Clinical effectiveness of usual care with or without antidepressant medication for primary care patients with minor or mild-major depression: a randomized equivalence trial

<p>Abstract</p> <p>Background</p> <p>Minor and mild-major depression are highly prevalent in primary care. There is insufficient evidence for the effectiveness of antidepressants in the treatment of minor and mild-major depression. We compared the effectiveness of usual primary care treatment, with or without antidepressants, in minor and mild-major depression.</p> <p>Methods</p> <p>A pragmatic patient-randomized equivalence trial with 52 weeks follow-up was conducted in The Netherlands. In total, 59 primary care physicians (PCPs) recruited and treated 181 adult patients with minor or mild-major depression. Patients were randomized to four consultations within 3 months of usual care plus antidepressants (UCandAD) or usual care alone (UCnoAD). The Montgomery Åsberg Depression Rating Scale (MADRS) was used to assess changes in severity of depressive symptoms. The predefined equivalence margin was set at five points. Multilevel analysis was used to analyze the data. Secondary outcome measures were the Short-Form 36 (SF-36), and the Client Satisfaction Questionnaire (CSQ-8).</p> <p>Results</p> <p>Patients received on average 3.0 (SD 1.4) 15-min consultations within 3 months with (n = 85) or without paroxetine (n = 96). Equivalence of UCandAD and UCnoAD was demonstrated in the intention-to-treat analyses as well as the per-protocol analysis after 6 weeks, but not at 13, 26 and 52 weeks follow-up. No statistical differences in effectiveness between treatment groups were found in the intention-to-treat analysis. No differences in the physical and mental functioning (SF-36) were found between the treatment groups. Patients allocated to UCandAD were slightly more satisfied with their treatment at 13 weeks follow-up (but not at 52 weeks follow-up) than patients allocated to UCnoAD. Preliminary analyses suggested that subgroups such as patients with mild-major (instead of a minor) depression might benefit from antidepressant treatment. Patients who were assigned to their preferred treatment (in particular to UCnoAD) were more often compliant and had better clinical outcomes.</p> <p>Conclusion</p> <p>UCandAD was as effective as UCnoAD over the first 6 weeks, but not at 13, 26, and 52 weeks. However, superiority of either treatment could not be demonstrated either. The question whether antidepressants add any clinical effect to usual care remains unresolved. We recommend future studies to look for subgroups of patients who may benefit from antidepressants.</p> <p>Trial registration</p> <p>Dutch Trial Registry ISRCN03007807.</p

A structural comparison of human serum transferrin and human lactoferrin

The transferrins are a family of proteins that bind free iron in the blood and bodily fluids. Serum transferrins function to deliver iron to cells via a receptor-mediated endocytotic process as well as to remove toxic free iron from the blood and to provide an anti-bacterial, low-iron environment. Lactoferrins (found in bodily secretions such as milk) are only known to have an anti-bacterial function, via their ability to tightly bind free iron even at low pH, and have no known transport function. Though these proteins keep the level of free iron low, pathogenic bacteria are able to thrive by obtaining iron from their host via expression of outer membrane proteins that can bind to and remove iron from host proteins, including both serum transferrin and lactoferrin. Furthermore, even though human serum transferrin and lactoferrin are quite similar in sequence and structure, and coordinate iron in the same manner, they differ in their affinities for iron as well as their receptor binding properties: the human transferrin receptor only binds serum transferrin, and two distinct bacterial transport systems are used to capture iron from serum transferrin and lactoferrin. Comparison of the recently solved crystal structure of iron-free human serum transferrin to that of human lactoferrin provides insight into these differences

Post translational changes to α-synuclein control iron and dopamine trafficking : a concept for neuron vulnerability in Parkinson's disease

Parkinson's disease is a multifactorial neurodegenerative disorder, the aetiology of which remains elusive. The primary clinical feature of progressively impaired motor control is caused by a loss of midbrain substantia nigra dopamine neurons that have a high α-synuclein (α-syn) and iron content. α-Syn is a neuronal protein that is highly modified post-translationally and central to the Lewy body neuropathology of the disease. This review provides an overview of findings on the role post translational modifications to α-syn have in membrane binding and intracellular vesicle trafficking. Furthermore, we propose a concept in which acetylation and phosphorylation of α-syn modulate endocytic import of iron and vesicle transport of dopamine during normal physiology. Disregulated phosphorylation and oxidation of α-syn mediate iron and dopamine dependent oxidative stress through impaired cellular location and increase propensity for α-syn aggregation. The proposition highlights a connection between α-syn, iron and dopamine, three pathological components associated with disease progression in sporadic Parkinson's disease

Computed tomography myocardial perfusion vs (15)O-water positron emission tomography and fractional flow reserve

Objectives: Computed tomography (CT) can perform comprehensive cardiac imaging. We compared CT coronary angiography (CTCA) and CT myocardial perfusion (CTP) with ¹⁵O-water positron emission tomography (PET) and invasive coronary angiography (ICA) with fractional flow reserve (FFR). Methods: 51 patients (63 (61–65) years, 80 % male) with known/suspected coronary artery disease (CAD) underwent 320-multidetector CTCA followed by “snapshot” adenosine stress CTP. Of these 22 underwent PET and 47 ICA/FFR. Obstructive CAD was defined as CTCA stenosis >50 % and CTP hypoperfusion, ICA stenosis >70 % or FFR <0.80. Results: PET hyperaemic myocardial blood flow (MBF) was lower in obstructive than non-obstructive territories defined by ICA/FFR (1.76 (1.32–2.20) vs 3.11 (2.44–3.79) mL/(g/min), P < 0.001) and CTCA/CTP (1.76 (1.32–2.20) vs 3.12 (2.44–3.79) mL/(g/min), P < 0.001). Baseline and hyperaemic CT attenuation density was lower in obstructive than non-obstructive territories (73 (71–76) vs 86 (84–88) HU, P < 0.001 and 101 (96–106) vs 111 (107–114) HU, P 0.001). PET hyperaemic MBF corrected for rate pressure product correlated with CT attenuation density (r = 0.579, P < 0.001). There was excellent per-patient sensitivity (96 %), specificity (85 %), negative predictive value (90 %) and positive predictive value (94 %) for CTCA/CTP vs ICA/FFR. Conclusion: CT myocardial attenuation density correlates with ¹⁵O-water PET MBF. CTCA and CTP can accurately identify obstructive CAD. Key Points: •CT myocardial perfusion can aid the assessment of suspected coronary artery disease. • CT attenuation density from “snapshot” imaging is a marker of myocardial perfusion. • CT myocardial attenuation density correlates with ¹⁵O-water PET myocardial blood flow. • CT attenuation density is lower in obstructive territories defined by invasive angiography. • Diagnostic accuracy of CTCA+CTP is comparable to invasive angiography + fractional flow reserve

Implementation of corticosteroids in treatment of COVID-19 in the ISARIC WHO Clinical Characterisation Protocol UK: prospective, cohort study

Background Dexamethasone was the first intervention proven to reduce mortality in patients with COVID-19 being treated in hospital. We aimed to evaluate the adoption of corticosteroids in the treatment of COVID-19 in the UK after the RECOVERY trial publication on June 16, 2020, and to identify discrepancies in care. Methods We did an audit of clinical implementation of corticosteroids in a prospective, observational, cohort study in 237 UK acute care hospitals between March 16, 2020, and April 14, 2021, restricted to patients aged 18 years or older with proven or high likelihood of COVID-19, who received supplementary oxygen. The primary outcome was administration of dexamethasone, prednisolone, hydrocortisone, or methylprednisolone. This study is registered with ISRCTN, ISRCTN66726260. Findings Between June 17, 2020, and April 14, 2021, 47 795 (75·2%) of 63 525 of patients on supplementary oxygen received corticosteroids, higher among patients requiring critical care than in those who received ward care (11 185 [86·6%] of 12 909 vs 36 415 [72·4%] of 50 278). Patients 50 years or older were significantly less likely to receive corticosteroids than those younger than 50 years (adjusted odds ratio 0·79 [95% CI 0·70–0·89], p=0·0001, for 70–79 years; 0·52 [0·46–0·58], p80 years), independent of patient demographics and illness severity. 84 (54·2%) of 155 pregnant women received corticosteroids. Rates of corticosteroid administration increased from 27·5% in the week before June 16, 2020, to 75–80% in January, 2021. Interpretation Implementation of corticosteroids into clinical practice in the UK for patients with COVID-19 has been successful, but not universal. Patients older than 70 years, independent of illness severity, chronic neurological disease, and dementia, were less likely to receive corticosteroids than those who were younger, as were pregnant women. This could reflect appropriate clinical decision making, but the possibility of inequitable access to life-saving care should be considered

SARS-CoV-2 Omicron-B.1.1.529 leads to widespread escape from neutralizing antibody responses

On 24th November 2021, the sequence of a new SARS-CoV-2 viral isolate Omicron-B.1.1.529 was announced, containing far more mutations in Spike (S) than previously reported variants. Neutralization titers of Omicron by sera from vaccinees and convalescent subjects infected with early pandemic Alpha, Beta, Gamma, or Delta are substantially reduced, or the sera failed to neutralize. Titers against Omicron are boosted by third vaccine doses and are high in both vaccinated individuals and those infected by Delta. Mutations in Omicron knock out or substantially reduce neutralization by most of the large panel of potent monoclonal antibodies and antibodies under commercial development. Omicron S has structural changes from earlier viruses and uses mutations that confer tight binding to ACE2 to unleash evolution driven by immune escape. This leads to a large number of mutations in the ACE2 binding site and rebalances receptor affinity to that of earlier pandemic viruses