Viral rebound upon stopping combined antiretroviral therapy poses a major barrier toward an HIV cure. Cellular and anatomical sources responsible for reinitiating viral replication remain a subject ...of ardent debate, despite extensive research efforts. To unravel the source of rebounding viruses, we conducted a large-scale HIV-STAR (HIV-1 sequencing before analytical treatment interruption to identify the anatomically relevant HIV reservoir) clinical trial. We collected samples from 11 participants and compared the genetic composition of (pro)viruses collected under treatment from different cellular and anatomical compartments with that of plasma viruses sampled during analytical treatment interruption. We found a remarkably heterogeneous source of viral rebound. In addition, irrespective of the compartment or cell subset, genetically identical viral expansions played a significant role in viral rebound. Our study suggests that although there does not seem to be a primary source for rebound HIV, cellular proliferation is an important driver of HIV persistence and should therefore be considered in future curative strategies.
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•HIV-1 sequences sampled from different reservoirs were compared to rebound viruses in 11 individuals•Rebound viruses can originate from various cellular and anatomical compartments•Cellular proliferation is an important driver of HIV persistence•Cure strategies should take into account the lack of a prominent HIV rebound origin
De Scheerder et al. conduct an in-depth investigation into the origins of HIV rebound. They show that viral rebound originates from multiple compartments and cell proliferation is a driver of viral persistence. Future HIV cure strategies will need to overcome the challenges associated with heterogeneous viral rebound.
Cerebral microbleeds are increasingly reported in critical ill patients with respiratory failure in need of mechanical ventilation and/or extracorporeal membrane oxygenation (ECMO). Typically, these ...critical illness-associated microbleeds involve the juxtacortical white matter and corpus callosum. Recently, this pattern was reported in patients with respiratory failure, suffering from COVID-19.
In this retrospective single-center study, we listed patients from March 11, 2020 to September 2, 2020, with laboratory-confirmed COVID-19, critical illness and cerebral microbleeds. Literature research was conducted through a methodical search on Pubmed databases on critical illness-associated microbleeds and cerebral microbleeds described in patients with COVID-19.
On 279 COVID-19 admissions, two cases of cerebral microbleeds were detected in critical ill patients with respiratory failure due to COVID-19. Based on review of existing literature critical illness-associated microbleeds tend to predominate in subcortical white matter and corpus callosum. Cerebral microbleeds in patients with COVID-19 tend to follow similar patterns as reported in critical illness-associated microbleeds. Hence, one patient with typical critical illness-associated microbleeds and COVID-19 is reported. However, a new pattern of widespread cortico-juxtacortical microbleeds, predominantly in the anterior vascular territory with relative sparing of deep gray matter, corpus callosum and infratentorial structures is documented in a second case. The possible etiologies of these microbleeds include hypoxia, hemorrhagic diathesis, brain endothelial erythrophagocytosis and/or cytokinopathies. An association with COVID-19 remains to be determined.
Further systematic investigation of microbleed patterns in patients with neurological impairment and COVID-19 is necessary.
•Critical illness-associated microbleeds have predilection sites at subcortical whitematter and corpus callosum.•Cerebral microbleeds in patients with COVID-19 tend to follow similar patterns as reported in critical illness-associated microbleeds.•An unusual pattern of cortico-juxtacortical microbleeds, predominantly in the anterior vascular territory with relative sparing of deep gray matter, corpus callosum and infratentorial structures is presented in a patient with COVID-19.•Further systematic investigation of microbleed patterns is necessary.
To estimate the additional impact of coping and of being dependent on caregivers, over and above the large effects of disability on utility after ischemic stroke.
A total of 539 patients were ...recruited into an observational, retrospective study when returning for a check-up between 3 and 36 months after an ischemic stroke. Patients' modified Rankin Scale (mRS), dependency on caregivers, the Brandtstädter and Renner Coping questionnaire (with summary scores: Tenacity of Goal Pursuit (TGP) and Flexible Goal Adjustment (FGA) coping styles), EQ-5D-3 L and co-morbidities were evaluated.
In multivariable regression, greater disability (mRS) resulted in large utility losses, between 0.06 for mRS 1 to 0.65 for mRS 5 (p < 0.0001). Dependency on caregivers caused an additional dis-utility of 0.104 (p = 0.0006) which varied by mRS (0.044, 0.060, 0.083, 0.115, 0.150 and 0.173 for mRS 0-5). The effect of coping on utility varied by coping style, by the disability level of the patient and by his or her dependency on caregivers. FGA coping was associated with additional increases in utility (p < 0.0001) over and above the effect of disability and dependency, whereas TGA had no significant impact. FGA coping was associated with larger utility changes among more disabled patients (0.018 to 0.105 additional utility, for mRS 0 to mRS 5 respectively). Dependent patients had more to gain from FGA coping than patients who function independently of caregivers: utility gains were between 0.049 and 0.072 for moderate to high levels of FGA coping. In contrast, the same positive evolution in FGA coping resulted in 0.039 and 0.057 utility gain among independent patients. Finally, we found that important stroke risk factors and co-morbidities, such as diabetes and atrial fibrillation, were not predictors of EQ-5D utility in a multivariable setting.
This study suggests that treatment strategies targeting flexible coping styles and decreasing dependency on caregivers may lead to significant gains in quality of life above and beyond treatment strategies that solely target disability.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In order to facilitate the diagnostic process for adult patients suffering from a rare disease, the Undiagnosed Disease Program (UD-PrOZA) was founded in 2015 at the Ghent University Hospital in ...Belgium. In this study we report the five-year results of our multidisciplinary approach in rare disease diagnostics.
Patients referred by a healthcare provider, in which an underlying rare disease is likely, qualify for a UD-PrOZA evaluation. UD-PrOZA uses a multidisciplinary clinical approach combined with state-of-the-art genomic technologies in close collaboration with research facilities to diagnose patients.
Between 2015 and 2020, 692 patients (94% adults) were referred of which 329 (48%) were accepted for evaluation. In 18% (60 of 329) of the cases a definite diagnosis was made. 88% (53 of 60) of the established diagnoses had a genetic origin. 65% (39 of 60) of the genetic diagnoses were made through whole exome sequencing (WES). The mean time interval between symptom-onset and diagnosis was 19 years. Key observations included novel genotype-phenotype correlations, new variants in known disease genes and the identification of three new disease genes. In 13% (7 of 53), identifying the molecular cause was associated with therapeutic recommendations and in 88% (53 of 60), gene specific genetic counseling was made possible. Actionable secondary findings were reported in 7% (12 of 177) of the patients in which WES was performed.
UD-PrOZA offers an innovative interdisciplinary platform to diagnose rare diseases in adults with previously unexplained medical problems and to facilitate translational research.
Recently, CT perfusion (CTP) has been proposed as a selection tool for stroke patients to be treated with endovascular thrombectomy. We investigated whether functional outcome following endovascular ...treatment was improved after the introduction of CTP.
This retrospective single-centre study includes all patients with a major vessel occlusion in the anterior circulation that received a CTP and underwent a mechanical thrombectomy from 2014 up to 2015. CTP were visually evaluated. Demographics, stroke and time data, procedural data, functional outcomes as measured by the modified Rankin Scale (mRS) and the association between these variables were studied. A comparison was made with the results of a similar local retrospective study from before the CTP "era".
Eighty-nine patients were included in this study. Median National Institutes of Health Stroke Scale (NIHSS) was 16 (Interquartile range 6). At three months, good functional outcome (GFO; mRS 0-2) was achieved in 48.4% and excellent functional outcome (EFO; mRS 0-1) in 34.4% of patients. The mortality rate at three months was 14.5%. GFO at one year was 44.8%, EFO was 31.3% and mortality 21.1%. The duration of the thrombectomy procedure and the EFO were associated (p = 0.032). The outcome improvement achieved with CTP was higher compared to the reference study (GFO 48.4% versus 44%; EFO 34.4% versus 29%) but remained below the statistical significance.
Mechanical thrombectomy for anterior circulation strokes based on CTP did not result in a significant functional outcome improvement. The duration of the thrombectomy procedure was the sole time-interval related to improved functional outcome.
Moyamoya disease (MMD) is a rare cerebrovascular disorder with unknown etiology. MMD is characterized by progressive narrowing of arteries of the brain and the formation of a compensatory network of ...fragile vessels. Genetic studies have identified RNF213, also known as mysterin, as a susceptibility gene for MMD, but the low penetrance in genetically susceptible individuals suggests that a second hit is necessary to trigger disease onset. Recently, several molecular studies uncovered RNF213 as a key antimicrobial protein with important functions in the immune system. In addition, an increasing number of clinical reports describe the development of moyamoya angiopathy (MMA) associated with infection or autoimmune disorders. Together, this growing body of molecular and clinical evidence points towards immune-related responses as second hits to trigger MMD onset.
Moyamoya disease (MMD) is a rare cerebrovascular disorder that develops in genetically predisposed individuals after triggering by an unknown second hit.An increasing number of reports describes the development of moyamoya angiopathy associated with infection or autoimmune disorders.RNF213, encoded by RNF213, so far the only strongly established MMD susceptibility gene, was recently discovered as a key antimicrobial protein and important immune effector.This growing body of clinical and molecular evidence strengthens the argument for infection and immune-related responses as second hits to trigger MMD onset.
Fibromuscular dysplasia (FMD) is an idiopathic, non-inflammatory, non-atherosclerotic vascular disease, resulting in focal narrowing of small and medium-sized arteries. Systematic recording of ...clinical data in central databases as in the US and France provided new insights into FMD. The main objectives of this multicentre study were to explore the epidemiology, pattern of vascular involvement, clinical manifestations, and management of FMD patients in Flanders.
Multicentre, retrospective registry of patients diagnosed with FMD based on medical imaging.
Hundred-twenty-three FMD patients (83.7 % female) were included. Mean age at FMD diagnosis was 57.3 years (SD 15.8). More than half of patients (59.5 %) were hypertensive at the time of diagnosis. Neurological complaints such as headache (26.4 %) and dizziness (23.1 %) were also frequently reported. FMD was discovered incidentally in 10 patients (8.3 %). Nearly one quarter (22.8 %) of patients experienced a cerebrovascular event. Aneurysms were found in one-fifth (20.3 %) of patients and 11.4 % had an arterial dissection. FMD affected most frequently the renal (85.3 %), carotid (74.7 %), and vertebral (39.8 %) arteries. Renovascular FMD was more prevalent in men, whereas cerebrovascular FMD was more frequent in women. Multiple affected sites were documented in 25 of 61 (41.0 %) patients, having two or more vascular beds imaged. Digital subtraction angiography was most frequently used for detecting FMD. One third (32.9 %) of patients received an interventional treatment, mainly patients with renovascular FMD (32.8 % underwent percutaneous transluminal angioplasty) and patients with an intracranial carotid aneurysm (36.4 % were treated by means of coiling).
Although differences existed, results of the Flemish registry were broadly in line with the US and French registries. Patient databases help to learn more about the natural history, progression, and management of FMD, based on real life clinical evidence.
Background and Purpose:
To identify factors associated with prior stroke at presentation in patients with cryptogenic stroke (CS) and patent foramen ovale (PFO).
Methods:
We studied cross-sectional ...data from the International PFO Consortium Study (NCT00859885). Patients with first-ever stroke and those with prior stroke at baseline were analyzed for an association with PFO-related (right-to-left shunt at rest, atrial septal aneurysm, deep venous thrombosis, pulmonary embolism, and Valsalva maneuver) and PFO-unrelated factors (age, gender, BMI, hypertension, diabetes mellitus, hypercholesterolemia, smoking, migraine, coronary artery disease, aortic plaque). A multivariable analysis was used to adjust effect estimation for confounding, e.g., owing to the age-dependent definition of study groups in this cross-sectional study design.
Results:
We identified 635 patients with first-ever and 53 patients with prior stroke. Age, BMI, hypertension, diabetes mellitus, hypercholesterolemia, coronary artery disease, and right-to-left shunt (RLS) at rest were significantly associated with prior stroke. Using a pre-specified multivariable logistic regression model, age (Odds Ratio 1.06), BMI (OR 1.06), hypercholesterolemia (OR 1.90) and RLS at rest (OR 1.88) were strongly associated with prior stroke.Based on these factors, we developed a nomogram to illustrate the strength of the relation of individual factors to prior stroke.
Conclusion:
In patients with CS and PFO, the likelihood of prior stroke is associated with both, PFO-related and PFO-unrelated factors.
To report the clinical, radiologic, biochemical, and molecular characteristics in a 46-year-old participant with adult-onset Leigh syndrome (LS), followed by parkinsonism.
Case description with ...diagnostic workup included blood and CSF analysis, skeletal muscle investigations, blue native polyacrylamide gel electrophoresis, whole exome sequencing targeting nuclear genes involved in mitochondrial transcription and translation, cerebral MRI, 123I-FP-CIT brain single-photon emission computed tomography (SPECT), and C-11 raclopride positron emission tomography (PET).
The participant was found to have a defect in the oxidative phosphorylation caused by a c.626C>T mutation in the gene coding for mitochondrial methionyl-tRNA formyltransferase (
), which is a pathogenic mutation affecting intramitochondrial protein translation. The proband had a normal concentration of lactate in blood and no abnormal microscopic findings in skeletal muscle. Cerebral MRI showed bilateral lesions in the striatum, mesencephalon, pons, and medial thalamus. Lactate concentration in CSF was increased. FP-CIT SPECT and C-11 raclopride PET demonstrated a defect in the dopaminergic system.
We report on a case with adult-onset LS related to a
mutation. Two years after the onset of symptoms of LS, the proband developed a parkinson-like disease. The c.626C>T mutation is the most common pathogenic mutation found in 22 patients reported earlier in the literature with a defect in
. The age of the previously reported cases varied between 14 months and 24 years. Our report expands the phenotypical spectrum of
-related neurologic disease and provides clinical evidence for involvement of
in extrapyramidal syndromes.
Clinical trials have shown a beneficial effect of mechanical thrombectomy in acute ischemic stroke patients treated within six up to even 12 h after symptom onset. This treatment was already ...performed in selected hospitals in Belgium before completion of the randomized controlled trials. Outcome data on these procedures in Belgium have not been published. We performed a retrospective multicenter study of all patients with acute ischemic stroke treated with mechanical endovascular therapy in four hospitals in Belgium. Clinical outcomes, as measured by the modified Rankin Scale (mRS), site of arterial occlusion, reperfusion and the association between these variables were studied. The study included 80 patients: 65 patients with an occlusion in the anterior circulation and 15 with an occlusion in the posterior circulation. Good functional outcome (GFO) rates, defined as mRS 0–2 at 90 days, were 42 % in all patients, 44 % in anterior circulation stroke and 34 % in posterior circulation stroke. Reperfusion was achieved in 78 % of patients; more (100 %) in patients with posterior compared to patients with anterior circulation stroke (72 %;
p
= 0.02). The rate of GFO was greater in patients with reperfusion versus patients in whom reperfusion was not achieved (adjusted OR 8.2, 95 % CI 2.0–34.2). Symptomatic intracerebral hemorrhage was documented in 5 % of all patients. Endovascular treatment with mechanical devices for acute ischemic stroke in Belgium results in GFO and reperfusion rates similar to recently published results in the endovascular-treated arms of randomized clinical trials. Rates of symptomatic intracranial hemorrhage are low and comparable to other cohort studies and clinical trials.
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