Stroke survivor cognitive decline and psychological wellbeing of family caregivers five years post-stroke: a cross-sectional analysis.
Family members frequently provide long-term care for stroke survivors, which can lead to psychological strain, particularly in the presence of cognitive decline. To profile anxious and depressive symptoms of family caregivers at 5 years post-stroke, and to explore associations with stroke survivor cognitive decline. As part of a 5-year follow-up of the Action on Secondary Prevention Interventions and Rehabilitation in Stroke (ASPIRE-S) cohort of stroke survivors, family members completed a self-report questionnaire. Symptoms of anxiety and depression were assessed using the HADS-A and CES-D. Cognitive decline in stroke survivors was assessed from the caregiver's perspective using the IQCODE, with cognitive performance assessed by the MoCA. Data were analyzed using logistic regression models. 78 family members participated; 25.5% exhibited depressive symptoms, 19.4% had symptoms of anxiety. Eleven stroke survivors (16.7%) had evidence of cognitive decline according to both the IQCODE and MoCA. Family members of stroke survivors with cognitive decline were significantly more likely to report symptoms of depression [age-adjusted OR (95% CI): 5.94 (1.14, 30.89)] or anxiety [age-adjusted OR (95% CI): 5.64 (1.24, 25.54)] than family members of stroke survivors without cognitive decline. One-fifth of family caregivers exhibited symptoms of anxiety and one-quarter symptoms of depression at 5 years post-stroke. Stroke survivor cognitive decline was significantly associated with both depressive and anxious symptoms of family caregivers. Family members play a key role in the care and rehabilitation of stroke patients; enhancing their psychological wellbeing and identifying unmet needs are essential to improving outcomes for stroke survivors and families.


Baseline and stress-induced glucocorticoid concentrations are not repeatable but covary within individual great tits (Parus major).
In evolutionary endocrinology, there is a growing interest in the extent and basis of individual variation in endocrine traits, especially circulating concentrations of hormones. This is important because if targeted by selection, such individual differences present the opportunity for an evolutionary response to selection. It is therefore necessary to examine whether hormone traits are repeatable in natural populations. However, research in this area is complicated by the fact that different hormone traits can be correlated. The nature of these trait correlations (i.e., phenotypic, within-, or among-individual) is critically relevant in terms of the evolutionary implications, and these in turn, depend on the repeatability of each hormone trait. By decomposing phenotypic correlations between hormone traits into their within- and among-individual components it is possible to describe the multivariate nature of endocrine traits and generate inferences about their evolution. In the present study, we repeatedly captured individual great tits (Parus major) from a wild population and measured plasma concentrations of corticosterone. Using a mixed-modeling approach, we estimated repeatabilities in both initial (cf. baseline; CORT0) and stress-induced concentrations (CORT30) and the correlations between those traits among- and within-individuals. We found a lack of repeatability in both CORT0 and CORT30. Moreover, we found a strong phenotypic correlation between CORT0 and CORT30, and due to the lack of repeatability for both traits, there was no among-individual correlation between these two traits-i.e., an individual's average concentration of CORT0 was not correlated with its average concentration of CORT30. Instead, the phenotypic correlation was the result of a strong within-individual correlation, which implies that an underlying environmental factor co-modulates changes in initial and stress-induced concentrations within the same individual over time. These results demonstrate that (i) a phenotypic correlation between two hormone traits does not imply that the traits are correlated among individuals; (ii) the importance of repeated sampling to partition within- and among-individual variances and correlations among labile physiological traits; and (iii) that environmental factors explain a considerable fraction of the variation and co-variation in hormone concentrations.


Factors influencing vaccine acceptance and hesitancy in three informal settlements in Lusaka, Zambia.
Heterogeneous coverage threatens to compromise the effectiveness of immunization programs in Zambia. Demand-creation initiatives are needed to address this; however, there is incomplete understanding of why vaccine coverage is suboptimal. We investigated overarching perceptions on vaccine acceptability, hesitancy, and accessibility at three informal settlements in Lusaka, Zambia. Nested within a cholera vaccination uptake study, we sought to understand overarching perceptions on vaccines' hesitancy in three informal settlements in Lusaka, Zambia. We conducted 48 focus group discussions with a convenience sample of laypersons, lay healthcare workers, neighbourhood health committee members and vaccinators. Both laypersons and community-based health actors reported high vaccine acceptance though several sources of hesitancy were reported. Traditional remedies, alcohol use and religious beliefs emerged as drivers of vaccine hesitancy, likely reinforced by a background of distrust towards western medicine. Also mentioned were previous adverse events, fear of injections and low perceived need for immunization. Limited understanding of how vaccines work and overlapping local terms for vaccine and other medical concepts created confusion and inaccurate views and expectations. Some reported refusing injections to avoid pain and perceived risk of infection. Discussants emphasised the importance of education and preferred mobile immunization campaigns, with weekend to reach those with poor access and delivered by a combination of professional and volunteer workers. Vaccine hesitancy in Zambia is underpinned by many factors including personal experiences with vaccinations, alternative belief models, limited knowledge, deep misunderstanding about how vaccines work, and barriers to access. To overcome these, community-driven models that incorporate factual communication by professionals and operate outside of traditional hours, may help. Better research to understand community preferences for vaccine uptake could inform interventions to improve immunization coverage in Zambia.


Family therapy for autism spectrum disorders.
Autism spectrum disorders (ASDs) are characterised by impairments in communication and reciprocal social interaction. These impairments can impact on relationships with family members, augment stress and frustration, and contribute to behaviours that can be described as challenging. Family members of individuals with ASD can experience high rates of carer stress and burden, and poor parental efficacy. While there is evidence to suggest that individuals with ASD and family members derive benefit from psychological interventions designed to reduce stress and mental health morbidity, and enhance coping, most studies to date have targeted the needs of either individuals with ASD, or family members. We wanted to examine whether family (systemic) therapy, aimed at enhancing communication, relationships or coping, is effective for individuals with ASD and their wider family network. To evaluate the clinical effectiveness and acceptability of family therapy as a treatment to enhance communication or coping for individuals with ASD and their family members. If possible, we will also seek to establish the economic costs associated with family therapy for this clinical population. On 16 January 2017 we searched CENTRAL, MEDLINE, Embase, 10 other databases and three trials registers. We also handsearched reference lists of existing systematic reviews and contacted study authors in the field. Randomised controlled trials (RCTs) and quasi-RCTs investigating the effectiveness of family therapy for young people or adults with ASD or family members, or both, delivered via any modality and for an unspecified duration, compared with either standard care, a wait-list control, or an active intervention such as an alternative type of psychological therapy. Two authors independently screened each title and abstract and all full-text reports retrieved. To enhance rigour, 25% of these were independently screened by a third author. The search yielded 4809 records. Of these, we retrieved 37 full-text reports for further scrutiny, which we subsequently excluded as they did not meet the review inclusion criteria, and identified one study awaiting classification. Few studies have examined the effectiveness of family therapy for ASD, and none of these are RCTs. Further research studies employing methodologically robust trial designs are needed to establish whether family therapy interventions are clinically beneficial for enhancing communication, strengthening relationships, augmenting coping and reducing mental health morbidity for individuals with ASD and family members.


Synergistic activity of IDH1 inhibitor BAY1436032 with azacitidine in IDH1 mutant acute myeloid leukemia.
Mutant IDH1 (mIDH1) inhibitors have shown single-agent activity in relapsed/refractory AML, though most patients eventually relapse. We evaluated the efficacy and molecular mechanism of the combination treatment with azacitidine, which is currently the standard of care in older AML patients, and mIDH1 inhibitor BAY1436032. Both compounds were evaluated in vivo as single agents and in combination with sequential (azacitidine, followed by BAY1436032) or simultaneous application in two human IDH1 mutated AML xenograft models. Combination treatment significantly prolonged survival compared to single agent or control treatment (P<.005). The sequential combination treatment depleted leukemia stem cells (LSC) by 470-fold. Interestingly, the simultaneous combination treatment depleted LSCs by 33,150-fold compared to control mice. This strong synergy is mediated through inhibition of MAPK/ERK and RB/E2F signaling. Our data strongly argues for the concurrent application of mIDH1 inhibitors and azacitidine and predicts improved outcome of this regimen in IDH1 mutated AML patients.


Bronchogenic cyst and pharyngeal fistular in an 81 year old female: A case report.
Bronchogenic cyst is a rare clinical; entity that occurs due to an anomalous development of the ventral foregut; they are usually single but may be multiple and can be filled with fluid or mucus. They have been found all along the transoesophageal course, in perihilar or intraparenchymal sites, with predilection for the area around the carina. The location of the cyst depends on the embryonic stage of development at which the anomaly occurs. When the abnormal budding occurs during the early development, the cyst tends to be located along the tracheobronchial tree. The cysts that develop later during the late development are more peripheral and may be located within the lung parenchyma. Bronchogenic cysts have also been described in more remote locations, including neck, interatrial septum, abdomen, and retroperitoneal space. Past reports emphasised that a bronchogenic cyst is usually asymptomatic and presents as an incidental finding, but more recent reports suggest that the majority of adults with bronchogenic cysts ultimately become symptomatic. The actual natural history and percentage of asymptomatic bronchogenic cyst in adults are not known because of the absence of long-term follow up of a large group of patients with asymptomatic cyst. Symptomatic patients usually present with symptomatic related to cyst infection or compression of adjacent structures. Presentation in the elderly population is quite rare. It has been reported that approximately 0.6% of such cyst are noted in patients above the age of 60 years. Total documented cases of patients presenting after the age of 70 years have been noted to be only 8 in 2002.


How to optimize OCT image.
Quantization, which maps real values of raw data to a series of fixed gray levels, is an inevitable step in Optical Coherence Tomography (OCT) image formation. Three new quantization methods, Minimum Distortion, Information Expansion and Maximum Entropy are applied in the specific problem. Quantization results of a capillary with milk and the femoralis of rabbit are shown in this paper. Comparisons with the present log-based methods show that a suitable quantization method significantly increases contrast, SNR and visual fineness of the final image and reduces quantization error effectively. Applicability of different quantization methods is also discussed.


Effectiveness of a primary care-based integrated mobile health intervention for stroke management in rural China (SINEMA): A cluster-randomized controlled trial.
Managing noncommunicable diseases through primary healthcare has been identified as the key strategy to achieve universal health coverage but is challenging in most low- and middle-income countries. Stroke is the leading cause of death and disability in rural China. This study aims to determine whether a primary care-based integrated mobile health intervention (SINEMA intervention) could improve stroke management in rural China. Based on extensive barrier analyses, contextual research, and feasibility studies, we conducted a community-based, two-arm cluster-randomized controlled trial with blinded outcome assessment in Hebei Province, rural Northern China including 1,299 stroke patients (mean age: 65.7 [SD:8.2], 42.6% females, 71.2% received education below primary school) recruited from 50 villages between June 23 and July 21, 2017. Villages were randomly assigned (1:1) to either the intervention or control arm (usual care). In the intervention arm, village doctors who were government-sponsored primary healthcare providers received training, conducted monthly follow-up visits supported by an Android-based mobile application, and received performance-based payments. Participants received monthly doctor visits and automatically dispatched daily voice messages. The primary outcome was the 12-month change in systolic blood pressure (BP). Secondary outcomes were predefined, including diastolic BP, health-related quality of life, physical activity level, self-reported medication adherence (antiplatelet, statin, and antihypertensive), and performance in "timed up and go" test. Analyses were conducted in the intention-to-treat framework at the individual level with clusters and stratified design accounted for by following the prepublished statistical analysis plan. All villages completed the 12-month follow-up, and 611 (intervention) and 615 (control) patients were successfully followed (3.4% lost to follow-up among survivors). The program was implemented with high fidelity, and the annual program delivery cost per capita was US$24.3. There was a significant reduction in systolic BP in the intervention as compared with the control group with an adjusted mean difference: -2.8 mm Hg (95% CI -4.8, -0.9; p = 0.005). The intervention was significantly associated with improvements in 6 out of 7 secondary outcomes in diastolic BP reduction (p < 0.001), health-related quality of life (p = 0.008), physical activity level (p < 0.001), adherence in statin (p = 0.003) and antihypertensive medicines (p = 0.039), and performance in "timed up and go" test (p = 0.022). We observed reductions in all exploratory outcomes, including stroke recurrence (4.4% versus 9.3%; risk ratio [RR] = 0.46, 95% CI 0.32, 0.66; risk difference [RD] = 4.9 percentage points [pp]), hospitalization (4.4% versus 9.3%; RR = 0.45, 95% CI 0.32, 0.62; RD = 4.9 pp), disability (20.9% versus 30.2%; RR = 0.65, 95% CI 0.53, 0.79; RD = 9.3 pp), and death (1.8% versus 3.1%; RR = 0.52, 95% CI 0.28, 0.96; RD = 1.3 pp). Limitations include the relatively short study duration of only 1 year and the generalizability of our findings beyond the study setting. In this study, a primary care-based mobile health intervention integrating provider-centered and patient-facing technology was effective in reducing BP and improving stroke secondary prevention in a resource-limited rural setting in China. ClinicalTrials.gov NCT03185858.


Mobilising context as complex and dynamic in evaluations of complex health interventions.
The relationship between healthcare interventions and context is widely conceived as involving complex and dynamic interactions over time. However, evaluations of complex health interventions frequently fail to mobilise such complexity, reporting context and interventions as reified and demarcated categories. This raises questions about practices shaping knowledge about context, with implications for who and what we make visible in our research. Viewed through the lens of case study research, we draw on data collected for the Triple C study (focused on Case study, Context and Complex interventions), to critique these practices, and call for system-wide changes in how notions of context are operationalised in evaluations of complex health interventions. The Triple C study was funded by the Medical Research Council to develop case study guidance and reporting principles taking account of context and complexity. As part of this study, a one-day workshop with 58 participants and nine interviews were conducted with those involved in researching, evaluating, publishing, funding and developing policy and practice from case study research. Discussions focused on how to conceptualise and operationalise context within case study evaluations of complex health interventions. Analysis focused on different constructions and connections of context in relation to complex interventions and the wider social forces structuring participant's accounts. We found knowledge-making practices about context shaped by epistemic and political forces, manifesting as: tensions between articulating complexity and clarity of description; ontological (in)coherence between conceptualisations of context and methods used; and reified versions of context being privileged when communicating with funders, journals, policymakers and publics. We argue that evaluations of complex health interventions urgently requires wide-scale critical reflection on how context is mobilised - by funders, health services researchers, journal editors and policymakers. Connecting with how scholars approach complexity and context across disciplines provides opportunities for creatively expanding the field in which health evaluations are conducted, enabling a critical standpoint to long-established traditions and opening up possibilities for innovating the design of evaluations of complex health interventions.


Longitudinal development of visual working memory precision in childhood and early adolescence.
Visual working memory (VWM) is the ability to hold in mind visual information for brief periods of time. The current study investigated VWM precision development longitudinally. Participants (N = 40, aged 7-11 years) completed delayed reproduction sequential VWM tasks at baseline and two years later. Results show age-related improvement in recall precision on both 1-item and 3-item VWM tasks, suggesting development during childhood and early adolescence in the resolution with which both single and multiple items are stored in VWM. Probabilistic modelling of response distribution data suggests age-related improvement in precision is attributable to a specific decrease in the variability (noisiness) of stored feature representations. This highlights a novel developmental mechanism which may underlie longitudinal improvement in VWM performance, crucially without invoking improvement in the number of items that can be stored. VWM precision provides a sensitive metric with which to track developmental changes longitudinally, shedding light on underlying cognitive mechanisms.


Preclinical evaluation of three polyspecific antivenoms against the venom of Echis ocellatus: Neutralization of toxic activities and antivenomics.
Snakebite envenoming has a heavy burden in the public health in sub-Saharan Africa. The viperid species Echis ocellatus (carpet viper or saw-scaled viper) is the medically most important snake in the savannahs of western sub-Saharan Africa. Several antivenoms are being distributed and used in this region for the treatment of envenomings by E. ocellatus, but the preclinical efficacy of some of these antivenoms has not been assessed. The present study evaluated the preclinical efficacy against E. ocellatus venom of three polyspecific antivenoms: (a) Snake Venom Antiserum (Pan Africa), manufactured by Premium Serums and Vaccines (India); (b) Snake Venom Antiserum (Africa), manufactured by VINS Bioproducts (India); and (c) Antivipmyn(®) Africa, manufactured by Instituto Bioclon (Mexico). Antivenomics analysis revealed the ability of the three antivenoms to immunocapture the majority of components of the venoms of E. ocellatus from Cameroon, Nigeria and Mali, although their maximal immunocapturing capability varied. Bioclon and Premium Serums antivenoms were effective in the neutralization of lethal, hemorrhagic and in vitro coagulant activities of the venom of E. ocellatus from Cameroon, albeit with different potencies. VINS antivenom neutralized hemorrhagic activity of this venom, but failed to neutralize lethality at the highest antivenom dose tested, and had a low neutralizing efficacy against in vitro coagulant effect.


Potential attractants for detecting and removing invading Gambian giant pouched rats (Cricetomys gambianus).
Native to Africa, Gambian giant pouched rats (Gambian rats; Cricetomys gambianus Waterh.) are a threatening invasive species on a Florida island, Grassy Key. Gambian giant pouched rats shifted from a domestic pet to invading species after suspected release from a pet breeder. Because of the large size of Gambian rats (weighing up to 2.8 kg), they pose a serious threat to native species (particularly nesting species) and agricultural crops, especially if Gambian rats invade mainland Florida. Also, Gambian rats pose a threat from disease, as they were implicated in a monkeypox outbreak in the midwestern United States in 2003. The United States Department of Agriculture's Wildlife Services has initiated eradication and detection efforts in the Florida Keys, but trapping the sparse population of Gambian rats has proven difficult. Fifteen attractants that could be used in traps for capturing or detecting single or paired Gambian rats were tested. It was found that conspecific scents (i.e. feces and urine) from other Gambian rats were the best treatment for attracting single and paired Gambian rats. Single Gambian rats explored more attractant types than paired Gambian rats. Effective attractants for use with Gambian rats have been identified, and multiple attractant types should be used to capture or detect the sparse population. It is recommended that mainly urine and feces from Gambian rats be used, but peanut butter, anise, ginger and fatty acid scent could also be useful for attracting the currently small population of Gambian rats on Grassy Key.


Protective responses against skin-dwelling microfilariae of Onchocerca lienalis in severe combined immunodeficient mice.
Inoculation of severe combined immunodeficient (SCID) mice with microfilariae of Onchocerca lienalis results in a sustained infection of the skin, extending for months beyond the point at which the parasites are eliminated from immunocompetent BALB/c controls. Reconstitution of SCID mice with spleen cells, thymocytes, or CD4+-cell-enriched splenocytes from naive BALB/c donors confers the ability to mount a protective immune response, leading to the rapid elimination of microfilariae. High levels of interleukin-5 and low levels of gamma interferon in the sera of reconstituted SCID mice during the destruction of microfilariae suggest that this protective immune response is directed by Th2 lymphocytes, mirroring that observed in immunocompetent controls. Unexpectedly, abbreviation of primary infections of unreconstituted SCID mice with the drug ivermectin induces resistance to reinfection with microfilariae at a level equivalent to that induced in secondarily infected, immunocompetent controls. In contrast to protection mediated by adoptive reconstitution, resistance induced by ivermectin-abbreviated infection occurs in the absence of T cells and in association with negligible levels of serum interleukin-5 and gamma interferon. This points to the activation of some alternative host defense mechanism that operates after the clearance of therapeutic levels of drug. Such a response could have important implications for the treatment of human onchocerciasis and may go some way in explaining the long-term suppression of microfilariae observed in patients after treatment with ivermectin.


Testing multiple substrates for terrestrial biodiversity monitoring using environmental DNA metabarcoding.
Biological surveys based on visual identification of the biota are challenging, expensive and time consuming, yet crucial for effective biomonitoring. DNA metabarcoding is a rapidly developing technology that can also facilitate biological surveys. This method involves the use of next generation sequencing technology to determine the community composition of a sample. However, it is uncertain as to what biological substrate should be the primary focus of metabarcoding surveys. This study aims to test multiple sample substrates (soil, scat, plant material and bulk arthropods) to determine what organisms can be detected from each and where they overlap. Samples (n = 200) were collected in the Pilbara (hot desert climate) and Swan Coastal Plain (hot Mediterranean climate) regions of Western Australia. Soil samples yielded little plant or animal DNA, especially in the Pilbara, probably due to conditions not conducive to long-term preservation. In contrast, scat samples contained the highest overall diversity with 131 plant, vertebrate and invertebrate families detected. Invertebrate and plant sequences were detected in the plant (86 families), pitfall (127 families) and vane trap (126 families) samples. In total, 278 families were recovered from the survey, 217 in the Swan Coastal Plain and 156 in the Pilbara. Aside from soil, 22%-43% of the families detected were unique to the particular substrate, and community composition varied significantly between substrates. These results demonstrate the importance of selecting appropriate metabarcoding substrates when undertaking terrestrial surveys. If the aim is to broadly capture all biota then multiple substrates will be required.


A Qualitative Investigation of Healthcare Engagement Among Young Adult Gay Men in New York City: A P18 Cohort Substudy.
We used in-depth interviews with a cohort of young adult gay men (YAGM) to provide a more detailed understanding of their current healthcare engagement, including experiences with the healthcare system, provider knowledge of healthcare needs, and desired provider characteristics. Qualitative interviews were conducted with a sample of 40 YAGM in New York City. The interview guide examined healthcare engagement across key developmental stages: childhood (birth-12), adolescence (13-18), young adulthood (19-22), and the present (23-26). All transcripts were coded using a consensual qualitative research approach to identify crosscutting topics. The interviews were conducted between September and October 2015. The following topics were identified: experiences with the healthcare system, provider knowledge of healthcare needs, and desired provider characteristics. Common barriers to healthcare access were financial concerns, lack of insurance, and dissatisfaction with the care provided. Reasons for dissatisfaction with care were based on perceptions of providers' anti-gay attitudes, judgment of same-sex sexual behavior, and lack of provider knowledge about YAGM's health needs. This often led men in this study to seek sexual healthcare from providers other than their primary care provider. When asked about desired provider characteristics, participants noted that basic demographics were of less importance than skills-based characteristics such as rapport, comfort discussing sexual health issues, and knowledge of YAGM's health. YAGM have unique challenges to engaging in healthcare, including provider stigma and lack of provider knowledge of YAGM's health needs, which are not faced by other young adult populations. The results from this study highlight the need for more extensive and standardized training in medical school and as part of continuing medical education for healthcare providers.


The fate of Arabidopsis thaliana homeologous CNSs and their motifs in the Paleohexaploid Brassica rapa.
Following polyploidy, duplicate genes are often deleted, and if they are not, then duplicate regulatory regions are sometimes lost. By what mechanism is this loss and what is the chance that such a loss removes function? To explore these questions, we followed individual Arabidopsis thaliana-A. thaliana conserved noncoding sequences (CNSs) into the Brassica ancestor, through a paleohexaploidy and into Brassica rapa. Thus, a single Brassicaceae CNS has six potential orthologous positions in B. rapa; a single Arabidopsis CNS has three potential homeologous positions. We reasoned that a CNS, if present on a singlet Brassica gene, would be unlikely to lose function compared with a more redundant CNS, and this is the case. Redundant CNSs go nondetectable often. Using this logic, each mechanism of CNS loss was assigned a metric of functionality. By definition, proved deletions do not function as sequence. Our results indicated that CNSs that go nondetectable by base substitution or large insertion are almost certainly still functional (redundancy does not matter much to their detectability frequency), whereas those lost by inferred deletion or indels are approximately 75% likely to be nonfunctional. Overall, an average nondetectable, once-redundant CNS more than 30 bp in length has a 72% chance of being nonfunctional, and that makes sense because 97% of them sort to a molecular mechanism with "deletion" in its description, but base substitutions do cause loss. Similarly, proved-functional G-boxes go undetectable by deletion 82% of the time. Fractionation mutagenesis is a procedure that uses polyploidy as a mutagenic agent to genetically alter RNA expression profiles, and then to construct testable hypotheses as to the function of the lost regulatory site. We show fractionation mutagenesis to be a "deletion machine" in the Brassica lineage.


Dropout from exercise programs for seniors: a prospective cohort study.
This study examines dropout incidence, moment of dropout, and switching behavior in organized exercise programs for seniors in the Netherlands, as determined in a prospective cohort study (with baseline measurements at the start of the exercise program and follow-up after 6 months; N = 1,725, response rate 73%). Participants were community-living individuals 50+ who participated in different forms of organized exercise programs. The average dropout incidence was 0.15 per 6 months, which is lower than that for the general population. The dropout incidence and the timing of dropout differed substantially between the exercise programs. In total, 31% of people who dropped out of one type of exercise program switched to another type of exercise. The type of program and exercise had a strong effect on differences in this switching behavior. It is recommended that switching behavior be monitored in future studies.


Presynaptic resurgent Na+ currents sculpt the action potential waveform and increase firing reliability at a CNS nerve terminal.
Axonal and nerve terminal action potentials often display a depolarizing after potential (DAP). However, the underlying mechanism that generates the DAP, and its impact on firing patterns, are poorly understood at axon terminals. Here, we find that at calyx of Held nerve terminals in the rat auditory brainstem the DAP is blocked by low doses of externally applied TTX or by the internal dialysis of low doses of lidocaine analog QX-314. The DAP is thus generated by a voltage-dependent Na(+) conductance present after the action potential spike. Voltage-clamp recordings from the calyx terminal revealed the expression of a resurgent Na(+) current (I(NaR)), the amplitude of which increased during early postnatal development. The calyx of Held also expresses a persistent Na(+) current (I(NaP)), but measurements of calyx I(NaP) together with computer modeling indicate that the fast deactivation time constant of I(NaP) minimizes its contribution to the DAP. I(NaP) is thus neither sufficient nor necessary to generate the calyx DAP, whereas I(NaR) by itself can generate a prominent DAP. Dialysis of a small peptide fragment of the auxiliary β4 Na(+) channel subunit into immature calyces (postnatal day 5-6) induced an increase in I(NaR) and a larger DAP amplitude, and enhanced the spike-firing precision and reliability of the calyx terminal. Our results thus suggest that an increase of I(NaR) during postnatal synaptic maturation is a critical feature that promotes precise and resilient high-frequency firing.


Analysis of México's Narco-War Network (2007-2011).
Since December 2006, more than a thousand cities in México have suffered the effects of the war between several drug cartels, amongst themselves, as well as with Mexican armed forces. Sources are not in agreement about the number of casualties of this war, with reports varying from 30 to 100 thousand dead; the economic and social ravages are impossible to quantify. In this work we analyze the official report of casualties in terms of the location and the date of occurrence of the homicides. We show how the violence, as reflected by the number of casualties, has increased over time and spread across the country. Next, based on the correlations between cities in the changes of the monthly number of casualties attributed to organized crime, we construct a narco-war network where nodes are the affected cities and links represent correlations between them. We find that close geographical distance between violent cities does not imply a strong correlation amongst them. We observe that the dynamics of the conflict has evolved in short-term periods where a small core of violent cities determines the main theatre of the war at each stage. This kind of analysis may also help to describe the emergence and propagation of gang-related violence waves.


First-time imaging of effects of inspired oxygen concentration on regional lung volumes and breathing pattern during hypergravity.
Aeroatelectasis can develop in aircrew flying the latest generation high-performance aircraft. Causes alleged are relative hyperoxia, increased gravity in the head-to-foot direction (+Gz), and compression of legs and stomach by anti-G trousers (AGT). We aimed to assess, in real time, the effects of hyperoxia, +Gz accelerations and AGT inflation on changes in regional lung volumes and breathing pattern evaluated in an axial plane by electrical impedance tomography (EIT). The protocol mimicked a routine peacetime flight in combat aircraft. Eight subjects wearing AGT were studied in a human centrifuge during 1 h 15 min exposure of +1 to +3.5Gz. They performed this sequence three times, breathing AIR, 44.5 % O2 or 100 % O2. Continuous recording of functional EIT enabled uninterrupted assessment of regional lung volumes at the 5th intercostal level. Breathing pattern was also monitored. EIT data showed that +3.5Gz, compared with any moment without hypergravity, caused an abrupt decrease in regional tidal volume (VT) and regional end-expiratory lung volume (EELV) measured in the EIT slice, independently of inspired oxygen concentration. Breathing AIR or 44.5 % O2, sub-regional EELV measured in the EIT slice decreased similarly in dorsal and ventral regions, but sub-regional VT measured in the EIT slice decreased significantly more dorsally than ventrally. Breathing 100 % O2, EELV and VT decreased similarly in both regions. Inspired tidal volume increased in hyperoxia, whereas breathing frequency increased in hypergravity and hyperoxia. Our findings suggest that hypergravity and AGT inflation cause airway closure and air trapping in gravity-dependent lung regions, facilitating absorption atelectasis formation, in particular during hyperoxia.


Medical infrared imaging (thermography) of type I thoracolumbar disk disease in chondrodystrophic dogs.
To: (1) determine the success of medical infrared imaging (MII) in identifying dogs with TLIVDD, (2) compare MII localization with magnetic resonance imaging (MRI) results and surgical findings, and (3) determine if the MII pattern returns to that of normal dogs 10 weeks after decompression surgery. Prospective case series. Chondrodystrophic dogs (n = 58) with Type I TLIVDD and 14 chondrodystrophic dogs with no evidence of TLIVDD. Complete neurologic examination, MII, and MRI studies were performed on all dogs. Dogs with type I TLIVDD had decompressive surgery and follow-up MII was performed at 10 weeks. Pattern analysis software was used to differentiate between clinical and control dogs, and statistical analysis using anatomic regions of interest on the dorsal views were used to determine lesion location. Recheck MII results were compared with control and pre-surgical images. Computer recognition pattern analysis was 90% successful in differentiating normal dogs from dogs affected by TLIVDD and 97% successful in identifying the abnormal intervertebral disc space in dogs with TLIVDD. Statistical comparisons of the ROI mean temperature were unable to determine the location of the disc herniation. Recheck MII patterns did not normalize and more closely resembled the clinical group. MII was 90% successful differentiating between normal dogs and 97% successful in identifying the abnormal intervertebral disc space in dogs with TLIVDD. Abnormal intervertebral disc space localization using ROI mean temperature analysis was not successful. MII patterns 10 weeks after surgery do not normalize.


Cigarette Filter Ventilation and its Relationship to Increasing Rates of Lung Adenocarcinoma.
The 2014 Surgeon General's Report on smoking and health concluded that changing cigarette designs have caused an increase in lung adenocarcinomas, implicating cigarette filter ventilation that lowers smoking machine tar yields. The Food and Drug Administration (FDA) now has the authority to regulate cigarette design if doing so would improve public health. To support a potential regulatory action, two weight-of-evidence reviews were applied for causally relating filter ventilation to lung adenocarcinoma. Published scientific literature (3284 citations) and internal tobacco company documents contributed to causation analysis evidence blocks and the identification of research gaps. Filter ventilation was adopted in the mid-1960s and was initially equated with making a cigarette safer. Since then, lung adenocarcinoma rates paradoxically increased relative to other lung cancer subtypes. Filter ventilation 1) alters tobacco combustion, increasing smoke toxicants; 2) allows for elasticity of use so that smokers inhale more smoke to maintain their nicotine intake; and 3) causes a false perception of lower health risk from "lighter" smoke. Seemingly not supportive of a causal relationship is that human exposure biomarker studies indicate no reduction in exposure, but these do not measure exposure in the lung or utilize known biomarkers of harm. Altered puffing and inhalation may make smoke available to lung cells prone to adenocarcinomas. The analysis strongly suggests that filter ventilation has contributed to the rise in lung adenocarcinomas among smokers. Thus, the FDA should consider regulating its use, up to and including a ban. Herein, we propose a research agenda to support such an effort.


Oldest cingulate skulls provide congruence between morphological and molecular scenarios of armadillo evolution.
The cingulates of the mammalian order Xenarthra present a typical case of disagreement between molecular and morphological phylogenetic studies. We report here the discovery of two new skulls from the Late Oligocene Salla Beds of Bolivia (approx. 26 Ma), which are the oldest known well-preserved cranial remains of the group. A new taxon is described: Kuntinaru boliviensis gen. et sp. nov. A phylogenetic analysis clusters K. boliviensis together with the armadillo subfamily Tolypeutinae. These skulls document an early spotty occurrence for the Tolypeutinae at 26 Ma, in agreement with the temporal predictions of previous molecular studies. The fossil record of tolypeutines is now characterized by a unique occurrence in the Late Oligocene, and a subsequent 12 Myr lack in the fossil record. It is noteworthy that the tolypeutines remain decidedly marginal in the Late Palaeogene and Early Neogene deposits, whereas other cingulate groups diversify. Also, the anatomical phylogenetic analysis herein, which includes K. boliviensis, is congruent with recent molecular phylogenetic analyses. Kuntinaru boliviensis is the oldest confident calibration point available for the whole Cingulata.


The power of single molecule real-time sequencing technology in the de novo assembly of a eukaryotic genome.
Second-generation sequencers (SGS) have been game-changing, achieving cost-effective whole genome sequencing in many non-model organisms. However, a large portion of the genomes still remains unassembled. We reconstructed azuki bean (Vigna angularis) genome using single molecule real-time (SMRT) sequencing technology and achieved the best contiguity and coverage among currently assembled legume crops. The SMRT-based assembly produced 100 times longer contigs with 100 times smaller amount of gaps compared to the SGS-based assemblies. A detailed comparison between the assemblies revealed that the SMRT-based assembly enabled a more comprehensive gene annotation than the SGS-based assemblies where thousands of genes were missing or fragmented. A chromosome-scale assembly was generated based on the high-density genetic map, covering 86% of the azuki bean genome. We demonstrated that SMRT technology, though still needed support of SGS data, achieved a near-complete assembly of a eukaryotic genome.


Oxygen metabolism in human placenta mitochondria.
Due to the high metabolic demands of the placental tissue during gestation, we decide to analyzed the mitochondrial bioenergetic functions in the human term placenta. Different mitochondrial morphological parameters, membrane potential and cardiolipin content were determined by flow cytometry. Oxygen uptake, hydrogen peroxide production and cytochrome P450 content, were also measured. Some apoptotic mitochondrial proteins were also analyzed by western blot. Two isolated mitochondrial fractions were observed: large/heavy and small/light with different functional characteristics. Oxygen uptake showed a respiratory control (RC) of 3.4 ± 0.3 for the heavy mitochondria, and 1.1 ± 0.4 for light mitochondria, indicating a respiratory dysfunction in the light fraction. Good levels of polarization were detected in the heavy fraction, meanwhile the light population showed a collapsed ΔΨm. Increased levels of cytochrome P450, higher levels of hydrogen peroxide, and low cardiolipin content were described for the light fraction. Three pro-apoptotic proteins p53, Bax, and cytochrome c were found increased in the heavy mitochondrial fraction; and deficient in the light fraction. The heavy mitochondrial fraction showed an improved respiratory function. This mitochondrial fraction, being probably from cytotrophoblast cells showed higher content of proteins able to induce apoptosis, indicating that these cells can effectively execute an apoptotic program in the presence of a death stimulus. Meanwhile the light and small organelles probably from syncytiotrophoblast, with a low oxygen metabolism, low level of ΔΨm, and increased hydrogen peroxide production, may not actively perform an apoptotic process due to their deficient energetic level. This study contributes to the characterization of functional parameters of human placenta mitochondria in order to understand the oxygen metabolism during the physiological process of gestation.


The role of C4 metabolism in the marine diatom Phaeodactylum tricornutum.
Diatoms are important players in the global carbon cycle. Their apparent photosynthetic affinity for ambient CO(2) is much higher than that of ribulose 1,5-bisphosphate carboxylase/oxygenase (Rubisco), indicating that a CO(2)-concentrating mechanism (CCM) is functioning. However, the nature of the CCM, a biophysical or a biochemical C(4), remains elusive. Although (14)C labeling experiments and presence of complete sets of genes for C(4) metabolism in two diatoms supported the presence of C(4), other data and predicted localization of the decarboxylating enzymes, away from Rubisco, makes this unlikely. We used RNA-interference to silence the single gene encoding pyruvate-orthophosphate dikinase (PPDK) in Phaeodactylum tricornutum, essential for C(4) metabolism, and examined the photosynthetic characteristics. The mutants possess much lower ppdk transcript and PPDK activity but the photosynthetic K(1/2) (CO(2)) was hardly affected, thus clearly indicating that the C(4) route does not serve the purpose of raising the CO(2) concentration in close proximity of Rubisco in P. tricornutum. The photosynthetic V(max) was slightly reduced in the mutant, possibly reflecting a metabolic constraint that also resulted in a larger lipid accumulation. We propose that the C(4) metabolism does not function in net CO(2) fixation but helps the cells to dissipate excess light energy and in pH homeostasis.


CodonTest: modeling amino acid substitution preferences in coding sequences.
Codon models of evolution have facilitated the interpretation of selective forces operating on genomes. These models, however, assume a single rate of non-synonymous substitution irrespective of the nature of amino acids being exchanged. Recent developments have shown that models which allow for amino acid pairs to have independent rates of substitution offer improved fit over single rate models. However, these approaches have been limited by the necessity for large alignments in their estimation. An alternative approach is to assume that substitution rates between amino acid pairs can be subdivided into rate classes, dependent on the information content of the alignment. However, given the combinatorially large number of such models, an efficient model search strategy is needed. Here we develop a Genetic Algorithm (GA) method for the estimation of such models. A GA is used to assign amino acid substitution pairs to a series of rate classes, where is estimated from the alignment. Other parameters of the phylogenetic Markov model, including substitution rates, character frequencies and branch lengths are estimated using standard maximum likelihood optimization procedures. We apply the GA to empirical alignments and show improved model fit over existing models of codon evolution. Our results suggest that current models are poor approximations of protein evolution and thus gene and organism specific multi-rate models that incorporate amino acid substitution biases are preferred. We further anticipate that the clustering of amino acid substitution rates into classes will be biologically informative, such that genes with similar functions exhibit similar clustering, and hence this clustering will be useful for the evolutionary fingerprinting of genes.


Adaptive clinical trial designs in oncology.
Adaptive designs have become popular in clinical trial and drug development. Unlike traditional trial designs, adaptive designs use accumulating data to modify the ongoing trial without undermining the integrity and validity of the trial. As a result, adaptive designs provide a flexible and effective way to conduct clinical trials. The designs have potential advantages of improving the study power, reducing sample size and total cost, treating more patients with more effective treatments, identifying efficacious drugs for specific subgroups of patients based on their biomarker profiles, and shortening the time for drug development. In this article, we review adaptive designs commonly used in clinical trials and investigate several aspects of the designs, including the dose-finding scheme, interim analysis, adaptive randomization, biomarker-guided randomization, and seamless designs. For illustration, we provide examples of real trials conducted with adaptive designs. We also discuss practical issues from the perspective of using adaptive designs in oncology trials.


An object-relational model for structured representation of medical knowledge.
Domain specific knowledge is often not static but continuously evolving. This is especially true for the medical domain. Furthermore, the lack of standardized structures for presenting knowledge makes it difficult or often impossible to assess new knowledge in the context of existing knowledge. Possibilities to compare knowledge easily and directly are often not given. It is therefore of utmost importance to create a model that allows for comparability, consistency and quality assurance of medical knowledge in specific work situations. For this purpose, we have designed on object-relational model based on structured knowledge elements that are dynamically reusable by different multi-media-based tools for case-based documentation, disease course simulation, and decision support. With this model, high-level components, such as patient case reports or simulations of the course of a disease, and low-level components (e.g., diagnoses, symptoms or treatments) as well as the relationships between these components are modeled. The resulting schema has been implemented in AMOS II, on object-relational multi-database system supporting different views with regard to search and analysis depending on different work situations.


Prospective evaluation of pain, swelling, and disability from copperhead envenomation.
In light of the existing controversy regarding antivenin treatment for copperhead envenomation, a more detailed analysis of the disability from this species is needed. Our objective was to prospectively determine the duration of pain, swelling, and functional disability, i.e., residual venom effects, in patients with copperhead envenomation. Patients with venomous snakebite reported to the North Texas Poison Center between April 2009 and November 2011 were assessed. Patients with confirmed envenomations were contacted by a specialist in poison information. Day zero was the day of the bite and verbal phone consent for study enrollment was obtained at that time. The patient (or their guardian) was contacted by phone daily thereafter, and asked to rate their pain, edema/swelling, and disability using the modified DASH and LEFS scales. Patients were followed to resolution of all symptoms or return to baseline. About 104 cases of venomous snakebite were followed; of which 17 were excluded due to being a dry bites (5) or for having insufficient data during follow-up (11) or due to coagulopathy (1). Overall, residual venom effects from copperhead bites for most patients last between 7 and 13 days. Median time to complete pain resolution was 7 days (mean = 10.7 days). Median length of time to resolution of swelling was 10 days (mean = 13 days) and median length of time to resolution of functional disability was 9 days (mean = 12.2 days). Residual venom effects from copperhead envenomation in this study had a slightly shorter duration than some other studies. Data are skewed due to outliers where residual venom effects lasted for up to 89 days. Initial reoccurrence of some symptoms may be seen. Antivenom (AV) is currently being used for a large percentage of patients with copperhead envenomation. Finally, no differences in duration of venom effects were seen based on age or location of bite. Our study suggests that residual venom effects from copperhead species persist for between 10 and 13 days but may persist for months. Future studies are necessary to identify risk factors for severe/prolonged injury and to define the benefit of AV in patients with copperhead envenomation.


Ethical and societal problems in organ transplantation.
Transplantation medicine, like no other medical specialty, is connected with a wide range of very difficult ethical issues. Among those are: availability of the treatment, consent for cadaveric donation, allocation of available organs, new categories of living unrelated donors and economic aspects of this method of treatment. Authors discuss sensitive aspects in societal perception of the Polish Transplantation Act, ethical issues of living donor kidney transplantation, the role of mass media and economic aspects of transplantation.


SPARX-R computerized therapy among adolescents in youth offenders' program: Step-wise cohort study.
Youth offenders have high rates of unmet mental health needs, including elevated rates of subclinical or clinical depression. Computerized cognitive behavioral therapy (cCBT) has been shown to be effective for depression, and cognitive behavioral therapy (CBT) is among the most effective psychological treatments for offence related behaviours. We planned to evaluate the impact of SPARX-R 1.0 (the first iteration of a revised version of SPARX cCBT) for adolescents in a community day program (Mentoring Youth New Directions or MYND) for male recidivist youth aged between 14 and 17 years. Recruitment and retention in the trial were lower than anticipated. In this brief report we present main findings and discuss implications. We developed a stepwise cohort design to investigate the acceptability and effectiveness of SPARX-R in a complex, real-world setting. Participants were allocated to the MYND program only (treatment as usual), or MYND with the addition of SPARX-R. All adolescents referred to MYND within a specified period were assigned to one of four social workers, as per usual practice. Each social worker was randomized to begin SPARX-R with consenting new clients from one of four time points. Assessments were completed within the first two weeks of commencing the MYND program and then at 10 and 20 weeks after commencement. We solicited brief feedback on SPARX-R from young people and staff who used it. Of 64 eligible youth who began MYND during the trial period, 51 consented but 25 stopped attending MYND despite court orders or because their court orders were changed. Nineteen participants were randomized to SPARX-R but only two completed two or more levels of the 7-level program, so it was not possible to evaluate the impact as planned. The four participants who provided feedback were indifferent or negative about SPARX-R. Staff advised that technical difficulties (such as loading or saving problems) were off putting and that SPARX-R was slow and not appealing to their clients. Computerized CBT was not successfully implemented in this group, highlighting challenges in retention in this non-residential justice program. The findings also indicate that computerized therapies of proven acceptability and effectiveness in one setting may be unappealing in another. Implementation and equity efforts need to consider and test the specialist needs of diverse groups.


Swallow-tail substituted liquid crystalline perylene bisimides: synthesis and thermotropic properties.
Tailor-made synthesis and structure-property relationship of several swallow-tail N-substituted perylene bisimide (PBI) dyes are presented. PBI derivatives were synthesized by two distinct synthetic approaches, the details being evaluated herein. All the PBIs carry either alkyl swallow-tail or oligoethylenglycolether (OEG) swallow-tail moieties as N-substituents, and many of them are unsymmetrically substituted. We avoided substitution at bay positions of the perylene core to maintain the planarity and strong pi-pi interactions, which favor intermolecular order and charge carrier transport. The thermotropic behavior, which is strongly influenced by the nature of the substituents was investigated using differential scanning calorimetry (DSC), polarization optical microscopy (POM), and X-ray diffraction measurements (XRD). The introduction of OEG swallow-tail units facilitates thermotropic liquid crystalline behavior in most cases and the unsymmetrical substitution allowed the tuning of the mesophase-width. The mesophases exhibit characteristic columnar hexagonal (Col(h)) packing arising from pi-pi interactions between cofacially orientated perylene molecules. Thus, the inherent tendency of PBI molecules for crystallization could be effectively suppressed by incorporating flexible OEG swallow-tail units only at imide positions. This molecular design was crucial to obtain liquid crystallinity and intracolumnar long-range order. The substituents did not influence the electronic energy levels such as HOMO and LUMO.


Metabolomics Reveals Cryptic Interactive Effects of Species Interactions and Environmental Stress on Nitrogen and Sulfur Metabolism in Seagrass.
Eutrophication of estuaries and coastal seas is accelerating, increasing light stress on subtidal marine plants and changing their interactions with other species. To date, we have limited understanding of how such variations in environmental and biological stress modify the impact of interactions among foundational species and eventually affect ecosystem health. Here, we used metabolomics to assess the impact of light reductions on interactions between the seagrass Zostera marina, an important habitat-forming marine plant, and the abundant and commercially important blue mussel Mytilus edulis. Plant performance varied with light availability but was unaffected by the presence of mussels. Metabolomic analysis, on the other hand, revealed an interaction between light availability and presence of M. edulis on seagrass metabolism. Under high light, mussels stimulated seagrass nitrogen and energy metabolism. Conversely, in low light mussels impeded nitrogen and energy metabolism, and enhanced responses against sulfide toxicity, causing inhibited oxidative energy metabolism and tissue degradation. Metabolomic analysis thereby revealed cryptic changes to seagrass condition that could not be detected by traditional approaches. Our findings suggest that coastal eutrophication and associated reductions in light may shift seagrass-bivalve interactions from mutualistic to antagonistic, which is important for conservation management of seagrass meadows.


Challenges to peer support in low- and middle-income countries during COVID-19.
A recent editorial urged those working in global mental health to "change the conversation" on coronavirus disease (Covid-19) by putting more focus on the needs of people with severe mental health conditions. UPSIDES (Using Peer Support In Developing Empowering mental health Services) is a six-country consortium carrying out implementation research on peer support for people with severe mental health conditions in high- (Germany, Israel), lower middle- (India) and low-income (Tanzania, Uganda) settings. This commentary briefly outlines some of the key challenges faced by UPSIDES sites in low- and middle-income countries as a result of Covid-19, sharing early lessons that may also apply to other services seeking to address the needs of people with severe mental health conditions in similar contexts. The key take-away from experiences in India, Tanzania and Uganda is that inequalities in terms of access to mobile technologies, as well as to secure employment and benefits, put peer support workers in particularly vulnerable situations precisely when they and their peers are also at their most isolated. Establishing more resilient peer support services requires attention to the already precarious situation of people with severe mental health conditions in low-resource settings, even before a crisis like Covid-19 occurs. While it is essential to maintain contact with peer support workers and peers to whatever extent is possible remotely, alternatives to face-to-face delivery of psychosocial interventions are not always straightforward to implement and can make it more difficult to observe individuals' reactions, talk about emotional issues and offer appropriate support. In environments where mental health care was already heavily medicalized and mostly limited to medications issued by psychiatric institutions, Covid-19 threatens burgeoning efforts to pursue a more holistic and person-centered model of care for people with severe mental health conditions. As countries emerge from lockdown, those working in global mental health will need to redouble their efforts not only to make up for lost time and help individuals cope with the added stressors of Covid-19 in their communities, but also to regain lost ground in mental health care reform and in broader conversations about mental health in low-resource settings.


Recognizing young children with high potential: U-STARS∼PLUS.
Hands-on science is the ideal platform for observing young children's ability to solve problems, think deeply, and use their creative ingenuity to explore the world around them. Science is naturally interesting and offers authentic reasons to read for information and use math skills to collect, compile, and analyze data. This chapter will share one approach to nurturing and recognizing young children with high-potential: U-STARS∼PLUS (Using Science, Talents, and Abilities to Recognize Students∼Promoting Learning for Underrepresented Students). Each of the five components (high-end learning environments; teacher's observations of potential; engaging science activities; partnerships with parents; and capacity building for system change) will be explained. Concrete examples will be given for each area showing how it works and why it is important. Special attention will be paid to the needs of educationally vulnerable gifted children who remain underserved: racially, ethnically, and linguistically different; economically disadvantaged, and children who are twice exceptional (2e).


A Review on Detection and Treatment Methods of Sleep Apnea.
This paper presents a review on detection and treatment methods of sleep apnea. Sleep apnea is the most common type of breathing-related sleep disorder. It manifests in a variety of behaviours from teeth grinding to night terrors as involuntary night-time events. The most common sleep disorders are narcolepsy, hypersomnia, sleep talking, sleep walking, and bedwetting. Sleep apnea (somnipathy) is a serious sleep disorder that pauses breathing while sleeping. Breathing pauses occur 30 times or more during sleep and it lasts for few seconds to minutes, when normal breathing starts after this pause. Untreated sleep apnea patients stop breathing, which happens up to hundreds of times during sleep that ultimately results in atrial fibrillation, cardiac arousal, stroke, brain tumor and other vascular diseases at the age of 65 that causes death. Smokers are at a greater threat for sleep apnea. Several studies have suggested that a person who smokes more than two packs a day has 40 times the risk of sleep apnea then nonsmokers. This review includes the discussion about detection of sleep apnea from heart rate and respiratory events. The published literature of sleep apnea and methods of treatment are also discussed.


Understanding spatial patterns in rape reporting delays.
Under-reporting and delayed reporting of rape crime are severe issues that can complicate the prosecution of perpetrators and prevent rape survivors from receiving needed support. Building on a massive database of publicly available criminal reports from two US cities, we develop a machine learning framework to predict delayed reporting of rape to help tackle this issue. Motivated by large and unexplained spatial variation in reporting delays, we build predictive models to analyse spatial, temporal and socio-economic factors that might explain this variation. Our findings suggest that we can explain a substantial proportion of the variation in rape reporting delays using only openly available data. The insights from this study can be used to motivate targeted, data-driven policies to assist vulnerable communities. For example, we find that younger rape survivors and crimes committed during holiday seasons exhibit longer delays. Our insights can thus help organizations focused on supporting survivors of sexual violence to provide their services at the right place and time. Due to the non-confidential nature of the data used in our models, even community organizations lacking access to sensitive police data can use these findings to optimize their operations.


Ex-vivo liver perfusion for organ preservation: Recent advances in the field.
Liver transplantation is the optimal treatment for end-stage liver disease but is limited by the severe shortage of donor organs. This shortage has prompted increased utilization of marginal grafts from DCD and extended criteria donors, which poorly tolerate cold storage in comparison to standard criteria grafts. Ex-vivo liver perfusion (EVLP) technology has emerged as a potential alternative to cold storage for organ preservation, but there is no consensus regarding the optimal temperature or conditions for EVLP. Herein, we review recent advances in both pre-clinical and clinical studies, organized by perfusion temperature (hypothermic, subnormothermic, normothermic).


Analyzing the effect of APOE on Alzheimer's disease progression using an event-based model for stratified populations.
Alzheimer's disease (AD) is the most common form of dementia and is phenotypically heterogeneous. APOE is a triallelic gene which correlates with phenotypic heterogeneity in AD. In this work, we determined the effect of APOE alleles on the disease progression timeline of AD using a discriminative event-based model (DEBM). Since DEBM is a data-driven model, stratification into smaller disease subgroups would lead to more inaccurate models as compared to fitting the model on the entire dataset. Hence our secondary aim is to propose and evaluate novel approaches in which we split the different steps of DEBM into group-aspecific and group-specific parts, where the entire dataset is used to train the group-aspecific parts and only the data from a specific group is used to train the group-specific parts of the DEBM. We performed simulation experiments to benchmark the accuracy of the proposed approaches and to select the optimal approach. Subsequently, the chosen approach was applied to the baseline data of 417 cognitively normal, 235 mild cognitively impaired who convert to AD within 3 years, and 342 AD patients from the Alzheimers Disease Neuroimaging Initiative (ADNI) dataset to gain new insights into the effect of APOE carriership on the disease progression timeline of AD. In the ε4 carrier group, the model predicted with high confidence that CSF Amyloidβ42 and the cognitive score of Alzheimer's Disease Assessment Scale (ADAS) are early biomarkers. Hippocampus was the earliest volumetric biomarker to become abnormal, closely followed by the CSF Phosphorylated Tau181 (PTAU) biomarker. In the homozygous ε3 carrier group, the model predicted a similar ordering among CSF biomarkers. However, the volume of the fusiform gyrus was identified as one of the earliest volumetric biomarker. While the findings in the ε4 carrier and the homozygous ε3 carrier groups fit the current understanding of progression of AD, the finding in the ε2 carrier group did not. The model predicted, with relatively low confidence, CSF Neurogranin as one of the earliest biomarkers along with cognitive score of Mini-Mental State Examination (MMSE). Amyloid β42 was found to become abnormal after PTAU. The presented models could aid understanding of the disease, and in selecting homogeneous group of presymptomatic subjects at-risk of developing symptoms for clinical trials.


Disordered eating and eating disorders in aquatic sports.
Disordered eating behavior (DE) and eating disorders (EDs) are of great concern because of their associations with physical and mental health risks and, in the case of athletes, impaired performance. The syndrome originally known as the Female Athlete Triad, which focused on the interaction of energy availability, reproductive function, and bone health in female athletes, has recently been expanded to recognize that Relative Energy Deficiency in Sport (RED-S) has a broader range of negative effects on body systems with functional impairments in both male and female athletes. Athletes in leanness-demanding sports have an increased risk for RED-S and for developing EDs/DE. Special risk factors in aquatic sports related to weight and body composition management include the wearing of skimpy and tight-fitting bathing suits, and in the case of diving and synchronized swimming, the involvement of subjective judgments of performance. The reported prevalence of DE and EDs in athletic populations, including athletes from aquatic sports, ranges from 18 to 45% in female athletes and from 0 to 28% in male athletes. To prevent EDs, aquatic athletes should practice healthy eating behavior at all periods of development pathway, and coaches and members of the athletes' health care team should be able to recognize early symptoms indicating risk for energy deficiency, DE, and EDs. Coaches and leaders must accept that DE/EDs can be a problem in aquatic disciplines and that openness regarding this challenge is important.


Improving Pain Management and Long-Term Outcomes Following High-Energy Orthopaedic Trauma (Pain Study).
Poor pain control after orthopaedic trauma is a predictor of physical disability and numerous negative long-term outcomes. Despite increased awareness of the negative consequences of poorly controlled pain, analgesic therapy among hospitalized patients after orthopaedic trauma remains inconsistent and often inadequate. The Pain study is a 3 armed, prospective, double-blind, multicenter randomized trial designed to evaluate the effect of standard pain management versus standard pain management plus perioperative nonsteroidal anti-inflammatory drugs or pregabalin in patients of ages 18-85 with extremity fractures. The primary outcomes are chronic pain, opioid utilization during the 48 hours after definitive fixation and surgery for nonunion in the year after fixation. Secondary outcomes include preoperative and postoperative pain intensity, adverse events and complications, physical function, depression, and post-traumatic stress disorder. One year treatment costs are also compared between the groups.


Does long-term survival exist in pancreatic adenocarcinoma?
We conducted a population-based study to investigate long-term survival in patients diagnosed with a (suspected) pancreatic adenocarcinoma. All patients diagnosed with a pancreatic adenocarcinoma or with a pathologically unverified tumour of the pancreas between 1993 and 2008 in the South of the Netherlands were selected from the Netherlands Cancer Registry (NCR). Medical charts of patients who were alive five years or longer since diagnosis were reviewed. A total of 2 564 patients were included, of whom 1 365 had a pancreatic adenocarcinoma and 1 199 had a pathologically unverified pancreatic tumour. Five-year survival of patients with pathologically verified adenocarcinomas was 1.7% (24 of 1 365 patients). Twenty-one-one of these 24 long-term survivors were among the 207 cases that underwent surgical resection as initial treatment; five-year survival after resection thus being 10.1%. Half of the long-term survivors who underwent surgical resection still eventually died of recurrent disease. Five-year survival among patients with clinically suspected but microscopically unverified pancreatic tumours was 1.3% (16 of 1 199 patients). In 15 of these 16 long-term survivors the initial clinical diagnosis was revised: 14 had benign disease and one a premalignant tumour. Long-term survival among patients with pancreatic adenocarcinoma is extremely rare. As long-term survival in clinically suspected but pathologically unverified cancer is very unlikely, repeated fine needle aspiration or, preferably, histological biopsy is recommended in order to establish an alternative diagnosis in patients who survive longer than expected (more than 6-12 months).


Complement receptor 1 is a sialic acid-independent erythrocyte receptor of Plasmodium falciparum.
Plasmodium falciparum is a highly lethal malaria parasite of humans. A major portion of its life cycle is dedicated to invading and multiplying inside erythrocytes. The molecular mechanisms of erythrocyte invasion are incompletely understood. P. falciparum depends heavily on sialic acid present on glycophorins to invade erythrocytes. However, a significant proportion of laboratory and field isolates are also able to invade erythrocytes in a sialic acid-independent manner. The identity of the erythrocyte sialic acid-independent receptor has been a mystery for decades. We report here that the complement receptor 1 (CR1) is a sialic acid-independent receptor for the invasion of erythrocytes by P. falciparum. We show that soluble CR1 (sCR1) as well as polyclonal and monoclonal antibodies against CR1 inhibit sialic acid-independent invasion in a variety of laboratory strains and wild isolates, and that merozoites interact directly with CR1 on the erythrocyte surface and with sCR1-coated microspheres. Also, the invasion of neuraminidase-treated erythrocytes correlates with the level of CR1 expression. Finally, both sialic acid-independent and dependent strains invade CR1 transgenic mouse erythrocytes preferentially over wild-type erythrocytes but invasion by the latter is more sensitive to neuraminidase. These results suggest that both sialic acid-dependent and independent strains interact with CR1 in the normal red cell during the invasion process. However, only sialic acid-independent strains can do so without the presence of glycophorin sialic acid. Our results close a longstanding and important gap in the understanding of the mechanism of erythrocyte invasion by P. falciparum that will eventually make possible the development of an effective blood stage vaccine.


Absence of BRAF and NRAS mutations in uveal melanoma.
Uveal melanoma (UM) and cutaneous melanoma (CM) differ significantly in their epidemiological, clinical, immunophenotypical, and cytogenetic features, but the molecular basis for these differences has not been delineated. CMs frequently harbor an activating mutation in either NRAS or the RAS-regulated kinase BRAF, suggesting that either of these oncogenes may increase signaling through the mitogen-activated protein (MAP) kinase pathway and promote melanoma development. The aim of this study was to examine BRAF and NRAS gene mutations in UM. Genomic DNA from CM and UM was screened for mutations in BRAF exons 11 and 15 and NRAS exons 1 and 2 using a combination of denaturing high-performance liquid chromatography and direct sequencing. Mutations in BRAF exon 15 were detected in 16 (36.4%) of 44 CMs and 0 (0%) of 62 UMs. The most common mutation in CM was V599E, but a novel point mutation (L596Q) was identified in two cases and an in-frame deletion/insertion (VKSRWK599-604D) was discovered in one case. No BRAF exon 11 mutations were observed among seven CMs and nine UMs that were wild-type for exon 15. Mutation of NRAS exon 2 was rare in CM [1 (3.7%) of 27] and absent in UM [0 (0%) of 47]. No NRAS exon 1 mutations were detected in either type of melanoma. We conclude that UMs arise independent of oncogenic BRAF and NRAS mutations, an observation that may have implications for therapies targeted to the NRAS-BRAF pathway.


Bioremediation in Fractured Rock: 2. Mobilization of Chloroethene Compounds from the Rock Matrix.
A mass balance is formulated to evaluate the mobilization of chlorinated ethene compounds (CE) from the rock matrix of a fractured mudstone aquifer under pre- and postbioremediation conditions. The analysis relies on a sparse number of monitoring locations and is constrained by a detailed description of the groundwater flow regime. Groundwater flow modeling developed under the site characterization identified groundwater fluxes to formulate the CE mass balance in the rock volume exposed to the injected remediation amendments. Differences in the CE fluxes into and out of the rock volume identify the total CE mobilized from diffusion, desorption, and nonaqueous phase liquid dissolution under pre- and postinjection conditions. The initial CE mass in the rock matrix prior to remediation is estimated using analyses of CE in rock core. The CE mass mobilized per year under preinjection conditions is small relative to the total CE mass in the rock, indicating that current pump-and-treat and natural attenuation conditions are likely to require hundreds of years to achieve groundwater concentrations that meet regulatory guidelines. The postinjection CE mobilization rate increased by approximately an order of magnitude over the 5 years of monitoring after the amendment injection. This rate is likely to decrease and additional remediation applications over several decades would still be needed to reduce CE mass in the rock matrix to levels where groundwater concentrations in fractures achieve regulatory standards.


Blood levels of selected hormones in patients with multiple sclerosis.
Hormonal studies in patients with multiple sclerosis are rare and they often produce results which are difficult to interpret. These investigations, however, are becoming more and more important as they may cast some light on possible interrelationships between hormonal and immune systems. The aim of the present work was to investigate endocrine function in patients with multiple sclerosis on the basis of blood levels of selected pituitary (TSH, ACTH, GH) and thyroid hormones (T3, T4), and cortisol. Forty-nine MS subjects, including 25 menstruating women, 6 post-menopausal women and 18 men were included in the analysis. The hormones were measured by radioimmunoassay and immunoradiometric assay kids. Pituitary function in respect of TSH, corticotropin and growth hormone secretion was normal. Both men and women suffering from multiple sclerosis manifested low serum T3 concentrations coexisting with normal T4 levels which may indicate changed peripheral conversion pathway of thyroid hormones. On the other hand, the disturbances in pituitary-adrenal cortex system in respect of glycocorticosteroid secretion were not observed. Normal function in respect to pituitary hormones (TSH, corticotropin, growth hormone) and normal T4 level versus low serum T3 concentration may indicate changes in peripheral conversion pathway of thyroid hormones in MS patients.


Field and laboratory responses of male leaf roller moths, Choristoneura rosaceana and Pandemis pyrusana, to pheromone concentrations in an attracticide paste formulation.
Male leafroller moths, Choristoneura rosaceana (Harris) (Lepidoptera: Tortricidae) and Pandemis pyrusana (Kearfott), were evaluated for responses to a paste formulation loaded with a range of concentrations of the two species' pheromone blends and evaluated in a laboratory wind tunnel and in the field. Response criteria were flight, flight towards the pheromone source, and contact with the pheromone source for the wind tunnel assays, and capture of moths in traps for the field tests. In the wind tunnel and field, responses of males of both species to the paste generally increased as the pheromone concentration in the paste was increased. There was little response by either species to paste with less than 0.16% pheromone. The relationship between pheromone concentration and response for P. pyrusana was linear and for C. rosaceana was sinusoidal over the range of pheromone concentrations tested. These patterns were seen both in the wind tunnel and in the field. Initial release rates from the paste of (Z)-11-tetradecenyl acetate, the main component of the pheromone blends of both species was 3.6-3.8 ng/h. Inhibitory thresholds for responses were not reached for either species, using pheromone concentrations as high as 16%, in either the wind tunnel or the field. For both species, response of males to rubber septa with one mg pheromone loads was similar to the response to the paste with pheromone at concentrations greater than 3-4%. For C. rosaceana, rates of contact with the paste in the wind tunnel were statistically similar to rates of contact in response to conspecific females, with paste pheromone concentrations above 1.6%. Response rates for males of P. pyrusana were significantly lower to the paste than to conspecific females at all paste pheromone concentrations tested. Overall, the optimum pheromone concentration in the paste for moth attraction to contact was 3.2 % for C. rosaceana and 8% for P. pyrusana.


Alignment of Carbon Nanotubes in Carbon Nanotube Fibers Through Nanoparticles: A Route for Controlling Mechanical and Electrical Properties.
This is the first study that describes how semiconducting ZnO can act as an alignment agent in carbon nanotubes (CNTs) fibers. Because of the alignment of CNTs through the ZnO nanoparticles linking groups, the CNTs inside the fibers were equally distributed by the attraction of bonding forces into sheetlike bunches, such that any applied mechanical breaking load was equally distributed to each CNT inside the fiber, making them mechanically robust against breaking loads. Although semiconductive ZnO nanoparticles were used here, the electrical conductivity of the aligned CNT fiber was comparable to bare CNT fibers, suggesting that the total electron movement through the CNTs inside the aligned CNT fiber is not disrupted by the insulating behavior of ZnO nanoparticles. A high degree of control over the electrical conductivity was also demonstrated by the ZnO nanoparticles, working as electron movement bridges between CNTs in the longitudinal and crosswise directions. Well-organized surface interface chemistry was also observed, which supports the notion of CNT alignment inside the fibers. This research represents a new area of surface interface chemistry for interfacially linked CNTs and ZnO nanomaterials with improved mechanical properties and electrical conductivity within aligned CNT fibers.


Industrial and agricultural ammonia point sources exposed.
Through its important role in the formation of particulate matter, atmospheric ammonia affects air quality and has implications for human health and life expectancy1,2. Excess ammonia in the environment also contributes to the acidification and eutrophication of ecosystems3-5 and to climate change6. Anthropogenic emissions dominate natural ones and mostly originate from agricultural, domestic and industrial activities7. However, the total ammonia budget and the attribution of emissions to specific sources remain highly uncertain across different spatial scales7-9. Here we identify, categorize and quantify the world's ammonia emission hotspots using a high-resolution map of atmospheric ammonia obtained from almost a decade of daily IASI satellite observations. We report 248 hotspots with diameters smaller than 50 kilometres, which we associate with either a single point source or a cluster of agricultural and industrial point sources-with the exception of one hotspot, which can be traced back to a natural source. The state-of-the-art EDGAR emission inventory10 mostly agrees with satellite-derived emission fluxes within a factor of three for larger regions. However, it does not adequately represent the majority of point sources that we identified and underestimates the emissions of two-thirds of them by at least one order of magnitude. Industrial emitters in particular are often found to be displaced or missing. Our results suggest that it is necessary to completely revisit the emission inventories of anthropogenic ammonia sources and to account for the rapid evolution of such sources over time. This will lead to better health and environmental impact assessments of atmospheric ammonia and the implementation of suitable nitrogen management strategies.


Gibberellic acid: a growth factor in the unicellular alga Gymnodinium breve.
Gibberellic acid stimulates growth in the unicellular alga Gymnodinium breve (dinoflagellate). The maximum effect was obtained with 10(-7) molar gibberellic acid, whereas concentrations greater than 5 x 10(-7) mole per liter were inhibitory. The effect of the compound is observed as a marked shortening of the lag period, which is normally 6 to 8 days after innoculation.


A distributed representation of internal time.
This article pursues the hypothesis that a scale-invariant representation of history could support performance in a variety of learning and memory tasks. This representation maintains a conjunctive representation of what happened when that grows continuously less accurate for events further and further in the past. Simple behavioral models using a few operations, including scanning, matching and a "jump back in time" that recovers previous states of the history, describe a range of behavioral phenomena. These behavioral applications include canonical results from the judgment of recency task over short and long scales, the recency and contiguity effect across scales in episodic recall, and temporal mapping phenomena in conditioning. A growing body of neural data suggests that neural representations in several brain regions have qualitative properties predicted by the representation of temporal history. Taken together, these results suggest that a scale-invariant representation of temporal history may serve as a cornerstone of a physical model of cognition in learning and memory.


Deletion of vascular endothelial growth factor C (VEGF-C) and VEGF-D is not equivalent to VEGF receptor 3 deletion in mouse embryos.
Lymphatic vessels play an important role in the regulation of tissue fluid balance, immune responses, and fat adsorption and are involved in diseases including lymphedema and tumor metastasis. Vascular endothelial growth factor (VEGF) receptor 3 (VEGFR-3) is necessary for development of the blood vasculature during early embryogenesis, but later, VEGFR-3 expression becomes restricted to the lymphatic vasculature. We analyzed mice deficient in both of the known VEGFR-3 ligands, VEGF-C and VEGF-D. Unlike the Vegfr3(-/-) embryos, the Vegfc(-/-); Vegfd(-/-) embryos displayed normal blood vasculature after embryonic day 9.5. Deletion of Vegfr3 in the epiblast, using keratin 19 (K19) Cre, resulted in a phenotype identical to that of the Vegfr3(-/-) embryos, suggesting that this phenotype is due to defects in the embryo proper and not in placental development. Interestingly, the Vegfr3(neo) hypomorphic mutant mice carrying the neomycin cassette between exons 1 and 2 showed defective lymphatic development. Overexpression of human or mouse VEGF-D in the skin, under the K14 promoter, rescued the lymphatic hypoplasia of the Vegfc(+/-) mice in the K14-VEGF-D; Vegfc(+/-) compound mice, suggesting that VEGF-D is functionally redundant with VEGF-C in the stimulation of developmental lymphangiogenesis. Our results suggest VEGF-C- and VEGF-D-independent functions for VEGFR-3 in the early embryo.


Prostaglandin E2 induces apoptosis in resting immature and mature human lymphocytes: a c-Myc-dependent and Bcl-2-independent associated pathway.
Prostaglandin E2 (PGE2) is a known negative regulator of T lymphocyte proliferation. Previously we have indirectly evidentiated the involvement of PGE2 in apoptosis of lymphocytes both in vitro and in vivo. We have evaluated a possible direct effect of PGE2 on apoptosis. To this end we have investigated the in vitro effects of PGE2 on cell death, and its possible correlation with c-Myc and Bcl-2 proteins. We used freshly isolated unstimulated human lymphocytes from neonatal thymus, cord blood and adult peripheral blood. PGE2 induced DNA fragmentation in both peripheral and cord blood at 10(-7) to 10(-5) M concentrations, even though this induction was delayed in peripheral blood with respect to cord blood. Apoptosis induced by PGE2 was always associated with a dose-dependent increase of cellular steady state c-Myc protein levels, whereas Bcl-2 protein levels were not substantially affected. Unstimulated thymocytes showed spontaneous DNA fragmentation that occurred earlier and at higher levels in PGE2-(10(-5) M) treated cells with respect to untreated controls. Also in these cells, PGE2 produced an early increase of c-Myc protein expression, although Bcl-2 protein levels remained unchanged. In conclusion, PGE2 induces apoptosis with different kinetics on immature and mature T cells: this induction is associated with the increase of c-Myc protein expression and seems to be independent from Bcl-2 regulation.


A mitochondrial encephalomyopathy. A combined 31P magnetic resonance and biochemical investigation.
A 15-year-old girl presented with recurrent encephalopathic episodes, epilepsy, myopathy and chronic lactic acidosis. A muscle biopsy revealed the presence of ragged red fibres and mitochondria with paracrystalline inclusions. Biochemical studies on freshly isolated skeletal muscle mitochondria demonstrated a deficiency of NADH-CoQ reductase activity. Investigation of her gastrocnemius muscle at rest by phosphorus nuclear magnetic resonance displayed a reduced phosphocreatine concentration with elevated levels of inorganic phosphate and ADP. Abnormalities were also apparent in her brain spectrum. It is therefore possible that the mitochondrial defect present in skeletal muscle is also being expressed in the brain.


Trends in cerebral palsy among infants of very low birthweight (<1500 g) or born prematurely (<32 weeks) in 16 European centres: a database study.
The risk of cerebral palsy, the commonest physical disability of children in western Europe, is higher in infants of very low birthweight (VLBW)--those born weighing less than 1500 g--and those from multiple pregnancies than in infants of normal birthweight. An increasing proportion of infants from both of these groups survive into childhood. This paper describes changes in the frequency and distribution of cerebral palsy by sex and neurological subtype in infants with a birthweight below 1000 g and 1000-1499 g in the period 1980-96. A group of 16 European centres, Surveillance of Cerebral Palsy in Europe, agreed a standard definition of cerebral palsy and inclusion and exclusion criteria. Data for children with cerebral palsy born in the years 1980-96 were pooled. The data were analysed to describe the distribution and prevalence of cerebral palsy in VLBW infants. Prevalence trends were expressed as both per 1000 livebirths and per 1000 neonatal survivors. There were 1575 VLBW infants born with cerebral palsy; 414 (26%) were of birthweight less than 1000 g and 317 (20%) were from multiple pregnancies. 1426 (94%) had spastic cerebral palsy, which was unilateral (hemiplegic) in 336 (24%). The birth prevalence fell from 60.6 (99%CI 37.8-91.4) per 1000 liveborn VLBW infants in 1980 to 39.5 (28.6-53.0) per 1000 VLBW infants in 1996. This decline was related to a reduction in the frequency of bilateral spastic cerebral palsy among infants of birthweight 1000-1499 g. The frequency of cerebral palsy was higher in male than female babies in the group of birthweight 1000-1499 g (61.0 [53.8-68..2] vs 49.5 [42.8-56.2] per 1000 livebirths; p=0.0025) but not in the group of birthweight below 1000 g. These data from a large population base provide evidence that the prevalence of cerebral palsy in children of birthweight less than 1500 g has fallen, which has important implications for parents, health services, and society.


Protective effects of erythropoietin and N-acetylcysteine on methotrexate-induced lung injury in rats.
Methotrexate (MTX) is known to have deleterious side effects on lung tissue. We aimed to investigate the effects of erythropoietin (EPO) and N-acetyl-cysteine (NAC) on MTX-induced lung injury in rats. Animal experiment. Twenty-six female Sprague-Dawley rats were divided into 4 groups. Sham group, 0.3 mL saline; MTX group, 5 mg/kg MTX; EPO group, 5mg/kg MTX and 2000 IU/kg EPO; NAC group, 5 mg/kg MTX and 200 mg/kg NAC were administered once daily for 4 consecutive days. Malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT) and inflammation and congestion scores in lung tissues were evaluated. In MTX group MDA were significantly higher, CAT and SOD were significantly lower than in sham, EPO and NAC groups (p<0.005). In EPO group MDA, CAT, and SOD were higher, but not significant than those in group NAC (p>0.005). In group MTX both scores were significantly higher than in sham (p<0.005). The congestion score of group MTX was significantly higher than those of group EPO and NAC (p<0.005). EPO and NAC have significant preventive effects on MTX-induced lung injury in rats. Decreased antioxidant capacity and increased MDA level may cause the oxidative damage in MTX group. Also, higher antioxidant capacity and lower MDA level may be a response to oxidative stress in EPO and NAC groups.


A field investigation of hearing protection and hearing enhancement in one device: for soldiers whose ears and lives depend upon it.
Operational hearing protection and maintenance of audibility of signals and speech are considered force multipliers in military operations, increasing Soldier survivability and lethality. The in-field research described in this paper was conducted to examine operational performance effects of three different hearing enhancement protection systems (HEPS) that are intended to provide both protection and audibility. The experiment utilized operationally-defined measures in full-scale, simulated combat scenarios with Army ROTC Cadet Soldiers as subjects. The Soldiers' operational performance was evaluated in two missions: reconnaissance and raid (attack on enemy camp). Both missions had substantial hearing requirements, including communications, signal detection/recognition, and distance judgments. Operational performance was measured by objective metrics of Squad performance, including the distances required to detect an enemy insurgent camp under each HEPS, and by subjective metrics, such as the Army's dimensions of combat-related mission success as evaluated by Army Officers who served as training leaders/observers. Other subjective ratings were obtained after each training exercise from both the Officers and the Soldiers, including detailed impressions about each HEPS after extended use. Two of the three HEPS were electronic sound transmission devices (comprising an ambient sound pass-through filtering and amplification circuit): a Peltor Comtac II circumaural headset (NRR=21; 16 dB maximum gain); and a Communications Enhancement Protection System (CEPS) (NRR=29; 36 dB maximum gain). One passive, level-dependent HEPS was used, the yellow end of the Combat Arms Earplug, which provides amplitude-sensitive attenuation that sharply increases when the ambient sound is above about 110 dB (e.g., due to a gunshot), but which provides an NRR of 0 and very little attenuation below 1000 Hz in lower ambient noise levels. In the military mission entailing location of and attack on an enemy camp, the CEPS device resulted in the longest (earliest) average auditory detection distance of the camp (400 feet), followed by the Peltor (233 feet) and then the Combat Arms Earplug (150 feet), in comparison to detection by the unprotected, normal ear at about 220 feet. Commanding officers' ratings of mission performance and overall success slightly favored the electronic HEPS, but these ratings were dependent upon the particular mission undertaken. Ergonomics and usability issues abounded with the electronic HEPS, and the Soldiers' subjective ratings showed variability across all three devices, with device preference depending upon the particular dimension being rated (e.g., comfort vs. hearing ability). Clearly, the results of this in-field experiment demonstrate that more development is needed to achieve the levels of hearing performance and user acceptance from the HEPS that is desirable and needed for combat conditions. In this vein, it is important to note that HEPS designs are continually evolving, and certain upgrades to the three devices evaluated in the late 2006 timeframe of this study have occurred and further evaluations are thus warranted.


Rate Control Yields Better Clinical Outcomes Over a Median Follow-Up of 20 Months Compared to Rhythm Control Strategy in Patients With a History of Atrial Fibrillation: A Retrospective Cohort Study.
Clinical management of patients with a history of atrial fibrillation (AF) focuses on the goal of preventing AF recurrences, or, if this is impossible due to the fact that the arrhythmia has by now become permanent, it is aimed at the control of the ventricular response. In patients with AF, an important topic is the comparative evaluation in the mid/long-term of clinical outcomes arising from the various therapeutic regimens, including pharmacological approaches as well as radiofrequency catheter ablation (abl). In the present cohort retrospective study, 175 cases of paroxysmal, persistent or long-lasting persistent AF have been grouped depending on therapeutic approach: abl-isolated or followed by chronic use of antiarrhythmics (74 cases), drug treatment for rate control strategy (60 cases), drug treatment for rhythm control strategy (41 cases). The effects respectively exerted by the three treatment modalities on the primary endpoint, namely a composite of death, disabling stroke, severe bleeding and cardiac arrest , have been compared through a median follow-up of 20 months (interquartile range = 18 - 24 months) using the Cox proportional-hazards regression analysis. As documented by the Cox model, an increased risk of the primary composite endpoint was associated with the rhythm control strategy, as well as with the AF recurrences during the follow-up (for the former, hazard ratio (HR): 3.3159, 95% CI: 1.5415 to 7.1329, P = 0.0023; for the latter, HR: 1.0448, 95% CI: 1.0020 to 1.0895, P = 0.0410). Even hypertension was associated with an increased risk (HR: 1.1040; 95% CI: 1.0112 to 1.9662; P = 0.0477). On the contrary, a rate control strategy predicted a decreased risk of experiencing the primary endpoint (HR: 0.0711; 95% CI: 0.0135 to 0.3738; P = 0.0019) while abl did not exert a statistically significant effect on the same outcome. AF abl decreases the arrhythmic episodes but does not provide a statistically significant protection against the composite of death, disabling stroke, major bleeding and cardiac arrest after a 20-month follow-up. Moreover, in patients with a history of AF, rate control compared to rhythm control strategy provides better clinical outcomes over a mid-term follow-up.