Certolizumab pegol, abatacept, tocilizumab or active conventional treatment in early rheumatoid arthritis: 48-week clinical and radiographic results of the investigator-initiated randomised controlled NORD-STAR trial.

BACKGROUND: The optimal first-line treatment in early rheumatoid arthritis (RA) is debated. We compared clinical and radiographic outcomes of active conventional therapy with each of three biological treatments with different modes of action. METHODS: Investigator-initiated, randomised, blinded-assessor study. Patients with treatment-naïve early RA with moderate-severe disease activity were randomised 1:1:1:1 to methotrexate combined with (1) active conventional therapy: oral prednisolone (tapered quickly, discontinued at week 36) or sulfasalazine, hydroxychloroquine and intra-articular glucocorticoid injections in swollen joints; (2) certolizumab pegol; (3) abatacept or (4) tocilizumab. Coprimary endpoints were week 48 Clinical Disease Activity Index (CDAI) remission (CDAI ≤2.8) and change in radiographic van der Heijde-modified Sharp Score, estimated using logistic regression and analysis of covariance, adjusted for sex, anticitrullinated protein antibody status and country. Bonferroni's and Dunnet's procedures adjusted for multiple testing (significance level: 0.025). RESULTS: Eight hundred and twelve patients were randomised. Adjusted CDAI remission rates at week 48 were: 59.3% (abatacept), 52.3% (certolizumab), 51.9% (tocilizumab) and 39.2% (active conventional therapy). Compared with active conventional therapy, CDAI remission rates were significantly higher for abatacept (adjusted difference +20.1%, p<0.001) and certolizumab (+13.1%, p=0.021), but not for tocilizumab (+12.7%, p=0.030). Key secondary clinical outcomes were consistently better in biological groups. Radiographic progression was low, without group differences.The proportions of patients with serious adverse events were abatacept, 8.3%; certolizumab, 12.4%; tocilizumab, 9.2%; and active conventional therapy, 10.7%. CONCLUSIONS: Compared with active conventional therapy, clinical remission rates were superior for abatacept and certolizumab pegol, but not for tocilizumab. Radiographic progression was low and similar between treatments. TRIAL REGISTRATION NUMBER: NCT01491815.

Electroencephalographic Changes in Sleep During Acute and Subacute Phases After Sports-Related Concussion.

Purpose: Little is known about sleep after a concussion, a form of mild traumatic brain injury. Given the importance of sleep for both maintaining brain health and recovery from injury, we sought to examine sleep acutely and subacutely after concussion. Methods: Athletes who experienced a sports-related concussion were invited to participate. Participants underwent overnight sleep studies within 7 days of the concussion (acute phase), and again eight-weeks after the concussion (subacute phase). Changes in sleep from both the acute and subacute phases were compared to population normative values. Additionally, changes in sleep from acute to subacute phase were analysed. Results: When compared to normative data, the acute and subacute phases of concussion showed longer total sleep time (p < 0.005) and fewer arousals (p < 0.005). The acute phase showed longer rapid eye movement sleep latency (p = 0.014). The subacute phase showed greater total sleep spent in Stage N3% (p = 0.046), increased sleep efficiency (p < 0.001), shorter sleep onset latency (p = 0.013), and reduced wake after sleep onset (p = 0.013). Compared to the acute phase, the subacute phase experienced improved sleep efficiency (p = 0.003), reduced wake after sleep onset (p = 0.02), and reduced latencies for both stage N3 sleep (p = 0.014) and rapid eye movement sleep (p = 0.006). Conclusion: This study indicated sleep during both the acute and subacute phases of SRC was characterised by longer and less disrupted sleep, along with improvements in sleep from the acute to subacute phases of SRC.

Should We Lose Sleep Over Sleep Disturbances After Sports-Related Concussion? A Scoping Review of the Literature.

OBJECTIVE: A single, severe traumatic brain injury can result in chronic sleep disturbances that can persist several years after the incident. In contrast, it is unclear whether there are sleep disturbances after a sports-related concussion (SRC). Considering growing evidence of links between sleep disturbance and neurodegeneration, this review examined the potential links between diagnosed SRCs and sleep disturbances to provide guidance for future studies. METHODS: The scoping review undertook a systematic search of key online databases (Scopus, MEDLINE, SportDiscus, and Web of Science) using predetermined search terms for any articles that examined sleep after concussion. A screening criterion using agreed inclusion and exclusion criteria was utilized to ensure inclusion of relevant articles. DESIGN: This scoping review is guided by the PRSIMA Scoping Review report. RESULTS: Ten studies met the inclusion criteria, reporting on 896 adults who had experienced an SRC. Comparison with 1327 non-SRC adults occurred in 8 studies. Nine studies subjectively examined sleep, of which all but one study reported sleep disturbances after an SRC. Three studies objectively measured sleep, with 2 studies indicating large coefficients of variation of sleep duration, suggesting a range of sleep responses after an SRC. The only study to examine overnight polysomnography showed no differences in sleep metrics between those with and without an SRC. No studies examined interventions to improve sleep outcomes in people with concussion. CONCLUSIONS: This scoping review indicates preliminary evidence of sleep disturbances following an SRC. The heterogeneity of methodology used in the included studies makes consensus on the results difficult. Given the mediating role of sleep in neurodegenerative disorders, further research is needed to identify physiological correlates and pathological mechanisms of sleep disturbances in SRC-related neurodegeneration and whether interventions for sleep problems improve recovery from concussion and reduce the risk of SRC-related neurodegeneration.

Syphilis with vision loss. / Syfilis med synstap.

BACKGROUND: Neurosyphilis is a rare cause of vision loss that can mimic the presentation of other diseases, including giant cell arteritis. CASE PRESENTATION: A man in his sixties presented to the university hospital with a four-day history of right eye vision loss. He experienced a headache, myalgia and fatigue. Right eye vision was limited to finger counting at 2 metres and a relative afferent pupillary defect was present. He was tender over the right temporal area and had a decreased pulse in the right temporal artery. A pink maculopapular rash was present on the trunk. Laboratory testing showed elevated inflammatory parameters with ESR 50. Ischaemic optic neuropathy caused by giant cell arteritis was suspected, and treatment with high dose steroids was initiated. Expanded history revealed travel to Thailand five months prior to presentation and unprotected sex with multiple female partners. A non-painful sore had developed on his penis that resolved after 14 days. INTERPRETATION: Neurosyphilis was suspected and the diagnosis was subsequently confirmed. The patient received appropriate antibiotic therapy, and four months later his vision had almost normalised.

Association Between Childhood Behavioral Problems and Insomnia Symptoms in Adulthood.

Importance: Life-course determinants of insomnia, particularly the long-term association of childhood behavioral problems with insomnia later in life, are unknown. As childhood behaviors are measurable and potentially modifiable, understanding their associations with insomnia symptoms may provide novel insights into early intervention strategies to reduce the burden. Objective: To investigate the association between behavioral problems at 5, 10, and 16 years of age and self-reported insomnia symptoms at 42 years of age. Design, Setting, and Participants: This cohort study used data from the United Kingdom 1970 Birth Cohort Study, an ongoing large-scale follow-up study. Participants were followed up from birth (1970) to age 42 years (2012). Missing data were imputed via multiple imputation. Statistical analysis was performed from February 1 to July 15, 2019. Exposures: Behavior measured at 5, 10, and 16 years of age using the Rutter Behavioral Scale (RBS). Children's behavior was classified as normal (≤80th percentile), moderate behavioral problems (>80th to ≤95th percentile), and severe behavioral problems (>95th percentile) based on their RBS score. Main Outcomes and Measures: Self-reported difficulties initiating or maintaining sleep (DIMS) were collected using a self-administered questionnaire at 42 years of age. Log-binomial logistic regression, adjusted for several potential confounders, was used to estimate the association of childhood behavioral problems with insomnia symptoms in adulthood. Sensitivity analyses were conducted to check robustness of the findings. Results: Participants were followed up from a baseline age of 5 years (n = 8050; 3854 boys and 4196 girls), 10 years (n = 9090; 4365 boys and 4725 girls), or 16 years (n = 7653; 3575 boys and 4078 girls) until age 42 years. There was a 39% higher risk of DIMS (odds ratio [OR], 1.39; 95% CI, 1.04-1.84; P = .06 for trend) for participants with severe behavioral problems at 5 years of age compared with those with a normal RBS score. The odds of DIMS plus not feeling rested on waking (DIMS plus) in participants with severe behavioral problems at 5 years of age were 29% higher (odds ratio, 1.29; 95% CI, 0.97-1.70; P = .14 for trend) than participants with a normal RBS score, although this result was not statistically significant. Moderate and severe behavioral problems at 16 years of age were positively associated with DIMS and DIMS plus (moderate: OR, 1.28; 95% CI, 1.07-1.52; severe: OR, 1.67; 95% CI, 1.22-2.30; P < .001 for trend) and DIMS plus (moderate: OR, 1.32; 95% CI, 1.11-1.56; severe: OR, 1.47; 95% CI, 1.09-1.98; P < .001 for trend). Externalizing behavioral problems at 5 and 10 years of age were positively associated with insomnia symptoms at 42 years of age. Conclusions and Relevance: This study is the first to show associations of early-life behavioral problems, particularly early- and middle-childhood externalizing problems, with insomnia symptoms in adulthood. These findings underline the importance of addressing insomnia from a life-course perspective and considering the benefits of early behavioral intervention to sleep health.

Effect of 1†month of zopiclone on obstructive sleep apnoea severity and symptoms: a randomised controlled trial.

Hypnotic use in obstructive sleep apnoea (OSA) is contraindicated due to safety concerns. Recent studies indicate that single-night hypnotic use worsens hypoxaemia in some and reduces OSA severity in others depending on differences in pathophysiology. However, longer clinical trial data are lacking. This study aimed to determine the effects of 1 month of zopiclone on OSA severity, sleepiness and alertness in patients with low-moderate respiratory arousal thresholds without major overnight hypoxaemia.69 participants completed a physiology screening night with an epiglottic catheter to quantify arousal threshold. 30 eligible patients (apnoea-hypopnoea index (AHI) 22±11 events·h-1) then completed standard in-laboratory polysomnography (baseline) and returned for two additional overnight sleep studies (nights 1 and 30) after receiving either nightly zopiclone (7.5 mg) or placebo during a 1-month, double-blind, randomised, parallel trial (ANZCTR identifier ANZCTRN12613001106729).The change in AHI from baseline to night 30 was not different between zopiclone versus placebo groups (-5.9±10.2 versus -2.4±5.5 events·h-1; p=0.24). Similarly, hypoxaemia, next-day sleepiness and driving simulator performance were not different.1 month of zopiclone does not worsen OSA severity, sleepiness or alertness in selected patients without major overnight hypoxaemia. As the first study to assess the effect of a hypnotic on OSA severity and sleepiness beyond single-night studies, these findings provide important safety data and insight into OSA pathophysiology.

Statistical Learning Is Not Affected by a Prior Bout of Physical Exercise.

This study examined the effect of a prior bout of exercise on implicit cognition. Specifically, we examined whether a prior bout of moderate intensity exercise affected performance on a statistical learning task in healthy adults. A total of 42 participants were allocated to one of three conditions-a control group, a group that exercised for 15 min prior to the statistical learning task, and a group that exercised for 30 min prior to the statistical learning task. The participants in the exercise groups cycled at 60% of their respective V˙O2 max. Each group demonstrated significant statistical learning, with similar levels of learning among the three groups. Contrary to previous research that has shown that a prior bout of exercise can affect performance on explicit cognitive tasks, the results of the current study suggest that the physiological stress induced by moderate-intensity exercise does not affect implicit cognition as measured by statistical learning.

Concurrent movement impairs incidental but not intentional statistical learning.

The effect of concurrent movement on incidental versus intentional statistical learning was examined in two experiments. In Experiment 1, participants learned the statistical regularities embedded within familiarization stimuli implicitly, whereas in Experiment 2 they were made aware of the embedded regularities and were instructed explicitly to learn these regularities. Experiment 1 demonstrated that while the control group were able to learn the statistical regularities, the resistance-free cycling group and the exercise group did not demonstrate learning. This is in contrast with the findings of Experiment 2, where all three groups demonstrated significant levels of learning. The results suggest that the movement demands, rather than the physiological stress, interfered with statistical learning. We suggest movement activates the striatum, which is not only responsible for motor control but also plays a role in incidental learning.

Statistical learning under incidental versus intentional conditions.

Statistical learning (SL) studies have shown that participants are able to extract regularities in input they are exposed to without any instruction to do so. This and other findings, such as the fact that participants are often unable to verbalize their acquired knowledge, suggest that SL can occur implicitly or incidentally. Interestingly, several studies using the related paradigms of artificial grammar learning and serial response time tasks have shown that explicit instructions can aid learning under certain conditions. Within the SL literature, however, very few studies have contrasted incidental and intentional learning conditions. The aim of the present study was to investigate the effect of having prior knowledge of the statistical regularities in the input when undertaking a task of visual sequential SL. Specifically, we compared the degree of SL exhibited by participants who were informed (intentional group) versus those who were uninformed (incidental group) about the presence of embedded triplets within a familiarization stream. Somewhat surprisingly, our results revealed that there were no statistically significant differences (and only a small effect size) in the amount of SL exhibited between the intentional versus the incidental groups. We discuss the ways in which this result can be interpreted and suggest that short presentation times for stimuli in the familiarization stream in our study may have limited the opportunity for explicit learning. This suggestion is in line with recent research revealing a statistically significant difference (and a large effect size) between intentional versus incidental groups using a very similar visual sequential SL task, but with longer presentation times. Finally, we outline a number of directions for future research.

Changes in the hemagglutinin of H5N1 viruses during human infection--influence on receptor binding.

As avian influenza A(H5N1) viruses continue to circulate in Asia and Africa, global concerns of an imminent pandemic persist. Recent experimental studies suggest that efficient transmission between humans of current H5N1 viruses only requires a few genetic changes. An essential step is alteration of the virus hemagglutinin from preferential binding to avian receptors for the recognition of human receptors present in the upper airway. We have identified receptor-binding changes which emerged during H5N1 infection of humans, due to single amino acid substitutions, Ala134Val and Ile151Phe, in the hemagglutinin. Detailed biological, receptor-binding, and structural analyses revealed reduced binding of the mutated viruses to avian-like receptors, but without commensurate increased binding to the human-like receptors investigated, possibly reflecting a receptor-binding phenotype intermediate in adaptation to more human-like characteristics. These observations emphasize that evolution in nature of avian H5N1 viruses to efficient binding of human receptors is a complex multistep process.

Structures of receptor complexes formed by hemagglutinins from the Asian Influenza pandemic of 1957.

The viruses that caused the three influenza pandemics of the twentieth century in 1918, 1957, and 1968 had distinct hemagglutinin receptor binding glycoproteins that had evolved the capacity to recognize human cell receptors. We have determined the structure of the H2 hemagglutinin from the second pandemic, the "Asian Influenza" of 1957. We compare it with the 1918 "Spanish Influenza" hemagglutinin, H1, and the 1968 "Hong Kong Influenza" hemagglutinin, H3, and show that despite its close overall structural similarity to H1, and its more distant relationship to H3, the H2 receptor binding site is closely related to that of H3 hemagglutinin. By analyzing hemagglutinins of potential H2 avian precursors of the pandemic virus, we show that the human receptor can be bound by avian hemagglutinins that lack the human-specific mutations of H2 and H3 pandemic viruses, Gln-226Leu, and Gly-228Ser. We show how Gln-226 in the avian H2 receptor binding site, together with Asn-186, form hydrogen bond networks through bound water molecules to mediate binding to human receptor. We show that the human receptor adopts a very similar conformation in both human and avian hemagglutinin-receptor complexes. We also show that Leu-226 in the receptor binding site of human virus hemagglutinins creates a hydrophobic environment near the Sia-1-Gal-2 glycosidic linkage that favors binding of the human receptor and is unfavorable for avian receptor binding. We consider the significance for the development of pandemics, of the existence of avian viruses that can bind to both avian and human receptors.

Structure of influenza hemagglutinin in complex with an inhibitor of membrane fusion.

The influenza surface glycoprotein hemagglutinin (HA) is a potential target for antiviral drugs because of its key roles in the initial stages of infection: receptor binding and the fusion of virus and cell membranes. The structure of HA in complex with a known inhibitor of membrane fusion and virus infectivity, tert-butyl hydroquinone (TBHQ), shows that the inhibitor binds in a hydrophobic pocket formed at an interface between HA monomers. Occupation of this site by TBHQ stabilizes the neutral pH structure through intersubunit and intrasubunit interactions that presumably inhibit the conformational rearrangements required for membrane fusion. The nature of the binding site suggests routes for the chemical modification of TBHQ that could lead to the development of more potent inhibitors of membrane fusion and potential anti-influenza drugs.

Haemagglutinin mutations responsible for the binding of H5N1 influenza A viruses to human-type receptors.

H5N1 influenza A viruses have spread to numerous countries in Asia, Europe and Africa, infecting not only large numbers of poultry, but also an increasing number of humans, often with lethal effects. Human and avian influenza A viruses differ in their recognition of host cell receptors: the former preferentially recognize receptors with saccharides terminating in sialic acid-alpha2,6-galactose (SAalpha2,6Gal), whereas the latter prefer those ending in SAalpha2,3Gal (refs 3-6). A conversion from SAalpha2,3Gal to SAalpha2,6Gal recognition is thought to be one of the changes that must occur before avian influenza viruses can replicate efficiently in humans and acquire the potential to cause a pandemic. By identifying mutations in the receptor-binding haemagglutinin (HA) molecule that would enable avian H5N1 viruses to recognize human-type host cell receptors, it may be possible to predict (and thus to increase preparedness for) the emergence of pandemic viruses. Here we show that some H5N1 viruses isolated from humans can bind to both human and avian receptors, in contrast to those isolated from chickens and ducks, which recognize the avian receptors exclusively. Mutations at positions 182 and 192 independently convert the HAs of H5N1 viruses known to recognize the avian receptor to ones that recognize the human receptor. Analysis of the crystal structure of the HA from an H5N1 virus used in our genetic experiments shows that the locations of these amino acids in the HA molecule are compatible with an effect on receptor binding. The amino acid changes that we identify might serve as molecular markers for assessing the pandemic potential of H5N1 field isolates.

The structure of H5N1 avian influenza neuraminidase suggests new opportunities for drug design.

The worldwide spread of H5N1 avian influenza has raised concerns that this virus might acquire the ability to pass readily among humans and cause a pandemic. Two anti-influenza drugs currently being used to treat infected patients are oseltamivir (Tamiflu) and zanamivir (Relenza), both of which target the neuraminidase enzyme of the virus. Reports of the emergence of drug resistance make the development of new anti-influenza molecules a priority. Neuraminidases from influenza type A viruses form two genetically distinct groups: group-1 contains the N1 neuraminidase of the H5N1 avian virus and group-2 contains the N2 and N9 enzymes used for the structure-based design of current drugs. Here we show by X-ray crystallography that these two groups are structurally distinct. Group-1 neuraminidases contain a cavity adjacent to their active sites that closes on ligand binding. Our analysis suggests that it may be possible to exploit the size and location of the group-1 cavity to develop new anti-influenza drugs.

Printed covalent glycan array for ligand profiling of diverse glycan binding proteins.

Here we describe a glycan microarray constructed by using standard robotic microarray printing technology to couple amine functionalized glycans to an amino-reactive glass slide. The array comprises 200 synthetic and natural glycan sequences representing major glycan structures of glycoproteins and glycolipids. The array has remarkable utility for profiling the specificity of a diverse range of glycan binding proteins, including C-type lectins, siglecs, galectins, anticarbohydrate antibodies, lectins from plants and microbes, and intact viruses.

Subtle manipulation of egg sex ratio in birds.

Mothers are predicted to overproduce male or female eggs when the relative fitness gains from one sex are higher and outweigh the costs of manipulation. However, in birds such biases are often difficult to distinguish from differential embryo or chick mortality. Using a molecular technique to identify the sex of early embryos, we aim to determine the effect of maternal nutrition on zebra finch (Taeniopygia guttata) egg sex ratios after 2 days of incubation, which is as close to conception as is currently possible. We found no overall bias in the sex ratio of eggs laid and sex did not differ with relative laying order under any diet regime. However, mothers on a low-quality diet did produce a female bias in small clutches and a slight male bias in large clutches. On a high-quality diet, mothers produced a male bias in small clutches and a female bias in large clutches. Those on a standard diet produced a roughly even sex ratio, irrespective of clutch size. These observed biases in egg sex are partly in line with predictions that, in this species, daughters suffer disproportionately from poor rearing conditions. Thus, when relatively malnourished, mothers should only rear daughters in small broods and vice versa. Sex-ratio patterns in this species therefore appear to be subtle.

X-ray structure of the hemagglutinin of a potential H3 avian progenitor of the 1968 Hong Kong pandemic influenza virus.

We have determined the structure of the HA of an avian influenza virus, A/duck/Ukraine/63, a member of the same antigenic subtype, H3, as the virus that caused the 1968 Hong Kong influenza pandemic, and a possible progenitor of the pandemic virus. We find that structurally significant differences between the avian and the human HAs are restricted to the receptor-binding site particularly the substitutions Q226L and G228S that cause the site to open and residues within it to rearrange, including the conserved residues Y98, W153, and H183. We have also analyzed complexes formed by the HA with sialopentasaccharides in which the terminal sialic acid is in either alpha2,3- or alpha2,6-linkage to galactose. Comparing the structures of complexes in which an alpha2,3-linked receptor analog is bound to the H3 avian HA or to an H5 avian HA leads to the suggestion that all avian influenza HAs bind to their preferred alpha2,3-linked receptors similarly, with the analog in a trans conformation about the glycosidic linkage. We find that alpha2,6-linked analogs are bound by both human and avian HAs in a cis conformation, and that the incompatibility of an alpha2,6-linked receptor with the alpha2,3-linkage-specific H3 avian HA-binding site is partially resolved by a small change in the position and orientation of the sialic acid. We discuss our results in relation to the mechanism of transfer of influenza viruses between species.

H5 avian and H9 swine influenza virus haemagglutinin structures: possible origin of influenza subtypes.

There are 15 subtypes of influenza A virus (H1-H15), all of which are found in avian species. Three caused pandemics in the last century: H1 in 1918 (and 1977), H2 in 1957 and H3 in 1968. In 1997, an H5 avian virus and in 1999 an H9 virus caused outbreaks of respiratory disease in Hong Kong. We have determined the three-dimensional structures of the haemagglutinins (HAs) from H5 avian and H9 swine viruses closely related to the viruses isolated from humans in Hong Kong. We have compared them with known structures of the H3 HA from the virus that caused the 1968 H3 pandemic and of the HA--esterase--fusion (HEF) glycoprotein from an influenza C virus. Structure and sequence comparisons suggest that HA subtypes may have originated by diversification of properties that affected the metastability of HAs required for their membrane fusion activities in viral infection.