The landscape of rare genetic variants in familial Waldenström macroglobulinemia.

Waldenström macroglobulinemia (WM) is a rare hematological malignancy. Risk for WM is elevated 20-fold among first-degree relatives of patients with WM. However, the list of variants and genes that cause WM remains incomplete. In this study we analyzed exomes from 64 WM pedigrees for evidence of genetic susceptibility for this malignancy. We determined the frequency of pathogenic (P) or likely pathogenic (LP) variants among patients with WM; performed variant- and gene-level association analyses with the set of 166 WM cases and 681 unaffected controls; and examined the segregation pattern of deleterious variants among affected members in each pedigree. We identified P/LP variants in TREX1 and SAMHD1 (genes that function at the interface between innate immune response, genotoxic surveillance, and DNA repair) segregating in patients with WM from 2 pedigrees. There were additional P/LP variants in cancer-predisposing genes (eg, POT1, RECQL4, PTPN11, PMS2). In variant- and gene-level analyses, no associations were statistically significant after multiple testing correction. On a pathway level, we observed involvement of genes that play a role in telomere maintenance (q-value = 0.02), regulation of innate immune response (q-value = 0.05), and DNA repair (q-value = 0.08). Affected members of each pedigree shared multiple deleterious variants (median, n = 18), but the overlap between the families was modest. In summary, P/LP variants in highly penetrant genes constitute a modest proportion of the deleterious variants; each pedigree is largely unique in its genetic architecture, and multiple genes are likely involved in the etiology of WM.

Solar distillation of human urine to recover non-potable water and metal phosphate mineral.

Human urine is a readily available nutrient source that can complement commercial fertilizer production, which relies on finite mineral resources and global supply chains. This study evaluated the effectiveness of a simplified solar distillation process for urine to recover phosphorus (P) and nitrogen for agricultural use and water for non-potable purposes. Synthetic fresh, synthetic hydrolyzed, real fresh, and real hydrolyzed urine were exposed to direct sunlight for 6 h in a simple distillation apparatus, which produced distillation bottoms and distillate. Metal phosphate precipitation in the distillation bottoms was evaluated to recover P. The non-potable water was recovered as distillate. Hydrolyzed urine recovered more metal phosphate solid in the distillation bottoms and had a higher conductivity in the distillate than fresh urine. Hydrolyzed urine also achieved greater distillate volume recovery than fresh urine. Hydrolyzed urine had a greater presence of UV-absorbing organics in the distillate than fresh urine and therefore produced a lower-quality product water. There was no significant correlation between the daily high air temperature and the volume of distillate recovered. This study provides a comprehensive data set on simplified solar distillation of human urine considering the fate of nutrients and water for different types of urine.

Gene-Level Associations in Patients With and Without Pathogenic Germline Variants in CDKN2A and Pancreatic Cancer.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is a component of familial melanoma due to germline pathogenic variants (GPVs) in CDKN2A. However, it is unclear what role this gene or other genes play in its etiology. MATERIALS AND METHODS: We analyzed 189 cancer predisposition genes using parametric rare-variant association (RVA) tests and nonparametric permutation tests to identify gene-level associations in PDAC for patients with (CDKN2A+) and without (CDKN2A-) GPV. Exome sequencing was performed on 84 patients with PDAC, 47 CDKN2A+ and 37 CDKN2A-. After variant filtering, various RVA tests and permutation tests were run separately by CDKN2A status. Genes with the strongest nominal associations were evaluated in patients with PDAC from The Cancer Genome Atlas and the UK Biobank (UKB). A secondary analysis including only GPV from UKB was also performed. RESULTS: In RVA tests, ERCC4 and RET showed the most compelling evidence as plausible PDAC candidate genes for CDKN2A+ patients. In contrast, the findings in CDKN2A- patients provided evidence for HMBS, EPCAM, and MRE11 as potential new candidate genes and confirmed ATM, BRCA2, and PALB2 as PDAC genes, consistent with findings in The Cancer Genome Atlas and the UKB. As expected, CDKN2A- patients were more likely to harbor GPVs from the 189 genes investigated. When including only GPVs from UKB, significant associations with PDAC were seen for ATM, BRCA2, and CDKN2A. CONCLUSION: These results suggest that variants in other genes likely play a role in PDAC in all patients and that PDAC in CDKN2A+ patients has a distinct etiology from PDAC in CDKN2A- patients.

Removal of perfluoroalkyl acids and common drinking water contaminants by weak-base anion exchange resins: Impacts of solution pH and resin properties.

The underlying chemistry of weak-base (WB) anion exchange resins (AERs) for contaminant removal from water is not well documented in the literature. To address this, batch adsorption experiments were conducted at pH 4, 7, and 10 using two representative WB-AERs (polyacrylic IRA67 and polystyrene IRA96) and two representative strong-base (SB) AERs (polyacrylic IRA458 and polystyrene A520E), of differing polymer composition, for the removal of nitrate, sulfate, 3-phenylpropionic acid (3-PPA) as surrogate for natural organic matter, and six perfluoroalkyl acids (PFAAs). Under acidic (pH 4) and neutral (pH 7) conditions, the selectivity of AERs for each contaminant was predominantly influenced by polymer composition followed by the size of the resin functional group. This result reflected the WB-AERs being fully protonated and functioning identical to SB-AERs. Isotherm model parameters revealed WB-AER had higher capacity than SB-AER with analogous polymer composition and porosity regardless of resin selectivity for each contaminant. Under basic conditions (≥ pH 10), contaminant removal by WB-AERs declined due to deprotonation of the tertiary amine functional groups. Removal of PFAAs by the more hydrophobic polystyrene WB-AER (IRA96) remained approximately constant with changing pH, which was possibly due to electrostatic interactions with remaining protonated amine functional groups on the resin.

Quality Improvement to Address Surgical Burden of Disease at a Large Tertiary Public Hospital in Peru.

BACKGROUND: In resource-limited settings, there is a unique opportunity for using process improvement strategies to address the lack of access to surgical care. By implementing organizational changes in the surgical admission process, we aimed to decrease wait times, increase surgical volume, and improve patient satisfaction for elective general surgery procedures at a public tertiary hospital in Lima, Peru. METHODS: During the first phase of the intervention, Plan-Do-Study-Act (PDSA) cycles were performed to ensure the surgery waitlist included up-to-date clinical information. In the second phase, Lean Six Sigma methodology was used to adapt the admission and scheduling process for elective general surgery patients. After six months, outcomes were compared to baseline data using Wilcoxon rank-sum test. RESULTS: At the conclusion of phase one, 87.0% (488/561) of patients on the new waitlist had all relevant clinical data documented, improved from 13.3% (2/15) for the pre-existing list. Time from admission to discharge for all surgeries improved from 5 to 4 days (p<0.05) after the intervention. Median wait times from admission to operation for elective surgeries were unchanged at 4 days (p=0.076) pre- and post-intervention. There was a trend toward increased weekly elective surgical volume from a median of 9 to 13 cases (p=0.24) and increased patient satisfaction rates for elective surgery from 80.5 to 83.8% (p=0.62), although these were not statistically significant. CONCLUSION: The process for scheduling and admitting elective surgical patients became more efficient after our intervention. Time from admission to discharge for all surgical patients improved significantly. Other measured outcomes improved, though not with statistical significance. Main challenges included gaining buy-in from all participants and disruptions in surgical services from bed shortages.

Universal Bell Correlations Do Not Exist.

We prove that there is no finite-alphabet nonlocal box that generates exactly those correlations that can be generated using a maximally entangled pair of qubits. More generally, we prove that if some finite-alphabet nonlocal box is strong enough to simulate arbitrary local projective measurements of a maximally entangled pair of qubits, then that nonlocal box cannot itself be simulated using any finite amount of entanglement. We also give a quantitative version of this theorem for approximate simulations, along with a corresponding positive result.

Multiple rare variants in high-risk pancreatic cancer-related genes may increase risk for pancreatic cancer in a subset of patients with and without germline CDKN2A mutations.

The risk of pancreatic cancer (PC) is increased in melanoma-prone families but the causal relationship between germline CDKN2A mutations and PC risk is uncertain, suggesting the existence of non-CDKN2A factors. One genetic possibility involves patients having mutations in multiple high-risk PC-related genes; however, no systematic examination has yet been conducted. We used next-generation sequencing data to examine 24 putative PC-related genes in 43 PC patients with and 23 PC patients without germline CDKN2A mutations and 1001 controls. For each gene and the four pathways in which they occurred, we tested whether PC patients (overall or CDKN2A+ and CDKN2A- cases separately) had an increased number of rare nonsynonymous variants. Overall, we identified 35 missense variants in PC patients, 14 in CDKN2A+ and 21 in CDKN2A- PC cases. We found nominally significant associations for mismatch repair genes (MLH1, MSH2, MSH6, PMS2) in all PC patients and for ATM, CPA1, and PMS2 in CDKN2A- PC patients. Further, nine CDKN2A+ and four CDKN2A- PC patients had rare potentially deleterious variants in multiple PC-related genes. Loss-of-function variants were only observed in CDKN2A- PC patients, with ATM having the most pathogenic variants. Also, ATM variants (n = 5) were only observed in CDKN2A- PC patients with a family history that included digestive system tumors. Our results suggest that a subset of PC patients may have increased risk because of germline mutations in multiple PC-related genes.

Evaluation of a tissue-mimicking thermochromic phantom for radiofrequency ablation.

PURPOSE: This work describes the characterization and evaluation of a tissue-mimicking thermochromic phantom (TMTCP) for direct visualization and quantitative determination of temperatures during radiofrequency ablation (RFA). METHODS: TMTCP material was prepared using polyacrylamide gel and thermochromic ink that permanently changes color from white to magenta when heated. Color vs temperature calibration was generated in matlab by extracting RGB color values from digital photographs of phantom standards heated in a water bath at 25-75 °C. RGB and temperature values were plotted prior to curve fitting in mathematica using logistic functions of form f(t) = a + b/(1 + e((c(t-d)))), where a, b, c, and d are coefficients and t denotes temperature. To quantify temperatures based on TMTCP color, phantom samples were heated to temperatures blinded to the investigators, and two methods were evaluated: (1) visual comparison of sample color to the calibration series and (2) in silico analysis using the inverse of the logistic functions to convert sample photograph RGB values to absolute temperatures. For evaluation of TMTCP performance with RFA, temperatures in phantom samples and in a bovine liver were measured radially from an RF electrode during heating using fiber-optic temperature probes. Heating and cooling rates as well as the area under the temperature vs time curves were compared. Finally, temperature isotherms were generated computationally based on color change in bisected phantoms following RFA and compared to temperature probe measurements. RESULTS: TMTCP heating resulted in incremental, permanent color changes between 40 and 64 °C. Visual and computational temperature estimation methods were accurate to within 1.4 and 1.9 °C between 48 and 67 °C, respectively. Temperature estimates were most accurate between 52 and 62 °C, resulting in differences from actual temperatures of 0.6 and 1.6 °C for visual and computational methods, respectively. Temperature measurements during RFA using fiber-optic probes matched closely with maximum temperatures predicted by color changes in the TMTCP. Heating rate and cooling rate, as well as the area under the temperature vs time curve were similar for TMTCP and ex vivo liver. CONCLUSIONS: The TMTCP formulated for use with RFA can be used to provide quantitative temperature information in mild hyperthermic (40-45 °C), subablative (45-50 °C), and ablative (>50 °C) temperature ranges. Accurate visual or computational estimates of absolute temperatures and ablation zone geometry can be made with high spatial resolution based on TMTCP color. As such, the TMTCP can be used to assess RFA heating characteristics in a controlled, predictable environment.

Carotid-Cavernous Fistula Manifesting as Symptomatic Bradycardia: A Unique Presentation.

A 54-year-old female with vertigo and sarcoidosis presented to the emergency department with a 4-day history of generalised malaise, headache, fever, and near syncope. She was noted to have severe bradycardia and was admitted for possible pacemaker implantation. During the admission, the patient voiced left eye complaints, the workup of which revealed a left internal carotid aneurysm that ruptured, causing a direct carotid-cavernous fistula. The patient underwent multiple procedures to tamponade the fistula, and the bradycardia resolved, avoiding pacemaker implantation.

Rapid Short MRI Sequence Useful in Eliminating Stroke Mimics Among Acute Stroke Patients Considered for Intravenous Thrombolysis.

BACKGROUND: Acute stroke teams are challenged by IV-tPA decision making in patients with acute neurological symptoms when the diagnosis is unclear. The purpose of this study was to evaluate the ability of the rapid Brain Attack Team (BAT) MRI in selecting patients for IV-tPA administration who present acutely to the emergency room with stroke-like symptoms and an unclear diagnosis. METHODS: Consecutive patients were identified who presented within 4.5 hours of onset of stroke-like symptoms and considered for treatment with IV-tPA. When the diagnosis was not clear, a 9-minute BAT MRI was obtained. Stroke risk factors and NIH stroke scale obtained on presentation were compared between patients in whom BAT MRI was obtained and those in whom BAT MRI was not obtained. Similarly, comparisons were made between patients in whom BAT MRI detected abnormalities and those in whom BAT MRI did not detect abnormalities. BAT MRIs were analyzed to determine if radiological findings impacted clinical management and discharge diagnosis. RESULTS: In a 30-month period, 432 patients presenting with acute stroke-like symptoms were identified. Of these patients, 82 received BAT MRI. Patients receiving BAT MRI were younger, more likely to be smokers, and less likely to be selected for IV-tPA administration compared to those in whom a more definitive diagnosis of stroke precluded a BAT MRI. Of the 82 BAT MRIs, 25 were read as positive for acute ischemia. The patients with acute ischemia on BAT MRI were older, more likely to be males, have a history of hypercholesterolemia and atrial fibrillation, and more likely to be selected for IV-tPA administration compared to those with a negative BAT MRI. Of the 57 BAT MRIs read as negative for acute ischemia or hemorrhage, discharge diagnoses included TIA, MRI negative stroke, conversion/functional disorder, and multiple other illnesses. CONCLUSION: In patients with acute stroke-like symptoms, BAT MRI may be used to confirm acute ischemic stroke, exclude stroke mimics, and assess candidacy for IV-tPA.

CT Angiography and Presentation NIH stroke Scale in Predicting TIA in Patients Presenting with Acute Stroke Symptoms.

Patient candidacy for acute stroke intervention, is currently assessed using brain computed tomography angiography (CTA) evidence of significant stenosis/occlusion (SSO) with a high National Institutes of Health Stroke Scale (NIHSS) (>6). This study examined the association between CTA without significant stenosis/occlusion (NSSO) and lower NIHSS (≤ 6) with transient ischemic attack (TIA) and other good clinical outcomes at discharge. Patients presenting <8 hours from stroke symptom onset, had an NIHSS assessment and brain CTA performed at presentation. Good clinical outcomes were defined as: discharge diagnosis of TIA, modified Rankin Score [mRS] ≤ 1, and home as the discharge disposition. Eighty-five patients received both an NIHSS at presentation and a CTA at 4.2 ± 2.2 hours from stroke symptom onset. Patients with NSSO on CTA as well as those with NIHSS≤6 had better outcomes at discharge (p<0.001). NIHSS ≤ 6 were more likely than NSSO (p=0.01) to have a discharge diagnosis of TIA (p<0.001). NSSO on CTA and NIHSS ≤ 6 also correlated with fewer deaths (p<0.001). Multivariable analyses showed NSSO on CTA (Adjusted OR: 5.8 95% CI: 1.2-27.0, p=0.03) independently predicted the discharge diagnosis of TIA. Addition of NIHSS ≤ 6 to NSSO on CTA proved to be a stronger independent predictor of TIA (Adjusted OR 18.7 95% CI: 3.5-98.9, p=0.001).

An evaluation of thymidine phosphorylase as a means of preventing thymidine rescue from the thymidylate synthase inhibitor raltitrexed.

The antitumour effect of thymidylate synthase inhibitors such as raltitrexed (RTX) may be reversed by salvage of thymidine (Thd). Since thymidine phosphorylase (TP) depletes Thd, the potential for tumour-selective depletion of Thd using antibody-mediated delivery of TP to tumours was investigated. In vitro studies demonstrated that 25 x 10(-3) units/ml TP depleted extracellular Thd (3 microM) and restored sensitivity to the growth inhibitory effects of RTX in Lovo and HT29 cell lines. Thymidine concentrations in xenograft tumours were inversely proportional to the activity of TP in the tumour, and the presence of a subcutaneous Lovo xenograft reduced plasma Thd concentrations from 0.92 +/- 0.07 to 0.37 +/- 0.04 microM. Intravenous administration of native TP enzyme depleted plasma Thd to 5 nM, but following rapid elimination of TP, plasma Thd returned to pretreatment values. There was no effect on tumour TP or Thd. Conjugation of TP to the A5B7 F(ab)2 antibody fragment, which targets carcinoembryonic antigen (CEA) expressed on colorectal cell-lines such as Lovo, did result in selective accumulation of TP in the tumour. However, there was no tumour-selective depletion of Thd and there did not appear to be any potential benefit of combining antibody-targeted TP with RTX.

Combined transvenous and transarterial embolization of a tentorial-incisural dural arteriovenous malformation followed by primary stent placement in the associated stenotic straight sinus. Case report.

Dural arteriovenous malformations (AVMs) involving the tentoria-incisura are associated with an aggressive clinical course characterized by subarachnoid and intracranial hemorrhage (ICH). In these lesions, venous outflow obstruction precipitates leptomeningeal venous drainage, resulting in the arterialization of pial veins and the formation of venous aneurysms, both of which are prone to hemorrhage. Stenotic lesions of the dural sinuses also contribute to the development of retrograde leptomeningeal drainage, which is responsible for the aggressive clinical course of the dural AVM. Endovascular approaches are successful in the treatment of these lesions and of any potential venous outflow obstruction caused by stenosis of a dural sinus. The authors report on a patient with a tentorial-incisural dural AVM and an accompanying stenotic venous sinus. A combined transvenous and transarterial embolization procedure was performed, resulting in complete obliteration of the dural AVM, followed by primary stent placement across a stenotic segment of the straight sinus and normalization of venous outflow. The authors conclude that dural AVMs can be treated safely by using a combined transarterial and transvenous approach and that an extensive search for venous outflow obstruction often reveals stenosis of a draining sinus. Consideration should be given to primary stent placement in the stenotic sinus to protect against ICH.