Citations

Background: Owing to the many unique disease characteristics of Parkinson disease (PD)—namely resting tremors, muscular rigidity, and poor bone quality—we hypothesized that this patient population would have inferior outcomes with surgical management of acute distal radius fractures (DRFs) compared with the literature available on the general population. Methods: This is a retrospective observational study performed at a single, level 1, academic center from 2001 to 2020 capturing all adult patients with an isolated, acute, and closed DRF that ultimately underwent operative treatment. International Classification of Diseases 10 codes were used to identify 30 patients for manual chart review. Several patient and fracture characteristics were accounted for and complications, reoperations, and failures of surgical intervention were recorded. Results: There was a total of 7/30 failures (23%), 6/30 reoperations (20%), and 12 complications in 9/30 wrists (complication rate, 30%) at a mean latest follow-up of 11 months (1.2-158 months). Of the 7 failures, 5 were due to loss of reduction, and 2 of them were deep infections with mean time to failure of 8.3 weeks (range, 11 days-5.2 months). Conclusions: This study found a high rate of complications, reoperations, and early failure despite a short follow-up period and a small cohort of patients with PD treated surgically for a DRF. We recommend locked plating if suitable for the fracture type and early involvement of a multidisciplinary team to assist with medical optimization of PD to increase chances of a successful outcome.

Abstract Background We evaluated the analytical sensitivity and specificity of 4 rapid antigen diagnostic tests (Ag RDTs) for severe acute respiratory syndrome coronavirus 2, using reverse transcription quantitative PCR (RT-qPCR) as the reference method and further characterizing samples using droplet digital quantitative PCR (ddPCR) and a mass spectrometric antigen test. Methods Three hundred fifty (150 negative and 200 RT-qPCR positive) residual PBS samples were tested for antigen using the BD Veritor lateral flow (LF), ACON LF, ACON fluorescence immunoassay (FIA), and LumiraDx FIA. ddPCR was performed on RT-qPCR–positive samples to quantitate the viral load in copies/mL applied to each Ag RDT. Mass spectrometric antigen testing was performed on PBS samples to obtain a set of RT-qPCR–positive, antigen-positive samples for further analysis. Results All Ag RDTs had nearly 100% specificity compared to RT-qPCR. Overall analytical sensitivity varied from 66.5% to 88.3%. All methods detected antigen in samples with viral load >1 500 000 copies/mL RNA, and detected ≥75% of samples with viral load of 500 000 to 1 500 000 copies/mL. The BD Veritor LF detected only 25% of samples with viral load between 50 000 to 500 000 copies/mL, compared to 75% for the ACON LF device and >80% for LumiraDx and ACON FIA. The ACON FIA detected significantly more samples with viral load <50 000 copies/mL compared to the BD Veritor. Among samples with detectable antigen and viral load <50 000 copies/mL, sensitivity of the Ag RDT varied between 13.0% (BD Veritor) and 78.3% (ACON FIA). Conclusions Ag RDTs differ significantly in analytical sensitivity, particularly at viral load <500 000 copies/mL.

Abstract Background: Use of menopausal hormone therapy (MHT) is associated with increased risk for breast cancer. However, the relevant mechanisms and its interaction with genetic variants are not fully understood. Methods: We conducted a genome-wide interaction analysis between MHT use and genetic variants for breast cancer risk in 27,585 cases and 34,785 controls from 26 observational studies. All women were post-menopausal and of European ancestry. Multivariable logistic regression models were used to test for multiplicative interactions between genetic variants and current MHT use. We considered interaction p-values<5x10-8 as genome-wide significant, and p-values<1x10-5 as suggestive. Linkage disequilibrium (LD)-based clumping was performed to identify independent candidate variants.Results: None of the 9.7 million genetic variants tested for interactions with MHT use reached genome-wide significance. Only 213 variants, representing 18 independent loci, had p-values<1x105. The strongest evidence was found for rs4674019 (p-value=2.27x10-7), which showed genome-wide significant interaction (p-value=3.8x10-8) with current MHT use when analysis was restricted to population-based studies only. Limiting the analyses to combined estrogen-progesterone MHT use only or to estrogen receptor (ER) positive cases did not identify any genome-wide significant evidence of interactions. Conclusions: In this large genome-wide SNP-MHT interaction study of breast cancer, we found no strong support for common genetic variants modifying the effect of MHT on breast cancer risk. These results suggest that common genetic variation has limited impact on the observed MHT–breast cancer risk association.

Abstract BACKGROUND Low bone mineral density (BMD) on dual energy x-ray absorptiometry (DXA) is likely a risk factor for proximal junctional kyphosis (PJK) and proximal junctional failure (PJF). However, prior instrumentation and degenerative changes can preclude a lumbar BMD measurement. Hounsfield units (HU) represent an alternative method to estimate BMD via targeted measurements at the intended operative levels. OBJECTIVE To determine if patients with lower HU at the upper instrumented vertebrae (UIV) and vertebral body superior to the UIV (UIV + 1) are at greater risk for PJK and PJF. METHODS A retrospective chart review identified patients at least 50 yr of age who underwent instrumented lumbar fusion with pelvic fixation, a UIV from T10 to L2, and a preoperative computed tomography (CT) encompassing the UIV. HU were measured at the UIV, UIV + 1, and the L3-L4 vertebral bodies. RESULTS A total of 150 patients (80 women and 70 men) were included with an average age of 66 yr and average follow-up of 32 mo. Multivariable logistic regression analysis with an area under the curve (AUC) of 0.89 demonstrated HU at the UIV/UIV + 1 as the only independent predictor of PJK/PJF with an odds ratio of 0.94 ( P -value = .031) for a change in a single HU. Patients with HU at UIV/UIV + 1 of <110 (n = 35), 110 to 160 (n = 73), and >160 (n = 42) had a rate of PJK/PJF of 63%, 27%, and 12%, respectively ( P -value < .001). CONCLUSION Patients with lower HU at the UIV and UIV + 1 were significantly associated with PJK and PJF, with an optimal cutoff of 122 HU that maximizes sensitivity and specificity.

Abstract BackgroundCopy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data.ResultsGene burden tests detected the strongest association for deletions in BRCA1 (P= 3.7E-18). Nine other genes were associated with a p-value < 0.01 including known susceptibility genes CHEK2 (P= 0.0008), ATM (P= 0.002) and BRCA2 (P= 0.008). Outside the known genes we detected associations with p-values < 0.001 for either overall or subtype-specific breast cancer at nine deletion regions and four duplication regions. Three of the deletion regions were in established common susceptibility loci.ConclusionsThis is the first genome-wide analysis of rare CNVs in a large breast cancer case-control dataset. We detected associations with exonic deletions in established breast cancer susceptibility genes. We also detected suggestive associations with non-coding CNVs in known and novel loci with large effects sizes. Larger sample sizes will be required to reach robust levels of statistical significance.

BACKGROUND Enteroendocrine cells (EECs) in the gastrointestinal (GI) epithelium are specialized sensors of luminal chemicals and forces. Upon stimulation, EECs release a variety of neurotransmitters and hormones, but cellular mechanisms of excitation‐secretion coupling are poorly understood. We recently discovered that a population of EECs expresses the mechanosensitive ion channel Piezo2, which is necessary for force‐dependent intracellular Ca2+ increase and serotonin release. However, the molecular mechanism that links Piezo2 and serotonin release is unknown. In other sensory systems, the Cacna1h ‐encoded t‐type voltage‐gated calcium channel Cav3.2 is important in mechanotransduction for linking mechanical activation with neurotransmitter release. AIM to determine if Cav3.2 is expressed and functionally relevant in EECs. METHODS Quantitative RT‐PCR for Cacna1h mRNA expression was evaluated in colon epithelium of control and NeuroD1 Cre x RiboTag mice, in which actively transcribed mRNA specifically from EECs is tagged with hemagglutinin (HA). NeuroD1 Cre x tdTomato colon cross‐sections were fixed and immunolabeled with anti‐Cav3.2 antibody. Single primary NeuroD1 cre x GCaMP5 EECs were mechanically stimulated and Cav3.2 role in mechanotransduction was tested by pharmacology (Ca2+ free, nickel, mibefradil, ω‐agatoxin IVA) and Cacna1h siRNA knockdown. RESULTS Murine colon epithelium expressed Cav3.2 mRNA. In NeuroD1 Cre x RiboTag mouse, HA co‐localized with EEC marker Chromogranin A (Chga). NeuroD1+ EEC ribosomal trapped mRNA was enriched for markers of epithelium (Vil1), EEC (Chga), and enriched 7.0‐fold for Cav3.2 (n=3, p<0.05 compared to whole epithelium). Immunohistochemistry in NeuroD1 Cre x tdTomato showed that Cav3.2 co‐localized specifically with tdTomato (NeuroD1+) EECs. In primary NeuroD1+ EECs, Cav3.2 inhibition by all pharmacologic agents and siRNA knockdown inhibited mechanically induced Ca2+ response (96±1% for Ca2+ free, 71±9% nickel, 61±6% mibefradil, 80±4% ω‐agatoxin IVA and 96±1% Cav3.2 siRNA, n=3–18, p<0.05 compared to control untreated cells or cells treated with non‐targeted siRNA). CONCLUSIONS Cav3.2 is densely and specifically expressed in mouse colon EECs and it is important for regulating Ca2+ in EEC mechanotransduction. Future studies will determine how Cav3.2 channels contribute to EEC electrical excitability, excitation‐secretion coupling, and ultimately EEC Cav3.2 roles in GI physiology. Support or Funding Information Supported by NIH DK106456, NIH DK084567, and AGA RSA This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Thiopurine drugs such as 6‐mercaptopurine (6‐MP) and 6‐thioguanine (6‐TG) are effective immunosuppressants and antineoplastic agents. We used a genome‐wide approach to identify genes that might contribute to individual variation in thiopurine response. Basal gene expression profiles, genome‐wide SNP data, and 6‐MP and 6‐TG Cell growth inhibition (GI50) values were generated for 200 Coriell Institute “Human Variation Panel” lymphoblastoid cell lines. Gene expression and genome‐wide SNPs were correlated with GI50 values to identify candidate genes that might contribute to thiopurine response. We identified 104 expression probes and 161 SNPs, as well as 315 gene probes and 579 SNPs that correlated significantly with GI50 values for 6‐MP and 6‐TG, respectively (P<10 −5 and 10 −6 , respectively). Three genes, CD83 , TXNDC13 and SNAP23 , contained SNPs that contributed significantly to both 6‐MP and 6‐TG cytotoxicity and were also significantly associated with expression levels (P<10 −4 ), suggesting a “three‐way model” involving genotype, gene expression and cytotoxicity. GBP5 , a gene with an expression level that correlated negatively with 6‐MP and 6‐TG GI50 values, sensitized leukemia cells when overexpressed. Functional studies of the remainder of the candidate genes are being performed. These results may enhance our ability to predict thiopurine response phenotypes. NIH GM28157.

Background: Inflammatory myofibroblastic tumor is a rare, poorly understood tumor that has been found to occur in almost every organ tissue. Its location within the central nervous system is uncommon, and patients tend to present with nonspecific symptoms. Case Description: A female in her eighth decade presented to neurosurgery clinic with complaints of headache and dizziness. Initial imaging was consistent with a low-grade, benign brain lesion in the region of the left choroidal fissure. She was recommended for observation but returned 1 month later with progressive symptoms and doubling of the lesion size. She underwent surgical resection and was found to have an IMT arising from the wall of the left anterior choroidal artery. Conclusion: Intracranial IMT remains a rare and poorly understood entity. The present case demonstrates a novel presentation of IMT in an adult patient and exemplifies the heterogeneity of the disease presentation.