Electroconvulsive therapy-induced volumetric brain changes converge on a common causal circuit in depression.

Neurostimulation is a mainstream treatment option for major depression. Neuromodulation techniques apply repetitive magnetic or electrical stimulation to some neural target but significantly differ in their invasiveness, spatial selectivity, mechanism of action, and efficacy. Despite these differences, recent analyses of transcranial magnetic stimulation (TMS) and deep brain stimulation (DBS)-treated individuals converged on a common neural network that might have a causal role in treatment response. We set out to investigate if the neuronal underpinnings of electroconvulsive therapy (ECT) are similarly associated with this causal depression network (CDN). Our aim here is to provide a comprehensive analysis in three cohorts of patients segregated by electrode placement (N = 246 with right unilateral, 79 with bitemporal, and 61 with mixed) who underwent ECT. We conducted a data-driven, unsupervised multivariate neuroimaging analysis Principal Component Analysis (PCA) of the cortical and subcortical volume changes and electric field (EF) distribution to explore changes within the CDN associated with antidepressant outcomes. Despite the different treatment modalities (ECT vs TMS and DBS) and methodological approaches (structural vs functional networks), we found a highly similar pattern of change within the CDN in the three cohorts of patients (spatial similarity across 85 regions: r = 0.65, 0.58, 0.40, df = 83). Most importantly, the expression of this pattern correlated with clinical outcomes (t = -2.35, p = 0.019). This evidence further supports that treatment interventions converge on a CDN in depression. Optimizing modulation of this network could serve to improve the outcome of neurostimulation in depression.

Can the DEX/CRH test or markers of oxidative stress distinguish work-related stress from major depressive disorder and normal controls?

Hypothalamic-pituitary-adrenal (HPA)-axis hyperactivity measured by the combined dexamethasone-CRH test (DEX-CRH test) has been found in patients with major depressive disorder (MDD), whereas hypoactivity has been found in patients with work-related stress. We aimed to investigate the DEX-CRH test as a biomarker to distinguish between MDD and work-related stress (exhaustion disorder - ED). We hypothesized that there would be lower cortisol and ACTH response in participants with ED compared to MDD and healthy controls (HC). Also, we explored if the cortisol response of those patients interacted with robust markers of oxidative stress. Thirty inpatients with MDD and 23 outpatients with ED were recruited. Plasma cortisol and ACTH were sampled during a DEX-CRH test. The main outcome measure, area under the curve (AUC) for cortisol and ACTH, was compa-red between MDD vs. ED participants and a historical HC group. Secondary markers of oxidative stress urinary 8-oxodG and 8-oxoGuo; quality of sleep and psychometrics were obtained. Cortisol concentrations were higher in MDD and ED participants compared to HC, and no differences in AUC cortisol and ACTH were found between ED vs. MDD. Compared to ED, MDD participants had higher stress symptom severity and a lower sense of well-being. No differences in oxidative stress markers or quality of sleep between the groups were found. The result indicates that the patients with ED, like patients with MDD, are non-suppressors in DEX-CRH test and not hypocortisolemic as suggested.

Prescription patterns in unipolar depression: A nationwide Danish register-based study of 113,175 individuals followed for 10 years.

BACKGROUND: Evidence-based use of antidepressant medications is of major clinical importance. We aimed to uncover precription patterns in a large cohort of patients with unipolar depression. MATERIAL AND METHODS: Using Danish nationwide registers, we identified individuals with a first-time hospital diagnosis of unipolar depression between January 1st, 2001, and December 31st, 2016. Redemeed prescriptions of antidepressants from five years before to five years after diagnosis were retreived. Lithium and relevant antipsychotics were included. Data were analyzed with descriptive statistics including sunburst plots. Cox regressions were used to rank the risk of treatment failure according to antidepressant category and depression severity, as measured by hazard ratios of drug shift. RESULTS: The full study population consisted of 113,175 individuals. Selective Serotonin Reuptake Inhibitors was the predominantly prescribed first-line group, both before (55.4%) and after (47.7%) diagnosis and across depression severities. Changes of treatment strategy were frequent; 60.8%, 33.7%, and 17.1% reached a second, third, and fourth treatment trial after the hospital diagnosis, respectively. More than half of patients continued their pre-diagnosis antidepressant after diagnosis. The risk of change of treatment strategy was generally lower in mild-moderate depression and higher in severe depression, with tricyclic antidepressants carrying the highest risk in the former and the lowest risks in the latter. Overall, prescribing were often not in accordance with guidelines. CONCLUSION: These findings uncover a potential for improving the clinical care for patients with unipolar depression through optimization of the use of marketed antidepressants.

Effects of sporadic inclusion body myositis on skeletal muscle fibre type specific morphology and markers of regeneration and inflammation.

Sporadic inclusion body myositis (sIBM) is a subgroup of idiopathic inflammatory myopathies characterised by progressive muscle weakness and skeletal muscle inflammation. Quantitative data on the myofibre morphology in sIBM remains scarce. Further, no previous study has examined fibre type association of satellite cells (SC), myonuclei number, macrophages, capillaries, and myonuclear domain (MD) in sIBM patients. Muscle biopsies from sIBM patients (n = 18) obtained previously (NCT02317094) were included in the analysis for fibre type-specific myofibre cross-sectional area (mCSA), SCs, myonuclei and macrophages, myonuclear domain, and capillarisation. mCSA (p < 0.001), peripheral myonuclei (p < 0.001) and MD (p = 0.005) were higher in association with type 1 (slow-twitch) than type 2 (fast-twitch) fibres. Conversely, quiescent SCs (p < 0.001), centrally placed myonuclei (p = 0.03), M1 macrophages (p < 0.002), M2 macrophages (p = 0.013) and capillaries (p < 0.001) were higher at type 2 fibres compared to type 1 fibres. In contrast, proliferating (Pax7+/Ki67+) SCs (p = 0.68) were similarly associated with each fibre type. Type 2 myofibres of late-phase sIBM patients showed marked signs of muscle atrophy (i.e. reduced mCSA) accompanied by higher numbers of associated quiescent SCs, centrally placed myonuclei, macrophages and capillaries compared to type 1 fibres. In contrast, type 1 fibres were suffering from pathological enlargement with larger MDs as well as fewer nuclei and capillaries per area when compared with type 2 fibres. More research is needed to examine to which extent different therapeutic interventions including targeted exercise might alleviate these fibre type-specific characteristics and countermeasure their consequences in impaired functional performance.

µ-Opioid Receptor Activation Reduces Glutamate Release in the preBötzinger Complex in Organotypic Slice Cultures.

The inspiratory rhythm generator, located in the brainstem preBötzinger Complex (preBötC), is dependent on glutamatergic signaling and is affected profoundly by opioids. Here, we used organotypic slice cultures of the newborn mouse brainstem of either sex in combination with genetically encoded sensors for Ca2+, glutamate, and GABA to visualize Ca2+, glutamatergic and GABAergic signaling during spontaneous rhythm and in the presence of DAMGO. During spontaneous rhythm, the glutamate sensor SF-iGluSnFR.A184S revealed punctate synapse-like fluorescent signals along dendrites and somas in the preBötC with decay times that were prolonged by the glutamate uptake blocker (TFB-TBOA). The GABA sensor iGABASnFR showed a more diffuse fluorescent signal during spontaneous rhythm. Rhythmic Ca2+- and glutamate transients had an inverse relationship between the spontaneous burst frequency and the burst amplitude of the Ca2+ and glutamate signals. A similar inverse relationship was observed when bath applied DAMGO reduced spontaneous burst frequency and increased the burst amplitude of Ca2+, glutamate and GABA transient signals. However, a hypoxic challenge reduced both burst frequency and Ca2+ transient amplitude. Using a cocktail that blocked glutamatergic, GABAergic, and glycinergic transmission to indirectly measure the release of glutamate/GABA in response to an electrical stimulus, we found that DAMGO reduces the release of glutamate in the preBötC but has no effect on GABA release. This suggest that the opioid mediated slowing of respiratory rhythm involves presynaptic reduction of glutamate release, which would impact the ability of the network to engage in recurrent excitation, and may result in the opioid-induced slowing of inspiratory rhythm.SIGNIFICANCE STATEMENT:Opioids slow down breathing rhythm by affecting neurons in the preBötC and other brainstem regions. Here, we used cultured slices of the preBötC to better understand this effect by optically recording Ca2+, glutamate and GABA transients during preBötC activity. Spontaneous rhythm showed an inverse relationship between burst frequency and burst amplitude in the Ca2+ and glutamate signals. Application of the opioid DAMGO slowed the rhythm, with a concomitant increase in Ca2+, glutamate and GABA signals. When rhythm was blocked pharmacologically, DAMGO reduced the presynaptic release of glutamate, but not GABA. These data suggest the mechanism of action of opioids involves presynaptic reduction of glutamate release, which may play an important role in the opioid-induced slowing of inspiratory rhythm.

A polygenic risk score to help discriminate primary adrenal insufficiency of different etiologies.

BACKGROUND: Autoimmune Addison's disease (AAD) is the most common cause of primary adrenal insufficiency (PAI). Despite its exceptionally high heritability, tools to estimate disease susceptibility in individual patients are lacking. We hypothesized that polygenic risk score (PRS) for AAD could help investigate PAI pathogenesis in pediatric patients. METHODS: We here constructed and evaluated a PRS for AAD in 1223 seropositive cases and 4097 controls. To test its clinical utility, we reevaluated 18 pediatric patients, whose whole genome we also sequenced. We next explored the individual PRS in more than 120 seronegative patients with idiopathic PAI. RESULTS: The genetic susceptibility to AAD-quantified using PRS-was on average 1.5 standard deviations (SD) higher in patients compared with healthy controls (p < 2e - 16), and 1.2 SD higher in the young patients compared with the old (p = 3e - 4). Using the novel PRS, we searched for pediatric patients with strikingly low AAD susceptibility and identified cases of monogenic PAI, previously misdiagnosed as AAD. By stratifying seronegative adult patients by autoimmune comorbidities and disease duration we could delineate subgroups of PRS suggesting various disease etiologies. CONCLUSIONS: The PRS performed well for case-control differentiation and susceptibility estimation in individual patients. Remarkably, a PRS for AAD holds promise as a means to detect disease etiologies other than autoimmunity.

Collagenase-producing bacteria are common in anastomotic leakage after colorectal surgery: a systematic review.

PURPOSE: Some gut bacteria can produce enzymes (collagenases) that can break down collagen in the intestinal wall. This could be a part of the pathophysiology of anastomotic leakage (AL). This systematic review aimed to investigate if such bacteria were present more frequently in AL patients versus non-AL patients following colorectal surgery. METHODS: This systematic review was reported according to the PRISMA and AMSTAR guidelines. Before the literature search, a study protocol was registered at PROSPERO (CRD42022363454). We searched PubMed, EMBASE, Google Scholar, and Cochrane CENTRAL on April 9th, 2023, for randomized and observational human studies of AL following colorectal surgery with information on gastrointestinal bacteria. The primary outcome was bacteria with the potential to produce collagenase. The risk of bias was assessed with the Newcastle-Ottawa Scale, as all studies were observational. RESULTS: We included 15 studies, with a total of 52,945 patients, of which 1,747 had AL, and bacteriological information from feces, mucosa, the resected specimen, or drain fluid was presented. In 10 of the 15 studies, one or more collagenase-producing bacteria were identified in the patients with AL. Neither the bacteria nor the collagenase production were quantified in any of the studies. The studies varied greatly in terms of sample material, analytical method, and time of collection. Studies using DNA sequencing methods did not report findings of collagenase-producing bacteria. CONCLUSION: Collagenase-producing bacteria are more common in patients with AL following colorectal surgery than in patients without AL, but the significance is unclear. From the current studies, it is not possible to determine the pathogenicity of the individual gut bacteria.

TGFBR3L is associated with gonadotropin production in non-functioning gonadotroph pituitary neuroendocrine tumours.

PURPOSE: Transforming growth factor-beta receptor 3-like (TGFBR3L) is a pituitary enriched membrane protein selectively detected in gonadotroph cells. TGFBR3L is named after transforming growth factor-beta receptor 3 (TGFBR3), an inhibin A co-receptor in mice, due to sequence identity to the C-terminal region. We aimed to characterize TGFBR3L detection in a well-characterized, prospectively collected cohort of non-functioning pituitary neuroendocrine tumours (NF-PitNETs) and correlate it to clinical data. METHODS: 144 patients operated for clinically NF-PitNETs were included. Clinical, radiological and biochemical data were recorded. Immunohistochemical (IHC) staining for FSHß and LHß was scored using the immunoreactive score (IRS), TGFBR3L and TGFBR3 were scored by the percentage of positive stained cells. RESULTS: TGFBR3L staining was selectively present in 52% of gonadotroph tumours. TGFBR3L was associated to IRS of LHß (median 2 [IQR 0-3] in TGFBR3L negative and median 6 [IQR 3-9] in TGFBR3L positive tumours, p < 0.001), but not to the IRS of FSHß (p = 0.32). The presence of TGFBR3L was negatively associated with plasma gonadotropin concentrations in males (P-FSH median 5.5 IU/L [IQR 2.9-9.6] and median 3.0 [IQR 1.8-5.6] in TGFBR3L negative and positive tumours respectively, p = 0.008) and P-LH (median 2.8 IU/L [IQR 1.9-3.7] and median 1.8 [IQR 1.1-3.0] in TGFBR3L negative and positive tumours respectively, p = 0.03). TGFBR3 stained positive in 22% (n = 25) of gonadotroph tumours with no correlation to TGFBR3L. CONCLUSION: TGFBR3L was selectively detected in half (52%) of gonadotroph NF-PitNETs. The association to LHß staining and plasma gonadotropins suggests that TGFBR3L may be involved in hormone production in gonadotroph NF-PitNETs.

Surface temperature determination using long range thermal emission spectroscopy based on a first order scanning Fabry-Pérot interferometer.

Determination of the surface temperature of different materials based on thermographic imaging is a difficult task as the thermal emission spectrum is both temperature and emissivity dependent. Without prior knowledge of the emissivity of the object under investigation, it makes up a temperature-emissivity underdetermined system. This work demonstrates the possibility of recognizing specific materials from hyperspectral thermal images (HSTI) in the wavelength range from 8-14 µm. The hyperspectral images were acquired using a microbolometer sensor array in combination with a scanning 1st order Fabry-Pérot interferometer acting as a bandpass filter. A logistic regression model was used to successfully differentiate between polyimide tape, sapphire, borosilicate glass, fused silica, and alumina ceramic at temperatures as low as 34.0 ± 0.05 °C. Each material was recognized with true positive rates above 94% calculated from individual pixel spectra. The surface temperature of the samples was subsequently predicted using pre-fitted partial least squares (PLS) models, which predicted all surface temperature values with a common root mean square error (RMSE) of 1.10 °C and thereby outperforming conventional thermography. This approach paves the way for a practical solution to the underdetermined temperature-emissivity system.

Selective hydrogenation of graphene on Ir(111): an X-ray standing wave study.

A combined high resolution X-ray photoelectron spectroscopy and X-ray standing wave study into the adsorption structure of hydrogenated graphene on Ir(111) is presented. By exploiting the unique absorption profiles and significant modulations in signal intensity found within the X-ray standing wave results, we refine the fitting of the C 1s X-ray photoelectron spectra, allowing us to disentangle the contributions from hydrogenation of graphene in different high-symmetry regions of the moiré supercell. We clearly demonstrate that hydrogenation in the FCC regions results in the formation of a graphane-like structure, giving a standalone component that is separated from the component assigned to the similar structure in the HCP regions. The contribution from dimer structures in the ATOP regions is found to be minor or negligible. This is in contrast to the previous findings where a dimer structure was assumed to contribute significantly to the sp3 part of the C 1s spectra. The corrugation of the remaining pristine parts of the H-graphene is shown to increase with the H coverage, reflecting an increasing number and size of pinning centers of the graphene to the Ir(111) substrate with increasing H exposure.

Effects of blood-flow restricted resistance training on mechanical muscle function and thigh lean mass in sIBM patients.

Sporadic inclusion body myositis (sIBM) is an idiopathic inflammatory muscle disease associated with skeletal muscle inflammation and a parallel progressive decline in muscle strength and physical function. Eventually, most sIBM patients require use of wheelchair after about 10 years of diagnosis and assistance to perform activities of daily living. This study presents data from a randomized controlled intervention trial (NCT02317094) that examined the effect of 12 weeks low-load blood-flow restricted (BFR) resistance training on maximal muscle strength, power, rate of force development (RFD), thigh lean mass (TLM), and voluntary muscle activation (VA) in sIBM patients. A time-by-group interaction in knee extensor strength was observed in the stronger leg (p ≤ 0.033) but not the weaker leg. Within-group changes were observed with BFR training (BFR) manifested by increased knee extensor strength in the strongest leg (+13.7%, p = 0.049), whereas non-exercising patients (CON) showed reduced knee extensor strength (-7.7%, p = 0.018). Maximal leg extensor power obtained for the stronger leg remained unchanged following BFR training (+9.5%, p = 0.37) while decreasing in CON (-11.1%, p = 0.05). No changes in TLM were observed. VA declined post-training (p = 0.037) in both BFR (-6.3% points) and CON (-7.5% points). The present data indicate that BFR resistance training can attenuate the rate of decline in mechanical muscle function typically experienced by sIBM patients. The preservation of muscle mass and mechanical muscle function with BFR resistance training may be considered of high clinical importance in sIBM patients to countermeasure the disease-related decline in physical function.

Accounting for symptom heterogeneity can improve neuroimaging models of antidepressant response after electroconvulsive therapy.

Depression symptom heterogeneity limits the identifiability of treatment-response biomarkers. Whether improvement along dimensions of depressive symptoms relates to separable neural networks remains poorly understood. We build on work describing three latent symptom dimensions within the 17-item Hamilton Depression Rating Scale (HDRS) and use data-driven methods to relate multivariate patterns of patient clinical, demographic, and brain structural changes over electroconvulsive therapy (ECT) to dimensional changes in depressive symptoms. We included 110 ECT patients from Global ECT-MRI Research Collaboration (GEMRIC) sites who underwent structural MRI and HDRS assessments before and after treatment. Cross validated random forest regression models predicted change along symptom dimensions. HDRS symptoms clustered into dimensions of somatic disturbances (SoD), core mood and anhedonia (CMA), and insomnia. The coefficient of determination between predicted and actual changes were 22%, 39%, and 39% (all p < .01) for SoD, CMA, and insomnia, respectively. CMA and insomnia change were predicted more accurately than HDRS-6 and HDRS-17 changes (p < .05). Pretreatment symptoms, body-mass index, and age were important predictors. Important imaging predictors included the right transverse temporal gyrus and left frontal pole for the SoD dimension; right transverse temporal gyrus and right rostral middle frontal gyrus for the CMA dimension; and right superior parietal lobule and left accumbens for the insomnia dimension. Our findings support that recovery along depressive symptom dimensions is predicted more accurately than HDRS total scores and are related to unique and overlapping patterns of clinical and demographic data and volumetric changes in brain regions related to depression and near ECT electrodes.

Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction.

Myocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance. When MI occurs early in life, genetic inheritance is a major component to risk. Previously, rare mutations in low-density lipoprotein (LDL) genes have been shown to contribute to MI risk in individual families, whereas common variants at more than 45 loci have been associated with MI risk in the population. Here we evaluate how rare mutations contribute to early-onset MI risk in the population. We sequenced the protein-coding regions of 9,793 genomes from patients with MI at an early age (≤50 years in males and ≤60 years in females) along with MI-free controls. We identified two genes in which rare coding-sequence mutations were more frequent in MI cases versus controls at exome-wide significance. At low-density lipoprotein receptor (LDLR), carriers of rare non-synonymous mutations were at 4.2-fold increased risk for MI; carriers of null alleles at LDLR were at even higher risk (13-fold difference). Approximately 2% of early MI cases harbour a rare, damaging mutation in LDLR; this estimate is similar to one made more than 40 years ago using an analysis of total cholesterol. Among controls, about 1 in 217 carried an LDLR coding-sequence mutation and had plasma LDL cholesterol > 190 mg dl(-1). At apolipoprotein A-V (APOA5), carriers of rare non-synonymous mutations were at 2.2-fold increased risk for MI. When compared with non-carriers, LDLR mutation carriers had higher plasma LDL cholesterol, whereas APOA5 mutation carriers had higher plasma triglycerides. Recent evidence has connected MI risk with coding-sequence mutations at two genes functionally related to APOA5, namely lipoprotein lipase and apolipoprotein C-III (refs 18, 19). Combined, these observations suggest that, as well as LDL cholesterol, disordered metabolism of triglyceride-rich lipoproteins contributes to MI risk.

An in silico kinetic model of 8-oxo-7,8-dihydro-2-deoxyguanosine and 8-oxo-7,8-dihydroguanosine metabolism from intracellular formation to urinary excretion.

Oxidatively generated DNA damage is of paramount importance in a wide range of physiological and pathophysiological processes. Urinary 8-oxo-7,8-dihydro-2-deoxyguanosine (8-oxodG) is often used as an outcome marker in studies on the role of oxidatively generated DNA damage, but its exact relation to intracellular damage levels and variations in DNA repair have been unclear. Using a new approach of quantitative kinetic modeling inspired by pharmacokinetics, we find evidence that in steady state - i.e. when systemic consequences of given change in damage or cellular removal rates have stabilized - the urinary excretion of 8-oxodG is closely correlated to rates of damage and intracellular 8-oxodG levels, but independent of the rate of cellular removal. Steady state was calculated to occur within approximately 12 h. A similar pattern was observed in a model of the corresponding RNA marker 8-oxo-7,8-dihydroguanosine (8-oxoGuo), but with steady-state occurring slower (up to 5 d). These data have significant implications for the planning of studies and interpretation of data involving urinary 8-oxodG/8-oxoGuo excretion as outcome.HighlightsThe kinetics of 8-oxodG/8-oxoGuo formation, removal and excretion were simulated in silico.The model was based on existing data on 8-oxodG/8-oxoGuo levels and removal/excretion rates.Intracellular 8-oxodG/8-oxoGuo was closely correlated with urinary excretion in steady state.Changes in removal rates did not influence urinary excretion of 8-oxodG/8-oxoGuo.

Rotational Coherence Spectroscopy of Molecules in Helium Nanodroplets: Reconciling the Time and the Frequency Domains.

Alignment of OCS, CS_{2}, and I_{2} molecules embedded in helium nanodroplets is measured as a function of time following rotational excitation by a nonresonant, comparatively weak ps laser pulse. The distinct peaks in the power spectra, obtained by Fourier analysis, are used to determine the rotational, B, and centrifugal distortion, D, constants. For OCS, B and D match the values known from IR spectroscopy. For CS_{2} and I_{2}, they are the first experimental results reported. The alignment dynamics calculated from the gas-phase rotational Schrödinger equation, using the experimental in-droplet B and D values, agree in detail with the measurement for all three molecules. The rotational spectroscopy technique for molecules in helium droplets introduced here should apply to a range of molecules and complexes.

Conflicts of interest in clinical guidelines, advisory committee reports, opinion pieces, and narrative reviews: associations with recommendations.

BACKGROUND: Treatment and diagnostic recommendations are often made in clinical guidelines, reports from advisory committee meetings, opinion pieces such as editorials, and narrative reviews. Quite often, the authors or members of advisory committees have industry ties or particular specialty interests which may impact on which interventions are recommended. Similarly, clinical guidelines and narrative reviews may be funded by industry sources resulting in conflicts of interest. OBJECTIVES: To investigate to what degree financial and non-financial conflicts of interest are associated with favourable recommendations in clinical guidelines, advisory committee reports, opinion pieces, and narrative reviews. SEARCH METHODS: We searched PubMed, Embase, and the Cochrane Methodology Register for studies published up to February 2020. We also searched reference lists of included studies, Web of Science for studies citing the included studies, and grey literature sources. SELECTION CRITERIA: We included studies comparing the association between conflicts of interest and favourable recommendations of drugs or devices (e.g. recommending a particular drug) in clinical guidelines, advisory committee reports, opinion pieces, or narrative reviews. DATA COLLECTION AND ANALYSIS: Two review authors independently included studies, extracted data, and assessed risk of bias. When a meta-analysis was considered meaningful to synthesise our findings, we used random-effects models to estimate risk ratios (RRs) with 95% confidence intervals (CIs), with RR > 1 indicating that documents (e.g. clinical guidelines) with conflicts of interest more often had favourable recommendations. We analysed associations for financial and non-financial conflicts of interest separately, and analysed the four types of documents both separately (pre-planned analyses) and combined (post hoc analysis). MAIN RESULTS: We included 21 studies analysing 106 clinical guidelines, 1809 advisory committee reports, 340 opinion pieces, and 497 narrative reviews. We received unpublished data from 11 studies; eight full data sets and three summary data sets. Fifteen studies had a risk of confounding, as they compared documents that may differ in other aspects than conflicts of interest (e.g. documents on different drugs used for different populations). The associations between financial conflicts of interest and favourable recommendations were: clinical guidelines, RR: 1.26, 95% CI: 0.93 to 1.69 (four studies of 86 clinical guidelines); advisory committee reports, RR: 1.20, 95% CI: 0.99 to 1.45 (four studies of 629 advisory committee reports); opinion pieces, RR: 2.62, 95% CI: 0.91 to 7.55 (four studies of 284 opinion pieces); and narrative reviews, RR: 1.20, 95% CI: 0.97 to 1.49 (four studies of 457 narrative reviews). An analysis combining all four document types supported these findings (RR: 1.26, 95% CI: 1.09 to 1.44). One study investigating specialty interests found that the association between including radiologist guideline authors and recommending routine breast cancer screening was RR: 2.10, 95% CI: 0.92 to 4.77 (12 clinical guidelines). AUTHORS' CONCLUSIONS: We interpret our findings to indicate that financial conflicts of interest are associated with favourable recommendations of drugs and devices in clinical guidelines, advisory committee reports, opinion pieces, and narrative reviews. However, we also stress risk of confounding in the included studies and the statistical imprecision of individual analyses of each document type. It is not certain whether non-financial conflicts of interest impact on recommendations.

Cut-off values for sufficient cortisol response to low dose Short Synacthen Test after surgery for non-functioning pituitary adenoma.

OBJECTIVE: The aim was to study the prevalence of secondary adrenal insufficiency before and after surgery for non-functioning pituitary adenomas, as well as determine risk factors for developing secondary adrenal insufficiency. A secondary aim was to determine adequate p-cortisol response to a 1-µg Short Synacthen Test after surgery. DESIGN: Longitudinal cohort study. METHODS: One hundred seventeen patients (52/65 females/males, age 59 years) undergoing primary surgery for clinically non-functioning pituitary adenomas were included. P-cortisol was measured in morning blood samples. Three months after surgery, a Short Synacthen Test was performed. RESULTS: All tumours were macroadenomas (mean size 26.9 mm, range 13-61 mm). The surgical indications were visual impairment (93), tumour growth (16), pituitary apoplexy (6) and headache (2). Before surgery, 17% of the patients had secondary adrenal insufficiency (SAI), decreasing to 15% 3 months postoperatively. Risk of SAI was increased in patients operated for pituitary apoplexy (p < 0.001), while age, sex, tumour size and complication rate were not different from the remaining cohort. Three months after surgery, all patients with baseline p-cortisol ≥ 172 nmol/l (6.2 µg/dl) and peak p-cortisol during Short Synacthen Test ≥ 320 nmol/l (11.6 µg/dl) tapered cortisone unproblematically. In patients with intact hypothalamic-pituitary-adrenal axis, p-cortisol peaked < 500 nmol/l (18.1 µg/dl) during Short Synacthen Test in 48% of patient. CONCLUSION: Pituitary surgery is safe and transsphenoidal surgery rarely causes new SAI. Relying solely on morning p-cortisol for diagnosing secondary adrenal insufficiency gives false positives and the Short Synacthen Test remains useful. A peak p-cortisol ≥ 320 during (11.6 µg/dl) Short Synacthen Test indicates a sufficient response, while < 309 nmol/l (11.2 µg/dl) indicates secondary adrenal insufficiency.

Depressive Symptom Dimensions in Treatment-Resistant Major Depression and Their Modulation With Electroconvulsive Therapy.

OBJECTIVE: Symptom heterogeneity in major depressive disorder obscures diagnostic and treatment-responsive biomarker identification. Whether symptom constellations are differentially changed by electroconvulsive therapy (ECT) remains unknown. We investigate the clustering of depressive symptoms over the ECT index and whether ECT differentially influences symptom clusters. METHODS: The 17-item Hamilton Depression Rating Scale (HDRS-17) was collected from 111 patients with current depressive episode before and after ECT from 4 independent participating sites of the Global ECT-MRI Research Collaboration. Exploratory factor analysis of HDRS-17 items pre- and post-ECT treatment identified depressive symptom dimensions before and after ECT. A 2-way analysis of covariance was used to determine whether baseline symptom clusters were differentially changed by ECT between treatment remitters (defined as patients with posttreatment HDRS-17 total score ≤8) and nonremitters while controlling for pulse width, titration method, concurrent antidepressant treatment, use of benzodiazepine, and demographic variables. RESULTS: A 3-factor solution grouped pretreatment HDRS-17 items into core mood/anhedonia, somatic, and insomnia dimensions. A 2-factor solution best described the symptoms at posttreatment despite poorer separation of items. Among remitters, core mood/anhedonia symptoms were significantly more reduced than somatic and insomnia dimensions. No differences in symptom dimension trajectories were observed among nonremitting patients. CONCLUSIONS: Electroconvulsive therapy targets the underlying source of depressive symptomatology and may confer differential degrees of improvement in certain core depressive symptoms. Our findings of differential trajectories of symptom clusters over the ECT index might help related predictive biomarker studies to refine their approaches by identifying predictors of change along each latent symptom dimension.

Community-based football in men with prostate cancer: 1-year follow-up on a pragmatic, multicentre randomised controlled trial.

BACKGROUND: Physical exercise has been shown to be effective in relation to fatigue, aerobic fitness, and lower body strength in men with prostate cancer. However, research into the clinically relevant effects of interventions conducted in heterogeneous patient populations and in real-life clinical practice settings is warranted. METHODS AND FINDINGS: We conducted a pragmatic, multicentre, parallel randomised controlled trial in 5 Danish urological departments. Recruitment began in May 2015, the first participant was randomised in June 2015, and the last participant was included in February 2017. In total, 214 men with prostate cancer were randomly assigned to either 6 months of free-of-charge football training twice weekly at a local club (football group [FG]) (n = 109) or usual care (usual care group [UG]) (n = 105), including brief information on physical activity recommendations at randomisation. Participants were on average 68.4 (SD 6.2) years old, 157 (73%) were retired, 87 (41%) were on castration-based treatment, 19 (9%) had received chemotherapy, and 41 (19%) had skeletal metastases at baseline. In this 1-year follow-up study, we evaluated the effects of community-based football training on the following outcomes: primary outcome, quality of life; secondary outcomes: continuation of football after 6 months, hip and lumbar spine bone mineral density (BMD), mental health score, fat and lean body mass, and safety outcomes, i.e., fractures, falls, and hospital admissions. Intention to treat (ITT) and per protocol (PP) analyses were conducted. No statistically significant between-group difference was observed in change in prostate-cancer-specific quality of life (ITT: 1.9 points [95% CI -1.9 to 5.8], p = 0.325; PP: 3.6 points [95% CI -0.9 to 8.2], p = 0.119). A statistically significant between-group difference was observed in change in total hip BMD, in favour of FG (0.007 g/cm2 [95% CI 0.004 to 0.013], p = 0.037). No differences were observed in change in lumbar spine BMD or lean body mass. Among patients allocated to football, 59% chose to continue playing football after the end of the 6-month intervention period. At 1-year follow-up in the PP population, FG participants had more improvement on the Mental Component Summary (2.9 [95% CI 0.0 to 5.7], p = 0.048 points higher) than UG participants, as well as a greater loss of fat mass (-0.9 kg [95% CI -1.7 to -0.1], p = 0.029). There were no differences between groups in relation to fractures or falls. Hospital admissions were more frequent in UG compared to FG (33 versus 20; the odds ratio based on PP analysis was 0.34 for FG compared to UG). There were 3 deaths in FG and 4 in UG. Main limitations of the study were the physically active control group and assessment of physical activity by means of self-report. CONCLUSIONS: In this trial, participants allocated to football appeared to have improved hip BMD and fewer hospital admissions. Men who played football more than once a week for 1 year lost fat mass and reported improved mental health. Community-based football proved to be acceptable, even when club membership was not subsidised. TRIAL REGISTRATION: ClinicalTrials.gov NCT02430792.