Although it is well recognized that autism is associated with altered patterns of over- and under-connectivity, specifics are still a matter of debate. Little has been done so far to synthesize ...available literature using whole-brain electroencephalography (EEG) and magnetoencephalography (MEG) recordings.
1) To systematically review the literature on EEG/MEG functional and effective connectivity in autism spectrum disorder (ASD), 2) to synthesize and critically appraise findings related with the hypothesis that ASD is characterized by long-range underconnectivity and local overconnectivity, and 3) to provide, based on the literature, an analysis of tentative factors that are likely to mediate association between ASD and atypical connectivity (e.g., development, topography, lateralization).
Literature reviews were done using PubMed and PsychInfo databases. Abstracts were screened, and only relevant articles were analyzed based on the objectives of this paper. Special attention was paid to the methodological characteristics that could have created variability in outcomes reported between studies.
Our synthesis provides relatively strong support for long-range underconnectivity in ASD, whereas the status of local connectivity remains unclear. This observation was also mirrored by a similar relationship with lower frequencies being often associated with underconnectivity and higher frequencies being associated with both under- and over-connectivity. Putting together these observations, we propose that ASD is characterized by a general trend toward an under-expression of lower-band wide-spread integrative processes compensated by more focal, higher-frequency, locally specialized, and segregated processes. Further investigation is, however, needed to corroborate the conclusion and its generalizability across different tasks. Of note, abnormal lateralization in ASD, specifically an elevated left-over-right EEG and MEG functional connectivity ratio, has been also reported consistently across studies.
The large variability in study samples and methodology makes a systematic quantitative analysis (i.e. meta-analysis) of this body of research impossible. Nevertheless, a general trend supporting the hypothesis of long-range functional underconnectivity can be observed. Further research is necessary to more confidently determine the status of the hypothesis of short-range overconnectivity. Frequency-band specific patterns and their relationships with known symptoms of autism also need to be further clarified.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In this randomized trial comparing ACGME duty-hour policies with more flexible policies for surgical residents, the flexible policies resulted in noninferior patient outcomes and no significant ...difference in residents' satisfaction with overall well-being and education quality.
In response to concerns about patient safety and resident well-being, the Accreditation Council for Graduate Medical Education (ACGME) introduced national regulations in 2003 that limited resident duty periods to 80 hours per week, capped overnight shift lengths, and mandated minimum time off between shifts.
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Concerns persisted,
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and in 2011, the ACGME implemented further restrictions to shorten maximum shift lengths for interns and increase time off after overnight on-call duty for residents.
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Although most observers agree that some duty-hour regulation was necessary, critics cite a weak evidence base for the 2003 and 2011 reforms.
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The global coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has made the development of a vaccine a top biomedical priority. In this ...study, we developed a series of DNA vaccine candidates expressing different forms of the SARS-CoV-2 spike (S) protein and evaluated them in 35 rhesus macaques. Vaccinated animals developed humoral and cellular immune responses, including neutralizing antibody titers at levels comparable to those found in convalescent humans and macaques infected with SARS-CoV-2. After vaccination, all animals were challenged with SARS-CoV-2, and the vaccine encoding the full-length S protein resulted in >3.1 and >3.7 log
reductions in median viral loads in bronchoalveolar lavage and nasal mucosa, respectively, as compared with viral loads in sham controls. Vaccine-elicited neutralizing antibody titers correlated with protective efficacy, suggesting an immune correlate of protection. These data demonstrate vaccine protection against SARS-CoV-2 in nonhuman primates.
Neuroimaging studies in autism spectrum disorders (ASDs) have provided inconsistent evidence of cortical abnormality. This is probably due to the small sample sizes used in most studies, and ...important differences in sample characteristics, particularly age, as well as to the heterogeneity of the disorder. To address these issues, we assessed abnormalities in ASD within the Autism Brain Imaging Data Exchange data set, which comprises data from approximately 1100 individuals (~6-55 years). A subset of these data that met stringent quality control and inclusion criteria (560 male subjects; 266 ASD; age = 6-35 years) were used to compute age-specific differences in cortical thickness in ASD and the relationship of any such differences to symptom severity of ASD. Our results show widespread increased cortical thickness in ASD, primarily left lateralized, from 6 years onwards, with differences diminishing during adulthood. The severity of symptoms related to social affect and communication correlated with these cortical abnormalities. These results are consistent with the conjecture that developmental patterns of cortical thickness abnormalities reflect delayed cortical maturation and highlight the dynamic nature of morphological abnormalities in ASD.
Knowing the maturational schedule of typical brain development is critical to our ability to identify deviations from it; such deviations have been related to cognitive performance and even ...developmental disorders. Chronological age can be predicted from brain images with considerable accuracy, but with limited spatial specificity, particularly in the case of the cerebral cortex. Methods using multi-modal data have shown the greatest accuracy, but have made limited use of cortical measures. Methods using complex measures derived from voxels throughout the brain have also shown great accuracy, but are difficult to interpret in terms of cortical development. Measures based on cortical surfaces have yielded less accurate predictions, suggesting that perhaps cortical maturation is less strongly related to chronological age than is maturation of deep white matter or subcortical structures. We question this suggestion. We show that a simple metric based on the white/gray contrast at the inner border of the cortex is a good predictor of chronological age. We demonstrate this in two large datasets: the NIH Pediatric Data, with 832 scans of typically developing children, adolescents, and young adults; and the Pediatric Imaging, Neurocognition, and Genetics data, with 760 scans of individuals in a similar age-range. Further, our usage of an elastic net penalized linear regression model reveals the brain regions which contribute most to age-prediction. Moreover, we show that the residuals of age-prediction based on this white/gray contrast metric are not merely random errors, but are strongly related to IQ, suggesting that this metric is sensitive to aspects of brain development that reflect cognitive performance.
Tumors have high energetic and anabolic needs for rapid cell growth and proliferation, and the serine biosynthetic pathway was recently identified as an important source of metabolic intermediates ...for these processes. We integrated metabolic tracing and transcriptional profiling of a large panel of non-small cell lung cancer (NSCLC) cell lines to characterize the activity and regulation of the serine/glycine biosynthetic pathway in NSCLC. Here we show that the activity of this pathway is highly heterogeneous and is regulated by NRF2, a transcription factor frequently deregulated in NSCLC. We found that NRF2 controls the expression of the key serine/glycine biosynthesis enzyme genes PHGDH, PSAT1 and SHMT2 via ATF4 to support glutathione and nucleotide production. Moreover, we show that expression of these genes confers poor prognosis in human NSCLC. Thus, a substantial fraction of human NSCLCs activates an NRF2-dependent transcriptional program that regulates serine and glycine metabolism and is linked to clinical aggressiveness.
The current antibiotic resistance crisis has led to increased pressure to prioritize strategies to tackle the issue, with a strong focus being placed on the development of novel antimicrobials. ...However, one major obstacle that is often overlooked is persister cells, which are refractory to antibiotic treatment. Tackling persistence is a challenge because these cell types are extremely difficult to study and, consequently, little is known about their physiology and the factors that lead to their emergence. Here, four experts contemplate the main physiological features that define persistence and the implications of persistence for antibiotic treatment regimens, and consider what the study of bacterial persistence has taught us about the heterogeneity of bacterial populations.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In this international, nonrandomized study, vismodegib, an oral inhibitor of the ligand that activates the hedgehog pathway, showed responses in patients with locally advanced or metastatic ...basal-cell carcinoma who had inoperable disease or for whom surgery was inappropriate.
Basal-cell carcinoma is the most common cancer. It is estimated that more than 2.1 million new patients were treated for nonmelanoma skin cancer in 2006 in the United States
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; approximately 80% of nonmelanoma skin cancers are basal-cell carcinomas. Although most basal-cell carcinomas are readily treated by means of various surgical methods, these lesions occasionally progress to an advanced state that is no longer amenable to surgery or radiation therapy (locally advanced basal-cell carcinoma) or, more rarely, the lesions spread to distant sites (metastatic basal-cell carcinoma). When this study was designed, there was no approved therapy for advanced basal-cell carcinoma. . . .
Background Primary analysis from the pivotal ERIVANCE BCC study resulted in approval of vismodegib, a Hedgehog pathway inhibitor indicated for treatment of adults with metastatic or locally advanced ...basal cell carcinoma (BCC) that has recurred after surgery or for patients who are not candidates for surgery or radiation. Objective An efficacy and safety analysis was conducted 12 months after primary analysis. Methods This was a multinational, multicenter, nonrandomized, 2-cohort study in patients with measurable and histologically confirmed locally advanced or metastatic BCC taking oral vismodegib (150 mg/d). Primary outcome measure was objective response rate (complete and partial responses) assessed by independent review facility. Results After 12 months of additional follow-up, median duration of exposure to vismodegib was 12.9 months. Objective response rate increased from 30.3% to 33.3% in patients with metastatic disease, and from 42.9% to 47.6% in patients with the locally advanced form. Median duration of response in patients with locally advanced BCC increased from 7.6 to 9.5 months. No new safety signals emerged with extended treatment duration. Limitations Limitations include low prevalence of advanced BCC and challenges of designing a study with heterogenous manifestations. Conclusion The 12-month update of the study confirms the efficacy and safety of vismodegib in management of advanced BCC.
Abstract Background Autism Spectrum Disorder (ASD) is a developmental disorder defined by behavioural features that emerge during the first years of life. Research indicates that abnormalities in ...brain connectivity are associated with these behavioural features. However, inclusion of individuals past the age of onset of the defining behaviours complicates interpretation of the observed abnormalities: they may be cascade effects of earlier neuropathology and behavioural abnormalities. Our recent study of network efficiency in a cohort of 24-month-olds at high and low familial risk for ASD reduced this confound; we reported reduced network efficiencies in toddlers classified as ASD. The current study maps the emergence of these inefficiencies in the first year of life. Methods The study utilizes data from 260 infants at 6 and 12 months of age, including 116 infants with longitudinal data. As in our earlier study, we use diffusion data to obtain measures of the length and strength of connections between brain regions in order to compute network efficiency. We assess group differences in efficiency within linear mixed-effects models determined by the Akaike information criterion. Results Inefficiencies in high-risk infants later classified as ASD were detected from 6 months onward in regions involved in low-level sensory processing. Additionally, within the high-risk infants, these inefficiencies predicted 24-month symptom severity. Conclusion These results suggest that infants with ASD, even before 6 months of age, have deficits in connectivity related to low-level processing, which contribute to a developmental cascade affecting brain organization, and eventually higher-level cognitive processes and social behaviour.
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