Inappropriate Acetazolamide Use for a Hiker Who Developed Acute Kidney Injury.

Prophylactic use of acetazolamide (ACZ) to prevent acute mountain sickness (AMS) is a common practice among high altitude travelers and mountaineers. With its use comes a possible risk of acute kidney injury (AKI). We present a case in which a 56-year-old male hiker in Grand Canyon National Park developed acute exertional rhabdomyolysis and subsequent AKI while taking prophylactic ACZ to prevent AMS. This medication was prescribed despite the hiker encountering only moderate altitude at Grand Canyon with a planned descent within <24 h. The resulting AKI was determined to be the combined result of acute exertional rhabdomyolysis and dehydration/hypovolemia, with the ACZ, a diuretic, as a contributing factor. Medical providers need to recognize the risks/benefits with ACZ use for AMS prophylaxis and avoid prescribing it to individuals whose altitude exposure and activity fall outside the clinical practice guidelines recommended for use.

Modulation of Host Physiology and Pathophysiology by the Gut Microbiome.

The human gut microbiome is a highly dynamic community of bacteria, fungi, viruses, archaea, and protozoans that resides within the gastrointestinal tract [...].

Templated microbiology comments with candiduria to enhance antimicrobial stewardship.

Objective: To evaluate the effect of templated microbiology reporting comments on antifungal utilization in patients with candiduria. Design: In this retrospective, quasi-experimental study, we evaluated a preimplementation cohort (June 2018-January 2019) compared with a postimplementation cohort (June 2019-January 2020). Setting: A multisite health system including 1 academic hospital and 4 community hospitals. Patients: Patients were aged ≥18 years, were hospitalized, and had candiduria documented at least once during their admission. The study included 156 patients in the preimplementation period and 141 patients in the postimplementation period. Methods: In June 2019, Saint Luke's Health System implemented the use of templated comments for urine cultures with Candida spp growth. When Candida is isolated, the following comment appears in the microbiology result section: "In the absence of symptoms, Candida is generally considered normal flora. No therapy indicated unless high risk (pregnant, neonate, or neutropenic) or undergoing urologic procedure. If Foley catheter present, remove or replace when able." The primary outcome was rate of antifungal prescribing. Results: Antifungal administration within 72 hours of a culture identifying a Candida spp occurred in 75 patients in the preimplementation group and 48 patients in the postimplementation group (48.1% vs 34.0%; P = .02). We did not detect a difference between groups in antifungal administration between 73 and 240 hours (1.3% vs 3.5%; P = .26), nor did we detect a difference in median antifungal duration (4 vs 3 days; P = .43). Conclusion: Using a templated comment with urine cultures reduced antifungal prescription rates in hospitalized patients with candiduria. This strategy is a low-resource technique to improve antimicrobial stewardship.

The efficacy of public health information for encouraging radon gas awareness and testing varies by audience age, sex and profession.

Radioactive radon inhalation is a leading cause of lung cancer and underlies an ongoing public health crisis. Radon exposure prevention strategies typically begin by informing populations about health effects, and their initial efficacy is measured by how well and how fast information convinces individuals to test properties. This communication process is rarely individualized, and there is little understanding if messages impact diverse demographics equally. Here, we explored how 2,390 people interested in radon testing differed in their reaction to radon's public health information and their subsequent decision to test. Only 20% were prompted to radon test after 1 encounter with awareness information, while 65% required 2-5 encounters over several months, and 15% needed 6 to > 10 encounters over many years. People who most delayed testing were more likely to be men or involved in engineering, architecture, real estate and/or physical science-related professions. Social pressures were not a major factor influencing radon testing. People who were the least worried about radon health risks were older and/or men, while negative emotional responses to awareness information were reported more by younger people, women and/or parents. This highlights the importance of developing targeted demographic messaging to create effective radon exposure prevention strategies.

Younger North Americans are exposed to more radon gas due to occupancy biases within the residential built environment.

Residential buildings can concentrate radioactive radon gas, exposing occupants to particle radiation that increases lung cancer risk. This has worsened over time in North America, with newer residences containing greater radon. Using data from 18,971 Canadian households, we calculated annual particle radiation dose rates due to long term residential radon exposure, and examined this as a function of occupant demographics. The current particle radiation dose rate to lungs from residential radon in Canada is 4.08 mSv/y from 108.2 Bq/m3, with 23.4% receiving 100-2655 mSv doses that are known to elevate human cancer risk. Notably, residences built in the twenty-first century are occupied by significantly younger people experiencing greater radiation dose rates from radon (mean age of 46 at 5.01 mSv/y), relative to older groups more likely to occupy twentieth century-built properties (mean age of 53 at 3.45-4.22 mSv/y). Newer, higher radon-containing properties are also more likely to have minors, pregnant women and an overall higher number of occupants living there full time. As younger age-of-exposure to radon equates to greater lifetime lung cancer risk, these data reveal a worst case scenario of exposure bias. This is of concern as, if it continues, it forecasts serious future increases in radon-induced lung cancer in younger people.

Effects of germline and somatic events in candidate BRCA-like genes on breast-tumor signatures.

Mutations in BRCA1 and BRCA2 cause deficiencies in homologous recombination repair (HR), resulting in repair of DNA double-strand breaks by the alternative non-homologous end-joining pathway, which is more error prone. HR deficiency of breast tumors is important because it is associated with better responses to platinum salt therapies and PARP inhibitors. Among other consequences of HR deficiency are characteristic somatic-mutation signatures and gene-expression patterns. The term "BRCA-like" (or "BRCAness") describes tumors that harbor an HR defect but have no detectable germline mutation in BRCA1 or BRCA2. A better understanding of the genes and molecular events associated with tumors being BRCA-like could provide mechanistic insights and guide development of targeted treatments. Using data from The Cancer Genome Atlas (TCGA) for 1101 breast-cancer patients, we identified individuals with a germline mutation, somatic mutation, homozygous deletion, and/or hypermethylation event in BRCA1, BRCA2, and 59 other cancer-predisposition genes. Based on the assumption that BRCA-like events would have similar downstream effects on tumor biology as BRCA1/BRCA2 germline mutations, we quantified these effects based on somatic-mutation signatures and gene-expression profiles. We reduced the dimensionality of the somatic-mutation signatures and expression data and used a statistical resampling approach to quantify similarities among patients who had a BRCA1/BRCA2 germline mutation, another type of aberration in BRCA1 or BRCA2, or any type of aberration in one of the other genes. Somatic-mutation signatures of tumors having a non-germline aberration in BRCA1/BRCA2 (n = 80) were generally similar to each other and to tumors from BRCA1/BRCA2 germline carriers (n = 44). Additionally, somatic-mutation signatures of tumors with germline or somatic events in ATR (n = 16) and BARD1 (n = 8) showed high similarity to tumors from BRCA1/BRCA2 carriers. Other genes (CDKN2A, CTNNA1, PALB2, PALLD, PRSS1, SDHC) also showed high similarity but only for a small number of events or for a single event type. Tumors with germline mutations or hypermethylation of BRCA1 had relatively similar gene-expression profiles and overlapped considerably with the Basal-like subtype; but the transcriptional effects of the other events lacked consistency. Our findings confirm previously known relationships between molecular signatures and germline or somatic events in BRCA1/BRCA2. Our methodology represents an objective way to identify genes that have similar downstream effects on molecular signatures when mutated, deleted, or hypermethylated.

Urologic Surgery and COVID-19: How the Pandemic Is Changing the Way We Operate.

The coronavirus disease 2019 (COVID-19) pandemic has had a global impact on all aspects of health care, including surgical procedures. For urologists, it has affected and will continue to influence how we approach the care of patients preoperatively, intraoperatively, and postoperatively. A risk-benefit assessment of each patient undergoing surgery should be performed during the COVID-19 pandemic based on the urgency of the surgery and the risk of viral illness and transmission. Patients with advanced age and comorbidities have a higher incidence of mortality. Routine preoperative testing and symptom screening is recommended to identify those with COVID-19. Adequate personal protective equipment (PPE) for the surgical team is essential to protect health care workers and ensure an adequate workforce. For COVID-19 positive or suspected patients, the use of N95 respirators is recommended if available. The anesthesia method chosen should attempt to minimize aerosolization of the virus. Negative pressure rooms are strongly preferred for intubation/extubation and other aerosolizing procedures for COVID-19 positive patients or when COVID status is unknown. Although transmission has not yet been shown during laparoscopic and robotic procedures, efforts should be made to minimize the risk of aerosolization. Ultra-low particulate air filters are recommended for use during minimally invasive procedures to decrease the risk of viral transmission. Thorough cleaning and sterilization should be performed postoperatively with adequate time allowed for the operating room air to be cycled after procedures. COVID-19 patients should be separated from noninfected patients at all levels of care, including recovery, to decrease the risk of infection. Future directions will be guided by outcomes and infection rates as social distancing guidelines are relaxed and more surgical procedures are reintroduced. Recommendations should be adapted to the local environment and will continue to evolve as more data become available, the shortage of testing and PPE is resolved, and a vaccine and therapeutics for COVID-19 are developed.

ACE overexpression in myeloid cells increases oxidative metabolism and cellular ATP.

Angiotensin-converting enzyme (ACE) affects blood pressure. In addition, ACE overexpression in myeloid cells increases their immune function. Using MS and chemical analysis, we identified marked changes of intermediate metabolites in ACE-overexpressing macrophages and neutrophils, with increased cellular ATP (1.7-3.0-fold) and Krebs cycle intermediates, including citrate, isocitrate, succinate, and malate (1.4-3.9-fold). Increased ATP is due to ACE C-domain catalytic activity; it is reversed by an ACE inhibitor but not by an angiotensin II AT1 receptor antagonist. In contrast, macrophages from ACE knockout (null) mice averaged only 28% of the ATP levels found in WT mice. ACE overexpression does not change cell or mitochondrial size or number. However, expression levels of the electron transport chain proteins NDUFB8 (complex I), ATP5A, and ATP5ß (complex V) are significantly increased in macrophages and neutrophils, and COX1 and COX2 (complex IV) are increased in macrophages overexpressing ACE. Macrophages overexpressing ACE have increased mitochondrial membrane potential (24% higher), ATP production rates (29% higher), and maximal respiratory rates (37% higher) compared with WT cells. Increased cellular ATP underpins increased myeloid cell superoxide production and phagocytosis associated with increased ACE expression. Myeloid cells overexpressing ACE indicate the existence of a novel pathway in which myeloid cell function can be enhanced, with a key feature being increased cellular ATP.

Radon exposure is rising steadily within the modern North American residential environment, and is increasingly uniform across seasons.

Human-made buildings can artificially concentrate radioactive radon gas of geologic origin, exposing occupants to harmful alpha particle radiation emissions that damage DNA and increase lung cancer risk. We examined how North American residential radon exposure varies by modern environmental design, occupant behaviour and season. 11,727 residential buildings were radon-tested using multiple approaches coupled to geologic, geographic, architectural, seasonal and behavioural data with quality controls. Regional residences contained 108 Bq/m3 geometric mean radon (min < 15 Bq/m3; max 7,199 Bq/m3), with 17.8% ≥ 200 Bq/m3. Pairwise analysis reveals that short term radon tests, despite wide usage, display limited value for establishing dosimetry, with precision being strongly influenced by time of year. Regression analyses indicates that the modern North American Prairie residential environment displays exceptionally high and worsening radon exposure, with more recent construction year, greater square footage, fewer storeys, greater ceiling height, and reduced window opening behaviour all associated with increased radon. Remarkably, multiple test approaches reveal minimal winter-to-summer radon variation in almost half of properties, with the remainder having either higher winter or higher summer radon. This challenges the utility of seasonal correction values for establishing dosimetry in risk estimations, and suggests that radon-attributable cancers are being underestimated.

Outcome of arthroscopic debridement of cartilage injury in the equine distal interphalangeal joint.

The purpose of this study was to report long-term outcome following arthroscopic debridement of articular cartilage lesions of the distal interphalangeal joint, diagnosed with high-field magnetic resonance imaging. Diagnosis was based on the results of diagnostic anesthesia, magnetic resonance imaging (MRI), and arthroscopy. Ten horses underwent arthroscopic evaluation for cartilage injury and received various intra-articular therapies after surgery. Three of ten horses had lesions that were surgically inaccessible. Four horses became sound and returned to their preoperative level of athleticism, and 1 horse returned to performance with continued intermittent lameness. None of the horses with an inaccessible lesion achieved soundness. Duration of lameness before surgery, preoperative evidence of degenerative joint disease, and surgical accessibility of cartilage injury did not exhibit clear influence on outcome. As a primary cause of lameness, articular cartilage injury of the distal interphalangeal joint carries a guarded prognosis for soundness with surgical therapy.

Résultat d'un débridement arthroscopique d'une blessure du cartilage dans l'articulation interphalangienne distale. Le but de cette étude consistait à signaler les résultats à long terme après un débridement arthroscopique des lésions du cartilage articulaire de l'articulation interphalangienne distale, diagnostiqués par résonance magnétique de haute résolution. Le diagnostic s'est fondé sur les résultats de l'anesthésie diagnostique, de l'image par résonance magnétique (IRM) et de l'arthroscopie. Dix chevaux ont subi une évaluation arthroscopique d'une blessure du cartilage et reçu diverses thérapies intra-articulaires après la chirurgie. Trois des dix chevaux avaient des lésions qui étaient inaccessibles par chirurgie. Quatre chevaux se sont rétablis et sont retournés à leur niveau préopératoire de constitution athlétique et un cheval est retourné à la performance avec une boiterie intermittente persistante. Aucun des chevaux avec une lésion inaccessible ne s'est rétabli. La durée de la boiterie avant la chirurgie, les signes préopératoires de maladie articulaire dégénérative et l'accessibilité chirurgicale d'une blessure du cartilage n'ont pas eu une influence claire sur les résultats. Comme cause principale de boiterie, la blessure du cartilage articulaire de l'articulation interphalangienne distale comporte un pronostic réservé pour le rétablissement avec une thérapie chirurgicale.(Traduit par Isabelle Vallières).

Human iPSC-Derived Blood-Brain Barrier Chips Enable Disease Modeling and Personalized Medicine Applications.

The blood-brain barrier (BBB) tightly regulates the entry of solutes from blood into the brain and is disrupted in several neurological diseases. Using Organ-Chip technology, we created an entirely human BBB-Chip with induced pluripotent stem cell (iPSC)-derived brain microvascular endothelial-like cells (iBMECs), astrocytes, and neurons. The iBMECs formed a tight monolayer that expressed markers specific to brain vasculature. The BBB-Chip exhibited physiologically relevant transendothelial electrical resistance and accurately predicted blood-to-brain permeability of pharmacologics. Upon perfusing the vascular lumen with whole blood, the microengineered capillary wall protected neural cells from plasma-induced toxicity. Patient-derived iPSCs from individuals with neurological diseases predicted disease-specific lack of transporters and disruption of barrier integrity. By combining Organ-Chip technology and human iPSC-derived tissue, we have created a neurovascular unit that recapitulates complex BBB functions, provides a platform for modeling inheritable neurological disorders, and advances drug screening, as well as personalized medicine.

Suppression of SIRT1 in Diabetic Conditions Induces Osteogenic Differentiation of Human Vascular Smooth Muscle Cells via RUNX2 Signalling.

Vascular calcification is associated with significant morbidity and mortality within diabetes, involving activation of osteogenic regulators and transcription factors. Recent evidence demonstrates the beneficial role of Sirtuin 1 (SIRT1), an NAD+ dependant deacetylase, in improved insulin sensitivity and glucose homeostasis, linking hyperglycaemia and SIRT1 downregulation. This study aimed to determine the role of SIRT1 in vascular smooth muscle cell (vSMC) calcification within the diabetic environment. An 80% reduction in SIRT1 levels was observed in patients with diabetes, both in serum and the arterial smooth muscle layer, whilst both RUNX2 and Osteocalcin levels were elevated. Human vSMCs exposed to hyperglycaemic conditions in vitro demonstrated enhanced calcification, which was positively associated with the induction of cellular senescence, verified by senescence-associated ß-galactosidase activity and cell cycle markers p16 and p21. Activation of SIRT1 by SRT1720 reduced Alizarin red staining by a third, via inhibition of the RUNX2 pathway and prevention of senescence. Conversely, inhibition of SIRT1 via Sirtinol and siRNA increased RUNX2 by over 50%. These findings demonstrate the key role that SIRT1 plays in preventing calcification in a diabetic environment, through the inhibition of RUNX2 and senescence pathways, suggesting a downregulation of SIRT1 may be responsible for perpetuating vascular calcification in diabetes.

In Vitro and In Vivo Proteomic Comparison of Human Neural Progenitor Cell-Induced Photoreceptor Survival.

Retinal degenerative diseases lead to blindness with few treatments. Various cell-based therapies are aimed to slow the progression of vision loss by preserving light-sensing photoreceptor cells. A subretinal injection of human neural progenitor cells (hNPCs) into the Royal College of Surgeons (RCS) rat model of retinal degeneration has aided in photoreceptor survival, though the mechanisms are mainly unknown. Identifying the retinal proteomic changes that occur following hNPC treatment leads to better understanding of neuroprotection. To mimic the retinal environment following hNPC injection, a co-culture system of retinas and hNPCs is developed. Less cell death occurs in RCS retinal tissue co-cultured with hNPCs than in retinas cultured alone, suggesting that hNPCs provide retinal protection in vitro. Comparison of ex vivo and in vivo retinas identifies nuclear factor (erythroid-derived 2)-like 2 (NRF2) mediated oxidative response signaling as an hNPC-induced pathway. This is the first study to compare proteomic changes following treatment with hNPCs in both an ex vivo and in vivo environment, further allowing the use of ex vivo modeling for mechanisms of retinal preservation. Elucidation of the protein changes in the retina following hNPC treatment may lead to the discovery of mechanisms of photoreceptor survival and its therapeutic for clinical applications.

Proteomic Architecture of Human Coronary and Aortic Atherosclerosis.

BACKGOUND: The inability to detect premature atherosclerosis significantly hinders implementation of personalized therapy to prevent coronary heart disease. A comprehensive understanding of arterial protein networks and how they change in early atherosclerosis could identify new biomarkers for disease detection and improved therapeutic targets. METHODS: Here we describe the human arterial proteome and proteomic features strongly associated with early atherosclerosis based on mass spectrometry analysis of coronary artery and aortic specimens from 100 autopsied young adults (200 arterial specimens). Convex analysis of mixtures, differential dependent network modeling, and bioinformatic analyses defined the composition, network rewiring, and likely regulatory features of the protein networks associated with early atherosclerosis and how they vary across 2 anatomic distributions. RESULTS: The data document significant differences in mitochondrial protein abundance between coronary and aortic samples (coronary>>aortic), and between atherosclerotic and normal tissues (atherosclerotic<

Gut Microbiota-Produced Tryptamine Activates an Epithelial G-Protein-Coupled Receptor to Increase Colonic Secretion.

Tryptamine, a tryptophan-derived monoamine similar to 5-hydroxytryptamine (5-HT), is produced by gut bacteria and is abundant in human and rodent feces. However, the physiologic effect of tryptamine in the gastrointestinal (GI) tract remains unknown. Here, we show that the biological effects of tryptamine are mediated through the 5-HT4 receptor (5-HT4R), a G-protein-coupled receptor (GPCR) uniquely expressed in the colonic epithelium. Tryptamine increases both ionic flux across the colonic epithelium and fluid secretion in colonoids from germ-free (GF) and humanized (ex-GF colonized with human stool) mice, consistent with increased intestinal secretion. The secretory effect of tryptamine is dependent on 5-HT4R activation and is blocked by 5-HT4R antagonist and absent in 5-HT4R-/- mice. GF mice colonized by Bacteroides thetaiotaomicron engineered to produce tryptamine exhibit accelerated GI transit. Our study demonstrates an aspect of host physiology under control of a bacterial metabolite that can be exploited as a therapeutic modality. VIDEO ABSTRACT.

An exclusive metabolic niche enables strain engraftment in the gut microbiota.

The dense microbial ecosystem in the gut is intimately connected to numerous facets of human biology, and manipulation of the gut microbiota has broad implications for human health. In the absence of profound perturbation, the bacterial strains that reside within an individual are mostly stable over time 1 . By contrast, the fate of exogenous commensal and probiotic strains applied to an established microbiota is variable, generally unpredictable and greatly influenced by the background microbiota2,3. Therefore, analysis of the factors that govern strain engraftment and abundance is of critical importance to the emerging field of microbiome reprogramming. Here we generate an exclusive metabolic niche in mice via administration of a marine polysaccharide, porphyran, and an exogenous Bacteroides strain harbouring a rare gene cluster for porphyran utilization. Privileged nutrient access enables reliable engraftment of the exogenous strain at predictable abundances in mice harbouring diverse communities of gut microbes. This targeted dietary support is sufficient to overcome priority exclusion by an isogenic strain 4 , and enables strain replacement. We demonstrate transfer of the 60-kb porphyran utilization locus into a naive strain of Bacteroides, and show finely tuned control of strain abundance in the mouse gut across multiple orders of magnitude by varying porphyran dosage. Finally, we show that this system enables the introduction of a new strain into the colonic crypt ecosystem. These data highlight the influence of nutrient availability in shaping microbiota membership, expand the ability to perform a broad spectrum of investigations in the context of a complex microbiota, and have implications for cell-based therapeutic strategies in the gut.

Association of Blood Glucose and Clinical Outcome after Mechanical Thrombectomy for Acute Ischemic Stroke.

BACKGROUND: Elevated blood glucose levels following acute ischemic stroke have been associated with adverse clinical outcomes in thrombolytic and nonthrombolytic treated patients. The current study examined multiple blood glucose parameters and their association with modified Rankin Scale (mRS) score at 3 months following mechanical thrombectomy and hospital discharge. METHODS: Acute ischemic stroke patients undergoing mechanical thrombectomy with a retrievable stent at two stroke centers were studied. Admission blood glucose level, maximum blood glucose during the hospital stay, and serial blood glucose measurements within the first 24 h of hospital admission were recorded. Variability in blood glucose level was represented by the standard deviation of the serial measurements within the first 24 h. The following demographic and clinical data was also collected: age, sex, baseline NIHSS score, onset-to-reperfusion times, hemoglobin A1c, and stroke mechanism. RESULTS: 79 patients were identified; at 3 months, 35 patients had an mRS score of 0-2 and 44 had had an mRS of 3-6. Among the blood glucose variables, standard deviation of blood glucose in the first 24 h following admission and maximum blood glucose during hospital stay were significantly higher in the mRS 3-6 group. In multivariate logistic regression analysis, only the standard deviation of blood glucose remained significant (OR = 1.07, 95% CI = 1.02-1.11, p = 0.003) in a model that adjusted for admission NIHSS score (p = 0.016) and number of stent retriever passes (p = 0.042). CONCLUSIONS: Greater blood glucose variability following acute ischemic stroke is associated with worse clinical outcome in patients undergoing mechanical thrombectomy.

Modeling Psychomotor Retardation using iPSCs from MCT8-Deficient Patients Indicates a Prominent Role for the Blood-Brain Barrier.

Inactivating mutations in the thyroid hormone (TH) transporter Monocarboxylate transporter 8 (MCT8) cause severe psychomotor retardation in children. Animal models do not reflect the biology of the human disease. Using patient-specific induced pluripotent stem cells (iPSCs), we generated MCT8-deficient neural cells that showed normal TH-dependent neuronal properties and maturation. However, the blood-brain barrier (BBB) controls TH entry into the brain, and reduced TH availability to neural cells could instead underlie the diseased phenotype. To test potential BBB involvement, we generated an iPSC-based BBB model of MCT8 deficiency, and we found that MCT8 was necessary for polarized influx of the active form of TH across the BBB. We also found that a candidate drug did not appreciably cross the mutant BBB. Our results therefore clarify the underlying physiological basis of this disorder, and they suggest that circumventing the diseased BBB to deliver active TH to the brain could be a viable therapeutic strategy.

Tunable Expression Tools Enable Single-Cell Strain Distinction in the Gut Microbiome.

Applying synthetic biology to engineer gut-resident microbes provides new avenues to investigate microbe-host interactions, perform diagnostics, and deliver therapeutics. Here, we describe a platform for engineering Bacteroides, the most abundant genus in the Western microbiota, which includes a process for high-throughput strain modification. We have identified a novel phage promoter and translational tuning strategy and achieved an unprecedented level of expression that enables imaging of fluorescent-protein-expressing Bacteroides stably colonizing the mouse gut. A detailed characterization of the phage promoter has provided a set of constitutive promoters that span over four logs of strength without detectable fitness burden within the gut over 14 days. These promoters function predictably over a 1,000,000-fold expression range in phylogenetically diverse Bacteroides species. With these promoters, unique fluorescent signatures were encoded to allow differentiation of six species within the gut. Fluorescent protein-based differentiation of isogenic strains revealed that priority of gut colonization determines colonic crypt occupancy.