[Association between heart rate and all-cause death and coronary event in the Chinese cohort: 16 years follow up results].
To evaluate the association between resting heart rate (HR) and all-cause death and coronary heart disease (CHD) events in the Chinese cohort. Data were obtained from the PRC-USA Cooperative Study on Cardiovascular and Cardiopulmonary Epidemiology. Baseline screen surveys were conducted in 1983 and 1984 from people aged 35 to 59 years living in urban or rural areas of Beijing and Guangzhou. Follow-up visits were performed for end point events of all-cause death and first CHD events every two years till 2005. Resting HR was determined from 5 consecutive intervals between R waves on the 12-lead electrocardiogram. A total of 9856 (4805 males) people were included in the study and the mean follow up duration was 16.2 years. There were 1523 deaths, including 200 CHD events during the follow up period. Mean resting HR was 67.9 beat per minute (bpm) in men and 71.6 bpm in women respectively which had a trend to increase with aging. Cox Proportional Hazards model indicated the relative risk of all-cause death increased constantly with the increase of HR percentile after control of age, fasting glucose, serum cholesterol, serum triglyceride, body mass index, systolic blood pressure and diastolic blood pressure. With HR 60-89 bpm as control group, the relative risk and 95% confidence interval in group HR < 50 bpm, 50 - 59 bpm, 90 - 99 bpm and > or = 100 bpm were 0.76 (0.49 - 1.17), 0.87 (0.75 - 1.02), 1.33 (1.06 - 1.68), 1.48 (1.03 - 2.14) respectively. However there was no significant correlation between HR and CHD events in studied population. The risk of total death increased significantly in people with HR > or = 90 bpm suggesting higher resting heart rate might be an independent risk factor for all-cause death in the Chinese population.


Estimated blood alcohol concentrations achieved by consuming supersized alcopops.
Producers of supersized alcopops have ignored requests from a number of state attorneys general to reduce the alcohol concentration in these products. To the contrary, new flavor options have since been released that contain even greater alcohol content so that some alcopop products now contain 5.5 standard alcoholic drinks in a single-serving can. Though alcohol content of supersized alcopops has risen, little attention has been paid to the blood alcohol concentration (BAC) level consumers can expect to achieve from drinking these products. To estimate BAC levels expected from consuming one or two cans of supersized alcopop, relative to beer. Median weight data from the National Health and Nutrition Examination Survey were used in Matthews and Miller's (1979) BAC estimation formula. Consuming a single supersized alcopop over the course of 2 hours can put youth and young adults well over the legal per se driving limit of 0.08 g/dL. Consuming two cans puts them at risk of alcohol poisoning. Estimates provided here show that supersized alcopop consumers obtain dangerously high BAC levels. Reductions in the alcohol content of supersized alcopops should be an urgent priority for public health policy and law.


Effect of phosphate-buffered sucrose flush solution upon the initial phase of ischaemic acute renal failure in the rat.
1. Experiments were performed upon anaesthetized rats to investigate the effect upon the initial 4 h of ischaemic acute renal failure of intrarenal flush with phosphate buffer (PB), sucrose alone and phosphate-buffered sucrose (PBS) solutions of differing compositions. 2. Kidneys flushed with PB immediately before 45 min pedicle clamp ischaemia exhibited a post-ischaemic function similar to that of control, non-flushed kidneys: they were isosthenuric and non-oliguric with a clearance of inulin (Cin) depressed to 10% of the pre-ischaemic value. 3. Kidneys flushed with 50 mmol/l sucrose in saline before ischaemia became isosthenuric, oliguric and had a more severely depressed post-ischaemic Cin compared with non-flushed kidneys. 4. Kidneys flushed with PBS containing either 50 (PBS50) or 140 (PBS140) mmol/l sucrose at pH 7 became polyuric after ischaemia, produced concentrated urine and had Cin values significantly higher than control kidneys. 5. Raising the pH of the PBS50 to 7.4 resulted in isosthenuric, polyuric kidneys that had a post-ischaemic Cin not significantly different from that of the control group. 6. It is concluded that the severity of the initial phase of ischaemic acute renal failure was significantly reduced by intrarenal flush with a PBS solution of pH 7; flush with PB or sucrose alone had no protective action.


Infection and medication-related osteonecrosis of the jaw.
Medication-related osteonecrosis of the jaw (MRONJ), although initially believed to be exclusively associated with bisphosphonates, has been implicated in recent reports with additional drugs, especially the bone antiresorptive denosumab. The pathophysiology has not been fully elucidated, and no causal association between bone antiresorptive regimens and MRONJ has yet been established. However, reduced bone turnover and infection, an almost universal finding, are thought to be central to the pathogenesis of MRONJ. Both bisphosphonates and denosumab, through different pathways of action, significantly reduce the rate of bone turnover and potentially reduce the efficacy of the host defense against infection. Recent evidence questions the simplified etiology of low bone turnover causing MRONJ and offers evidence on the prominent role of infection instead. The management of MRONJ remains a significant clinical challenge, with little progress having been made on treatment. The aim of this article is to explore the current theories on the etiology of MRONJ and to emphasize the importance of infection in the development of this devastating pathology.


Hofmeister effect of anions on calcium translocation by sarcoplasmic reticulum Ca(2+)-ATPase.
The occurrence of Hofmeister (specific ion) effects in various membrane-related physiological processes is well documented. For example the effect of anions on the transport activity of the ion pump Na(+), K(+)-ATPase has been investigated. Here we report on specific anion effects on the ATP-dependent Ca(2+) translocation by the sarcoplasmic reticulum Ca(2+)-ATPase (SERCA). Current measurements following ATP concentration jumps on SERCA-containing vesicles adsorbed on solid supported membranes were carried out in the presence of different potassium salts. We found that monovalent anions strongly interfere with ATP-induced Ca(2+) translocation by SERCA, according to their increasing chaotropicity in the Hofmeister series. On the contrary, a significant increase in Ca(2+) translocation was observed in the presence of sulphate. We suggest that the anions can affect the conformational transition between the phosphorylated intermediates E1P and E2P of the SERCA cycle. In particular, the stabilization of the E1P conformation by chaotropic anions seems to be related to their adsorption at the enzyme/water and/or at the membrane/water interface, while the more kosmotropic species affect SERCA conformation and functionality by modifying the hydration layers of the enzyme.


Characterization of clustered MHC-linked olfactory receptor genes in human and mouse.
Olfactory receptor (OR) loci frequently cluster and are present on most human chromosomes. They are members of the seven transmembrane receptor (7-TM) superfamily and, as such, are part of one of the largest mammalian multigene families, with an estimated copy number of up to 1000 ORs per haploid genome. As their name implies, ORs are known to be involved in the perception of odors and possibly also in other, nonolfaction-related, functions. Here, we report the characterization of ORs that are part of the MHC-linked OR clusters in human and mouse (partial sequence only). These clusters are of particular interest because of their possible involvement in olfaction-driven mate selection. In total, we describe 50 novel OR loci (36 human, 14 murine), making the human MHC-linked cluster the largest sequenced OR cluster in any organism so far. Comparative and phylogenetic analyses confirm the cluster to be MHC-linked but divergent in both species and allow the identification of at least one ortholog that will be useful for future regulatory and functional studies. Quantitative feature analysis shows clear evidence of duplications of blocks of OR genes and reveals the entire cluster to have a genomic environment that is very different from its neighboring regions. Based on in silico transcript analysis, we also present evidence of extensive long-distance splicing in the 5'-untranslated regions and, for the first time, of alternative splicing within the single coding exon of ORs. Taken together with our previous finding that ORs are also polymorphic, the presented data indicate that the expression, function, and evolution of these interesting genes might be more complex than previously thought.


Partner age differences and associated sexual risk behaviours among adolescent girls and young women in a cash transfer programme for schooling in Malawi.
Age disparities in sexual relationships have been proposed as a key risk factor for HIV transmission in Sub-Saharan Africa, but evidence remains inconclusive. The SIHR study, a cluster randomised trial of a cash transfer programme in Malawi, found that young women in the intervention groups were less likely to have had a sexual partner aged 25 or older, and less likely to test positive for HIV and HSV-2 at follow-up compared to control groups. We examined the hypotheses that girls in the intervention groups had smaller age differences than control groups and that large age differences were associated with relationship-level HIV transmission risk factors: inconsistent condom use, sex frequency, and relationship duration. We conducted an analysis of schoolgirls in the Schooling, Income, and Health Risk (SIHR) study aged 13-22 at baseline (n = 2907). We investigated the effects of study arm, trial stage and participant age on age differences in sexual relationships using a linear mixed-effects model. Cumulative-link mixed-effects models were used to estimate the effect of relationship age difference on condom use and sex frequency, and a Cox proportional hazard model was used to estimate the effect of relationship age difference on relationship duration. We controlled for the girl's age, number of partners, study group and study round. Girls receiving cash transfers, on average, had smaller age differences in relationships compared to controls, though the estimated difference was not statistically significant (- 0.43 years; 95% CI: -1.03, 0.17). The older the participant was, the smaller her age differences (- 0.67 per 4-year increase in age; 95% CI: -0.99, - 0.35). Among controls, after the cash transfers had ended the average age difference was 0.82 years larger than during the intervention (95% CI: 0.43, 1.21), suggesting a possible indirect effect of the study on behaviour in the community as a whole. Across treatment groups, larger age differences in relationships were associated with lower levels of condom use, more frequent sex, and longer relationship durations. Cash-transfer programmes may prevent HIV transmission in part by encouraging young women to form age-similar relationships, which are characterised by increased condom use and reduced sex frequency. The benefits of these programmes may extend to those who are not directly receiving the cash.


Bariatric surgery for people with diabetes and morbid obesity: an evidence-based analysis.
In June 2008, the Medical Advisory Secretariat began work on the Diabetes Strategy Evidence Project, an evidence-based review of the literature surrounding strategies for successful management and treatment of diabetes. This project came about when the Health System Strategy Division at the Ministry of Health and Long-Term Care subsequently asked the secretariat to provide an evidentiary platform for the Ministry's newly released Diabetes Strategy.After an initial review of the strategy and consultation with experts, the secretariat identified five key areas in which evidence was needed. Evidence-based analyses have been prepared for each of these five areas: insulin pumps, behavioural interventions, bariatric surgery, home telemonitoring, and community based care. For each area, an economic analysis was completed where appropriate and is described in a separate report.To review these titles within the Diabetes Strategy Evidence series, please visit the Medical Advisory Secretariat Web site, http://www.health.gov.on.ca/english/providers/program/mas/masabout.html,DIABETES STRATEGY EVIDENCE PLATFORM: Summary of Evidence-Based AnalysesContinuous Subcutaneous Insulin Infusion Pumps for Type 1 and Type 2 Adult Diabetics: An Evidence-Based AnalysisBehavioural Interventions for Type 2 Diabetes: An Evidence-Based AnalysisBARIATRIC SURGERY FOR PEOPLE WITH DIABETES AND MORBID OBESITY: An Evidence-Based SummaryCommunity-Based Care for the Management of Type 2 Diabetes: An Evidence-Based AnalysisHome Telemonitoring for Type 2 Diabetes: An Evidence-Based AnalysisApplication of the Ontario Diabetes Economic Model (ODEM) to Determine the Cost-effectiveness and Budget Impact of Selected Type 2 Diabetes Interventions in Ontario The purpose of this evidence-based analysis was to examine the effectiveness and cost-effectiveness of bariatric surgery for the management of diabetes in morbidly obese people. This report summarized evidence specific to bariatric surgery and the improvement of diabetes from the full evidence-based analysis of bariatric surgery for the treatment of morbid obesity completed by the Medical Advisory Secretariat (MAS) in January 2005. To view the full report, please visit the MAS website at: http://www.health.gov.on.ca/english/providers/program/mas/tech/techmn.html. CONDITION AND TARGET POPULATION Obesity is defined as an excessive accumulation of body fat as measured by the body mass index (BMI) and calculated as body weight in kilograms (kg) divided by height in metres squared (m(2)). People with a BMI over 30 kg/m(2) are considered obese in most countries. The condition is associated with the development of several diseases, including hypertension, diabetes mellitus (type 2 diabetes), hyperlipidemia, coronary artery disease, obstructive sleep apnea, depression, and cancers of the breast, uterus, prostate, and colon. Clinically severe, or morbid obesity, is commonly defined by a BMI of at least 40 kg/m(2), or a BMI of at least 35 kg/m(2) if there are comorbid conditions such as diabetes, cardiovascular disease, or arthritis. The prevalence of morbid obesity among people with type 2 diabetes has been examined and of 2,460 patients with type 2 diabetes, 52% (n = 1,279) were obese (BMI ≥ 30 kg/m(2)) and 23% (n = 561) had a BMI ≥ 35 kg/m(2). BARIATRIC SURGERY: Men and women with morbid obesity may be eligible for surgical intervention. There are numerous surgical options available, all of which can be divided into two general types, both of which can be performed either as open surgery or laparoscopically: malabsorptive - bypassing parts of the gastrointestinal tract to limit the absorption of food, andrestrictive - decreasing the size of the stomach in order for the patient to feel satiated with a smaller amount foodSurgery for morbid obesity is usually considered a last resort for people who have attempted first-line medical management (e.g. diet, behaviour modification, increased physical activity, and drugs) but who have not lost weight permanently. Surgery is restricted to people with morbid obesity (BMI ≥ 40 kg/m(2)) or those with a BMI of at least 35 kg/m(2) and serious comorbid conditions. Details of the full literature search can be found in the 2005 evidence-based analysis of bariatric surgery (http://www.health.gov.on.ca/english/providers/program/mas/tech/techmn.html). Briefly, a literature search was conducted examining published works from January 1996 to December 2004, including OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), The Cochrane Library, and the International Agency for Health Technology Assessment/Centre for Review and Dissemination. Data on the effectiveness or cost-effectiveness of bariatric surgery for the improvement of diabetesSystematic reviews, randomized controlled trials (RCTs), and observational controlled prospective studies that had >100 patientsRandomized controlled trials (RCTs), systematic reviews and meta-analyses Duplicate publications (superseded by another publication by the same investigator group, with the same objective and data)Non-English-language articlesNon-systematic reviews, letters, and editorialsAnimal and in-vitro studiesCase reports, case seriesStudies that did not examine the outcomes of interest Improvement or resolution of diabetesThe quality of the studies was examined according to the GRADE Working Group criteria for grading quality of evidence. There is evidence that bariatric surgery is effective for improvement and resolution of diabetes in patients who are morbidly obese (BMI≥35 kg/m(2)). The quality of evidence for the use of bariatric surgery for the resolution or improvement of diabetes in morbidly obese people, according to the GRADE quality-of-evidence criteria, was found to be moderate (see ES Table 1). Comparison of various bariatric techniques: No prospective, long-term direct comparison is available between malabsorptive and restrictive techniques.Retrospective subgroup analyses from a large observational study showed greater improvement and resolution of diabetes using malabsorptive techniques rather than purely restrictive methods.There is evidence from a meta-analysis that malabsorptive techniques are better than other banding techniques in terms of improvement and resolution of diabetes. Bariatric surgery, morbid obesity, comorbidity, diabetes ES Table 1:GRADE Quality of Evidence for Bariatric Surgery for the Resolution or Improvement of DiabetesOutcomeQuality AssessmentSummary of FindingsDesignQualityConsistencyDirectnessOtherNo. of PatientsEffectQualityImprovement in HbA1c indiabetic and glucoseintolerant patientsMeta-analysisModerate*ConsistentDirectNonen=171-2.70% (-5.0% to -0.70%)weighted mean change(range)ModerateResolution or improvement of diabetes(Studies reporting combinationas well as studies that only usedthe term "improved", but not thestudies reporting only resolution)Meta-analysisModerate*ConsistentDirectNone414/485(n resolved orimproved/nevaluated)86.0% (78.4% to 93.7%)mean% (95% CI)ModerateResolution of diabetes(diabetes disappeared or nolonger required therapy)Meta-analysisModerate*ConsistentDirectNone1417/1846(n resolved/nevaluated)76.8% (70.7% to 82.9%)mean% (95% CI)ModerateRecovery of diabetes(fasting plasma glucose level ofless than 126 mg per decilitre[7.0 mmol per litre])Observationalprospectivecontrolled studyModerate*ConsistentSomeuncertainty(†)Someuncertainty(‡)control n=84intervention n=1183.45 (1.64 to 7.28)OR (95% CI) at 10 yrsModerate*Downgraded due to study design (not randomized controlled trial)†Unlikely to be an important uncertainty. Inclusion criteria for the SOS study not specific to conventional definition of "morbidly obese" patients (BMI ≥ 40 or ≥ 35 kg/m(2) with comorbid conditions)‡Unlikely to be an important uncertainty. Control group not standardized, however, this lends to the pragmatic nature of the study.


Cytochromes P450 reconstituted with NADPH: P450 reductase mimic the activating and detoxicating metabolism of the anticancer drug ellipticine in microsomes.
Ellipticine is a potent antineoplastic agent exhibiting multiple action mechanisms. Recently, we found that after cytochrome P450 (CYP)-mediated oxidation ellipticine forms covalent DNA adducts. Ellipticine oxidation by isolated CYP and its binding to DNA is the target of this study. High performance liquid chromatography (HPLC) was employed for separation and characterization of ellipticine metabolites generated by CYPs. The (32)P-postlabeling technique was utilized to determine ellipticine-DNA adducts. Purified CYP enzymes reconstituted with NADPH:CYP reductase oxidized ellipticine to up to five metabolites, 7-hydroxy-, 9-hydroxy-, 12-hydroxy-, 13-hydroxyellipticine and ellipticine N(2)-oxide. However, only CYP1A1 was capable to form all metabolites. Using the reconstituted enzymatic system, we demonstrated that the detoxication ellipticine metabolites, 7-hydroxyellipticine and 9-hydroxyellipticine, are mainly generated by CYP1A1 and 1A2, while those responsible for DNA binding, 13-hydroxy-, 12-hydroxyellipticine and ellipticine N(2)-oxide, by CYP3A1 and 2C3. Likewise, the most efficient CYPs forming DNA adducts from ellipticine were CYP3A1 and 2C3. The results showed that the system of purified CYPs reconstituted with NADPH: CYP reductase proved for ellipticine oxidation provide a true reflection of the situation in the microsomal membrane.


A neotropical snail host of Schistosoma mansoni introduced into Africa and consequences for the schistosomiasis transmission Biomphalaria tenagophila in Kinshasa (Democratic Republic of Congo).
Malacological surveys carried out in the early 1970s in water bodies of the Kinshasa area, Lower Zaire (Democratic Republic of Congo), showed the appearance of a Biomphalaria species which was identified as Biomphalaria camerunensis. In 1976, other surveys confirmed the presence of the species in several sites and showed numerous infected snails with Schistosoma mansoni, demonstrating for the first time an active transmission of the parasite responsible of the intestinal schistosomiasis in this area. The most recent malacological sampling was carried out by one of us in 1994 in Mangungu River and revealed the presence of apparently the same snail species. However, conchological, anatomical and molecular studies showed that this snail may be considered as an introduced neotropical species, B. tenagophila. To our knowledge, this is the second example of the introduction of a neotropical snail host of schistosomes into Africa.


Tcrd Rearrangement Redirects a Processive Tcra Recombination Program to Expand the Tcra Repertoire.
Adaptive immunity depends on diverse T cell receptor repertoires generated by variable, diversity, and joining (V[D]J) recombination. Here, we define the principles by which combinatorial diversity is generated in the murine Tcra repertoire. Tcra and Tcrd gene segments share the Tcra-Tcrd locus, with interspersed Vα and Vδ segments undergoing Vδ-Dδ-Jδ rearrangement in CD4-CD8- thymocytes and then multiple rounds of Vα-Jα rearrangement in CD4+CD8+ thymocytes. We document stepwise, highly coordinated proximal-to-distal progressions of Vα and Jα use on individual Tcra alleles, limiting combinatorial diversity. This behavior is supported by an extended chromatin conformation in CD4+CD8+ thymocytes, with only nearby Vα and Jα segments contacting each other. Tcrd rearrangements can use distal Vδ segments due to a contracted Tcra-Tcrd conformation in CD4-CD8- thymocytes. These rearrangements expand the Tcra repertoire by truncating the Vα array to permit otherwise disfavored Vα-Jα combinations. Therefore, recombination events at two developmental stages with distinct chromatin conformations synergize to promote Tcra repertoire diversity.


Student acceptability of high-stakes e-assessment in dental education: using privacy screen filters to control cheating.
Acceptability is a required quality for a sound assessment. For students, acceptability of a test is strongly influenced by perception of fairness. Computer-based assessment has been reported to be preferred by students provided that strict controls to prevent cheating are in place. This may be difficult to achieve as e-assessments are often taken in learning environments where computer screens are close together. In this study, 138 Year 5 dental students completed an e-assessment followed by an onscreen post-assessment questionnaire about the acceptability, fairness, and effectiveness of using privacy screen filters installed in front of their monitors to prevent cheating. Ninety-one percent of students in this study considered that taking a summative e-assessment with privacy screen filters was acceptable, 86 percent expressed the view that filters contributed to a fairer test, and 54 percent reported the filters made it easier or did not make any difference to read the screen. In addition, 60 percent gave positive comments and feedback, mainly focused on prevention of cheating. These findings suggest that privacy filters, originally developed for data protection in banks, medicine, and business, have potential in e-assessment in higher education. They provide an effective way of hampering cheating and improve student acceptability and confidence in the fairness of computer-delivered assessments.


Prevalence of depression in hospitalized patients with congestive heart failure.
Prevalence estimates of depression in hospitalized patients with congestive heart failure (CHF) differ considerably across studies. This article reports the prevalence of depression in a larger sample of hospitalized patients with CHF and identifies demographic, medical, psychosocial, and methodological factors that may affect prevalence estimates. A modified version of the Diagnostic Interview Schedule was administered to a series of 682 hospitalized patients with CHF to determine the prevalence of DSM-IV major and minor depression; 613 patients also completed the Beck Depression Inventory. Medical, demographic, and social data were obtained from hospital chart review, echocardiography, and patient interview. In the sample as a whole, 20% of the patients met the DSM-IV criteria for a current major depressive episode, 16% for a minor depressive episode, and 51% scored above the cutoff for depression on the Beck Depression Inventory (>or=10). However, the prevalence of major depression differed significantly between strata defined by the functional severity of heart failure, age, gender, employment status, dependence in activities of daily living, and past history of major depression. For example, the prevalence ranged from as low as 8% among patients in New York Heart Association class I failure to as high as 40% among patients in class IV. The prevalence of depression in hospitalized patients with CHF is similar to rates found in post-myocardial infarction patients. However, it is considerably higher in certain subgroups, such as patients with class III or IV heart failure. Further research is needed on the prognostic importance and treatment of comorbid depression in CHF.


General practice trainees' telehealth use during the COVID-19 pandemic: a cross-sectional study.
Prompted by the COVID-19 pandemic, remuneration was introduced for Australian general practice telehealth consultations. General practitioner (GP) trainees' telehealth use is of clinical, educational, and policy importance. The aim of this study was to assess the prevalence and associations of telehealth versus face-to-face consultations amongst Australian GP registrars (vocational GP trainees). Cross-sectional analysis of data from the Registrar Clinical Encounters in Training (ReCEnT) study, from 2020 to 2021 (three 6-month terms), including registrars in 3 of Australia's 9 Regional Training Organisations. In ReCEnT, GP registrars record details of 60 consecutive consultations, 6 monthly. The primary analysis used univariate and multivariable logistic regression, with outcome of whether the consultation was conducted via telehealth (phone and videoconference) or face-to-face. 1,168 registrars recorded details of 102,286 consultations, of which 21.4% (95% confidence interval [CI]: 21.1%-21.6%) were conducted via telehealth. Statistically significant associations of a telehealth consultation included shorter consultation duration (odds ratio [OR] 0.93, 95% CI: 0.93-0.94; and mean 12.9 versus 18.7 min); fewer problems addressed per consultation (OR 0.92, 95% CI: 0.87-0.97); being less likely to seek assistance from a supervisor (OR 0.86, 95% CI: 0.76-0.96) while being more likely to generate learning goals (OR 1.18, 95% CI: 1.02-1.37); and being more likely to arrange a follow-up consultation (OR 1.18, 95% CI: 1.02-1.35). That telehealth consultations were shorter, with higher rates of follow-up, has GP workforce/workload implications. That telehealth consultations were less likely to involve in-consultation supervisor support, but more likely to generate learning goals, has educational implications.


Lethal and sublethal effects of endosulfan on Apolygus lucorum (Hemiptera: Miridae).
Various pesticides directly impact insect pest populations through acute toxicity (lethal) effects, but they also cause a range of indirect (sublethal) effects on pest physiology or behavior. In this study, we describe both lethal and sublethal effects of endosulfan on the survival, development, and fecundity of Apolygus lucorum Meyer-Dür (Hemiptera: Miridae), an important pest of Bacillus thuringiensis (Bt) cotton, Gossypium hirsutum L., in China. We quantify pesticide effects on adult mirids as well as on subsequent (F1, F2) generations. Toxicity bioassays determined the median lethal concentration (LC50) for adult A. lucorum as 0.58 ppm. To evaluate the sublethal effect of endosulfan, we used LC20 and LC40 concentrations at 0.30 ppm and 0.48 ppm, respectively. Sublethal concentrations of endosulfan significantly reduced longevity and fecundity of female adults, but slightly affected male longevity. We also found sublethal effects on the F1 generation, through a reduction of egg hatching rate, nymphal mortality, adult molting rate, and adult fecundity, and on the F2 generation, through a decrease of egg hatching rate. These results show that endosulfan has far greater effects on A. lucorum than estimated by acute toxicity tests, and the effects of this pesticide on surviving mirids can be comparatively long-lived. This pesticide likely causes severe disruptions of A. lucorum population dynamics, with single endosulfan application, invoking a great reduction of population growth of resident mirid populations. We discuss implications of this work for control programs for A. lucorum on Bt cotton.


Concern about Falling and Complexity of Free-Living Physical Activity Patterns in Well-Functioning Older Adults.
Fall-related psychological concerns are common among older adults, potentially contributing to functional decline as well as to restriction of activities and social participation. To effectively prevent such negative consequences, it is important to understand how even very low concern about falling could affect physical activity behavior in everyday life. We hypothesized that concern about falling is associated with a reduction in diversity, dynamics, and performance of daily activities, and that these features can be comprehensively quantified in terms of complexity of physical activity patterns. A sample of 40 community-dwelling older adults were assessed for concern about falling using the Falls Efficacy Scale-International (FES-I). Free-living physical activity was assessed using a set of metrics derived from data recorded with a chest-worn tri-axial accelerometer. The devised metrics characterized physical activity behavior in terms of endurance (total locomotion time, longest locomotion period, usual walking cadence), performance (cadence of longest locomotion period, locomotion periods with at least 30 steps and 100 steps/min), and complexity of physical activity patterns. Complexity was quantified according to variations in type, intensity, and duration of activities, and was considered as an adaptive response to environmental exigencies over the course of the day. Based on FES-I score, participants were classified into two groups: not concerned at all/fully confident (n = 25) and concerned/less confident (n = 15). Demographic and health-related variables did not differ significantly between groups. Comparison of physical activity behavior indicated no significant differences for endurance-related metrics. In contrast, performance and complexity metrics were significantly lower in the less confident group compared to the fully confident group. Among all metrics, complexity of physical activity patterns appeared as the most discriminative feature between fully confident and less confident participants (p = 0.001, non-parametric Cliff's delta effect size = 0.63). These results extend our understanding of the interplay between low concern about falling and physical activity behavior of community-dwelling older persons in their everyday life context. This information could serve to better design and evaluate personalized intervention programs in future prospective studies.


On detection of multiple object instances using Hough transforms.
Hough transform-based methods for detecting multiple objects use nonmaxima suppression or mode seeking to locate and distinguish peaks in Hough images. Such postprocessing requires the tuning of many parameters and is often fragile, especially when objects are located spatially close to each other. In this paper, we develop a new probabilistic framework for object detection which is related to the Hough transform. It shares the simplicity and wide applicability of the Hough transform but, at the same time, bypasses the problem of multiple peak identification in Hough images and permits detection of multiple objects without invoking nonmaximum suppression heuristics. Our experiments demonstrate that this method results in a significant improvement in detection accuracy both for the classical task of straight line detection and for a more modern category-level (pedestrian) detection problem.


Internet-delivered treatment for substance abuse: a multisite randomized controlled trial.
Computer-delivered interventions have the potential to improve access to quality addiction treatment care. The objective of this study was to evaluate the effectiveness of the Therapeutic Education System (TES), an Internet-delivered behavioral intervention that includes motivational incentives, as a clinician-extender in the treatment of substance use disorders. Adult men and women (N=507) entering 10 outpatient addiction treatment programs were randomly assigned to receive 12 weeks of either treatment as usual (N=252) or treatment as usual plus TES, with the intervention substituting for about 2 hours of standard care per week (N=255). TES consists of 62 computerized interactive modules covering skills for achieving and maintaining abstinence, plus prize-based motivational incentives contingent on abstinence and treatment adherence. Treatment as usual consisted of individual and group counseling at the participating programs. The primary outcome measures were abstinence from drugs and heavy drinking (measured by twice-weekly urine drug screens and self-report) and time to dropout from treatment. Compared with patients in the treatment-as-usual group, those in the TES group had a lower dropout rate (hazard ratio=0.72, 95% CI=0.57, 0.92) and a greater abstinence rate (odds ratio=1.62, 95% CI=1.12, 2.35). This effect was more pronounced among patients who had a positive urine drug or breath alcohol screen at study entry (N=228) (odds ratio=2.18, 95% CI=1.30, 3.68). Internet-delivered interventions such as TES have the potential to expand access and improve addiction treatment outcomes. Additional research is needed to assess effectiveness in non-specialty clinical settings and to differentiate the effects of the community reinforcement approach and contingency management components of TES.


Hippocampal place fields emerge upon single-cell manipulation of excitability during behavior.
The origin of the spatial receptive fields of hippocampal place cells has not been established. A hippocampal CA1 pyramidal cell receives thousands of synaptic inputs, mostly from other spatially tuned neurons; however, how the postsynaptic neuron's cellular properties determine the response to these inputs during behavior is unknown. We discovered that, contrary to expectations from basic models of place cells and neuronal integration, a small, spatially uniform depolarization of the spatially untuned somatic membrane potential of a silent cell leads to the sudden and reversible emergence of a spatially tuned subthreshold response and place-field spiking. Such gating of inputs by postsynaptic neuronal excitability reveals a cellular mechanism for receptive field origin and may be critical for the formation of hippocampal memory representations.


Bipartite binding of the N terminus of Skp2 to cyclin A.
Skp2 and cyclin A are cell-cycle regulators that control the activity of CDK2. Cyclin A acts as an activator and substrate recruitment factor of CDK2, while Skp2 mediates the ubiquitination and subsequent destruction of the CDK inhibitor protein p27. The N terminus of Skp2 can interact directly with cyclin A but is not required for p27 ubiquitination. To gain insight into this poorly understood interaction, we have solved the 3.2 Å X-ray crystal structure of the N terminus of Skp2 bound to cyclin A. The structure reveals a bipartite mode of interaction with two motifs in Skp2 recognizing two discrete surfaces on cyclin A. The uncovered binding mechanism allows for a rationalization of the inhibitory effect of Skp2 on CDK2-cyclin A kinase activity toward the RxL motif containing substrates and raises the possibility that other intermolecular regulators and substrates may use similar non-canonical modes of interaction for cyclin targeting.


Long-term effects of drinking-water treatment residuals on dissolved phosphorus export from vegetated buffer strips.
The export of dissolved phosphorus (P) in surface runoff from agricultural land can lead to water quality degradation. Surface application of aluminium (Al)-based water treatment residuals (Al-WTRs) to vegetated buffer strip (VBS) soils can enhance P removal from surface runoff during single runoff events. However, the longer-term effects on P removal in VBSs following application of products such as Al-WTR remain uncertain. We used field experimental plots to examine the long-term effects of applying a freshly generated Al-WTR to VBSs on dissolved P export during multiple runoff events, occurring between 1 day and 42 weeks after the application of Al-WTR. Vegetated buffer strip plots amended with Al-WTR significantly reduced soluble reactive P and total dissolved P concentrations in surface runoff compared to both unamended VBS plots and control plots. However, the effectiveness of Al-WTR decreased over time, by approximately 70% after 42 weeks compared to a day following Al-WTR application. Reduced performance did not appear to be due to drying of Al-WTR in the field. Instead, the development of preferential flow paths as well as burying of Al-WTR with freshly deposited sediments may explain these observations. Better understanding of the processes controlling long-term P removal by Al-WTR is required for effective management of VBSs.


Moonlight Drives Ocean-Scale Mass Vertical Migration of Zooplankton during the Arctic Winter.
In extreme high-latitude marine environments that are without solar illumination in winter, light-mediated patterns of biological migration have historically been considered non-existent [1]. However, diel vertical migration (DVM) of zooplankton has been shown to occur even during the darkest part of the polar night, when illumination levels are exceptionally low [2, 3]. This paradox is, as yet, unexplained. Here, we present evidence of an unexpected uniform behavior across the entire Arctic, in fjord, shelf, slope and open sea, where vertical migrations of zooplankton are driven by lunar illumination. A shift from solar-day (24-hr period) to lunar-day (24.8-hr period) vertical migration takes place in winter when the moon rises above the horizon. Further, mass sinking of zooplankton from the surface waters and accumulation at a depth of ∼50 m occurs every 29.5 days in winter, coincident with the periods of full moon. Moonlight may enable predation of zooplankton by carnivorous zooplankters, fish, and birds now known to feed during the polar night [4]. Although primary production is almost nil at this time, lunar vertical migration (LVM) may facilitate monthly pulses of carbon remineralization, as they occur continuously in illuminated mesopelagic systems [5], due to community respiration of carnivorous and detritivorous zooplankton. The extent of LVM during the winter suggests that the behavior is highly conserved and adaptive and therefore needs to be considered as "baseline" zooplankton activity in a changing Arctic ocean [6-9]. VIDEO ABSTRACT.


Subthalamic nucleus stimulation improves Parkinson's disease-associated camptocormia in parallel to its preoperative levodopa responsiveness.
The aim of this work was to identify factors predictive of postoperative improvement of camptocormia in patients with Parkinson's disease (PD) treated by subthalamic nucleus (STN) stimulation. Camptocormia, one of the most disabling features of PD, often responds poorly to medical therapies. The reported effects of deep brain stimulation on PD-associated camptocormia vary, and preoperative characteristics affecting the surgical outcome remain unclear. We evaluated 17 patients with camptocormia whose preoperative off-medication thoracolumbar angle exceeded 45°. We used photographs to measure their thoracolumbar angle preoperatively, 3 months after surgery, and at the last follow-up (mean 36.5 months postoperatively) in status on-medication and off-medication. The patient age, duration of PD and camptocormia, daily medications, Unified Parkinson's Disease Rating Scale (UPDRS) subscores and the Schwab-England activity of daily living scale (S-E) were also recorded. Univariate analysis was performed to identify factors predictive of the postoperative improvement of camptocormia. STN stimulation significantly improved the UPDRS subscores and S-E, and resulted in a reduction of daily medications 3 months post-treatment. The preoperative thoracolumbar angle (mean±SD) in status off-medication (84.0±29.5°) was significantly ameliorated 3 months postoperatively (49.8±29.3°) and at the last follow-up (54.8±28.3°). There was no correlation between the postoperative camptocormia improvement rate and preoperative parameters other than the duration and severity of camptocormia and the levodopa responsiveness of the thoracolumbar angle. Symptom duration negatively affected levodopa responsiveness. STN stimulation improves PD-associated camptocormia in parallel with preoperative levodopa responsiveness. Long symptom duration interferes with levodopa responsiveness.


Phase I study of decitabine-mediated gene expression in patients with cancers involving the lungs, esophagus, or pleura.
The DNA methylation paradox, manifested as derepression of cancer-testis antigens, and silencing of tumor suppressors during malignant transformation, provides the rationale for the utilization of chromatin remodeling agents for cancer therapy. A phase I trial was done to examine pharmacokinetics, toxicities, and gene expression mediated by 5-aza-2'-deoxycytidine (DAC) in patients with thoracic malignancies. Thirty-five patients with cancers refractory to standard therapy received continuous 72-hour DAC infusions using a phase I dose-escalation schema. Each full course of therapy consisted of two identical 35-day cycles. Plasma DAC levels were evaluated by liquid chromatography-mass spectrometry techniques. Quantitative reverse transcription-PCR, methylation-specific PCR, and immunohistochemical techniques were used to evaluate NY-ESO-1, MAGE-3, and p16 expression in tumor biopsies. Long oligonucleotide arrays were used to evaluate gene expression profiles in laser-captured tumor cells before and after DAC exposure. Thirty-five patients were evaluable for toxicities; 25 were evaluable for treatment response. Myelosuppression constituted dose-limiting toxicity. The maximum tolerated dose of DAC was 60 to 75 mg/m(2) depending on the number of prior cytotoxic chemotherapy regimens. No objective responses were observed. Plasma DAC concentrations approximated thresholds for gene induction in cultured cancer cells. Target gene induction was observed in 36% of patients. Posttreatment antibodies to NY-ESO-1 were detected in three patients exhibiting NY-ESO-1 induction in their tumor tissues. Complex, heterogeneous gene expression profiles were observed in pretreatment and posttreatment tissues. Prolonged DAC infusions can modulate gene expression in primary thoracic malignancies. These findings support further evaluation of DNA-demethylating agents alone or in combination with other regimens targeting induced gene products for the treatment of these neoplasms.


A sinister bias for calling fouls in soccer.
Distinguishing between a fair and unfair tackle in soccer can be difficult. For referees, choosing to call a foul often requires a decision despite some level of ambiguity. We were interested in whether a well documented perceptual-motor bias associated with reading direction influenced foul judgments. Prior studies have shown that readers of left-to-right languages tend to think of prototypical events as unfolding concordantly, from left-to-right in space. It follows that events moving from right-to-left should be perceived as atypical and relatively debased. In an experiment using a go/no-go task and photographs taken from real games, participants made more foul calls for pictures depicting left-moving events compared to pictures depicting right-moving events. These data suggest that two referees watching the same play from distinct vantage points may be differentially predisposed to call a foul.


Skeletal muscle myofibrillar and sarcoplasmic protein synthesis rates are affected differently by altitude-induced hypoxia in native lowlanders.
As a consequence to hypobaric hypoxic exposure skeletal muscle atrophy is often reported. The underlying mechanism has been suggested to involve a decrease in protein synthesis in order to conserve O(2). With the aim to challenge this hypothesis, we applied a primed, constant infusion of 1-(13)C-leucine in nine healthy male subjects at sea level and subsequently at high-altitude (4559 m) after 7-9 days of acclimatization. Physical activity levels and food and energy intake were controlled prior to the two experimental conditions with the aim to standardize these confounding factors. Blood samples and expired breath samples were collected hourly during the 4 hour trial and vastus lateralis muscle biopsies obtained at 1 and 4 hours after tracer priming in the overnight fasted state. Myofibrillar protein synthesis rate was doubled; 0.041±0.018 at sea-level to 0.080±0.018%⋅hr(-1) (p<0.05) when acclimatized to high altitude. The sarcoplasmic protein synthesis rate was in contrast unaffected by altitude exposure; 0.052±0.019 at sea-level to 0.059±0.010%⋅hr(-1) (p>0.05). Trends to increments in whole body protein kinetics were seen: Degradation rate elevated from 2.51±0.21 at sea level to 2.73±0.13 µmol⋅kg(-1)⋅min(-1) (p = 0.05) at high altitude and synthesis rate similar; 2.24±0.20 at sea level and 2.43±0.13 µmol⋅kg(-1)⋅min(-1) (p>0.05) at altitude. We conclude that whole body amino acid flux is increased due to an elevated protein turnover rate. Resting skeletal muscle myocontractile protein synthesis rate was concomitantly elevated by high-altitude induced hypoxia, whereas the sarcoplasmic protein synthesis rate was unaffected by hypoxia. These changed responses may lead to divergent adaptation over the course of prolonged exposure.


Internet use by patients with bipolar disorder: Results from an international multisite survey.
There is considerable international interest in online education of patients with bipolar disorder, yet little understanding of how patients use the Internet and other sources to seek information. 1171 patients with a diagnosis of bipolar disorder in 17 countries completed a paper-based, anonymous survey. 81% of the patients used the Internet, a percentage similar to the general public. Older age, less education, and challenges in country telecommunications infrastructure and demographics decreased the odds of using the Internet. About 78% of the Internet users looked online for information on bipolar disorder or 63% of the total sample. More years of education in relation to the country mean, and feeling very confident about managing life decreased the odds of seeking information on bipolar disorder online, while having attended support groups increased the odds. Patients who looked online for information on bipolar disorder consulted medical professionals plus a mean of 2.3 other information sources such as books, physician handouts, and others with bipolar disorder. Patients not using the Internet consulted medical professionals plus a mean of 1.6 other information sources. The percentage of patients with bipolar disorder who use the Internet is about the same as the general public. Other information sources remain important.


Antibacterial activity of mupirocin (pseudomonic acid), a new antibiotic for topical use.
Mupirocin (pseudomonic acid A), an antibiotic produced by Pseudomonas fluorescens, showed a high level of activity against staphylococci and streptococci and against certain gram-negative bacteria, including Haemophilus influenzae and Neisseria gonorrhoeae, but was much less active against most gram-negative bacilli an anaerobes. Nearly all clinical isolates of Staphylococcus aureus and Staphylococcus epidermidis, including multiply resistant strains, were susceptible (mupirocin MIC, less than or equal to 0.5 microgram/ml). There was no cross-resistance between mupirocin and clinically available antibiotics, and the selection of resistant variants in vitro occurred at a low frequency. Mupirocin was highly bound (95% bound) to the protein of human serum, and activity was reduced 10- to 20-fold in the presence of human serum. The activity of mupirocin was not greatly influenced by inoculum size but was significantly enhanced in acid medium. In tests of bactericidal activity, MBCs were 8- to 32-fold higher than MICs and the antibiotic demonstrated a slow bactericidal action in time-kill tests, resulting in 90 to 99% killing after 24 h at 37 degrees C.


Nucleotide and phospholipid-dependent control of PPXD and C-domain association for SecA ATPase.
The SecA ATPase motor is a central component of the eubacterial protein translocation machinery. It is comprised of N- and C-domain substructures, where the N-domain is comprised of two nucleotide-binding domains that flank a preprotein-binding domain (PPXD), while the C-domain binds phospholipids as well as SecB chaperone. Our recent crystal structure of Bacillus subtilis SecA protomer [Hunt, J. F., Weinkauf, S., Henry, L., Fak, J. J., McNicholas, P., Oliver, D. B., and Deisenhofer, J. (2002) Science 297, 2018-2026] along with experimental support for the correct dimer structure [Ding, H., Hunt, J. F., Mukerji, I., and Oliver, D. (2003) Biochemistry 42, 8729-8738] have now allowed us to study SecA structural dynamics during interaction with various translocation ligands and to relate these findings to current models of SecA-dependent protein translocation. In this paper, we utilized fluorescence resonance energy transfer methodology with genetically engineered SecA proteins containing unique pairs of tryptophan and fluorophore-labeled cysteine residues within the PPXD and C-domains of SecA to investigate the interaction of these two domains and their response to temperature, model membranes, and nucleotide. Consistent with the crystal structure of SecA, we found that the PPXD and C-domains are proximal to one another in the ground state. Increasing temperature or binding to model membranes promoted a loosening of PPXD and C-domain association, while ADP binding promoted a tighter association. A similar pattern of PPXD and C-domain association was obtained also for Escherichia coli SecA protein. Furthermore, a hyperactive Azi-PrlD SecA protein of E. coli had increased PPXD and C-domain separation, consistent with its activation in the ground state. Interestingly, PPXD and C-domain separation occurred prior to the onset of major temperature-induced conformational changes in both the PPXD and C-domains of SecA. Our results support a model in which PPXD and C-domain proximity is important for regulating the initial stages of SecA activation, and they serve also as a template for future structural studies aimed at elucidation of the chemomechanical cycle of SecA-dependent protein translocation.


Common genetic variants account for differences in gene expression among ethnic groups.
Variation in DNA sequence contributes to individual differences in quantitative traits, but in humans the specific sequence variants are known for very few traits. We characterized variation in gene expression in cells from individuals belonging to three major population groups. This quantitative phenotype differs significantly between European-derived and Asian-derived populations for 1,097 of 4,197 genes tested. For the phenotypes with the strongest evidence of cis determinants, most of the variation is due to allele frequency differences at cis-linked regulators. The results show that specific genetic variation among populations contributes appreciably to differences in gene expression phenotypes. Populations differ in prevalence of many complex genetic diseases, such as diabetes and cardiovascular disease. As some of these are probably influenced by the level of gene expression, our results suggest that allele frequency differences at regulatory polymorphisms also account for some population differences in prevalence of complex diseases.


Succession of sulfur-oxidizing bacteria in the microbial community on corroding concrete in sewer systems.
Microbially induced concrete corrosion (MICC) in sewer systems has been a serious problem for a long time. A better understanding of the succession of microbial community members responsible for the production of sulfuric acid is essential for the efficient control of MICC. In this study, the succession of sulfur-oxidizing bacteria (SOB) in the bacterial community on corroding concrete in a sewer system in situ was investigated over 1 year by culture-independent 16S rRNA gene-based molecular techniques. Results revealed that at least six phylotypes of SOB species were involved in the MICC process, and the predominant SOB species shifted in the following order: Thiothrix sp., Thiobacillus plumbophilus, Thiomonas intermedia, Halothiobacillus neapolitanus, Acidiphilium acidophilum, and Acidithiobacillus thiooxidans. A. thiooxidans, a hyperacidophilic SOB, was the most dominant (accounting for 70% of EUB338-mixed probe-hybridized cells) in the heavily corroded concrete after 1 year. This succession of SOB species could be dependent on the pH of the concrete surface as well as on trophic properties (e.g., autotrophic or mixotrophic) and on the ability of the SOB to utilize different sulfur compounds (e.g., H2S, S0, and S2O3(2-)). In addition, diverse heterotrophic bacterial species (e.g., halo-tolerant, neutrophilic, and acidophilic bacteria) were associated with these SOB. The microbial succession of these microorganisms was involved in the colonization of the concrete and the production of sulfuric acid. Furthermore, the vertical distribution of microbial community members revealed that A. thiooxidans was the most dominant throughout the heavily corroded concrete (gypsum) layer and that A. thiooxidans was most abundant at the highest surface (1.5-mm) layer and decreased logarithmically with depth because of oxygen and H2S transport limitations. This suggested that the production of sulfuric acid by A. thiooxidans occurred mainly on the concrete surface and the sulfuric acid produced penetrated through the corroded concrete layer and reacted with the sound concrete below.


Arsenic exposure, telomere length, and expression of telomere-related genes among Bangladeshi individuals.
Inorganic arsenic is a carcinogen whose mode of action may involve telomere dysfunction. Recent epidemiological studies suggest that chronic arsenic exposure is associated with longer telomeres and altered expression of telomere-related genes in peripheral blood. In this study, we evaluated the association of urinary arsenic concentration with expression of telomere-related genes and telomere length in Bangladeshi individuals with a wide range of arsenic exposure through naturally contaminated drinking water. We used linear regression models to estimate associations between urinary arsenic and array-based expression measures for 69 telomere related genes using mononuclear cell RNA samples from 1799 individuals. Association between arsenic exposure and a qPCR-based telomere length measure was assessed among 167 individuals. Urinary arsenic was positively associated with expression of WRN, and negatively associated with TERF2, DKC1, TERF2IP and OBFC1 (all P<0.00035, Bonferroni-corrected threshold). We detected interaction between urinary arsenic and arsenic metabolism efficiency in relation to expression of WRN (P for interaction =0.00008). In addition, we observed that very high arsenic exposure was associated with longer telomeres compared to very low exposure (P=0.02). Our findings suggest that arsenic's carcinogenic mode of action may involve alteration of telomere maintenance and/or telomere damage. This study extends our knowledge regarding the effect of arsenic on telomere length and expression of telomere-related genes.


Cord Blood Hepcidin: Cross-Sectional Correlates and Associations with Anemia, Malaria, and Mortality in a Tanzanian Birth Cohort Study.
Hepcidin, the master regulator of bioavailable iron, is a key mediator of anemia and also plays a central role in host defense against infection. We hypothesized that measuring hepcidin levels in cord blood could provide an early indication of interindividual differences in iron regulation with quantifiable implications for anemia, malaria, and mortality-related risk. Hepcidin concentrations were measured in cord plasma from a birth cohort (N = 710), which was followed for up to 4 years in a region of perennial malaria transmission in Muheza, Tanzania (2002-2006). At the time of delivery, cord hepcidin levels were correlated with inflammatory mediators, iron markers, and maternal health conditions. Hepcidin levels were 30% (95% confidence interval [CI]: 12%, 44%) lower in children born to anemic mothers and 48% (95% CI: 11%, 97%) higher in placental malaria-exposed children. Relative to children in the lowest third, children in the highest third of cord hepcidin had on average 2.5 g/L (95% CI: 0.1, 4.8) lower hemoglobin levels over the duration of follow-up, increased risk of anemia and severe anemia (adjusted hazard ratio [HR] [95% CI]: 1.18 [1.03, 1.36] and 1.34 [1.08, 1.66], respectively), and decreased risk of malaria and all-cause mortality (adjusted HR [95% CI]: 0.78 [0.67, 0.91] and 0.34 [0.14, 0.84], respectively). Although longitudinal measurements of hepcidin and iron stores are required to strengthen causal inference, these results suggest that hepcidin may have utility as a biomarker indicating children's susceptibility to anemia and infection in early life.


A- to B-form transition in DNA between gold surfaces.
Molecular dynamics simulations have been performed to characterize the conformation of DNA that is present when DNA links gold nanoparticles to form nanoparticle superlattice crystals. To model the DNA-linked gold nanoparticles, four strands of DNA are used to connect two gold surfaces, with a small interstrand separation and high added salt to match experiment. A-form DNA was assumed for the initial conformation, as this form of DNA has a length per base-pair that matches lengths that have been inferred from X-ray measurements. The DNA structure was monitored for 40 ns, and the distributions of the slide and z(p) coordinates were obtained from the simulations. We find that all the double-stranded DNA (ds-DNA) strands transform from A- to B-DNA during the simulations. In addition, single-stranded DNAa (ss-DNAs) that are used to connect the ds-DNA to each surface are found to become adsorbed on the gold surfaces during this process, and the ds-DNAs bend (∼143°) at their junctions with the two gold surfaces to accommodate the observed distance between gold surfaces using B-form DNA. We infer from this that the short length of DNA between the gold surfaces is not due to the presence of A-DNA.


The influence of age, sex, population group, and dentition on the mandibular angle as measured on a South African sample.
The mandibular angle is measured in physical anthropological assessments of human remains to possibly assist with the determination of sex and population affinity. The purpose of this investigation was to establish how the mandibular angle changes with age and loss of teeth among the sexes in South African population groups. The angles of 653 dried adult mandibles from the Pretoria Bone Collection were measured with a mandibulometer. Males and females of both South African whites and blacks were included. To compensate for imbalances in numbers among subgroups, type IV ANOVA testing was applied. No association was found between age and angle within either of the populations, within sexes, or within dentition groups. The angle was the most obtuse in individuals without molars and with an uneven distribution of molars, and most acute in the group with an even distribution of molars on both sides. Statistically significant differences (P < 0.001) were found in the angle between the two population groups and sexes in the overall sample as well as in the subgroup with absent molar teeth (P = 0.003 for sex, males more acute angle, and P = 0.001 for population group, blacks more acute angle), although a very large overlap existed. No significant differences could be demonstrated between the sexes or populations within the subgroups with molars. We concluded that the loss of molars, especially if complete or uneven, has a considerable effect on the mandibular angle. In the assessment of human remains, the mandibular angle is not very usable in determining sex.


Combined surgical resection and iridium 192 implantation for locally advanced and recurrent desmoid tumors.
Thirty-eight histologically confirmed desmoid tumors were treated with conservative surgical resection and interstitial iridium 192. Patients included in this series constituted a poor prognostic group. Seventy five percent (75%) had previous recurrences of their disease and 50% had tumors 8 cm or greater in size. In addition, 16% of the patients had gross residual disease after surgical excision and 79% had positive or close margins of resection. With a median follow-up of 5.5 years, the 5-year actuarial in-field local control rate was 75% and the overall local control rate was 66%. Four of the 12 local recurrences developed at the periphery of the implant volume and four patients failed at least 3 cm or more beyond the treated volume. After salvage therapy, the 5-year actuarial local control rate was 95%. Two patients required amputation for recurrent disease. Thirty of 34 patients remain free of disease with an excellent functional result achieved. The authors conclude that surgical resection and postoperative interstitial iridium 192 is effective therapy for patients with desmoid tumors. Despite the fact that most patients in this series had bulky, recurrent tumors, excellent long-term local control and limb function were achieved.


Clinical and laboratory characteristics of the COVID-19 disease in adult patients.
In December 2019, a new coronavirus, SARS-CoV-2, appeared in Wuhan, China. This virus is the cause of the COVID-19 disease. This infection later spread to the whole world. The goal of this article is to present the clinical and laboratory characteristics of patients with COVID-19 treated in the Faculty Hospital Pilsen. In this monocentric, retrospective study, clinical and biochemical data of 89 adult patients with COVID-19 was analyzed. These patients were in the care of the Faculty Hospital Pilsen between March 14 and April 7. In this cohort, made up of 89 patients, 63 were treated as outpatients and 26 were hospitalized. 10 patients required intensive care. The most common symptoms among patients were cough and fever. Dyspnea was present in 29 patients. A CT scan showed bilateral pneumonia in 23 of the admitted patients. Fever and bilateral pneumonia were significantly more common in patients ≥ 60 years old (p=0.047, and p=0.001, respectively). Of lab results, the patients in intensive care had significantly higher values of C-reactive protein, procalcitonin, lactate dehydrogenase, interleukin 6, myoglobin and ferritin. The most common symptoms of COVID-19 are fever and cough. These two symptoms are simultaneously present in more than half the cases. Approximately 1/10th of patients requires intensive care. Higher values of lactate dehydrogenase, myoglobin and ferritin on patient admission appear to be a strong predictive factor of the patient's status progressing into requiring ICU attention.


Significance of epitrochlear lymph node involvement in Hodgkin disease.
Epitrochlear involvement in Hodgkin disease (HD) is a rare event, with only limited data available describing this unique presentation, its treatment, and long term outcome. Between 1968 and 1997, 1180 patients with clinical stage (CS) IA-IIB HD were treated at the Harvard Longwood Area Hospitals, among whom 11 were identified to have presented with epitrochlear lymphadenopathy (1%). Together with 6 CS III-IV patients also with clinically involved epitrochlear lymph nodes at diagnosis, these 17 patients form the basis of the current study. The clinical characteristics, histopathologic distribution, and treatment details are described. Two radiation therapy techniques were used: the "single field" and "separate-field" techniques. The median dose to the epitrochlear region was 3600 centigrays. Survival outcome was calculated by the Kaplan-Meier method. The median follow-up was 17 years. The actuarial 15-year freedom from recurrence, cause specific survival, and overall survival (OS) rates for the 17 patients were 70%, 88%, and 70%, respectively. Among the CS IA-IIB patients, the 15-year OS rates of the 1169 patients and 11 patients without and with epitrochlear involvement were 80% and 90%, respectively. Two of the 11 CS IA-IIB and 3 of the 6 CS III-IV patients experienced recurrence. None of the recurrences involved the epitrochlear or ipsilateral brachial region regardless of the treatment technique, and no complications from the local radiation therapy were observed. Feasible and effective radiation therapy techniques are available for patients with HD with epitrochlear involvement. If appropriately treated, the prognosis of patients with this unique presentation appears to be similar to that of other HD patients.


Evaluation and optimization of DNA extraction and purification procedures for soil and sediment samples.
We compared and statistically evaluated the effectiveness of nine DNA extraction procedures by using frozen and dried samples of two silt loam soils and a silt loam wetland sediment with different organic matter contents. The effects of different chemical extractants (sodium dodecyl sulfate [SDS], chloroform, phenol, Chelex 100, and guanadinium isothiocyanate), different physical disruption methods (bead mill homogenization and freeze-thaw lysis), and lysozyme digestion were evaluated based on the yield and molecular size of the recovered DNA. Pairwise comparisons of the nine extraction procedures revealed that bead mill homogenization with SDS combined with either chloroform or phenol optimized both the amount of DNA extracted and the molecular size of the DNA (maximum size, 16 to 20 kb). Neither lysozyme digestion before SDS treatment nor guanidine isothiocyanate treatment nor addition of Chelex 100 resin improved the DNA yields. Bead mill homogenization in a lysis mixture containing chloroform, SDS, NaCl, and phosphate-Tris buffer (pH 8) was found to be the best physical lysis technique when DNA yield and cell lysis efficiency were used as criteria. The bead mill homogenization conditions were also optimized for speed and duration with two different homogenizers. Recovery of high-molecular-weight DNA was greatest when we used lower speeds and shorter times (30 to 120 s). We evaluated four different DNA purification methods (silica-based DNA binding, agarose gel electrophoresis, ammonium acetate precipitation, and Sephadex G-200 gel filtration) for DNA recovery and removal of PCR inhibitors from crude extracts. Sephadex G-200 spin column purification was found to be the best method for removing PCR-inhibiting substances while minimizing DNA loss during purification. Our results indicate that for these types of samples, optimum DNA recovery requires brief, low-speed bead mill homogenization in the presence of a phosphate-buffered SDS-chloroform mixture, followed by Sephadex G-200 column purification.


Segregation of complex acoustic scenes based on temporal coherence.
In contrast to the complex acoustic environments we encounter everyday, most studies of auditory segregation have used relatively simple signals. Here, we synthesized a new stimulus to examine the detection of coherent patterns ('figures') from overlapping 'background' signals. In a series of experiments, we demonstrate that human listeners are remarkably sensitive to the emergence of such figures and can tolerate a variety of spectral and temporal perturbations. This robust behavior is consistent with the existence of automatic auditory segregation mechanisms that are highly sensitive to correlations across frequency and time. The observed behavior cannot be explained purely on the basis of adaptation-based models used to explain the segregation of deterministic narrowband signals. We show that the present results are consistent with the predictions of a model of auditory perceptual organization based on temporal coherence. Our data thus support a role for temporal coherence as an organizational principle underlying auditory segregation. DOI:http://dx.doi.org/10.7554/eLife.00699.001.


Berberine promotes osteogenic differentiation of mesenchymal stem cells with therapeutic potential in periodontal regeneration.
Periodontal disease is a bacterial infection-associated disease of the periodontal tissues characterized by the destruction of tooth-supporting structures, including alveolar bone. The ideal goal of periodontal therapy is the complete regeneration of alveolar bone in a healthy microenvironment free of infection. In this study, we found that berberine, a benzylisoquinoline plant alkaloid from Coptidis Rhizoma, strongly inhibited the growth of Porphyromonas gingivalis. Gingipain is the most important virulence factor of Porphyromonas gingivalis in the process of periodontal tissue destruction. Berberine also had an inhibitory effect on gingipain activity in a concentration dependent manner. Remarkably, berberine restored the downregulation of osteogenesis-related genes expression in bone mesenchymal stem cells (BMSCs) induced by Porphyromonas gingivalis infection, and significantly increased the expression of osteogenesis-related genes such as OSX, COLI, ALP, OCN and OPN compared to the control group. This results suggested that berberine may directly promote osteogenesis. Further in-vitro studies demonstrated that berberine statistically significantly promoted the osteogenic differentiation of BMSCs at concentrations of 1-10 μM. In the research on the mechanisms, we found that both total β-catenin and nuclear β-catenin accumulation were statistically significantly increased by berberine. And the transcriptional activity of β-catenin/TCF was about 2 folds higher than the control group. Furthermore, Wnt signalling specific inhibitor DKK-1 blocked the above effects of berberine. These demonstrated that Wnt/β-catenin signalling pathway was involved in the osteogenic differentiation induced by berberine. The antibacterial actions in combination with the promotion role in osteogenic differentiation position berberine as a prospective drug for periodontal tissue regeneration.


Kernel machine methods for integrative analysis of genome-wide methylation and genotyping studies.
Many large GWAS consortia are expanding to simultaneously examine the joint role of DNA methylation in addition to genotype in the same subjects. However, integrating information from both data types is challenging. In this paper, we propose a composite kernel machine regression model to test the joint epigenetic and genetic effect. Our approach works at the gene level, which allows for a common unit of analysis across different data types. The model compares the pairwise similarities in the phenotype to the pairwise similarities in the genotype and methylation values; and high correspondence is suggestive of association. A composite kernel is constructed to measure the similarities in the genotype and methylation values between pairs of samples. We demonstrate through simulations and real data applications that the proposed approach can correctly control type I error, and is more robust and powerful than using only the genotype or methylation data in detecting trait-associated genes. We applied our method to investigate the genetic and epigenetic regulation of gene expression in response to stressful life events using data that are collected from the Grady Trauma Project. Within the kernel machine testing framework, our methods allow for heterogeneity in effect sizes, nonlinear, and interactive effects, as well as rapid P-value computation.


Resurrecting social infrastructure as a determinant of urban tuberculosis control in Delhi, India.
The key to universal coverage in tuberculosis (TB) management lies in community participation and empowerment of the population. Social infrastructure development generates social capital and addresses the crucial social determinants of TB, thereby improving program performance. Recently, there has been renewed interest in the concept of social infrastructure development for TB control in developing countries. This study aims to revive this concept and highlight the fact that documentation on ways to operationalize urban TB control is required from a holistic development perspective. Further, it explains how development of social infrastructure impacts health and development outcomes, especially with respect to TB in urban settings. A wide range of published Government records pertaining to social development parameters and TB program surveillance, between 2001 and 2011 in Delhi, were studied. Social infrastructure development parameters like human development index along with other indicators reflecting patient profile and habitation in urban settings were selected as social determinants of TB. These include adult literacy rates, per capita income, net migration rates, percentage growth in slum population, and percentage of urban population living in one-room dwelling units. The impact of the Revised National Tuberculosis Control Program on TB incidence was assessed as an annual decline in new TB cases notified under the program. Univariate linear regression was employed to examine the interrelationship between social development parameters and TB program outcomes. The decade saw a significant growth in most of the social development parameters in the State. TB program performance showed 46% increment in lives saved among all types of TB cases per 100,000 population. The 7% reduction in new TB case notifications from the year 2001 to 2011, translates to a logarithmic decline of 5.4 new TB cases per 100,000 population. Except per capita income, literacy, and net migration rates, other social determinants showed significant correlation with decline in new TB cases per 100,000 population. Social infrastructure development leads to social capital generation which engenders positive growth in TB program outcomes. Strategies which promote social infrastructure development should find adequate weightage in the overall policy framework for urban TB control in developing countries.


Reasons for Journal Impact Factor Changes: Influence of Changing Source Items.
Both the concept and the application of the impact factor (IF) have been subject to widespread critique, including concerns over its potential manipulation. This study provides a systematic analysis of significant journal Impact Factor changes, based on the relative contribution of either one or both variables of the IF equation (i.e. citations / articles as the numerator / denominator of the quotient). A cohort of JCR-listed journals which faced the most dramatic absolute IF changes between 2013 and 2014 (ΔIF ≥ 3.0, n = 49) was analyzed for the causes resulting in IF changes that theses journals have experienced in the last five years. Along with the variation by number of articles and citations, this analysis includes the relative change of both variables compared to each other and offers a classification of `valid`and `invalid`scenarios of IF variation in terms of the intended goal of the IF to measure journal quality. The sample cohort features a considerable incidence of IF increases (18%) which are qualified as `invalid`according to this classification because the IF increase is merely based on a favorably changing number of articles (denominator). The results of this analysis point out the potentially delusive effect of IF increases gained through effective shrinkage of publication output. Therefore, careful consideration of the details of the IF equation and possible implementation of control mechanisms versus the volatile factor of number of articles may help to improve the expressiveness of this metric.


Do pregnant women living in higher well-being populations in the USA experience lower risk of preterm delivery? A cross-sectional study.
To determine if preterm birth, defined as gestational age <37 weeks, is lower for women living in counties with higher well-being, after accounting for known individual risk factors. Cross-sectional study of all US births in 2011. We obtained birth data from the National Center for Health Statistics which included 3 938 985 individuals. Primary outcome measure was maternal risk of preterm delivery by county; primary independent variable was county-level well-being as measured by the Gallup-Sharecare Well-Being Index (WBI). Women living in counties with higher population well-being had a lower rate of preterm delivery. The rate of preterm birth in counties in the lowest WBI quintile was 13.1%, while the rate of preterm birth in counties in the highest WBI quintile was 10.9%. In the model adjusted for maternal risk factors (age, race, Hispanic ethnicity, smoking status, timing of initiation of prenatal visits, multiparity, maternal insurance payer), the association was slightly attenuated with an absolute difference of 1.9% (95% CI 1.7% to 2.1%; p<0.001). Pregnant women who live in areas with higher population well-being have lower risk of preterm birth, even after accounting for individual risk factors.


Intravascular lesions of the hand.
Intravascular lesions of the hand comprise reactive and neoplastic entities. The clinical diagnosis of such lesions is often difficult, and usually requires pathologic examination. We present the largest series to date of intravascular lesions affecting the hand. A retrospective review of intravascular (arterial and venous) lesions involving the hand was conducted. Data regarding clinicopathologic findings were analyzed. We identified 10 patients with intravascular lesions of their hands including thromboemboli (n = 3), reactive intravascular conditions such as papillary endothelial hyperplasia or Masson's tumor (n = 2) and fasciitis (n = 1), as well as vascular neoplasms including pyogenic granuloma (n = 2) and angioleiomyoma (n = 2). Blood vessel injury and/or venous thrombosis may predispose to several intravascular lesions of the hand. Recognition of reactive entities from neoplastic conditions is important.


Defective tumor necrosis factor release from Crohn's disease macrophages in response to Toll-like receptor activation: relationship to phenotype and genome-wide association susceptibility loci.
Recent work provides evidence of a failure of acute inflammation in Crohn's disease (CD), and suggests that the primary defect operates at the level of the macrophage and cytokine release. Here we extend the characterization of the innate immune defect in CD by investigating the macrophage response to Toll-like receptor (TLR) agonists and assess potential links between genome-wide association study (GWAS) susceptibility loci, disease phenotype, and therapeutic regimens on tumor necrosis factor α (TNF) release. Peripheral blood-derived macrophages were cultured from control subjects and patients with CD, stimulated with TLR ligands, and the release of TNF measured. Genomic DNA was purified from blood and genotyped for 34 single nucleotide polymorphisms (SNPs) identified as being associated with CD by GWAS. All stimuli resulted in a reduction (32%-48%) in TNF release from macrophages derived from CD patients (n = 28-101) compared to those from healthy control (HC) subjects. All phenotypes demonstrated impaired TNF release, with the greatest defect in patients with colonic disease. There was no detectable relationship between the level of TNF released and the presence of GWAS susceptibility loci in CD patients. Reduced TNF levels were not influenced by age, gender, or use of aminosalicylate (5-ASA) medication. This study supports the hypothesis of defective proinflammatory cytokine secretion and an innate immunodeficiency in CD. Abnormal TNF secretion is evident downstream of multiple TLRs, affects all disease phenotypes, and is unrelated to 34 polymorphisms associated with CD by GWAS.


3'-Chloro-3 alpha-(diphenylmethoxy)tropane but not 4'-chloro-3 alpha-(diphenylmethoxy)tropane produces a cocaine-like behavioral profile.
A series of 2'- and 3'-substituted and 3',3"-disubstituted 3 alpha-(diphenylmethoxy)tropane analogs were designed and synthesized as novel probes for the dopamine transporter. All the analogs were evaluated for displacement of [3H]WIN 35,428 binding at the dopamine transporter and for inhibition of [3H]dopamine uptake in rat caudate putamen. Compounds were observed to monophasically displace [3H]WIN 35,428 binding to the dopamine transporter with affinities of 21.6-1836 nM (Ki). Generally, meta-substituted compounds were more potent than benztropine and equipotent to or slightly less potent than their previously reported para-substituted homologs in inhibiting [3H]WIN 35,428 binding. However, these same meta-substituted analogs were typically less potent than the 4'-substituted analogs in inhibiting [3H]dopamine uptake. Ortho-substituted analogs were generally less potent in both binding and inhibition of uptake at the dopamine transporter than either benztropine or other aryl-substituted homologs. The analogs were also tested for binding at norepinephrine and serotonin transporters as well as muscarinic m1 receptors. None of the compounds in the present study bound with high affinity to either the norepinephrine or serotonin transporters, but all bound to muscarinic m1 receptors with high affinity (K1 = 0.41-2.52 nM). Interestingly, 3'-chloro-3 alpha-(diphenylmethoxy)tropane (5c) produced effects like cocaine in animals trained to discriminate 10 mg/kg cocaine from saline, unlike its 4'-Cl homolog and all of the previously evaluated benztropine analogs. Further evaluation of compound 5c and the other benztropine analogs will undoubtedly prove useful in the elucidation of the role of the dopamine transporter in the reinforcing effects of cocaine and the ultimate identification of a cocaine-abuse treatment.


Anesthesia Provider Training and Practice Models: A Survey of Africa.
In Africa, most countries have fewer than 1 physician anesthesiologist (PA) per 100,000 population. Nonphysician anesthesia providers (NPAPs) play a large role in the workforce of many low- and middle-income countries (LMICs), but little information has been systematically collected to describe existing human resources for anesthesia care models. An understanding of existing PA and NPAP training pathways and roles is needed to inform anesthesia workforce planning, especially for critically underresourced countries. Between 2016 and 2018, we conducted electronic, phone, and in-person surveys of anesthesia providers in Africa. The surveys focused on the presence of anesthesia training programs, training program characteristics, and clinical scope of practice after graduation. One hundred thirty-one respondents completed surveys representing data for 51 of 55 countries in Africa. Most countries had both PA and NPAP training programs (57%; mean, 1.6 pathways per country). Thirty distinct training pathways to become an anesthesia provider could be discriminated on the basis of entry qualification, duration, and qualification gained. Of these 30 distinct pathways, 22 (73%) were for NPAPs. Physician and NPAP program durations were a median of 48 and 24 months (ranges: 36-72, 9-48), respectively. Sixty percent of NPAP pathways required a nursing background for entry, and 60% conferred a technical (eg, diploma/license) qualification after training. Physicians and NPAPs were trained to perform most anesthesia tasks independently, though few had subspecialty training (such as regional or cardiac anesthesia). Despite profound anesthesia provider shortages throughout Africa, most countries have both NPAP and PA training programs. NPAP training pathways, in particular, show significant heterogeneity despite relatively similar scopes of clinical practice for NPAPs after graduation. Such heterogeneity may reflect the varied needs and resources for different settings, though may also suggest lack of consensus on how to train the anesthesia workforce. Lack of consistent terminology to describe the anesthesia workforce is a significant challenge that must be addressed to accelerate workforce research and planning efforts.


Channel waveguide lasers in Nd:GGG crystals fabricated by femtosecond laser inscription.
Buried channel waveguides have been fabricated in Nd:GGG crystals by using the femtosecond laser inscription. The waveguides are confined between two filaments with propagation losses of 2.0 dB/cm. Stable continuous wave laser oscillation at ~1061 nm has been demonstrated at room temperature. Under 808 nm optical excitation, a pump threshold of 29 mW and a slope efficiency of 25% have been obtained.


Mediterranean-Style Diet for the Primary and Secondary Prevention of Cardiovascular Disease: A Cochrane Review.
Diet plays a major role in cardiovascular disease (CVD) risk. To determine the effectiveness of a Mediterranean-style diet for the primary and secondary prevention of CVD. We searched for randomised controlled trials (RCTs) of Mediterranean-style diets in healthy adults and those at increased risk of CVD (primary prevention) and with established CVD (secondary prevention). Thirty RCTs were included, 22 in primary prevention and eight in secondary prevention. Clinical endpoints were reported in two trials where there was moderate quality evidence for a reduction in strokes for primary prevention, and low quality evidence for a reduction in total and CVD mortality in secondary prevention. We found moderate quality evidence of improvement in CVD risk factors for primary prevention and low quality evidence of little or no effect in secondary prevention. There is still some uncertainty regarding the effects of a Mediterranean-style diet in CVD prevention.


The Pre-Transplant Profile of Cardiovascular Risk Factors and Its Impact on Long-Term Mortality After Liver Transplantation.
BACKGROUND Cardiovascular disease (CVD) is an important aggravating factor for orthotopic liver transplantation (OLT) outcomes. CVD still seems to be one of the most common cause of death in the long-term post-transplant period. Nevertheless, there are some limited data regarding the optimal strategy of risk assessment during OLT candidate evaluation. MATERIAL AND METHODS Routine pre-transplant cardiac workup in 360 patients with end stage liver disease (ESLD) included electrocardiogram, echocardiography, and exercise stress testing. The aim of this retrospective study was an analysis of the impact of cardiovascular risk profile on overall mortality in the 2-year follow-up of 160 patients who underwent liver transplantation. RESULTS Cardiovascular risk factors or a history of CVD were found in 23.1% of patients who received transplants. The cardiovascular risk factors most common in our group of transplant recipients with ESLD were: diabetes (26.3%), hypertension (25.6%), and hepatopulmonary syndrome (23.1%). Only 3.8% of patients had a positive exercise test. Coronary angiography revealed at least 50% stenosis in some epicardial arteries in 1.9% of patients. The risk of death in long-term follow-up of liver transplant recipients was most strongly associated with 3 cardiac variables: history of coronary artery disease (CAD), angiographically confirmed coronary stenosis, and reduced ejection fraction (EF). CONCLUSIONS Our study identified pre-transplant CAD with its consequences as a factor associated with increased risk of negative post-transplant outcomes.


Policy Strategies for the "New Normal" in Healthcare to Ensure Access to High-Quality Cancer Care.
In recent years, oncology has seen a rapid increase in the introduction of high-cost innovative therapies while scrutiny around drug pricing has simultaneously amplified. Significant policy shifts impacting health coverage and benefit design are also being implemented, including narrow network health plans, uncertainty around the Affordable Care Act insurance exchanges, and threats to preexisting condition protections. Shifting health coverage policy combined with high drug prices and outdated reimbursement systems may create barriers to patient access to innovation and high-quality cancer care. To understand how trends in health policy are impacting the oncology ecosystem, NCCN convened the NCCN Policy Summit: Policy Strategies for the "New Normal" in Healthcare to Ensure Access to High-Quality Cancer Care on June 25, 2018. The summit included discussion of how innovation is changing cancer treatment, care delivery, and ways health systems are responding; the impact of narrow networks on access to academic cancer centers; and how the evolving health policy landscape is affecting access to high-quality cancer care for patients.


Distinct Growth Phases in Early Life Associated With the Risk of Type 1 Diabetes: The TEDDY Study.
This study investigates two-phase growth patterns in early life and their association with development of islet autoimmunity (IA) and type 1 diabetes (T1D). The Environmental Determinants of Diabetes in the Young (TEDDY) study followed 7,522 genetically high-risk children in Sweden, Finland, Germany, and the U.S. from birth for a median of 9.0 years (interquartile range 5.7-10.6) with available growth data. Of these, 761 (10.1%) children developed IA and 290 (3.9%) children were diagnosed with T1D. Bayesian two-phase piecewise linear mixed models with a random change point were used to estimate children's individual growth trajectories. Cox proportional hazards models were used to assess the effects of associated growth parameters on the risks of IA and progression to T1D. A higher rate of weight gain in infancy was associated with increased IA risk (hazard ratio [HR] 1.09 [95% CI 1.02, 1.17] per 1 kg/year). A height growth pattern with a lower rate in infancy (HR 0.79 [95% CI 0.70, 0.90] per 1 cm/year), higher rate in early childhood (HR 1.48 [95% CI 1.22, 1.79] per 1 cm/year), and younger age at the phase transition (HR 0.76 [95% CI 0.58, 0.99] per 1 month) was associated with increased risk of progression from IA to T1D. A higher rate of weight gain in early childhood was associated with increased risk of progression from IA to T1D (HR 2.57 [95% CI 1.34, 4.91] per 1 kg/year) in children with first-appearing GAD autoantibody only. Growth patterns in early life better clarify how specific growth phases are associated with the development of T1D.


Is the macromolecule signal tissue-specific in healthy human brain? A (1)H MRS study at 7 Tesla in the occipital lobe.
The macromolecule signal plays a key role in the precision and the accuracy of the metabolite quantification in short-TE (1) H MR spectroscopy. Macromolecules have been reported at 1.5 Tesla (T) to depend on the cerebral studied region and to be age specific. As metabolite concentrations vary locally, information about the profile of the macromolecule signal in different tissues may be of crucial importance. The aim of this study was to investigate, at 7T for healthy subjects, the neurochemical profile differences provided by macromolecule signal measured in two different tissues in the occipital lobe, predominantly composed of white matter tissue or of grey matter tissue. White matter-rich macromolecule signal was relatively lower than the gray matter-rich macromolecule signal from 1.5 to 1.8 ppm and from 2.3 to 2.5 ppm with mean difference over these regions of 7% and 12% (relative to the reference peak at 0.9 ppm), respectively. The neurochemical profiles, when using either of the two macromolecule signals, were similar for 11 reliably quantified metabolites (CRLB < 20%) with relatively small concentration differences (< 0.3 μmol/g), except Glu (± 0.8 μmol/g). Given the small quantification differences, we conclude that a general macromolecule baseline provides a sufficiently accurate neurochemical profile in occipital lobe at 7T in healthy human brain.


Factors influencing the desire to provide MS patient care in clinical practice among physiatrists.
Rehabilitation care is an important part of care for individuals with multiple sclerosis (MS). Little is known about factors influencing physiatrists' desire to provide MS care. This study examines factors associated with physiatrists' attitudes towards providing MS care. We collaborated with the American Academy of Physical Medicine and Rehabilitation to survey a sample of 300 U.S. physiatrists. Analyses examined the association of exposure to MS care resources during residency, physician demographic and practice characteristics with attitudes toward providing MS care. Physiatrists indicating negative factors limiting the number of MS patients seen in clinical practice were more likely to practice in a setting other than a major city and less likely to have interacted with MS specialists during residency. Physiatrists indicating factors having a positive influence on providing MS patient care were more likely to practice within a major city, see one or more MS patients per week, and serve as the primary physiatrist directing care for one or more MS patients. Physiatrists indicated positive and negative attitudes towards MS care. Increasing exposure to MS patients, providing resources for MS care, and participating in continuing education on MS, may encourage physiatrists to provide MS patient care.


Effect of acute high-intensity resistance exercise on optic nerve sheath diameter and ophthalmic artery blood flow pulsatility.
Exertional hypertension associated with acute high-intensity resistance exercise (RE) increases both intravascular and intracranial pressure (ICP), maintaining cerebrovascular transmural pressure. Carotid intravascular pressure pulsatility remains elevated after RE. Whether ICP also remains elevated after acute RE in an attempt to maintain the vessel wall transmural pressure is unknown. Optic nerve sheath diameter (ONSD), a valid proxy of ICP, was measured in 20 participants (6 female; 24 ± 4 yr, 24.2 ± 3.9 kg m(-)(2)) at rest (baseline), following a time-control condition, and following RE (5 sets, 5 repetition maximum bench press, 5 sets 10 repetition maximum biceps curls) using ultrasound. Additionally, intracranial hemodynamic pulsatility index (PI) was assessed in the ophthalmic artery (OA) by using Doppler. Aortic pulse wave velocity (PWV) was obtained from synthesized aortic pressure waveforms obtained via a brachial oscillometric cuff and carotid pulse pressure was measured by using applanation tonometry. Aortic PWV (5.2 ± 0.5-6.0 ± 0.7 m s(-1), P < 0.05) and carotid pulse pressure (45 ± 17-59 ± 19 mm Hg, P < 0.05) were significantly elevated post RE compared with baseline. There were no significant changes in ONSD (5.09 ± 0.7-5.09 ± 0.7 mm, P > 0.05) or OA flow PI (1.35 ± 0.2-1.38 ± 0.3, P > 0.05) following acute RE. In conclusion, during recovery from acute high-intensity RE, there are increases in aortic stiffness and extracranial pressure pulsatility in the absence of changes in ICP and flow pulsatility. These findings may have implications for alterations in cerebral transmural pressure and cerebral aneurysmal wall stress following RE.