The composition of the gut microbiota is linked to multiple diseases, including Parkinson’s disease (PD). Abundance of bacteria producing short-chain fatty acids (SCFAs) and fecal SCFA concentrations ...are reduced in PD. SCFAs exert various beneficial functions in humans. In the interventional, monocentric, open-label clinical trial “Effects of Resistant Starch on Bowel Habits, Short Chain Fatty Acids and Gut Microbiota in Parkinson’sDisease” (RESISTA-PD; ID: NCT02784145), we aimed at altering fecal SCFAs by an 8-week prebiotic intervention with resistant starch (RS). We enrolled 87 subjects in three study-arms: 32 PD patients received RS (PD + RS), 30 control subjects received RS, and 25 PD patients received solely dietary instructions. We performed paired-end 100 bp length metagenomic sequencing of fecal samples using the BGISEQ platform at an average of 9.9 GB. RS was well-tolerated. In the PD + RS group, fecal butyrate concentrations increased significantly, and fecal calprotectin concentrations dropped significantly after 8 weeks of RS intervention. Clinically, we observed a reduction in non-motor symptom load in the PD + RS group. The reference-based analysis of metagenomes highlighted stable alpha-diversity and beta-diversity across the three groups, including bacteria producing SCFAs. Reference-free analysis suggested punctual, yet pronounced differences in the metagenomic signature in the PD + RS group. RESISTA-PD highlights that a prebiotic treatment with RS is safe and well-tolerated in PD. The stable alpha-diversity and beta-diversity alongside altered fecal butyrate and calprotectin concentrations call for long-term studies, also investigating whether RS is able to modify the clinical course of PD.
The six-transmembrane helix (6 TM) tetrameric cation channels form the largest ion channel family, some members of which are voltage-gated and others are not. There are no reported channel structures ...to match the wealth of functional data on the non-voltage-gated members. We determined the structure of the transmembrane regions of the bacterial cyclic nucleotide-regulated channel MlotiK1, a non-voltage-gated 6 TM channel. The structure showed how the S1-S4 domain and its associated linker can serve as a clamp to constrain the gate of the pore and possibly function in concert with ligand-binding domains to regulate the opening of the pore. The structure also led us to hypothesize a new mechanism by which motions of the S6 inner helices can gate the ion conduction pathway at a position along the pore closer to the selectivity filter than the canonical helix bundle crossing.
Idiopathic rapid eye movement sleep behavior disorder (iRBD)--a parasomnia characterized by dream enactments--is a risk marker for the development of Parkinson disease (PD) and other ...alpha-synucleinopathies. The pathophysiology of iRBD is likely due to dysfunction of brainstem nuclei that regulate REM sleep. Diffusion tensor imaging (DTI) is a method for studying microstructural brain tissue integrity in vivo. We investigated whether DTI detects microstructural abnormalities in the brain of patients with iRBD--compared with age-matched control subjects--as an in vivo potential indicator for changes related to "preclinical (premotor)" neuropathology in PD.
N/A.
Patients with iRBD (n = 12) and age-matched healthy control subjects (n = 12) were studied.
At a 1.5T MRI maschine, whole-head DTI scans of fractional anisotropy, axial diffusivity (a potential marker of neuronal loss), and radial diffusivity (a potential marker of glial pathology) were analyzed using track-based spatial statistics, and 2 types of group analysis tools (FreeSurfer and FSL).
We found significant microstructural changes in the white matter of the brainstem (P < 0.0001), the right substantia nigra, the olfactory region, the left temporal lobe, the fornix, the internal capsule, the corona radiata, and the right visual stream of the patients with iRBD.
Changes were identified in regions known to be involved in REM-sleep regulation and/or to exhibit neurodegenerative pathology in iRBD and/or early PD. The study findings suggest that iRBD-related microstructural abnormalities can be detected in vivo with DTI, a widely available MRI technique.
The study meta-analytically integrates results from three decades of human capital research in entrepreneurship. Based on 70 independent samples (
N
=
24,733), we found a significant but small ...relationship between human capital and success (
r
c
=
.098). We examined theoretically derived moderators of this relationship referring to conceptualizations of human capital, to context, and to measurement of success. The relationship was higher for outcomes of human capital investments (knowledge/skills) than for human capital investments (education/experience), for human capital with high task-relatedness compared to low task-relatedness, for young businesses compared to old businesses, and for the dependent variable size compared to growth or profitability. Findings are relevant for practitioners (lenders, policy makers, educators) and for future research. Our findings show that future research should pursue moderator approaches to study the effects of human capital on success. Further, human capital is most important if it is task-related and if it consists of outcomes of human capital investments rather than human capital investments; this suggests that research should overcome a static view of human capital and should rather investigate the processes of learning, knowledge acquisition, and the transfer of knowledge to entrepreneurial tasks.
In the United States, the National Cancer Institute National Cancer Clinical Trials Network (NCTN) groups have conducted publicly funded oncology research for 50 years. The combined impact of all ...adult network group trials has never been systematically examined.
We identified randomized, phase III trials from the adult NCTN groups, reported from 1980 onward, with statistically significant findings for ≥ 1 clinical, time-dependent outcomes. In the subset of trials in which the experimental arm improved overall survival, gains in population life-years were estimated by deriving trial-specific hazard functions and hazard ratios to estimate the experimental treatment benefit and then mapping this trial-level benefit onto the US cancer population using registry and life-table data. Scientific impact was based on citation data from Google Scholar. Federal investment costs per life-year gained were estimated. The results were derived through December 31, 2020.
One hundred sixty-two trials comprised of 108,334 patients were analyzed, representing 29.8% (162/544) of trials conducted. The most common cancers included breast (34), gynecologic (28), and lung (14). The trials were cited 165,336 times (mean, 62.2 citations/trial/year); 87.7% of trials were cited in cancer care guidelines in favor of the recommended treatment. These studies were estimated to have generated 14.2 million (95% CI, 11.5 to 16.5 million) additional life-years to patients with cancer, with projected gains of 24.1 million (95% CI, 19.7 to 28.2 million) life-years by 2030. The federal investment cost per life-year gained through 2020 was $326 in US dollars.
NCTN randomized trials have been widely cited and are routinely included in clinical guidelines. Moreover, their conduct has predicted substantial improvements in overall survival in the United States for patients with oncologic disease, suggesting they have contributed meaningfully to this nation's health. These findings demonstrate the critical role of government-sponsored research in extending the lives of patients with cancer.
Endophilin is a key protein involved in clathrin-mediated endocytosis. Previous computational and experimental work suggested that the N-terminal helix is embedded into the membrane to induce ...curvature; however, the role of the SH3 domain remains controversial. To address this issue, we performed computer simulations of the endophilin dimer in solution to understand the interaction between the N-BAR and SH3 domains and its effect on biological function. We predict that the helix binds to the SH3 domain through hydrophobic and salt-bridge interactions. This protects the hydrophobic residues on both domains and keeps the SH3 domain near the end of the N-BAR domain, in agreement with previous experimental results. The complex has a binding strength similar to a few hydrogen bonds (13.0 ± 0.6 kcal/mol), and the SH3 domain stabilizes the structure of the N-terminal helix in solution. Electrostatic calculations show a large region of strongly positive electrostatic potential near the N-terminal that can orient the helix toward the membrane and likely embed the helix into the membrane surface. This predicted mechanism suggests that endophilin can select for both curvature and electrostatic potential when interacting with membranes, highlighting the importance of the SH3 domain in regulating the function of endophilin.
Since the onset of the COVID-19 pandemic, there have been calls for COVID-19 clinical trials to be fully representative of all demographic groups. However, limited evidence is available about the ...sex, racial, and ethnic representation among COVID-19 prevention and treatment trials.
To investigate whether female participants and racial and ethnic minority individuals are adequately represented in COVID-19 prevention and treatment trials in the US.
Identified studies were registered on ClinicalTrials.gov or published in the PubMed database from October 2019 to February 2022.
Included studies must have provided the number of enrolled participants by sex, race, or ethnicity. Only interventional studies conducted in the US for the primary purpose of the diagnosis, prevention, or treatment of (or supportive care for) COVID-19 conditions were included.
Data on counts of enrollments by demographic variables (sex, race, and ethnicity) and location (country and state) were abstracted. Studies were broadly categorized by primary purpose as prevention (including vaccine and diagnosis studies) vs treatment (including supportive care studies). A random effects model for single proportions was used. Trial estimates were compared with corresponding estimates of representation in the US population with COVID-19.
Sex, racial, and ethnic representation in COVID-19 clinical trials compared with their representation in the US population with COVID-19.
Overall, 122 US-based COVID-19 clinical trials comprising 176 654 participants were analyzed. Studies were predominantly randomized trials (n = 95) for treatment of COVID-19 (n = 103). Sex, race, and ethnicity were reported in 109 (89.3%), 95 (77.9%), and 87 (71.3%) trials, respectively. Estimated representation in prevention and treatment trials vs the US population with COVID-19 was 48.9% and 44.6% vs 52.4% for female participants; 23.0% and 36.6% vs 17.7% for Hispanic or Latino participants; 7.2% and 16.5% vs 14.1% for Black participants; 3.8% and 4.6% vs 3.7% for Asian participants; 0.2% and 0.9% vs 0.2% for Native Hawaiian or Other Pacific Islander participants; and 1.3% and 1.4% vs 1.1% for American Indian or Alaska Native participants. Compared with expected rates in the COVID-19 reference population, female participants were underrepresented in treatment trials (85.1% of expected; P < .001), Black participants (53.7% of expected; P = .003) and Asian participants (64.4% of expected; P = .003) were underrepresented in prevention trials, and Hispanic or Latino participants were overrepresented in treatment trials (206.8% of expected; P < .001).
In this systematic review and meta-analysis, aggregate differences in representation for several demographic groups in COVID-19 prevention and treatment trials in the US were found. Strategies to better ensure diverse representation in COVID-19 studies are needed, especially for prevention trials.
Stroke is among the most common causes of death and disability worldwide. Despite the relevance of stroke-related disease burden, which is constantly increasing due to the demographic change in ...industrialized countries with an ageing population and consecutively an increase in age-associated diseases, there is sparse evidence concerning acute stroke treatment and treatment-related outcome in the elderly patient group. This retrospective study aimed at analysing patient characteristics, therapy-related complications and functional outcome in stroke patients aged 90 years or older who underwent acute stroke treatment (i.e. intravenous thrombolysis, mechanical thrombectomy, or both).
We identified files of all inpatient stays at the Department of Neurology at Saarland University Medical Center (tertiary care level with a comprehensive stroke unit) between June 2011 and December 2018 and filtered for subjects aged 90 years or older at the time of admission. We reviewed patient files for demographic data, symptoms upon admission, (main) diagnoses, comorbidities, and administered therapies. For patients admitted due to acute stroke we reviewed files for therapy-related complications and functional outcome. We compared the modified Rankin scale (mRS) scores upon admission and at discharge for these patients.
We identified 566 inpatient stays of subjects aged 90 years or older. Three hundred sixty-seven of the 566 patients (64.8%) were admitted and discharged due to symptoms indicative of stroke. Two hundred eleven patients received a diagnosis of ischaemic stroke. These 211 patients were analysed subsequently. Sixty-four patients qualified for acute stroke treatment (intravenous thrombolysis n = 22, mechanical thrombectomy n = 26, intravenous thrombolysis followed by mechanical thrombectomy n = 16) and showed a significant improvement in their functional status as measured by change in mRS score (admission vs. discharge, p 0.001) with 7 (10.9%) observed potentially therapy-related complications (relevant drop in haemoglobin n = 2, subarachnoidal haemorrhage n = 1, cerebral haemorrhage n = 3, extracranial bleeding n = 1). One intravenous thrombolysis was stopped because of an uncontrollable hypertensive crisis. Patients who did not qualify for these treatments (including those declining acute treatment) did not show a change of their functional status between admission and discharge (p 0.064).
Our data indicate that acute stroke treatment is effective and safe in the oldest old. Age alone is no criterion to withhold an acute intervention even in oldest old stroke patients.
Background
The diagnosis of idiopathic epilepsy (IE) in dogs is based on exclusion of other potential causes of seizures. Recently, a novel magnetic resonance imaging (MRI) sequence that utilizes a ...variant of the rotary saturation approach has been suggested to detect weak transient magnetic field oscillations generated by neuronal currents in humans with epilepsy.
Hypothesis/Objectives
Effects on the magnetic field evoked by intrinsic epileptic activity can be detected by MRI in the canine brain. As proof‐of‐concept, the novel MRI sequence to detect neuronal currents was applied in dogs.
Animals
Twelve dogs with IE and 5 control dogs without a history of epileptic seizures were examined.
Methods
Prospective case‐control study as proof‐of‐concept. All dogs underwent a clinical neurological examination, scalp electroencephalography, cerebrospinal fluid analysis, and MRI. The MRI examination included a spin‐locking (SL) experiment applying a low‐power on‐resonance radiofrequency pulse in a predefined frequency domain in the range of oscillations generated by the epileptogenic tissue.
Results
In 11 of 12 dogs with IE, rotary saturation effects were detected by the MRI sequence. Four of 5 control dogs did not show rotary saturation effects. One control dog with a diagnosis of neuronal ceroid lipofuscinosis had SL‐related effects, but did not have epileptic seizures clinically.
Conclusions and Clinical Importance
The proposed MRI method detected neuronal currents in dogs with epileptic seizures and represents a potential new line of research to investigate neuronal currents possibly related to IE in dogs.
Results from NA61/SHINE Unger, M
EPJ Web of conferences,
01/2013, Letnik:
52
Journal Article
Recenzirano
Odprti dostop
In this paper we summarize recent results from NA61/SHINE relevant for heavy ion physics, neutrino oscillations and the interpretation of air showers induced by ultra-high energy cosmic rays.
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