Long-term use of proton pump inhibitors (PPIs) has been associated with a wide variety of potentially serious adverse effects including a possible increased risk of dementia. Studies evaluating this ...association have reached divergent conclusions. We aimed to evaluate this proposed association further and to assess the quality of the evidence in its support.
We searched MEDLINE, EMBASE, ISI Web of Science, and Cochrane databases for studies examining a link between PPI use and dementia, up to February 2019. Studies reporting summary results as hazard ratio (HR) or odds ratio (OR) were pooled using the DerSimonian and Laird random-effects model for meta-analyses. Methodological quality of individual observational studies was assessed using the Newcastle-Ottawa scale and the overall quality of evidence rated as per the GRADE approach.
We identified and included 11 observational studies comprising 642,949 subjects; 64% were women. Most studies were short-term ranging from 5 to 10 years. There were 158,954 PPI users and 483,995 nonusers. For studies summarizing data as adjusted HR, pooled HR for all causes of dementia was 1.10 (0.88-1.37); for Alzheimer dementia only, it was 1.06 (0.72-1.55). For studies summarizing data as adjusted OR, pooled OR for all causes of dementia was 1.03 (0.84-1.25) and for Alzheimer dementia only 0.96 (0.82-1.11). Per Newcastle-Ottawa scale assessment, 10 studies were of high quality and 1 was of moderate quality. By applying GRADE methodology, quality of evidence for both outcomes was very low.
We found no evidence to support the proposed association between PPI use and an increased risk of dementia. PPI use among patients who have a valid indication for it, should not be curtailed because of concerns about dementia risk.
Hereditary disorders are frequently caused by genetic variants that affect pre‐messenger RNA splicing. Though genetic variants in the canonical splice motifs are almost always disrupting splicing, ...the pathogenicity of variants in the noncanonical splice sites (NCSS) and deep intronic (DI) regions are difficult to predict. Multiple splice prediction tools have been developed for this purpose, with the latest tools employing deep learning algorithms. We benchmarked established and deep learning splice prediction tools on published gold standard sets of 71 NCSS and 81 DI variants in the ABCA4 gene and 61 NCSS variants in the MYBPC3 gene with functional assessment in midigene and minigene splice assays. The selection of splice prediction tools included CADD, DSSP, GeneSplicer, MaxEntScan, MMSplice, NNSPLICE, SPIDEX, SpliceAI, SpliceRover, and SpliceSiteFinder‐like. The best‐performing splice prediction tool for the different variants was SpliceRover for ABCA4 NCSS variants, SpliceAI for ABCA4 DI variants, and the Alamut 3/4 consensus approach (GeneSplicer, MaxEntScacn, NNSPLICE and SpliceSiteFinder‐like) for NCSS variants in MYBPC3 based on the area under the receiver operator curve. Overall, the performance in a real‐time clinical setting is much more modest than reported by the developers of the tools.
The choice of splice prediction tool depends on the dataset. However, deep learning tools show promising results for variants tested in midigene splice assays.
Using exome sequencing, the underlying variants in many persons with autosomal recessive diseases remain undetected. We explored autosomal recessive Stargardt disease (STGD1) as a model to identify ...the missing heritability.
Sequencing of ABCA4 was performed in 8 STGD1 cases with one variant and p.Asn1868Ile in trans, 25 cases with one variant, and 3 cases with no ABCA4 variant. The effect of intronic variants was analyzed using in vitro splice assays in HEK293T cells and patient-derived fibroblasts. Antisense oligonucleotides were used to correct splice defects.
In 24 of the probands (67%), one known and five novel deep-intronic variants were found. The five novel variants resulted in messenger RNA pseudoexon inclusions, due to strengthening of cryptic splice sites or by disrupting a splicing silencer motif. Variant c.769-784C>T showed partial insertion of a pseudoexon and was found in cis with c.5603A>T (p.Asn1868Ile), so its causal role could not be fully established. Variant c.4253+43G>A resulted in partial skipping of exon 28. Remarkably, antisense oligonucleotides targeting the aberrant splice processes resulted in (partial) correction of all splicing defects.
Our data demonstrate the importance of assessing noncoding variants in genetic diseases, and show the great potential of splice modulation therapy for deep-intronic variants.
ABCA4-associated disease, a recessive retinal dystrophy, is hallmarked by a large proportion of patients with only one pathogenic ABCA4 variant, suggestive for missing heritability.
By locus-specific ...analysis of ABCA4, combined with extensive functional studies, we aimed to unravel the missing alleles in a cohort of 67 patients (p), with one (p = 64) or no (p = 3) identified coding pathogenic variants of ABCA4.
We identified eight pathogenic (deep-)intronic ABCA4 splice variants, of which five are novel and six structural variants, four of which are novel, including two duplications. Together, these variants account for the missing alleles in 40.3% of patients. Furthermore, two novel variants with a putative cis-regulatory effect were identified. The common hypomorphic variant c.5603A>T p.(Asn1868Ile) was found as a candidate second allele in 43.3% of patients. Overall, we have elucidated the missing heritability in 83.6% of our cohort. In addition, we successfully rescued three deep-intronic variants using antisense oligonucleotide (AON)-mediated treatment in HEK 293-T cells and in patient-derived fibroblast cells.
Noncoding pathogenic variants, novel structural variants, and a common hypomorphic allele of the ABCA4 gene explain the majority of unsolved cases with ABCA4-associated disease, rendering this retinopathy a model for missing heritability in autosomal recessive disorders.
Nonalcoholic steatohepatitis (NASH) is one of the top 3 indications for liver transplantation (LT) in Western countries. It is unknown whether renal dysfunction at the time of LT has any effect on ...post‐LT outcomes in recipients with NASH. From the United Network for Organ Sharing–Standard Transplant Analysis and Research data set, we identified 4088 NASH recipients who received deceased donor LT. We divided our recipients a priori into 3 categories: group 1 with estimated glomerular filtration rate (eGFR) <30 mL/minute/1.73 m2 at the time of LT and/or received dialysis within 2 weeks preceding LT (n = 937); group 2 with recipients who had eGFR ≥30 mL/minute/1.73 m2 and who did not receive renal replacement therapy prior to LT (n = 2812); and group 3 with recipients who underwent simultaneous liver‐kidney transplantation (n = 339). We examined the association of pretransplant renal dysfunction with death with a functioning graft, all‐cause mortality, and graft loss using competing risk regression and Cox proportional hazards models. The mean ± standard deviation age of the cohort at baseline was 58 ± 8 years, 55% were male, 80% were Caucasian, and average exception Model for End‐Stage Liver Disease score was 24 ± 9. The median follow‐up period was 5 years (median, 1816 days; interquartile range, 1090‐2723 days). Compared with group 1 recipients, group 2 recipients had 19% reduced trend for risk for death with a functioning graft (subhazard ratio SHR, 0.81; 95% confidence interval CI, 0.64‐1.02) and similar risk for graft loss (SHR, 1.25; 95% CI, 0.59‐2.62), whereas group 3 recipients had similar risk for death with a functioning graft (SHR, 1.23; 95% CI, 0.96‐1.57) and graft loss (SHR, 0.18; 95% CI, 0.02‐1.37) using an adjusted competing risk regression model. In conclusion, recipients with preserved renal function before LT showed a trend toward lower risk of death with a functioning graft compared with SLKT recipients and those with pretransplant severe renal dysfunction in patients with NASH.
Risk of venous thromboembolism (VTE) in patients with inflammatory bowel disease (IBD) is well established; however, there is paucity of data on the potential added risk of VTE in patients with IBD ...with Clostridium difficile infection (CDI). We sought to study the difference in VTE rates in hospitalized patients with IBD with CDI compared to those without CDI.
We queried Nationwide Inpatient Sample from year 2011 to identify patients ≥18 years of age with a discharge diagnosis of IBD (i.e., Crohn's disease and ulcerative colitis) based on ICD-9-CM codes 555.xx and 556.xx, respectively. Patients were further divided into 2 groups: those with and without CDI. To adjust and control for potential baseline differences between groups, 1:1 propensity matching was performed. Multivariate regression analysis was used to evaluate the difference in VTE rates in 2 groups.
Of 312,147 patients with the discharge diagnosis of IBD, 12,560 (4%) had CDI. VTE was present 6% in group with CDI versus 3% in group without CDI (P < 0.001). On performing multivariate analysis after propensity-score matching, CDI was significantly associated with VTE (adjusted odds ratio 1.7, 95% confidence interval 1.4-2.2, P < 0.001). On subgroup analysis, Crohn's disease with CDI had a higher association with VTE compared with Crohn's disease only. Similarly, ulcerative colitis with CDI had a higher association with VTE compared with ulcerative colitis only.
Rate of VTE was higher in hospitalized patients with IBD with CDI compared with those without CDI, necessitating extra vigilance in this patient population.
In the current world, where diabetes is day by day becoming a very common and fatal disease, it's important that proper measures be taken in order to deal with it. As per the studies, early ...prediction of diabetes can lead to improved treatment to avoid further complications of the disease, and in order to do so efficiently, machine learning techniques are a great deal. In this study, various factors are taken into consideration, like blood pressure, pregnancy, glucose level, age, insulin, skin thickness, and diabetes pedigree function, which together can be useful to predict whether a person has a risk of developing diabetes or not and help society with the early diagnosis of diabetes. This model is trained using three main classification algorithms, namely support vector, random forest, and decision tree classifiers. The prediction results of each of the classifiers are summarized in this study, and the decision tree gives 78.89% accuracy.
This article proposes a diode-clamped resonant dc/dc converter having overload capability. The electric motor is able to demand short-time peak torque during sudden acceleration phase or long-time ...excessive torque when the automobiles are overloaded; it can also suffer from a short circuit fault of winding. Then, conventional full-bridge resonant dc/dc converters employing the secondary-side switching undergo very high current spike at the semiconductor devices on the secondary side when the load exceeds its threshold. By incorporating resonant diode-clamped cell, we have removed the high current spike occurred at the secondary-side power devices. In addition, its secondary-side switches can be completely turned off with zero-voltage-switching so that all of the active devices can be softly switched. Furthermore, the proposed converter can survive when its output nodes are short-circuited. Comparisons present the benefit of the proposed converter over conventional converters that use the secondary-side switching.
Hepatocellular carcinoma (HCC) is primary hepatic malignancy with a high incidence of recurrence. The risk of recurrence directly correlates to patient’s overall prognosis. Management of advanced HCC ...involves a combination of surgical resection, locoregional therapy, and systemic treatment. Distant metastases are rare, and intraventricular cardiac metastases are even more infrequent. This brief review details an illustrative case of cardiac metastasis after curative treatment of primary HCC and then summarizes the literature on risk factors, treatment options, and patient prognosis in the setting of distant metastases from HCC. Prognosis of metastasis to the heart is generally poor, and available evidence emphasizes the importance of maintaining regular posttreatment screening for metastases in patients with HCC. Given the variable presentation and high risk of recurrence, it is critical to have individualized multimodality treatment plans.
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