to highlight a selection bias with respect to shooter assignment, in which coaches choose their most skilled offensive players early in shoot-out rounds and are less likely to select players with poor past performances. Finally, given that per-shot data for shoot-outs do not currently exist in a single location for public use, we provide both our data and source code for other researchers interested in studying shoot-out outcomes.


Development of a practice-based research program.
To establish an infrastructure to collect accurate data from ambulatory settings. The program was developed through an iterative model governed by a process of formative evaluation. The three iterations were a needs assessment, feasibility study and pilot project. Necessary program components were identified as infrastructure, practitioner-researcher partnership, centralized data management and standardized quality assurance measures. Volunteer chiropractors and their staff collected data on patients in their practices in ambulatory settings in the U.S. and Canada. Evaluative measures were counts of participants, patients and completed forms. Standardized, validated and reliable measures collected by patient self-report were used to assess treatment outcomes. These included the SF-36 or SF-12 Health Survey, the Pain Disability Index, and the Global Well-Being Scale. For characteristics for which appropriate standardized instruments were not available, questionnaires were designed and and pilot-tested before use. Information was gathered on practice and patient characteristics and treatment outcomes, but for this report, only those data concerning process evaluation are reported. Through the three program iterations, 65 DCs collected data on 1360 patients, 663 of whom were new patients. Follow-up data recorded by doctors were obtained for more than 70% of patients; a maximum of 50% of patient-completed follow-up forms were collected in the three iterations. This program is capable of providing data for descriptive epidemiology of ambulatory patients, and, with continued effort to maximize follow-up, may have utility in providing insight into utilization patterns and patient outcomes.


Deep phenotyping towards precision psychiatry of first-episode depression - the Brain Drugs-Depression cohort.
Major Depressive Disorder (MDD) is a heterogenous brain disorder, with potentially multiple psychosocial and biological disease mechanisms. This is also a plausible explanation for why patients do not respond equally well to treatment with first- or second-line antidepressants, i.e., one-third to one-half of patients do not remit in response to first- or second-line treatment. To map MDD heterogeneity and markers of treatment response to enable a precision medicine approach, we will acquire several possible predictive markers across several domains, e.g., psychosocial, biochemical, and neuroimaging. All patients are examined before receiving a standardised treatment package for adults aged 18-65 with first-episode depression in six public outpatient clinics in the Capital Region of Denmark. From this population, we will recruit a cohort of 800 patients for whom we will acquire clinical, cognitive, psychometric, and biological data. A subgroup (subcohort I, n = 600) will additionally provide neuroimaging data, i.e., Magnetic Resonance Imaging, and Electroencephalogram, and a subgroup of patients from subcohort I unmedicated at inclusion (subcohort II, n = 60) will also undergo a brain Positron Emission Tomography with the [11C]-UCB-J tracer binding to the presynaptic glycoprotein-SV2A. Subcohort allocation is based on eligibility and willingness to participate. The treatment package typically lasts six months. Depression severity is assessed with the Quick Inventory of Depressive Symptomatology (QIDS) at baseline, and 6, 12 and 18 months after treatment initiation. The primary outcome is remission (QIDS ≤ 5) and clinical improvement (≥ 50% reduction in QIDS) after 6 months. Secondary endpoints include remission at 12 and 18 months and %-change in QIDS, 10-item Symptom Checklist, 5-item WHO Well-Being Index, and modified Disability Scale from baseline through follow-up. We also assess psychotherapy and medication side-effects. We will use machine learning to determine a combination of characteristics that best predict treatment outcomes and statistical models to investigate the association between individual measures and clinical outcomes. We will assess associations between patient characteristics, treatment choices, and clinical outcomes using path analysis, enabling us to estimate the effect of treatment choices and timing on the clinical outcome. The BrainDrugs-Depression study is a real-world deep-phenotyping clinical cohort study of first-episode MDD patients. Registered at clinicaltrials.gov November 15th, 2022 (NCT05616559).


Anaphylaxis diagnosis and treatment at an emergency department in Puerto Rico.
Anaphylaxis is a severe, potentially life-threatening systemic allergic reaction. Most cases of anaphylaxis are encountered and managed at Emergency Departments (ED). We aimed to evaluate all cases of anaphylaxis and of acute allergic reactions presenting to the ED of the Veterans Affairs Caribbean Healthcare System (VACHS) to assess each patient's presentation, the possible cause of that individual's allergic reaction or anaphylaxis, and the treatment or treatments that that person received. We conducted a retrospective review of all of the cases seen at the ED from July 2007 through July 2009 in which a diagnosis of either anaphylaxis (ICD-9-CM 995.0) or allergic reaction (ICD-9-CM 995.3) was made. We reviewed the diagnosis of each case using the anaphylaxis guidelines and compared the presentations, causes, treatments, and outcomes of patients with recognized or unrecognized anaphylaxis. The study included 135 adults. Six patients (4.4%) were diagnosed with anaphylaxis and 129 patients (95.6%) were found to have been suffering from allergic reactions. Among the patients diagnosed with allergic reactions, 25 (23%) met the diagnostic criteria for anaphylaxis but were not recognized as having experienced it. The most common causes for anaphylaxis were food (41.9%), medication (38.7%), and insect bites or stings (12.9%); in 12.9% of the cases, a cause could not be determined. There were no statistically significant differences between groups in terms of demographics, causes, or symptoms. Significant differences were found in patient vital signs upon ED arrival. There was under-treatment, particularly among subjects with unrecognized anaphylaxis. Only 67% of recognized and 4% of unrecognized anaphylaxis were treated with epinephrine (p<0.001). It was more likely for subjects whose anaphylaxis was recognized to be admitted than was the case for patients whose anaphylaxis went unrecognized or who were merely suffering from allergic reactions (p<0.001). Anaphylaxis is under-diagnosed and under-treated in ED patients receiving care at the VACHS. There is a need to improve anaphylaxis recognition and treatment in the ED setting and, in addition, to better identify barriers to optimal health care.


A targeted systematic review of cost analyses for implementation of simulation-based education in healthcare.
Over the past two decades, there has been an increase in the use of simulation-based education for training healthcare providers in technical and non-technical skills. Simulation education and research programs have mostly focused on the impact on clinical knowledge and improvement of technical skills rather than on cost. To study and characterize existing evidence to inform multi-stakeholder investment decisions, we performed a systematic review of the literature on costs in simulation-based education in medicine in general and in neonatal resuscitation as a particular focus. We conducted a systematic literature search of the PubMed database using two targeted queries. The first searched for cost analyses of healthcare simulation-based education more broadly, and the second was more narrowly focused on cost analyses of neonatal resuscitation training. The more general query identified 47 qualified articles. The most common specialties for education interventions were surgery (51%); obstetrics, gynecology, or pediatrics (11%); medicine, nursing, or medical school (11%); and urology (9%), accounting for over 80% of articles. The neonatal resuscitation query identified five qualified articles. The two queries identified seven large-scale training implementation studies, one in the United States and six in low-income countries. There were two articles each from Tanzania and India and one article each from Zambia and Ghana. Methods, definitions, and reported estimates varied across articles, implying interpretation, comparison, and generalization of program effects are challenging. More work is needed to understand the costs, processes, and outcomes likely to make simulation-based education programs cost-effective and scalable. To optimize return on investments in training, assessing resource requirements, associated costs, and subsequent outcomes can inform stakeholders about the potential sustainability of SBE programs. Healthcare stakeholders and decision makers will benefit from more transparent, consistent, rigorous, and explicit assessments of simulation-based education program development and implementation costs in low- and high-income countries.


Measuring the impact of a continuing medical education program on patient blood pressure.
An increased focus on hypertension prevention and control, especially in high-risk populations, may have a substantial impact on cardiovascular health outcomes. A continuing medical education (CME) program trained primary care providers in evidence-based guidelines for hypertension prevention and control. This study evaluated its effectiveness in reducing patients' blood pressure for the sessions occurring from 2003 to 2007. Using the Hypertension Initiative Database, 8183 patients of CME providers (CME patients) were paired with controls and changes in blood pressure, provider visits, prescription months, and the proportion of patients with blood pressure <140/90 mm Hg before and after the intervention date were estimated. In the 2-year period before training and the 2-year period afterwards, CME patients' systolic blood pressure decreased by 1.99 mm Hg and diastolic blood pressure decreased by 1.49 mm Hg. The CME patients displayed an increase in provider visits but no statistically significant change in prescription months. Restricting the analysis to the subsample of patients with uncontrolled hypertension (>140/90 mm Hg), the changes in blood pressure were similar in magnitude to those in the entire population. The CME program, by promoting evidence-based practice, improves patients' blood pressure and could serve as a positive model for future hypertension interventions.


Sea-level lowering during the illinoian glaciation: evidence from a bahama "blue hole".
Stalagmites have been recovered from 45 meters below sea level in an underwater karstic cave ("blue hole") near Andros Island in the Bahamas. Uranium series ages, corrected for contamination of the sample by young marine carbonate replacements, show that the speleothem was deposited between 160,000 and 139,000 years before the present. This period corresponds to the Illinoian glacial event and demonstrates that sea level must have been lowered by at least 42 meters (allowing for subsidence) from its present position during this time.


Analysis of a mesoscale infiltration and water seepage test in unsaturated fractured rock: Spatial variabilities and discrete fracture patterns.
A mesoscale (21 m in flow distance) infiltration and seepage test was recently conducted in a deep, unsaturated fractured rock system at the crossover point of two underground tunnels. Water was released from a 3 mx4 m infiltration plot on the floor of an alcove in the upper tunnel, and seepage was collected from the ceiling of a niche in the lower tunnel. Significant temporal and (particularly) spatial variabilities were observed in both measured infiltration and seepage rates. To analyze the test results, a three-dimensional unsaturated flow model was used. A column-based scheme was developed to capture heterogeneous hydraulic properties reflected by these spatial variabilities observed. Fracture permeability and van Genuchten alpha parameter [van Genuchten, M.T., 1980. A closed-form equation for predicting the hydraulic conductivity of unsaturated soils. Soil Sci. Soc. Am. J. 44, 892-898] were calibrated for each rock column in the upper and lower hydrogeologic units in the test bed. The calibrated fracture properties for the infiltration and seepage zone enabled a good match between simulated and measured (spatially varying) seepage rates. The numerical model was also able to capture the general trend of the highly transient seepage processes through a discrete fracture network. The calibrated properties and measured infiltration/seepage rates were further compared with mapped discrete fracture patterns at the top and bottom boundaries. The measured infiltration rates and calibrated fracture permeability of the upper unit were found to be partially controlled by the fracture patterns on the infiltration plot (as indicated by their positive correlations with fracture density). However, no correlation could be established between measured seepage rates and density of fractures mapped on the niche ceiling. This lack of correlation indicates the complexity of (preferential) unsaturated flow within the discrete fracture network. This also indicates that continuum-based modeling of unsaturated flow in fractured rock at mesoscale or a larger scale is not necessarily conditional explicitly on discrete fracture patterns.


Prison suicide in 12 countries: an ecological study of 861 suicides during 2003-2007.
Although suicide rates among prisoners are high and vary between countries, it is uncertain whether this reflects the importation of risk from the general population or is associated with incarceration rates. We collected data on suicides and undetermined deaths in 12 countries (Australia, Belgium, Canada, Denmark, England and Wales, Finland, Ireland, Netherlands, New Zealand, Norway, Scotland, and Sweden) directly from their prison administrations for 2003-2007. These were compared with rates of suicides in the general population separately by gender using Pearson's correlations. In addition, they were compared with rates of incarceration. Linear regression was used to examine any association after adjustment for rates of incarceration. Data were collected on 861 suicides in prison, of which 810 were in men. In the men, crude relative rates of suicide were at least three times higher than the general population. Western European countries had similar rates of prisoner suicide which were mostly higher than those in Australia, Canada, and New Zealand. There was no association between rates of suicide in prisoners and general population rates or rates of incarceration. In the women, inmate suicide rates varied widely and were mostly raised compared with rates in the general population. In addition, these rates did not appear to be associated with general population rates of suicide. Rates of prison suicide do not reflect general population suicide rates, suggesting that variations in prison suicide rates reflect differences in criminal justice systems including, possibly, the provision of psychiatric care in prison.


The impact of cognitive control on children's goal monitoring in a time-based prospective memory task.
The present study investigated whether developmental changes in cognitive control may underlie improvements of time-based prospective memory. Five-, 7-, 9-, and 11-year-olds (N = 166) completed a driving simulation task (ongoing task) in which they had to refuel their vehicle at specific points in time (PM task). The availability of cognitive control resources was experimentally manipulated by imposing a secondary task that required divided attention. Children completed the driving simulation task both in a full-attention condition and a divided-attention condition where they had to carry out a secondary task. Results revealed that older children performed better than younger children on the ongoing task and PM task. Children performed worse on the ongoing and PM tasks in the divided-attention condition compared to the full-attention condition. With respect to time monitoring in the final interval prior to the PM target, divided attention interacted with age such that older children's time monitoring was more negatively affected by the secondary task compared to younger children. Results are discussed in terms of developmental shifts from reactive to proactive monitoring strategies.


Neuroanatomical, sensorimotor and cognitive deficits in adult rats with white matter injury following prenatal ischemia.
Perinatal brain injury including white matter damage (WMD) is highly related to sensory, motor or cognitive impairments in humans born prematurely. Our aim was to examine the neuroanatomical, functional and behavioral changes in adult rats that experienced prenatal ischemia (PI), thereby inducing WMD. PI was induced by unilateral uterine artery ligation at E17 in pregnant rats. We assessed performances in gait, cognitive abilities and topographical organization of maps, and neuronal and glial density in primary motor and somatosensory cortices, the hippocampus and prefrontal cortex, as well as axonal degeneration and astrogliosis in white matter tracts. We found WMD in corpus callosum and brainstem, and associated with the hippocampus and somatosensory cortex, but not the motor cortex after PI. PI rats exhibited mild locomotor impairments associated with minor signs of spasticity. Motor map organization and neuronal density were normal in PI rats, contrasting with major somatosensory map disorganization, reduced neuronal density, and a marked reduction of inhibitory interneurons. PI rats exhibited spontaneous hyperactivity in open-field test and short-term memory deficits associated with abnormal neuronal density in related brain areas. Thus, this model reproduces in adult PI rats the main deficits observed in infants with a perinatal history of hypoxia-ischemia and WMD.


International technical cooperation to low- and middle-income countries during the COVID-19 pandemic.
This paper reports on the current status of international technical cooperation, reflecting the views of the Bureau of International Health Cooperation of the National Center for Global Health and Medicine (NCGM) during the COVID-19 pandemic. To appropriately respond to the pandemic, the need for assistance to low- and middle-income countries has increased. Since 2020, there has been a shift from on-site to online international technical cooperation to avoid human contact. While online solutions increased the number of participants in international conferences and training, business travel costs and time were reduced. However, it became necessary to consider not only effective labor-management practices to enable participation in meetings held in different time zones but also quicker ways to develop online training materials, which took a long time. In the future, a hybrid format combining offline and online international technical cooperation will become mainstream.


Distinct roles of Akt1 and Akt2 in regulating cell migration and epithelial-mesenchymal transition.
The Akt family of kinases are activated by growth factors and regulate pleiotropic cellular activities. In this study, we provide evidence for isoform-specific positive and negative roles for Akt1 and -2 in regulating growth factor-stimulated phenotypes in breast epithelial cells. Insulin-like growth factor-I receptor (IGF-IR) hyperstimulation induced hyperproliferation and antiapoptotic activities that were reversed by Akt2 down-regulation. In contrast, Akt1 down-regulation in IGF-IR-stimulated cells promoted dramatic neomorphic effects characteristic of an epithelial-mesenchymal transition (EMT) and enhanced cell migration induced by IGF-I or EGF stimulation. The phenotypic effects of Akt1 down-regulation were accompanied by enhanced extracellular signal-related kinase (ERK) activation, which contributed to the induction of migration and EMT. Interestingly, down-regulation of Akt2 suppressed the EMT-like morphological conversion induced by Akt1 down-regulation in IGF-IR-overexpressing cells and inhibited migration in EGF-stimulated cells. These results highlight the distinct functions of Akt isoforms in regulating growth factor-stimulated EMT and cell migration, as well as the importance of Akt1 in cross-regulating the ERK signaling pathway.


Modularity of protein function: chimeric interleukin 1 beta s containing specific protease inhibitor loops retain function of both molecules.
Although it is widely recognized that many proteins contain discrete functional domains, it is less certain whether smaller, less obviously discrete, units of structure will retain their specific function when transplanted into a different context. The observation that the potent inflammatory cytokine human interleukin 1 beta has the same overall structure as soybean trypsin inhibitor (STI) (Kunitz) prompted us to replace a tight turn in the cytokine sequence with the large loop in soybean trypsin inhibitor that binds to the active site of trypsin. Wild-type interleukin 1 beta (IL-1 beta) is highly resistant to proteolysis, but the chimeric STI/IL is specifically cleaved by trypsin, apparently in the inserted loop. Other chimeric interleukins have also been constructed, by replacing the same tight turn with inhibitory loops from other protein protease inhibitors: turkey ovomucoid inhibitor (TOI), a chymotrypsin inhibitor, and alpha 1-antitrypsin (AT), an elastase inhibitor. Although these loops come from proteins not related structurally to interleukin 1, they confer specific protease sensitivity or inhibition on the chimeric cytokine. The cytokine properties of these chimeric interleukins have also been evaluated. The chimeras formed from human IL-1 beta and all inhibitory loops tested bind to the interleukin 1 receptor with reasonable affinity. The typical cellular effects of IL-1, however, are not observed with all the recombinant proteins, thus confirming that receptor binding and signal transduction can be uncoupled. When these results are taken together with the results of site-directed mutagenesis of IL-1, reported in this paper and elsewhere, they allow the receptor and intracellular transduction sites on the protein to be mapped in detail.


CXD101 and nivolumab in patients with metastatic microsatellite-stable colorectal cancer (CAROSELL): a multicentre, open-label, single-arm, phase II trial.
Patients with microsatellite stable (MSS) colorectal carcinoma (CRC) do not respond to immune checkpoint inhibitors. Preclinical models suggested synergistic anti-tumour activity combining CXD101 and anti-programmed cell death protein 1 treatment; therefore, we assessed the clinical combination of CXD101 and nivolumab in heavily pre-treated patients with MSS metastatic CRC (mCRC). This single-arm, open-label study enrolled patients aged 18 years or older with biopsy-confirmed MSS CRC; at least two lines of systemic anticancer therapies (including oxaliplatin and irinotecan); at least one measurable lesion; Eastern Cooperative Oncology Group performance status of 0, 1 or 2; predicted life expectancy above 3 months; and adequate organ and bone marrow function. Nine patients were enrolled in a safety run-in study to define a tolerable combination schedule of CXD101 and nivolumab, followed by 46 patients in the efficacy assessment phase. Patients in the efficacy assessment cohort were treated orally with 20 mg CXD101 twice daily for 5 consecutive days every 3 weeks, and intravenously with 240 mg nivolumab every 2 weeks. The primary endpoint was immune disease control rate (iDCR). Between 2018 and 2020, 55 patients were treated with CXD101 and nivolumab. The combination therapy was well tolerated with the most frequent grade 3 or 4 adverse events being neutropenia (18%) and anaemia (7%). Immune-related adverse reactions commonly ascribed to checkpoint inhibitors were surprisingly rare although we did see single cases of pneumonitis, hypothyroidism and hypopituitarism. There were no treatment-related deaths. Of 46 patients assessable for efficacy, 4 (9%) achieved partial response and 18 (39%) achieved stable disease, translating to an immune disease control rate of 48%. The median overall survival (OS) was 7.0 months (95% confidence interval 5.13-10.22 months). The primary endpoint was met in this phase II study, which showed that the combination of CXD101 and nivolumab, at full individual doses in the treatment of advanced or metastatic MSS CRC, was both well tolerated and efficacious.


Niraparib in Patients with Newly Diagnosed Advanced Ovarian Cancer.
Niraparib, an inhibitor of poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP), has been associated with significantly increased progression-free survival among patients with recurrent ovarian cancer after platinum-based chemotherapy, regardless of the presence or absence of BRCA mutations. The efficacy of niraparib in patients with newly diagnosed advanced ovarian cancer after a response to first-line platinum-based chemotherapy is unknown. In this randomized, double-blind, phase 3 trial, we randomly assigned patients with newly diagnosed advanced ovarian cancer in a 2:1 ratio to receive niraparib or placebo once daily after a response to platinum-based chemotherapy. The primary end point was progression-free survival in patients who had tumors with homologous-recombination deficiency and in those in the overall population, as determined on hierarchical testing. A prespecified interim analysis for overall survival was conducted at the time of the primary analysis of progression-free survival. Of the 733 patients who underwent randomization, 373 (50.9%) had tumors with homologous-recombination deficiency. Among the patients in this category, the median progression-free survival was significantly longer in the niraparib group than in the placebo group (21.9 months vs. 10.4 months; hazard ratio for disease progression or death, 0.43; 95% confidence interval [CI], 0.31 to 0.59; P<0.001). In the overall population, the corresponding progression-free survival was 13.8 months and 8.2 months (hazard ratio, 0.62; 95% CI, 0.50 to 0.76; P<0.001). At the 24-month interim analysis, the rate of overall survival was 84% in the niraparib group and 77% in the placebo group (hazard ratio, 0.70; 95% CI, 0.44 to 1.11). The most common adverse events of grade 3 or higher were anemia (in 31.0% of the patients), thrombocytopenia (in 28.7%), and neutropenia (in 12.8%). No treatment-related deaths occurred. Among patients with newly diagnosed advanced ovarian cancer who had a response to platinum-based chemotherapy, those who received niraparib had significantly longer progression-free survival than those who received placebo, regardless of the presence or absence of homologous-recombination deficiency. (Funded by GlaxoSmithKline; PRIMA/ENGOT-OV26/GOG-3012 ClinicalTrials.gov number, NCT02655016.).


Clinical psychopathology in youth at familial high risk for psychosis.
While the course of psychopathology has been explored from an index mental health diagnosis onwards, there are few detailed, prospective studies of the occurrence of clinical psychopathology in youth with familial risk for severe mental illnesses such as psychosis. We sought to describe the appearance of Axis I psychopathology in a unique sample of adolescents with a family history of schizophrenia (FHR). One hundred and sixty two first- and second-degree relatives (mean age 15.7 ± 3.6; range 8-25) of probands with schizophrenia or schizoaffective disorder were assessed at baseline and annual intervals for up to 3 years, focusing on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) Axis I psychopathology. Fourteen individuals (8.6%) developed a psychotic disorder. One hundred and five subjects (65%) met criteria for an Axis I disorder over the course of the study, the most common of which was a depressive episode (40 subjects; 25%). Of the 148 individuals who did not develop psychosis, 91 (61%) had one or more Axis I disorders compared with 10/14 converters who had a comorbid Axis I disorder (71%). Ordered by increasing age of onset, diagnoses included cognitive and externalizing disorders, anxiety disorders, affective disorders, substance use disorders and psychotic disorders. In addition to an elevated risk of psychosis, young FHR relatives manifest a broad range of non-psychotic Axis I psychopathology in childhood and adolescence. This breadth of diagnoses has implications for the structure and function of mental health services for young people.


The dissolution of double Holliday junctions.
Double Holliday junctions (dHJS) are important intermediates of homologous recombination. The separate junctions can each be cleaved by DNA structure-selective endonucleases known as Holliday junction resolvases. Alternatively, double Holliday junctions can be processed by a reaction known as "double Holliday junction dissolution." This reaction requires the cooperative action of a so-called "dissolvasome" comprising a Holliday junction branch migration enzyme (Sgs1/BLM RecQ helicase) and a type IA topoisomerase (Top3/TopoIIIα) in complex with its OB (oligonucleotide/oligosaccharide binding) fold containing accessory factor (Rmi1). This review details our current knowledge of the dissolution process and the players involved in catalyzing this mechanistically complex means of completing homologous recombination reactions.


Seventy Years with the Globus Pallidus: Pallidal Surgery for Movement Disorders Between 1947 and 2017.
The year 2017 marks the 70th anniversary of the birth of human stereotactic neurosurgery. The first procedure was a pallidotomy for Huntington's disease. However, it was for Parkinson's disease that pallidotomy was soon adopted worldwide. Pallidotomy was abandoned in the late 1950s in favor of thalamotomy because of the latter's more striking effect on tremor. The advent of levodopa put a halt to all surgery for PD. In the mid-1980s, Laitinen reintroduced the posteroventral pallidotomy of Leksell, and this procedure spread worldwide thanks to its efficacy on most parkinsonian symptoms including levodopa-induced dyskinesias and thanks to basic scientific work confirming the role of the globus pallidus internus in the pathophysiology of PD. With the advent of deep brain stimulation of the subthalamic nucleus, pallidotomy was again abandoned, and even DBS of the GPi has been overshadowed by STN DBS. The GPi reemerged in the late 1990s as a major stereotactic target for DBS in dystonia and, recently, in Tourette syndrome. Lately, lesioning of the GPI is being proposed to treat refractory status dystonicus or to treat DBS withdrawal syndrome in PD patients. Hence, the pallidum as a stereotactic target for either lesioning or DBS has been the phoenix of functional stereotactic neurosurgery, constantly abandoned and then rising again from its ashes. This review is a tribute to the pallidum on its 70th anniversary as a surgical target for movement disorders, analyzing its ebbs and flows and highlighting its merits, its versatility, and its resilience. © 2017 International Parkinson and Movement Disorder Society.


The midline posterior elbow incision. An anatomical appraisal.
The formation of a painful neuroma after operations on the medial or lateral sides of the elbow is a common problem. Our aim was to determine the relationship of the cutaneous nerves to the three usual skin incisions around the elbow. In 18 freshly frozen cadaver arms we made three standard 16 cm incisions in the skin medially, laterally, and posteriorly and explored them using loupe magnification. The number of nerves crossing each incision was determined by gross observation and their diameter measured by electronic microcallipers. In ten arms, biopsies of the nerves in each incision were sent for histological examination. We found significantly more cutaneous nerves crossing the medial and lateral incisions than the posterior. The diameter of the nerves crossing the posterior incision was significantly smaller than those crossing the lateral incision. Cutaneous nerves are at considerable risk of injury when medial or lateral incisions are used to approach the elbow, but the posterior approach carries less hazard. The routine use of the posterior incision may reduce the incidence of symptomatic paraesthesia and the formation of a painful neuroma after operation.


The regulation of copper stress response genes in the polychaete Nereis diversicolor during prolonged extreme copper contamination.
Polychaetes are frequented in toxicological studies, one reason being that some members occupy shallow burrows in sediments and are maximally exposed to the contaminants that accumulate within them. We have been studying one population of the polychaete Nereis (Hediste) diversicolor exhibiting inheritable tolerance to extreme copper contamination in estuarine sediment. Using transcriptome sequencing data we have identified a suite of genes with putative roles in metal detoxification and tolerance, and measured their regulation. Copper tolerant individuals display significantly different gene expression profiles compared to animals from a nearby population living without remarkable copper levels. Gene transcripts encoding principle copper homeostasis proteins including membrane copper ion transporters, copper ion chaperones and putative metallothionein-like proteins were significantly more abundant in tolerant animals occupying contaminated sediment. In contrast, those encoding antioxidants and cellular repair pathways were unchanged. Nontolerant animals living in contaminated sediment showed no difference in copper homeostasis-related gene expression but did have significantly elevated levels of mRNAs encoding Glutathione Peroxidase enzymes. This study represents the first use of functional genomics to investigate the copper tolerance trait in this species and provides insight into the mechanism used by these individuals to survive and flourish in conditions which are lethal to their conspecifics.


Power of data mining methods to detect genetic associations and interactions.
Genetic association studies, thus far, have focused on the analysis of individual main effects of SNP markers. Nonetheless, there is a clear need for modeling epistasis or gene-gene interactions to better understand the biologic basis of existing associations. Tree-based methods have been widely studied as tools for building prediction models based on complex variable interactions. An understanding of the power of such methods for the discovery of genetic associations in the presence of complex interactions is of great importance. Here, we systematically evaluate the power of three leading algorithms: random forests (RF), Monte Carlo logic regression (MCLR), and multifactor dimensionality reduction (MDR). We use the algorithm-specific variable importance measures (VIMs) as statistics and employ permutation-based resampling to generate the null distribution and associated p values. The power of the three is assessed via simulation studies. Additionally, in a data analysis, we evaluate the associations between individual SNPs in pro-inflammatory and immunoregulatory genes and the risk of non-Hodgkin lymphoma. The power of RF is highest in all simulation models, that of MCLR is similar to RF in half, and that of MDR is consistently the lowest. Our study indicates that the power of RF VIMs is most reliable. However, in addition to tuning parameters, the power of RF is notably influenced by the type of variable (continuous vs. categorical) and the chosen VIM.


Cladophialophora bantiana (Previously Cladosporium trichoides): First Report of a Case in Brazil.
Cladophialophora bantiana (Cladosporium trichoides) is a black fungus recorded rarely as a cause of brain abscess. Only 21 cases have been reported in the literature world-wide. We describe the first case seen in Brazil. A 30 year old, previously healthy female, HIV negative, came to the hospital with a clinical diagnosis of brain tumor. After biopsy and culture of the lesion, it was found that she had an abscess due to Cladosporium trichoides. During the following five months, the patient underwent three more surgical brain interventions to totally remove the area of compromised tissue. In addition to surgery, amphotericin B, both intravenously and intrathecally, was used followed by itraconazole orally, without success. Six months after the first surgical intervention, the patient died. The worldwide experience with diagnosis and treatment of patients with this diseases is reviewed.


Determining clinically relevant features in cytometry data using persistent homology.
Cytometry experiments yield high-dimensional point cloud data that is difficult to interpret manually. Boolean gating techniques coupled with comparisons of relative abundances of cellular subsets is the current standard for cytometry data analysis. However, this approach is unable to capture more subtle topological features hidden in data, especially if those features are further masked by data transforms or significant batch effects or donor-to-donor variations in clinical data. We present that persistent homology, a mathematical structure that summarizes the topological features, can distinguish different sources of data, such as from groups of healthy donors or patients, effectively. Analysis of publicly available cytometry data describing non-naïve CD8+ T cells in COVID-19 patients and healthy controls shows that systematic structural differences exist between single cell protein expressions in COVID-19 patients and healthy controls. We identify proteins of interest by a decision-tree based classifier, sample points randomly and compute persistence diagrams from these sampled points. The resulting persistence diagrams identify regions in cytometry datasets of varying density and identify protruded structures such as 'elbows'. We compute Wasserstein distances between these persistence diagrams for random pairs of healthy controls and COVID-19 patients and find that systematic structural differences exist between COVID-19 patients and healthy controls in the expression data for T-bet, Eomes, and Ki-67. Further analysis shows that expression of T-bet and Eomes are significantly downregulated in COVID-19 patient non-naïve CD8+ T cells compared to healthy controls. This counter-intuitive finding may indicate that canonical effector CD8+ T cells are less prevalent in COVID-19 patients than healthy controls. This method is applicable to any cytometry dataset for discovering novel insights through topological data analysis which may be difficult to ascertain otherwise with a standard gating strategy or existing bioinformatic tools.


Mutations of the BRCA2 gene in ovarian carcinomas.
Inherited mutations in the recently discovered BRCA2 gene are believed to be responsible for a significant fraction of early-onset hereditary breast cancers. Unlike BRCA1, however, which confers a high risk to both breast and ovarian cancer, the incidence of ovarian cancer appears to be much lower In BRCA2-linked families, causing uncertainty as to the relevance of BRCA2 to hereditary ovarian cancer. Numerous allelotype studies indicate that allelic deletions Including the BRCA2 locus on chromosome 13q are common in ovarian cancers in general, suggesting that somatic mutations of this gene may be involved in sporadic ovarian tumorigenesis. The purpose of this study was to test the hypothesis that germline or somatic mutations of BRCA2 are associated with hereditary and/or sporadic ovarian cancers, respectively. The entire 10.2-kb coding region of BRCA2 was screened for mutations in 130 consecutive ovarian tumors, the only selection criterion being a pathological diagnosis of epithelial ovarian carcinoma. Loss of heterozygosity at markers flanking BRCA2 was observed in 56% of the tumors. Four germline mutations and two somatic mutations were identified; two of the germline mutations are recurrent, having been previously described. Remarkably, the patients with germline mutations were late-onset cases with no medical or family histories suggestive of hereditary cancer. These data suggest that mutations of BRCA2 are rare in sporadic ovarian cancers, and that the proportion of ovarian cancers resulting from hereditary predisposition may be higher than previously suspected based on estimates derived from studies of highly penetrant genetic loci.


Elevated serum IgG4 concentration in patients with primary sclerosing cholangitis.
Biliary strictures, similar to primary sclerosing cholangitis (PSC), have been reported in patients with autoimmune pancreatitis, which is characterized by elevated serum IgG4 levels and responsiveness to corticosteroids. We sought to determine the frequency of elevated IgG4 in patients with PSC and to clinically compare PSC patients with elevated and normal IgG4 levels. We measured serum IgG4 in 127 patients with PSC and 87 patients with primary biliary cirrhosis, as disease controls. Demographic, clinical, and laboratory characteristics were compared between the PSC groups with normal and elevated IgG4 (>140 mg/dL). Elevated IgG4 was found in 12 PSC patients (9%) versus one PBC patient (1.1%) (p= 0.017). Patients with elevated IgG4 had higher total bilirubin (p= 0.009), alkaline phosphatase (p= 0.01), and PSC Mayo risk score (p= 0.038), and lower frequency of IBD (p < 0.0001). Importantly, the time to liver transplantation was shorter in patients with elevated IgG4 (1.7 vs 6.5 yr, p= 0.0009). The type of biliary involvement (intrahepatic, extrahepatic, or both) and pancreatic involvement were similar in both groups. A small proportion of PSC patients had elevated serum IgG4. In these patients parameters of liver disease severity were more pronounced and time to liver transplantation was shorter, suggesting a more severe disease course. It is possible that this subset of patients behaves similarly to autoimmune pancreatitis patients with biliary strictures, and could potentially respond to corticosteroids. Testing PSC patients for IgG4 and treating those with elevated levels with corticosteroids in clinical trials should be considered.


Reduced lung cancer incidence attributable to decreased tobacco use in urban Shanghai.
Lung cancer has been the most common type of cancer in the world for several decades, and by 2008, there were approximately 1.61 million new cases, representing 12.7 % of all new cancers. It has been well known for many years that smoking causes lung cancer. Tobacco control measures have been regarded as the principal causes of the declines in smoking-related mortality, including mortality from lung cancer. The Joinpoint Regression Program was used to analyze the long-term trends in lung cancer incidence rates from 1983 to 2008 in urban Shanghai. In addition, this study estimates how many fewer cases of lung cancer have occurred in urban Shanghai because of tobacco control activities. The lung cancer incidence rate among males decreased slightly by 0.6 % [95 % confidence interval (95 % CI) -0.1 to 1.3 %] from 1983 to 1999 and then declined rapidly at a rate of 3.8 % (95 % CI 2.1-5.4 %). Among females, the cancer incidence rate decreased by 0.1 % (95 % CI -0.2 to 0.5 %) from 1983 to 2008. Overall, we estimated that approximately 2,711 cases of lung cancer were averted among urban men in Shanghai between 2000 and 2008 because of the reduction in tobacco smoking. The reduction in tobacco smoking is a major factor in the decrease in the incidence rate of lung cancer. Sustained progress in tobacco control is essential.


Sirt3 mediates the protective effect of hydrogen in inhibiting ROS-induced retinal senescence.
Hydrogen possesses antioxidative effects and cures numerous types of ophthalmopathy, but the mechanism of hydrogen on ROS-induced retinal senescence remains elusive. In this study, retinal morphology revealed that hydrogen reduced the number and size of vitreous black deposits in Bruch's membrane in NaIO3 mice. Hydrogen also reduced ROS levels in the retina as assessed by DHE staining. Moreover, this result was consistent with the downregulation of expression of the oxidative stress hallmark OGG1. These findings suggested that hydrogen can reduce retinal oxidative stress induced by NaIO3, and this result was further verified using the antioxidant ALCAR. Mechanistic analysis revealed that hydrogen significantly inhibited the downregulation of Sirt3 expression, and this notion was confirmed using AICAR, which restores Sirt3 expression and activity. Moreover, hydrogen reduced the expression of p53, p21 and p16 and the number of blue-green precipitations in the retinas of NaIO3 mice as assessed by SA-β-gal staining. We also found that hydrogen decreased the expression of the DNA damage-related protein ATM, cyclinD1 and NF-κB but increased the expression of the DNA repair-related protein HMGB1, suggesting that hydrogen inhibits senescence in retinas of NaIO3 mice. Additionally, OCT examination revealed that hydrogen suppressed retinal high reflex formation significantly and prevented the retina from thinning. This result was supported by ERG assays that demonstrated that hydrogen prevented the reduction in a- and b-wave amplitude induced by NaIO3 in mice. Thus, our data suggest that hydrogen may inhibit retinal senescence by suppressing the downregulation of Sirt3 expression through reduced oxidative stress reactions.


Characterizing the dynamics underlying global spread of epidemics.
Over the past few decades, global metapopulation epidemic simulations built with worldwide air-transportation data have been the main tool for studying how epidemics spread from the origin to other parts of the world (e.g., for pandemic influenza, SARS, and Ebola). However, it remains unclear how disease epidemiology and the air-transportation network structure determine epidemic arrivals for different populations around the globe. Here, we fill this knowledge gap by developing and validating an analytical framework that requires only basic analytics from stochastic processes. We apply this framework retrospectively to the 2009 influenza pandemic and 2014 Ebola epidemic to show that key epidemic parameters could be robustly estimated in real-time from public data on local and global spread at very low computational cost. Our framework not only elucidates the dynamics underlying global spread of epidemics but also advances our capability in nowcasting and forecasting epidemics.