Lower urinary tract symptoms and pelvic floor muscle exercise adherence after 15 years.
Pelvic floor muscle training effectively treats female stress urinary incontinence. However, data on long-term efficacy and adherence are sparse. Our aims were to assess current lower urinary tract symptoms and exercise adherence 15 years after ending organized training. Originally, 52 women with urodynamic stress urinary incontinence were randomly assigned to home or intensive exercise. After 6 months, 60% in the intensive group were almost or completely continent, compared with 17% in the home group. Fifteen years later, all original study subjects were invited to complete a postal questionnaire assessing urinary symptoms (using validated outcome tools) and current pelvic floor muscle training. Response rate was 90.4%. There were no differences in any urinary outcomes or satisfaction between the 2 study groups as a whole or when restricted to those without intervening stress urinary incontinence surgery. One half of both groups had stress urinary incontinence surgery during the 15-year follow-up period. Twenty-eight percent performed pelvic floor muscle training at least weekly; this rate did not differ by original group assignment or operated status. More operated women reported severe incontinence (P = .03) and leakage that interfered with daily life (P = .04) than did nonoperated women. There were no other differences between operated and nonoperated women. The marked benefit of intensive pelvic floor muscle training seen short-term was not maintained 15 years later. Long-term adherence to training is low. Urinary symptoms were equally common in both operated and nonoperated women. Further studies are needed to understand factors associated with long-term effectiveness of stress urinary incontinence treatments.


[Schwannoma of the obturatorius nerve as differential diagnosis in cystic adnexa tumors].
We report on a case of benign retroperitoneal schwannoma involving the obturator nerve. Discussing the difficulties of diagnosis and treatment the following became clear: 1.) Clinical examination, ultrasound and computed tomography are not helpful to differentiate a retroperitoneal schwannoma from a cystic ovarian tumour; this problem can perhaps be overcome by MR imaging. 2.) The diagnosis should be borne in mind in cases of retroperitoneal tumours of unclear origin. Appropriate surgery is necessary to avoid nerve damage and paralysis.


X-inactivation and marker studies in three families with incontinentia pigmenti: implications for counselling and gene localisation.
Familial incontinentia pigmenti (IP) is an X-linked dominant disorder with an extremely variable clinical presentation. Ambiguous diagnosis can complicate genetic counselling and attempts to refine the gene location in Xq28. Marked skewing of X-inactivation patterns is a hallmark of IP and provides a means for investigating uncertain cases. We have conducted X-inactivation studies in three families where Xq28 marker studies were at odds with the original clinical assessment. The results indicate that no recombination between the disease locus and Xq28 loci has occurred and suggest that mosaicism is responsible for the discrepancy in one family.


Fatal car occupant injuries after car lorry collisions.
All deaths from road accidents in certain areas and periods were studied. Analysis of 224 deaths to car occupants from collisions between cars and lorries showed that such accidents were the commonest cause of death for car occupants on motorways and link roads. The impacts were such that relatively poor protection could be given by occupant restraint systems. Collisions of cars into the rear of lorries caused the most severe injuries; most of these accidents occurred at night.The traffic characteristics of cars and lorries are largely incompatible and increase the likelihood of collisions and of extremely severe injuries to car occupants. Some reduction in deaths may be expected from making lorries more conspicuous and eliminating the rear overhang. More fundamental measures are segregation of lorries from cars and return of traffic to railways.


Interactions in stanene centred van der Waals trilayers structures of boron-nitride and graphene: effect of mirror symmetry on electronic interactions.
Dispersion-corrected density functional theory was used to investigate structures consisting of a stanene layer sandwiched between atomically-thin boron nitride and graphene. The parameters controlling the mirror symmetry, lattice rotation and stacking sequences were varied systematically to generate fifteen candidate trilayers. Two types of structural buckling occur in the heterostructures depending on whether the lattice vectors are co-aligned or non-collinear. The configurations with the honeycomb lattices rotated by π/6 with respect to the stanene generally have lower binding energy. In the majority of the trilayers, the electronic structures deviate strongly from the band structures of the isolated components. The boron nitride/stanene/boron nitride structure is identified as a special case where stanene has an electronic structure that is not perturbed by interlayer interactions and resembles the ideal monolayer form. For the other candidate structures, however, interlayer interactions drive significant modifications in the electronic structure thus indicating emergent features that go beyond the pure van der Waals description.


Individuals' Long Term Use of Cognitive Behavioural Skills to Manage their Depression: A Qualitative Study.
Cognitive Behavioural Therapy (CBT) aims to teach people skills to help them self-manage their depression. Trial evidence shows that CBT is an effective treatment for depression and individuals may experience benefits long-term. However, there is little research about individuals' continued use of CBT skills once treatment has finished. To explore whether individuals who had attended at least 12 sessions of CBT continued to use and value the CBT skills they had learnt during therapy. Semi-structured interviews were held with participants from the CoBalT trial who had received CBT, approximately 4 years earlier. Interviews were audio-recorded, transcribed and analysed thematically. 20 participants were interviewed. Analysis of the interviews suggested that individuals who viewed CBT as a learning process, at the time of treatment, recalled and used specific skills to manage their depression once treatment had finished. In contrast, individuals who viewed CBT only as an opportunity to talk about their problems did not appear to utilize any of the CBT skills they had been taught and reported struggling to manage their depression once treatment had ended. Our findings suggest individuals may value and use CBT skills if they engage with CBT as a learning opportunity at the time of treatment. Our findings underline the importance of the educational model in CBT and the need to emphasize this to individuals receiving treatment.


Clinical application of ultrasound-guided totally implantable venous access ports implantation via the posterior approach of the internal jugular vein.
To determine the feasibility and safety of ultrasound-guided totally implantable venous access port (TIVAP) implantation via the posterior approach of the internal jugular vein (IJV). From September 2021 to August 2022, 88 oncology patients underwent ultrasound-guided implantation of TIVAPs via the posterior approach of the IJV for the administration of chemotherapy. The catheter tip was adjusted to be positioned at the cavoatrial junction under fluoroscopic guidance. Clinical data including surgical success, success rate for the first attempt, intraoperative, and postoperative complications were all collected and analyzed. All patients underwent successful surgery (100%), whereby 58 were via the right IJV and 30 via the left IJV, and the success rate for the first attempt was 96.59% (85/88). The operation time was 20 to 43 min, with an average of 26.59 ± 6.18 min with no intraoperative complications. The Follow-up duration ranged from 1-12 months (mean 5.28 ± 3.07) and the follow-up rate was 100%. The rate of postoperative complications was 4.55% (4/88), including port-site infection in two cases, fibrin sheath formation in one case, and port flip in one case. No other complications were observed during follow-up. Ultrasound-guided TIVAP implantation via the posterior approach of the IJV is feasible, safe, and effective, with a low rate of intraoperative and postoperative complications. Not only was the curvature of the catheter device smooth, but patients were satisfied with the comfort and cosmetic appearance. Additionally, we could reduce the possible complications of pinching and kinking of the catheter by using this approach. Therefore, further large-sample, prospective and randomized controlled trials are warranted.


Child development and refractive errors in preschool children.
Many parents are concerned about their child's development. The purpose of this study is to determine whether parental concerns about overall development are associated with significant refractive errors among urban preschool children. A cross-sectional population-based study was conducted to evaluate the prevalence of ocular disorders in white and African American children aged 6 through 71 months in Baltimore, Maryland. A comprehensive eye examination with cycloplegic refraction was performed. Parental concerns about development were measured with the Parents' Evaluation of Developmental Status screening tool. Of 2546 eligible children 2381 (93.5%), completed the refraction and the parental interview. Parental concerns about development were present in 510 of the 2381 children evaluated [21.4%; 95% confidence intervals (CI): 9.8 to 23.1]. The adjusted odds ratios [OR] of parental concerns with hyperopia [≥3.00 diopters (D)] was 1.26 (95% CI: 0.90 to 1.74), with myopia (≥1.00 D) was 1.29 (95% CI: 0.83 to 2.03), with astigmatism (≥1.50 D) was 1.44 (95% CI: 1.08 to 1.93) irrespective of the type of astigmatism, and with anisometropia (≥2.00 D) was 2.61 (95% CI: 1.07 to 6.34). The odds of parental concerns about development significantly increased in children older than 36 months with hyperopia ≥3.00 D, astigmatism ≥1.50 D, or anisometropia ≥2.00 D. Parental concerns about general developmental problems were associated with some types of refractive error, astigmatism ≥1.50 D and anisometropia ≥2.00 D, in children aged 6 to 71 months. Parental concerns were also more likely in children older than 36 months with hypermetropia, astigmatism, or anisometropia. Parental concerns were not associated with myopia. Because of the potential consequences of uncorrected refractive errors, children whose parents have expressed concerns regarding development should be referred for an eye examination with cycloplegic refraction to rule out significant refractive errors.


The ethnoepidemiology of obesity.
The prevalence of overweight and obesity varies significantly across ethnic groups and among aboriginal people in Canada and appears to be increasing overall in children and youth, which will have significant health consequences in the future. Individual health behaviours, genetic predisposition, and community-level factors all contribute to the high burden of overweight and obesity across communities in Canada. Preliminary studies indicate that individuals who live in neighbourhoods in Canada with increased walkability, fewer fast food outlets, and higher socioeconomic status have lower rates of overweight/obesity when compared with other neighbourhoods. However, more research is required to understand the impact of community level factors on overweight/obesity trends in Canadian ethnic groups, including children and youth, and aboriginal people.


The battle between hoping and suffering: a conceptual model of hope within a context of spinal cord injury.
The aim of this longitudinal study was to explore 10 patients' experiences of the meaning they attribute to the substance of hope and the process of hoping during the first 3 to 4 years following a spinal cord injury. This qualitative study is a synthesis of three empirical studies of hope and the overall aim was to deepen the understanding of the phenomenon of hope, based on the text representing the main contextual findings, to develop a theoretical framework on hope within a context of spinal cord injury, illustrated in the conceptual model. In correspondence with Ricoeur, this conceptual model, which was developed from a new understanding, based on a new text of the phenomenon of hope, develops a new and deeper understanding of the meaning of hope. Findings revealed 9 themes: universal hope, uncertain hope, hope as a turning point, the power of hope, boundless creative and flexible hope, enduring hope, despairing hope, body-related hope, and existential hope. The conceptual model was derived from these themes, illustrated as The Battle between Hoping and Suffering and The Road of Hope. The interpretations also revealed a distinction between being in hope and having hope, and having a hope of improvements was the main focus at the early stage of rehabilitation, whereas being in hope as being just fine was the main focus after 3 to 4 years of rehabilitation.


The essential Ubc4/Ubc5 function in yeast is HECT E3-dependent, and RING E3-dependent pathways require only monoubiquitin transfer by Ubc4.
The ubiquitin (Ub)-conjugating enzymes Ubc4 and Ubc5 are involved in a variety of ubiquitination pathways in yeast, including Rsp5- and anaphase-promoting complex (APC)-mediated pathways. We have found the double deletion of UBC4 and UBC5 genes in yeast to be lethal. To investigate the essential pathway disrupted by the ubc4/ubc5 deletion, several point mutations were inserted in Ubc4. The Ubc4 active site mutation C86A and the E3-binding mutations A97D and F63A were both unable to rescue the lethal phenotype, indicating that an active E3/E2∼Ub complex is required for the essential function of Ubc4/Ubc5. A mutation that specifically eliminates RING E3-catalyzed isopeptide formation but not HECT E3 transthiolation (N78S-Ubc4) rescued the lethal phenotype. Thus, the essential redundant function performed by Ubc4 and Ubc5 in yeast is with a HECT-type E3, likely the only essential HECT in yeast, Rsp5. Our results also suggest that Ubc1 can weakly replace Ubc4 to transfer mono-Ub with APC, but Ubc4 cannot replace Ubc1 for poly-Ub chain extension on APC substrates. Finally, the backside Ub-binding mutant S23R-Ubc4 has no observable effect in yeast. Together, our results are consistent with a model in which Ubc4 and Ubc5 are 1) the primary E2s for Rsp5 in yeast and 2) act as monoubiquitinating E2s in RING E3-catalyzed pathways, in contrast to the processive human ortholog UbcH5.


Creating a child abuse policy that reflects an ethic of care.
The primary purpose of child abuse policy is to guide the action of health care providers and so ensure that the fundamental rights of those the policy intended to protect are not compromised. This discussion paper explores the ethical considerations underlying child abuse policy from bioethical and from caring ethical perspectives, both of which are outlined briefly. A process that could be used to create or analyse existing child abuse policy, in relation to underlying ethical considerations, definitions of child abuse, level of health care, resourcing needs and relationship to employment policy is outlined. A hypothetical example of such a policy is used to illustrate elements of this process. Assuming that policy is designed to direct action, it is argued that if child abuse policies were rewritten to reflect an ethic of care the quality and scope of health care provided to children and their families would improve. Consequently, stated government objectives of improving child health services, as well as primary health care aims of achieving equitable, accessible and affordable health care for children in New Zealand would be better facilitated.


Alternative pathways for the in vivo repair of O6-alkylguanine and O4-alkylthymine in Escherichia coli: the adaptive response and nucleotide excision repair.
The in vivo removal of three different O-alkylated bases from DNA was measured in Escherichia coli. Using monoclonal antibodies specific for O6-methylguanine, O6-ethylguanine and O4-ethylthymine we have monitored the removal of these lesions from six different strains to assess the relative contributions of the adaptive response and of nucleotide excision repair. During the first hour after DNA alkylation, O6-methylguanine, O6-ethylguanine and O4-ethylthymine lesions were repaired almost exclusively by nucleotide excision, except when the adaptive response was being constitutively expressed. In wild-type E. coli the adaptive response began to contribute to O6-methylguanine repair about one hour after alkylation, the time required for the full induction of the ada DNA methyltransferase. In contrast, the adaptive response did not play such a large role in the repair of O6-ethylguanine and O4-ethylthymine in wild-type E. coli, presumably because DNA ethylation damage is a poor inducer of the adaptive response; possible reasons for this poor induction are discussed. The repair of all three O-alkylated lesions was virtually absent in ada- uvr- bacteria suggesting that no alternative pathway is available for their repair, at least during the first two hours after alkylation. When the repair of O-alkylated bases was compromised by an ada- or by a uvr- mutation, the bacteria became more sensitive to alkylation induced killing and mutation.


College Students' Knowledge Concerning Oropharyngeal Cancer, Human Papillomavirus, and Intent Toward Being Examined.
The purpose of this study was to assess college students' knowledge of oral/oropharyngeal cancer and the relationship of human papillomavirus (HPV) to oropharyngeal cancer. Data were also collected to determine their perceived susceptibility to oropharyngeal cancer and awareness of emotions toward and intentions to receive an oral cancer examination in order to design tailored messages for promoting oropharyngeal cancer prevention on college campuses. Two hundred ten baccalaureate students in nonhealth majors from a public southeastern university were surveyed. Descriptive statistics were calculated, and multiple regression analysis was conducted to determine the predictors of knowledge of oral/oropharyngeal cancer and the HPV and intentions to be examined. Results indicated most were unaware of oropharyngeal cancer, did not understand the purpose of an oral cancer examination, and could not affirm they had received one or had one explained to them. Results also indicated poor understanding of some of the signs and risk factors of oropharyngeal cancer, especially HPV. In addition, oral/oropharyngeal cancer knowledge and negative emotions were predictors of examination intentions, confirming current behavioral theories that postulate rational decisions require collaboration from both cognitive and affective systems. Recommendations are offered for tailored educational communications and strategies about oropharyngeal cancer on college campuses.


High mobility N-type transistors based on solution-sheared doped 6,13-bis(triisopropylsilylethynyl)pentacene thin films.
An N-Type organic thin-film transistor (OTFT) based on doped 6,13-Bis(triisopropylsilylethynyl)pentacene is presented. A transition from p-type to n-type occurrs with increasing doping concentrations, and the highest performing n-channel OTFTs are obtained with 50 mol% dopant. X-ray diffraction, scanning Auger microscopy, and secondary ionization mass spectrometry are used to characterize the morphology of the blends. The high performance of the obtained transistors is attributed to the highly crystalline and aligned nature of the doped thin films.


From concept to reality: Transforming agriculture through innovative rhizosphere engineering for plant health and productivity.
The plant rhizosphere is regarded as a microbial hotspot due to a wide array of root exudates. These root exudates comprise diverse organic compounds such as phenolic, polysaccharides, flavonoids, fatty acids, and amino acids that showed chemotactic responses towards microbial communities and mediate significant roles in root colonization. The rhizospheric microbiome is a crucial driver of plant growth and productivity, contributing directly or indirectly by facilitating nutrient acquisition, phytohormone modulation, and phosphate solubilization under normal and stressful conditions. Moreover, these microbial candidates protect plants from pathogen invasion by secreting antimicrobial and volatile organic compounds. To enhance plant fitness and yield, rhizospheric microbes are frequently employed as microbial inoculants. However, recent developments have shifted towards targeted rhizosphere engineering or microbial recruitments as a practical approach to constructing desired plant rhizospheres for specific outcomes. The rhizosphere, composed of plants, microbes, and soil, can be modified in several ways to improve inoculant efficiency. Rhizosphere engineering is achieved through three essential mechanisms: a) plant-mediated modifications involving genetic engineering, transgenics, and gene editing of plants; b) microbe-mediated modifications involving genetic alterations of microbes through upstream or downstream methodologies; and c) soil amendments. These mechanisms shape the rhizospheric microbiome, making plants more productive and resilient under different stress conditions. This review paper comprehensively summarizes the various aspects of rhizosphere engineering and their potential applications in maintaining plant health and achieving optimum agricultural productivity.


[Nature of the membrane depolarization of a nerve cell during the application of protein S-100 antibodies].
Application of antibodies to S-100 protein (the antibody concentration in the micropipette being 0.05 mg/ml) induced 13 +/- 4 mV depolarization of the membrane of snail Helix neurons. Non-immune gamma-globulin used in the control experiments caused no changes in the membrane potential. Antibody-induced depolarization was accompanied by a 2.5 nA inward current which was voltage-independent in the range of membrane potential from 50 to 110 mV. Hyperpolarization observed after the rinsing of antibodies was effectively blocked by a specific blocker of monovalent cation transport, ouabain, at a concentration of 5 X 10(-4) M. The absence of antibody-induced changes in the passive membrane conduction and the activation of electrogenic transport mechanisms after the antibody removal suggest possible involvement of Na, K- ATPase into the effect described.


Correlation between acrasins and spore germination inhibitors in cellular slime molds.
Discadenine,3-(3-amino-3-carboxypropyl)-N6-delta 2-isopentenyladenine, which inhibits spore germination, was previously found in Dictyostelium discoideum. Studies on the distribution of discadenine in different species of cellular slime molds by high-pressure liquid chromatography showed that discadenine is present in D. discoideum, Dictyostelium purpureum, and Dictyostelium mucoroides, but not in Dictyostelium minutum, Polysphondylium violaceum, or Polysphondylium pallidum. Discadenine synthetase, which is involved in biosynthesis of discadenine with N6-delta 2-isopentenyladenine as substrate, was only detected in cells of the former three species. In addition, discadenine inhibited spore germination only in these three species. These results clearly demonstrate that discadenine is produced as an inhibitor of spore germination in the species of cellular slime molds in which the acrasin is cyclic adenosine 5'-monophosphate (AMP). This means that there is a structural and biochemical correlation between the spore germination inhibitor and the acrasin, since 5'-AMP, a direct precursor in discadenine biosynthesis, can be derived from cyclic AMP by hydrolysis with cyclic AMP phosphodiesterase.


Association Among Blood Transfusion, Sepsis, and Decreased Long-term Survival After Colon Cancer Resection.
To investigate the potential additive effects of blood transfusion and sepsis on colon cancer disease-specific survival, cardiovascular disease-specific survival, and overall survival after colon cancer surgery. Perioperative blood transfusions are associated with infectious complications and increased risk of cancer recurrence through systemic inflammatory effects. Furthermore, recent studies have suggested an association among sepsis, subsequent systemic inflammation, and adverse cardiovascular outcomes. However, no study has investigated the association among transfusion, sepsis, and disease-specific survival in postoperative patients. The New York State Cancer Registry and Statewide Planning and Research Cooperative System were queried for stage I to III colon cancer resections from 2004 to 2011. Propensity-adjusted survival analyses assessed the association of perioperative allogeneic blood transfusion, sepsis, and 5-year colon cancer disease-specific survival, cardiovascular disease-specific survival, and overall survival. Among 24,230 patients, 29% received a transfusion and 4% developed sepsis. After risk adjustment, transfusion and sepsis were associated with worse colon cancer disease-specific survival [(+)transfusion: hazard ratio (HR) 1.19, 95% confidence interval (CI) 1.09-1.30; (+)sepsis: HR 1.84, 95% CI 1.44-2.35; (+)transfusion/(+)sepsis: HR 2.27, 95% CI 1.87-2.76], cardiovascular disease-specific survival [(+)transfusion: HR 1.18, 95% CI 1.04-1.33; (+)sepsis: HR 1.63, 95% CI 1.14-2.31; (+)transfusion/(+)sepsis: HR 2.04, 95% CI 1.58-2.63], and overall survival [(+)transfusion: HR 1.21, 95% CI 1.14-1.29; (+)sepsis: HR 1.76, 95% CI 1.48-2.09; (+)transfusion/(+)sepsis: HR 2.36, 95% CI 2.07-2.68] relative to (-)transfusion/(-)sepsis. Additional analyses suggested an additive effect with those who both received a blood transfusion and developed sepsis having even worse survival. Perioperative blood transfusions are associated with shorter survival, independent of sepsis, after colon cancer resection. However, receiving a transfusion and developing sepsis has an additive effect and is associated with even worse survival. Restrictive perioperative transfusion practices are a possible strategy to reduce sepsis rates and improve survival after colon cancer surgery.


Photochemical Internalization with Fimaporfin: Enhanced Bleomycin Treatment for Head and Neck Cancer.
Head and neck squamous cell carcinoma (HNSCC) still represents the world's sixth most common tumor entity, with increasing incidence. The reachability of light makes HNSCC suitable for light-based therapies such as Photochemical Internalization (PCI). The drug Bleomycin is cytotoxic and used as an anti-tumor medication. Since Bleomycin is endocytosed as a relatively large molecule, part of it is degraded in lysosomes before reaching its intracellular target. The goal of our study was to improve the intracellular availability of Bleomycin with PCI. We investigate the intracellular delivery of Bleomycin after PCI with the photosensitizer Fimaporfin. A systematic variation of Bleomycin and Fimaporfin concentrations and light irradiation led to the pronounced cell death of HNSCC cells. After optimization, the same level of tumor cell death of 75% was reached with a 20-fold lower Bleomycin concentration. This would allow treatment of HNSCC with high local tumor cell death and reduce the side effects of Bleomycin, e.g., lung fibrosis, at the same time. This demonstrates the increased efficacy of the anti-tumor medication Bleomycin in combination with PCI.


Population Pharmacokinetics of Hydroxychloroquine in COVID-19 Patients: Implications for Dose Optimization.
In the absence of characterization on pharmacokinetics and reference concentrations for hydroxychloroquine in COVID-19 patients, the dose and treatment duration for hydrochloroquine are currently empirical, mainly based on in vitro data, and may vary across national guidelines and clinical study protocols. The aim of this paper is to describe the pharmacokinetics of hydroxychloroquine in COVID-19 patients, considered to be a key step toward its dosing optimization. We have developed a population pharmacokinetic model for hydroxychloroquine in COVID-19 patients using prospectively collected pharmacokinetic data from patients either enrolled in a clinical trial or treated with hydroxychloroquine as part of standard of care in two tertiary Belgian hospitals. The final population pharmacokinetic model was a one-compartment model with first-order absorption and elimination. The estimated parameter values were 9.3/h, 860.8 L, and 15.7 L/h for the absorption rate constant, the central compartment volume, and the clearance, respectively. The bioavailability factor was fixed to 0.74 based on previously published models. Model validations by bootstraps, prediction corrected visual predictive checks, and normalized prediction distribution errors gave satisfactory results. Simulations were performed to compare the exposure obtained with alternative dosing regimens. The developed models provide useful insight for the dosing optimization of hydroxychloroquine in COVID-19 patients. The present results should be used in conjunction with exposure-efficacy and exposure-safety data to inform optimal dosing of hydroxychloroquine in COVID-19.


Association of Nonobstructive Chronic Bronchitis With Respiratory Health Outcomes in Adults.
Chronic bronchitis has been associated with cigarette smoking as well as with e-cigarette use among young adults, but the association of chronic bronchitis in persons without airflow obstruction or clinical asthma, described as nonobstructive chronic bronchitis, with respiratory health outcomes remains uncertain. To assess whether nonobstructive chronic bronchitis is associated with adverse respiratory health outcomes in adult ever smokers and never smokers. This prospective cohort study included 22 325 adults without initial airflow obstruction (defined as the ratio of forced expiratory volume in the first second [FEV1] to forced vital capacity [FVC] of <0.70) or clinical asthma at baseline. The National Heart, Lung, and Blood Institute (NHLBI) Pooled Cohorts Study harmonized and pooled data from 9 US general population-based cohorts. Thus present study is based on data from 5 of these cohorts. Participants were enrolled from August 1971 through May 2007 and were followed up through December 2018. Nonobstructive chronic bronchitis was defined by questionnaire at baseline as both cough and phlegm for at least 3 months for at least 2 consecutive years. Lung function was measured by prebronchodilator spirometry. Hospitalizations and deaths due to chronic lower respiratory disease and respiratory disease-related mortality were defined by events adjudication and administrative criteria. Models were stratified by smoking status and adjusted for anthropometric, sociodemographic, and smoking-related factors. The comparison group was participants without nonobstructive chronic bronchitis. Among 22 325 adults included in the analysis, mean (SD) age was 53.0 (16.3) years (range, 18.0-95.0 years), 58.2% were female, 65.9% were non-Hispanic white, and 49.6% were ever smokers. Among 11 082 ever smokers with 99 869 person-years of follow-up, participants with nonobstructive chronic bronchitis (300 [2.7%]) had accelerated decreases in FEV1 (4.1 mL/y; 95% CI, 2.1-6.1 mL/y) and FVC (4.7 mL/y; 95% CI, 2.2-7.2 mL/y), increased risks of chronic lower respiratory disease-related hospitalization or mortality (hazard ratio [HR], 2.2; 95% CI, 1.7-2.7), and greater respiratory disease-related (HR, 2.0; 95% CI, 1.1-3.8) and all-cause mortality (HR, 1.5; 95% CI, 1.3-1.8) compared with ever smokers without nonobstructive chronic bronchitis. Among 11 243 never smokers with 120 004 person-years of follow-up, participants with nonobstructive chronic bronchitis (151 [1.3%]) had greater rates of chronic lower respiratory disease-related hospitalization or mortality (HR, 3.1; 95% CI, 2.1-4.5) compared with never smokers without nonobstructive chronic bronchitis. Nonobstructive chronic bronchitis was not associated with FEV1:FVC decline or incident airflow obstruction. The presence of at least 1 of the component symptoms of nonobstructive chronic bronchitis (ie, chronic cough or phlegm), which was common in both ever smokers (11.0%) and never smokers (6.7%), was associated with adverse respiratory health outcomes. The findings suggest that nonobstructive chronic bronchitis is associated with adverse respiratory health outcomes, particularly in ever smokers, and may be a high-risk phenotype suitable for risk stratification and targeted therapies.


A systematic review and meta-analysis of school-based interventions with health education to reduce body mass index in adolescents aged 10 to 19 years.
Adolescents are increasingly susceptible to obesity, and thus at risk of later non-communicable diseases, due to changes in food choices, physical activity levels and exposure to an obesogenic environment. This review aimed to synthesize the literature investigating the effectiveness of health education interventions delivered in school settings to prevent overweight and obesity and/ or reduce BMI in adolescents, and to explore the key features of effectiveness. A systematic search of electronic databases including MEDLINE, CINAHL, PsychINFO and ERIC for papers published from Jan 2006 was carried out in 2020, following PRISMA guidelines. Studies that evaluated health education interventions in 10-19-year-olds delivered in schools in high-income countries, with a control group and reported BMI/BMI z-score were selected. Three researchers screened titles and abstracts, conducted data extraction and assessed quality of the full text publications. A third of the papers from each set were cross-checked by another reviewer. A meta-analysis of a sub-set of studies was conducted for BMI z-score. Thirty-three interventions based on 39 publications were included in the review. Most studies evaluated multi-component interventions using health education to improve behaviours related to diet, physical activity and body composition measures. Fourteen interventions were associated with reduced BMI/BMI z-score. Most interventions (n = 22) were delivered by teachers in classroom settings, 19 of which trained teachers before the intervention. The multi-component interventions (n = 26) included strategies such as environment modifications (n = 10), digital interventions (n = 15) and parent involvement (n = 16). Fourteen studies had a low risk of bias, followed by 10 with medium and nine with a high risk of bias. Fourteen studies were included in a random-effects meta-analysis for BMI z-score. The pooled estimate of this meta-analysis showed a small difference between intervention and control in change in BMI z-score (- 0.06 [95% CI -0.10, - 0.03]). A funnel plot indicated that some degree of publication bias was operating, and hence the effect size might be inflated. Findings from our review suggest that school-based health education interventions have the public health potential to lower BMI towards a healthier range in adolescents. Multi-component interventions involving key stakeholders such as teachers and parents and digital components are a promising strategy.


Mir106b-25 and Mir17-92 Are Crucially Involved in the Development of Experimental Neuroinflammation.
MicroRNAs (miRNAs) are single-stranded RNA that have key roles in the development of the immune system and are involved in the pathogenesis of various autoimmune diseases. We previously demonstrated that two members of the miR106b-25 cluster and the miR17-92 paralog cluster were upregulated in T regulatory cells from multiple sclerosis (MS) patients. The aim of the present work was to clarify the impact of miR106b-25 and miR17-92 clusters in MS pathogenesis. Here, we show that the mice lacking miR17-92 specifically in CD4+ T cells or both total miR106b-25 and miR17-92 in CD4+ T cells (double knockout) are protected from Experimental Autoimmune Encephalomyelitis (EAE) development while depletion of miR106b-25 only does not influence EAE susceptibility. We suggest that the absence of miR106b does not protect mice because of a mechanism of compensation of miR17-92 clusters. Moreover, the decrease of neuroinflammation was found to be associated with a significant downregulation of pro-inflammatory cytokines (GM-CSF, IFNγ, and IL-17) in the spinal cord of double knockout EAE mice and a reduction of Th17 inflammatory cells. These results elucidate the effect of miR106b-25 and miR17-92 deletion in MS pathogenesis and suggest that their targeted inhibition may have therapeutic effect on disease course.


Molecular characterization of Korean rabies virus isolates.
The nucleoprotein (N) and glycoprotein (G) of 11 Korean rabies virus (RABV) isolates collected from animals diagnosed with rabies between 2008 and 2009 were subjected to molecular and phylogenetic analyses. Six isolates originated from domestic animals (cattle and dogs) and five were obtained from wild free-ranging raccoon dogs. The similarities in the nucleotide sequences of the N gene among all Korean isolates ranged from 98.1 to 99.8%, while those of the G gene ranged from 97.9 to 99.3%. Based on the nucleotide analysis of the N and G genes, the Korean RABV isolates were confirmed as genotype I of Lyssavirus and classified into four distinct subgroups with high similarity. Phylogenetic analysis showed that the Korean isolates were most closely related to the non-Korean NeiMeng1025B and 857r strains, which were isolated from rabid raccoon dogs in Eastern China and Russia, respectively. These findings suggest that the Korean RABV isolates originated from a rabid raccoon dog in Northeastern Asia. Genetic analysis of the Korean RABV isolates revealed no substitutions at several antigenic sites, indicating that the isolates circulating in Korea may be pathogenic in several hosts.


Broadcast spawning by Pocillopora species on the Great Barrier Reef.
The coral genus Pocillopora is one of the few to include some species that broadcast spawn gametes and some species that brood larvae, although reports of reproductive mode and timing vary within and among species across their range. Notably, the ubiquitous Pocillopora damicornis has been described as both a brooder and spawner, although evidence of broadcast spawning is rare. Here, we report observations of broadcast-spawning in four species of Pocillopora on the Great Barrier Reef (GBR), including P. damicornis. All species spawned predictably during the early morning, two days following the full moon, and spawning was observed in multiple months over the summer period (November to February). Eggs and sperm were free-spawned concurrently. Eggs were negatively buoyant and contained Symbiodinium. This newfound knowledge on the mode, timing and regularity of broadcast spawning in Pocillopora spp. on the GBR brings us one step closer to elucidating the complex reproductive ecology of these species.


The problems of morbidity and therapy in borderline hypertension.
The aim of the trial was to see whether it was possible to improve morbidity and mortality in both males and females with diastolic pressures between 90 and 109 mm Hg. The initial calculations suggested that it would be necessary to screen between 250-500,000 people to obtain 18-36,000 subjects. This was the number predicted to obtain a statistically significant end-point on current knowledge of morbidity and mortality in this age range. The initial aim was to mount a trial of feasibility with the following objectives: (1) To recruit up to 1000 adults of both sexes aged 35 to 64 years with diastolic pressures in the 90-109 mm Hg range. (2) To determine the acceptability of the trial to asymptomatic subjects as well as their physicians. (3) To show that selected drugs (bendrofluazide and propranolol) adequately control pressure without undue side-effects. (4) To assess the psychological effects of inclusion in the trial. (5) To examine the cost and efficiency of different types of recruitment and supervision. These objectives have now been largely achieved with over 1500 subjects in the study at 2 1/2 years and a drop-out rate of about 13% in all. It appears that the best method of recruitment and supervision is through family practices with supporting staff, particularly in the screening phase. Both the selected drugs reduce the blood pressure significantly and although the placebo groups also show a maintained fall of pressure, the difference from the treated groups is significant. There is no evidence of increased psychological stress by inclusion in the trial and those with psychological symptoms at the outset improve in comparison with their control subjects outside the trial. In order to reach an end-point which will give data of statistical significance, the trial should now be expanded as rapidly as possible towards the goal of recruiting 18-36,000 subjects.


Interprofessional Field Experiences in Occupational Safety and Health.
Field trips are beneficial to students, because they provide experiences outside of the traditional classroom. Incorporating field trips into graduate programs can increase students' exposures to real world experiences so that they can incorporate that knowledge as they complete their program. The purpose of the project was to collect and analyze graduate student feedback on 13 in-person interprofessional field trips focused on occupational safety and health. Data were collected through post-field trip structured discussions. Content analysis was used to determine themes. Five themes emerged from the data: Personal Value, Networking and Meeting, Health and Safety Planning and Policy, Environment, and Logistics and Planning. Field trips are valuable learning experiences for graduate students. The field trips in this study offered concrete experiences in occupational safety and health. Post-field trip, students provided feedback through structured discussions, which allowed for reflective observation. Overall, students found personal value in the field trips, observed health and safety procedures and policies in action, learned about various work environments, and provided input on the logistics and planning of field trips.


Bayesian modelling of compositional heterogeneity in molecular phylogenetics.
In molecular phylogenetics, standard models of sequence evolution generally assume that sequence composition remains constant over evolutionary time. However, this assumption is violated in many datasets which show substantial heterogeneity in sequence composition across taxa. We propose a model which allows compositional heterogeneity across branches, and formulate the model in a Bayesian framework. Specifically, the root and each branch of the tree is associated with its own composition vector whilst a global matrix of exchangeability parameters applies everywhere on the tree. We encourage borrowing of strength between branches by developing two possible priors for the composition vectors: one in which information can be exchanged equally amongst all branches of the tree and another in which more information is exchanged between neighbouring branches than between distant branches. We also propose a Markov chain Monte Carlo (MCMC) algorithm for posterior inference which uses data augmentation of substitutional histories to yield a simple complete data likelihood function that factorises over branches and allows Gibbs updates for most parameters. Standard phylogenetic models are not informative about the root position. Therefore a significant advantage of the proposed model is that it allows inference about rooted trees. The position of the root is fundamental to the biological interpretation of trees, both for polarising trait evolution and for establishing the order of divergence among lineages. Furthermore, unlike some other related models from the literature, inference in the model we propose can be carried out through a simple MCMC scheme which does not require problematic dimension-changing moves. We investigate the performance of the model and priors in analyses of two alignments for which there is strong biological opinion about the tree topology and root position.


Home blood pressure monitoring in CKD.
Blood pressure (BP) control is the mainstay of stalling the progression of cardiorenal disease, yet the performance characteristics of BPs obtained in the clinic (CBPs) by routine or standardized methods or at home (HBP) in diagnosing hypertension or assessing its control are unknown. Two hundred thirty-two patients (20% black; 4% women; mean age, 67 years; 35% with diabetes) with chronic kidney disease (CKD) underwent a single 24-hour ambulatory BP (ABP) monitoring (ABPM) and concomitant recording of CBP and HBP for 1 week. Hypertension is defined as systolic BP of 130 mm Hg or greater or diastolic BP of 80 mm Hg or greater on average awake 24-hour ABPM. Average ABP was 135.2 +/- 15.9/75.6 +/- 11.0 mm Hg. Thirty-five percent of patients had isolated systolic hypertension; 3%, isolated diastolic hypertension; 27%, combined systolic and diastolic hypertension; and 35%, normotension or well-controlled BP. The prevalence of "white-coat effect" was estimated as 28% to 30% by means of CBPs and 24% by means of HBPs. Well-controlled BP in the clinic, but poorly controlled BP by means of ABPM, masked hypertension, was seen in 26% to 29% by means of CBPs, but only 13% with HBP monitoring. In patients with CKD, HBP is superior in reducing the misclassification of hypertension caused by the white-coat effect and masked hypertension commonly seen with CBPs. An average HBP of approximately 140/80 mm Hg appears to be the best correlate of hypertension defined by means of ABPM.


Stress and coping and behavioral organization.
This article presents a new integrative theoretical framework for stress and coping centered on the concept of behavioral organization and the notions that stress disorganizes behavior and coping aims at reorganizing it. Functional analysis of behavioral organization leads to identification of four core domains of control and to a functional classification of types of stressful conditions, types of negative emotions, and types of coping functions linked directly to the control domains. The control domains are represented cognitively by four postulated kinds of beliefs or views people hold with respect to undertaking an action: performance, process, prospect, and profit beliefs. The four basic control beliefs form the core of the present coping belief model of coping. Recognition of the underlying structure of behavior, and of functional categories of stress and coping related to it, can advance theory and research on stress and coping by enriching its psychological content, improving research designs, and leading to reexamination, reinterpretation, and integration of findings existing in the literature that presently are fragmented and unconnected.


Angiotensinogen Thr235 variant is associated with abnormal physiologic change of the uterine spiral arteries in first-trimester decidua.
The angiotensinogen Thr235 polymorphism associated with preeclampsia is tightly linked to a mutation in the angiotensinogen promoter A(-6), which may lead to elevated expression in decidual spiral arteries. We hypothesize that locally elevated angiotensin II levels play a role in failed physiologic change leading to preeclampsia. Our objective was to determine whether spiral artery morphologic characteristics were different in first-trimester decidual samples from women homozygous for the angiotensinogen Thr235 allele and women homozygous for the normal angiotensinogen Met235 allele. We used quantitative histologic analysis to study 1266 spiral artery cross-sections in decidual samples obtained from normal pregnancies (n = 53) terminated at 8 weeks' gestation. To define vessel characteristics before pregnancy-induced remodeling, we also examined 60 arteries in nonpregnant endometrial control samples (n = 5). We measured the aspect ratio, media area, and external diameter of each cross-section with Image-Pro plus software. Maternal angiotensinogen genotypes were determined by means of mutagenically separated polymerase chain reaction. Average spiral artery morphologic measurements were compared between genotypes with the Student t test. The media area/external diameter ratio was lower in decidual samples than in endometrial samples (P <.0001), consistent with pregnancy-induced physiologic changes. Women homozygous for the angiotensinogen Thr235 allele (n = 11) had a greater area/diameter ratio than did women homozygous for the normal angiotensinogen Met235 allele (n = 11, P <.05). Samples from heterozygous women (n = 31) had intermediate values. Our results suggest that the angiotensinogen Thr235 allele predisposes women toward abnormal physiologic change, potentially beginning the cascade of events leading to preeclampsia.


Expanding the histological spectrum of salivary gland neoplasms with HMGA2::WIF1 fusion emphasising their malignant potential: a report of eight cases.
Recently, HMGA2::WIF1 fusion has been reported in pleomorphic adenoma (PAs) originating from the parotid gland with a characteristic canalicular adenoma (CAA)-like pattern. However, it is unclear whether HMGA2::WIF1 fusion may occur in salivary gland carcinoma or tumours originating from the minor salivary glands. We herein conducted a detailed clinicopathological review of eight salivary gland tumours harbouring HMGA2::WIF1 fusions. The reviewed diagnoses of salivary gland neoplasms with HMGA2::WIF1 fusion were PA (n = four), myoepithelioma (n = one), myoepithelial carcinoma ex PA (n = two) and high-grade carcinoma with basaloid features (n = one). Two tumours originated from the minor salivary glands. Six tumours (80%) contained areas reminiscent of CAA characterised by interconnected trabeculae/canaliculi of monotonous oncocytic or cuboidal tumour cells associated with a hypocellular, hyalinised to myxoid stroma. Areas typical of PA were seen in four (50%) cases. All tumours showed diffuse S100 and CK7 immunopositivity. Adverse events were detected in two cases, including local recurrence in a patient with PA, and local and distant recurrences and disease-related death in a patient with a high-grade carcinoma of the minor salivary gland of the buccal space, showing tumour necrosis and perineural invasion. Salivary gland neoplasms with HMGA2::WIF1 fusion are predominantly characterised by CAA/striated duct adenoma-like histology and a S100+/CK7+ immunoprofile. These tumours are not always benign, as among all reported cases approximately 20% showed malignancy (six of 28) and adverse outcome (three of 15), including recurrence, distant metastasis and disease-specific mortality.


Dose-response of women's health-related quality of life (HRQoL) and life satisfaction to physical activity.
To examine the dose-response relationship between health related quality of life (HRQoL) and life satisfaction (outcomes) and duration of recreational physical activity (exposure). Further, to explore whether these relationships depend on type of physical activity (PA). 793 Australian rural-living women self-reported on duration of recreational PA; HRQoL via SF-36 Mental Component Summary (MCS) and Physical Component Summary (PCS); and a life satisfaction scale. ANOVAs and ANCOVAs investigated differences in outcomes (MCS, PCS, and life satisfaction) between tertiles of exposure to recreational PA, and types of PA (club sport, gymnasium, walking), with adjustment for potential confounders. A significant positive dose-response relationship was found between PCS and level of PA. Furthermore, this relationship depended on type of PA, with club-sport participants recording higher PCS than non-club-sport participants in all but the highest tertile of exposure. Life satisfaction and MCS were not significantly related to level of PA. Physical health was positively associated with level of recreational PA, with club sport participation contributing greater benefits at low to moderate exposures than participation in gymnasium or walking activities.


Responses of biomass allocation across two vegetation types to climate fluctuations in the northern Qinghai-Tibet Plateau.
The Qinghai-Tibet Plateau (QTP) is particularly sensitive to global climate change, especially to elevated temperatures, when compared with other ecosystems. However, few studies use long-term field measurements to explore the interannual variations in plant biomass under climate fluctuations. Here, we examine the interannual variations of plant biomass within two vegetation types (alpine meadow and alpine shrub) during 2008-2017 and their relationships with climate variables. The following results were obtained. The aboveground biomass (AGB) and belowground biomass (BGB) response differently to climate fluctuations, the AGB in KPM was dominated by mean annual precipitation (MAP), whereas the AGB in PFS was controlled by mean annual air temperature (MAT). However, the BGB of both KPM and PFS was only weakly affected by climate variables, suggesting that the BGB in alpine ecosystems may remain as a stable carbon stock even under future global climate change. Furthermore, the AGB in PFS was significantly higher than KPM, while the BGB and R/S in KPM were significantly higher than PFS, reflecting the KPM be more likely to allocate more photosynthates to roots. Interestingly, the proportion of 0-10 cm root biomass increased in KPM and PFS, whereas the other proportions both decreased, reflecting a shift in biomass toward the surface layer. Our results could provide a new sight for the prediction how alpine ecosystem response to future climate change.


[The polymorphism of matrix Gla-protein gene in ischemic atherothrombotic stroke patients].
Matrix Gla protein (MGP) gene allelic polymorphism in 170 patients with ischemic atherothrombotic stroke (IATS) and in 124 healthy people was determined. It was shown that in patients with IATS interrelation of main homozygotes, heterozygotes and minor homozygotes is 61,2, 31,2, 7,6% for T-138 --> C (rs1800802) promoter polymorphism (in control -59.7, 35.6, 4.8%, P = 0.521 by chi2-test); 35.9, 48.8, 15.3% for G(-7) --> A (rs1800801) polymorphism of promotor (in control--43.5, 50.0, 6.5%, P = 0.051); 39.4, 48.8, 11.8% for Thr83 --> Ala (rs4236) polymorphism of 4 exon (in control - 34.7, 53.2, 12.1%, P = 0.701). Significant differences in the frequency of G(-7) --> A polymorphism between patients with IATS and control group were revealed only for women (P = 0.022). The results obtained suggest that the A/A-variant of MGP gene promotor (G(-7) --> A polymorphism) is associated with an increased risk of IATS in female persons in the Ukrainian population.


Impact of the crystal size of crystalline active pharmaceutical compounds on loading into microneedles.
Microneedle (MN) technology offers a promising platform for the delivery of a wide variety of active pharmaceutical compounds into and/or through the skin. Yet, the low loading capacity of MNs limits their clinical translation. The solid state of loaded compounds, crystallinity versus amorphousness and crystal size of the former, could greatly affect their loading. Here, we investigated the effect of the crystal size of crystalline compounds on their loading into dissolving MNs, prepared using the solvent-casting technique. A model crystalline compound was subjected to crystal size reduction via wet bead milling and loaded into dissolving MNs. A range of crystal sizes, from micro to nano, was obtained via different milling periods. The obtained crystals were characterized for their size, morphology, and sedimentation behavior. Besides, their content, solid state inside the MNs, and impact on the MN mechanical strength were assessed. The crystals exhibited size-dependent sedimentation, which dramatically affected their loading inside the MNs. However, crystal size and sedimentation demonstrated a negligible effect on the mechanical strength and sharpness of the needles, hence no anticipated impact on the MNs' drug delivery efficiency. The elucidation of the correlation between the crystal size and MN loading opens new potentials to address a major drawback in MN technology.


Oral surgery. Diagnostic, prognostic, and treatment planning considerations.
The surgical management of a patient begins at the moment of presentation for treatment and does not end until the problem is resolved and health restored. Alternatively, referral may be good management in some cases. Any procedure accomplished along the way is but one event in the course of overall surgical management. A regard for the basic requirements and principles of good surgery integrated with a careful consideration of the treatment planning and prognostic indicators for the removal of teeth completes a sequential evaluation of the total patient, his pathosis and his ability to tolerate and respond to the treatment. Guiding principles, careful procedures and continued postoperative concern form a triad of good practice.


Neurons and Nobel Prizes: a centennial history of neuropathology.
Camillo Golgi and Santiago Ramón Y Cajal were selected as joint Nobel Prize recipients in 1906, "in recognition of their work on the structure of the nervous system." This posthumous Festschrift is written in celebration and commemoration of the 90th anniversary of that event, and the reader is invited to participate in an entertaining journey through the history of neuropathology, as it evolved from the time of Golgi and Cajal. The story, of necessity, is written in broad descriptive terms, highlighting major events and personalities, and strives for continuity of narration and coherence of presentation. The historical framework reflects the personal experience and purview of the author and his mentor, Kenneth M. Earle, who began their careers in neurology and neurosurgery, respectively. Emphasis on the close interface linking clinical neuroscience and neuropathology indicates the antecedents of the latter discipline as well as the overlap characterizing current modes of investigation at the cellular and molecular levels. This article is intended to provide a younger generation of neurologists and neurosurgeons with a review of what has gone before as a foundation for their current studies and future careers.


Photoinduced force microscopy as a novel method for the study of microbial nanostructures.
A detailed comparison of the capabilities of electron microscopy and nano-infrared (IR) microscopy for imaging microbial nanostructures has been carried out for the first time. The surface sensitivity, chemical specificity, and non-destructive nature of spectroscopic mapping is shown to offer significant advantages over transmission electron microscopy (TEM) for the study of biological samples. As well as yielding important topographical information, the distribution of amides, lipids, and carbohydrates across cross-sections of bacterial (Escherichia coli, Staphylococcus aureus) and fungal (Candida albicans) cells was demonstrated using PiFM. The unique information derived from this new mode of spectroscopic mapping of the surface chemistry and biology of microbial cell walls and membranes, may provide new insights into fungal/bacterial cell function as well as having potential use in determining mechanisms of antimicrobial resistance, especially those targeting the cell wall.


The trifecta of adulthood: Housing, partnering and childbearing trajectories.
Substantial changes in residential transitions and family formation patterns have been observed in Western societies, but less attention has been paid to the de-standardisation of adulthood pathways in East Asian contexts, where unique social, economic and cultural circumstances may produce diverse trajectories that are less explored in existing theoretical and empirical frameworks. Adopting a life course perspective, this study identifies the multi-trajectories of housing, partnering and childbearing across adulthood in Taiwan, a setting marked by high housing costs and low fertility rates. Data from the Taiwanese Panel Study of Family Dynamics 2000-2020 (N = 6,931) were used for group-based trajectory modelling, and mixed-effects multinomial regression was employed to examine the likelihood of group membership given early-life resources and social origin. Six common housing-partnering-childbearing trajectories were identified. The most prevalent living arrangement was living in parental homes (50.7%), followed by rental homes (25%), self-owned homes (15.5%) and dorms or other (8.8%). Union formation generally precedes childbearing, whereas housing transitions may occur at various time points. Young adults' home-leaving and homeownership access appear to be closely related to their parental backgrounds, such as their parents' educational attainment and occupational status. Overall, the findings are consistent with the de-standardisation of pathways to adulthood, demonstrating the diversity in adult trajectories and the lack of a single dominant pattern.


MicroRNA-32 inhibits the proliferation, migration and invasion of human colon cancer cell lines by targeting E2F transcription factor 5.
MicroRNAs to be essential therapeutic targets for the treatment of diseases such as cancer. Colon cancer is one of the prevalent cancers and causes tremendous human mortality. The treatment of colon cancer is limited by late diagnosis and lack of efficient therapeutic targets. Herein, the therapeutic potential of the miR-32 was explored in colon cancer. Expression analysis was carried out by quantitative Real-time polymerase chain reaction (qRT-PCR). Transfections were performed by Lipofectamine® 2000 reagent. The cell counting kit 8 (CCK-8) assay was used to determine cell viability. The 4', 6-diamidino-2-phenylindole (DAPI) and annexin V/Propidium Iodide (PI) assays were used for the detection of apoptosis. Transwell assays were used to determine cell migration and invasion. The expression of the proteins was estimated by Western blotting. The results showed that the expression of miR-32 was aberrantly downregulated in all colon cancer cells. Overexpression of miR-32 caused significant (p<0.01) decline in the viability in SW-948 cells via induction of apoptosis. The induction of apoptosis was also accompanied by the upregulation of Bax and downregulation of Bcl-2 expression. Overexpression of miR-32 also caused the arrest of the SW-498 cells in the G2/M phase of cell cycle and inhibited their migration and invasion. TargetScan analysis showed E2F transcription factor 5 (E2F5) to be the potential target of miR-32, which was also confirmed by dual luciferase reporter assay. The expression of E2F5 was significantly (p<0.01) upregulated in the colon cancer cells and overexpression of miR-32 caused a considerable decline in the expression of E2F5 in the SW-948 cells. E2F5 silencing also inhibited the growth of the SW-948 cells via induction of apoptosis and G2/M cell cycle arrest. MiR-32 overexpression also inhibited the migration and invasion of the SW-948 cells. However, rescue assay revealed E2F5 to be essential for the tumor suppressive effects of miR-32. The findings of the present study reveal that miR-32 acts as a tumor suppressor in colon cancer cells and may have therapeutic implications in colon cancer treatment.


[Subpartal diagnosis of umbilical cord encirclement using color-coded Doppler ultrasonography and correlation with cardiotocographic changes during labor].
Umbilical cord complications are the most common cause of pathologic fetal heart tones during delivery. The inauguration of colour-coded Doppler ultrasound in obstetrics has made the definite diagnosis of umbilical cord encirclement during delivery possible. The prospective study introduced here examines the question of how exactly an encirclement can be seen by Doppler during delivery, its influence on cardiotocographic results, delivery mode, and fetal outcome. 107 patients in labour with cervical dilatation were examined in a prospective study using colour-coded Doppler ultrasound to determine cases of umbilical cord encirclement. In 50 cases, encirclement could be visualised, 48 of which were confirmed post partum. Encirclement could be ruled out in 57 other cases. A sensitivity of 96% and specificity of 100% resulted. No significant differences could be found with regard to mode of delivery and fetal outcome. However, the umbilical cord in cases of encirclement was significantly longer than when no encirclement occurred. Assessment of fetal heart tones demonstrated a significantly higher rate of variable decelerations in the patient group with umbilical cord encirclement compared to that without. In conclusion, our results show that the early diagnosis of umbilical cord encirclement during delivery allows appropriate assessment of fetal heart tone changes,justifying temporising management under continuous monitoring with possible micro-blood analysis.


The breathing conundrum-interoceptive sensitivity and anxiety.
Cognitive and affective processing has been the central focus of brain-related functions in psychology and psychiatry for many years. Much less attention has been paid to what could be considered the primary function of the brain, to regulate the function of the body. Recent developments, which include the conceptualization of interoception as a process consisting of integrating the information coming from the inside of the body in the central nervous system and the appreciation that complex emotional processes are fundamentally affected by the processing and regulation of somatic states, have profoundly changed the view of the function and dysfunction of the brain. This review focuses on the relationship between breathing and anxiety. Several anxiety disorders have been associated with altered breathing, perception of breathing, and response to manipulations of breathing. Both clinical and experimental research studies are reviewed that relate breathing dysfunctions to anxiety. Altered breathing may be useful as a physiological marker of anxiety as well as a treatment target using interoceptive interventions.


Mechanical unloading versus neurohumoral stimulation on myocardial structure and endocrine function In vivo.
BACKGROUND-Mechanical load and humoral stimuli such as endothelin (ET) and angiotensin II (Ang II) are potent modulators of cardiac structure and endocrine function, specifically gene expression and production and release of atrial natriuretic peptide (ANP). We define the contribution of mechanical load compared with neurohumoral stimulation in vivo with specific focus on myocardial and circulating ANP during chronic myocardial unloading produced by thoracic inferior vena caval constriction (TIVCC). METHODS AND RESULTS-TIVCC was produced by banding the IVC for 10 days in 7 dogs, whereas in the 6 control dogs, the band was not constricted. TIVCC was characterized by a decrease in cardiac output, right atrial pressure, and left ventricular (LV) end-diastolic diameter and marked activation of ET and Ang II in plasma and atrial and ventricular myocardium. Despite neurohumoral stimulation, LV mass index and myocyte diameters in unloaded hearts decreased, reflecting myocyte atrophy. The total number of myocytes in the LV remained unchanged. Atrial stores of ANP increased, but plasma ANP did not change, in association with a trend toward ANP gene expression to decrease in unloaded hearts. CONCLUSIONS-Chronic mechanical unloading of the heart results in myocardial atrophy and lack of activation of ANP synthesis despite marked neurohumoral stimulation by the growth promoters ET and Ang II.


Symptom Clusters and Quality of Life over 1 Year in Breast Cancer Patients Receiving Adjuvant Chemotherapy.
Evidence is scant regarding symptom clusters and quality of life (QOL) over 1 year in women who receive adjuvant breast cancer chemotherapy (CTX). Our purpose was to identify the prevalence and severity of individual symptoms, symptom clusters, and QOL in women receiving adjuvant breast cancer CTX from baseline over 1 year. Symptoms were identified in a sample (n = 219) at three times: baseline (prior to the first adjuvant CTX treatment), 1 month after the last CTX (approximately 6 months after baseline), and 1 year after baseline. The Hospital Anxiety and Depression Scale and Symptom Experience Scale measured symptoms. The Medical Outcomes Study, Short-Form Survey, measured QOL. Exploratory factor analysis identified symptom clusters at each time and core symptoms in clusters over time. The prevalence and severity of 10 symptoms decreased over time (P < 0.05). Fatigue, sleep disturbance, and pain were most prevalent; all were of mild severity. Two symptom clusters were identified at baseline and one met internal consistency reliability criteria at the later times. Core symptoms were identified. Both the physical and mental component scores of QOL improved over time (P < 0.01), but physical was below the general population norms 1 year after baseline. The symptom experience was dynamic, and symptom clusters changed over 1 year. Despite mild severity, core symptoms and clusters persisted over 1 year, and physical health was below the general population norms. Breast cancer survivors with persistent single and co-occurring symptoms need to be taught to manage the patterns of symptoms over time because they may not resolve by 1 year.


Targeting the carbohydrates on HIV-1: Interaction of oligomannose dendrons with human monoclonal antibody 2G12 and DC-SIGN.
It is widely accepted that the heavily glycosylated glycoprotein gp120 on the surface of HIV-1 shields peptide epitopes from recognition by the immune system and may promote infection in vivo by interaction with dendritic cells and transport to tissue rich in CD4(+) T cells such as lymph nodes. A conserved cluster of oligomannose glycans on gp120 has been identified as the epitope recognized by the broadly HIV-1-neutralizing monoclonal antibody 2G12. Oligomannose glycans are also the ligands for DC-SIGN, a C-type lectin found on the surface of dendritic cells. Multivalency is fundamental for carbohydrate-protein interactions, and mimicking of the high glycan density on the virus surface has become essential for designing carbohydrate-based HIV vaccines and antiviral agents. We report an efficient synthesis of oligomannose dendrons, which display multivalent oligomannoses in high density, and characterize their interaction with 2G12 and DC-SIGN by a glycan microarray binding assay. The solution and the surface binding analysis of 2G12 to a prototype oligomannose dendron clearly demonstrated the efficacy of dendrimeric display. We further showed that these glycodendrons inhibit the binding of gp120 to 2G12 and recombinant dimeric DC-SIGN with IC(50) in the nanomolar range. A second-generation Man(9) dendron was identified as a potential immunogen for HIV vaccine development and as a potential antiviral agent.


Natural Language Processing: Chances and Challenges in Dentistry.
Natural language processing (NLP) is an intersection between Computer Science and Linguistic which aims to enable machines to process and understand human language. We here summarized applications and limitations of NLP in dentistry. Narrative review. NLP has evolved increasingly fast. For the dental domain, relevant NLP applications are text classification (e.g., symptom classification) and natural language generation and understanding (e.g., clinical chatbots assisting professionals in office work and patient communication). Analyzing large quantities of text will allow understanding diseases and their trajectories and support a more precise and personalized care. Speech recognition systems may serve as virtual assistants and facilitate automated documentation. However, to date, NLP has rarely been applied in dentistry. Existing research focuses mainly on rule-based solutions for narrow tasks. Technologies such as Recurrent Neural Networks and Transformers have been shown to surpass the language processing capabilities of such rule-based solutions in many fields, but are data-hungry (i.e., rely on large amounts of training data), which limits their application in the dental domain at present. Technologies such as federated or transfer learning or data sharing concepts may allow to overcome this limitation, while challenges in terms of explainability, reproducibility, generalizability and evaluation of NLP in dentistry remain to be resolved for enabling approval of such technologies in medical devices and services. NLP will become a cornerstone of a number of applications in dentistry. The community is called to action to improve the current limitations and foster reliable, high-quality dental NLP. NLP for text classification (e.g., dental symptom classification) and language generation and understanding (e.g., clinical chatbots, speech recognition) will support administrative tasks in dentistry, provide deeper insights for clinicians and support research and education.


Study of circulating microRNA-125b levels in serum exosomes in advanced melanoma.
Malignant melanoma is an aggressive tumor that produces exosomes, which contain microRNAs (miRNAs) that could be of utility in following tumoral cell dysregulation. MicroR-125b is a miRNA whose down-regulation seems to be implicated in melanoma progression. To analyze miR-125b levels in serum, and in exosomes obtained from serum, from patients with advanced melanoma. Serum samples were obtained from 21 patients with advanced melanoma, from 16 disease-free patients with melanoma, and from 19 healthy volunteers. Exosomes were isolated from serum by precipitation, and miR-16 and miR-125b levels were quantified by real-time polymerase chain reaction. MicroR-16, but not miR-125b, was detected in all samples, and miR-16 levels were significantly higher in serum than they were in exosomes. MicroR-16 expression levels did not differ significantly between the 2 groups (patients with melanoma and healthy donors). There was a significant relationship between miR-125b and miR-16 levels in exosomes. Additionally, miR-125b levels in exosomes were significantly lower in patients with melanoma compared with disease-free patients with melanoma and healthy controls. Exosomes can provide a suitable material to measure circulating miRNA in melanoma, and miR-16 can be used as an endogenous normalizer. Lower levels of miR-125b in exosomes obtained from serum are associated with advanced melanoma disease, probably reflecting the tumoral cell dysregulation.


Deregulation of c-myc gene expression in human colon carcinoma is not accompanied by amplification or rearrangement of the gene.
The structure and expression of the c-myc oncogene were examined in 29 primary human colon adenocarcinomas. Dot blot hybridization of total RNA showed that 21 tumors (72%) had considerably elevated expression of c-myc (5- to 40-fold) relative to normal colonic mucosa. These data were corroborated by Northern blots of polyadenylated RNA, which showed a 2.3-kilobase transcript. Southern analysis of the c-myc locus in these tumors indicated the absence of amplification or DNA rearrangement in a 35-kilobase region encompassing the gene. In a parallel study, elevated expression of c-myc without amplification or DNA rearrangement was also observed in three of six colon carcinoma cell lines examined; in addition, unlike a normal colon cell line control, these three cell lines exhibited constitutive, high-level expression of the gene during their growth in cultures. These results indicate that elevated expression of the c-myc oncogene occurs frequently in primary human colon carcinomas and that the mechanism involved in the regulation of c-myc expression is altered in tumor-derived cell lines.


Sandwiched gold/PNIPAm/gold microstructures for smart plasmonics application: towards the high detection limit and Raman quantitative measurements.
A smart plasmonic sensor, comprising a layer of a stimuli-responsive polymer sandwiched between two gold layers, is reported. As a stimuli-responsive material, a monolayer of poly(N-isopropylacrylamide) (PNIPAm) crosslinked globules is used. A quasi-periodic structure of the top gold layer facilitates efficient excitation and serves as a support for plasmon excitation and propagation. The intermediate layer of PNIPAm efficiently entraps targeted molecules from solutions. The sensor structure was optimized for efficient light focusing in the "active" PNIPAm layer. The optimization was based on the time-resolved finite-element simulations, which take into account the thickness of gold layers, size of PNIPAm globules and Raman excitation wavelength (780 nm). The prepared structures were characterized using SEM, AFM, UV-Vis refractometry and goniometry. Additional AFM scans were performed in water at two temperatures corresponding to the collapsed and swollen PNIPAm states. The Raman measurements demonstrate a high detection limit and perfect reproducibility of the Raman scattering signal for the prepared sensor. In addition, the use of created SERS structures for the detection of relevant molecules in the medical, biological and safety fields was demonstrated.


Cysteine-independent Catalase-like Activity of Vertebrate Peroxiredoxin 1 (Prx1).
Peroxiredoxins (Prxs) are a ubiquitous family of antioxidant proteins that are known as thioredoxin peroxidases. Here we report that Prx1 proteins from Tetraodon nigroviridis and humans also possess a previously unknown catalase-like activity that is independent of Cys residues and reductants but dependent on iron. We identified that the GVL motif was essential to the catalase (CAT)-like activity of Prx1 but not to the Cys-dependent thioredoxin peroxidase (POX) activity, and we generated mutants lacking POX and/or CAT activities for individually delineating their functional features. We discovered that the TnPrx1 POX and CAT activities possessed different kinetic features in reducing H2O2. The overexpression of wild-type TnPrx1 and mutants differentially regulated the intracellular levels of reactive oxygen species and p38 phosphorylation in HEK-293T cells treated with H2O2. These observations suggest that the dual antioxidant activities of Prx1 may be crucial for organisms to mediate intracellular redox homeostasis.


Solution calorimetric and stopped-flow kinetic studies of the reaction of *Cr(CO)3C5Me5 with PhSe-SePh and PhTe-TePh. Experimental and theoretical estimates of the Se-Se, Te-Te, H-Se, and H-Te bond strengths.
The kinetics of the oxidative addition of PhSeSePh and PhTeTePh to the stable 17-electron complex *Cr(CO)3C5Me5 have been studied utilizing stopped-flow techniques. The rates of reaction are first-order in each reactant, and the enthalpy of activation decreases in going from Se (deltaH(double dagger) = 7.0 +/- 0.5 kcal/mol, deltaS(double dagger) = -22 +/- 3 eu) to Te (deltaH(double dagger) = 4.0 +/- 0.5 kcal/mol, deltaS(double dagger) = -26 +/- 3 eu). The kinetics of the oxidative addition of PhSeH and *Cr(CO)3C5Me5 show a change in mechanism in going from low (overall third-order) to high (overall second-order) temperatures. The enthalpies of the oxidative addition of PhE-EPh to *Cr(CO)3C5Me5 in toluene solution have been measured and found to be -29.6, -30.8, and -28.9 kcal/mol for S, Se, and Te, respectively. These data are combined with enthalpies of activation from kinetic studies to yield estimates for the solution-phase PhE-EPh bond strengths of 46, 41, and 33 kcal/mol for E = S, Se, and Te, respectively. The corresponding Cr-EPh bond strengths are 38, 36, and 31 kcal/mol. Two methods have been used to determine the enthalpy of hydrogenation of PhSeSePh in toluene on the basis of reactions of HSPh and HSePh with either *Cr(CO)3C5Me5 or 2-pyridine thione. These data lead to a thermochemical estimate of 72 kcal/mol for the PhSe-H bond strength in toluene solution, which is in good agreement with kinetic studies of H atom transfer from HSePh at higher temperatures. The reaction of H-Cr(CO)3C5Me5 with PhSe-SePh is accelerated by the addition of a Cr radical and occurs via a rapid radical chain reaction. In contrast, the reaction of PhTe-TePh and H-Cr(CO)3C5Me5 does not occur at any appreciable rate at room temperature, even in the presence of added Cr radicals. This is in keeping with a low PhTe-H bond strength blocking the chain and implies that H-TePh < or = 63 kcal/mol. Structural data are reported for PhSe-Cr(CO)3C5Me5 and PhS-Cr(CO)3C5Me5. The two isostructural complexes do not show signs of an increase in steric strain in terms of metal-ligand bonds or angles as the Cr-EPh bond is shortened in going from Se to S. Bond strength estimates of the PhE-H and PhE-EPh derived from density functional theory calculations are in reasonable agreement with experimental data for E = Se but not for E = Te. The nature of the singly occupied molecular orbital of the *EPh radicals is calculated to show increasing localization on the chalcogenide atom in going from S to Se to Te.


A synthetic 18-norsteroid distinguishes between two neuroactive steroid binding sites on GABAA receptors.
In the absence of GABA, neuroactive steroids that enhance GABA-mediated currents modulate binding of [35S]t-butylbicyclophosphorothionate in a biphasic manner, with enhancement of binding at low concentrations (site NS1) and inhibition at higher concentrations (site NS2). In the current study, compound (3alpha,5beta,17beta)-3-hydroxy-18-norandrostane-17-carbonitrile (3alpha5beta-18-norACN), an 18-norsteroid, is shown to be a full agonist at site NS1 and a weak partial agonist at site NS2 in both rat brain membranes and heterologously expressed GABAA receptors. 3alpha5beta-18-norACN also inhibits the action of a full neurosteroid agonist, (3alpha,5alpha,17beta)-3-hydroxy-17-carbonitrile (3alpha5alphaACN), at site NS2. Structure-activity studies demonstrate that absence of the C18 methyl group and the 5beta-reduced configuration both contribute to the weak agonist effect at the NS2 site. Electrophysiological studies using heterologously expressed GABAA receptors show that 3alpha5beta-18-norACN potently and efficaciously potentiates the GABA currents elicited by low concentrations of GABA but that it has low efficacy as a direct activator of GABAA receptors. 3alpha5beta-18-norACN also inhibits direct activation of GABAA receptors by 3alpha5alphaACN. 3alpha5beta-18-norACN also produces loss of righting reflex in tadpoles and mice, indicating that action at NS1 is sufficient to mediate the sedative effects of neurosteroids. These data provide insight into the pharmacophore required for neurosteroid efficacy at the NS2 site and may prove useful in the development of selective agonists and antagonists for neurosteroid sites on the GABAA receptor.


[Evaluation of the OS-EM parameter with automatic quantitative analysis for cerebral blood flow of the ECD tool].
The parameters of reconstruction iteration and subset of the ordered subset expectation maximization (OS-EM) method have a great impact on image quality. In a cerebral blood flow (CBF) examination, it is critical to produce consistent results when analyzing clinical data. We evaluated the number of iterations and subset of the OS-EM method to stabilize image quality using a normal case and an infarction case. In the maximum likelihood expectation maximization (ML-EM) method, it was confirmed that the convergence of an infarction case was somewhat delayed compared with a normal case. With the OS-EM method, we have obtained the same results. Based on the rCBF values, we postulate that the iteration value is more than 8 and the subset value is less than 10. Furthermore, multiplying the iteration by a subset value ranging from 50 to 60 helps in stabilizing the quality of CBF imaging.


Role of nucleotide identity in effective CRISPR target escape mutations.
Prokaryotes use primed CRISPR adaptation to update their memory bank of spacers against invading genetic elements that have escaped CRISPR interference through mutations in their protospacer target site. We previously observed a trend that nucleotide-dependent mismatches between crRNA and the protospacer strongly influence the efficiency of primed CRISPR adaptation. Here we show that guanine-substitutions in the target strand of the protospacer are highly detrimental to CRISPR interference and interference-dependent priming, while cytosine-substitutions are more readily tolerated. Furthermore, we show that this effect is based on strongly decreased binding affinity of the effector complex Cascade for guanine-mismatched targets, while cytosine-mismatched targets only minimally affect target DNA binding. Structural modeling of Cascade-bound targets with mismatches shows that steric clashes of mismatched guanines lead to unfavorable conformations of the RNA-DNA duplex. This effect has strong implications for the natural selection of target site mutations that lead to effective escape from type I CRISPR-Cas systems.


Acinetobacter baumannii: an emerging multidrug-resistant threat.
Amid the recent attention focused on the growing impact of methicillin-resistant Staphylococcus aureus and multidrug-resistant Pseudomonas aeruginosa infections, the pathogen Acinetobacter baumannii has been stealthily gaining ground as an agent of serious nosocomial and community-acquired infection. Historically, Acinetobacter spp. have been associated with opportunistic infections that were rare and of modest severity; the last two decades have seen an increase in both the incidence and seriousness of A. baumannii infection, with the main targets being patients in intensive-care units. Although this organism appears to have a predilection for the most vulnerable patients, community-acquired A. baumannii infection is an increasing cause for concern. The increase in A. baumannii infections has paralleled the alarming development of resistance it has demonstrated. The persistence of this organism in healthcare facilities, its inherent hardiness and its resistance to antibiotics results in it being a formidable emerging pathogen. This review aims to put into perspective the threat posed by this organism in hospital and community settings, describes new information that is changing our view of Acinetobacter virulence and resistance, and calls for greater understanding of how this multifaceted organism came to be a major pathogen.


Prognostic factors and patterns of failure in advanced stage Hodgkin lymphoma treated with combined modality therapy.
The role of irradiation to non-bulky and bulky sites of disease in advanced stage Hodgkin lymphoma is controversial. We aimed to review the long-term outcomes of patients treated with combined modality therapy to clarify the role of consolidative radiotherapy. Patients with stage III or IV Hodgkin lymphoma treated with Stanford V chemotherapy and consolidative radiotherapy to initial sites of disease ≥5 cm were analyzed retrospectively to determine patient outcomes, patterns of failure, and factors associated with treatment failure. A total of 170 patients were analyzed. Overall survival was 91.2%, freedom from progression was 80.6%, and progression-free survival was 78.9% at 10 years. 5 patients (2.9%) had refractory disease and 27 patients (15.9%) relapsed after treatment. Only an International Prognostic Score (IPS) greater than 2 predicted disease progression. 19 out of 27 relapses occurred exclusively outside of the radiation treatment field, and 17 out of 27 relapses occurred exclusively at original sites of disease. However, only 11 of 170 patients (6.5%) relapsed exclusively at original, non-bulky sites of disease not treated with radiation therapy. The cumulative incidence of local failure at 10 years was 4.6% for unirradiated sites and 2.6% for irradiated sites. Patients with advanced stage Hodgkin lymphoma treated with combined modality therapy including consolidative radiotherapy to bulky disease sites had excellent long-term outcomes. Given the low frequency of isolated failures at initial sites, our results suggest that selective radiation therapy to sites at high risk of relapse may be feasible.


High resolution single strand conformation polymorphism analysis using formamide and ethidium bromide staining.
Single strand conformation polymorphism (SSCP) analysis using ethidium bromide can be improved by adding formamide as the denaturant. This gives higher resolution than previous SSCP methods; it had 100% sensitivity in the discrimination of 14 PCR samples from two different genes, even for a long fragment close to the upper limit of 250 base pairs. This modified procedure is a rapid, simple, safe, and yet highly sensitive method for detecting structural differences in DNA fragments.


Dominant-negative mutations of CEBPA, encoding CCAAT/enhancer binding protein-alpha (C/EBPalpha), in acute myeloid leukemia.
The transcription factor C/EBPalpha (for CCAAT/enhancer binding protein-alpha; encoded by the gene CEBPA) is crucial for the differentiation of granulocytes. Conditional expression of C/EBPalpha triggers neutrophilic differentiation, and no mature granulocytes are observed in Cebpa-mutant mice. Here we identify heterozygous mutations in CEBPA in ten patients with acute myeloid leukemia (AML). We found that five mutations in the amino terminus truncate the full-length protein, but did not affect a 30-kD protein initiated further downstream. The mutant proteins block wild-type C/EBPalpha DNA binding and transactivation of granulocyte target genes in a dominant-negative manner, and fails to induce granulocytic differentiation. Ours is the first report of CEBPA mutations in human neoplasia, and such mutations are likely to induce the differentiation block found in AML.


Pertussis outbreak, southeastern Minnesota, 2012.
To describe clinical and laboratory findings from the 2012 southeastern Minnesota pertussis outbreak. Patients were selected for 2 parts of the study. In the first part, nasopharyngeal swabs from a convenience sample of 265 unique patients were used for both the clinician-requested polymerase chain reaction (PCR) test and culture. B pertussis isolates were tested for macrolide susceptibility and typed using whole genome sequencing and pulsed-field gel electrophoresis. Pertactin gene sequences were analyzed to identify pertactin-deficient B pertussis. In the second part, all patients seen at Mayo Clinic in Rochester, Minnesota, who had PCR results positive for Bordetella pertussis or Bordetella parapertussis between January 1, 2012, and December 31, 2012, were analyzed for patient demographic features and vaccination records. One hundred sixty patients had results positive for B pertussis, and 21 patients had results positive for B parapertussis. Among the 265 swabs cultured, B pertussis was detected by both culture and PCR in 11. One swab was positive for B pertussis by culture alone, and 13 were positive by PCR alone. Polymerase chain reaction detected B pertussis more frequently than did culture (P=.001). No macrolide resistance was detected. All 12 isolates tested had an altered pertactin gene, including 9 with a signal sequence deletion, 2 with insertion sequence disruptions, and 1 with a premature stop codon. Nine and 3 isolates were pertactin types prn1 and prn2, respectively. Whole genome sequencing and pulsed-field gel electrophoresis detected the presence of multiple B pertussis strains. The mean age of patients with pertussis was younger than that of those without pertussis (15.6 and 25.5 years, respectively; P=.002). Compared with those whose test results were negative for B pertussis, fewer patients with positive results had received whole-cell pertussis vaccine (P=.02). In the subgroup who had received acellular vaccine exclusively, the time since the most recent pertussis vaccination in those with results positive for B pertussis was longer than that in those with negative results (1363 vs 1010 days; P=.004). The 2012 pertussis outbreak in southeastern Minnesota included multiple strains of B pertussis, all putatively lacking pertactin. Our findings may indicate decreased efficacy of (and waning immunity from) acellular vaccines as contributors to the outbreak.


Conditional mutagenesis of Gata6 in SF1-positive cells causes gonadal-like differentiation in the adrenal cortex of mice.
Transcription factor GATA6 is expressed in the fetal and adult adrenal cortex and has been implicated in steroidogenesis. To characterize the role of transcription factor GATA6 in adrenocortical development and function, we generated mice in which Gata6 was conditionally deleted using Cre-LoxP recombination with Sf1-cre. The adrenal glands of adult Gata6 conditional knockout (cKO) mice were small and had a thin cortex. Cytomegalic changes were evident in fetal and adult cKO adrenal glands, and chromaffin cells were ectopically located at the periphery of the glands. Corticosterone secretion in response to exogenous ACTH was blunted in cKO mice. Spindle-shaped cells expressing Gata4, a marker of gonadal stroma, accumulated in the adrenal subcapsule of Gata6 cKO mice. RNA analysis demonstrated the concomitant upregulation of other gonadal-like markers, including Amhr2, in the cKO adrenal glands, suggesting that GATA6 inhibits the spontaneous differentiation of adrenocortical stem/progenitor cells into gonadal-like cells. Lhcgr and Cyp17 were overexpressed in the adrenal glands of gonadectomized cKO vs control mice, implying that GATA6 also limits sex steroidogenic cell differentiation in response to the hormonal changes that accompany gonadectomy. Nulliparous female and orchiectomized male Gata6 cKO mice lacked an adrenal X-zone. Microarray hybridization identified Pik3c2g as a novel X-zone marker that is downregulated in the adrenal glands of these mice. Our findings offer genetic proof that GATA6 regulates the differentiation of steroidogenic progenitors into adrenocortical cells.


Dog behaviours in veterinary consultations: Part II. The relationship between the behaviours of dogs and their owners.
Dogs synchronise their behaviour with those of their owners when confronted with an unfamiliar situation and interactions with their owners have been shown to decrease the dog's stress levels in some instances. However, whether owners may help manage dog anxiety during veterinary consultations remains unclear. In Part I, we compared the behaviour of dogs in the presence or absence of their owners during consultations, which consisted in three phases: exploration, examination, and greeting. Our findings suggest that allowing owners to attend consultations may be beneficial for dogs. In Part II, we investigated the direct relationship between owners' actions and their dog's behaviour. Using the videos from Part I, we examined whether: (1) dogs interact more when their owner is more interactive; (2) owners' stress scores are related to canine stress-related behaviour and emotional state; (3) owners' actions influence canine stress-related behaviours, emotional state and tolerance to manipulations; (4) canine stress-related behaviours and emotional state are associated with increased eye contact with their owners. We analysed the recordings of 29 dog-owner dyads submitted to a veterinary consultation in Part I. The behaviours of the dogs and their owners were analysed, and their emotional states were scored. The ease of manipulations was also scored. Despite limitations (e.g. no physical contact during examinations, no invasive procedures, aggressive dogs excluded, no male owners, limited sample size), our study showed a link between dog and owner behaviours: when owners attended an examination, their negative behaviours intensified the signs of anxiety in their dogs. Additionally, visual and verbal attempts to comfort their dog had no significant effect. However, we observed that the more dogs displayed stress-related behaviours, the more they established eye contact with their owners, suggesting that dogs seek information (through social referencing) or reassurance from their owners.


Multiple explanations in Darwinian evolutionary theory.
Variational evolutionary theory as advocated by Darwin is not a single theory, but a bundle of related but independent theories, namely: (a) variational evolution; (b) gradualism rather than large leaps; (c) processes of phyletic evolution and of speciation; (d) causes for the formation of varying individuals in populations and for the action of selective agents; and (e) all organisms evolved from a common ancestor. The first four are nomological-deductive explanations and the fifth is historical-narrative. Therefore evolutionary theory must be divided into nomological and historical theories which are both testable against objective empirical observations. To be scientific, historical evolutionary theories must be based on well corroborated nomological theories, both evolutionary and functional. Nomological and general historical evolutionary theories are well tested and must be considered as strongly corroborated scientific theories. Opponents of evolutionary theory are concerned only with historical evolutionary theories, having little interest in nomological theory. Yet given a well corroborated nomological evolutionary theory, historical evolutionary theories follow automatically. If understood correctly, both forms of evolutionary theories stand on their own as corroborated scientific theories and should not be labeled as facts.


Inactivation of bacterial exotoxins and endotoxin by iron. In vitro studies.
After incubation with various agents in vitro, the lethal effects of aqueous solutions of Cl. perfringens alpha toxin, C. diphtheriae toxin, and E. coli endotoxin were tested in mice, guinea pigs, and rabbits, respectively. Iron, copper, cysteine, ascorbic acid, and versene counteracted the lethal effects of alpha toxin in mice, while magnesium, manganese, zinc, and citrate did not. Iron also counteracted the lethal effects of diphtheria toxin in guinea pigs. After incubation of endotoxin with iron, its lethal effects and tissue-necrotizing actions in rabbits were counteracted. However, the pyrogenic properties of the toxin were not affected. The solubilities of perfringens alpha toxin and diphtheria toxin were markedly reduced after incubation with detoxifying metals, and resolubilization of these toxins with chelators resulted in partial restoration of toxicity. Addition of versene to detoxified endotoxin also resulted in partial recovery of lethal effectiveness. The inactivation of bacterial toxins by iron under in vitro conditions is not specific to this metal, is a reversible process, and may be due to desolubilization, reduction, or to competition by the metal for sites on the toxin normally bound by other cations in vivo. Although no evidence is presented in this paper to support the view that there is a relationship between the inactivation of endotoxin and the storage iron in the reticuloendothelial system of shocked animals, the observation of an in vitro inactivation of endotoxin by inorganic iron warrants consideration of such a mechanism.