The effects of health sector market factors and vulnerable group membership on access to alcohol, drug, and mental health care.
This study adapts Andersen's Behavioral Model to determine if health sector market conditions affect vulnerable subgroups' use of alcohol, drug, and mental health services (ADM) differently than the general population, focusing specifically on community-level predisposing and enabling characteristics. Wave 2 data (2000-2001) from the Health Care for Communities study, supplemented with cases from wave 1 (1997-1998), were merged with area characteristics taken from Census, Area Resource File (ARF), and other data sources. The study used four-level hierarchical logistic regression to examine access to ADM care from any provider and specialty ADM access. Interactions between community-level predisposing and enabling vulnerability characteristics with individual race/ethnicity, age, income category, and insurance type were explored. Nonwhites, the poor, uninsured, and elderly had lower likelihoods of service use, but interactions between race/ethnicity, income, age and insurance status with community-level vulnerability factors were not statistically significant for any service use. For ADM specialty care, those with Medicare, Medicaid, private fully managed, and private partially managed insurance, the likelihood of utilization was higher in areas with higher HMO penetration. However, for those with other insurance or no insurance plan, the likelihood of utilization was lower in areas with higher HMO penetration. Community-level enabling factors explain part of the effect of disadvantaged status but, with the exception of the effect of HMO penetration on the relationship between insurance and specialty care use, do not modify any of the residual individual-level effects of disadvantage. Interventions targeting both structural and individual levels may be necessary to address the problem of health disparities. More research with longitudinal data is necessary to sort out the causal direction of social context and ADM access outcomes, and whether policy interventions to change health sector market conditions can shift ADM treatment utilization.


Five Essential Elements of Immediate and Mid-Term Mass Trauma Intervention: Empirical Evidence.
Given the devastation caused by disasters and mass violence, it is critical that intervention policy be based on the most updated research findings. However, to date, no evidence-based consensus has been reached supporting a clear set of recommendations for intervention during the immediate and the mid-term post mass trauma phases. Because it is unlikely that there will be evidence in the near or mid-term future from clinical trials that cover the diversity of disaster and mass violence circumstances, we assembled a worldwide panel of experts on the study and treatment of those exposed to disaster and mass violence to extrapolate from related fields of research, and to gain consensus on intervention principles. We identified five empirically supported intervention principles that should be used to guide and inform intervention and prevention efforts at the early to mid-term stages. These are promoting: 1) a sense of safety, 2) calming, 3) a sense of self- and community efficacy, 4) connectedness, and 5) hope.


A DEAD-box-family protein is required for nucleocytoplasmic transport of yeast mRNA.
An enormous variety of primary and secondary mRNA structures are compatible with export from the nucleus to the cytoplasm. Therefore, there seems to be a mechanism for RNA export which is independent of sequence recognition. There nevertheless is likely to be some relatively uniform mechanism which allows transcripts to be packaged as ribonucleoprotein particles, to gain access to the periphery of the nucleus and ultimately to translocate across nuclear pores. To study these events, we and others have generated temperature-sensitive recessive mRNA transport (mtr) mutants of Saccharomyces cerevisiae which accumulate poly(A)+ RNA in the nucleus at 37 degrees C. Several of the corresponding genes have been cloned. Upon depletion of one of these proteins, Mtr4p, conspicuous amounts of nuclear poly(A)+ RNA accumulate in association with the nucleolus. Corresponding dense material is also seen by electron microscopy. MTR4 is essential for growth and encodes a novel nuclear protein with a size of approximately 120 kDa. Mtr4p shares characteristic motifs with DEAD-box RNA helicases and associates with RNA. It therefore may well affect RNA conformation. It shows extensive homology to a human predicted gene product and the yeast antiviral protein Ski2p. Critical residues of Mtr4p, including the mtr4-1 point mutation, have been identified. Mtr4p may serve as a chaperone which translocates or normalizes the structure of mRNAs in preparation for export.


Research directions: new clinical frontiers.
One of the greatest remaining challenges facing nephrology research is obtaining data with detail and precision for the three large, yet "forgotten," populations that span the spectrum of kidney disease: patients with chronic renal insufficiency (CRI), peritoneal dialysis patients, and kidney transplant patients. Studies of these populations, particularly the CRI group, are hampered by the relative mobility of these patients, the lack of stringent epidemiologic or clinical definitions, and the tendency to extrapolate data from hemodialysis populations into other clinical settings. This article suggests a two-pronged approach to a research agenda: first, by recognizing the need for better data regarding the natural history of these kidney failure subsets and their comorbidities; and second, by directing greater effort at identifying rational, efficacious, and cost-effective interventions to influence their natural history positively. Specific efforts are suggested in all three populations. For patients with CRI, studies should be directed at (1) identifying high-risk patients; (2) determining methods for making optimal referrals to the nephrologist; (3) identifying and managing CRI, its complications, and its comorbid conditions; and (4) establishing processes for the smooth transition to dialysis. The peritoneal dialysis population will benefit from studies addressing the treatment of anemia and its ability to modify cardiovascular illness and quality of life. Kidney transplant studies should also focus on the identification and management of comorbid conditions, as well as the effects of various interventions on quality of life. Rational evidence-based care of these conditions, which are critically important to patients, their families, and the health care system in general, must await the conduct of well-designed prospective observational and interventional trials.


Olanzapine Prevents the PCP-induced Reduction in the Neurite Outgrowth of Prefrontal Cortical Neurons via NRG1.
Accumulating evidence suggests that reducing neurite outgrowth and synaptic plasticity plays a critical role in the pathology of cognitive deficits in schizophrenia. The N-methyl-D-aspartate receptor antagonist phencyclidine (PCP) can induce symptoms of schizophrenia as well as reduce dendritic spine density and neurite growth. The antipsychotic drug olanzapine may improve these deficits. This study aimed to investigate: (1) if olanzapine prevents PCP-induced suppression of neurite outgrowth and synaptic protein expression; (2) if olanzapine affects the Akt-GSK3 signaling pathway; and (3) the role of neuregulin 1 (NRG1) in this process. Immunofluorescence revealed that PCP treatment for 24 hours reduces both neurite length (28.5%) and the number of neurite branches (35.6%) in primary prefrontal cortical neuron cultures. PCP reduced protein and mRNA expressions of synaptophysin (24.9% and 23.2%, respectively) and PSD95 (31.5% and 21.4%, respectively), and the protein expression of p-Akt (26.7%) and p-GSK3β (35.2%). Olanzapine co-treatment prevented these PCP-induced effects in normal neurons but not in neurons from NRG1-knockout mice. These results indicate that NRG1 mediates the preventive effects of olanzapine on the PCP-induced impairment of neurite outgrowth and synaptic protein expression. This study provides potential targets for interventions on improving the efficacy of olanzapine on preventing cognitive deficits in schizophrenia.


Internet-delivered cognitive behavioural therapy for adults with mild to moderate depression and high cardiovascular disease risks: a randomised attention-controlled trial.
Mild to moderate depression is common in those with cardiovascular disease and undertreated. We aimed to evaluate the effectiveness of internet-delivered Cognitive Behaviour Therapy (iCBT) on depressive symptom severity and adherence to medical advice and lifestyle interventions in adults with mild to moderate depression and high cardiovascular disease (CVD) risks. Randomised double-blind, 12 week attention-controlled trial comparing an iCBT programme (E-couch) with an internet-delivered attention control health information package (HealthWatch, n = 282). The primary outcome was depression symptom level on the nine-item Patient Health Questionnaire (PHQ-9) (trial registration: ACTRN12610000085077). 487/562 (88%) participants completed the endpoint assessment. 383/562 (70%) were currently treated for cardiovascular disease and 314/562 (56%) had at least one other comorbid condition. In ITT analysis of 562 participants iCBT produced a greater decline in the mean PHQ-9 score compared to the attention control of 1.06 (95% CI: 0.23-1.89) points, with differences between the two arms increasing over the intervention period (time by treatment effect interaction p = .012). There were also larger improvements in adherence (2.16 points; 95% CI: 0.33-3.99), reductions in anxiety (0.96 points; 95% CI: 0.19-1.73), and a greater proportion engaging in beneficial physical activity (Odds Ratio 1.91, 95%CI: 1.01-3.61) in the iCBT participants but no effect upon disability, or walking time/day. There were no withdrawals due to study related adverse events. In people with mild to moderate depression and high levels of CVD risk factors, a freely accessible iCBT programme (http://www.ecouch.anu.edu.au) produced a small, but robust, improvement in depressive symptoms, adherence and some health behaviours. Australian and New Zealand Clinical Trials Registry ACTRN12610000085077.


Readmission after endoscopic transsphenoidal pituitary surgery: analysis of 584 consecutive cases.
Hospital readmission is a key component in value-based healthcare models but there are limited data about the 30-day readmission rate after endonasal endoscopic transsphenoidal surgery (EETS) for pituitary adenoma. The objective of this study was to determine the incidence and identify factors associated with 30-day readmission after EETS for pituitary adenoma. The authors analyzed a prospectively acquired database of patients who underwent EETS for pituitary adenoma from 2005 to 2018 at NewYork-Presbyterian Hospital, Weill Cornell Medicine. Clinical, socioeconomic, and radiographic data were reviewed for cases of unplanned readmission within 30 days of surgery and, as a control group, for all other patients in the series who were not readmitted. Statistical significance was determined with an alpha < 0.05 using Pearson's chi-square and Fisher's exact tests for categorical variables and the independent-samples t-test for continuous variables. Of 584 patients undergoing EETS for pituitary adenoma, 27 (4.6%) had unplanned readmission within 30 days. Most readmissions occurred within the first week after surgery, with a mean time to readmission of 6.6 ± 3.9 days. The majority of readmissions (59%) were for hyponatremia. These patients had a mean sodium level of 120.6 ± 4.6 mEq/L at presentation. Other causes of readmission were epistaxis (11%), spinal headache (11%), sellar hematoma (7.4%), CSF leak (3.7%), nonspecific headache (3.7%), and pulmonary embolism (3.7%). The postoperative length of stay was significantly shorter for patients who were readmitted than for the controls (2.7 ± 1.0 days vs 3.9 ± 3.2 days; p < 0.05). Patients readmitted for hyponatremia had an initial length of stay of 2.6 ± 0.9 days, the shortest of any cause for readmission. The mean BMI was significantly lower for readmitted patients than for the controls (26.4 ± 3.9 kg/m2 vs 29.3 ± 6.1 kg/m2; p < 0.05). Readmission after EETS for pituitary adenoma is a relatively rare phenomenon, with delayed hyponatremia being the primary cause. The study results demonstrate that shorter postoperative length of stay and lower BMI were associated with 30-day readmission.


Effects of increasing afterload on left ventricular output in fetal lambs.
Fetal ventricular performance has been considered limited because ventricular output does not increase with rapid volume expansion above mean left atrial pressures (mLAPs) of 5-7 mm Hg. To explore relations between preload, afterload, and stroke volume (SV) in the fetal left ventricle, we instrumented 126-129 days gestation fetal lambs with ascending aortic electromagnetic flow transducers, vascular catheters, and inflatable occluders around the aortic isthmus (n = 8) or descending aorta (n = 7). At 24-48 hours after surgery, blood was withdrawn or infused to reach various mLAPs. The aorta was then slowly occluded as aortic flow and mean arterial pressure (MAP) were measured continuously. Isthmus constriction produced linear decreases in SV as MAP increased; mLAP was unchanged. Descending aortic constriction produced no decrease in SV until high MAPs were reached. SV decreased as MAP increased further, and mLAP rose significantly. The curve relating mLAP and SV before constriction showed little increase in SV above mLAPs of 5-7 mm Hg; however, when curves were derived relating SV and mLAP at relatively constant MAPs, SV continued to increase even above an mLAP of 8-10 mm Hg. Our studies indicate that the fetal left ventricle responds to progressive increases in mLAP to at least 10 mm Hg. The lack of increase in SV above an mLAP of 5-7 mm Hg with rapid volume expansion is related to the concomitant increase in MAP and afterload.


A crucial function of SGT1 and HSP90 in inflammasome activity links mammalian and plant innate immune responses.
The family of mammalian Nod-like receptors (NLRs) consists of critical intracellular immune proteins structurally related to plant resistance proteins. The NLRs NALP3 and IPAF, for example, can each form a multiprotein proinflammatory complex called the 'inflammasome', and mutations in the gene encoding Nod2, another NLR, are positively associated with Crohn disease. Here we show that many NLRs interacted with the ubiquitin ligase-associated protein SGT1 and heat-shock protein 90 (HSP90), both of which have plant orthologs essential for R-protein responses. 'Knockdown' of SGT1 by small interfering RNA or chemical inhibition of HSP90 abrogated inflammasome activity, and inhibition of HSP90 blocked Nod2-mediated activation of the transcription factor NF-kappaB and reduced NALP3-mediated gout-like inflammation in mice. Our data demonstrate a similarity in one type of innate immunity in plants and mammals that is consistent with convergent evolution of a shared mechanism.


The development of expertise in paediatric rehabilitation therapists: the roles of motivation, openness to experience, and types of caseload experience.
A transdisciplinary approach was taken to study the nature of variables associated with the development of expertise in 71 paediatric rehabilitation therapists (i.e. physical, occupational, speech, behavioural, and recreational therapists). Six groups of practising therapists were identified based on expertise status (novice, intermediate, and expert, as determined by a multifaceted assessment battery), and their level of clinical experience (10 years or less, more than 10 years). Scores for these six therapist groups were examined on three variables generally considered to be associated with the development of expertise--motivation, openness to experience (as defined by the critical-thinking dispositions of truth-seeking, open-mindedness, and cognitive maturity), and features of their clinical caseload experience (i.e. breadth of experience as measured by number of different client age groups worked with, the complexity of clients' needs, and experience in delivering services to adolescents, school-age children, preschoolers, and infants). Low-experience experts ('young stars') had the highest motivation, truth-seeking, and open-mindedness scores of all groups, the highest percentage of clients with complex service needs, and were more likely to work with adolescents. The major differences between therapists who attain expertise quickly versus those who remain novices after many years of experience appear to be motivation and complexity of work experiences. Implications for supporting the development of expertise in practising therapists are discussed.


Systematic review and meta-analysis of clinical trials examining the effect of hyperbaric oxygen therapy in people with diabetes-related lower limb ulcers.
To examine the efficacy of hyperbaric oxygen therapy in healing diabetes-related lower limb ulcers through a meta-analysis of randomized clinical trials. A literature search was conducted to identify appropriate clinical trials. Inclusion required randomized study design and reporting of the proportion of diabetes-related lower limb ulcers that healed. A meta-analysis was performed to examine the effect of hyperbaric oxygen therapy on ulcer healing. The secondary outcomes were minor and major amputations. Nine randomized trials involving 585 participants were included. People allocated to hyperbaric oxygen therapy were more likely to have complete ulcer healing (relative risk 1.95, 95% CI 1.51-2.52; P<0.001), and less likely to require major (relative risk 0.54, 95% CI 0.36-0.81; P=0.003) or minor (relative risk 0.68, 95% CI 0.48-0.98; P=0.040) amputations than control groups. Sensitivity analyses suggested the findings were dependent on the inclusion of one trial. Adverse events included ear barotrauma and a seizure. Many of the trials were noted to have methodological weaknesses including absence of blinding of outcome assessors, lack of a justifiable sample size calculation and limited follow-up. This meta-analysis suggests hyperbaric oxygen therapy improves the healing of diabetes-related lower limb ulcers and reduces the requirement for amputation. Confidence in these results is limited by significant design weaknesses of previous trials and inconsistent findings. A more rigorous assessment of the efficacy of hyperbaric the efficacy of hyperbaric oxygen therapy is needed.


Early-onset group B streptococcal infection after a combined maternal and neonatal group B streptococcal chemoprophylaxis strategy.
In January 1995, a combined maternal and neonatal protocol for prevention of early-onset group B streptococcal (GBS) infection was implemented that consisted of a risk factor-based approach for maternal intrapartum chemoprophylaxis using ampicillin combined with a single intramuscular dose of penicillin given to all newborns within 1 hour of delivery. The objective of this study was to review the cases of early-onset GBS infections that occurred from 1995 to 1999 to identify factors associated with their continued occurrence despite implementation of a GBS chemoprophylaxis protocol. Infants <or=72 hours of age with early-onset GBS infection born at Parkland Memorial Hospital in Dallas from January 1995 to December 1999 were identified through a prospective laboratory-based surveillance system. Maternal and infant medical records were reviewed for clinical and demographic data. There were 32 cases (0.47/1000 live births) of early-onset GBS infection for the 5-year period. This represented a 76% reduction compared with the rate from 1986 to 1994 (1.95/1000), when there was no protocol for GBS chemoprophylaxis. Thirteen cases (41%) did not have any identifiable maternal risk factor. Of the 19 cases (59%) with risk factors, maternal intrapartum fever was the most frequent (15 [79%]), followed by prematurity (6 [32%]) and prolonged rupture of membranes (6 [32%]). Among the 19 mothers with risk factors, 15 (79%) mothers received intrapartum chemoprophylaxis, and 12 (80%) of the 15 mothers had intrapartum fever. Only 33% of mothers with risk factors received >or=2 doses of intrapartum chemoprophylaxis, and among those with intrapartum fever, 25% received >or=2 doses. None of the 32 infants with early-onset GBS infection received the combination of intrapartum ampicillin and postnatal penicillin. A combined obstetric and neonatal chemoprophylaxis protocol significantly reduced early-onset GBS infection. Maternal intrapartum fever was the most frequent risk factor associated with failure of chemoprophylaxis.


Iron redox transformations in continuously photolyzed acidic solutions containing natural organic matter: kinetic and mechanistic insights.
In this work, the various pathways contributing to the formation and decay of Fe(II) in photolyzed acidic solutions containing Suwannee River fulvic acid (SRFA) are investigated. Results of experimental and computational studies suggest that ligand to metal charge transfer (LMCT), superoxide-mediated iron reduction and interaction with reduced organic species that are present intrinsically in SRFA each contribute to Fe(III) reduction with LMCT the most likely dominant pathway under these conditions. Fe(II) oxidation occurs as a result of its interaction with a variety of light-generated species including (i) short-lived organic species, (ii) relatively stable semiquinone-like organic species, and (iii) hydroperoxy radicals. While not definitive, a hypothesis that the short-lived organic species are similar to peroxyl radicals appears most consistent with our experimental and modeling results. The semiquinone-like organic species formed during photolysis by superoxide-mediated oxidation of reduced organic moieties are long-lived in the dark but prone to rapid oxidation by singlet oxygen ((1)O2) under irradiated conditions and thus play a minor role in Fe(II) oxidation in the light. A kinetic model is developed that adequately describes all aspects of the experimental data obtained and which is capable of predicting Fe(II) oxidation rates and Fe(III) reduction rates in the presence of natural organic matter and light.


Phosphoglycerate mutase 1 coordinates glycolysis and biosynthesis to promote tumor growth.
It is unclear how cancer cells coordinate glycolysis and biosynthesis to support rapidly growing tumors. We found that the glycolytic enzyme phosphoglycerate mutase 1 (PGAM1), commonly upregulated in human cancers due to loss of TP53, contributes to biosynthesis regulation in part by controlling intracellular levels of its substrate, 3-phosphoglycerate (3-PG), and product, 2-phosphoglycerate (2-PG). 3-PG binds to and inhibits 6-phosphogluconate dehydrogenase in the oxidative pentose phosphate pathway (PPP), while 2-PG activates 3-phosphoglycerate dehydrogenase to provide feedback control of 3-PG levels. Inhibition of PGAM1 by shRNA or a small molecule inhibitor PGMI-004A results in increased 3-PG and decreased 2-PG levels in cancer cells, leading to significantly decreased glycolysis, PPP flux and biosynthesis, as well as attenuated cell proliferation and tumor growth.


Repair and Reconstruction of Medial- and Lateral-sided Knee Injuries.
Surgical treatment of medial and lateral knee injuries using repair and/or reconstruction techniques is often necessary to restore knee ligament stability and optimize function. Successful execution of these repairs and reconstructions requires a sound understanding of basic anatomy and biomechanics. Against this backdrop, numerous repair and reconstruction techniques have been developed. Although medial knee injuries are often amenable to healing, posterolateral knee injuries often do not heal after a complete tear. Posterolateral corner repair should be attempted only in acute lateral knee injuries and never for midsubstance tears. Postoperative rehabilitation follows a period approach, with an emphasis on early range-of-motion exercises and protection of the surgical repair or reconstruction. By following these approaches to medial and lateral knee repairs and reconstructions, it is possible to restore stability to an injured knee and expedite return to desired levels of activity.


Polio survivors' perceptions of the meaning of quality of life and strategies used to promote participation in everyday activities.
The term 'post-polio syndrome' (PPS) is used to describe new and late manifestations of poliomyelitis that occur later in life. Research in this area has focused upon health status rather than its effect on quality of life. To gain an in-depth understanding of the meaning of quality of life for polio survivors and to determine the type of strategies that are used by people with PPS and the support that they consider as important to facilitate participation in everyday life activities that have an impact on their quality of life. Six focus groups were conducted with 51 participants from two regions in England. Data were audio-taped and analysed using thematic analysis. Our research found that polio survivors used terms used to describe quality of life which could be associated with that of happiness. Our research has identified resolvable factors that influence quality of life namely inaccessible environments, attitudes of health-care professionals and societal attitudes. Polio survivors have tried alternative therapies, chiefly acupuncture and massage, and found them to be effective in enhancing their quality of life. It is suggested that health-care professionals should consider factors which influence happiness and implement a person-centred approach with the views of the polio survivor being listened to. The three factors that influenced quality of life could be resolved by health-care professionals and by society. With regard to strategies used, we suggest that polio survivors should have access to the treatments that they perceive as important, although further research is required to design optimal interventions for this client group.


Using lot quality assurance sampling to improve immunization coverage in Bangladesh.
To determine areas of low vaccination coverage in five cities in Bangladesh (Chittagong, Dhaka, Khulna, Rajshahi, and Syedpur). Six studies using lot quality assurance sampling were conducted between 1995 and 1997 by Basic Support for Institutionalizing Child Survival and the Bangladesh National Expanded Programme on Immunization. BCG vaccination coverage was acceptable in all lots studied; however, the proportion of lots rejected because coverage of measles vaccination was low ranged from 0% of lots in Syedpur to 12% in Chittagong and 20% in Dhaka's zones 7 and 8. The proportion of lots rejected because an inadequate number of children in the sample had been fully vaccinated varied from 11% in Syedpur to 30% in Dhaka. Additionally, analysis of aggregated, weighted immunization coverage showed that there was a high BCG vaccination coverage (the first administered vaccine) and a low measles vaccination coverage (the last administered vaccine) indicating a high drop-out rate, ranging from 14% in Syedpur to 36% in Dhaka's zone 8. In Bangladesh, where resources are limited, results from surveys using lot quality assurance sampling enabled managers of the National Expanded Programme on Immunization to identify areas with poor vaccination coverage. Those areas were targeted to receive focused interventions to improve coverage. Since this sampling method requires only a small sample size and was easy for staff to use, it is feasible for routine monitoring of vaccination coverage.


Probing endoplasmic reticulum dynamics using fluorescence imaging and photobleaching techniques.
This unit describes approaches and tools for studying the dynamics and organization of endoplasmic reticulum (ER) membranes and proteins in living cells using fluorescence microscopy. The ER plays a key role in secretory protein biogenesis, calcium regulation, and lipid synthesis. However, study of these processes has often been restricted to biochemical assays that average millions of lysed cells or imaging of static fixed cells. With new fluorescent protein (FP) reporter tools, sensitive commercial microscopes, and photobleaching techniques, investigators can interrogate the behaviors of ER proteins, membranes, and stress pathways in single live cells. Solutions are described for imaging challenges relevant to the ER, including the mobility of ER membranes, a range of ER structures, and the influence of post-translational modifications on FP reporters. Considerations for performing photobleaching assays for ER proteins are discussed. Finally, reporters and drugs for studying misfolded secretory protein stress and the unfolded protein response are described.


Perivascular iron deposition and other vascular damage in multiple sclerosis.
Evidence of damage to cerebral vein walls was sought in 70 cases of multiple sclerosis. Seventy control cases were also examined. The multiple sclerosis cases showed venous intramural fibrinoid deposition (7%), recent haemorrhages (17%), old haemorrhages revealed by haemosiderin deposition (30%), thrombosis (6%) and thickened veins (19%). In all, 41% of all multiple sclerosis cases showed some evidence of vein damage. Occasional control cases showed haemosiderin deposition in the brain but, unlike the multiple sclerosis cases, these were diffuse and almost entirely related to coexistent cardiovascular or cerebrovascular disease. Haemosiderin deposition was common in the substantia nigra and other pigmented nuclei in all cases. It is concluded that the cerebral vein wall in multiple sclerosis is subject to chronic inflammatory damage, which promotes haemorrhage and increased permeability, and constitutes a form of vasculitis.


Environmental variation alters the fitness effects of rifampicin resistance mutations in Pseudomonas aeruginosa.
The fitness effects of antibiotic resistance mutations in antibiotic-free conditions play a key role in determining the long-term maintenance of resistance. Although resistance is usually associated with a cost, the impact of environmental variation on the cost of resistance is poorly understood. Here, we test the impact of heterogeneity in temperature and resource availability on the fitness effects of antibiotic resistance using strains of the pathogenic bacterium Pseudomonas aeruginosa carrying clinically important rifampicin resistance mutations. Although the rank order of fitness was generally maintained across environments, fitness effects relative to the wild type differed significantly. Changes in temperature had a profound impact on the fitness effects of resistance, whereas changes in carbon substrate had only a weak impact. This suggests that environmental heterogeneity may influence whether the costs of resistance are likely to be ameliorated by second-site compensatory mutations or by reversion to wild-type rpoB. Our results highlight the need to consider environmental heterogeneity and genotype-by-environment interactions for fitness in models of resistance evolution.


The effect and safety of highly standardized Ginger (Zingiber officinale) and Echinacea (Echinacea angustifolia) extract supplementation on inflammation and chronic pain in NSAIDs poor responders. A pilot study in subjects with knee arthrosis.
The study aimed to evaluate the effect of Zingiber officinale and Echinacea angustifolia extract supplementation (25 mg of ginger and 5 mg of Echinacea) for 30 days on inflammation and chronic pain in knee osteoarthritis (OA). Consecutive nonsteroidal anti-inflammatory-drugs (NSAIDs) poor responders with chronic inflammation and pain due to knee arthrosis were assessed (15 subjects, age: 67.2 ± 7.9, body mass index: 30.6 ± 7.1, men/women:2/13). The primary endpoint was to determine pain improvement from baseline to Day 30 by Tegner Lysholm Knee Scoring. The secondary endpoints were the assessment of Visual Analog Scale for Pain, health-related quality of life, by the ShortForm36 (SF-36), anthropometric parameters, hydration. After supplementation, a significant improvement of 12.27 points was observed for Lysholm scale score (p < 0.05), SF-36 (p < 0.05), and a decrease in -0.52 cm in knee circumference (left) (p < 0.01). This pilot study provides feasibility and safety data for the use of highly standardised ginger and Echinacea extract supplementation in people with knee OA.


Causal Role of Thalamic Interneurons in Brain State Transitions: A Study Using a Neural Mass Model Implementing Synaptic Kinetics.
Experimental studies on the Lateral Geniculate Nucleus (LGN) of mammals and rodents show that the inhibitory interneurons (IN) receive around 47.1% of their afferents from the retinal spiking neurons, and constitute around 20-25% of the LGN cell population. However, there is a definite gap in knowledge about the role and impact of IN on thalamocortical dynamics in both experimental and model-based research. We use a neural mass computational model of the LGN with three neural populations viz. IN, thalamocortical relay (TCR), thalamic reticular nucleus (TRN), to study the causality of IN on LGN oscillations and state-transitions. The synaptic information transmission in the model is implemented with kinetic modeling, facilitating the linking of low-level cellular attributes with high-level population dynamics. The model is parameterized and tuned to simulate alpha (8-13 Hz) rhythm that is dominant in both Local Field Potential (LFP) of LGN and electroencephalogram (EEG) of visual cortex in an awake resting state with eyes closed. The results show that: First, the response of the TRN is suppressed in the presence of IN in the circuit; disconnecting the IN from the circuit effects a dramatic change in the model output, displaying high amplitude synchronous oscillations within the alpha band in both TCR and TRN. These observations conform to experimental reports implicating the IN as the primary inhibitory modulator of LGN dynamics in a cognitive state, and that reduced cognition is achieved by suppressing the TRN response. Second, the model validates steady state visually evoked potential response in humans corresponding to periodic input stimuli; however, when the IN is disconnected from the circuit, the output power spectra do not reflect the input frequency. This agrees with experimental reports underpinning the role of IN in efficient retino-geniculate information transmission. Third, a smooth transition from alpha to theta band is observed by progressive decrease of neurotransmitter concentrations in the synaptic clefts; however, the transition is abrupt with removal of the IN circuitry in the model. The results imply a role of IN toward maintaining homeostasis in the LGN by suppressing any instability that may arise due to anomalous synaptic attributes.


Multispectral metamaterial absorber.
We present the simulation, implementation, and measurement of a multispectral metamaterial absorber (MSMMA) and show that we can realize a simple absorber structure that operates in the mid-IR and terahertz (THz) bands. By embedding an IR metamaterial absorber layer into a standard THz metamaterial absorber stack, a narrowband resonance is induced at a wavelength of 4.3 μm. This resonance is in addition to the THz metamaterial absorption resonance at 109 μm (2.75 THz). We demonstrate the inherent scalability and versatility of our MSMMA by describing a second device whereby the MM-induced IR absorption peak frequency is tuned by varying the IR absorber geometry. Such a MSMMA could be coupled with a suitable sensor and formed into a focal plane array, enabling multispectral imaging.


Silver-promoted decarboxylative amidation of α-keto acids with amines.
A general and effective method for the synthesis of amides through decarboxylative amidation of α-keto acids with amines has been developed. The reaction proceeded smoothly to afford the corresponding amide products in good yield under air and shows excellent functional group tolerance. In addition, the protocol can be further applied in the synthesis of heterocyclic compounds like benzimidazoles.


Direct measurement of a photoconductive receiver's temporal response by dithered-edge sampling.
We present the results of a direct measurement of the temporal response of a terahertz (THz) photoconductive receiver obtained by dithered-edge sampling. The receiver response has structure that accounts for the negative-going leading edge of the pulse shape that is often seen in measurements made with these receivers in a conventional sampling arrangement. We show that the THz pulse shape measured by conventional photoconductive sampling is indeed a cross correlation of the pulse with the measured receiver's response.


The Perforation of the Superior Vena Cava Secondary to the Left Subclavian Dialysis Catheter.
The perforation of the superior vena cava during the placement of dialysis catheter and consequent hemothorax is a rare serious complication. Dialysis catheter was placed in the left subclavian vein in a 69-year-old male patient with chronic renal insufficiency who was hospitalized for intracerebral hematoma. During hemodialysis a day after the procedure, the patient was noted having right-sided hemothorax, causing lethargy, dyspnea, hypotension, and bradycardia. Right tube thoracostomy was performed and 1500 cc of hemorrhagic fluid was drained. Under general anesthesia, the right posterolateral thoracotomy was performed and the tip of the dialysis catheter was found in the pleural space, penetrating the anteromedial side of the superior vena cava. The perforation area was repaired by suturing with 3-0 prolene, and the dialysis catheter was removed externally. Postoperative period was uneventful, and tube thoracostomy was terminated on day 4. Establishing the diagnosis early and accurately and performing appropriate surgery would be lifesaving in superior vena cava perforation due to dialysis catheter.


Mind the gap? The platform trial as a working environment.
Trials have become bigger and more complicated due to the complexity introduced by biomarker stratification, and the advent of multi-arm multi-stage trials, and umbrella and basket platform designs. The trials unit at University College London has been at the forefront of this work, with ground-breaking trials such as STAMPEDE and FOCUS4. The trial management and data management teams on these trials have summarised the operational challenges, to enable the broader clinical trials community to learn from their experiences. In a small-scale qualitative study, we examined the personal experience of individual researchers working on these trials. We found reports of high workloads, with potentially significant stress for individuals and with an impact on their career choices. We conclude that there was an initial underestimation of the work required and of the inherent, largely unanticipated, challenges. We discuss the importance of fully understanding these trials' resource requirements, both for those writing grant applications and critically, for those with responsibility for deciding on funding. The working environment was characterised by three features: complexity, scale and heightened expectations. These features are highly attractive for professional development and engender high levels of loyalty and commitment. We observed a trade-off between these intrinsic rewards and the continuous demands of overlapping tasks, balancing a mix of routine and high-profile work, and the changing nature of pivotal roles. Such demands present challenges for colleague relationships, by enhancing the potential for competition and by disrupting the natural opportunities to pause, review and celebrate team achievements. In addition, molecular stratification in effect brings the patient into the trial office, as a specific individual, despite anonymisation, who is owed test results and a treatment decision. We discuss these observations with a view to interconnecting the need for compassion for patients with caring for the researchers engaged in the research ecosystem who are aiming to produce much hoped-for advances in medical science. There is a need for increased awareness of the challenge these studies place on those throughout the team delivering the study. Such considerations must influence leaders and funders, both in their initial budget considerations and throughout delivery.


Parental Body Mass Index and Behavioral Problems in Their Offspring: A Danish National Birth Cohort Study.
Maternal obesity has been associated with increased risk of offspring behavioral problems. We examined whether this association could be explained by familial factors by comparing associations for maternal body mass index (BMI) with associations for paternal BMI. We studied 38,314 children born to mothers enrolled in the Danish National Birth Cohort during 1996-2002. Data on maternal BMI was collected at 15 weeks of gestation, and paternal BMI was assessed when the child was 18 months old. When the child was 7 years old, the Strengths and Difficulties Questionnaire was completed by the parents. We estimated odds ratios for behavioral problems in offspring born to overweight/obese parents, and we found that maternal BMI was associated with offspring behavioral problems. Maternal BMI of 25.0-29.9 was associated with a 33% (odds ratio = 1.33, 95% confidence interval: 1.13, 1.57) higher risk of total difficulties in offspring, and maternal BMI of ≥30.0 was associated with an 83% (odds ratio = 1.83, 95% confidence interval: 1.49, 2.25) higher risk. Paternal obesity was also associated with higher risk of offspring behavioral problems, but stronger associations were observed with maternal prepregnancy obesity. Our results suggest that part of the association between maternal BMI and behavioral problems can be accounted for by genetic and social factors, but environmental risk factors may also contribute to the etiology of behavioral problems.


Structural basis for recognition of H3K56-acetylated histone H3-H4 by the chaperone Rtt106.
Dynamic variations in the structure of chromatin influence virtually all DNA-related processes in eukaryotes and are controlled in part by post-translational modifications of histones. One such modification, the acetylation of lysine 56 (H3K56ac) in the amino-terminal α-helix (αN) of histone H3, has been implicated in the regulation of nucleosome assembly during DNA replication and repair, and nucleosome disassembly during gene transcription. In Saccharomyces cerevisiae, the histone chaperone Rtt106 contributes to the deposition of newly synthesized H3K56ac-carrying H3-H4 complex on replicating DNA, but it is unclear how Rtt106 binds H3-H4 and specifically recognizes H3K56ac as there is no apparent acetylated lysine reader domain in Rtt106. Here, we show that two domains of Rtt106 are involved in a combinatorial recognition of H3-H4. An N-terminal domain homodimerizes and interacts with H3-H4 independently of acetylation while a double pleckstrin-homology (PH) domain binds the K56-containing region of H3. Affinity is markedly enhanced upon acetylation of K56, an effect that is probably due to increased conformational entropy of the αN helix of H3. Our data support a mode of interaction where the N-terminal homodimeric domain of Rtt106 intercalates between the two H3-H4 components of the (H3-H4)(2) tetramer while two double PH domains in the Rtt106 dimer interact with each of the two H3K56ac sites in (H3-H4)(2). We show that the Rtt106-(H3-H4)(2) interaction is important for gene silencing and the DNA damage response.


Crystal phase-dependent nanophotonic resonances in InAs nanowire arrays.
Nanostructures have many material, electronic, and optical properties that are not found in bulk systems and that are relevant for technological applications. For example, nanowires realized from III-V semiconductors can be grown into a wurtzite crystal structure. This crystal structure does not naturally exist in bulk where these materials form the zinc-blende counterpart. Being able to concomitantly grow these nanowires in the zinc-blende and/or wurtzite crystal structure provides an important degree of control for the design and optimization of optoelectronic applications based on these semiconductor nanostructures. However, the refractive indices of this new crystallographic phase have so far not been elucidated. This shortcoming makes it impossible to predict and utilize the full potential of these new nanostructured materials for optoelectronics applications: a careful design and optimization of optical resonances by tuning the nanostructure geometry is needed to achieve optimal performance. Here, we report and analyze striking differences in the optical response of nanophotonic resonances in wurtzite and zinc-blende InAs nanowire arrays. Specifically, through reflectance measurements we find that the resonance can be tuned down to λ ≈ 380 nm in wurtzite nanowires by decreasing the nanowire diameter. In stark contrast, a similar tuning to below λ ≈ 500 nm is not possible in the zinc-blende nanowires. Furthermore, we find that the wurtzite nanowires can absorb twice as strongly as the zinc-blende nanowires. We attribute these strikingly large differences in resonant behavior to large differences between the refractive indices of the two crystallographic phases realized in these nanostructures. We anticipate our findings to be relevant for other III-V materials as well as for all material systems that manifest polytypism. Taken together, our results demonstrate crystal phase engineering as a potentially new design dimension for optoelectronics applications.


Fracture after radiation therapy for femoral metastasis: incidence, timing and clinical features.
We analyzed 428 femoral metastases initially treated with radiotherapy between 2002 and 2011 to clarify the clinical details of post-irradiation fractures of femoral metastasis. Patients included 161 men and 167 women, with a mean age of 62 years. Fracture incidence, fracture site, fracture risk based on X-ray images before radiotherapy, and interval from completion of radiotherapy to fracture occurrence were assessed. In addition, 24 pathological specimens obtained during 27 surgeries for these fractures were examined. Fractures occurred in 7.7% of 428 femoral metastases (total 33: 28 actual fractures and five virtual fractures with progressive pain and bone destruction). The fracture rate was 7.8% in the proximal femur and 1.5% in the shaft (P = 0.001). Fractures occurred a median of 4.4 months after radiotherapy, with 39.4% occurring within 3 months and 63.6% within 6 months. Among femurs with high fracture risk according to Harrington's criteria or Mirels' score, the fracture rate was 13.9% and 11.8%, respectively. Viable tumor cells were detected in all five patients with painful virtual fracture, in 85.7% of femurs with actual fractures that occurred within 3 months, and in only 25.0% of actual fractures occurring after 3 months. Post-irradiation fractures of femoral metastasis most frequently occurred within 3 months after radiotherapy, and were more common in the peritrochanteric area than in the shaft. Radiological evidence of impending fracture did not correlate with a high fracture rate. Actual fractures occurring after more than 3 months were likely caused by post-irradiation fragility of the femur, without viable tumor cells.


Sex differences in astrocyte and microglia responses immediately following middle cerebral artery occlusion in adult mice.
Epidemiological studies report that infarct size is decreased and stroke outcomes are improved in young females when compared to males. However, mechanistic insight is lacking. We posit that sex-specific differences in glial cell functions occurring immediately after ischemic stroke are a source of dichotomous outcomes. In this study we assessed astrocyte Ca2+ dynamics, aquaporin 4 (AQP4) polarity, S100β expression pattern, as well as, microglia morphology and phagocytic marker CD11b in male and female mice following 60min of middle cerebral artery (MCA) occlusion. We reveal sex differences in the frequency of intracellular astrocyte Ca2+ elevations (F(1,86)=8.19, P=0.005) and microglia volume (F(1,40)=12.47, P=0.009) immediately following MCA occlusion in acute brain slices. Measured in fixed tissue, AQP4 polarity was disrupted (F(5,86)=3.30, P=0.009) and the area of non-S100β immunoreactivity increased in ipsilateral brain regions after 60min of MCA occlusion (F(5,86)=4.72, P=0.007). However, astrocyte changes were robust in male mice when compared to females. Additional sex differences were discovered regarding microglia phagocytic receptor CD11b. In sham mice, constitutively high CD11b immunofluorescence was observed in females when compared to males (P=0.03). When compared to sham, only male mice exhibited an increase in CD11b immunoreactivity after MCA occlusion (P=0.006). We posit that a sex difference in the presence of constitutive CD11b has a role in determining male and female microglia phagocytic responses to ischemia. Taken together, these findings are critical to understanding potential sex differences in glial physiology as well as stroke pathobiology which are foundational for the development of future sex-specific stroke therapies.


The Potential Role of Yogurt in Weight Management and Prevention of Type 2 Diabetes.
Yogurt is a semisolid fermented milk product that originated centuries ago and is viewed as an essential food and important source of nutrients in the diet of humans. Over the last 30 years, overweight and obesity have become characteristic of Western and developing countries, which has led to deleterious health outcomes, including cardiovascular disease, type 2 diabetes, hypertension, and other chronic conditions. Recent epidemiological and clinical evidence suggests that yogurt is involved in the control of body weight and energy homeostasis and may play a role in reducing the risk for type 2 diabetes partly via the replacement of less healthy foods in the diet, its food matrix, the effect of specific nutrients such as calcium and protein on appetite control and glycemia, and alteration in gut microbiota. This review will discuss the specific properties that make yogurt a unique food among the dairy products, epidemiological and clinical evidence supporting yogurt's role in body weight, energy balance, and type 2 diabetes, including its potential mechanisms of action and gaps that need to be explored. Key teaching points • Several epidemiological and clinical studies have suggested a beneficial effect of yogurt consumption in the control of body weight and energy homeostasis, although this remains controversial. • Yogurt possesses unique properties, including its nutritional composition; lactic acid bacteria, which may affect gut microbiota; and food matrix, which may have a potential role in appetite and glycemic control. • Potential mechanisms of action of yogurt include an increase in body fat loss, decrease in food intake and increase in satiety, decrease in glycemic and insulin response, altered gut hormone response, replacement of less healthy foods, and altered gut microbiota. • The relative energy and nutrient content and contribution of a standard portion of yogurt to the overall diet suggest that the percentage daily intake of these nutrients largely contributes to nutrient requirements and provides a strong contribution to the regulation of energy metabolism.


Environmental benchmarks vs. ecological benchmarks for assessment and monitoring in Canada: is there a difference?
Environmental benchmarks are widely used in Canadian environmental assessment as a standard against which to monitor air or water quality in response to human activities in the environment. Recent work in Canada has developed the concept of ecological benchmarks as a complement to environmental benchmarks. However, implementation of ecological benchmarks may be challenging. This paper presents an analogy between ecological benchmarks and the more commonly used environmental benchmarks, as an attempt to increase understanding and use of ecological benchmarks in resource management, assessment, and monitoring. Ecological benchmarks, and their corresponding indicators, will be challenging to identify and use. However, through the use of the principles of adaptive management, effective ecological indicators and benchmarks can be established. Although it is essential that ecological benchmarks are site-specific, the analogy and general principles outlined here are applicable to assessment and monitoring in any part of the world.


Upright Radiation Therapy-A Historical Reflection and Opportunities for Future Applications.
Since the early days of megavoltage Radiation Therapy (RT), the potential of delivering treatment to a sub group of patients in an upright position has been recognized. Compared to lying horizontally, treating patients in an upright position offers potential benefits in terms of patient comfort especially for patients experiencing dyspnoea and saliva accumulation when lying down. Dosimetric benefits can also be gained from changes in the volume and location of lungs and heart in an upright position, which are potentially advantageous for clinical situations including Hodgkin's disease, lung and breast malignancies. Since the 1950's, upright stabilization mechanisms have ranged from standalone chair based apparatus to couch-top attachments with increasingly customizable solutions. The introduction of Computed-Tomography (CT) based three-dimensional (3D) dosimetry in the 1980's-90's necessitated image acquisition in a horizontal position (supine or prone), significantly reducing options for alternative patient positioning and upright techniques. Despite this, upright techniques have still been utilized where clinically indicated for palliative and novel approaches often involving non-standard treatment scenarios. More recently, a small number of centers have reported on specialized equipment capable of acquiring planning data with the patient in a vertical position. The possibility of acquiring planning quality Cone Beam CT (CBCT) on linear accelerators has recently reinvigorated the potential to deliver highly accurate and targeted treatments to patients in an upright position. This paper reflects on the historical applications of upright RT and explores new possibilities for this technology in modern RT departments.


Psychiatric morbidity in non-psychiatric geriatric inpatients.
To evaluate the profile of psychiatric disorders in geriatric inpatients. A total of 528 patients (age 65 years and above) admitted to various departments of the teaching hospital attached to the Government Medical College, Amritsar from 15 September 2001 to 14 September 2002 were included in the study. Psychiatric assessment of patients was made on the basis of psychogeriatric assessment scales (PAS) and present state examination (PSE-ninth edition, 1974). The ICD-10 criteria were used for psychiatric diagnoses. General medical conditions were diagnosed by consultants of the respective departments. The patients were finally assessed by the consultant of the Department of Psychiatry. The obtained data were analysed using the chi-square test. Of the 528 patients, 260 (49%) had psychiatric co-morbidity. The most common psychiatric disorder was depression (25.94%), followed by adjustment disorders (11%), anxiety disorders (4.54%), dementias (3.6%), delirium (3%), bipolar disorders (0.8%), and substance-related disorders (0.4%). The above findings emphasize the importance of consultation-liaison psychiatry, especially in geriatric patients.


The endogenous lipid anandamide is a full agonist at the human vanilloid receptor (hVR1).
The endogenous cannabinoid anandamide was identified as an agonist for the recombinant human VR1 (hVR1) by screening a large array of bioactive substances using a FLIPR-based calcium assay. Further electrophysiological studies showed that anandamide (10 or 100 microM) and capsaicin (1 microM) produced similar inward currents in hVR1 transfected, but not in parental, HEK293 cells. These currents were abolished by capsazepine (1 microM). In the FLIPR anandamide and capsaicin were full agonists at hVR1, with pEC(50) values of 5. 94+/-0.06 (n=5) and 7.13+/-0.11 (n=8) respectively. The response to anandamide was inhibited by capsazepine (pK(B) of 7.40+/-0.02, n=6), but not by the cannabinoid receptor antagonists AM630 or AM281. Furthermore, pretreatment with capsaicin desensitized the anandamide-induced calcium response and vice versa. In conclusion, this study has demonstrated for the first time that anandamide acts as a full agonist at the human VR1.


Brain-targeted delivery of a leucine-enkephalin analogue by retrometabolic design.
A brain-targeted chemical delivery system (CDS) based on retrometabolic drug design was applied to a Leu-enkephalin analogue, Try-D-Ala-Gly-Phe-D-Leu (DADLE). The molecular architecture of the peptide CDS disguises its peptide nature from neuropeptide-degrading enzymes and provides lipophilic, bioreversible functions for the penetration through the blood-brain barrier. These functions were provided by a targetor, a 1,4-dihydrotrigonellyl group, on the N-terminus and a bulky, lipophilic ester group on the C-terminus. A spacer amino acid residue was also inserted between the targetor and the parent peptide to assure the release of DADLE by specific enzymes. Four CDSs were synthesized by segment-coupling method that proved to be superior to sequential elongation in obtaining this type of peptide conjugates. Intravenous injection of the compounds produced a significant and long-lasting response in rats monitored by the tail-flick latency measurements. CDSs having the bulkier cholesteryl group showed a better efficacy than those having the smaller 1-adamantaneethyl ester. The spacer was the most important factor to manipulate the rate of DADLE release and, thus, the pharmacological activity; proline as a spacer produced more potent analgesia than alanine. The antinociceptive effect of the CDSs was naloxone-reversible and methylnaloxonium-irreversible, confirming that central opiate receptors were solely responsible for mediating analgesia induced by the peptide CDS that delivered, retained, and then released the peptide in the brain.


Implementation of an alert and response system in Haiti during the early stage of the response to the cholera epidemic.
The start of the cholera epidemic in Haiti quickly highlighted the necessity of the implementation of an Alert and Response (A&R) System to complement the existing national surveillance system. The national system had been able to detect and confirm the outbreak etiology but required external support to monitor the spread of cholera and coordinate response, because much of the information produced was insufficiently timely for real-time monitoring and directing of a rapid, targeted response. The A&R System was designed by the Pan American Health Organization/World Health Organization in collaboration with the Haiti Ministry of Health, and it was based on a network of partners, including any institution, structure, or individual that could identify, verify, and respond to alerts. The defined objectives were to (1) save lives through early detection and treatment of cases and (2) control the spread through early intervention at the community level. The operational structure could be broken down into three principle categories: (1) alert (early warning), (2) verification and assessment of the information, and (3) efficient and timely response in coordination with partners to avoid duplication. Information generated by the A&R System was analyzed and interpreted, and the qualitative information was critical in qualifying the epidemic and defining vulnerable areas, particularly because the national surveillance system reported incomplete data for more than one department. The A&R System detected a number of alerts unrelated to cholera and facilitated rapid access to that information. The sensitivity of the system and its ability to react quickly was shown in May of 2011, when an abnormal increase in alerts coming from several communes in the Sud-Est Department in epidemiological weeks (EWs) 17 and 18 were noted and disseminated network-wide and response activities were implemented. The national cholera surveillance system did not register the increase until EWs 21 and 22, and the information did not become available until EWs 23 and 24, when the peak of cases had already been reached. Although many of the partners reporting alerts during the peak of the cholera epidemic have since left Haiti, the A&R System has continued to function as an Early Warning (EWARN) System, and it continues to be developed with recent activities, such as the distribution of cell phones to enhance alert communication.


A guide to the standardized Mini-Mental State Examination.
The Mini-Mental State Examination (MMSE) is a widely used screening test for cognitive impairment in older adults. Because the guidelines for its application are brief, the administration and scoring of the test can vary between different individuals. This can diminish its reliability. Furthermore, some of the items must be changed to accommodate different settings, such as the clinic, home, or hospital. Because there are no time limits, it is not clear how long one should wait for a reply to a question. It is also not clear how one deals with answers that are "near misses." The goal of the Standardized Mini-Mental State Examination (SMMSE) was to impose strict guidelines for administration and scoring to improve the reliability of the instrument. The reliability of the MMSE was compared with the reliability of the SMMSE in 48 older adults who had the tests administered by university students on three different occasions to assess the interrater and intrarater reliability of the tests. The SMMSE had significantly better interrater and intrarater reliability compared with the MMSE: The interrater variance was reduced by 76% and the intrarater variance was reduced by 86%. It took less time to administer the SMMSE compared with the MMSE (average 10.5 minutes and 13.4 minutes, respectively). The intraclass correlation for the MMSE was .69, and .9 for the SMMSE. Administering and scoring the SMMSE on a task-by-task basis are discussed.


Vulnerability and agency in research participants' daily lives and the research encounter: A qualitative case study of participants taking part in scrub typhus research in northern Thailand.
Researchers have a responsibility to protect all participants, especially vulnerable participants, from harm. Vulnerability is increasingly understood to be context specific, yet limited guidance is available regarding the vulnerability and agency of research participants in different cultural settings. This study aims to explore research participants' daily vulnerability and agency, and how these interact with participants' research experiences in their own words. Researchers' views and responses were also explored. A qualitative study was conducted around two scrub typhus research studies in northern Thailand. A thematic analysis was carried out on 42 semi-structured interviews with research participants, their families, researchers and key informants. The majority of the research participants belonged to a hill tribe ethnic minority group. Common challenges were related to Thai language barriers, travel difficulties, uncertain legal status, unstable employment, lack of education and healthcare. We did not identify new vulnerabilities but we found that the extent of these vulnerabilities might be underestimated or even hidden from researchers in some cases. Despite these challenges people demonstrated agency in their daily lives and were often motivated and supported in this by family members. The majority of perceived research benefits were related to healthcare and gaining knowledge, while attending follow-up visits could be a burden for some. Our approach to research in culturally and socioeconomically diverse settings should be more responsive to participants' specific vulnerabilities and abilities evidenced in their daily life, rather than attributing vulnerability on the basis of membership of pre-defined 'vulnerable groups'. Researchers need to be aware and responsive towards the challenges participants face locally in order to minimise the burdens of research participation whilst allowing participants to benefit from research.


Fluorosis of the primary dentition: what does it mean for permanent teeth?
The prevalence of fluorosis of the permanent teeth has increased during the past few decades in the United States and Canada. However, primary-tooth fluorosis has been largely overlooked, because it is often difficult to recognize. This article describes primary-tooth fluorosis, both as characterized in the literature and as seen clinically. The authors review and summarize previous studies of primary-tooth fluorosis and discuss its etiology. In addition, the authors describe the condition, based on findings from the literature, and their own experiences in characterizing it as part of a longitudinal investigation of fluoride exposures, dental fluorosis and dental caries. Several studies indicate that primary-tooth fluorosis can be prevalent and severe in areas of very high water fluoride concentrations. In these areas, primary-tooth fluorosis is likely the result of both pre- and postnatal exposures. Studies have documented that primary-tooth fluorosis does occur in areas with optimal or suboptimal water fluoride concentrations, and that in these settings primary-tooth fluorosis is most likely caused by postnatal exposures and is seen most commonly in the primary molars. Primary-tooth fluorosis, however, is often more difficult to identify than fluorosis in permanent teeth, and clinicians may be unfamiliar with its characteristics and may not recognize its somewhat subtle appearance. Primary-tooth fluorosis may be related to occurrence of fluorosis in the permanent dentition, so that its recognition by the clinician should raise awareness of possible increased risk for the permanent dentition. The detection of primary-tooth fluorosis in a young child should prompt the clinician to carefully review the child's past fluoride exposures and current fluoride practices, as well as those of any younger siblings.


Dynamic responses, GPS positions and environmental conditions of two light rail vehicles in Pittsburgh.
We present DR-Train, the first long-term open-access dataset recording dynamic responses from in-service light rail vehicles. Specifically, the dataset contains measurements from multiple sensor channels mounted on two in-service light rail vehicles that run on a 42.2-km light rail network in the city of Pittsburgh, Pennsylvania. This dataset provides dynamic responses of in-service trains via vibration data collected by accelerometers, which enables a low-cost way of monitoring rail tracks more frequently. Such an approach will result in more reliable and economical ways to monitor rail infrastructure. The dataset also includes corresponding GPS positions of the trains, environmental conditions (including temperature, wind, weather, and precipitation), and track maintenance logs. The data, which is stored in a MAT-file format, can be conveniently loaded for various potential uses, such as validating anomaly detection and data fusion as well as investigating environmental influences on train responses.


Measurement of cortical thickness asymmetry in carotid occlusive disease.
Despite being considered an important anatomical parameter directly related to neuronal density, cortical thickness is not routinely assessed in studies of the human brain in vivo. This paucity has been largely due to the size and convoluted shape of the human cortex, which has made it difficult to develop automated algorithms that can measure cortical thickness efficiently and reliably. Since the development of such an algorithm by Fischl and Dale in 2000, the number of studies investigating the relationship between cortical thickness and other physiological parameters in the brain has been on the rise. There have been no studies however that have validated cortical asymmetry against known vascular anatomy. To this aim, using high-resolution MRI, we measured cortical thickness and volume in the primary motor (M1) and primary visual (V1) cortex in patients with unilateral, high-grade carotid occlusive disease (n = 29, age = 74 ± 10 years). These regions were selected based on the hypothesis that there will be thinning of the cortical thickness of M1 in the territory supplied by the occluded carotid artery, whereas V1 will show no asymmetry since its blood supply is provided by unaffected posterior arteries. To test for an effect of handedness, cortical thickness and volume were also measured in healthy volunteers (n = 8, age = 37 ± 13 years). In patients, we found thinner cortex in M1 on the occluded side (mean = 2.07 ± 0.19 mm vs 2.15 ± 0.20 mm, p = 0.0008) but no hemispheric difference in V1 (1.80 ± 0.17 mm in occluded vs 1.78 ± 0.16 mm in unoccluded, p = 0.31). Although the mean cortical volume of M1 in the occluded hemisphere was also lower, the difference did not reach statistical significance (p = 0.09). Similarly, in healthy controls, the results showed no hemispheric asymmetry in either cortical thickness or volume in either region (p > 0.1). To test for an orientation bias in the method, the analysis was repeated with images flipped from neurological to radiological orientation. While the algorithm did not yield identical results for the two orientations, the effect did not alter the findings of the study. These results provide a method for within-subject validation of a pathophysiological effect of carotid occlusive disease on the human cortex and warrant further investigation for underlying mechanisms.


Hydrogel lens monomer constituents modulate protein sorption.
To examine the effect of hydrogel lens monomer constituents on protein sorption. A series of hydroxyethylmethacrylate (HEMA)-based hydrogels with various amounts of methacrylic acid (MAA) or N-vinyl pyrrolidone (NVP) were synthesized. A radiolabel tracer technique was used to measure the amount of protein adsorbed on or penetrating into the hydrogels. Penetration of fluorescence-labeled proteins in the hydrogels was studied by laser scanning confocal microscopy. Single-protein solutions of human serum albumin (HSA) and hen egg lysozyme were studied. Inclusion of the comonomers MAA or NVP in hydrogels resulted in an increase in water content and also had a strong impact on protein sorption. An increase in the amount of MAA in the poly(HEMA-co-MAA) hydrogels increased lysozyme adsorption and penetration but reduced HSA adsorption. However, the amount of protein adsorbed for both HSA and lysozyme increased with the amount of NVP in the poly(HEMA-co-NVP) hydrogels. In contrast to the marked effect of MAA on protein sorption, in particular, on lysozyme sorption, NVP had little influence on protein sorption. When a hydrogel contains both MAA and NVP, MAA has the dominant effect on protein sorption-in particular, on lysozyme sorption. Furthermore, a large difference was observed in the amount of lysozyme adsorbed on the hydrogels that had similar water contents but little variation in adsorption of HSA. Negatively charged carboxyl groups of the MAA constituent may influence lysozyme sorption in two ways: by electrostatic attraction and by increasing the possibility for the small lysozyme molecule to penetrate the hydrogels. Interactions of the surface lactam groups of NVP with proteins may be attributable to the attraction of proteins to NVP. Water content is not a primary factor in determining protein adsorption. It appears that the monomer constituents, such as MAA or NVP, control protein adsorption.


Resveratrol and pterostilbene epigenetically restore PTEN expression by targeting oncomiRs of the miR-17 family in prostate cancer.
In recent years, not only has the role of miRNAs in cancer become increasingly clear but also their utilization as potential biomarkers and therapeutic targets has gained ground. Although the importance of dietary stilbenes such as resveratrol and pterostilbene as anti-cancer agents is well recognized, our understanding of their miRNA-targeting capabilities is still limited. In our previous study, we reported that resveratrol downregulates PTEN-targeting members of the oncogenic miR-17 family, which are overexpressed in prostate cancer. This study investigates the resveratrol and pterostilbene induced miRNA-mediated regulation of PTEN in prostate cancer. Here, we show that both compounds decrease the levels of endogenous as well as exogenously expressed miR-17, miR-20a and miR-106b thereby upregulating their target PTEN. Using functional luciferase reporter assays, we demonstrate that ectopically expressed miR-17, miR-20a and miR-106b directly target PTEN 3'UTR to reduce its expression, an effect rescued upon treatment with resveratrol and pterostilbene. Moreover, while stable lentiviral expression of miR-17/106a significantly decreased PTEN mRNA and protein levels and conferred survival advantage to the cells, resveratrol and more so pterostilbene was able to dramatically suppress these effects. Further, pterostilbene through downregulation of miR-17-5p and miR-106a-5p expression both in tumors and systemic circulation, rescued PTEN mRNA and protein levels leading to reduced tumor growth in vivo. Our findings implicate dietary stilbenes as an attractive miRNA-mediated chemopreventive and therapeutic strategy, and circulating miRNAs as potential chemopreventive and predictive biomarkers for clinical development in prostate cancer.


Discovery and complete genome sequence of a novel circovirus-like virus in the endangered rowi kiwi, Apteryx rowi.
Circoviruses are circular, non-enveloped, single-stranded DNA viruses around 2000 nucleotides (nt) in length and include the pathogenic species, Porcine circovirus 1 and Beak and feather disease virus, capable of causing significant morbidity and mortality. This group of viruses may be robust to degradation by external environments, and avian circoviruses are known to move between closely related hosts. Using a de novo metagenomic approach, followed by confirmatory PCR, we identify for the first time a circular Rep-encoding single-stranded (CRESS) DNA virus in New Zealand kiwi, Apteryx spp., derived from faecal matter of the rowi kiwi (A. rowi) showing signs of verminous dermatitis. The entire 2085 nt genome was cloned and sequenced and contains both capsid and replicase genes, as well as a conserved 9 nt motif. Phylogenetic analyses place it within Circoviridae, adjacent to other environmental CRESS-DNA viruses, and most closely related to badger circovirus-like virus (Meles meles circovirus-like virus). As the rowi is the most critically endangered kiwi, it is vital to understand the role of rowi kiwi circovirus-like virus as a possible pathogen and also any potential cross-species transmission.


Off pump coronary artery bypass surgery for significant left ventricular dysfunction: safety, feasibility, and trends in methodology over time--an early experience.
To examine the safety and applicability of off pump coronary artery bypass surgery (OPCAB) in patients with significant left ventricular dysfunction and to discuss the clinical implications for the surgical methods. Retrospective study. Tertiary care university affiliated referral centre. 353 consecutive patients with preoperative left ventricular ejection fraction < or = 35% who underwent coronary artery bypass over a three year period. Postoperative morbidity and mortality. 144 patients operated by OPCAB were compared with 209 patients operated by conventional coronary artery bypass. Multivariate and univariate analyses were performed on the pre- and postoperative variables to predict risk factors associated with hospital morbidity and mortality. Patients in the OPCAB group were more likely to be women and to have congestive heart failure, chronic obstructive pulmonary disease, hypertension, and diabetes; patients in the on pump group were more likely to have had a recent myocardial infarction and to have more severe angina pectoris and an urgent/emergent status. The groups did not differ significantly in length of stay, major postoperative complication rates, or mortality. Comparison of the impact of the procedures on surgical methods over time showed an increase in the use of OPCAB (13% to 67%), without any impact on morbidity or mortality. OPCAB is feasible and applicable for patients with depressed left ventricular function. This high risk group can potentially benefit from the off pump approach.


DNA sequences of genes encoding Acinetobacter calcoaceticus protocatechuate 3,4-dioxygenase: evidence indicating shuffling of genes and of DNA sequences within genes during their evolutionary divergence.
The DNA sequence of a 2,391-base-pair HindIII restriction fragment of Acinetobacter calcoaceticus DNA containing the pcaCHG genes is reported. The DNA sequence reveals that A. calcoaceticus pca genes, encoding enzymes required for protocatechuate metabolism, are arranged in a single transcriptional unit, pcaEFDBCHG, whereas homologous genes are arranged differently in Pseudomonas putida. The pcaG and pcaH genes represent separate reading frames respectively encoding the alpha and beta subunits of protocatechuate 3,4-dioxygenase (EC 184.108.40.206); previously a single designation, pcaA, had been used to represent DNA encoding this enzyme. The alpha and beta protein subunits appear to share common ancestry with each other and with catechol 1,2-dioxygenases from A. calcoaceticus and P. putida. Marked conservation of amino acid sequence is observed in a region containing two histidyl residues and two tyrosyl residues that appear to ligate iron within each oxygenase. In some regions within the aligned oxygenase sequences, DNA sequences appear to be conserved at a level beyond the extent that might have been demanded by selection at the level of protein. In other regions, divergence of DNA sequences appears to have been achieved by substitution of DNA sequence from one genetic segment into another. The results are interpreted to be the consequence of sequence exchange by gene conversion between slipped strands of DNA during evolutionary divergence; mismatch repair between slipped strands may contribute to the maintenance of DNA sequence in divergent genes.


Whole Cell Active Inhibitors of Mycobacterial Lipoamide Dehydrogenase Afford Selectivity over the Human Enzyme through Tight Binding Interactions.
Tuberculosis remains a leading cause of death from a single bacterial infection worldwide. Efforts to develop new treatment options call for expansion into an unexplored target space to expand the drug pipeline and bypass resistance to current antibiotics. Lipoamide dehydrogenase is a metabolic and antioxidant enzyme critical for mycobacterial growth and survival in mice. Sulfonamide analogs were previously identified as potent and selective inhibitors of mycobacterial lipoamide dehydrogenase in vitro but lacked activity against whole mycobacteria. Here we present the development of analogs with improved permeability, potency, and selectivity, which inhibit the growth of Mycobacterium tuberculosis in axenic culture on carbohydrates and within mouse primary macrophages. They increase intrabacterial pyruvate levels, supporting their on-target activity within mycobacteria. Distinct modalities of binding between the mycobacterial and human enzymes contribute to improved potency and hence selectivity through induced-fit tight binding interactions within the mycobacterial but not human enzyme, as indicated by kinetic analysis and crystallography.


Calcium-permeable ion channels in pain signaling.
The detection and processing of painful stimuli in afferent sensory neurons is critically dependent on a wide range of different types of voltage- and ligand-gated ion channels, including sodium, calcium, and TRP channels, to name a few. The functions of these channels include the detection of mechanical and chemical insults, the generation of action potentials and regulation of neuronal firing patterns, the initiation of neurotransmitter release at dorsal horn synapses, and the ensuing activation of spinal cord neurons that project to pain centers in the brain. Long-term changes in ion channel expression and function are thought to contribute to chronic pain states. Many of the channels involved in the afferent pain pathway are permeable to calcium ions, suggesting a role in cell signaling beyond the mere generation of electrical activity. In this article, we provide a broad overview of different calcium-permeable ion channels in the afferent pain pathway and their role in pain pathophysiology.


THE EFFECT OF CHLORINATION OF NUCLEOTIDE BASES ON THE CONFORMATIONAL PROPERTIES OF THYMIDINE MONOPHOSPHATE.
Recent studies on Escherichia coli bacteria cultivation, in which DNA thymine was replaced with 5-chlorouracil have refreshed the problem of understanding the changes to physical properties of DNA monomers resultant from chemical modifications. These studies have shown that the replacement did not affect the normal activities and division of the bacteria, but has significantly reduced its life span. In this paper a comparative analysis was carried out by the methods of computational experiment of a set of 687 possible conformers of natural monomeric DNA unit (2'-deoxyribonucleotide thymidine monophosphate) and 660 conformers of 5-chloro-2'-deoxyuridine monophosphate - a similar molecules in which the natural nitrogenous base thymine is substituted with 5-chlorouracil. Structures of stable conformers of the modified deoxyribonucleotide have been obtained and physical factors, which determine their variation from the conformers of the unmodified molecule have been analyzed. A comparative analysis of the elastic properties of conformers of investigated molecules and non-covalent interactions present in them was conducted. The results can be usedfor planning experiments on synthesis of artficial DNA suitable for incorporation into living organisms.


Consent for organ transplantation and autopsies.
The Human Tissue Act of 1983 had its origin in the first successful heart transplant operation performed by Professor Christiaan Barnard and his team in December 1967. Under the new constitution, however, the Act needs to be reviewed, because different ethical and legal demands. The Act is in some instances very controversial. For instance it is stated in the Act that the eyes of the deceased may be removed without the consent of the relatives. Although this may be allowable by law, it would be considered to be highly unethical and against the constitutional right of the individual. Regulations relating to the general control human bodies, the use of tissue, blood and gametes of living person and other issues currently covered by the Human Tissue Act will be revised and addressed in the proposed National Health Bill.


Combined liver and (heart-)lung transplantation in liver transplant candidates with refractory portopulmonary hypertension.
Portopulmonary hypertension (PPHT) has a prevalence of 5-10% in liver transplantation (LiTx) candidates. Mild PPHT is reversible with LiTx, but more severe PPHT is a contraindication to LiTx given the high intraoperative mortality due to heart failure. Prostacyclin can reduce PPHT to a level at which LiTx can be performed. In patients refractory to that treatment, combined (heart-)lung-LiTx is the only life-saving option. We report two cases of (heart-)lung-LiTx in patients with refractory severe PPHT. Patient 1, a 52-year-old female with viral cirrhosis and severe refractory PPHT, received a double-lung Tx followed by LiTx. After liver reperfusion, fatal heart failure occurred. Patient 2, a 42-year-old male with viral hepatitis and congenital liver fibrosis, also suffered from severe refractory PPHT. He successfully received an en bloc heart-lung Tx followed by LiTx. The rationale to replace the heart was an anticipated risk of intraoperative right heart failure after liver reperfusion and the technical ease of heart-lung versus double-lung Tx. Severe refractory PPHT is a fatal condition seen as a contraindication to LiTx. This condition can be treated by replacing thoracal organs in addition to the liver. Additional evidence via development of a registry is required to further support application of liver-(heart-)lung Tx in patients with severe refractory PPHT.


Performance and nutrient metabolism by nursing calves supplemented with limited or unlimited corn or soyhulls.
Five-month-old Angus x Hereford reciprocal crossbred nursing steer calves on fescue pasture were used to determine the effects of 1) limiting supplemental feed intake and 2) soyhulls and corn as sources of supplemental (creep) feed in an 84-d study. The treatments were 1) control (no creep feed), 2) limited intake of corn (1 kg/d), 3) unlimited intake of corn, 4) limited intake of soyhulls (1 kg/d), and 5) unlimited intake of soyhulls. Before weaning, there were no differences in supplemental feed efficiency ([supplemented gain--control gain]/supplement intake) or calf gain between corn or soyhulls. Calf gain before weaning increased linearly (P < .05) as intake of creep feed increased, but supplemental feed efficiency did not differ between limited and unlimited supplements. Feedlot performance by the calves was not affected by any of the previous treatments. Calves that consumed an unlimited level of creep feed had greater (P < .05) quality grades than the control group that did not consume creep feed, but no other carcass traits were influenced by treatment. In a metabolism study, fescue DM intake decreased linearly (P < .001) with increasing levels of creep feed, whereas milk DM intake was not affected by level of creep feed. Digestible DM intake increased linearly (P < .001) with increasing intake of creep feed. No differences (P < .18) were observed in digestible DM intake as a result of creep feed source. Apparent total tract DM digestibility increased (P < .05) with increasing level of creep feed intake but did not differ between sources.(ABSTRACT TRUNCATED AT 250 WORDS)


World guidelines for falls prevention and management for older adults: a global initiative.
falls and fall-related injuries are common in older adults, have negative effects on functional independence and quality of life and are associated with increased morbidity, mortality and health related costs. Current guidelines are inconsistent, with no up-to-date, globally applicable ones present. to create a set of evidence- and expert consensus-based falls prevention and management recommendations applicable to older adults for use by healthcare and other professionals that consider: (i) a person-centred approach that includes the perspectives of older adults with lived experience, caregivers and other stakeholders; (ii) gaps in previous guidelines; (iii) recent developments in e-health and (iv) implementation across locations with limited access to resources such as low- and middle-income countries. a steering committee and a worldwide multidisciplinary group of experts and stakeholders, including older adults, were assembled. Geriatrics and gerontological societies were represented. Using a modified Delphi process, recommendations from 11 topic-specific working groups (WGs), 10 ad-hoc WGs and a WG dealing with the perspectives of older adults were reviewed and refined. The final recommendations were determined by voting. all older adults should be advised on falls prevention and physical activity. Opportunistic case finding for falls risk is recommended for community-dwelling older adults. Those considered at high risk should be offered a comprehensive multifactorial falls risk assessment with a view to co-design and implement personalised multidomain interventions. Other recommendations cover details of assessment and intervention components and combinations, and recommendations for specific settings and populations. the core set of recommendations provided will require flexible implementation strategies that consider both local context and resources.


Elastic-instability triggered pattern formation.
Recent experiments have exploited elastic instabilities in membranes to create complex patterns. However, the rational design of such structures poses many challenges, as they are products of nonlinear elastic behavior. We pose a simple model for determining the orientational order of such patterns using only linear elasticity theory which correctly predicts the outcomes of several experiments. Each element of the pattern is modeled by a "dislocation dipole" located at a point on a lattice, which then interacts elastically with all other dipoles in the system. We explicitly consider a membrane with a square lattice of circular holes under uniform compression and examine the changes in morphology as it is allowed to relax in a specified direction.


Radiation-induced lung damage promotes breast cancer lung-metastasis through CXCR4 signaling.
Radiotherapy is a mainstay in the postoperative treatment of breast cancer as it reduces the risks of local recurrence and mortality after both conservative surgery and mastectomy. Despite recent efforts to decrease irradiation volumes through accelerated partial irradiation techniques, late cardiac and pulmonary toxicity still occurs after breast irradiation. The importance of this pulmonary injury towards lung metastasis is unclear. Preirradiation of lung epithelial cells induces DNA damage, p53 activation and a secretome enriched in the chemokines SDF-1/CXCL12 and MIF. Irradiated lung epithelial cells stimulate adhesion, spreading, growth, and (transendothelial) migration of human MDA-MB-231 and murine 4T1 breast cancer cells. These metastasis-associated cellular activities were largely mimicked by recombinant CXCL12 and MIF. Moreover, an allosteric inhibitor of the CXCR4 receptor prevented the metastasis-associated cellular activities stimulated by the secretome of irradiated lung epithelial cells. Furthermore, partial (10%) irradiation of the right lung significantly stimulated breast cancer lung-specific metastasis in the syngeneic, orthotopic 4T1 breast cancer model.Our results warrant further investigation of the potential pro-metastatic effects of radiation and indicate the need to develop efficient drugs that will be successful in combination with radiotherapy to prevent therapy-induced spread of cancer cells.


Do retinopathy signs in non-diabetic individuals predict the subsequent risk of diabetes?
Isolated retinopathy signs are common in non-diabetic individuals and have been shown to be associated with impaired glucose metabolism. In a cohort of people without diabetes, the association of these retinopathy signs and subsequent development of diabetes were examined. A population based cohort study of 7992 people aged 49-73 years without diabetes was conducted. Retinal photographs of these participants were evaluated for the presence of retinopathy signs according to a standardised protocol. Incident cases of diabetes were identified prospectively. After a follow up of 3 years, 291 (3.6%) people developed incident diabetes. In the total cohort, retinopathy was not significantly associated with incident diabetes (4.7% v 3.6%, multivariable adjusted odds ratio (OR) 1.1, 95% confidence intervals (CI), 0.7 to 1.9). However, among participants with a positive family history of diabetes, retinopathy was associated with incident diabetes (10.4% v 4.8%, multivariable adjusted OR 2.3, 95% CI, 1.0 to 5.3). Among participants without a family history of diabetes, retinopathy was not associated with incident diabetes In individuals with a family history of diabetes, retinopathy signs predict subsequent risk of clinical diabetes.


Cortical processing of complex sound: a way forward?
The organization of the cortical auditory system remains controversial. In particular, the extent to which there is regional specialization in the cortical processing of complex sound is unclear. Here, we ask whether we are currently asking the right questions of auditory cortex, or using the appropriate techniques to do so. A key factor that will promote such understanding in the future will be increasing dialogue between workers using electrophysiological recording methods to assess the response properties of single neurons and those using imaging techniques to map regional organization. In the future, further insights will be obtained by efforts to test hypotheses developed on the basis of one approach by the use of the other. Imaging can tell the neurophysiologists where to look, and work on single neurons can constrain network models based on imaging. There is a crucial need for better understanding of the anatomy of the auditory cortex in different species and for comparative studies that will underpin both approaches.


PixelClipper: Supporting Public Engagement and Conversation About Visualizations.
In this article, we present PixelClipper, a tool built for facilitating data engagement events. PixelClipper supports conversations around visualizations in public settings through annotation and commenting capabilities. It is recognized that understanding data is important for an informed society. However, even when visualizations are available on the web, open data is not yet reaching all audiences. Public facilitated events centered around data visualizations may help bridge this gap. PixelClipper is designed to promote discussion and engagement with visualizations in public settings. It allows viewers to quickly and expressively extract visual clippings from visualizations and add comments to them. Ambient and facilitator displays attract attention by showing clippings. They function as entry points to the full visualizations while supporting deeper conversations about the visualizations and data. We describe the design goals of PixelClipper, share our experiences from deploying it, and discuss its future potential in supporting data visualization engagement events.


Alien interference: disruption of infochemical networks by invasive insect herbivores.
Insect herbivores trigger various biochemical changes in plants, and as a consequence, affect other organisms that are associated with these plants. Such plant-mediated indirect effects often involve herbivore-induced plant volatiles (HIPVs) that can be used as cues for foraging herbivores and their natural enemies, and are also known to affect pollinator attraction. In tightly co-evolved systems, the different trophic levels are expected to display adaptive response to changes in HIPVs caused by native herbivores. But what if a new herbivore invades such a system? Current literature suggests that exotic herbivores have the potential to affect HIPV production, and that plant responses to novel herbivores are likely to depend on phylogenetic relatedness between the invader and the native species. Here we review the different ways exotic herbivores can disrupt chemically mediated interactions between plants and the key users of HIPVs: herbivores, pollinators, and members of the third (i.e. predators and parasitoids) and fourth (i.e. hyperparasitoids) trophic levels. Current theory on insect invasions needs to consider that disruptive effects of invaders on infochemical networks can have a short-term impact on the population dynamics of native insects and plants, as well as exerting potentially negative consequences for the functioning of native ecosystems.


Rational design of yolk-shell nanostructures for photocatalysis.
Photocatalysis is a promising route to convert solar energy into chemical energy directly, providing an alternative solution to environment and natural resource problems. Theoretically, all photocatalytic reactions are driven by charge carriers whose behavior can be divided into charge generation, separation, migration and surface reactions. Efficiencies of charge utilization in every step determine the overall performance of photocatalysis. Yolk-shell (YS) structures can provide an ideal platform for the efficient utilization of charge carriers. Typically, a YS structure is constructed from a hollow shell and an inner core, which can enhance light scattering in the hollow space and provide a large surface to create sufficient active sites, both of which can significantly improve the efficacy of charge utilization. Additionally, many strategies can be adopted to modify the YS structure for further enhancement of charge behaviors in every step. Existing reviews about YS structures mainly concentrate on the universality of the application of YSs, while the strategies to improve photocatalytic performance based on YSs have not been elaborately illustrated. This review describes the classification, synthesis, formation mechanism of YS structures and the rational regulation of the behaviors of photogenerated charge carriers, aiming at their effective utilization based on YS structures in heterogeneous photocatalytic reactions.


High-throughput sequencing for biology and medicine.
Advances in genome sequencing have progressed at a rapid pace, with increased throughput accompanied by plunging costs. But these advances go far beyond faster and cheaper. High-throughput sequencing technologies are now routinely being applied to a wide range of important topics in biology and medicine, often allowing researchers to address important biological questions that were not possible before. In this review, we discuss these innovative new approaches-including ever finer analyses of transcriptome dynamics, genome structure and genomic variation-and provide an overview of the new insights into complex biological systems catalyzed by these technologies. We also assess the impact of genotyping, genome sequencing and personal omics profiling on medical applications, including diagnosis and disease monitoring. Finally, we review recent developments in single-cell sequencing, and conclude with a discussion of possible future advances and obstacles for sequencing in biology and health.