Call for consistent coding in diabetes mellitus using the Royal College of General Practitioners and NHS pragmatic classification of diabetes.
The prevalence of diabetes is increasing with growing levels of obesity and an aging population. New practical guidelines for diabetes provide an applicable classification. Inconsistent coding of diabetes hampers the use of computerised disease registers for quality improvement, and limits the monitoring of disease trends. To develop a consensus set of codes that should be used when recording diabetes diagnostic data. The consensus approach was hierarchical, with a preference for diagnostic/disorder codes, to define each type of diabetes and non-diabetic hyperglycaemia, which were listed as being completely, partially or not readily mapped to available codes. The practical classification divides diabetes into type 1 (T1DM), type 2 (T2DM), genetic, other, unclassified and non-diabetic fasting hyperglycaemia. We mapped the classification to Read version 2, Clinical Terms version 3 and SNOMED CT. T1DM and T2DM were completely mapped to appropriate codes. However, in other areas only partial mapping is possible. Genetics is a fastmoving field and there were considerable gaps in the available labels for genetic conditions; what the classification calls 'other' the coding system labels 'secondary' diabetes. The biggest gap was the lack of a code for diabetes where the type of diabetes was uncertain. Notwithstanding these limitations we were able to develop a consensus list. It is a challenge to develop codes that readily map to contemporary clinical concepts. However, clinicians should adopt the standard recommended codes; and audit the quality of their existing records.


Psychoeducation for chronic cognitive impairment and reduced early readmissions amongst pulmonary inpatients.
Patients with chronic pulmonary disease have been found to have among the highest rates of early (30 days) readmissions by the Center for Medicare and Medicaid Services. Proactive identification and psychoeducational intervention for the effect of chronic cognitive impairment on readmission have not been tested in this population. This is a pre-post quality improvement study for service-wide inpatient pulmonary readmission rates in chronic pulmonary disease. We examined the impact of screening patients for likely cognitive impairment and providing patients/families with psychoeducation regarding 'forgetfulness' on 30-day readmission rates on an inpatient pulmonary service. We observed a 50% decline in early readmissions (25.7% > 12.3%) for the inpatient pulmonary service after initiation of screening and psychoeducation of patients/families for improved adherence despite cognitive impairment (t = -2.53, df= 17, p = 0.011). A randomly assigned, controlled clinical trial is warranted.


Atypical Development of Attentional Control Associates with Later Adaptive Functioning, Autism and ADHD Traits.
Autism is frequently associated with difficulties with top-down attentional control, which impact on individuals' mental health and quality of life. The developmental processes involved in these attentional difficulties are not well understood. Using a data-driven approach, 2 samples (N = 294 and 412) of infants at elevated and typical likelihood of autism were grouped according to profiles of parent report of attention at 10, 15 and 25 months. In contrast to the normative profile of increases in attentional control scores between infancy and toddlerhood, a minority (7-9%) showed plateauing attentional control scores between 10 and 25 months. Consistent with pre-registered hypotheses, plateaued growth of attentional control was associated with elevated autism and ADHD traits, and lower adaptive functioning at age 3 years.


Framing the decision to contract out elderly care and primary health care services - perspectives of local level politicians and civil servants in Finland.
In the literature there are only few empirical studies that analyse the decision makers' reasoning to contract out health care and social services to private sector. However, the decisions on the delivery patterns of health care and social services are considered to be of great importance as they have a potential to influence citizens' access to services and even affect their health. This study contributes to filling this cap by exploring the frames used by Finnish local authorities as they talk about contracting out of primary health care and elderly care services. Contracting with the private sector has gained increasing popularity, in Finland, during the past decade, as a practise of organising health care and social services. Interview data drawn from six municipalities through thematic group interviews were used. The data were analysed applying frame analysis in order to reveal the underlying reasoning for the decisions. Five argumentation frames were found: Rational reasoning; Pragmatic realism; Promoting diversity among providers; Good for the municipality; Good for the local people. The interviewees saw contracting with the private sector mostly as a means to improve the performance of public providers, to improve service quality and efficiency and to boost the local economy. The decisions to contract out were mainly argued through the good for the municipal administration, political and ideological commitments, available resources and existing institutions. This study suggests that the policy makers use a number of grounds to justify their decisions on contracting out. Most of the arguments were related to the benefits of the municipality rather than on what is best for the local people. The citizens were offered the role of active consumers who are willing to purchase services also out-of-pocket. This development has a potential to endanger the affordability of the services and lead to undermining some of the traditional principles of the Nordic welfare state.


Association between sensitivity of viral thymidine kinase-associated acyclovir-resistant herpes simplex virus type 1 and virulence.
Acyclovir (ACV)-resistant (ACVr) herpes simplex virus type 1 (HSV-1) infections are concern in immunocompromised patients. Most clinical ACVr HSV-1 isolates have mutations in the viral thymidine kinase (vTK) genes. The vTK-associated ACVr HSV-1 shows reduced virulence, but the association between the level of resistance and the virulence of the vTK-associated ACVr HSV-1 is still unclear. The virulence in mice of 5 vTK-associated ACVr HSV-1 clones with a variety of ACV sensitivities, when inoculated through intracerebral and corneal routes, was evaluated in comparison with ACV-sensitive (ACVs) parent HSV-1 TAS. Although all the 5 ACVr HSV-1 clones and ACVs HSV-1 TAS showed a similar single-step growth capacity in vitro, the virulence of ACVr HSV-1 clones significantly decreased. A 50% lethal dose (LD50) of each clone was closely correlated with 50% inhibitory concentrations (IC50), demonstrating that the higher the ACV-sensitvity, the the higher the virulence among the ACVr clones. One of the ACVr HSV-1 clones with a relatively low IC50 value maintained similar virulence to that of the parent TAS. The infection in mice with ACVr HSV-1 due to a single amino acid substitution in vTK induced local diseases, keratitis and dermatitis, while vTK-deficient clone did not. A statistically significant correlation between the virulence and susceptibility to ACV among ACVr HSV-1 clones was demonstrated.


Racial and geographic variation in effects of maternal education and neighborhood-level measures of socioeconomic status on gestational age at birth: Findings from the ECHO cohorts.
Preterm birth occurs at excessively high and disparate rates in the United States. In 2016, the National Institutes of Health (NIH) launched the Environmental influences on Child Health Outcomes (ECHO) program to investigate the influence of early life exposures on child health. Extant data from the ECHO cohorts provides the opportunity to examine racial and geographic variation in effects of individual- and neighborhood-level markers of socioeconomic status (SES) on gestational age at birth. The objective of this study was to examine the association between individual-level (maternal education) and neighborhood-level markers of SES and gestational age at birth, stratifying by maternal race/ethnicity, and whether any such associations are modified by US geographic region. Twenty-six ECHO cohorts representing 25,526 mother-infant pairs contributed to this disseminated meta-analysis that investigated the effect of maternal prenatal level of education (high school diploma, GED, or less; some college, associate's degree, vocational or technical training [reference category]; bachelor's degree, graduate school, or professional degree) and neighborhood-level markers of SES (census tract [CT] urbanicity, percentage of black population in CT, percentage of population below the federal poverty level in CT) on gestational age at birth (categorized as preterm, early term, full term [the reference category], late, and post term) according to maternal race/ethnicity and US region. Multinomial logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CIs). Cohort-specific results were meta-analyzed using a random effects model. For women overall, a bachelor's degree or above, compared with some college, was associated with a significantly decreased odds of preterm birth (aOR 0.72; 95% CI: 0.61-0.86), whereas a high school education or less was associated with an increased odds of early term birth (aOR 1.10, 95% CI: 1.00-1.21). When stratifying by maternal race/ethnicity, there were no significant associations between maternal education and gestational age at birth among women of racial/ethnic groups other than non-Hispanic white. Among non-Hispanic white women, a bachelor's degree or above was likewise associated with a significantly decreased odds of preterm birth (aOR 0.74 (95% CI: 0.58, 0.94) as well as a decreased odds of early term birth (aOR 0.84 (95% CI: 0.74, 0.95). The association between maternal education and gestational age at birth varied according to US region, with higher levels of maternal education associated with a significantly decreased odds of preterm birth in the Midwest and South but not in the Northeast and West. Non-Hispanic white women residing in rural compared to urban CTs had an increased odds of preterm birth; the ability to detect associations between neighborhood-level measures of SES and gestational age for other race/ethnic groups was limited due to small sample sizes within select strata. Interventions that promote higher educational attainment among women of reproductive age could contribute to a reduction in preterm birth, particularly in the US South and Midwest. Further individual-level analyses engaging a diverse set of cohorts are needed to disentangle the complex interrelationships among maternal education, neighborhood-level factors, exposures across the life course, and gestational age at birth outcomes by maternal race/ethnicity and US geography.


Internal parasites of the two subspecies of the West Indian manatee Trichechus manatus.
The West Indian manatee Trichechus manatus is divided into 2 subspecies: the Antillean (T. m. manatus) and Florida (T. m. latirostris) manatees. This study reports sample prevalence of manatee parasites from populations of these 2 subspecies in different geographical locations. Although necropsy is a valuable diagnostic tool for parasite infections, the need for antemortem diagnostic techniques is important. Fecal samples collected during necropsies of Antillean manatees (n = 3) in Puerto Rico and Florida manatees (n = 10) in Crystal River, Florida, as well as from live-captured Florida manatees (n = 11) were evaluated using centrifugal flotation with sucrose and ethyl acetate sedimentation to compare parasites from each of the populations. Although both fecal examination methods provided similar results, the centrifugal flotation method required less time for diagnosis. The most common parasite eggs found in both populations included the trematodes Pulmonicola cochleotrema and Nudacotyle undicola, oocysts of the coccidian Eimeria spp., and eggs of the ascarid Heterocheilus tunicatus. Eggs of the trematode Chiorchis groschafti were found in both populations of manatees; however, eggs of a related species, Chiorchis fabaceus, were abundant in the Florida samples, but not found in Puerto Rico populations. Trematode eggs of Moniligerum blairi were found in both populations, but were more common in the Florida manatee (42%) than the Antillean manatee (33%). To our knowledge, this is the first report of both Eimeria manatus and Eimeria nodulosa oocysts in Antillean manatees from Puerto Rico.


Early autologous fresh whole blood transfusion leads to less allogeneic transfusions and is safe.
The practice of transfusing ones' own shed whole blood has obvious benefits such as reducing the need for allogeneic transfusions and decreasing the need for other fluids that are typically used for resuscitation in trauma. It is not widely adopted in the trauma setting because of the concern of worsening coagulopathy and the inflammatory process. The aim of this study was to assess outcomes in trauma patients receiving whole blood autotransfusion (AT) from hemothorax. This is a multi-institutional retrospective study of all trauma patients who received autologous whole blood transfusion from hemothorax from two Level I trauma centers. Patients who received AT were matched to patients who did not receive AT (No-AT) using propensity score matching in a 1:1 ratio for admission age, sex, mechanism, type of injury, Injury Severity Score (ISS), Glasgow Coma Scale (GCS) score, systolic blood pressure, heart rate, hemoglobin, international normalized ratio (INR), prothrombin time, partial prothrombin time, and lactate. AT was defined as transfusion of autologous blood from patient's hemothorax, which was collected from the chest tubes and anticoagulated with citrate phosphorous dextrose. Outcome measures were in-hospital complications, 24-hour INR, and mortality. In-hospital complications were defined as adult respiratory distress syndrome, sepsis, disseminated intravascular coagulation, renal insufficiency, and transfusion-related acute lung injury. A total of 272 patients (AT, 136; No-AT, 136) were included. There was no difference in admission age (p = 0.6), ISS (p = 0.56), head Abbreviated Injury Scale (AIS) score (p = 0.42), systolic blood pressure (p = 0.88), and INR (p = 0.62) between the two groups. There was no significant difference in in-hospital complications (p = 0.61), mortality (p = 0.51), and 24-hour postadmission INR (0.31) between the AT and No-AT groups. Patients who received AT had significantly lower packed red blood cell (p = 0.01) and platelet requirements (p = 0.01). Cost of transfusions (p = 0.01) was significantly lower in the AT group compared with the No-AT group. The autologous transfusion of the patient's shed blood collected through chest tubes for hemothorax was found to be safe without complications in this study. It also reduced the need for allogeneic transfusions and decreased hospital costs. This study demonstrates safety data that would help in designing larger prospective multicenter studies to determine whether this practice is truly safe and effective. Epidemiologic/prognostic study, level III.


Apurinic/apyrimidinic endonuclease 1 is a key modulator of aluminum-induced neuroinflammation.
Chronic administration of Aluminum is proposed as an environmental factor that may affect several enzymes and other biomolecules related to neurotoxicity and Alzheimer's disease (AD). APE1 a multifunctional protein, functions in DNA repair and plays a key role in cell survival versus cell death upon stimulation with cytotoxic agent, making it an attractive emerging therapeutic target. The promising protective effect of resveratrol (resv), which is known to exert potent anti-inflammatory effects on neurotoxicity induced by aluminum chloride (AlCl₃), may be derived from its own antioxidant properties. In the present work we investigated the modulation of APE1 expression during AlCl₃-induced neuroinflammation (25 mg/Kg body weight by oral gavages) in experimental rats. We tested the hypothesis that a reactive oxygen species (ROS)-scavenger, resveratrol at 0.5 mg/kg bodyweight, which is known to exert potent anti-inflammatory effects, would attenuate central inflammation and modulate APE1 expression in AlCl₃-fed rats. Neuroinflammation-induced genes including β-secretase (BACE), amyloid-β precursor protein (APP), presenilin 2 (PSEN-2) and sirt-2 were determined by RT-PCR. APE1 is determined at mRNA and protein levels and confirmed by immunohistochemistry. The expression of pro-inflammatory cytokines (TNF-α, IL6) and iNOS by the rat brain extract were measured by RT-PCR. Our results indicate that resveratrol may attenuate AlCl₃-induced direct neuroinflammation in rats, and its mechanisms are, at least partly, due to maintaining high APE1 level. Resveratrol co-administration with aluminum chloride exerted more protective effect than pre-administration or treatment of induced rats. A significant elevation of APE1 at both mRNA and protein levels was observed in addition to a marked reduction in β-secretase and amyloid-β. We found that AlCl₃ stimulated the expression of TNF-α, IL-6, and iNOS in rat brain in which NF-κB was involved. Resveratrol inhibited AlCl₃-induced expression and release of TNF-α, IL-6, and iNOS in rat brain. These findings establish a role for APE1 as a master regulator of AlCl₃ dependent inflammatory responses in rat brain. In addition, there was an ameliorative change with resveratrol against AlCl₃-induced neurotoxicity. These results suggest that rat brain cells produce pro-inflammatory cytokines in response to AlCl₃ in a similar pattern, and further suggest that resveratrol exerts anti-inflammatory effects in rat brain, at least partly, by inhibiting different pro-inflammatory cytokines and key signaling molecules. It might be a potential agent for treatment of neuroinflammation-related diseases, such as AD.


Reversing motor adaptation deficits in the ageing brain using non-invasive stimulation.
Healthy ageing in man is associated with a decline in motor adaptation. Transcranial direct current stimulation (TDCS) over the primary motor cortex (M1) or the lateral cerebellum can improve motor adaptation in young and older adults, but as yet no direct comparisons of TDCS effects exist between the two age groups and the two stimulation sites. TDCS over M1 enhanced the motor adaptation in both age groups by ∼30% relative to their respective non-stimulated groups and improved the performance of older adults to the extent that it compared with that of young adults without stimulation. The study suggests that the plastic mechanisms activated by TDCS that underpin improvements in motor behaviour in young adults remain available in older adults. The results indicate that TDCS may be a useful tool to help combat the normal decline in motor performance seen in normal healthy ageing. Healthy ageing is characterised by deterioration of motor performance. In normal circumstances motor adaptation corrects for movements' inaccuracies and as such, it is critical in maintaining optimal motor control. However, motor adaptation performance is also known to decline with age. Anodal transcranial direct current stimulation (TDCS) of the cerebellum and the primary motor cortex (M1) have been found to improve visuomotor adaptation in healthy young and older adults. However, no study has directly compared the effect of TDCS on motor adaptation between the two age populations. The aim of our study was to investigate whether the application of anodal TDCS over the lateral cerebellum and M1 affected motor adaptation in young and older adults similarly. Young and older participants performed a visuomotor rotation task and concurrently received TDCS over the left M1, the right cerebellum or received sham stimulation. Our results replicated the finding that older adults are impaired compared to the young adults in visuomotor adaptation. At the end of the adaptation session, older adults displayed a larger error (-17 deg) than the young adults (-10 deg). The stimulation of the lateral cerebellum did not change the adaptation in both age groups. In contrast, anodal TDCS over M1 improved initial adaptation in both age groups by around 30% compared to sham and this improvement lasted up to 40 min after the end of the stimulation. These results demonstrate that TDCS of M1 can enhance visuomotor adaptation, via mechanisms that remain available in the ageing population.


Low frequency of delayed ischemic events on MRI after flow diversion for intracranial aneurysms.
The rate of silent ischemia detected on Magnetic Resonance Imaging (MRI) in the long-term follow-up period following endovascular treatment of intracranial aneurysms with the Pipeline Embolization Device (PED) is not well established. The purpose of this study was to evaluate the occurrence rate of silent ischemia detected on MRI in patients undergoing treatment of intracranial aneurysms with PED receiving at least 6 months of MRI follow-up. We evaluated our institution's database of patients receiving PED treatment of intracranial aneurysms. Imaging records were searched to identify which patients received an MRI at least six-months postoperatively. MR images were reviewed for evidence of new infarction and medical records were reviewed to determine the clinical outcome. Of the 68 patients with MR imaging following aneurysm treatment with PED, 40 patients had an MRI at least six months following treatment with the PED. Of patients with MRI at ≥6 months following PED treatment, 2/40 (5.0%) had a new infarct. Of these, one had a lacunar infarct which was likely non-embolic and one patient had a punctate infarction in the contralateral centrum semiovale. None of these infarcts were symptomatic. In this study, a small number of silent ischemic events (5.0%) was found on routine long-term follow-up MRI of patients undergoing flow diversion. These events did not lead to any neurologic deficits. Our findings add to the available evidence on the long-term safety of flow diversion for the treatment of intracranial aneurysms.


THE PRODUCTION OF EXPERIMENTAL NEPHRITIS BY REPEATED PROTEID INTOXICATION.
The repeated injection of small doses of horse serum and egg-white in dogs, cats, rabbits, and guinea pigs that have been sensitized to these proteins, causes injury to the cells of various organs and tissues with resulting inflammatory reactions. The changes are especially marked after intraperitoneal injections in the peritoneum and after intravenous injections in the livers of rabbits and cats, and in the myocardium and kidneys of all groups of animals. In dogs and rabbits, especially, there develops a well marked nephritis characterized by degeneration and necrosis of the epithelium of the loops of Henle, of the collecting tubules, and less frequently of the convoluted tubules. This is accompanied by an extensive small round cell infiltration of the interstitial tissue and later the formation of connective tissue. Together with these changes there are acute and chronic alterations in the glomeruli of all groups of animals. Egg-white in large doses is itself injurious to the kidney of animals, but this slight primary toxicity is probably greatly enhanced through previous sensitization of the animal.


Effects of 2.45-GHz microwave radiation and phorbol ester 12-O-tetradecanoylphorbol-13-acetate on dimethylhydrazine-induced colon cancer in mice.
The purpose of this study was to investigate the effects of 2.45 GHz microwave (MW) radiation on dimethylhydrazine (DMH)-induced colon cancer in mice. The subjects were 115 Balb/c mice 4 weeks of age. The animals were divided into group A (control), group B (DMH), group C (DMH+MW), and group D [DMH + 12-O-tetradecanoylphorbol-13- acetate (TPA)]. Radiation (10 mW/cm2) was delivered dorsally with the E field parallel to the mouse's long body axis in an anechoic chamber. Radiations were administered 3 hr daily, 6 days per week, over a period of 5 months. The average SAR was estimated to be 10-12 W/kg. During the course of radiation treatments, DMH was injected once per week. The tumor promoter TPA was administered once per week for 10 weeks, from the third week on, after the initial treatment. The incidence of tumors did not significantly differ between the three test groups (groups B, C, and D; P > 0.25). However, the number of tumors, the size of the tumors, and the incidence of protuberant and infiltrative types in tumor-bearing animals were higher in group D compared to groups B and C (P < 0.05). No difference was found between groups B and C (P > 0.25). The study indicates that 2.45 GHz microwave radiation at 10 mW/cm2 power density did not promote DMH-induced colon cancers in young mice. The study also showed that TPA could accelerate colon tumor production if a tumor was initiated.


Ten year recurrence after first ever stroke in a Japanese community: the Hisayama study.
Very few population based cohort studies have focused on the long term recurrence of stroke. To examine 10 year cumulative recurrence rates for stroke in a Japanese cohort according to pathological type and clinical subtype of brain infarction. During a 32 year follow up of 1621 subjects >/=40 years of age, 410 developed first ever stroke. These were followed up prospectively for 10 years after stroke onset. During follow up, 108 (26%) experienced recurrent stroke. The cumulative recurrence rates were 35.3% at five years and 51.3% at 10 years. The 10 year recurrence rates of subarachnoid haemorrhage (SAH), brain haemorrhage, and brain infarction were 70.0%, 55.6%, and 49.7%, respectively; the difference between SAH and brain infarction was significant (p = 0.004). Most recurrent episodes after SAH or brain haemorrhage happened within a year after the index stroke, whereas recurrence of brain infarction increased consistently throughout the observation period. Cardioembolic stroke had a higher recurrence rate (75.2%) than lacunar infarction (46.8%) (p = 0.049). The 10 year risk of stroke recurrence increased with age after lacunar or atherothrombotic brain infarction, but not after the other types or subtypes. After atherothrombotic brain infarction, cardioembolic stroke, or SAH, the type and subtype of most recurrent strokes were the same as for the index stroke, but recurrence after lacunar infarction or brain haemorrhage showed divergent patterns. Japanese people have higher recurrence rates of stroke than other populations. Recurrence rate after a first brain infarct increases consistently through the next 10 years.


Dose-response effects of spectrum research cigarettes.
Experimental cigarettes are needed to conduct studies examining the effects of varying doses of nicotine content on smoking behavior. The National Institute on Drug Abuse contracted with Research Triangle Institute to make such cigarettes available to researchers. The goal of this study was to determine whether cigarettes that vary in nicotine content produce an expected dose-response effect. Two studies were conducted. The first study recruited subjects from 3 sites and consisted of a single, within-subject laboratory session. Subjects first smoked 4 puffs on their usual-brand cigarette and then in double-blind, random-order, smoked 4 puffs on each experimental cigarette that contained either low nicotine (LN, 0.4 mg/g), intermediate nicotine (IN, 5.7-5.8 mg/g), or high nicotine (HN, 11.4-12.8 mg/g). Each puffing bout was separated by a 30-min interval. Subjects completed questionnaires and were assessed for vital signs after each cigarette. The second study involved 1 site and used a between-subject design in which subjects were assigned to 1 of the 3 experimental cigarettes for 1 week. Subjective responses and biomarkers of exposure were assessed. In the first study, significant dose-response effects were observed, particularly between the LN and HN cigarettes. The second study showed decreases in cigarette smoking and exposure biomarkers predominantly in the LN group, with no changes in the HN cigarette group. These results are similar to those observed in prior literature, confirming that these experimental cigarettes can be used safely and with the expected pharmacological effects.


Giant ectopic liver, hepatocellular carcinoma and pachydermia-a rare genetic syndrome?
Ectopic liver is a very uncommon developmental anomaly that predisposes to the development of hepatocellular carcinoma. We describe the second documented case of a hepatocellular carcinoma developing in the primary liver of a patient with a rare and uncharacterized genetic symptom complex. Also present was the largest ectopic liver ever reported, measuring 12 cm in diameter which contained a solitary focus of metastatic hepatocellular carcinoma. The primary hepatocellular carcinoma is believed to have arisen in the native liver from a hepatic adenoma that was diagnosed 15 years earlier. The patient's uncharacterised condition featured prominent thick, yellow skin over the dorsum of the fingers, and was associated with follicular hyperkeratosis, abnormal plantar creases, digital clubbing, misshaped ears, a lingua plicata and an angioleiomyolipoma of the right kidney. This unique case of hepatocellular carcinoma arising from liver cell adenoma in a patient with an uncharacterised condition featuring a large ectopic liver invites discussion of the role of local factors in carcinogenesis in the parent liver but not the ectopic liver. It also underlines the imperative ongoing need for clinical autopsies.


In vivo fluorescence imaging of large-vessel thrombosis in mice.
Experimental studies of large-vessel thrombosis have been adapted for applications in mice, but they proffer limited quantifiable information in outcome measures. This study presents a novel approach for evaluating large-vessel thrombogenesis with temporally/spatially quantifiable measures and normalization methods for interanimal comparisons. Shuttered, beam-expanded lasers provided uniform narrow-wavelength illumination of a ×100 microsurgical field with a large depth of focus. Thrombosis was generated in murine carotid arteries and femoral veins by brief vascular surface electrolytic injury. Thrombus-targeting fluorophores were injected systemically and subsequently localized at the site of thrombus induction. A low-light digital video camera with filter wheel provided target-specific image acquisition over a 60-minute interval. Platelets accumulated with a subsequent fibrin border emerging to stabilize the clot in both arteries and veins. Coagulation enzyme complexes colocalized with fibrin deposition. Large arteries underwent cyclic massive thromboembolization, whereas veins showed gradual shedding of microemboli and clot contraction. Systemic administration of fibrin- and platelet-inhibiting compounds reduced their respective targets but also often inhibited their clotting counterparts (platelets and fibrin, respectively) in both arteries and veins. Intermediate-level magnified image capture represents a novel approach for analysis of fluorescence-based in vivo imaging, with quantitative application to the study of large-vessel thrombosis.


An infectious clone of human parainfluenza virus type 3.
A full-length clone of the human parainfluenza virus type 3 (HPIV-3) genome (called pHPIV-3) was constructed, and recombinant, infectious HPIV-3 was generated by transfecting pHPIV-3 and support plasmids encoding the HPIV-3 NP, P, and L proteins into HeLa cells infected with a vaccinia virus recombinant which expresses T7 RNA polymerase. T7 RNA polymerase promoters on the transfected plasmids direct the synthesis of transcripts encoding the NP, P, and L proteins and a full-length, positive-sense copy of the HPIV-3 genome. Generation of virus was dependent on transfection of pHPIV-3 and the HPIV-3 P- and L-encoding plasmids. However, a plasmid encoding the NP protein was not required since NP was expressed from pHPIV-3. Recovered virus was neutralized by anti-HPIV-3 antisera and shown to contain specific base substitutions characteristic of pHPIV-3. Recombination was shown to occur during recovery, as viruses with two distinct genotypes and phenotypes were isolated. The ability to produce infectious HPIV-3 engineered to contain specific alterations within the HPIV-3 genes and cis-acting elements expedites the study of all aspects of the virus replication cycle. Additionally, analysis of mutations may lead to the identification of attenuating genotypes, a key step in the development of a live virus vaccine.


Bergmann's Body Size Rule Operates in Facultatively Endothermic Insects: Evidence from a Complex of Cryptic Bumblebee Species.
According to Bergmann's rule we expect species with larger body size to inhabit locations with a cooler climate, where they may be well adapted to conserve heat and resist starvation. This rule is generally applied to endotherms. In contrast, body size in ectothermic invertebrates has been suggested to follow the reverse ecogeographic trend: these converse Bergmann's patterns may be driven by the ecological constraints of shorter season length and lower food availability in cooler high latitude locations. Such patterns are particularly common in large insects due to their longer development times. As large and facultatively endothermic insects, bumblebees could thus be expected to follow either trend. In this investigation, we studied body size of three bumblebee species over a large spatial area and investigated whether interspecific trends in body size correspond to differences in their distribution consistent with either Bergmann's or a converse Bergmann's rule. We examined the body size of queens, males and workers of the Bombus lucorum complex of cryptic bumblebee species from across the whole of Great Britain. We found interspecific differences in body size corresponding to Bergmann's rule: queens and males of the more northerly distributed, cool-adapted, species were largest. In contrast, the mean body size of the worker caste did not vary between the three species. These differences in body size may have evolved under selection pressures for thermoregulation or starvation resistance. We suggest that this case study in facultatively endothermic insects may help clarify the selection pressures governing Bergmann rule trends more generally.


Determination of oxygen relaxivity in oxygen nanobubbles at 3 and 7 Tesla.
Oxygen-loaded nanobubbles have shown potential for reducing tumour hypoxia and improving treatment outcomes, however, it remains difficult to noninvasively measure the changes in partial pressure of oxygen (PO2) in vivo. The linear relationship between PO2 and longitudinal relaxation rate (R1) has been used to noninvasively infer PO2 in vitreous and cerebrospinal fluid, and therefore, this experiment aimed to investigate whether R1 is a suitable measurement to study oxygen delivery from such oxygen carriers. T1 mapping was used to measure R1 in phantoms containing nanobubbles with varied PO2 to measure the relaxivity of oxygen (r1Ox) in the phantoms at 7 and 3 T. These measurements were used to estimate the limit of detection (LOD) in two experimental settings: preclinical 7 T and clinical 3 T MRI. The r1Ox in the nanobubble solution was 0.00057 and 0.000235 s-1/mmHg, corresponding to a LOD of 111 and 103 mmHg with 95% confidence at 7 and 3 T, respectively. This suggests that T1 mapping could provide a noninvasive method of measuring a > 100 mmHg oxygen delivery from therapeutic nanobubbles.


[Met5]-enkephalin preserves diffusion metrics in EAE mice.
Multiple sclerosis is a chronic progressive neurological disorder that has few distinctive biomarkers associated with disease progression or response to therapy. This research investigated whether non-invasive imaging correlated with animal behavior and morphological indicators of disease in response to serum levels of [Met5]-enkephalin. Using the experimental autoimmune encephalomyelitis (EAE) model, adult female C57BL/6 J mice were randomized to receive daily injections of 0.1 mg/kg naltrexone (NTX) (= low dose naltrexone, LDN), 10 mg/kg Opioid Growth Factor (OGF) (chemically termed [Met5]-enkephalin) or saline beginning at the time of disease induction. Daily composite behavior scores were recorded over a 30-day period based on tail tone, gait, righting reflex, and limb strength. Prior to disease onset (day 7), and at peak disease (day 18), mice were imaged and tissues (blood and spinal cord) collected at day 30 for serum analyses of OGF and morphology. Serum OGF levels of EAE mice treated with saline were significantly reduced from baseline and from normal mice. Longitudinal cohort data demonstrated an increase in fractional anisotropy in all cohorts by day 18. There was a significant decrease in radial diffusivity in the saline group seen at day 18 whereas the axial diffusivity was not altered amongst treatment groups. Treatment with OGF or LDN resulted in mean diffusivity rates that were comparable to baseline (normal) levels at days 7 and 18. Luxol fast blue staining of the lumbar spinal cords demonstrated a 16 % reduction in myelin staining in saline treated EAE animals when compared to OGF and LDN treated EAE mice. Immunohistochemistry with Olig2 (pan-oligodendrocyte marker) and myelin basic protein (MBP) revealed that OGF and LDN treatment restored the area (%) of MBP and number of oligodendrocytes to that of normal spinal cord (∼75 %). Saline treated EAE mice had more demyelination and fewer oligodendrocytes than normal mice. Collectively, these data suggest that a panel of biomarkers including imaging, serum biomarker levels, and behavior correlate with progression of disease, and may begin to validate use of specific non-invasive markers for MS.


Predictors of cardiovascular events in patients with hypertension and left ventricular hypertrophy: the Losartan Intervention for Endpoint reduction in hypertension study.
We assessed readily available patient characteristics, including albuminuria (not included in traditional cardiovascular risk scores), as predictors of cardiovascular events in hypertension with left ventricular hypertrophy (LVH) and developed risk algorithms/scores for outcomes. The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study compared effects of losartan-based versus atenolol-based therapy on cardiovascular events in 9193 patients with hypertension and LVH. Univariate and multivariate analyses identified baseline variables with significant impact on development of the primary composite endpoint (cardiovascular death, stroke and myocardial infarction) and its components. Multivariate analysis used a Cox regression model with stepwise selection process. Risk scores were developed from coefficients of risk factors from the multivariate analysis, validated internally using naïve and jack-knife procedures, checked for discrimination and calibration, and compared with Framingham coronary heart disease and other risk scores. LIFE risk scores showed increasing endpoint rates with increasing quintile (first to fifth quintile, composite endpoint 2.8-26.7%, cardiovascular death 0.5-14.4%, stroke 1.2-11.3%, myocardial infarction 1.4-8.1%) and were confirmed with a jack-knife approach that adjusts for potentially optimistic bias. The Framingham coronary heart disease and other risk scores overestimated risk in lower risk patients and underestimated risk in higher risk patients, except for myocardial infarction. A number of patient characteristics predicted cardiovascular events in patients with hypertension and LVH. Risk scores developed from these patient characteristics, including albuminuria, strongly predicted outcomes and may improve risk assessment of patients with hypertension and LVH and planning of clinical trials.


Diagnostic potential of differentially regulated microRNAs among endometriosis, endometrioid ovarian cancer, and endometrial cancer.
There is an increased risk of developing endometrioid ovarian and endometrial cancer in patients with endometriosis and there are no definitive diagnostic biomarkers available for these three associated diseases. Therefore, we evaluated the diagnostic potential of differentially expressed microRNAs (miRNAs) from the tissue samples of endometriosis, endometrioid ovarian cancer, and endometrial cancer to establish them as biomarkers for these diseases. Ten samples of each, i.e., endometriosis, endometrioid ovarian cancer, endometrial cancer and control healthy endometrium were enrolled after obtaining ethical clearance. Differential expression of miR-16, miR-20a, miR-99b, miR-125a, miR-143, and miR-145 and some of their target genes, i.e., vascular endothelial growth factor (VEGF), hypoxia inducible factor 1A (HIF1A), cyclooxygenase 2 (COX2), and tumor necrosis factor (TNF) were quantified using quantitative reverse transcription polymerase chain reaction. Receiver operating characteristic (ROC) curve analysis was performed to predict the diagnostic potential. miR-16 and miR-20a were significantly downregulated, whereas miR-99b, miR-125a, and miR-143 were significantly upregulated in all three diseased samples. miR-145 was significantly upregulated in endometriosis and endometrioid ovarian cancer but significantly downregulated in endometrial cancer. mRNA levels of VEGF, HIF1A, COX2, and TNF were significantly increased in all three diseased samples as compared to control samples. ROC curve analysis revealed that for endometriosis, miR-99b, and miR-125a were giving highest area under curve (AUC) (0.950 and 0.733, respectively), for endometrioid carcinoma of ovary miR-143 was giving highest AUC (0.933) and for endometrioid endometrial cancer miR-16 (AUC = 0.815), miR-99b (AUC = 0.920), and miR-145 (AUC = 0.985) were found to be best predictors. These findings suggest that these miRNAs can act as good predictors and discriminators of these three diseases and might serve as potential biomarkers for them.


Nuclear proteins of the bovine esophageal epithelium. II. The NuMA gene gives rise to multiple mRNAs and gene products reactive with monoclonal antibody W1.
Treatment of small cells derived from the basal layer of bovine esophageal epithelium, with Triton X-100, urea and sonication resulted in a nuclear residue that was used as an immunogen for generation of monoclonal antibodies directed against nuclear components. One such antibody, designated W1, was found to label the nuclei of all cells examined. In interphase cells, the target antigen of antibody W1 was diffusely distributed in the nucleus. During metaphase, however, the W1 antigen formed prominent crescents at the poles of the mitotic spindle, diminished gradually in anaphase, and finally redistributed into the regenerating daughter nuclei. Western blotting with antibody W1 yielded a prominent polypeptide of M(r) approximately 230,000. The amino acid sequence, deduced from the nucleotide sequence of several overlapping cDNA clones that span the entire coding region, revealed that the W1 polypeptide was identical to the Nuclear Mitotic Apparatus (NuMA) protein, with a long alpha-helical central core flanked by two nonhelical domains. Interestingly, most cDNA sequences were identical to each other, except for six sequence blocks which were either inserted or deleted in individual cDNA clones. Analysis of the cDNA sequences of various clones, coupled with polymerase chain reaction amplification of cellular mRNA and genomic Southern blotting with region-specific probes, all indicated that multiple mRNA species were present in U-251 human glioma cells, derived from alternative splicing of the RNA transcript from a single NuMA/W1 gene. Besides the predominant form of the mRNA giving rise to the polypeptide of M(r) approximately 230,000, two other forms of mRNA, which arise as a result of alternative splicing and which use different translation termination codons, may yield lower molecular weight polypeptide products. Consistent with this notion, polypeptides of M(r) approximately 195,000 and approximately 194,000 have been observed in this and other studies on the NuMA/W1 protein. These data suggest that multiple isoforms of the NuMA polypeptides generated by alternative mRNA splicing may play some important functions which remain to be characterized.


Are medical students adequately prepared to provide quality care for patients with epilepsy? A cross-sectional study of their knowledge and attitude.
This study assessed preparedness of Palestinian medical students as future physicians to care for patients with epilepsy through assessing their knowledge and attitude. The current study was conducted in a cross-sectional design. A pre-validated study tool was used to collect sociodemographic and academic details of the students, test their knowledge using a 16-item test, and test their attitude using a 13-item test. A total of 386 medical students completed the study tool. The median knowledge score was 75.0% (range: 62.5% to 87.5%). The median attitude score was 81.5% (range: 73.8% to 89.2%). Knowledge and attitude scores correlated positively (Spearman's rho = 0.25, p-value < 0.001). Students who were in their clinical training stage (OR = 4.22, 95% CI of 2.54 to 7.01), who had received a course/part of a course on epilepsy (OR = 2.55, 95% CI of 1.26 to 5.17), who perceived their knowledge of epilepsy as moderate (OR = 3.14, 95% CI of 1.87 to 5.28), and those who perceived their knowledge of epilepsy as high (OR = 11.91, 95% CI of 2.47 to 57.41) were more likely to score ≥ 70% in the knowledge test compared to those who were in their basic training stage, who had not received a course/part of a course on epilepsy, and who perceived their knowledge of epilepsy as low, respectively. Findings of the current investigation may indicate that inclusion of courses on epilepsy early in the medical curriculum might promote knowledge of medical students with regard to epilepsy.


Bone loss in inflammatory arthritis: mechanisms and treatment strategies.
Focal bone loss in inflammatory arthritis begins early in the disease process and can contribute to patient morbidity. Current treatment strategies primarily target suppression of the inflammatory cascade with varying success in limiting the progression of focal bone destruction. This review outlines the current understanding of the mechanisms mediating inflammation-induced focal bone loss in rheumatoid arthritis and other inflammatory arthritides and highlights recent studies in animal models of arthritis that have contributed to our knowledge of this process. Bone-resorbing osteoclasts have been identified as important effector cells in inflammation-induced bone loss in both experimental animal models and human rheumatoid arthritis and psoriatic arthritis. The RANK/RANKL (receptor activator of nuclear factor-kappaB and RANK ligand) pathway has been shown to be essential for osteoclast differentiation in inflammatory arthritis. In addition, in vitro and in vivo studies have demonstrated that many cytokines and growth factors elaborated by inflamed synovial tissues may contribute to osteoclast differentiation and activation. Elucidation of the mechanisms mediating osteoclast differentiation and function has identified new pathways for potential targeted therapeutic intervention for focal bone loss in inflammatory arthritis. Challenges in the application of this approach are that therapies targeting the osteoclast would need to be used in combination with effective anti-inflammatory agents, and that pathways mediating osteoclast differentiation and function would need to remain at least partially functional to allow for continued skeletal remodeling.


Propionibacterium acnes-induced iNOS and COX-2 protein expression via ROS-dependent NF-κB and AP-1 activation in macrophages.
Propionibacterium acnes (P. acnes), a gram-positive anaerobic bacterium, plays a critical role in the development of inflammatory lesion as a result of cytokines production by keratinocytes and macrophages activation. However, effect of P. acnes on iNOS/NO and COX-2/PGE2 production in macrophages is still uninvestigated. This study aimed at determining the reactive oxygen species (ROS), inducible nitric oxide (NO) synthase (iNOS)/nitric oxide (NO), and cyclooxygenase (COX)-2/prostaglandin (PG)E2 produced by macrophages upon P. acnes infection, and dissecting the mechanism of P. acnes-stimulated multiplicity of infection (MOI)-dependent increases in iNOS and COX-2 protein expressions in accordance with the elevation of NO and PGE2 production by RAW264.7 macrophages. Using an in vitro cell culture system, the effects of P. acnes on iNOS/NO, COX-2/PGE2, ROS production, ERK/JNK, and AP-1/NF-κB activation were examined via Western blotting, a flow cytometric analysis, and luciferase assay. In pharmacological studies, the ROS scavenger, N-acetyl cysteine (NAC), the NADPH oxidase inhibitor, diphenylene iodide (DPI), and mitogen-activated protein kinase (MAPK) inhibitors (U0126 and SP600125) were applied to investigate the mechanism. We found that P. acnes exposures increased iNOS/NO and COX-2/PGE2 expression in RAW264.7, J774A.1, and peritoneal macrophages via a MOI-dependent manner. Increased ROS production, ERK/JNK protein phosphorylation, and elevated AP-1/NF-κB luciferase activity are identified in P. acnes-induced iNOS/NO and COX-2/PGE2 production. Additionally, hispolon but not its analogs, hispolon methylether or dehydroxyhispolon, showed significant inhibition of P. acnes-induced iNOS/NO and COX-2/PGE2 production, indicating an important role of OH at C5 for hispolon's inhibition of P. acnes-induced inflammatory events in macrophages. ROS-dependent stimulation of ERK, JNK, NF-κB, and AP-1 activation contributes to P. acnes-induced iNOS/NO and COX-2/PGE2 in macrophages, and chemicals such as hispolon possessing ability to block iNOS/NO and COX-2/PGE2 production reserve potential to be further developed for treatment of the early phase of inflammation elicited by P. acnes.


Defining hyperandrogenism in polycystic ovary syndrome: measurement of testosterone and androstenedione by liquid chromatography-tandem mass spectrometry and analysis by receiver operator characteristic plots.
Hyperandrogenism is one of the diagnostic criteria for the polycystic ovary syndrome (PCOS) despite no agreed definition of hyperandrogenism. In part, this is due to the quality of testosterone immunoassays. We have developed liquid chromatography-tandem mass spectrometry methods for analysing testosterone and androstenedione (Ad) to study their reference ranges and diagnostic utility in PCOS. A consecutive series of 122 women attending a reproductive medicine clinic. Blood samples were taken during the early follicular phase for measurement of LH, FSH, oestradiol, Ad, testosterone and sex hormone-binding globulin (SHBG). Retrospective case note analysis was used to determine the clinical features and ultrasound findings. The incidence of PCOS was 13.9%. The reference interval for testosterone was <1.8 nmol/l and for Ad was 1.4-7.4 nmol/l. There were significant differences in total testosterone (P=0.001), Ad (P<0.05) and free androgen index (FAI; P<0.0001) between the women with and without PCOS. Diagnostic performance using receiver operator characteristic plots showed area under the curve (AUC) for FAI 0.81, testosterone 0.75 and Ad 0.66. The AUC for the LH:FSH ratio was 0.72. Our analysis of a consecutive series of women attending a reproductive clinic has provided an appropriate series on which to construct reference ranges for key androgens in women. Secondly, it has allowed us to conclude that early follicular serum testosterone measured using tandem mass spectrometry, FAI and the LH:FSH ratio are valuable laboratory tests in the diagnosis of PCOS.


Deletion analysis of the F plasmid oriT locus.
Functional domains of the Escherichia coli F plasmid oriT locus were identified by deletion analysis. DNA sequences required for nicking or transfer were revealed by cloning deleted segments of oriT into otherwise nonmobilizable pUC8 vectors and testing for their ability to promote transfer or to be nicked when tra operon functions were provided in trans. Removal of DNA sequences to the right of the central A + T-rich region (i.e., from the direction of traM) did not affect the susceptibility of oriT to nicking functions; however, transfer efficiency for oriT segments deleted from the right was progressively reduced over an 80- to 100-bp interval. Deletions extending toward the oriT nick site from the left did not affect the frequency of transfer if deletion endpoints lay at least 22 bp away from the nick site. Deletions or insertions in the central, A + T-rich region caused periodic variation in transfer efficiency, indicating that phase relationships between nicking and transfer domains of oriT must be preserved for full oriT function. These data show that the F oriT locus is extensive, with domains that individually contribute to transfer, nicking, and overall structure.


Low-frequency respiratory mechanics using ventilator-driven forced oscillations.
We evaluated the potential for using a fast Fourier transform (FFT) analysis applied to a standard ventilator waveform to estimate (< 2 Hz) frequency dependence of respiratory or lung resistance (R) and elastance (E). In four healthy humans we measured pressure and flow at the airway opening while applying sine wave forcing from 0.2 to 0.6 Hz at two tidal volumes (VT; 250 and 500 ml). We then applied a step inspiratory ventilator flow wave with relaxed expiration at the same VT and only 0.2 Hz. Step waveform data were also acquired from nine mechanically ventilated patients under intensive care unit conditions. Finally, we simultaneously measured total respiratory (rs), lung (L), and chest wall (cw) impedance data from two dogs (0.156-2 Hz) before and after severe pulmonary edema. Rrs and Ers were estimated by the FFT approach. Humans displayed a small frequency dependence in Rrs and Ers from 0.2 to 0.6 Hz, and both Rrs and Ers decreased at the higher VT. The spectral estimates of Rrs and Ers with the step ventilator wave were often qualitatively comparable to sine wave results below 0.6 Hz but became extremely erratic above the third harmonic. Conversely, in dogs the step wave produced reliable and stable estimates up to 2 Hz in all conditions. Nevertheless, Ecw and Ers still displayed clear and correlated oscillations with increasing frequency, whereas EL showed none. This suggests that nonlinear processes, most likely at the chest wall, contribute to periodic-like fluctuations in respiratory mechanical properties when estimated by applying FFT to a step ventilator wave. Moreover, in humans, but not dogs, a ventilator flow cycle contains insufficient signal energy beyond the third harmonic. We show that the amount of energy available at higher frequencies is largely governed by the mechanical time constant contributing to passive expiratory flow. In dogs the shorter time constant contributes to increased energy. In essence, the frequency content of the flow is subject dependent, and this is not a desirable situation for controlling the quality of the impedance spectra available from a standard ventilator wave.


Comparison of an interferon-gamma release assay with tuberculin skin testing in HIV-infected individuals.
Although interferon (IFN)-gamma release assays are approved for the diagnosis of latent tuberculosis infection (LTBI), limited data exist regarding their performance in HIV infection. To compare tuberculin skin test (TST) results to the commercial IFN-gamma release assay QuantiFERON-TB Gold In-Tube (QFT) for the diagnosis of LTBI in HIV-infected adults. A total of 294 HIV-infected subjects sampled from two San Francisco cohorts underwent TST, using 5 TU of purified protein derivative, and QFT, measuring IFN-gamma response to Mycobacterium tuberculosis-specific RD-1 antigens. Of 294 participants, 205 (70%) returned for an evaluable TST. Concordance between QFT and TST was 89.3% (kappa=0.37, p=0.007). However, in subjects with positive test results by either TST or QFT, only 28% (8/29) had positive test results by both modalities. TST-positive/QFT-negative discordant results were found in 5.1% of subjects and TST-negative/QFT-positive discordance in 5.6%. Indeterminate QFT results occurred in 5.1%, all due to a failure to respond to the phytohemagglutinin-positive control. Subjects with a CD4(+) count of less than 100 cells/mm(3) had a relative risk of an indeterminate result of 4.24 (95% confidence interval, 1.55-11.61; p=0.003) compared with those with a CD4(+) count of 100 or more. Overall concordance between QFT and TST in HIV infection was high, but agreement among subjects with positive tests by either modality was low.


Plasticity of the worker bumblebee brain in relation to age and rearing environment.
The environment experienced during development can dramatically affect the brain, with possible implications for sensory processing, learning, and memory. Although the effects of single sensory modalities on brain development have been repeatedly explored, the additive or interactive effects of multiple modalities have been less thoroughly investigated. We asked how experience with multisensory stimuli affected brain development in the bumblebee Bombus impatiens. First, to establish the timeline of brain development during early adulthood, we estimated regional brain volumes across a range of ages. We discovered significant age-related volume changes in nearly every region of the brain. Next, to determine whether these changes were dependent upon certain environmental stimuli, we manipulated the visual and olfactory stimuli available to newly emerged bumblebee workers in a factorial manner. Newly emerged bumblebees were maintained in the presence or absence of supplemental visual and/or olfactory stimuli for 7 days, after which the volumes of several brain regions were estimated. We found that the volumes of the mushroom body lobes and calyces were larger in the absence of visual stimuli. Additionally, visual deprivation was associated with the expression of larger antennal lobes, the primary olfactory processing regions of the brain. In contrast, exposure to plant-derived olfactory stimuli did not have a significant effect on brain region volumes. This study is the first to explore the separate and interactive effects of visual and olfactory stimuli on bee brain development. Assessing the timing and sensitivity of brain development is a first step toward understanding how different rearing environments differentially affect regional brain volumes in this species. Our findings suggest that environmental factors experienced during the first week of adulthood can modify bumblebee brain development in many subtle ways.


Significance of preoperatively observed detrusor overactivity as a predictor of continence status early after robot-assisted radical prostatectomy.
Several recent studies have reported the involvement of bladder dysfunction in the delayed recovery of urinary continence following radical prostatectomy (RP). The objective of this study was to investigate the significance of detrusor overactivity (DO) as a predictor of the early continence status following robot-assisted RP (RARP). This study included 84 consecutive patients with prostate cancer undergoing RARP. Urodynamic studies, including filling cystometry, pressure flow study, electromyogram of the external urethral sphincter and urethral pressure profile, were performed in these patients before surgery. Urinary continence was defined as the use of either no or one pad per day as a precaution only. DO was preoperatively observed in 30 patients (35.7%), and 55 (65.5%) and 34 (40.5%) were judged to be incontinent 1 and 3 months after RARP, respectively. At both 1 and 3 months after RARP, the incidences of incontinence in patients with DO were significantly higher than in those without DO. Of several demographic and urodynamic parameters, univariate analyses identified DO and maximal urethral closure pressure (MUCP) as significant predictors of the continence status at both 1 and 3 months after RARP. Furthermore, DO and MUCP appeared to be independently associated with the continence at both 1 and 3 months after RARP on multivariate analysis. These findings suggest that preoperatively observed DO could be a significant predictor of urinary incontinence early after RARP; therefore, it is recommended to perform urodynamic studies for patients who are scheduled to undergo RARP in order to comprehensively evaluate their preoperative vesicourethral functions.


Interventions aimed at improving the nursing work environment: a systematic review.
Nursing work environments (NWEs) in Canada and other Western countries have increasingly received attention following years of restructuring and reported high workloads, high absenteeism, and shortages of nursing staff. Despite numerous efforts to improve NWEs, little is known about the effectiveness of interventions to improve NWEs. The aim of this study was to review systematically the scientific literature on implemented interventions aimed at improving the NWE and their effectiveness. An online search of the databases CINAHL, Medline, Scopus, ABI, Academic Search Complete, HEALTHstar, ERIC, Psychinfo, and Embase, and a manual search of Emerald and Longwoods was conducted. (Quasi-) experimental studies with pre/post measures of interventions aimed at improving the NWE, study populations of nurses, and quantitative outcome measures of the nursing work environment were required for inclusion. Each study was assessed for methodological strength using a quality assessment and validity tool for intervention studies. A taxonomy of NWE characteristics was developed that would allow us to identify on which part of the NWE an intervention targeted for improvement, after which the effects of the interventions were examined. Over 9,000 titles and abstracts were screened. Eleven controlled intervention studies met the inclusion criteria, of which eight used a quasi-experimental design and three an experimental design. In total, nine different interventions were reported in the included studies. The most effective interventions at improving the NWE were: primary nursing (two studies), the educational toolbox (one study), the individualized care and clinical supervision (one study), and the violence prevention intervention (one study). Little is known about the effectiveness of interventions aimed at improving the NWE, and published studies on this topic show weaknesses in their design. To advance the field, we recommend that investigators use controlled studies with pre/post measures to evaluate interventions that are aimed at improving the NWE. Thereby, more evidence-based knowledge about the implementation of interventions will become available for healthcare leaders to use in rebuilding nursing work environments.


The impact of artificial light at night on nocturnal insects: A review and synthesis.
In recent decades, advances in lighting technology have precipitated exponential increases in night sky brightness worldwide, raising concerns in the scientific community about the impact of artificial light at night (ALAN) on crepuscular and nocturnal biodiversity. Long-term records show that insect abundance has declined significantly over this time, with worrying implications for terrestrial ecosystems. The majority of investigations into the vulnerability of nocturnal insects to artificial light have focused on the flight-to-light behavior exhibited by select insect families. However, ALAN can affect insects in other ways as well. This review proposes five categories of ALAN impact on nocturnal insects, highlighting past research and identifying key knowledge gaps. We conclude with a summary of relevant literature on bioluminescent fireflies, which emphasizes the unique vulnerability of terrestrial light-based communication systems to artificial illumination. Comprehensive understanding of the ecological impacts of ALAN on diverse nocturnal insect taxa will enable researchers to seek out methods whereby fireflies, moths, and other essential members of the nocturnal ecosystem can coexist with humans on an increasingly urbanized planet.


Species distribution models and impact factor growth in environmental journals: methodological fashion or the attraction of global change science.
In this work, I evaluate the impact of species distribution models (SDMs) on the current status of environmental and ecological journals by asking the question to which degree development of SDMs in the literature is related to recent changes in the impact factors of ecological journals. The hypothesis evaluated states that research fronts are likely to attract research attention and potentially drive citation patterns, with journals concentrating papers related to the research front receiving more attention and benefiting from faster increases in their impact on the ecological literature. My results indicate a positive relationship between the number of SDM related articles published in a journal and its impact factor (IF) growth during the period 2000-09. However, the percentage of SDM related papers in a journal was strongly and positively associated with the percentage of papers on climate change and statistical issues. The results support the hypothesis that global change science has been critical in the development of SDMs and that interest in climate change research in particular, rather than the usage of SDM per se, appears as an important factor behind journal IF increases in ecology and environmental sciences. Finally, our results on SDM application in global change science support the view that scientific interest rather than methodological fashion appears to be the major driver of research attraction in the scientific literature.


Validation of a Spanish version of the Airways Questionnaire 20: a short and simple instrument.
To describe the psychometric properties of the Spanish version of the Airways Questionnaire 20 (AQ20S) for asthma and COPD separately. Two hundred and eight patients (108 asthma, 100 COPD) filled in the AQ20S, the St. George's Respiratory Questionnaire (SGRQ), the Asthma Quality of Life Questionnaire (AQLQ) and the Chronic Respiratory Disease Questionnaire (CRQ). Clinical and physiological measurements were assessed concurrently. Clinically stable patients were asked to fill in again the AQ20S after 14 days. The same assessment as on baseline visit was repeated after 3 months. The AQ20S showed a satisfactory score distribution, with minimal floor and ceiling effects, high internal consistency (Cronbach's α > 0.80), and good test-retest reliability (ICC ≥ 0.87). The AQ20S showed a high correlation with the SGRQ in both asthma and COPD (r (s) > 0.75; P < 0.001), as well as with the AQLQ (r (s) = -0.72, P < 0.001) in asthma and with the CRQ (r (s) = -0.59; P < 0.001) in COPD. The AQ20S showed significant correlation with clinical and functional variables, similar to the SGRQ and the AQLQ in asthmatics, but weaker than the SGRQ in COPD patients. Changes in AQ20S scores correlated quite well with changes in other HRQoL questionnaires, both in asthma and COPD. The AQ20S showed psychometric properties similar to the original questionnaire. It was equally useful compared with the SGRQ and the AQLQ in asthma patients and slightly less useful than the SGRQ in COPD patients. Considering its simplicity, the AQ20S may be an alternative to more complex traditional questionnaires.


Developmental telomere attrition predicts impulsive decision-making in adult starlings.
Animals in a poor biological state face reduced life expectancy, and as a consequence should make decisions that prioritize immediate survival and reproduction over long-term benefits. We tested the prediction that if, as has been suggested, developmental telomere attrition is a biomarker of state and future life expectancy, then individuals who have undergone greater developmental telomere attrition should display greater choice impulsivity as adults. We measured impulsive decision-making in a cohort of European starlings (Sturnus vulgaris) in which we had previously manipulated developmental telomere attrition by cross-fostering sibling chicks into broods of different sizes. We show that as predicted by state-dependent optimality models, individuals who had sustained greater developmental telomere attrition and who had shorter current telomeres made more impulsive foraging decisions as adults, valuing smaller, sooner food rewards more highly than birds with less attrition and longer telomeres. Our findings shed light on the biological embedding of early adversity and support a functional explanation for its consequences that could be applicable to other species, including humans.


Standardized experiments in mutant mice reveal behavioural similarity on 129S5 and C57BL/6J backgrounds.
Behavioural analysis of mice carrying engineered mutations is widely used to identify roles of specific genes in components of the mammalian behavioural repertoire. The reproducibility and robustness of phenotypic measures has become a concern that undermines the use of mouse genetic models for translational studies. Contributing factors include low individual study power, non-standardized behavioural testing, failure to address confounds and differences in genetic background of mutant mice. We have examined the importance of these factors using a statistically robust approach applied to behavioural data obtained from three mouse mutations on 129S5 and C57BL/6J backgrounds generated in a standardized battery of five behavioural assays. The largest confounding effect was sampling variation, which partially masked the genetic background effect. Our observations suggest that strong interaction of mutation with genetic background in mice in innate and learned behaviours is not necessarily to be expected. We found composite measures of innate and learned behaviour were similarly impacted by mutations across backgrounds. We determined that, for frequently used group sizes, a single retest of a significant result conforming to the commonly used P < 0.05 threshold results in a reproducibility of 60% between identical experiments. Reproducibility was reduced in the presence of strain differences. We also identified a P-value threshold that maximized reproducibility of mutant phenotypes across strains. This study illustrates the value of standardized approaches for quantitative assessment of behavioural phenotypes and highlights approaches that may improve the translational value of mouse behavioural studies.


Mutational analysis of the early forespore/mother-cell signalling pathway in Bacillus subtilis.
Intercellular communication is a crucial phenomenon during spore development in Bacillus subtilis. It couples the establishment of a compartment-specific genetic program to the transcriptional activity of a sigma factor in the other compartment. It also keeps sigma factor activation in register with the morphological process. This study used directed mutagenesis to analyse the pathway that couples sigma E activation in the mother-cell to activation of sigma F in the forespore following asymmetric septation. Targets for mutagenesis in SpoIIGA (the receptor) were chosen based on the predicted topology of the protein when associated with the cell membrane. The results showed that a residue near the N terminus (D6), predicted to be exposed outside the cell, is required for receptor activity, whereas the major extracellular loop (between membrane domains IV and V) is dispensable for function. In contrast, mutations in SpoIIR (the signal) that partially blocked protein release (but not membrane translocation) had no effect on signal transduction. These results do not rule out the possibility that uncharacterized molecules intervene in the signalling pathway that establishes the mother-cell-specific developmental program during the early stage of sporulation.


Application of Isothermal Amplification Techniques for Identification of Madurella mycetomatis, the Prevalent Agent of Human Mycetoma.
Appropriate diagnosis and treatment of eumycetoma may vary significantly depending on the causative agent. To date, the most common fungus causing mycetoma worldwide is Madurella mycetomatis. This species fails to express any recognizable morphological characteristics, and reliable identification can therefore only be achieved with the application of molecular techniques. Recombinase polymerase amplification (RPA) and loop-mediated isothermal amplification (LAMP) are proposed as alternatives to phenotypic methods. Species-specific primers were developed to target the ribosomal DNA (rDNA) internal transcribed spacer (ITS) region of M. mycetomatis. Both isothermal amplification techniques showed high specificity and sufficient sensitivity to amplify fungal DNA and proved to be appropriate for detection of M. mycetomatis. Diagnostic performance of the techniques was assessed in comparison to conventional PCR using biopsy specimens from eumycetoma patients. RPA is reliable and easy to operate and has the potential to be implemented in areas where mycetoma is endemic. The techniques may be expanded to detect fungal DNA from environmental samples.


The Protective Effects of Probiotic Bacteria on Cadmium Toxicity in Rats.
One of the useful properties of probiotic bacteria is their capacity to bind different targets, thus eliminating them through feces. It is supposed that one of these targets could be cadmium, a widespread environmental toxicant that causes various disturbances in biological systems. This study examined the protective effects of probiotic supplementation against cadmium-induced toxicity in the rat. The experiment was conducted in the course of 5 weeks. Animals were divided into four groups: (1) controls, (2) probiotics treated, (3) cadmium treated, and (4) probiotics + cadmium treated. The cadmium concentration was measured in the blood, liver, kidney, and feces, as well as the blood alanine aminotransferase (ALT) and aspartate aminotransferase (AST) as biomarkers of the liver function. Histomorphological changes in the liver and kidney were also determined. Our results revealed that probiotics combined with cadmium increase this metal concentration in feces. As a result, blood, liver, and kidney Cd levels, as well as blood ALT and AST activities were lessened compared to the rat group treated with cadmium only. Besides, probiotics consumed simultaneously with cadmium attenuated histomorphological changes in the liver and kidney caused by cadmium. The rise in lactobacilli number in feces of rats treated simultaneously with cadmium and probiotics results in strong correlation with the increase of Cd concentration in their feces and the decrease of Cd concentration in their blood. We speculate that probiotics actively contribute to cadmium excretion through feces, probably, by its binding to their bacterial cell wall.


A back-to-back comparison of white light video endoscopy with autofluorescence endoscopy for adenoma detection in high-risk subjects.
To compare the sensitivity of autofluorescence endoscopy (AFE) and white light video endoscopy (WLE) for the detection of colorectal adenomas in high-risk patients belonging to Lynch syndrome (LS) or familial colorectal cancer (CRC) families. This was a prospective single-centre study carried out in a tertiary referral centre. The subjects were 75 asymptomatic patients originating from LS or familial CRC families. Patients were examined with either WLE followed by AFE or AFE followed by WLE. Back-to-back colonoscopy was performed by two blinded endoscopists. All lesions were removed during the second endoscopic procedure. Lesions missed during the second procedure were identified and removed on third pass. The sensitivity calculations for colorectal adenomas were based on histology results. The main outcome measures were the difference in sensitivity between WLE and AFE for the detection of adenomas in patients with LS or familial CRC. At least one adenoma was detected in 41 (55%) patients. WLE identified adenomas in 28/41 patients and AFE in 37/41 patients, corresponding to a 32% increase. In total 95 adenomas were detected, 65 by WLE and 87 by AFE, resulting in a significantly higher sensitivity of AFE compared with WLE (92% vs 68%; p=0.001). The additionally detected adenomas with AFE were significantly smaller than the adenomas detected by WLE (mean 3.0 mm vs 4.9 mm, p<0.01). AFE improves the detection of colorectal adenomas in patients with LS or familial CRC. The results of this study suggest that AFE may be preferable for surveillance of these high-risk patients.


Primary testicular diffuse large B-cell lymphoma: a population-based study on the incidence, natural history, and survival comparison with primary nodal counterpart before and after the introduction of rituximab.
We performed a population-based study of primary testicular diffuse large B-cell lymphoma (DLBCL) in the United States to determine its incidence and survival trends, prognostic factors, and clinical outcome compared with males with nodal DLBCL. The Surveillance, Epidemiology, and End Results database was reviewed to identify patients diagnosed between 1980 and 2005. To study the potential impact of the introduction of rituximab on survival, we used the year 2000 as cutoff point. We identified 769 patients with testicular DLBCL. The median age at diagnosis was 68.0 years. The incidence of DLBCL increased over time, with the highest rate among whites (twice that of blacks). The median overall survival (OS) for the whole group was 4.6 years, whereas the disease-specific survival (DSS) rates at 3, 5, and 15 years were 71.5%, 62.4%, and 43.0%, respectively. Independent predictors of worse DSS were older age, diagnosis before 1986, advanced stage, left testicular involvement, and not having surgery and radiation. The use of radiation did not change significantly over time. When testicular and nodal DLBCL patients were analyzed together, testicular primary was an independent predictor of better OS and DSS. Unlike nodal DLBCL, DSS did not improve in the patients with testicular DLBCL diagnosed after the year 2000. The incidence of testicular DLBCL is increasing. Compared with nodal DLBCL, testicular DLBCL patients have a better overall prognosis but are at higher risk of late disease-related deaths. The introduction of rituximab in clinical practice does not seem to improve their early outcome.


N-methyl-D-aspartate receptors of ganglion cells in rabbit retina.
1. Intracellular and extracellular recordings were obtained from ganglion cells in the rabbit retina. The effect of N-methyl-DL-aspartate (NMDLA) and N-methyl-D-aspartate (NMDA) antagonists were studied with the use of a perfusion method for drug application. 2. NMDLA excited all ganglion cell types and caused a characteristic burst firing pattern, which is not typical of physiological responses in the retina. When synaptic transmission was blocked with cobalt, NMDLA still excited ganglion cells, indicating a direct action. 3. A comparison of DL-2-amino-5-phosphonopentanoate (DL-AP-5) and DL-2-amino-7-phosphonoheptanoate (DL-AP-7) revealed that DL-AP-7 was a more specific NMDA antagonist. DL-AP-5 partially blocked the b-wave of the electroretinogram (ERG), an action typical of L-2-amino-4-phosphonobutyrate (L-APB), which specifically blocks on channels in the retina. 4. DL-AP-7 reversibly blocked the action of NMDLA on all ganglion cell types, but the effects of kainate (KA) and carbachol were unchanged. AP-7 was stereospecific and pharmacologically specific, with action typical of a competitive NMDA antagonist in the rabbit retina. 5. DL-AP-7 did not block light responses driven by center or surround stimulation for ON or OFF ganglion cells. Directional selectively was unchanged by DL-AP-7. However, most ganglion cells showed a reduction, typically 20-30%, in the number of action potentials produced by light stimulation. 6. In contrast to a previous report, we found no evidence that DL-AP-7 specifically inhibited sustained ON ganglion cells. The inhibition of sustained ON responses by DL-AP-5, previously attributed to NMDA antagonism, is probably because of the weak APB activity of L-AP-5. 7. We conclude that NMDA receptors do not mediate the major light-driven input to ganglion cells in the rabbit retina. By exclusion, transmission from bipolar cells to ganglion cells appears to be carried mostly by KA or quisqualate (QQ) receptors. However, because NMDA antagonists reduced the number of action potentials produced by light stimulation, it is likely that NMDA receptors carry a portion of the signal transmission to ganglion cells. The presence of NMDA receptors on third-order neurons is consistent with the release of glutamate from presynaptic neurons such as bipolar cells.


Bridging emotion theory and neurobiology through dynamic systems modeling.
Efforts to bridge emotion theory with neurobiology can be facilitated by dynamic systems (DS) modeling. DS principles stipulate higher-order wholes emerging from lower-order constituents through bidirectional causal processes--offering a common language for psychological and neurobiological models. After identifying some limitations of mainstream emotion theory, I apply DS principles to emotion-cognition relations. I then present a psychological model based on this reconceptualization, identifying trigger, self-amplification, and self-stabilization phases of emotion-appraisal states, leading to consolidating traits. The article goes on to describe neural structures and functions involved in appraisal and emotion, as well as DS mechanisms of integration by which they interact. These mechanisms include nested feedback interactions, global effects of neuromodulation, vertical integration, action-monitoring, and synaptic plasticity, and they are modeled in terms of both functional integration and temporal synchronization. I end by elaborating the psychological model of emotion-appraisal states with reference to neural processes.


Investigation of localized delivery of diclofenac sodium from poly(D,L-lactic acid-co-glycolic acid)/poly(ethylene glycol) scaffolds using an in vitro osteoblast inflammation model.
Nonunion fractures and large bone defects are significant targets for osteochondral tissue engineering strategies. A major hurdle in the use of these therapies is the foreign body response of the host. Herein, we report the development of a bone tissue engineering scaffold with the ability to release anti-inflammatory drugs, in the hope of evading this response. Porous, sintered scaffolds composed of poly(D,L-lactic acid-co-glycolic acid) (PLGA) and poly(ethylene glycol) (PEG) were prepared with and without the anti-inflammatory drug diclofenac sodium. Analysis of drug release over time demonstrated a profile suitable for the treatment of acute inflammation with ∼80% of drug released over the first 4 days and a subsequent release of around 0.2% per day. Effect of drug release was monitored using an in vitro osteoblast inflammation model, comprised of mouse primary calvarial osteoblasts stimulated with proinflammatory cytokines interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ). Levels of inflammation were monitored by cell viability and cellular production of nitric oxide (NO) and prostaglandin E2 (PGE2). The osteoblast inflammation model revealed that proinflammatory cytokine addition to the medium reduced cell viability to 33%, but the release of diclofenac sodium from scaffolds inhibited this effect with a final cell viability of ∼70%. However, releasing diclofenac sodium at high concentrations had a toxic effect on the cells. Proinflammatory cytokine addition led to increased NO and PGE2 production; diclofenac-sodium-releasing scaffolds inhibited NO release by ∼64% and PGE2 production by ∼52%, when the scaffold was loaded with the optimal concentration of drug. These observations demonstrate the potential use of PLGA/PEG scaffolds for localized delivery of anti-inflammatory drugs in bone tissue engineering applications.


Physical Disabilities and Low Cognitive Ability Increase Odds of Minor Sex Exchange among Adolescent Males in the United States.
Disability is a well-established risk factor for sexual violence victimization among both male and female children. Some research indicates that adolescent females with disabilities are at higher risk of experiencing minor sex exchange (a form of minor sex trafficking victimization) compared to females without disabilities, but there is a dearth of similar research among adolescent males. This study investigates whether physical disability and low cognitive ability are related to sex exchange among minor adolescent males. This cross-sectional analysis using data from a nationally representative cohort study, The National Longitudinal Study of Adolescent to Adult Health (Add Health), included 4,401 male participants who were age 18 or younger at Wave II. Unadjusted and adjusted logistic regression models estimated the odds of adolescent experiences of sex exchange by physical disability and cognitive ability. Both severe physical disability and low cognitive ability in adolescent males were significantly associated with increased odds of exchanging sex, results similar to those found in studies of adolescent females. Because of these associations for both males and females, disability should be taken into account when designing and implementing prevention and intervention programs related to sex trafficking. These results underscore the importance of addressing system-wide gaps contributing to the relationship between disability and the involvement of minors in commercial sex exchange.


The association between cholecystectomy and gastroesophageal reflux symptoms: a prospective controlled study.
A large controlled prospective observational study to compare pre- and postsurgery changes in reflux symptoms between cholecystectomy and hernia repair surgery patients. Six studies have suggested that gastroesophageal reflux worsens after cholecystectomy. However, all these studies had design limitations. We recruited 302 patients scheduled to undergo elective cholecystectomy (study group) or hernia repair (controls) at 2 hospitals. Both groups filled out the validated Reflux Symptom Score (RSS) and Gastrointestinal Symptom Rating Scale (GSRS) questionnaires 1 to 15 days prior to and 4 to 12 weeks after the operation. Changes in symptom scores between the pre and postsurgery assessments were measured, and compared between the 2 groups. Baseline RSS and GSRS reflux subscores were higher in the study group than controls (1.44 vs. 1.02 and 1.91 vs. 1.43, respectively; P < 0.05). There were no significant differences in any of the symptom score changes between the 2 groups except for the GSRS pain subscore, which decreased more in the study group than the control group (-0.59 vs. -0.10; P < 0.001). With regard to reflux, the RSS decreased by -0.34 in the study group and -0.14 in controls (P = 0.27), while the GSRS reflux subscore decreased by -0.32 in the study group and -0.05 in controls (P = 0.12). GSRS diarrhea and constipation subscores decreased slightly after surgery, to the same extent in both groups. This large prospective controlled study, the only one using validated reflux symptom questionnaires, shows that cholecystectomy does not lead to an increase in reflux symptoms. As expected, GSRS pain subscores were decreased in the cholecystectomy group but not the controls.


Characterization of structural elements in native autoinducing peptides and non-native analogues that permit the differential modulation of AgrC-type quorum sensing receptors in Staphylococcus aureus.
Staphylococcus aureus uses short macrocyclic peptides (i.e., autoinducing peptides, or AIPs) to assess its local population density in a cell-cell signaling mechanism called quorum sensing (QS). At high cell numbers, this pathogen can initiate many virulent behaviors that allow for the establishment of infection. Binding of the AIP signal to its cognate transmembrane AgrC-type receptor is a critical event in the QS signaling cascade; consequently, interference of AIP:receptor interactions may have the potential to prevent and eradicate certain S. aureus infections. To date, four pairs of AIP:AgrC receptors have been identified in S. aureus, each pair being utilized by a specific S. aureus group (I-IV). Other staphylococcal species also use closely related, but distinct, AIP:AgrC pairs to control QS. We seek to develop non-native ligands capable of intercepting AIP:AgrC binding in each S. aureus group and in related species. As these bacteria may use their respective AIP signal to attenuate the QS systems of other groups/species, such ligands would provide valuable chemical tools to probe possible interference mechanisms in a range of contexts. In the current study, we used solution-phase NMR techniques to characterize the 3-D structures of a set of known native and non-native peptides that have differential modulatory activity in certain AgrC receptors. Analysis of these structures revealed several distinct structural motifs that belay differential activity in selected S. aureus AgrC receptors (i.e., AgrC-I, AgrC-II, and AgrC-III). The results of this study can be leveraged for the design of new synthetic ligands with enhanced selectivities and potencies for these AgrC receptors.


Potential Biases in Estimating Absolute and Relative Case-Fatality Risks during Outbreaks.
Estimating the case-fatality risk (CFR)-the probability that a person dies from an infection given that they are a case-is a high priority in epidemiologic investigation of newly emerging infectious diseases and sometimes in new outbreaks of known infectious diseases. The data available to estimate the overall CFR are often gathered for other purposes (e.g., surveillance) in challenging circumstances. We describe two forms of bias that may affect the estimation of the overall CFR-preferential ascertainment of severe cases and bias from reporting delays-and review solutions that have been proposed and implemented in past epidemics. Also of interest is the estimation of the causal impact of specific interventions (e.g., hospitalization, or hospitalization at a particular hospital) on survival, which can be estimated as a relative CFR for two or more groups. When observational data are used for this purpose, three more sources of bias may arise: confounding, survivorship bias, and selection due to preferential inclusion in surveillance datasets of those who are hospitalized and/or die. We illustrate these biases and caution against causal interpretation of differential CFR among those receiving different interventions in observational datasets. Again, we discuss ways to reduce these biases, particularly by estimating outcomes in smaller but more systematically defined cohorts ascertained before the onset of symptoms, such as those identified by forward contact tracing. Finally, we discuss the circumstances in which these biases may affect non-causal interpretation of risk factors for death among cases.


Prediction of behind-the-wheel driving performance in patients with cerebral brain damage: a discriminant function analysis.
Rehabilitation specialists, particularly occupational therapists, are often involved in evaluating clients' fitness to resume driving after cerebral damage due to head injury or stroke. Their available methods include separate or combined administration of predriver, simulator, and behind-the-wheel evaluations. However, use of these methods without a theoretical model on which to base test selection has yielded some criticism and little research about the effectiveness of these methods in predicting driving performance. Using the authors' Cybernetic Model of Driving as the basis for assessing abilities and behaviors relevant to driving outcome, this study sought to determine the effectiveness of the evaluation methods by discriminant analysis and measurements of sensitivity in predicting behind-the-wheel failures. Comprehensive evaluations of 106 patients revealed that residual deficits in cognition per se did not render a person unfit to drive and underscored the importance of considering behaviors in determining fitness. The methods of evaluation were shown to be relatively sensitive in predicting outcome; off-road and on-road evaluation reached sensitivities of 90% and 92% with the inclusion of behavioral measures. Formulae for predicting outcome based on methods of evaluation are provided and reasons for failures in behind-the-wheel evaluations are discussed.


Ethanol tolerance and withdrawal severity in high drinking in the dark selectively bred mice.
Mouse lines are being selectively bred in replicate for high blood ethanol concentrations (BECs) achieved after limited access of ethanol (EtOH) drinking early in the circadian dark phase. High Drinking in the Dark-1 (HDID-1) mice are in selected generation S21, and the replicate HDID-2 line in generation S14. Tolerance and withdrawal symptoms are 2 of the 7 diagnostic criteria for alcohol dependence. Withdrawal severity has been found in mouse studies to be negatively genetically correlated with EtOH preference drinking. To determine other traits genetically correlated with high DID, we compared naïve animals from both lines with the unselected, segregating progenitor stock, HS/Npt. Differences between HDID-1 and HS would imply commonality of genetic influences on DID and these traits. Female HDID-1 and HDID-2 mice tended to develop less tolerance than HS to EtOH hypothermia after their third daily injection. A trend toward greater tolerance was seen in the HDID males. HDID-1, HDID-2, and control HS lines did not differ in the severity of acute or chronic withdrawal from EtOH as indexed by the handling-induced convulsion (HIC). Both HDID-1 and HDID-2 mice tended to have greater HIC scores than HS regardless of drug treatment. These results show that tolerance to EtOH's hypothermic effects may share some common genetic control with reaching high BECs after DID, a finding consistent with other data regarding genetic contributions to EtOH responses. Withdrawal severity was not negatively genetically correlated with DID, unlike its correlation with preference drinking, underscoring the genetic differences between preference drinking and DID. HDID lines showed greater basal HIC scores than HS, suggestive of greater central nervous system excitability.


Capsule Attention for Multimodal EEG-EOG Representation Learning With Application to Driver Vigilance Estimation.
Driver vigilance estimation is an important task for transportation safety. Wearable and portable brain-computer interface devices provide a powerful means for real-time monitoring of the vigilance level of drivers to help with avoiding distracted or impaired driving. In this paper, we propose a novel multimodal architecture for in-vehicle vigilance estimation from Electroencephalogram and Electrooculogram. To enable the system to focus on the most salient parts of the learned multimodal representations, we propose an architecture composed of a capsule attention mechanism following a deep Long Short-Term Memory (LSTM) network. Our model learns hierarchical dependencies in the data through the LSTM and capsule feature representation layers. To better explore the discriminative ability of the learned representations, we study the effect of the proposed capsule attention mechanism including the number of dynamic routing iterations as well as other parameters. Experiments show the robustness of our method by outperforming other solutions and baseline techniques, setting a new state-of-the-art. We then provide an analysis on different frequency bands and brain regions to evaluate their suitability for driver vigilance estimation. Lastly, an analysis on the role of capsule attention, multimodality, and robustness to noise is performed, highlighting the advantages of our approach.


Transient ST-segment in unstable angina. Clinical and hemodynamic significance.
The significance of the direction of the ST-segment shifts on the 12-lead electrocardiogram was evaluated in 82 consecutive patients with unstable angina. Eighteen patients with ST-segment elevation (group I) were compared with 64 patients with ST-segment depression (group II). There was no difference between group I and group II with regard to age, sex, or history of previous myocardial infarction. There also was no difference in the angiographic extent, location or severity of the coronary artery disease, collaterals, or resting hemodynamics. A larger proportion of patients in group I presented with recent onset angina. Life-threatening arrhythmias were more frequent in group I but were uncommon in both groups. A normal resting electrocardiogram was associated with normal ventricular function in both group I and group II but was associated with single vessel disease only in group I. An abnormal resting electrocardiogram was associated with multiple coronary vessel disease and abnormal ventricular function in both groups. Single vessel disease was encountered twice as frequently in group I but this difference was not statistically significant. Left main coronary artery disease was found only in group II.