Minocycline 200 mg or 400 mg versus placebo for mild Alzheimer's disease: the MADE Phase II, three-arm RCT

Background: Minocycline is an anti-inflammatory drug and protects against the toxic effects of β-amyloid in vitro and in animal models of Alzheimer’s disease. To the best of our knowledge, no randomised placebo-controlled clinical trials in patients with Alzheimer’s disease looking at the efficacy and tolerability of minocycline have been carried out. Objectives: The trial investigated whether or not minocycline was superior to placebo in slowing down the rate of decline in cognitive and functional ability over 2 years. The safety and tolerability of minocycline were also assessed. Design: A Phase II, three-arm, randomised, double-blind, multicentre trial with a semifactorial design. Participants continued on trial treatment for up to 24 months. Setting: Patients were identified from memory services, both within the 32 participating NHS trusts and within the network of memory services supported by the Dementias and Neurodegenerative Diseases Research Network (also known as DeNDRoN). Participants: Patients with standardised Mini Mental State Examination scores of > 23 points and with Alzheimer’s disease assessed by the National Institute on Aging–Alzheimer’s Association’s criteria were identified from memory services. Intervention: Patients with mild Alzheimer’s disease were randomly allocated 1 : 1 : 1 to receive one of three treatments: arm 1 – 400 mg per day of minocycline; arm 2 – 200 mg per day of minocycline; or arm 3 – placebo. Patients continued treatment for 24 months. Participants, investigators and outcome assessors were blind to treatment allocation. Main outcome measures: Primary outcome measures were decline in standardised Mini Mental State Examination and Bristol Activities of Daily Living Scale scores of combined minocycline treatment arms versus placebo, as analysed by intention-to-treat repeated measures regression. Results: Between 23 May 2014 and 14 April 2016, 554 participants were randomised. Of the 544 eligible participants, the mean age was 74.3 years and the average standardised Mini Mental State Examination score was 26.4 points. A total of 252 serious adverse events were reported, with the most common categories being neuropsychiatric and cardiocirculatory. Significantly fewer participants completed treatment with 400 mg of minocycline [29% (53/184)] than 200 mg [62% (112/181)] or placebo [64% (114/179)] (p < 0.0001), mainly because of gastrointestinal symptoms (p = 0.0008), dermatological side effects (p = 0.02) and dizziness (p = 0.01). Assessment rates were also lower in the 400-mg treatment arm: 68% (119 of 174 expected) for standardised Mini Mental State Examination scores at 24 months, compared with 82% (144/176) for the 200-mg treatment arm and 84% (140/167) for the placebo arm. Decline in standardised Mini Mental State Examination scores over the 24-month study period in the combined minocycline arms was similar to that in the placebo arm (4.1- vs. 4.3-point reduction; p = 0.9), as was the decline in the 400- and 200-mg treatment arms (3.3 vs. 4.7 points; p = 0.08). Likewise, worsening of Bristol Activities of Daily Living Scale scores over 24 months was similar in all trial arms (5.7, 6.6 and 6.2 points in the 400-mg treatment arm, 200-mg treatment arm and placebo arm, respectively; a p-value of 0.57 for minocycline vs. placebo and a p-value of 0.77 for 400 vs. 200 mg of minocycline). Results were similar in different patient subgroups and in sensitivity analyses adjusting for missing data. Limitations: Potential limitations of the study include that biomarkers were not used to confirm the diagnosis of Alzheimer’s disease, as these and apolipoprotein E (APOE) genotyping are not routinely available within the NHS. Compliance was also worse than expected and differential follow-up rates were observed, with fewer assessments obtained for the 400-mg treatment arm than for the 200-mg treatment and placebo arms. Conclusions: Minocycline does not delay the progress of cognitive or functional impairment in people with mild Alzheimer’s disease over a 2-year period. Minocycline at a dose of 400 mg is poorly tolerated in this population. Future work: The Minocycline in mild Alzheimer’s DiseasE (MADE) study provides a framework for a streamlined trial design that can be usefully applied to test other disease-modifying therapies

The relationship between shame, perfectionism and Anorexia Nervosa: a grounded theory study

Objectives The aim of this study was to explore the potential relationship between shame, perfectionism and Anorexia Nervosa (AN) and their impact on recovery from AN. Method Semi-structured interviews were conducted with 11 people currently accessing services for AN. Interviews were transcribed and analysed using constructivist-grounded theory methodology. Results A model was developed which found a vicious cycle between shame and perfectionism. Participants tried to alleviate their feelings of shame by striving for perfectionism, however failing caused them more shame. Participants who disclosed childhood trauma believed their shame preceded their perfectionism. Participants who did not disclose trauma either believed their perfectionism preceded shame or they were unsure of which occurred first. Participants' responses suggested the following pathways from perfectionism to AN: needing goals; the need for a perfect life including a perfect body and AN being something they could be perfect at. The pathways identified between shame and AN entailed mechanisms via which AN could be used to escape shame, either by seeking pride through AN, seeking to numb shame through AN, seeking to escape body shame and punishing the self. AN was found to feed back into shame in two ways: when people had AN they felt ashamed when they broke their dietary rules, and also simultaneously people felt ashamed of their AN as they were not able to recover. Shame and perfectionism influenced one another in a cyclical pattern, in which shame drove perfectionism and not attaining high standards led to shame. Shame and perfectionism also impacted on recovery in several ways. AN functioned to numb participants' emotions, becoming part of their identity over time. AN also brought respite from a constant striving towards perfectionism. The need for a perfect recovery also influenced their motivation to engage in treatment, and fear of a return of strong emotions was another deterrent to recovery. Conclusion The findings of this paper show perfectionism and shame to both be important in the aetiology and maintenance of AN and to have an impact on recovery from AN

Mental health in UK Biobank: development, implementation and results from an online questionnaire completed by 157 366 participants

Background UK Biobank is a well-characterised cohort of over 500 000 participants that offers unique opportunities to investigate multiple diseases and risk factors. Aims An online mental health questionnaire completed by UK Biobank participants was expected to expand the potential for research into mental disorders. Method An expert working group designed the questionnaire, using established measures where possible, and consulting with a patient group regarding acceptability. Case definitions were defined using operational criteria for lifetime depression, mania, anxiety disorder, psychotic-like experiences and self-harm, as well as current post-traumatic stress and alcohol use disorders. Results 157 366 completed online questionnaires were available by August 2017. Comparison of self-reported diagnosed mental disorder with a contemporary study shows a similar prevalence, despite respondents being of higher average socioeconomic status than the general population across a range of indicators. Thirty-five per cent (55 750) of participants had at least one defined syndrome, of which lifetime depression was the most common at 24% (37 434). There was extensive comorbidity among the syndromes. Mental disorders were associated with high neuroticism score, adverse life events and long-term illness; addiction and bipolar affective disorder in particular were associated with measures of deprivation. Conclusions The questionnaire represents a very large mental health survey in itself, and the results presented here show high face validity, although caution is needed owing to selection bias. Built into UK Biobank, these data intersect with other health data to offer unparalleled potential for crosscutting biomedical research involving mental health

Myasthenia gravis-like syndrome induced by expression of interferon gamma in the neuromuscular junction.

Abnormal humoral responses toward motor end plate constituents in muscle induce myasthenia gravis (MG). To study the etiology of this disease, and whether it could be induced by host defense molecules, we examined the consequences of interferon (IFN) gamma production within the neuromuscular junction of transgenic mice. The transgenic mice exhibited gradually increasing muscular weakness, flaccid paralysis, and functional disruption of the neuromuscular junction that was reversed after administration of an inhibitor of acetylcholinesterase, features which are strikingly similar to human MG. Furthermore, histological examination revealed infiltration of mononuclear cells and autoantibody deposition at motor end plates. Immunoprecipitation analysis indicated that a previously unidentified 87-kD target antigen was recognized by sera from transgenic mice and also by sera from the majority of human MG patients studied. These results suggest that expression of IFN-gamma at motor end plates provokes an autoimmune humoral response, similar to human MG, thus linking the expression of this factor with development of this disease

Mental health in UK Biobank - development, implementation and results from an online questionnaire completed by 157 366 participants: a reanalysis

Background UK Biobank is a well-characterised cohort of over 500 000 participants including genetics, environmental data and imaging. An online mental health questionnaire was designed for UK Biobank participants to expand its potential. Aims Describe the development, implementation and results of this questionnaire. Method An expert working group designed the questionnaire, using established measures where possible, and consulting a patient group. Operational criteria were agreed for defining likely disorder and risk states, including lifetime depression, mania/hypomania, generalised anxiety disorder, unusual experiences and self-harm, and current post-traumatic stress and hazardous/harmful alcohol use. Results A total of 157 366 completed online questionnaires were available by August 2017. Participants were aged 45–82 (53% were ≥65 years) and 57% women. Comparison of self-reported diagnosed mental disorder with a contemporary study shows a similar prevalence, despite respondents being of higher average socioeconomic status. Lifetime depression was a common finding, with 24% (37 434) of participants meeting criteria and current hazardous/harmful alcohol use criteria were met by 21% (32 602), whereas other criteria were met by less than 8% of the participants. There was extensive comorbidity among the syndromes. Mental disorders were associated with a high neuroticism score, adverse life events and long-term illness; addiction and bipolar affective disorder in particular were associated with measures of deprivation. Conclusions The UK Biobank questionnaire represents a very large mental health survey in itself, and the results presented here show high face validity, although caution is needed because of selection bias. Built into UK Biobank, these data intersect with other health data to offer unparalleled potential for crosscutting biomedical research involving mental health

SPIRITS 15c and SPIRITS 14buu: Two Obscured Supernovae in the Nearby Star-Forming Galaxy IC 2163

SPIRITS---SPitzer InfraRed Intensive Transients Survey---is an ongoing survey of nearby galaxies searching for infrared (IR) transients with Spitzer/IRAC. We present the discovery and follow-up observations of one of our most luminous ($M_{[4.5]} = -17.1\pm0.4$ mag, Vega) and red ($[3.6] - [4.5] = 3.0 \pm 0.2$ mag) transients, SPIRITS 15c. The transient was detected in a dusty spiral arm of IC 2163 ($D\approx35.5$ Mpc). Pre-discovery ground-based imaging revealed an associated, shorter-duration transient in the optical and near-IR (NIR). NIR spectroscopy showed a broad ($\approx 8400$ km s$^{-1}$), double-peaked emission line of He I at $1.083 \mu$m, indicating an explosive origin. The NIR spectrum of SPIRITS 15c is similar to that of the Type IIb SN 2011dh at a phase of $\approx 200$ days. Assuming $A_V = 2.2$ mag of extinction in SPIRITS 15c provides a good match between their optical light curves. The IR light curves and the extreme $[3.6]-[4.5]$ color cannot be explained using only a standard extinction law. Another luminous ($M_{4.5} = -16.1\pm0.4$ mag) event, SPIRITS 14buu, was serendipitously discovered in the same galaxy. The source displays an optical plateau lasting $\gtrsim 80$ days, and we suggest a scenario similar to the low-luminosity Type IIP SN 2005cs obscured by $A_V \approx 1.5$ mag. Other classes of IR-luminous transients can likely be ruled out in both cases. If both events are indeed SNe, this may suggest $\gtrsim 18\%$ of nearby core-collapse SNe are missed by currently operating optical surveys.Comment: 19 pages, 7 Figures, 4 Table

Pressure-independent enhancement of cardiac hypertrophy in natriuretic peptide receptor A–deficient mice

Mice lacking natriuretic peptide receptor A (NPRA) have marked cardiac hypertrophy and chamber dilatation disproportionate to their increased blood pressure (BP), suggesting, in support of previous in vitro data, that the NPRA system moderates the cardiac response to hypertrophic stimuli. Here, we have followed the changes in cardiac function in response to altered mechanical load on the heart of NPRA-null mice (Npr1–/–). Chronic treatment with either enalapril, furosemide, hydralazine, or losartan were all effective in reducing and maintaining BP at normal levels without affecting heart weight/body weight. In the reverse direction, we used transverse aortic constriction (TAC) to induce pressure overload. In the Npr1–/– mice, TAC resulted in a 15-fold increase in atrial natriuretic peptide (ANP) expression, a 55% increase in left ventricular weight/body weight (LV/BW), dilatation of the LV, and significant decline in cardiac function. In contrast, banded Npr1+/+ mice showed only a threefold increase in ANP expression, an 11% increase in LV/BW, a 0.2 mm decrease in LV end diastolic dimension, and no change in fractional shortening. The activation of mitogen-activated protein kinases that occurs in response to TAC did not differ in the Npr1+/+ and Npr1–/– mice. Taken together, these results suggest that the NPRA system has direct antihypertrophic actions in the heart, independent of its role in BP control

An Excess of Mid-Infrared Emission from the Type Iax SN 2014dt

Supernovae Type Iax (SNe Iax) are less energetic and less luminous than typical thermonuclear explosions. A suggested explanation for the observed characteristics of this subclass is a binary progenitor system consisting of a CO white dwarf primary accreting from a helium star companion. A single-degenerate explosion channel might be expected to result in a dense circumstellar medium (CSM), although no evidence for such a CSM has yet been observed for this subclass. Here we present recent Spitzer observations of the SN Iax 2014dt obtained by the SPIRITS program nearly one year post-explosion that reveal a strong mid-IR excess over the expected fluxes of more normal SNe Ia. This excess is consistent with 10^(−5) M_⊙ of newly formed dust, which would be the first time that newly formed dust has been observed to form in a Type Ia. The excess, however, is also consistent with a dusty CSM that was likely formed in pre-explosion mass-loss, thereby suggesting a single degenerate progenitor system. Compared to other SNe Ia that show significant shock interaction (SNe Ia-CSM) and interacting core-collapse events (SNe IIn), this dust shell in SN 2014dt is less massive. We consider the implications that such a pre-existing dust shell has for the progenitor system, including a binary system with a mass donor that is a red giant, a red supergiant, or an asymptotic giant branch star

Mental Health in UK Biobank Revised

Background UK Biobank is a well-characterised cohort of over 500 000 participants including genetics, environmental data and imaging. An online mental health questionnaire was designed for UK Biobank participants to expand its potential. Aims Describe the development, implementation and results of this questionnaire. Method An expert working group designed the questionnaire, using established measures where possible, and consulting a patient group. Operational criteria were agreed for defining likely disorder and risk states, including lifetime depression, mania/hypomania, generalised anxiety disorder, unusual experiences and self-harm, and current post-traumatic stress and hazardous/harmful alcohol use. Results A total of 157 366 completed online questionnaires were available by August 2017. Participants were aged 45–82 (53% were ≥65 years) and 57% women. Comparison of self-reported diagnosed mental disorder with a contemporary study shows a similar prevalence, despite respondents being of higher average socioeconomic status. Lifetime depression was a common finding, with 24% (37 434) of participants meeting criteria and current hazardous/harmful alcohol use criteria were met by 21% (32 602), whereas other criteria were met by less than 8% of the participants. There was extensive comorbidity among the syndromes. Mental disorders were associated with a high neuroticism score, adverse life events and long-term illness; addiction and bipolar affective disorder in particular were associated with measures of deprivation. Conclusions The UK Biobank questionnaire represents a very large mental health survey in itself, and the results presented here show high face validity, although caution is needed because of selection bias. Built into UK Biobank, these data intersect with other health data to offer unparalleled potential for crosscutting biomedical research involving mental health