Sanjay Basu and colleagues explain how models are increasingly used to inform public health policy yet readers may struggle to evaluate the quality of models. All models require simplifying assumptions, and there are tradeoffs between creating models that are more "realistic" versus those that are grounded in more solid data. Indeed, complex models are not necessarily more accurate or reliable simply because they can more easily fit real-world data than simpler models can. Please see later in the article for the Editors' Summary.

Psoriasis vulgaris is a common and often chronic inflammatory skin disease. The incidence of psoriasis in Western industrialized countries ranges from 1.5 to 2%. Patients afflicted with severe psoriasis vulgaris may experience a significant reduction in quality of life. Despite the large variety of treatment options available, patient surveys have revealed insufficient satisfaction with the efficacy of available treatments and a high rate of medication non-compliance (Richards et al. in J Am Acad Dermatol 41(4):581-583, 1999). To optimize the treatment of psoriasis in Germany, the Deutsche Dermatologische Gesellschaft (DDG) and the Berufsverband Deutscher Dermatologen (BVDD) have initiated a project to develop evidence-based guidelines for the management of psoriasis first published in 2006 and now updated in 2011. The Guidelines focus on induction therapy in cases of mild, moderate, and severe plaque-type psoriasis in adults. This short version of the guidelines presents the resulting series of therapeutic recommendations, which were based on a systematic literature search and discussed and approved by a team of dermatology experts. In addition to the therapeutic recommendations provided in this short version, the full version of the guidelines includes information on contraindications, adverse events, drug interactions, practicality, and costs, as well as detailed information on how best to apply the treatments described (for full version please see Nast et al. in JDDG Suppl 2:S1-S104, 2011 or http://www.psoriasis-leitlinie.de ).

When non-informative peripheral cues precede a target defined by a specific feature, cues that share the critical feature will capture attention while cues that do not will be effectively ignored. We tested whether different attentional control sets can be simultaneously maintained over distinct regions of space. Participants were instructed to respond only to specific colored targets at specific locations. Most trials included non-predictive cues whose location and/or color were either congruent or incongruent with the spatial and/or color properties of the impending target. We observed contingent capture only for cues that were consistent with the attentional control set applied to that region of space. This is the first demonstration that separate attentional control sets can be simultaneously maintained at distinct spatial locations, with implications for the flexibility of endogenous control over automatic attentional orienting.

The American Diabetes Association (ADA) "Standards of Medical Care in Diabetes" includes 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 multi-disciplinary expert committee, 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 Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/content/clinical-practice-recommendations.

BACKGROUND

Viral load (VL) is recommended for monitoring the response to highly active antiretroviral therapy (HAART) but is not routinely available in most low- and middle-income countries. The purpose of the study was to determine whether a CD4-based monitoring and switching strategy would provide a similar clinical outcome compared to the standard VL-based strategy in Thailand.

RESULTS

The Programs for HIV Prevention and Treatment (PHPT-3) non-inferiority randomized clinical trial compared a treatment switching strategy based on CD4-only (CD4) monitoring versus viral-load (VL). Consenting participants were antiretroviral-naïve HIV-infected adults (CD4 count 50-250/mm(3)) initiating non-nucleotide reverse transcriptase inhibitor (NNRTI)-based therapy. Randomization, stratified by site (21 public hospitals), was performed centrally after enrollment. Clinicians were unaware of the VL values of patients randomized to the CD4 arm. Participants switched to second-line combination with confirmed CD4 decline >30% from peak (within 200 cells from baseline) in the CD4 arm, or confirmed VL >400 copies/ml in the VL arm. Primary endpoint was clinical failure at 3 years, defined as death, new AIDS-defining event, or CD4 <50 cells/mm(3). The 3-year Kaplan-Meier cumulative risks of clinical failure were compared for non-inferiority with a margin of 7.4%. In the intent to treat analysis, data were censored at the date of death or at last visit. The secondary endpoints were difference in future-drug-option (FDO) score, a measure of resistance profiles, virologic and immunologic responses, and the safety and tolerance of HAART. 716 participants were randomized, 356 to VL monitoring and 360 to CD4 monitoring. At 3 years, 319 participants (90%) in VL and 326 (91%) in CD4 were alive and on follow-up. The cumulative risk of clinical failure was 8.0% (95% CI 5.6-11.4) in VL versus 7.4% (5.1-10.7) in CD4, and the upper-limit of the one-sided 95% CI of the difference was 3.4%, meeting the pre-determined non-inferiority criterion. Probability of switch for study criteria was 5.2% (3.2-8.4) in VL versus 7.5% (5.0-11.1) in CD4 (p=0.097). Median time from treatment initiation to switch was 11.7 months (7.7-19.4) in VL and 24.7 months (15.9-35.0) in CD4 (p=0.001). The median duration of viremia >400 copies/ml at switch was 7.2 months (5.8-8.0) in VL versus 15.8 months (8.5-20.4) in CD4 (p=0.002). FDO scores were not significantly different at time of switch. No adverse events related to the monitoring strategy were reported.

CONCLUSIONS

The 3-year rates of clinical failure and loss of treatment options did not differ between strategies although the longer-term consequences of CD4 monitoring would need to be investigated. These results provide reassurance to treatment programs currently based on CD4 monitoring as VL measurement becomes more affordable and feasible in resource-limited settings.

BACKGROUND

ClinicalTrials.govNCT00162682 Please see later in the article for the Editors' Summary.

BACKGROUND

Randomized clinical trials examining the optimal time to initiate combination antiretroviral therapy (cART) in HIV-infected adults with sputum smear-positive tuberculosis (TB) disease have demonstrated improved survival among those who initiate cART earlier during TB treatment. Since these trials incorporated rigorous diagnostic criteria, it is unclear whether these results are generalizable to the vast majority of HIV-infected patients with TB, for whom standard diagnostic tools are unavailable. We aimed to examine whether early cART initiation improved survival among HIV-infected adults who were diagnosed with TB in a clinical setting.

RESULTS

We retrospectively reviewed charts for 308 HIV-infected adults in Rwanda with a CD4 count ≤ 350 cells/µl and a TB diagnosis. We estimated the effect of cART on survival using marginal structural models and simulated 2-y survival curves for the cohort under different cART strategies:start cART 15, 30, 60, or 180 d after TB treatment or never start cART. We conducted secondary analyses with composite endpoints of (1) death, default, or lost to follow-up and (2) death, hospitalization, or serious opportunistic infection. Early cART initiation led to a survival benefit that was most marked for individuals with low CD4 counts. For individuals with CD4 counts of 50 or 100 cells/µl, cART initiation at day 15 yielded 2-y survival probabilities of 0.82 (95% confidence interval: [0.76, 0.89]) and 0.86 (95% confidence interval: [0.80, 0.92]), respectively. These were significantly higher than the probabilities computed under later start times. Results were similar for the endpoint of death, hospitalization, or serious opportunistic infection. cART initiation at day 15 versus later times was protective against death, default, or loss to follow-up, regardless of CD4 count. As with any observational study, the validity of these findings assumes that biases from residual confounding by unmeasured factors and from model misspecification are small.

CONCLUSIONS

Early cART reduced mortality among individuals with low CD4 counts and improved retention in care, regardless of CD4 count. Please see later in the article for the Editors' Summary.

Autophagosomes are the hallmark of autophagy, but despite their central role in this degradative pathway that involves vesicle transport to lysosomes or vacuoles, the mechanism underlying their biogenesis still remains largely unknown. Our current concepts about autophagosome biogenesis are based on models suggesting that a small autonomous cisterna grows into an autophagosome through expansion at its extremities. Recent findings have revealed that endoplasmic reticulum (ER) exit sites (ERES), specialized ER regions where proteins are sorted into the secretory system, are key players in the formation of autophagosomes. Owing to the morphological connection of nascent autophagosomes with the ER, this has raised several questions that challenge our current perception of autophagosome biogenesis, such as are ERES the compartments where autophagosome formation takes place? What is the functional relevance of this connection? Are these compartments providing essential molecules for the generation of autophagosomes and/or are they structural platforms where these vesicles emerge? In this Hypothesis, we discuss recent data that have implicated the ERES in autophagosome biogenesis and we propose two models to describe the possible role of this compartment at different steps in the process of autophagosome biogenesis. This article is part of a Focus on Autophagosome biogenesis. For further reading, please see related articles: 'Membrane dynamics in autophagosome biogenesis' by Sven R. Carlsson and Anne Simonsen (J. Cell Sci. 128, 193-205) and 'WIPI proteins: essential PtdIns3P effectors at the nascent autophagosome' by Tassula Proikas-Cezanne et al. (J. Cell Sci. 128, 207-217).

"Would you tell me please, which way I ought to go from here," asked Alice. "That depends a good deal on where you want to go to," said the cat. (Lewis Carroll, Alice's Adventures in Wonderland) A large number of epidemiological studies show positive correlations between increasing levels of particulate matter (PM) in urban air and short-term morbidity and mortality for diverse acute cardiopulmonary diseases. Brought about by PM increments, inflammation is thought to exacerbate preexisting inflammatory diseases. Experimental evidence suggests a hierarchical oxidative stress model, in which a weakened antioxidant defense, as observed in disease or induced by inhaled particles, increases the PM ability to cause lung inflammation, accounting for exacerbations that occur in asthmatics and in patients with chronic obstructive lung disease. The role of PM-induced inflammation leading to acute cardiovascular events such as arrhythmia, heart failure, and myocardial infarction is more speculative. There is neither clear-cut evidence in humans that inhaled PM could get as far as blood circulation nor that proinflammatory mediators are significantly released from inflamed lung tissues, nor that blood coagulability is critically altered. As a whole, data in humans indicate that short-term inflammatory responses to PM are not always detected; they are usually mild and loosely correlated with functional changes. Among these studies, the diversity of PM characteristics, dose metrics, and endpoints hampers a clear discerning of inflammatory mechanism(s). Thus, the question arises as to whether inflammation represents the mechanism of acute cardiopulmonary PM toxicities in susceptible individuals, or rather an event that may coexist with other relevant mechanism(s). This review article discusses the evidence in humans linking short-term PM increments to inflammation and to exacerbations of cardiopulmonary diseases. Although there is a large amount of data available, there still remains a gulf between the number of epidemiological and panel studies and that of controlled exposures. Research on controlled exposure needs expanding, so that the results of time-series and panel studies will be better understood and short-term standards for human exposure may be more confidently allocated.

BACKGROUND

Lateral pain in the elbow affects up to 3% of the population, and is considered an overload injury of the extensor tendons of the forearm where they attach at the lateral epicondyle. Although usually self-limiting, symptoms may persist for over 1 year in up to 20% of people.

METHODS

We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments for tennis elbow? We searched: Medline, Embase, The Cochrane Library, and other important databases up to November 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

RESULTS

We found 80 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

CONCLUSIONS

In this systematic review we present information relating to the effectiveness and safety of the following interventions: acupuncture, autologous whole blood injections, corticosteroid injections, combination physical therapies, exercise, extracorporeal shock wave therapy, iontophoresis, low-level laser therapy, manipulation, non-steroidal anti-inflammatory drugs (oral and topical), orthoses (bracing), platelet-rich plasma injections, pulsed electromagnetic field treatment, surgery, and ultrasound.

BACKGROUND

Perinatal common mental disorders (PCMDs) are a major cause of disability among women. Psychosocial interventions are one approach to reduce the burden of PCMDs. Working with care providers who are not mental health specialists, in the community or in antenatal health care facilities, can expand access to these interventions in low-resource settings. We assessed effects of such interventions compared to usual perinatal care, as well as effects of interventions based on intervention type, delivery method, and timing.

RESULTS

We conducted a systematic review, meta-analysis, and meta-regression. We searched databases including Embase and the Global Health Library (up to 7 July 2013) for randomized and non-randomized trials of psychosocial interventions delivered by non-specialist mental health care providers in community settings and antenatal health care facilities in low- and middle-income countries. We pooled outcomes from ten trials for 18,738 participants. Interventions led to an overall reduction in PCMDs compared to usual care when using continuous data for PCMD symptomatology (effect size [ES] -0.34; 95% CI -0.53, -0.16) but not binary categorizations for presence or absence of PCMDs (OR 0.62, 95% CI 0.35, 1.080 [corrected]. We found a significantly larger ES for psychological interventions (three studies; ES -0.46; 95% CI -0.58, -0.33) than for health promotion interventions (seven studies; ES -0.15; 95% CI -0.27, -0.02). Both individual (five studies; ES -0.18; 95% CI -0.34, -0.01) and group (three studies; ES -0.48; 95% CI -0.85, -0.11) interventions were effective compared to usual care, though delivery method was not associated with ES (meta-regression β coefficient -0.11; 95% CI -0.36, 0.14). Combined group and individual interventions (based on two studies) had no benefit compared to usual care, nor did interventions restricted to pregnancy (three studies). Intervention timing was not associated with ES (β 0.16; 95% CI -0.16, 0.49). The small number of trials and heterogeneity of interventions limit our findings.

CONCLUSIONS

Psychosocial interventions delivered by non-specialists are beneficial for PCMDs, especially psychological interventions. Research is needed on interventions in low-income countries, treatment versus preventive approaches, and cost-effectiveness. Please see later in the article for the Editors' Summary.

OBJECTIVE

Coronary lesions in diabetics (DM) are associated with a high recurrence following percutaneous coronary intervention (PCI), even after drug-eluting stent (DES) deployment. Encouraging clinical data of the drug-eluting balloon catheter (DEB) SeQuent Please warrant its investigation in these patients.

RESULTS

Eighty-four diabetic patients (60.8 ± 9.1 years, 76.2% male) were randomised to either the DEB SeQuent Please or the DES Taxus Liberté to compare the 9-month clinical and angiographic outcome of PCI in native coronary arteries. Comparing the DEB vs. the DES the 9-month results (follow-up DEB 39/45 [86.7%], DES 36/39 [92.3%]) are statistically not different at the 0.05 level for the primary endpoint of in-segment (0.37 ± 0.59 mm vs. 0.35 ± 0.63 mm) and in-stent (0.51 ± 0.61 mm vs. 0.53 ± 0.67 mm) late lumen loss, overall and cardiac deaths (2/45 [4.4%] and 3/45 [6.7%] vs. 0), target lesion revascularisation (3/45 [8.9%] vs. 4/39 [10.3%]), the total MACE rate (6/45 [13.3%] vs. 6/39 [15.4%]), and the event free survival after 10.2 ± 3.8 months (Kaplan-Meier analysis, p<0.80, log rank test).

CONCLUSIONS

The clinical and angiographic outcome of the combination of the drug-eluting balloon SeQuent Please with a cobalt chromium stent compared to the drug eluting Taxus stent are similar.

The American Diabetes Association (ADA) "Standards of Medical Care in Diabetes" includes 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, 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 Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.

Insufficient consumption of fruits and vegetables in childhood increases the risk of future non-communicable diseases, including cardiovascular disease. Interventions to increase consumption of fruit and vegetables, such as those focused on specific child-feeding strategies and parent nutrition education interventions in early childhood may therefore be an effective strategy in reducing this disease burden.

To assess the effectiveness, cost effectiveness and associated adverse events of interventions designed to increase the consumption of fruit, vegetables or both amongst children aged five years and under.

We searched CENTRAL, MEDLINE, Embase and two clinical trials registries to identify eligible trials on 25 January 2018. We searched Proquest Dissertations and Theses in November 2017. We reviewed reference lists of included trials and handsearched three international nutrition journals. We contacted authors of included studies to identify further potentially relevant trials.

We included randomised controlled trials, including cluster-randomised controlled trials and cross-over trials, of any intervention primarily targeting consumption of fruit, vegetables or both among children aged five years and under, and incorporating a dietary or biochemical assessment of fruit or vegetable consumption. Two review authors independently screened titles and abstracts of identified papers; a third review author resolved disagreements.

Two review authors independently extracted data and assessed the risks of bias of included studies; a third review author resolved disagreements. Due to unexplained heterogeneity, we used random-effects models in meta-analyses for the primary review outcomes where we identified sufficient trials. We calculated standardised mean differences (SMDs) to account for the heterogeneity of fruit and vegetable consumption measures. We conducted assessments of risks of bias and evaluated the quality of evidence (GRADE approach) using Cochrane procedures.

We included 63 trials with 178 trial arms and 11,698 participants. Thirty-nine trials examined the impact of child-feeding practices (e.g. repeated food exposure) in increasing child vegetable intake. Fourteen trials examined the impact of parent nutrition education in increasing child fruit and vegetable intake. Nine studies examined the impact of multicomponent interventions (e.g. parent nutrition education and preschool policy changes) in increasing child fruit and vegetable intake. One study examined the effect of a nutrition education intervention delivered to children in increasing child fruit and vegetable intake.We judged 14 of the 63 included trials as free from high risks of bias across all domains; performance, detection and attrition bias were the most common domains judged at high risk of bias for the remaining studies.There is very low quality evidence that child-feeding practices versus no intervention may have a small positive effect on child vegetable consumption equivalent to an increase of 3.50 g as-desired consumption of vegetables (SMD 0.33, 95% CI 0.13 to 0.54; participants = 1741; studies = 13). Multicomponent interventions versus no intervention may have a very small effect on child consumption of fruit and vegetables (SMD 0.35, 95% CI 0.04 to 0.66; participants = 2009; studies = 5; low-quality evidence), equivalent to an increase of 0.37 cups of fruit and vegetables per day. It is uncertain whether there are any short-term differences in child consumption of fruit and vegetables in meta-analyses of trials examining parent nutrition education versus no intervention (SMD 0.12, 95% CI -0.03 to 0.28; participants = 3078; studies = 11; very low-quality evidence).Insufficient data were available to assess long-term effectiveness, cost effectiveness and unintended adverse consequences of interventions. Studies reported receiving governmental or charitable funds, except for four studies reporting industry funding.

Despite identifying 63 eligible trials of various intervention approaches, the evidence for how to increase children's fruit and vegetable consumption remains limited. There was very low- and low-quality evidence respectively that child-feeding practice and multicomponent interventions may lead to very small increases in fruit and vegetable consumption in children aged five years and younger. It is uncertain whether parent nutrition education interventions are effective in increasing fruit and vegetable consumption in children aged five years and younger. Given that the quality of the evidence is very low or low, future research will likely change estimates and conclusions. Long-term follow-up is required and future research should adopt more rigorous methods to advance the field.This is a living systematic review. Living systematic reviews offer a new approach to review updating, in which the review is continually updated, incorporating relevant new evidence as it becomes available. Please refer to the Cochrane Database of Systematic Reviews for the current status of this review.

New approaches to the neurobiology of posttraumatic stress disorder (PTSD) are needed to address the reported crisis in PTSD drug development. These new approaches may require the field to move beyond a narrow fear-based perspective, as fear-based medications have not yet demonstrated compelling efficacy. Antidepressants, particularly recent rapid-acting antidepressants, exert complex effects on brain function and structure that build on novel aspects of the biology of PTSD, including a role for stressrelated synaptic dysconnectivity in the neurobiology and treatment ofPTSD. Here, we integrate this perspective within a broader framework-in other words, a dual pathology model of (a) stress-related synaptic loss arising from amino acid-based pathology and (b) stress-related synaptic gain related to monoamine-based pathology. Then, we summarize the standard and experimental (e.g., ketamine) pharmacotherapeutic options for PTSD and discuss their putative mechanism of action and clinical efficacy. Expected final online publication date for the Annual Review of Pharmacology and Toxicology Volume 59 is January 6, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

BACKGROUND

Dermal fillers have been increasingly used in minimally invasive facial esthetic procedures. This widespread use has led to a rise in reports of associated complications. The aim of this expert consensus report is to describe potential adverse events associated with dermal fillers and to provide guidance on their treatment and avoidance.

METHODS

A multidisciplinary group of experts in esthetic treatments convened to discuss the management of the complications associated with dermal fillers use. A search was performed for English, French, and Spanish language articles in MEDLINE, the Cochrane Database, and Google Scholar using the search terms "complications" OR "soft filler complications" OR "injectable complications" AND "dermal fillers" AND "Therapy". An initial document was drafted by the Coordinating Committee, and it was reviewed and modified by the experts, until a final text was agreed upon and validated.

RESULTS

The panel addressed consensus recommendations about the classification of filler complications according to the time of onset and about the clinical management of different complications including bruising, swelling, edema, infections, lumps and bumps, skin discoloration, and biofilm formation. Special attention was paid to vascular compromise and retinal artery occlusion.

CONCLUSIONS

Clinicians should be fully aware of the signs and symptoms related to complications and be prepared to confidently treat them. Establishing action protocols for emergencies, with agents readily available in the office, would reduce the severity of adverse outcomes associated with injection of hyaluronic acid fillers in the cosmetic setting. This document seeks to lay down a set of recommendations and to identify key issues that may be useful for clinicians who are starting to use dermal fillers. Additionally, this document provides a better understanding about the diagnoses and management of complications if they do occur.

UNASSIGNED

This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

BACKGROUND

Melasma is a common pigmentary disorder among Asian women. The available therapies such as bleaching agents, chemical peeling, laser, and intense pulsed light are not satisfactory or safe. In the search to find a new treatment therapy for melasma, oral administration of tranexamic acid (TA) was studied clinically in Chinese patients.

METHODS

The study enrolled 74 patients. Tranexamic acid tablets were prescribed at a dosage of 250 mg twice daily for a therapeutic period of 6 months. All the patients were followed up for more than 6 months after the treatment. The effects of treatment were evaluated by two physicians independently and by the patient based on improvement of pigmentation and reduction in melasma size. These were graded into four levels: excellent, good, fair, and poor.

RESULTS

After 6 months of treatment, the effects were graded as follows: excellent (10.8%, 8/74), good (54%, 40/74), fair (31.1%, 23/74), and poor (4.1%, 3/74). Side effects of TA such as gastrointestinal discomfort (5.4%) and hypomenorrhea (8.1%) were observed, but no severe complications were found. The recurrence of melasma was observed in seven cases (9.5%).

CONCLUSIONS

Oral administration of TA is an effective and safe therapy for the treatment of melasma.

METHODS

This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors at www.springer.com/00266.

PTEN is a tumor suppressor gene that classically dampens the PI3K/AKT/mTOR growth-promoting signaling cascade. PTEN dysfunction causes dysregulation of this and other pathways, resulting in overgrowth. Cowden syndrome, a hereditary cancer predisposition and overgrowth disorder, was the first Mendelian condition associated with germline PTEN mutations. Since then, significant advances by the research and medical communities have elucidated how clinical phenotypic manifestations result from the underlying germline PTEN mutations. With time, it became evident that PTEN mutations can result in a broad phenotypic spectrum, causing seemingly disparate disorders from cancer to autism. Hence, the umbrella term of PTEN hamartoma tumor syndrome (PHTS) was coined. Timely diagnosis and understanding the natural history of PHTS are vital because early recognition enables gene-informed management, particularly as related to high-risk cancer surveillance and addressing the neurodevelopmental symptoms. Expected final online publication date for the Annual Review of Medicine, Volume 71 is January 27, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Mitochondria are essential in most eukaryotes and are involved in numerous biological functions including ATP production, cofactor biosyntheses, apoptosis, lipid synthesis, and steroid metabolism. Work over the past two decades has uncovered the biogenesis of cellular iron-sulfur (Fe/S) proteins as the essential and minimal function of mitochondria. This process is catalyzed by the bacteria-derived iron-sulfur cluster assembly (ISC) machinery and has been dissected into three major steps: de novo synthesis of a [2Fe-2S] cluster on a scaffold protein; Hsp70 chaperone-mediated trafficking of the cluster and insertion into [2Fe-2S] target apoproteins; and catalytic conversion of the [2Fe-2S] into a [4Fe-4S] cluster and subsequent insertion into recipient apoproteins. ISC components of the first two steps are also required for biogenesis of numerous essential cytosolic and nuclear Fe/S proteins, explaining the essentiality of mitochondria. This review summarizes the molecular mechanisms underlying the ISC protein-mediated maturation of mitochondrial Fe/S proteins and the importance for human disease. Expected final online publication date for the Annual Review of Biochemistry, Volume 89 is June 22, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Archaea are ubiquitous and abundant members of the marine plankton. Once thought of as rare organisms found in exotic extremes of temperature, pressure, or salinity, archaea are now known in nearly every marine environment. Though frequently referred to collectively, the planktonic archaea actually comprise four major phylogenetic groups, each with its own distinct physiology and ecology. Only one group-the marine Thaumarchaeota-has cultivated representatives, making marine archaea an attractive focus point for the latest developments in cultivation-independent molecular methods. Here, we review the ecology, physiology, and biogeochemical impact of the four archaeal groups using recent insights from cultures and large-scale environmental sequencing studies. We highlight key gaps in our knowledge about the ecological roles of marine archaea in carbon flow and food web interactions. We emphasize the incredible uncultivated diversity within each of the four groups, suggesting there is much more to be done. Expected final online publication date for the Annual Review of Marine Science Volume 11 is January 3, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

BACKGROUND

Trials are vital in informing routine clinical care; however, current designs have major deficiencies. An overview of the various challenges that face modern clinical research and the methods that can be exploited to solve these challenges, in the context of personalised cancer treatment in the 21st century is provided.

OBJECTIVE

The purpose of this manuscript, without intending to be comprehensive, is to spark thought whilst presenting and discussing two important and complementary alternatives to traditional evidence-based medicine, specifically rapid learning health care and cohort multiple randomised controlled trial design. Rapid learning health care is an approach that proposes to extract and apply knowledge from routine clinical care data rather than exclusively depending on clinical trial evidence, (please watch the animation: http://youtu.be/ZDJFOxpwqEA). The cohort multiple randomised controlled trial design is a pragmatic method which has been proposed to help overcome the weaknesses of conventional randomised trials, taking advantage of the standardised follow-up approaches more and more used in routine patient care. This approach is particularly useful when the new intervention is a priori attractive for the patient (i.e. proton therapy, patient decision aids or expensive medications), when the outcomes are easily collected, and when there is no need of a placebo arm.

CONCLUSIONS

Truly personalised cancer treatment is the goal in modern radiotherapy. However, personalised cancer treatment is also an immense challenge. The vast variety of both cancer patients and treatment options makes it extremely difficult to determine which decisions are optimal for the individual patient. Nevertheless, rapid learning health care and cohort multiple randomised controlled trial design are two approaches (among others) that can help meet this challenge.

BACKGROUND

Bereavement by spousal death and child death in adulthood has been shown to lead to an increased risk of mortality. Maternal death in infancy or parental death in early childhood may have an impact on mortality but evidence has been limited to short-term or selected causes of death. Little is known about long-term or cause-specific mortality after parental death in childhood.

RESULTS

This cohort study included all persons born in Denmark from 1968 to 2008 (n = 2,789,807) and in Sweden from 1973 to 2006 (n = 3,380,301), and a random sample of 89.3% of all born in Finland from 1987 to 2007 (n = 1,131,905). A total of 189,094 persons were included in the exposed cohort when they lost a parent before 18 years old. Log-linear Poisson regression was used to estimate mortality rate ratio (MRR). Parental death was associated with a 50% increased all-cause mortality (MRR = 1.50, 95% CI 1.43-1.58). The risks were increased for most specific cause groups and the highest MRRs were observed when the cause of child death and the cause of parental death were in the same category. Parental unnatural death was associated with a higher mortality risk (MRR = 1.84, 95% CI 1.71-2.00) than parental natural death (MRR = 1.33, 95% CI 1.24-1.41). The magnitude of the associations varied according to type of death and age at bereavement over different follow-up periods. The main limitation of the study is the lack of data on post-bereavement information on the quality of the parent-child relationship, lifestyles, and common physical environment.

CONCLUSIONS

Parental death in childhood or adolescence is associated with increased all-cause mortality into early adulthood. Since an increased mortality reflects both genetic susceptibility and long-term impacts of parental death on health and social well-being, our findings have implications in clinical responses and public health strategies. Please see later in the article for the Editors' Summary.

The American Diabetes Association (ADA) "Standards of Medical Care in Diabetes" includes 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, 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 Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.

The American Diabetes Association (ADA) "Standards of Medical Care in Diabetes" includes 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, 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 Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.