In this paper we discuss the dualism of gene networks and their role in systems biology. We argue that gene networks (1) can serve as a conceptual framework, forming a fundamental level of a phenomenological description, and (2) are a means to represent and analyze data. The latter point does not only allow a systems analysis but is even amenable for a direct approach to study biological function. Here we focus on the clarity of our main arguments and conceptual meaning of gene networks, rather than the causal inference of gene networks from data. WIREs Syst Biol Med 2011 3 379-391 DOI: 10.1002/wsbm.134 For further resources related to this article, please visit the WIREs website.

BACKGROUND

Untreated syphilis in pregnancy is associated with adverse clinical outcomes for the infant. Most syphilis infections occur in sub-Saharan Africa (SSA), where coverage of antenatal screening for syphilis is inadequate. Recently introduced point-of-care syphilis tests have high accuracy and demonstrate potential to increase coverage of antenatal screening. However, country-specific cost-effectiveness data for these tests are limited. The objective of this analysis was to evaluate the cost-effectiveness and budget impact of antenatal syphilis screening for 43 countries in SSA and estimate the impact of universal screening on stillbirths, neonatal deaths, congenital syphilis, and disability-adjusted life years (DALYs) averted.

RESULTS

The decision analytic model reflected the perspective of the national health care system and was based on the sensitivity (86%) and specificity (99%) reported for the immunochromatographic strip (ICS) test. Clinical outcomes of infants born to syphilis-infected mothers on the end points of stillbirth, neonatal death, and congenital syphilis were obtained from published sources. Treatment was assumed to consist of three injections of benzathine penicillin. Country-specific inputs included the antenatal prevalence of syphilis, annual number of live births, proportion of women with at least one antenatal care visit, per capita gross national income, and estimated hourly nurse wages. In all 43 sub-Saharan African countries analyzed, syphilis screening is highly cost-effective, with an average cost/DALY averted of US$11 (range: US$2-US$48). Screening remains highly cost-effective even if the average prevalence falls from the current rate of 3.1% (range: 0.6%-14.0%) to 0.038% (range: 0.002%-0.113%). Universal antenatal screening of pregnant women in clinics may reduce the annual number of stillbirths by up to 64,000, neonatal deaths by up to 25,000, and annual incidence of congenital syphilis by up to 32,000, and avert up to 2.6 million DALYs at an estimated annual direct medical cost of US$20.8 million.

CONCLUSIONS

Use of ICS tests for antenatal syphilis screening is highly cost-effective in SSA. Substantial reduction in DALYs can be achieved at a relatively modest budget impact. In SSA, antenatal programs should expand access to syphilis screening using the ICS test. Please see later in the article for the Editors' Summary.

An effective immune system requires rapid and appropriate activation of inflammatory mechanisms but equally rapid and effective resolution of the inflammatory state. A review of the canonical host response to gram-negative bacteria, the lipopolysaccharide-Toll-like receptor 4 signaling cascade, highlights the induction of repressors that act at each step of the activation process. These inflammation suppressor genes are characterized by their induction in response to pathogen, typically late in the macrophage activation program, and include an expanding class of dominant-negative proteins derived from alternate splicing of common signaling components. Despite the expanse of anti-inflammatory mechanisms available to an activated macrophage, the frailty of this system is apparent in the large numbers of genes implicated in chronic inflammatory diseases. This apparent lack of redundancy between inflammation suppressor genes is discussed with regard to evolutionary benefits in generating a heterogeneous population of immune cells and consequential robustness in defense against new and evolving pathogens.

BACKGROUND

For several decades, global public health efforts have focused on the development and application of disease control programs to improve child survival in developing populations. The need to reliably monitor the impact of such intervention programs in countries has led to significant advances in demographic methods and data sources, particularly with large-scale, cross-national survey programs such as the Demographic and Health Surveys (DHS). Although no comparable effort has been undertaken for adult mortality, the availability of large datasets with information on adult survival from censuses and household surveys offers an important opportunity to dramatically improve our knowledge about levels and trends in adult mortality in countries without good vital registration. To date, attempts to measure adult mortality from questions in censuses and surveys have generally led to implausibly low levels of adult mortality owing to biases inherent in survey data such as survival and recall bias. Recent methodological developments and the increasing availability of large surveys with information on sibling survival suggest that it may well be timely to reassess the pessimism that has prevailed around the use of sibling histories to measure adult mortality.

RESULTS

We present the Corrected Sibling Survival (CSS) method, which addresses both the survival and recall biases that have plagued the use of survey data to estimate adult mortality. Using logistic regression, our method directly estimates the probability of dying in a given country, by age, sex, and time period from sibling history data. The logistic regression framework borrows strength across surveys and time periods for the estimation of the age patterns of mortality, and facilitates the implementation of solutions for the underrepresentation of high-mortality families and recall bias. We apply the method to generate estimates of and trends in adult mortality, using the summary measure (45)q(15)-the probability of a 15-y old dying before his or her 60th birthday-for 44 countries with DHS sibling survival data. Our findings suggest that levels of adult mortality prevailing in many developing countries are substantially higher than previously suggested by other analyses of sibling history data. Generally, our estimates show the risk of adult death between ages 15 and 60 y to be about 20%-35% for females and 25%-45% for males in sub-Saharan African populations largely unaffected by HIV. In countries of Southern Africa, where the HIV epidemic has been most pronounced, as many as eight out of ten men alive at age 15 y will be dead by age 60, as will six out of ten women. Adult mortality levels in populations of Asia and Latin America are generally lower than in Africa, particularly for women. The exceptions are Haiti and Cambodia, where mortality risks are comparable to many countries in Africa. In all other countries with data, the probability of dying between ages 15 and 60 y was typically around 10% for women and 20% for men, not much higher than the levels prevailing in several more developed countries.

CONCLUSIONS

Our results represent an expansion of direct knowledge of levels and trends in adult mortality in the developing world. The CSS method provides grounds for renewed optimism in collecting sibling survival data. We suggest that all nationally representative survey programs with adequate sample size ought to implement this critical module for tracking adult mortality in order to more reliably understand the levels and patterns of adult mortality, and how they are changing. Please see later in the article for the Editors' Summary.

BACKGROUND

Stillbirth is strongly related to impaired fetal growth. However, the relationship between fetal growth and stillbirth is difficult to determine because of uncertainty in the timing of death and confounding characteristics affecting normal fetal growth.

RESULTS

We conducted a population-based case-control study of all stillbirths and a representative sample of live births in 59 hospitals in five geographic areas in the US. Fetal growth abnormalities were categorized as small for gestational age (SGA) (<10th percentile) or large for gestational age (LGA) (>90th percentile) at death (stillbirth) or delivery (live birth) using population, ultrasound, and individualized norms. Gestational age at death was determined using an algorithm that considered the time-of-death interval, postmortem examination, and reliability of the gestational age estimate. Data were weighted to account for the sampling design and differential participation rates in various subgroups. Among 527 singleton stillbirths and 1,821 singleton live births studied, stillbirth was associated with SGA based on population, ultrasound, and individualized norms (odds ratio [OR] [95% CI]: 3.0 [2.2 to 4.0]; 4.7 [3.7 to 5.9]; 4.6 [3.6 to 5.9], respectively). LGA was also associated with increased risk of stillbirth using ultrasound and individualized norms (OR [95% CI]: 3.5 [2.4 to 5.0]; 2.3 [1.7 to 3.1], respectively), but not population norms (OR [95% CI]: 0.6 [0.4 to 1.0]). The associations were stronger with more severe SGA and LGA (<5th and >95th percentile). Analyses adjusted for stillbirth risk factors, subset analyses excluding potential confounders, and analyses in preterm and term pregnancies showed similar patterns of association. In this study 70% of cases and 63% of controls agreed to participate. Analysis weights accounted for differences between consenting and non-consenting women. Some of the characteristics used for individualized fetal growth estimates were missing and were replaced with reference values. However, a sensitivity analysis using individualized norms based on the subset of stillbirths and live births with non-missing variables showed similar findings.

CONCLUSIONS

Stillbirth is associated with both growth restriction and excessive fetal growth. These findings suggest that, contrary to current practices and recommendations, stillbirth prevention strategies should focus on both severe SGA and severe LGA pregnancies. Please see later in the article for the Editors' Summary.

BACKGROUND

We sought to define quality in telehealth and telecare with the aim of improving the proportion of patients who receive appropriate, acceptable and workable technologies and services to support them living with illness or disability.

METHODS

This was a three-phase study: (1) interviews with seven technology suppliers and 14 service providers, (2) ethnographic case studies of 40 people, 60 to 98 years old, with multi-morbidity and assisted living needs and (3) 10 co-design workshops. In phase 1, we explored barriers to uptake of telehealth and telecare. In phase 2, we used ethnographic methods to build a detailed picture of participants' lives, illness experiences and technology use. In phase 3, we brought users and their carers together with suppliers and providers to derive quality principles for assistive technology products and services.

RESULTS

Interviews identified practical, material and organisational barriers to smooth introduction and continued support of assistive technologies. The experience of multi-morbidity was characterised by multiple, mutually reinforcing and inexorably worsening impairments, producing diverse and unique care challenges. Participants and their carers managed these pragmatically, obtaining technologies and adapting the home. Installed technologies were rarely fit for purpose. Support services for technologies made high (and sometimes oppressive) demands on users. Six principles emerged from the workshops. Quality telehealth or telecare is 1) ANCHORED in a shared understanding of what matters to the user; 2) REALISTIC about the natural history of illness; 3) CO-CREATIVE, evolving and adapting solutions with users; 4) HUMAN, supported through interpersonal relationships and social networks; 5) INTEGRATED, through attention to mutual awareness and knowledge sharing; 6) EVALUATED to drive system learning.

CONCLUSIONS

Technological advances are important, but must be underpinned by industry and service providers following a user-centred approach to design and delivery. For the ARCHIE principles to be realised, the sector requires: (1) a shift in focus from product ('assistive technologies') to performance ('supporting technologies-in-use'); (2) a shift in the commissioning model from standardised to personalised home care contracts; and (3) a shift in the design model from 'walled garden', branded products to inter-operable components that can be combined and used flexibly across devices and platforms. Please see related article: http://dx.doi.org/10.1186/s12916-015-0305-8.

Cholinephosphotransferase (EC 2.7.8.2) catalyzes the formation of a phosphoester bond via the transfer of a phosphocholine moiety from CDP-choline to diacylglycerol forming phosphatidylcholine and releasing CMP. A motif, Asp113-Gly114-(X)2-Ala117-Arg118-(X)8-Gly127+ ++-(X)3-Asp131-(X)3-Asp135, located within the CDP-choline binding region of Saccharomyces cerevisiae cholinephosphotransferase (CPT1 ?/Author: Please confirm that a gene is meant here.) is also found in several other phospholipid synthesizing enzymes that catalyze the formation of a phosphoester bond utilizing a CDP-alcohol and a second alcohol as substrates. To determine if this motif is diagnostic of the above reaction type scanning alanine mutagenesis of the conserved residues within S. cerevisiae cholinephosphotransferase was performed. Enzyme activity was assessed in vitro using a mixed micelle enzyme assay and in vivo by determining the ability of the mutant enzymes to restore phosphatidylcholine synthesis from radiolabeled choline in an S. cerevisiae strain devoid of endogenous cholinephosphotransferase activity. Alanine mutants of Gly114, Gly127, Asp131, and Asp135 were inactive; mutants, Ala117 and Arg118 displayed reduced enzyme activity, and Asp113 displayed wild type activity. The analysis described is the first molecular characterization of a CDP-alcohol phosphotransferase motif and results predict a catalytic role utilizing a general base reaction proceeding through Asp131 or Asp135 via a direct nucleophilic attack of the hydroxyl of diacylglyerol on the phosphoester bond of CDP-choline that does not proceed via an enzyme bound intermediate. Residues Ala117 and Arg118 do not participate directly in catalysis but are likely involved in substrate binding or positioning with Arg118 predicted to associate with a phosphate moiety of CDP-choline.

BACKGROUND

Increasing active travel (walking, bicycling, and public transport) is promoted as a key strategy to increase physical activity and reduce the growing burden of noncommunicable diseases (NCDs) globally. Little is known about patterns of active travel or associated cardiovascular health benefits in low- and middle-income countries. This study examines mode and duration of travel to work in rural and urban India and associations between active travel and overweight, hypertension, and diabetes.

RESULTS

Cross-sectional study of 3,902 participants (1,366 rural, 2,536 urban) in the Indian Migration Study. Associations between mode and duration of active travel and cardiovascular risk factors were assessed using random-effect logistic regression models adjusting for age, sex, caste, standard of living, occupation, factory location, leisure time physical activity, daily fat intake, smoking status, and alcohol use. Rural dwellers were significantly more likely to bicycle (68.3% versus 15.9%; p<0.001) to work than urban dwellers. The prevalence of overweight or obesity was 50.0%, 37.6%, 24.2%, 24.9%; hypertension was 17.7%, 11.8%, 6.5%, 9.8%; and diabetes was 10.8%, 7.4%, 3.8%, 7.3% in participants who travelled to work by private transport, public transport, bicycling, and walking, respectively. In the adjusted analysis, those walking (adjusted risk ratio [ARR] 0.72; 95% CI 0.58-0.88) or bicycling to work (ARR 0.66; 95% CI 0.55-0.77) were significantly less likely to be overweight or obese than those travelling by private transport. Those bicycling to work were significantly less likely to have hypertension (ARR 0.51; 95% CI 0.36-0.71) or diabetes (ARR 0.65; 95% CI 0.44-0.95). There was evidence of a dose-response relationship between duration of bicycling to work and being overweight, having hypertension or diabetes. The main limitation of the study is the cross-sectional design, which limits causal inference for the associations found.

CONCLUSIONS

Walking and bicycling to work was associated with reduced cardiovascular risk in the Indian population. Efforts to increase active travel in urban areas and halt declines in rural areas should be integral to strategies to maintain healthy weight and prevent NCDs in India. Please see later in the article for the Editors' Summary.

BACKGROUND

Self-monitoring of blood glucose (SMBG) helps to improve glycemic control and empowerment of people with diabetes. It is particularly useful for people with diabetes who are using insulin as it facilitates insulin titration and detection of hypoglycemia. Despite this, the uptake of SMBG remains low in many countries, including Malaysia.

OBJECTIVE

This study aimed to explore the barriers and facilitators to SMBG, in people with type 2 diabetes using insulin.

METHODS

Qualitative methodology was employed to explore participants' experience with SMBG. Semistructured, individual in-depth interviews were conducted on people with type 2 diabetes using insulin who had practiced SMBG, in the primary care clinic of a teaching hospital in Malaysia. Participants were purposively sampled from different age groups, ethnicity, education level, and level of glycemic control (as reflected by the glycated hemoglobin [HbA1c]), to achieve maximum variation in sampling. All interviews were conducted using a topic guide and were audio-recorded, transcribed verbatim, checked, and analyzed using a thematic approach.

RESULTS

A total of 15 participants were interviewed, and thematic saturation was reached. The factors that influenced SMBG were mainly related to cost, participants' emotion, and the SMBG process. The barriers identified included: frustration related to high blood glucose reading; perception that SMBG was only for insulin titration; stigma; fear of needles and pain; cost of test strips and needles; inconvenience; unconducive workplace; and lack of motivation, knowledge, and self-efficacy. The facilitators were: experiencing hypoglycemic symptoms; desire to see the effects of dietary changes; desire to please the physician; and family motivation.

CONCLUSIONS

Participants' perceptions of the purpose of SMBG, the emotions associated with SMBG, and the complexity, pain, and cost related to SMBG as well as personal and family motivation are the key factors that health care providers must consider when advising people with diabetes on SMBG.

Nanostructure-Initiator Mass Spectrometry (NIMS) is a matrix-free desorption/ionization approach that is particularly well-suited for unbiased (untargeted) metabolomics. An overview of the NIMS technology and its application in the detection of biofluid and tissue metabolites are presented. (To listen to a podcast about this feature, please go to the Analytical Chemistry multimedia page at pubs.acs.org/page/ancham/audio/index.html .).

Since the discovery of sickle cell disease (SCD) in 1910, enormous strides have been made in the elucidation of the pathogenesis of its protean complications, which has inspired recent advances in targeted molecular therapies. In SCD, a single amino acid substitution in the β-globin chain leads to polymerization of mutant hemoglobin S, impairing erythrocyte rheology and survival. Clinically, erythrocyte abnormalities in SCD, manifest in hemolytic anemia and cycles of microvascular vaso-occlusion leading to endorgan ischemia-reperfusion injury and infarction. Vaso-occlusive events and intravascular hemolysis promote inflammation and redox instability that lead to progressive small- and large-vessel vasculopathy. Based on current evidence, the pathobiology of SCD is considered to be a vicious cycle of four major processes, all the subject of active study and novel therapeutic targeting: (a) hemoglobin S polymerization, (b) impaired biorheology and increased adhesion-mediated vaso-occlusion, (c) hemolysis-mediated endothelial dysfunction, and (d) concerted activation of sterile inflammation (Toll-like receptor 4- and inflammasome-dependent innate immune pathways). These molecular, cellular, and biophysical processes synergize to promote acute and chronic pain and end-organ injury and failure in SCD. This review provides an exhaustive overview of the current understanding of the molecular pathophysiology of SCD, how this pathophysiology contributes to complications of the central nervous and cardiopulmonary systems, and how this knowledge is being harnessed to develop current and potential therapies. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease Volume 14 is January 24, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

The American Diabetes Association (ADA) "Standards of Medical Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee (https://doi.org/10.2337/dc20-SPPC), are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations, please refer to the Standards of Care Introduction (https://doi.org/10.2337/dc20-SINT). Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.

BACKGROUND

The treatment of persistent symptoms attributed to Lyme disease remains controversial. We assessed whether longer-term antibiotic treatment of persistent symptoms attributed to Lyme disease leads to better outcomes than does shorter-term treatment.

METHODS

In a randomized, double-blind, placebo-controlled trial conducted in Europe, we assigned patients with persistent symptoms attributed to Lyme disease--either related temporally to proven Lyme disease or accompanied by a positive IgG or IgM immunoblot assay for Borrelia burgdorferi--to receive a 12-week oral course of doxycycline, clarithromycin plus hydroxychloroquine, or placebo. All study groups received open-label intravenous ceftriaxone for 2 weeks before initiating the randomized regimen. The primary outcome measure was health-related quality of life, as assessed by the physical-component summary score of the RAND-36 Health Status Inventory (RAND SF-36) (range, 15 to 61, with higher scores indicating better quality of life), at the end of the treatment period at week 14, after the 2-week course of ceftriaxone and the 12-week course of the randomized study drug or placebo had been completed.

RESULTS

Of the 281 patients who underwent randomization, 280 were included in the modified intention-to-treat analysis (86 patients in the doxycycline group, 96 in the clarithromycin-hydroxychloroquine group, and 98 in the placebo group). The SF-36 physical-component summary score did not differ significantly among the three study groups at the end of the treatment period, with mean scores of 35.0 (95% confidence interval [CI], 33.5 to 36.5) in the doxycycline group, 35.6 (95% CI, 34.2 to 37.1) in the clarithromycin-hydroxychloroquine group, and 34.8 (95% CI, 33.4 to 36.2) in the placebo group (P=0.69; a difference of 0.2 [95% CI, -2.4 to 2.8] in the doxycycline group vs. the placebo group and a difference of 0.9 [95% CI, -1.6 to 3.3] in the clarithromycin-hydroxychloroquine group vs. the placebo group); the score also did not differ significantly among the groups at subsequent study visits (P=0.35). In all study groups, the SF-36 physical-component summary score increased significantly from baseline to the end of the treatment period (P<0.001). The rates of adverse events were similar among the study groups. Four serious adverse events thought to be related to drug use occurred during the 2-week open-label ceftriaxone phase, and no serious drug-related adverse event occurred during the 12-week randomized phase.

CONCLUSIONS

In patients with persistent symptoms attributed to Lyme disease, longer-term antibiotic treatment did not have additional beneficial effects on health-related quality of life beyond those with shorter-term treatment. (Funded by the Netherlands Organization for Health Research and Development ZonMw; PLEASE ClinicalTrials.gov number, NCT01207739.).

Age-related declines in vision can have a major impact on the health and well-being of an older population. A review of research on aging and vision indicates that these declines occur at multiple levels of the visual system including optics, sensory processing, and perceptual processing and are not likely due to a systemic change in brain function (e.g., generalized slowing; common cause hypothesis) as a result of normal aging. In addition, declines in sensory and perceptual processing are not due to low-level explanations such as the amount of light that reaches the retina. Declines in visual performance are due to a variety of distinct factors that include spatial integration and difficulty in processing visual information in the presence of noise. Neurophysiological studies suggest that processing declines may be due in part to changes in cortical inhibition mediated by changes in the level of neurotransmitters associated with inhibition. Despite the widespread declines in function with normal aging, recent research suggests that perceptual learning can be used to dramatically improve visual function for older individuals. This research suggests a high degree of plasticity of the visual system among older populations and suggests that perceptual learning is an important tool for the recovery of age-related declines in vision. WIREs Cogn Sci 2012, 3:403-410. doi: 10.1002/wcs.1167 For further resources related to this article, please visit the WIREs website.

BACKGROUND

The Expanded Programme on Immunisation (EPI) provides an effective way of delivering intermittent preventive treatment for malaria (IPT) to infants. However, it is uncertain how IPT can be delivered most effectively to older children. Therefore, we have compared two approaches to the delivery of IPT to Gambian children: distribution by village health workers (VHWs) or through reproductive and child health (RCH) trekking teams. In rural areas, RCH trekking teams provide most of the health care to children under the age of 5 years in the Infant Welfare Clinic, and provide antenatal care for pregnant women.

RESULTS

During the 2006 malaria transmission season, the catchment populations of 26 RCH trekking clinics in The Gambia, each with 400-500 children 6 years of age and under, were randomly allocated to receive IPT from an RCH trekking team or from a VHW. Treatment with a single dose of sulfadoxine pyrimethamine (SP) plus three doses of amodiaquine (AQ) were given at monthly intervals during the malaria transmission season. Morbidity from malaria was monitored passively throughout the malaria transmission season in all children, and a random sample of study children from each cluster was examined at the end of the malaria transmission season. The primary study endpoint was the incidence of malaria. Secondary endpoints included coverage of IPTc, mean haemoglobin (Hb) concentration, and the prevalence of asexual malaria parasitaemia at the end of malaria transmission period. Financial and economic costs associated with the two delivery strategies were collected and incremental cost and effects were compared. A nested case-control study was used to estimate efficacy of IPT treatment courses. Treatment with SP plus AQ was safe and well tolerated. There were 49 cases of malaria with parasitaemia above 5,000/µl in the areas where IPT was delivered through RCH clinics and 21 cases in the areas where IPT was delivered by VHWs, (incidence rates 2.8 and 1.2 per 1,000 child months, respectively, rate difference 1.6 [95% confidence interval (CI) -0.24 to 3.5]). Delivery through VHWs achieved a substantially higher coverage level of three courses of IPT than delivery by RCH trekking teams (74% versus 48%, a difference of 27% [95% CI 16%-38%]). For both methods of delivery, coverage was unrelated to indices of wealth, with similar coverage being achieved in the poorest and wealthiest groups. The prevalence of anaemia was low in both arms of the trial at the end of the transmission season. Efficacy of IPTc against malaria during the month after each treatment course was 87% (95% CI 54%-96%). Delivery of IPTc by VHWs was less costly in both economic and financial terms than delivery through RCH trekking teams, resulting in incremental savings of US$872 and US$1,244 respectively. The annual economic cost of delivering at least the first dose of each course of IPTc was US$3.47 and US$1.63 per child using trekking team and VHWs respectively.

CONCLUSIONS

In this setting in The Gambia, delivery of IPTc to children 6 years of age and under by VHWs is more effective and less costly than delivery through RCH trekking clinics.

BACKGROUND

ClinicalTrials.gov NCT00376155. Please see later in the article for the Editors' Summary.

Nanomedicine is a relatively new field that is rapidly evolving. Formulation of drugs on the nanoscale imparts many physical and biological advantages. Such advantages can in turn translate into improved therapeutic efficacy and reduced toxicity. While approximately 50 nanotherapeutics have already entered clinical practice, a greater number of drugs are undergoing clinical investigation for a variety of indications. This review aims to examine all the nanoformulations that are currently undergoing clinical investigation and their outlook for ultimate clinical translation. WIREs Nanomed Nanobiotechnol 2017, 9:e1416. doi: 10.1002/wnan.1416 For further resources related to this article, please visit the WIREs website.

Hematide is an investigational pegylated synthetic peptide that stimulates erythropoiesis in animal models and is being developed for the treatment of anemia associated with chronic renal failure and cancer. This study evaluated the safety and pharmacodynamics of single, intravenous doses (0.025, 0.05, and 0.1 mg/kg) of Hematide in 28 healthy male volunteers. All doses of Hematide were well tolerated, with safety profiles similar to those of placebo. Hematide showed a dose-dependent increase in reticulocytes. The 0.1-mg/kg dose was associated with a statistically significant increase in hemoglobin (Hgb) from baseline compared to the placebo group (13.6 +/- 3.9 g/L [1.36 +/- 0.39 g/dL] versus 3.9 +/- 3.8 g/L [0.39 +/- 0.38 g/dL]; P < .001) that was sustained for longer than 1 month. These results support phase 2 studies in patients with anemia associated with chronic kidney disease or cancer and suggest that Hematide administered as infrequently as once a month may result in a sustained elevation of Hgb levels. (Please note that Hematide is a proposed trade name; the compound does not yet have a nonproprietary name.).

RNA editing, which adds sequence information to RNAs post-transcriptionally, is a widespread phenomenon throughout eukaryotes. The most complex form of this process is the uridine (U) insertion/deletion editing that occurs in the mitochondria of kinetoplastid protists. RNA editing in these flagellates is specified by trans-acting guide RNAs and entails the insertion of hundreds and deletion of dozens of U residues from mitochondrial RNAs to produce mature, translatable mRNAs. An emerging model indicates that the machinery required for trypanosome RNA editing is much more complicated than previously appreciated. A family of RNA editing core complexes (RECCs), which contain the required enzymes and several structural proteins, catalyze cycles of U insertion and deletion. A second, dynamic multiprotein complex, the Mitochondrial RNA Binding 1 (MRB1) complex, has recently come to light as another essential component of the trypanosome RNA editing machinery. MRB1 likely serves as the platform for kinetoplastid RNA editing, and plays critical roles in RNA utilization and editing processivity. MRB1 also appears to act as a hub for coordination of RNA editing with additional mitochondrial RNA processing events. This review highlights the current knowledge regarding the complex molecular machinery involved in trypanosome RNA editing. WIREs RNA 2016, 7:33-51. doi: 10.1002/wrna.1313 For further resources related to this article, please visit the WIREs website.

A survey of 392 women who had carried at least one pregnancy to term in Sagamu, South-Western Nigeria was conducted to determine the pattern of use of maternity services and assess factors that may influence the observed pattern. Majority of the women received antenatal care (84.6%) during their last pregnancy. Four-fifth of those who received ANC first attended the clinic during the second trimester (79.6%). The places of delivery were government facilities (54.8%), private hospital (24.5%), traditional birth attendants (13.5%) and spiritual healing homes (5.6%). Higher educational status and higher level of income positively affected the pattern of use of these services (p<0.05). Perceived quality of service was the most important factor which influenced the choice of facility for obstetric care. A considerable proportion of those who used traditional birth attendants (36.1%) used it to please their husbands. Our findings suggest that improving the socioeconomic status of men and women in the community is a key factor to improving utilization of maternity care services.

The natural breakdown of cells, tissues, and organ systems is a significant consequence of aging and is at least partially caused by a decreased ability to tolerate environmental stressors. Based on quantitative ultrastructural analysis using transmission electron microscopy and computer imaging, we show significant differences in hepatocyte morphology between young and old rats during a 48-hr recovery period following a 2-day heat stress protocol. Mitochondrial injury was greater overall in old compared with young rats. Autophagy was observed in both young and old rats, with autophagy greater overall in old compared with young hepatocytes. Lipid peroxidation and protein nitration were evaluated by localization and quantification of 4-hydroxy-2-nonenal (4-HNE)-modified protein adducts and 3-nitrotyrosine (3-NT) levels, respectively. Levels of 3-NT but not 4-HNE-protein adducts were significantly elevated in hepatocytes of old rats in comparison with young at 90 min after heat stress, suggesting a major role for reactive nitrogen species in the pathology observed at this time point. These results show a differential response of hepatocyte mitochondria to heat stress with aging, as well as greater levels of both autophagic and nitrative damage in old vs young hepatocytes. This manuscript contains online supplemental material at http://www.jhc.org. Please visit this article online to view these materials.

BACKGROUND

There are several guidelines addressing the issues around the use of NSAIDs. However, none has specifically addressed the upper versus lower gastrointestinal (GI) risk of COX-2 selective and non-selective compounds nor the interaction at both the GI and cardiovascular (CV) level of either class of drugs with low-dose aspirin. This Consensus paper aims to develop statements and guidance devoted to these specific issues through a review of current evidence by a multidisciplinary group of experts.

METHODS

A modified Delphi consensus process was adopted to determine the level of agreement with each statement and to determine the level of agreement with the strength of evidence to be assigned to the statement.

RESULTS

For patients with both low GI and CV risks, any non-selective NSAID (ns-NSAID) alone may be acceptable. For those with low GI and high CV risk, naproxen may be preferred because of its potential lower CV risk compared with other ns-NSAIDs or COX-2 selective inhibitors, but celecoxib at the lowest approved dose (200 mg once daily) may be acceptable. In patients with high GI risk, if CV risk is low, a COX-2 selective inhibitor alone or ns-NSAID with a proton pump inhibitor appears to offer similar protection from upper GI events. However, only celecoxib will reduce mucosal harm throughout the entire GI tract. When both GI and CV risks are high, the optimal strategy is to avoid NSAID therapy, if at all possible.

CONCLUSIONS

Time is now ripe for offering patients with osteoarthritis the safest and most cost-effective therapeutic option, thus preventing serious adverse events which could have important quality of life and resource use implications. Please see related article: http://dx.doi.org/10.1186/s12916-015-0291-x.

By using methods that permit the generation and manipulation of ultrasmall-volume droplets, researchers are pushing the boundaries of ultrasensitive chemical analyses. (To listen to a podcast about this feature, please go to the Analytical Chemistry Web site at pubs.acs.org/ancham.).

The American Diabetes Association (ADA) "Standards of Medical Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee (https://doi.org/10.2337/dc20-SPPC), are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations, please refer to the Standards of Care Introduction (https://doi.org/10.2337/dc20-SINT). Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.

Systematic reviews are characterized by a methodical and replicable methodology and presentation. They involve a comprehensive search to locate all relevant published and unpublished work on a subject; a systematic integration of search results; and a critique of the extent, nature, and quality of evidence in relation to a particular research question. The best reviews synthesize studies to draw broad theoretical conclusions about what a literature means, linking theory to evidence and evidence to theory. This guide describes how to plan, conduct, organize, and present a systematic review of quantitative (meta-analysis) or qualitative (narrative review, meta-synthesis) information. We outline core standards and principles and describe commonly encountered problems. Although this guide targets psychological scientists, its high level of abstraction makes it potentially relevant to any subject area or discipline. We argue that systematic reviews are a key methodology for clarifying whether and how research findings replicate and for explaining possible inconsistencies, and we call for researchers to conduct systematic reviews to help elucidate whether there is a replication crisis. Expected final online publication date for the Annual Review of Psychology Volume 70 is January 4, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.