Integrating cardiovascular risk assessment into mobile low-dose CT lung screenings in rural Appalachia: A comprehensive analysis of the relationship between lung cancer risk, coronary artery calcium burden, and cardiovascular risk reduction strategies.

Objective: Mobile low-dose computed tomography (LDCT) lung screenings are part of an outreach program in rural Appalachia to detect early lung cancer. Coronary artery calcium (CAC) scoring on LDCT can identify calcium deposits in coronary arteries and can prompt consideration of risk modification for prevention of cardiovascular disease (CVD) events. It is not known if Lung CT Screening Reporting & Data System (Lung-RADS) scoring correlates with CAC scores. There is no clear guidance for patients undergoing LDCT screenings to receive follow-up regarding CAC or prevention of associated CVD risk. Methods: This was a retrospective review of mobile LDCT LCS in adults with no known history of CVD. CT images were obtained at 100 kVp with a slice thickness of 3 mm. Agatston CAC scoring was performed retroactively. Lung-RADS scores were categorized as: Negative (1), Benign (2), Probably Benign (3), and Suspicious (4). CAC scoring was grouped as 0, 1-100, 101-399, and ≥400. Descriptive statistics and chi-square analyses were utilized. Results: A total of 526 LDCT screenings were included. Over 54 % of patients had coronary calcification on LDCT LCS. 161 patients (30.6 %) had a CAC score of ≥100 and 75 patients (14.3 %) had a CAC score ≥400. Of patients with a CAC score ≥100, 7.5 % received referrals for follow-up after the LDCT screen and 9.3 % had additional cardiac testing. Of those with a CAC score ≥100 not already on a statin (45.3 %) and not already on aspirin (63.3 %), few were started within 3 months of LDCT for prevention (8.2 % and 5.9 % respectively). Among patients with a Lung-RADS score of 4, 17 % had a CAC score >400, whereas only 12 % with a Lung-RADS score of 1 fell into the same CAC category. Higher Lung-RADS scores correlated with fewer patients with CAC of 0. A significant correlation was observed between higher Lung-RADS scores and elevated CAC scores (p = 0.02). Conclusion: In patients with no CVD history, coronary artery calcification was frequently identified on mobile LDCT lung screenings in rural communities. Patients with higher probabilities of malignant lung nodules may also be at increased risk for significant coronary artery disease. Calcium scoring from LDCT screenings allowed for simultaneous assessment of lung cancer and CVD risk. Unfortunately, few referrals or CVD prevention medications were initiated. Awareness of CAC score utility, follow-up for identified coronary calcifications, and consideration of primary prevention medications when indicated, would be beneficial in patients undergoing LDCT lung screenings, especially in rural areas with limited healthcare access.

Kismet/CHD7/CHD8 and Amyloid Precursor Protein-like Regulate Synaptic Levels of Rab11 at the Drosophila Neuromuscular Junction.

The transmembrane protein ß-amyloid precursor protein (APP) is central to the pathophysiology of Alzheimer's disease (AD). The ß-amyloid hypothesis posits that aberrant processing of APP forms neurotoxic ß-amyloid aggregates, which lead to the cognitive impairments observed in AD. Although numerous additional factors contribute to AD, there is a need to better understand the synaptic function of APP. We have found that Drosophila APP-like (APPL) has both shared and non-shared roles at the synapse with Kismet (Kis), a chromatin helicase binding domain (CHD) protein. Kis is the homolog of CHD7 and CHD8, both of which are implicated in neurodevelopmental disorders including CHARGE Syndrome and autism spectrum disorders, respectively. Loss of function mutations in kis and animals expressing human APP and BACE in their central nervous system show reductions in the glutamate receptor subunit, GluRIIC, the GTPase Rab11, and the bone morphogenetic protein (BMP), pMad, at the Drosophila larval neuromuscular junction (NMJ). Similarly, processes like endocytosis, larval locomotion, and neurotransmission are deficient in these animals. Our pharmacological and epistasis experiments indicate that there is a functional relationship between Kis and APPL, but Kis does not regulate appl expression at the larval NMJ. Instead, Kis likely influences the synaptic localization of APPL, possibly by promoting rab11 transcription. These data identify a potential mechanistic connection between chromatin remodeling proteins and aberrant synaptic function in AD.

Impact of frailty in hospitalized patients undergoing catheter ablation for atrial fibrillation.

BACKGROUND: Catheter Ablation (CA) is an effective treatment for atrial fibrillation (AF). However, frail elderly patients have been understudied due to their exclusion from landmark trials. OBJECTIVES: Our study aims to evaluate outcomes in this population. METHODS: The national readmission database (2016-2020) was queried, and frailty categories were defined based on hospital risk frailty scores ≦5 as low while >5 as intermediate/high frailty (IHF). We used multivariate regression and propensity-matched analysis to compare outcomes in patients undergoing CA for atrial fibrillation based on frailty index. RESULTS: Among 55 936 CAs for AF, 33,248 patients had low frailty, while 22 688 had intermediate/high frailty (IHF). After propensity matching (N 12 448), IHF patients were found to have higher adverse events, including mortality (3% vs. 0.3%, p < .001), stroke (1.9% vs. 0.2%, p < .001), acute heart failure (53.8% vs. 42.2%, p < .001), AKI (42.5% vs. 6.8%, p < .001), pericardial complications (2.8 vs. 1.6%, p < .001), respiratory complications (27.8 vs. 7.2%, p < .001), major adverse cardiovascular events (21.2 vs. 9.4%, p < .001) and net adverse events (76.7 vs. 55%, p < .001). IHF patients had higher readmissions at 30 (15.5 vs. 12.6%, p < .001), 90 (31.9 vs. 25.1%, p < .001), and 180-day (41 vs. 34.7%, p < .001) intervals. A higher median length of stay (LOS) (7 vs. 3 days, p < .001) and cost ($44 287 vs. $27 517, p < .001) at index admission and subsequent readmissions were also observed (p < .001). CONCLUSION: Intermediate/high frailty patients undergoing catheter ablation had worse clinical outcomes, higher healthcare burden, and readmission rates. LOS has decreased in both groups from 2016 to 2020; however, total cost has increased.

Townes-Brocks Syndrome Revealed by Kidney Gene Panel Testing.

Introduction: Townes-Brocks syndrome (TBS), a rare autosomal dominant genetic condition associated with SALL1 (Spalt like Transcription Factor 1), is reported to be present in 1:238,000 individuals in the general population. TBS is characterized by the triad of anorectal malformations, dysplastic ears, with or without hearing impairment, and hand or thumb anomalies. Although kidney involvement is less common in TBS, the disease can progress to kidney failure. Here, we sought to characterize the incidence of SALL1 variants in individuals undergoing broad-based genetic testing with a kidney gene panel and to quantify the presence of (extra)renal features. Methods: A retrospective analysis of the genetic data from a 385-gene panel identified cases with a pathogenic (P) or likely pathogenic (LP) variant in SALL1. Data including age, features, and disease progression were collected. Results: Of 35,044 samples, P or LP variants in SALL1 were identified in 22, yielding a prevalence of 1:1592 among patients tested for monogenic kidney disease, and 1:342 among cases identified with a monogenic kidney disease. Among this cohort, the median patient age was 23 years (range: 3 months-62 years) with chronic kidney disease (CKD) reported in 91% (20/22) of cases. Reported kidney features included renal agenesis/hypoplasia (7/22; 32%), focal segmental glomerulosclerosis (4/22; 18%), and kidney cysts (3/22; 14%). Confirmed extrarenal features included hearing loss and/or ear features (7/22; 32%), anorectal malformations (6/22; 27%) and hand or thumb abnormalities (4/22; 18%). Three patients (3/22; 14%) had both a priori TBS diagnoses and the traditional "triad." Conclusion: Traditionally, a molecular diagnosis was ascertained primarily in individuals presenting with cardinal features of TBS; therefore, individuals with mild or atypical presentations were often overlooked clinically. Our findings reveal that SALL1 P/LP variants could be a consequential contributor to monogenic kidney disease.

The CHD family chromatin remodeling enzyme, Kismet, promotes both clathrin-mediated and activity-dependent bulk endocytosis.

Chromodomain helicase DNA binding domain (CHD) proteins, including CHD7 and CHD8, remodel chromatin to enable transcriptional programs. Both proteins are important for proper neural development as heterozygous mutations in Chd7 and Chd8 are causative for CHARGE syndrome and correlated with autism spectrum disorders, respectively. Their roles in mature neurons are poorly understood despite influencing the expression of genes required for cell adhesion, neurotransmission, and synaptic plasticity. The Drosophila homolog of CHD7 and CHD8, Kismet (Kis), promotes neurotransmission, endocytosis, and larval locomotion. Endocytosis is essential in neurons for replenishing synaptic vesicles, maintaining protein localization, and preserving the size and composition of the presynaptic membrane. Several forms of endocytosis have been identified including clathrin-mediated endocytosis, which is coupled with neural activity and is the most prevalent form of synaptic endocytosis, and activity-dependent bulk endocytosis, which occurs during periods of intense stimulation. Kis modulates the expression of gene products involved in endocytosis including promoting shaggy/GSK3ß expression while restricting PI3K92E. kis mutants electrophysiologically phenocopy a liquid facets mutant in response to paradigms that induce clathrin-mediated endocytosis and activity-dependent bulk endocytosis. Further, kis mutants do not show further reductions in endocytosis when activity-dependent bulk endocytosis or clathrin-mediated endocytosis are pharmacologically inhibited. We find that Kis is important in postsynaptic muscle for proper endocytosis but the ATPase domain of Kis is dispensable for endocytosis. Collectively, our data indicate that Kis promotes both clathrin-mediated endocytosis and activity-dependent bulk endocytosis possibly by promoting transcription of several endocytic genes and maintaining the size of the synaptic vesicle pool.

The CHD Protein Kismet Restricts the Synaptic Localization of Cell Adhesion Molecules at the Drosophila Neuromuscular Junction.

The appropriate expression and localization of cell surface cell adhesion molecules must be tightly regulated for optimal synaptic growth and function. How neuronal plasma membrane proteins, including cell adhesion molecules, cycle between early endosomes and the plasma membrane is poorly understood. Here we show that the Drosophila homolog of the chromatin remodeling enzymes CHD7 and CHD8, Kismet, represses the synaptic levels of several cell adhesion molecules. Neuroligins 1 and 3 and the integrins αPS2 and ßPS are increased at kismet mutant synapses but Kismet only directly regulates transcription of neuroligin 2. Kismet may therefore regulate synaptic CAMs indirectly by activating transcription of gene products that promote intracellular vesicle trafficking including endophilin B (endoB) and/or rab11. Knock down of EndoB in all tissues or neurons increases synaptic FasII while knock down of EndoB in kis mutants does not produce an additive increase in FasII. In contrast, neuronal expression of Rab11, which is deficient in kis mutants, leads to a further increase in synaptic FasII in kis mutants. These data support the hypothesis that Kis influences the synaptic localization of FasII by promoting intracellular vesicle trafficking through the early endosome.

SARS-CoV-2 associated septic venous cavernous sinus thrombosis: A case report.

Cavernous sinus thrombosis (CST) is a life-threatening condition occurring due to an active infection, coagulation abnormalities, and trauma. Thromboembolic events are known complications secondary to novel coronavirus disease-19 (COVID-19) due to dysfunction in endothelial function and clotting factor dysfunction. We report a case of cavernous sinus thrombosis and delayed ophthalmic vein thrombosis associated with a preceding COVID-19 infection confirmed with a facial computed tomography (CT) scan. Clinicians should have a broad differential in patients with hypercoagulable states, as complications secondary to COVID-19 can be life-threatening.

A closer look at the synapse: dlg1[4K] enables cell-specific visualization of PSD-95/DLG1.

The PSD-95 homolog, DLG1, is important for excitatory synapse structure and function throughout the Drosophila nervous system. In this issue of Cell Reports Methods, Parisi et al. present a tool, dlg1[4K], that enables cell-specific DLG1 visualization without altering basal synaptic physiology. This tool will potentially enhance our understanding of neuronal development and function in both circuits and individual synapses.

Genetic Counseling in Kidney Disease: A Perspective.

As genetic testing is increasingly integrated into nephrology practice there is a growing need for partnership with genetic experts. Genetic counselors are ideally suited to fill this role. The value of genetic counseling is born out of the clinical value of genetic test results against the backdrop of the complexity of genetic testing. Genetic counselors who specialize in nephrology are trained to understand and explain the potential effects of genes on kidney disease, which can enable patients to make informed decisions about proceeding with genetic testing, navigating variants of uncertain significance, educating on extrarenal features of hereditary kidney disease, facilitating cascade testing, providing post-test education about testing results, and assisting with family planning. Genetic counselors can partner with the nephrologist and provide the knowledge needed to maximize the use of genetic testing for patients for nephrology consultation. Genetic counseling is more than an element or extension of genetic testing; it is a dynamic, shared conversation between the patient and the genetic counselor where concerns, sentiments, information, and education are exchanged, and value-based decision making is facilitated.

Diet, sex, and genetic predisposition to obesity and type 2 diabetes modulate motor and anxiety-related behaviors in mice, and alter cerebellar gene expression.

Obesity and type 2 diabetes (T2D) are serious health problems linked to neurobehavioral alterations. We compared motor function, anxiety-related behavior, and cerebellar gene expression in TALLYHO/Jng (TH), a polygenic model prone to insulin resistance, obesity, and T2D, and normal C57BL/6 J (B6) mice. Male and female mice were weaned onto chow or high fat (HF) diet at 4 weeks of age (wk), and experiments conducted at young (5 wk) and old (14 - 20 wk) ages. In the open field, distance traveled was significantly lower in TH (vs. B6). For old mice, anxiety-like behavior (time in edge zone) was significantly increased for TH (vs B6), females (vs males), and for both ages HF diet (vs chow). In Rota-Rod testing, latency to fall was significantly shorter in TH (vs B6). For young mice, longer latencies to fall were observed for females (vs males) and HF (vs chow). Grip strength in young mice was greater in TH (vs B6), and there was a diet-strain interaction, with TH on HF showing increased strength, whereas B6 on HF showed decreased strength. For older mice, there was a strain-sex interaction, with B6 males (but not TH males) showing increased strength compared to the same strain females. There were significant sex differences in cerebellar mRNA levels, with Tnfα higher, and Glut4 and Irs2 lower in females (vs males). There were significant strain effects for Gfap and Igf1 mRNA levels with lower in TH (vs B6). Altered cerebellar gene expression may contribute to strain differences in coordination and locomotion.

The CD63 homologs, Tsp42Ee and Tsp42Eg, restrict endocytosis and promote neurotransmission through differential regulation of synaptic vesicle pools.

The Tetraspanin (Tsp), CD63, is a transmembrane component of late endosomes and facilitates vesicular trafficking through endosomal pathways. Despite being widely expressed in the human brain and localized to late endosomes, CD63's role in regulating endo- and exocytic cycling at the synapse has not been investigated. Synaptic vesicle pools are highly dynamic and disruptions in the mobilization and replenishment of these vesicle pools have adverse neuronal effects. We find that the CD63 homologs, Tsp42Ee and Tsp42Eg, are expressed at the Drosophila neuromuscular junction to regulate synaptic vesicle pools through both shared and unique mechanisms. Tsp42Ee and Tsp42Eg negatively regulate endocytosis and positively regulate neurotransmitter release. Both tsp mutants show impaired locomotion, reduced miniature endplate junctional current frequencies, and increased endocytosis. Expression of human CD63 in Drosophila neurons leads to impaired endocytosis suggesting the role of Tsps in endocytosis is conserved. We further show that Tsps influence the synaptic cytoskeleton and membrane composition by regulating Futsch loop formation and synaptic levels of SCAR and PI(4,5)P2. Finally, Tsp42Ee and Tsp42Eg influence the synaptic localization of several vesicle-associated proteins including Synapsin, Synaptotagmin, and Cysteine String Protein. Together, our results present a novel function for Tsps in the regulation of vesicle pools and provide insight into the molecular mechanisms of Tsp-related synaptic dysfunction.

Is It Time to Utilize Genetic Testing for Living Kidney Donor Evaluation?

Living donor kidney transplantation is an effective strategy to mitigate the challenges of solid organ shortage. However, being a living kidney donor is not without risk, as donors may encounter short- and long-term complications including the risk of developing chronic kidney disease, end-stage kidney disease, hypertension, and possible pregnancy-related complications. Although the evaluation of potential living donors is a thorough and meticulous process with the intention of decreasing the chance of complications, particularly in donors who have lifetime risk projection, risk factors for kidney disease including genetic predispositions may be missed because they are not routinely investigated. This type of testing may not be offered to patients due to variability and decreased penetrance of symptoms and lack of availability of appropriate genetic testing and genetic specialists. We report a case of a middle-aged woman with a history of gestational diabetes and preeclampsia who underwent an uneventful living kidney donation. She developed postdonation nonnephrotic range proteinuria and microscopic hematuria. Given the risk of biopsy with a solitary kidney, genetic testing was performed and revealed autosomal dominant Alport syndrome. Our case underscores the utility of genetic testing. Hopefully, future research will examine the incorporation of predonation genetic testing into living kidney donor evaluation.

A Randomized Open-Label Study of Two Methods of Proton Pump Inhibitors Discontinuation.

Background Proton pump inhibitors (PPIs) are effective in treating gastroesophageal reflux disease (GERD). Unfortunately, they are often inappropriately prescribed and long-term use has potential adverse effects. A single best method for discontinuation of PPIs does not currently exist. The objective of this study was to determine if there is a significant difference in successfully discontinuing PPI use at 12 months between patients discontinuing abruptly or tapering first. Methodology We conducted a randomized trial with 38 patients diagnosed with GERD. We collected six weekly and then monthly surveys of symptoms based on the Dyspepsia Symptom Severity Index. Chart review at 12 months determined whether the patient was able to discontinue PPI. Results A Kaplan-Meier survival analysis at 12 months did not show a statistically significant difference between the abrupt and taper groups for discontinuation of PPI medication (p = 0.75). Cox regression analysis showed no association of alcohol use, smoking, or caffeine use with failure to discontinue PPI, but H2 blocker use was associated with a 79% reduction in risk of failure to discontinue PPI (p = 0.004). The taper group had significantly less symptoms 14, 18, 22, and 30 weeks after discontinuation. Conclusions Our study suggests that there is no difference in successful discontinuation of PPIs between abrupt and taper methods at 12 months; however, there are less symptoms in the taper method, and H2 blocker use is associated with success. Further study is needed with larger numbers of participants and randomization of H2 blocker use.

The histone demethylase KDM5 is required for synaptic structure and function at the Drosophila neuromuscular junction.

Mutations in the genes encoding the lysine demethylase 5 (KDM5) family of histone demethylases are observed in individuals with intellectual disability (ID). Despite clear evidence linking KDM5 function to neurodevelopmental pathways, how this family of proteins impacts transcriptional programs to mediate synaptic structure and activity remains unclear. Using the Drosophila larval neuromuscular junction (NMJ), we show that KDM5 is required presynaptically for neuroanatomical development and synaptic function. The Jumonji C (JmjC) domain-encoded histone demethylase activity of KDM5, which is expected to be diminished by many ID-associated alleles, is required for appropriate synaptic morphology and neurotransmission. The activity of the C5HC2 zinc finger is also required, as an ID-associated mutation in this motif reduces NMJ bouton number, increases bouton size, and alters microtubule dynamics. KDM5 therefore uses demethylase-dependent and independent mechanisms to regulate NMJ structure and activity, highlighting the complex nature by which this chromatin modifier carries out its neuronal gene-regulatory programs.

DYRK1A haploinsufficiency causes a new recognizable syndrome with microcephaly, intellectual disability, speech impairment, and distinct facies.

Dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1 A (DYRK1A ) is a highly conserved gene located in the Down syndrome critical region. It has an important role in early development and regulation of neuronal proliferation. Microdeletions of chromosome 21q22.12q22.3 that include DYRK1A (21q22.13) are rare and only a few pathogenic single-nucleotide variants (SNVs) in the DYRK1A gene have been described, so as of yet, the landscape of DYRK1A disruptions and their associated phenotype has not been fully explored. We have identified 14 individuals with de novo heterozygous variants of DYRK1A; five with microdeletions, three with small insertions or deletions (INDELs) and six with deleterious SNVs. The analysis of our cohort and comparison with published cases reveals that phenotypes are consistent among individuals with the 21q22.12q22.3 microdeletion and those with translocation, SNVs, or INDELs within DYRK1A. All individuals shared congenital microcephaly at birth, intellectual disability, developmental delay, severe speech impairment, short stature, and distinct facial features. The severity of the microcephaly varied from -2 SD to -5 SD. Seizures, structural brain abnormalities, eye defects, ataxia/broad-based gait, intrauterine growth restriction, minor skeletal abnormalities, and feeding difficulties were present in two-thirds of all affected individuals. Our study demonstrates that haploinsufficiency of DYRK1A results in a new recognizable syndrome, which should be considered in individuals with Angelman syndrome-like features and distinct facial features. Our report represents the largest cohort of individuals with DYRK1A disruptions to date, and is the first attempt to define consistent genotype-phenotype correlations among subjects with 21q22.13 microdeletions and DYRK1A SNVs or small INDELs.