Atypical Brain Aging and Its Association With Working Memory Performance in Major Depressive Disorder.

BACKGROUND: Patients with major depressive disorder (MDD) can present with altered brain structure and deficits in cognitive function similar to those seen in aging. However, the interaction between age-related brain changes and brain development in MDD remains understudied. In a cohort of adolescents and adults with and without MDD, we assessed brain aging differences and associations through a newly developed tool that quantifies normative neurodevelopmental trajectories. METHODS: A total of 304 participants with MDD and 236 control participants without depression were recruited and scanned from 3 studies under the Canadian Biomarker Integration Network for Depression. Volumetric data were used to generate brain centile scores, which were examined for 1) differences between participants with MDD and control participants; 2) differences between individuals with versus without severe childhood maltreatment; and 3) correlations with depressive symptom severity, neurocognitive assessment domains, and escitalopram treatment response. RESULTS: Brain centiles were significantly lower in the MDD group than in the control group. Brain centile was also significantly correlated with working memory in the control group but not the MDD group. No significant associations were observed between depression severity or antidepressant treatment response and brain centiles. Likewise, childhood maltreatment history did not significantly affect brain centiles. CONCLUSIONS: Consistent with previous work on machine learning models that predict brain age, brain centile scores differed in people diagnosed with MDD, and MDD was associated with differential relationships between centile scores and working memory. The results support the notion of atypical development and aging in MDD, with implications for neurocognitive deficits associated with aging-related cognitive function.

Considerations when asking about "disability" in disability inclusive research.

PURPOSE: There are several ways to include "disability" in research studies, which can be confusing or overwhelming for researchers, community members, and students. The aim of this paper is to share conceptualizations of disability and how to ask about "disability" in research studies. The paper provides a general introduction and brief analysis of the methodological approaches which can be used. METHODS: We used reviews of the literature and extensive discussions to identify key articles, books, websites, and reports that provide guidance and examples of asking about disability in research. RESULTS: Four primary approaches to asking study participants about disability were identified. For each of these, we provide background information, key points about the ways to use the approach including tools that have been developed, and example studies. A comparison table provides a high-level overview of similarities and differences in approaches. Other approaches and tools were also identified and are briefly described. CONCLUSION: Researchers involved in disability and rehabilitation research should be aware that there is not one best or singular way to ask about disability when conducting research. The approach or approaches chosen for a particular study need to match the purpose of the study. It is important that researchers take time to carefully consider their options and choose the best fit for their study.

There are several different ways to ask about disability and functioning when conducting research that aims to include a disability component or focus.Researchers need to carefully select the best option(s) for their study.Whenever possible, researchers should use more than one approach and should allow for more than one type of disability or impairment to be selected.Researchers often require training to understand how to include disability in research.Allow adequate time and resources for training research team members so that the tools are implemented correctly.

QTc interval prolongation independently associates with FGF23 and predicts mortality in predialysis CKD.

INTRODUCTION: QTc interval prolongation is increasingly frequent as CKD advances and predicts death in dialysis. However, predictors and mortality-risk in predialysis CKD are understudied. FGF23 induces left ventricular hypertrophy (LVH) which is associated with QTc interval prolongation and death, suggesting a possible pathway from FGF23 to death that entails LVH and QTc prolongation. We looked for links between FGF23 and prolonged QTc intervals mediated by LVH, and for deaths associated with QTc prolongation in a prospective observational cohort of patients with predialysis CKD. METHODS: Participants underwent protocolized baseline and semi-annual FGF23 testing, baseline and study end echocardiograms, and baseline and annual electrocardiograms over three years. RESULTS: 2,254 participants (34.1% female; mean age 68.7 years; mean glomerular filtration rate 41.4 ml/min/m2) enrolled. Baseline LVH (left ventricular mass index >131 g/m2 (>100 g/m2 if female)) was present in 10.8% and prolonged QTc intervals (>=500 ms) in 1.5%. One hundred thirty-eight (6.1%) participants died during the study. In generalized mixed effects regression, each unit increase in the natural log of FGF23 - but not LVH - predicted an odds ratio of 1.76 (1.15, 2.70, p=0.009) for prolonged QTc intervals independently of 15 other covariates. Mediation analysis showed that only 13% of FGF23's total effect on prolonged QTc intervals was mediated by LVH. Patients with prolonged QTc intervals had higher unadjusted (log rank p<0.001) and adjusted (hazard ratio 3.15 (1.38, 7.16, p=0.006)) mortality rates than those with QTc intervals <500 ms. CONCLUSIONS: QTc interval prolongation ≥500 ms was prospectively associated with FGF23 independently of LVH, and with a tripling of mortality-risk in patients with predialysis CKD.

The landscape of human SVA retrotransposons.

SINE-VNTR-Alu (SVA) retrotransposons are evolutionarily young and still-active transposable elements (TEs) in the human genome. Several pathogenic SVA insertions have been identified that directly mutate host genes to cause neurodegenerative and other types of diseases. However, due to their sequence heterogeneity and complex structures as well as limitations in sequencing techniques and analysis, SVA insertions have been less well studied compared to other mobile element insertions. Here, we identified polymorphic SVA insertions from 3646 whole-genome sequencing (WGS) samples of >150 diverse populations and constructed a polymorphic SVA insertion reference catalog. Using 20 long-read samples, we also assembled reference and polymorphic SVA sequences and characterized the internal hexamer/variable-number-tandem-repeat (VNTR) expansions as well as differing SVA activity for SVA subfamilies and human populations. In addition, we developed a module to annotate both reference and polymorphic SVA copies. By characterizing the landscape of both reference and polymorphic SVA retrotransposons, our study enables more accurate genotyping of these elements and facilitate the discovery of pathogenic SVA insertions.

Quantitative lateral flow immunoassay for rapid detection of procollagen type I N-terminal propeptide in the monitoring of osteoporosis treatment.

Appropriate follow-up after treatment initiation in patients with osteoporosis is challenging. Serum biomarkers may offer more efficient monitoring of bone mineral density (BMD) than the currently used dual X-ray absorptiometry; however, significant changes in BMD often occur over at least 12 months. During teriparatide treatment for osteoporosis, monitoring with markers such as procollagen type I propeptide (PINP), which is derived from osteoblasts, can provide clinically useful information for disease management. However, rapid and cost-effective methods for detecting serum PINP are lacking, necessitating a point-of-care test (POCT) for enhanced follow-up efficiency in osteoporosis management. For the quantitative detection of PINP, we developed a high-sensitivity lateral flow immunoassay with a stacking pad (sLFIA). We established a calibration equation based on the test line/control line ratio obtained from our PINP sLFIA results of various nonspiked serum samples to calculate the PINP concentrations in 40 serum samples and compared the result with those obtained using a fully automated electrochemiluminescence immunoassay. PINP concentrations between these two methods exhibited excellent correlation (R = 0.991). In addition, we assessed the serum PINP concentrations of patients with osteoporosis treated with teriparatide. At the 3-month follow-up, their PINP levels were nearly twice as high as those at baseline, thus implying that our method can be used for osteoporosis treatment monitoring. Our findings thus indicate that the PINP sLFIA can serve as a POCT for monitoring medication response and managing osteoporosis.

Gray matter volume drives the brain age gap in schizophrenia: a SHAP study.

Neuroimaging-based brain age is a biomarker that is generated by machine learning (ML) predictions. The brain age gap (BAG) is typically defined as the difference between the predicted brain age and chronological age. Studies have consistently reported a positive BAG in individuals with schizophrenia (SCZ). However, there is little understanding of which specific factors drive the ML-based brain age predictions, leading to limited biological interpretations of the BAG. We gathered data from three publicly available databases - COBRE, MCIC, and UCLA - and an additional dataset (TOPSY) of early-stage schizophrenia (82.5% untreated first-episode sample) and calculated brain age with pre-trained gradient-boosted trees. Then, we applied SHapley Additive Explanations (SHAP) to identify which brain features influence brain age predictions. We investigated the interaction between the SHAP score for each feature and group as a function of the BAG. These analyses identified total gray matter volume (group × SHAP interaction term ß = 1.71 [0.53; 3.23]; pcorr < 0.03) as the feature that influences the BAG observed in SCZ among the brain features that are most predictive of brain age. Other brain features also presented differences in SHAP values between SCZ and HC, but they were not significantly associated with the BAG. We compared the findings with a non-psychotic depression dataset (CAN-BIND), where the interaction was not significant. This study has important implications for the understanding of brain age prediction models and the BAG in SCZ and, potentially, in other psychiatric disorders.

Quantitative lateral flow immunoassay for rapid detection and monitoring of cerebrospinal fluid leakage following incidental durotomy.

Cerebrospinal fluid (CSF) leakage due to incidental durotomy is an inherent complication of spine surgery. With appropriate treatment, complications of CSF leakage, such as headache and even meningitis, can be reduced. CSF leakage could be detected on the basis of correlated clinical symptoms; diagnosis should be based on these symptoms and appropriate imaging studies. However, the diagnosis of CSF leakage remains a challenge, especially if incidental durotomy is unrecognized during surgery; even if incidental durotomy is detected and repaired intraoperatively, the severity of the leakage and quality of the primary dural repair are difficult to evaluate postoperatively. Rapid, inexpensive, and safe methods of detecting CSF-containing samples are currently lacking; hence, the development of a point-of-care test (POCT) method to improve diagnostic efficiency is necessary. We developed a high-sensitivity lateral flow immunoassay with a stacking pad (sLFIA) for quantitative detection of ß-trace protein (BTP), a specific CSF marker. The BTP concentration in 39 clinical samples was calculated using a calibration equation for test-line intensity and evaluated by a standard laboratory method. To avoid the hook effect, we diluted each sample prior to testing. The correlation coefficient between the enzyme-linked immunosorbent assay and our BTP sLFIA method was 0.991 A 75-fold sample dilution was applied owing to the hook effect point, identified as 175 ng mL-1. We established an optimal sample-specific cutoff point at a value of 4.0 µg mL-1 for CSF leakage in subfascial drainage samples following spinal posterior decompression. The sensitivity and specificity of the BTP sLFIA method were 90% and 97%, respectively, according to a receiver operating characteristic curve analysis. In addition, clinical samples from patients who underwent primary dural repair intraoperatively were tested, and CSF leakage was successfully diagnosed using our method. Finally, the quantitation of BTP in samples collected daily provided an accurate assessment of the severity of the residual leakage. Our results demonstrate that the BTP sLFIA method possesses the potential to serve as a POCT method for screening and monitoring postoperative CSF leakage.

Smartphone-assisted fluorescent analysis of polyT-Cu-nanoprobes using nucleic acid amplification test for the diagnosis of tuberculosis.

Tuberculosis is one of devastating infectious diseases in the world, and early diagnosis and treatment can help overcome this global burden. In this work, a new detection platform combining smartphone-assisted fluorescent analysis and highly sensitive fluorescent copper nanoprobes (CuNPs) in a specific nucleic acid amplification test (NAAT) for the diagnosis of tuberculosis (TB) was demonstrated and validated using clinical samples. To enhance the precision and accuracy of detection, polymerase chain reaction (PCR), padlock probe (PLP) ligation, and rolling circle amplification (RCA) were combined. Long poly(thymine) (polyT) single-stranded DNA was synthesized through RCA, and polyT-CuNPs were formed by adding copper(II) ions and sodium ascorbate as reducing agents; subsequently, the results were visualized through the excitation from a UV transilluminator and quantified with just a smartphone. After optimization, this proposed platform was validated by testing 18 residual DNA samples after TB PCR, including 8 TB-negative and 10 TB-positive samples, and exhibited a detection limit of 5 fg/µL. The findings indicate the potential of this platform for practical application, where it can be combined with a smartphone for image analysis to achieve accurate on-site detection of TB, especially in resource-limited settings.

Assessment of Pericardial Disease with Cardiovascular MRI.

Disorders of the pericardium are common and can result in significant morbidity and mortality. Advances in multimodality imaging have enhanced our ability to diagnose and stage pericardial disease and improve our understanding of the pathophysiology of the disease. Cardiovascular MRI (CMR) can be used to define pericardial anatomy, identify the presence and extent of active pericardial inflammation, and assess the hemodynamic consequences of pericardial disease. In this way, CMR can guide the judicial use of antiinflammatory and immune modulatory medications and help with timing of pericardiectomy. CMR can also be used to diagnose congenital disorders of the pericardium. Furthermore, CMR can be used to define pericardial masses and understand their malignant potential.

Development of a multiplex and sensitive lateral flow immunoassay for the diagnosis of periprosthetic joint infection.

The diagnosis of periprosthetic joint infection (PJI) remains a challenge. However, recent studies showed that synovial fluid biomarkers have demonstrated greater diagnostic accuracy than the currently used PJI diagnostic tests. In many diagnostic tests, combining several biomarkers into panels is critical for improving diagnostic efficiency, enhancing the diagnostic precision for specific diseases, and reducing cost. In this study, we prove that combining alpha-defensin and C-reactive protein (CRP) as biomarkers possesses the potential to provide accurate PJI diagnosis. To further verify the result, we developed a multi-target lateral flow immunoassay strip (msLFIA) with staking pad design to obtain on-site rapid response for clinical diagnosis of PJI. A total of 10 synovial fluid samples were tested using the msLFIA, and the results showed that the combined measurements of synovial fluid alpha-defensin and CRP levels were consistent with those obtained from a commercial enzyme-linked immunosorbent assay kit. In addition, we developed a multi-target lateral flow immunoassay strip (msLFIA) with staking pad design to obtain on-site rapid response for clinical diagnosis of PJI, which the multi-target design is used to increase specificity and the stacking pad design is to enhance detection sensitivity. As a result, the turnaround time of the highly sensitive test can be limited from several hours to 20 min. We expect that the developed msLFIA possesses the potential for routine monitoring of PJI as a convenient, low-cost, rapid and easy to use detection device for PJI.

Fluorescent Double-Stranded DNA-Templated Copper Nanoprobes for Rapid Diagnosis of Tuberculosis.

In this work, we investigate highly sensitive fluorescent Cu nanoparticles for use as rapid and specific nucleic acid amplification nanoprobes (NPs) for the diagnosis of tuberculosis. After applying polymerase chain reaction (PCR) to a tuberculosis (TB) sample, we demonstrate that the presence of the targeted IS6110 DNA sequence of TB can be easily and directly detected through the in situ formation of DNA-templated fluorescent Cu NPs and subsequently quantified using only a smartphone. Compared to traditional DNA analysis, this sensing platform does not require purification steps and eliminates the need for electrophoresis to confirm the PCR results. After optimization, this dsDNA-Cu NP-PCR method has the ability to analyze clinical TB nucleic acid samples at a detection limit of 5 fg/µL, and the fluorescent signal can be distinguished in only ∼3 min after the DNA has been amplified. Moreover, with the combination of smartphone-assisted imaging analysis, we can further reduce the instrument size/cost and enhance the portability. In this manner, we are able to eliminate the need for a fluorescent spectrophotometer to measure the clinical sample. These results demonstrate this platform's practical applicability, combining a smartphone and on-site analysis while retaining the detection performance, making it suitable for clinical DNA applications in resource-limited regions of the world.

Development a stacking pad design for enhancing the sensitivity of lateral flow immunoassay.

Lateral flow immunoassays (LFIAs) have wide application in point-of-care testing, particularly in resource-poor settings. To achieve signal amplification in a gold nanoparticle-based lateral flow assay without an additional procedure or the need for complex fabrication, a new and simple method was developed for using a "stacking pad" configuration that adds an additional membrane between the conjugation pad and test pad to the conventional AuNP-based LFIA format. This design helps to accumulate the antibody and antigen on the stacking pad, hence extending the antigen/antibody binding interactions to enhance the test's detection sensitivity. With the enhanced lateral flow assay, as low as 1 ng/mL of Protein A and 15.5 ng/mL of C-reactive protein can be visualized with the naked eye. We also successfully applied the stacking pad system in the analysis of C-reactive protein in human serum and synovial fluid samples. These results suggest that this stacking pad LFIA can provide sensitive and on-site prognosis for detection in synovial fluid and serum samples in resource-limited settings.

Transcatheter Mitral Valve Implantation in Degenerated Bioprosthetic Valves.

The use of bioprosthetic valves for mitral valve disease has been increasingly popular with both patients and physicians, and current practice uses these valves for increasingly younger patients. However, these valves are known to degenerate over time. Historically, reoperation was the only recourse for a failing bioprosthetic valve. Today, however, percutaneous options exist with the use of transcatheter valve implantation. Determining candidacy for this less invasive option requires careful evaluation with echocardiography. This review is focused on the echocardiographic evaluation required pre-, intra-, and postprocedurally during transcatheter mitral valve insertion.

Postural Tachycardia Syndrome and Vasovagal Syncope: A Hidden Case of Obstructive Cardiomyopathy without Severe Septal Hypertrophy.

A 36-year-old female with symptoms of orthostatic intolerance and syncope was diagnosed with vasovagal syncope on a tilt table test and with postural tachycardia syndrome (POTS) after a repeat tilt table test. However, an echocardiogram at our institution revealed obstructive cardiomyopathy without severe septal hypertrophy, with a striking increase in left ventricular outflow tract gradient from 7 mmHg at rest to 75 mmHg during Valsalva, with a septal thickness of only 1.3 cm. Cardiac MRI showed an apically displaced multiheaded posteromedial papillary muscle with suggestion of aberrant chordal attachments to the anterior mitral leaflet contributing to systolic anterior motion of the mitral valve. She underwent surgery with reorientation of the posterior medial papillary muscle head, resection of the tethering secondary chordae to the A1 segment of the mitral valve, chordal shortening and tacking of the chordae to the A1 and A2 segments of the mitral valve, and gentle septal myectomy. After surgery, she had significant improvement in her prior symptoms. To our knowledge, this is the first reported case of obstructive cardiomyopathy without severe septal hypertrophy with abnormalities in papillary muscle and chordal attachment, in a patient diagnosed with vasovagal syncope and POTS.

The unresolved problem of beta-2 microglobulin amyloid deposits in the intervertebral discs of long-term dialysis patients.

BACKGROUND: Dialysis-related destructive spondyloarthropathy caused by beta-2 microglobulin (ß2M) amyloid deposits in intervertebral discs is a major burden for patients undergoing long-term dialysis. This study aimed to quantify the presence of ß2M amyloid deposits in the intervertebral disc tissue of such patients and analyze whether there was a significant correlation between ß2M accumulation and the duration of dialysis. METHODS: Two groups of patients who had undergone surgery for degenerative spinal pathologies were selected: the dialysis group (n = 29) with long-term dialysis and the control group (n = 10) with no renal impairment. Tissue sections were prepared from specimens of intervertebral disc tissue obtained during spinal surgery and analyzed via histological staining, including immunohistochemistry (IHC) and Congo red. RESULTS: There was a statistically significant multifold increase of ß2M expression in the disc tissue of long-term dialysis patients when compared to non-dialysis patients, as shown by both IHC (0.019 ± 0.023 µm2 vs. 0.00020 ± 0.00033 µm2, respectively; p = 0.012) and Congo red staining (0.027 ± 0.041 µm2 vs. 9.240 × 10-5 ± 5.261 × 10-5 µm2, respectively; p = 0.047). We also note a moderate strength positive correlation between the duration of dialysis and positive IHC (r = 0.39; p = 0.015) and Congo-red staining (r = 0.42; p = 0.007). CONCLUSIONS: The problem of ß2M amyloidosis in long-term dialysis patients remains unresolved even with predominant use of high-flux dialysis membranes. This highlights the insufficiency of current dialysis modalities to effectively filter ß2M.

Thoracic aortic aneurysms: state of the art and current controversies.

INTRODUCTION: Complications of thoracic aortic aneurysms (TAA), including aortic rupture and dissection, are often catastrophic and prophylactic intervention can be lifesaving. Controversies exist regarding the standardization of aortic imaging techniques, the best metric for assessing aortic risk and the optimal threshold for intervention. Areas covered: This review summarizes recent temporal trends in TAA disease, provides an overview of the role of multi-modality imaging in diagnosis of the disease, and reviews controversies around surgical thresholds for intervention and medical therapies in the management of TAA disease. Expert commentary: While death from TAA appears to be declining, it remains an important cause of morbidity and mortality. Multi-modality imaging has revolutionized the diagnosis and follow up of TAAs but knowledge of the nuances of how images are acquired and measurements made are important. Emerging evidence suggests that the cross sectional area to height ratio may be a better measure of aortic risk, especially in those who do not meet current surgical thresholds. The use of medications to delay disease progression is controversial, but given the overall good safety profile of medications such as beta-blockers and angiotensin receptor blockers, they should be considered in all patients with TAA disease.