There is no consensus on the components of return-to-sport (RTS) testing following anterior cruciate ligament (ACL) reconstruction or whether passing RTS criteria can reduce a patient's risk of ...reinjury.
To determine whether impartial, criteria-based RTS decisions are associated with less risk of a second ACL injury (either graft failure or contralateral ACL injury).
In this systematic review with meta-analysis, the authors conducted an electronic literature search in PubMed/MEDLINE, Embase, CINAHL, SPORTDiscus, and ProQuest Dissertations and Theses Global using database-specific vocabulary related to ACL reconstruction and return to sport. Individual study quality was assessed using the modified Downs and Black checklist, and overall quality of evidence was determined with the Grading of Recommendations Assessment, Development and Evaluation scale. Pooled risk difference (passed versus failed RTS criteria), injury incidence proportion, and the diagnostic accuracy of each RTS criterion were calculated.
Four studies met the selection criteria. Overall, 42.7% (95% confidence interval CI: 18%, 69%) of patients passed RTS criteria, and 14.4% (95% CI: 8%, 21%) of those who passed experienced a second ACL injury (graft rupture or contralateral ACL injury). There was a nonsignificant 3% reduced risk of a second ACL injury after passing RTS criteria (risk difference, -3%; 95% CI: -16%, 10%; I
= 74%, P = .610). The evidence rating of the Grading of Recommendations Assessment, Development and Evaluation scale was "very low quality," due to imprecision and heterogeneity of the pooled risk difference estimate.
Passing RTS criteria did not show a statistically significant association with risk of a second ACL injury. The quality-of-evidence rating prevents a definitive conclusion on this question and indicates an opportunity for future research.
Prognosis, Level 2a-. J Orthop Sports Phys Ther 2019;49(2):43-54. Epub 30 Nov 2018. doi:10.2519/jospt.2019.8190.
The association between childhood diarrheal disease and linear growth faltering in developing countries is well described. However, the impact attributed to specific pathogens has not been ...elucidated, nor has the impact of recommended antibiotic treatment.
The Global Enteric Multicenter Study enrolled children with moderate to severe diarrhea (MSD) seeking healthcare at 7 sites in sub-Saharan Africa and South Asia. At enrollment, we collected stool samples to identify enteropathogens. Length/height was measured at enrollment and follow-up, approximately 60 days later, to calculate change in height-for-age z scores (ΔHAZ). The association of pathogens with ΔHAZ was tested using linear mixed effects regression models.
Among 8077 MSD cases analyzed, the proportion with stunting (HAZ below -1) increased from 59% at enrollment to 65% at follow-up (P < .0001). Pathogens significantly associated with linear growth decline included Cryptosporidium (P < .001), typical enteropathogenic Escherichia coli (P = .01), and untreated Shigella (P = .009) among infants (aged 0-11 months) and enterotoxigenic E. coli encoding heat-stable toxin (P < .001) and Cryptosporidium (P = .03) among toddlers (aged 12-23 months). Shigella-infected toddlers given antibiotics had improved linear growth (P = .02).
Linear growth faltering among children aged 0-23 months with MSD is associated with specific pathogens and can be mitigated with targeted treatment strategies, as demonstrated for Shigella.
Neurofilament light chain (NfL) is a promising biomarker of active axonal injury and neuronal degeneration. We aimed to characterise cross-sectional and longitudinal plasma NfL measurements and ...determine the age at which NfL concentrations begin to differentiate between carriers of the presenilin 1 (PSEN1) E280A (Glu280Ala) mutation and age-matched non-carriers from the Colombian autosomal dominant Alzheimer's disease kindred.
In this cross-sectional and longitudinal cohort study, members of the familial Alzheimer's disease Colombian kindred aged 8–75 years with no other neurological or health conditions were recruited from the Alzheimer's Prevention Initiative Registry at the University of Antioquia (Medellín, Colombia) between Aug 1, 1995, and Dec 15, 2018. We used a single molecule array immunoassay and log-transformed data to examine the relationship between plasma NfL concentrations and age, and establish the earliest age at which NfL concentrations begin to diverge between mutation carriers and non-carriers.
We enrolled a cohort of 1070 PSEN1 E280A mutation carriers and 1074 non-carriers with baseline assessments; of these participants, longitudinal measures (with a mean follow-up of 6 years) were available for 242 mutation carriers and 262 non-carriers. Plasma NfL measurements increased with age in both groups (p<0·0001), and began to differentiate carriers from non-carriers when aged 22 years (22 years before the estimated median age at mild cognitive impairment onset of 44 years), although the ability of plasma NfL to discriminate between carriers and non-carriers only reached high sensitivity close to the age of clinical onset.
Our findings further support the promise of plasma NfL as a biomarker of active neurodegeneration in the detection and tracking of Alzheimer's disease and the evaluation of disease-modifying therapies.
National Institute on Aging, National Institute of Neurological Disorders and Stroke, Banner Alzheimer's Foundation, COLCIENCIAS, the Torsten Söderberg Foundation, the Swedish Research Council, the Swedish Alzheimer Foundation, the Swedish Brain Foundation, and the Swedish state under the ALF-agreement.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Genome-wide association studies (GWAS) have identified many risk loci for Alzheimer's disease (AD)
, but how these loci confer AD risk is unclear. Here, we aimed to identify loci that confer AD risk ...through their effects on brain protein abundance to provide new insights into AD pathogenesis. To that end, we integrated AD GWAS results with human brain proteomes to perform a proteome-wide association study (PWAS) of AD, followed by Mendelian randomization and colocalization analysis. We identified 11 genes that are consistent with being causal in AD, acting via their cis-regulated brain protein abundance. Nine replicated in a confirmation PWAS and eight represent new AD risk genes not identified before by AD GWAS. Furthermore, we demonstrated that our results were independent of APOE e4. Together, our findings provide new insights into AD pathogenesis and promising targets for further mechanistic and therapeutic studies.
Full text
Available for:
GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
Abstract The pathophysiological process of Alzheimer’s disease (AD) is thought to begin many years before the diagnosis of AD dementia. This long “preclinical” phase of AD would provide a critical ...opportunity for therapeutic intervention; however, we need to further elucidate the link between the pathological cascade of AD and the emergence of clinical symptoms. The National Institute on Aging and the Alzheimer’s Association convened an international workgroup to review the biomarker, epidemiological, and neuropsychological evidence, and to develop recommendations to determine the factors which best predict the risk of progression from “normal” cognition to mild cognitive impairment and AD dementia. We propose a conceptual framework and operational research criteria, based on the prevailing scientific evidence to date, to test and refine these models with longitudinal clinical research studies. These recommendations are solely intended for research purposes and do not have any clinical implications at this time. It is hoped that these recommendations will provide a common rubric to advance the study of preclinical AD, and ultimately, aid the field in moving toward earlier intervention at a stage of AD when some disease-modifying therapies may be most efficacious.
Full text
Available for:
FZAB, GEOZS, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBJE, SBMB, UL, UM, UPUK
We generated an online brain pQTL resource for 7,376 proteins through the analysis of genetic and proteomic data derived from post-mortem samples of the dorsolateral prefrontal cortex of 330 older ...adults. The identified pQTLs tend to be non-synonymous variation, are over-represented among variants associated with brain diseases, and replicate well (77%) in an independent brain dataset. Comparison to a large study of brain eQTLs revealed that about 75% of pQTLs are also eQTLs. In contrast, about 40% of eQTLs were identified as pQTLs. These results are consistent with lower pQTL mapping power and greater evolutionary constraint on protein abundance. The latter is additionally supported by observations of pQTLs with large effects’ tending to be rare, deleterious, and associated with proteins that have evidence for fewer protein-protein interactions. Mediation analyses using matched transcriptomic and proteomic data provided additional evidence that pQTL effects are often, but not always, mediated by mRNA. Specifically, we identified roughly 1.6 times more mRNA-mediated pQTLs than mRNA-independent pQTLs (550 versus 341). Our pQTL resource provides insight into the functional consequences of genetic variation in the human brain and a basis for novel investigations of genetics and disease.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The purpose of our study was to determine radiation dose to the fetus at early gestation when contemporary MDCT scanners are used for common clinical indications.
Anthropomorphic phantoms were ...constructed to reflect a pregnant woman. Thermoluminescence dosimeters (TLDs) and metal oxide semiconductor field effect transistor (MOSFET) detectors were placed in appropriate locations to determine real-time radiation exposure to the fetus at 0 and 3 months' gestation. Imaging was performed on a 16-MDCT scanner using current institutional CT protocols: renal stone (140 kVp, 160 mA, rotation time of 0.5 sec, 16 x 0.625 mm), appendix (140 kVp, 340 mA, rotation time of 0.5 sec, 16 x 0.625 mm), and pulmonary embolus (140 kVp, 380 mA, rotation time of 0.8 sec, 16 x 1.25 mm).
The radiation dose to the fetus at 0 and 3 months, respectively, was as follows: renal stone protocol, 0.8-1.2 and 0.4-0.7 cGy; appendix protocol, 1.52-1.68 and 2-4 cGy; and pulmonary embolus protocol, 0.024-0.047 and 0.061-0.066 cGy.
Radiation doses to the fetus from institutional MDCT protocols that may be used during pregnancy (for pulmonary embolus, appendicitis, and renal colic) are below the level thought to induce neurologic detriment to the fetus. Imaging the mother for appendicitis theoretically may double the fetal risk for developing a childhood cancer. Radiation doses to the fetus from pulmonary embolus chest CT angiography are of the same magnitude as ventilation-perfusion (V/Q) scanning.
Each additional copy of the apolipoprotein E4 (APOE4) allele is associated with a higher risk of Alzheimer's dementia, while the APOE2 allele is associated with a lower risk of Alzheimer's dementia, ...it is not yet known whether APOE2 homozygotes have a particularly low risk. We generated Alzheimer's dementia odds ratios and other findings in more than 5,000 clinically characterized and neuropathologically characterized Alzheimer's dementia cases and controls. APOE2/2 was associated with a low Alzheimer's dementia odds ratios compared to APOE2/3 and 3/3, and an exceptionally low odds ratio compared to APOE4/4, and the impact of APOE2 and APOE4 gene dose was significantly greater in the neuropathologically confirmed group than in more than 24,000 neuropathologically unconfirmed cases and controls. Finding and targeting the factors by which APOE and its variants influence Alzheimer's disease could have a major impact on the understanding, treatment and prevention of the disease.
Revised diagnostic criteria for Alzheimer disease (AD) acknowledge a key role of imaging biomarkers for early diagnosis. Diagnostic accuracy depends on which marker (i.e., amyloid imaging, ...F-fluorodeoxyglucose FDG-PET, SPECT, MRI) as well as how it is measured (“metric”visual, manual, semiautomated, or automated segmentation/computation). We evaluated diagnostic accuracy of marker vs metric in separating AD from healthy and prognostic accuracy to predict progression in mild cognitive impairment. The outcome measure was positive (negative) likelihood ratio, LR+ (LR−), defined as the ratio between the probability of positive (negative) test outcome in patients and the probability of positive (negative) test outcome in healthy controls. Diagnostic LR+ of markers was between 4.4 and 9.4 and LR− between 0.25 and 0.08, whereas prognostic LR+ and LR− were between 1.7 and 7.5, and 0.50 and 0.11, respectively. Within metrics, LRs varied up to 100-foldLR+ from approximately 1 to 100; LR− from approximately 1.00 to 0.01. Markers accounted for 11% and 18% of diagnostic and prognostic variance of LR+ and 16% and 24% of LR−. Across all markers, metrics accounted for an equal or larger amount of variance than markers13% and 62% of diagnostic and prognostic variance of LR+, and 29% and 18% of LR−. Within markers, the largest proportion of diagnostic LR+ and LR− variability was within F-FDG-PET and MRI metrics, respectively. Diagnostic and prognostic accuracy of imaging AD biomarkers is at least as dependent on how the biomarker is measured as on the biomarker itself. Standard operating procedures are key to biomarker use in the clinical routine and drug trials.
OBJECTIVE: It is well established that regional cerebral metabolic rates for glucose assessed by 18Ffluorodeoxyglucose (FDG) positron emission tomography (PET) in patients with Alzheimer's disease in ...the mental resting state (eyes and ears covered) provide a sensitive, in vivo metabolic index of Alzheimer's disease dementia. Few studies, however, have evaluated longitudinal declines in regional cerebral glucose metabolism in patients with dementia caused by Alzheimer's disease. In addition, the available studies have not used recently developed brain mapping algorithms to characterize the progression of Alzheimer's disease throughout the brain, and none considered the statistical power of regional cerebral glucose metabolism in testing the ability of treatments to attenuate the progression of dementia. METHOD: The authors used FDG PET and a brain mapping algorithm to investigate cross-sectional reductions in regional cerebral glucose metabolism, longitudinal decline in regional cerebral glucose metabolism after a 1-year follow-up, and the power of this method to evaluate treatments for Alzheimer's disease in patients with mild to moderate dementia. PET scans were initially acquired in 14 patients with Alzheimer's disease and 34 healthy comparison subjects of similar age and sex. Repeat scans were obtained in the patients 1 year later. Power analyses for voxels showing maximal decline over the 1-year period in regional cerebral glucose metabolism (mg 100 g per minute) were computed to estimate the sample sizes needed to detect a significant treatment response in a 1-year, double-blind, placebo-controlled treatment study. RESULTS: The patients with Alzheimer's disease had significantly lower glucose metabolism than healthy comparison subjects in parietal, temporal, occipital, frontal, and posterior cingulate cortices. One year later, the patients with Alzheimer's disease had significant declines in glucose metabolism in parietal, temporal, frontal, and posterior cingulate cortices. Using maximal glucose metabolism reductions in the left frontal cortex, we estimated that as few as 36 patients per group would be needed to detect a 33% treatment response with one-tailed significance of p≤0.005 and 80% power in a 1-year, double-blind, placebo-controlled treatment study. CONCLUSIONS: These findings indicate that brain metabolism as assessed by FDG PET during mental rest is a sensitive marker of disease progression in Alzheimer's disease over a 1-year period. These findings also support the feasibility of using FDG PET as an outcome measure to test the ability of treatments to attenuate the progression of Alzheimer's disease.
PDF
