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Nurseries and greenhouses face challenges of limited water supply and increased demand for irrigation efficiency to minimize runoff and mitigate water loss to the environment. Overhead irrigation systems are among the most widely used methods for container plants, particularly in small container sizes. However, there is a lack of research examining the distribution uniformity (DU) of the most used sprinklers in nursery settings. Our study investigated the DU of different overhead sprinkler types and models commonly used in outdoor nurseries in the United States to guide greater adoption of higher irrigation efficiency technology. Catch-can experiments compared ten different sprinkler models in small (4.6 m × 4.6 m) and large (9.1 m × 9.1 m) square experimental plots in Irvine, California. We measured water volume, wind speed, and operating pressure, and calculated the application rate for 189 test runs conducted between Mar 2020 and May 2023. Our results show that of the models tested, the greatest DU was achieved by the Hunter MP2000 at 276 kPa (DU = 0.78 ± 0.05) in the small spacing, and the Senninger Xcel Wobbler with a 3.97 mm nozzle at 172 kPa (DU = 0.76 ± 0.06) in the large spacing. Wind speed and operating conditions affected the DU and spatial uniformity of irrigation among the ten models, highlighting the importance of maintaining operating pressures at the manufacturer's recommendations to ensure optimal application rates and DU. Together these results offer a quantitative comparison of sprinkler performance at different operating pressure and in a wide range of wind speeds, allowing users to select sprinkler models that best fit their operation and maximize water conservation.

Hexavalent chromium (Cr[VI]) is a widespread environmental pollutant in air and water that is primarily attributed to industrial pollution. The current maximum contaminant levels (MCLs) for drinking water from the World Health Organization and the U.S. Environmental Protection Agency (0.05 and 0.1 mg/L, respectively) were set based on contact dermatitis and warrant further toxicological investigation. While Cr(VI) is neurotoxic and accumulates in the brain, most animal studies only report whole-brain Cr, leaving large knowledge gaps. Few studies consider differences between ages or sexes, and fewer consider essential metal dyshomeostasis. We sought to investigate where Cr accumulates in the brain, considering sex and age differences, following a 90-day drinking water exposure to current MCLs. Here, we report Cr levels in six brain regions of rats exposed to drinking water Cr(VI). We observed Cr only accumulated in the hippocampus, and only in older females. We further assessed changes to essential metals in the hippocampus, observing opposite effects across sexes and between young rats compared to older rats. In sum, our data indicate drinking water Cr(VI) selectively targeted the hippocampus, with geriatric females accumulating the most Cr, and induced significant essential metal dyshomeostasis even in tissues lacking evident Cr accumulation.

Background Standard first-line therapies for metastatic colorectal cancer (mCRC) include fluoropyrimidine-containing regimens with oxaliplatin and/or irinotecan and a biologic agent. Immunotherapy may enhance antitumor activity in combination with standard therapies in patients with mCRC. Here, we present phase 2 results of nivolumab plus standard-of-care therapy (SOC; 5-fluorouracil/leucovorin/oxaliplatin/bevacizumab) versus SOC in the first-line treatment of patients with mCRC (CheckMate 9X8).Methods CheckMate 9X8 was a multicenter, open-label, randomized, phase 2/3 trial. Eligible patients were at least 18 years of age with unresectable mCRC and no prior chemotherapy for metastatic disease. Patients were randomized 2:1 to receive nivolumab 240 mg plus SOC or SOC alone every 2 weeks. The primary endpoint was progression-free survival (PFS) by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors V.1.1. Secondary endpoints included PFS by investigator assessment; objective response rate (ORR), disease control rate, duration of response, and time to response, all by BICR and investigator assessments; overall survival; and safety. Preplanned exploratory biomarker analyses were also performed.Results From February 2018 through April 2019, 310 patients were enrolled, of which 195 patients were randomized to nivolumab plus SOC (n=127) or SOC (n=68). At 21.5-month minimum follow-up, PFS with nivolumab plus SOC versus SOC did not meet the prespecified threshold for statistical significance; median PFS by BICR was 11.9 months in both arms (HR, 0.81 (95% CI, 0.53 to 1.23); p=0.30). Higher PFS rates after 12 months (18 months: 28% vs 9%), higher ORR (60% vs 46%), and durable responses (median 12.9 vs 9.3 months) were observed with nivolumab plus SOC versus SOC. Grade 3–4 treatment-related adverse events were reported in 75% versus 48% of patients; no new safety signals were identified.Conclusions The CheckMate 9X8 trial investigating first-line nivolumab plus SOC versus SOC in patients with mCRC did not meet its primary endpoint of PFS by BICR. Nivolumab plus SOC showed numerically higher PFS rates after 12 months, a higher response rate, and more durable responses compared with SOC alone, with acceptable safety. Further investigation to identify subgroups of patients with mCRC that may benefit from nivolumab plus SOC versus SOC in the first-line setting is warranted.Trial registration number NCT03414983.

We are facing a critical aging crisis, with geriatric populations (65+) growing to unprecedented proportions and ~4 million people (a 6.5-fold increase) expected to become centenarians by 2050. This is compounded by environmental pollution, which affects individuals of all ages and contributes to age-related diseases. As we have a limited understanding of how environmental pollutants affect older populations distinctly from younger populations, these longer-lived geriatric populations present a key knowledge gap. To address this knowledge gap, we employ a “Toxic Aging Coin” approach: heads consider how age impacts chemical toxicity, and tails consider how chemicals act as gerontogens—or how they accelerate biological aging. We employed this approach to investigate hexavalent chromium (Cr[VI]) impacts on female rats exposed to 0.05 or 0.1 mg Cr(VI)/L in drinking water for 90 days; these are the maximum contaminant levels (i.e., the highest levels permitted) from the World Health Organization and U.S. Environmental Protection Agency, respectively. During exposure, rats performed a battery of behavior assays to assess grip strength, locomotor coordination, anxiety, spatial memory, sociability, and social novelty preference. We observed age differences in Cr(VI) neurotoxicity, with grip strength, locomotor function, and spatial memory in middle-aged females being particularly affected. We further compared these results in females to results in males, noting many sex differences, especially in middle-aged rats. These data emphasize the need to consider age and sex as variables in toxicology and to revisit drinking water regulations for Cr(VI).

BackgroundAnatomic complications of the ureteroenteric anastomosis in ileal conduit (IC) cause significant morbidity in patients post-cystectomy and cystoprostatectomy. The Bricker technique has a perceived disadvantage of increased risk for stricture, whereas the Wallace technique runs the risk for ureteral malignancy affecting both ureteric ends, and bilateral ureteric obstruction from a stone lodged at the anastomosis. We aimed to evaluate the safety, efficacy, and stricture rate of a novel hybrid ureteroenteric anastomosis technique. We compared these outcomes to the Bricker and Wallace anastomosis techniques for IC urinary diversion (ICUD). MethodsWe performed a retrospective chart review of patients who had undergone ICUD after cystectomy for bladder cancer from 2011 to 2016. Patients were categorized into groups undergoing the Bricker, Wallace, and hybrid ureteroanastomosic techniques. Strictures were identified during clinical follow-up or hospital presentations with complications. ResultsWe identified 68 patients suitable for inclusion. They were separated by Bricker, Wallace, and hybrid anastomosis techniques, with 19 (27.9%), 20 (29.4%), and 29 (42.6%) patients, respectively. Ureteroenteric anastomotic strictures occurred in 9 patients (5 Bricker, 3 Wallace, 1 hybrid). This difference in stricture rates for Bricker versus hybrid (26.3% vs. 3.4%; OR, 10 [95% CI, 1.1 to 121.1]; P = 0.02) was significant but was comparable for Wallace versus hybrid (15.0% vs. 3.4%; OR, 4.9 [0.7 to 66.0]; P = 0.15) and for Bricker versus Wallace (26.3% vs. 15.0%; OR, 2 [0.4 to 8.6]; P = 0.87). 15 patients (51%) in the hybrid group required oral antibiotics for a symptomatic urinary tract infection compared with 4 (21%) with Bricker and 8 (40%) with Wallace (P = 0.10). Median post-cystectomy follow-up and stricture formation time were 16 months (IQR, 4–36) and 9 months (7–32), respectively. ConclusionThe hybrid technique is a safe and efficacious alternative to the Bricker and Wallace anastomoses. It carries with it a risk for urinary tract infection that is eclipsed by substantially lowered rates of ureteric strictures requiring intervention while maintaining the advantage of separating the two ureters.

ObjectiveTo characterize academic urology Twitter presence and interaction by subspecialty designation. MethodsUsing Twitter application programming interface of available data, 94000 specific tweets were extracted for the analysis through the Twitter Developer Program. Academic urologists were defined based on American Urological Association (AUA) residency program registration of 143 residency programs, with a total of 2377 faculty. Two of 3-factor verification (name, location, specialty) of faculty Twitter account was used. Additional faculty information including sex, program location, and subspecialty were manually recorded. All elements of microblogging were captured through Anaconda Navigator. Analyzed tweets were further evaluated using natural language processing for sentiment association, mentions, and quote tweeted and retweeted. Network analysis based on interactions of academic urologist within specialty for given topic were analyzed using D3 in JavaScript. Analysis was performed in Python and R. ResultsWe identified 143 residency programs with a total of 2377 faculty (1975 men and 402 women). Among all faculty, 945 (39.7%) had registered Twitter accounts, with the majority being men (759 [80.40%] versus 185 [19.60%]). Although there were more male academic urologists across programs, women within academic urology were more likely to have a registered Twitter account overall (46% versus 38.5%) compared with men. When assessing registered accounts by sex, there was a peak for male faculty in 2014 (10.05% of all accounts registered) and peak for female faculty in 2015 (2.65%). There was no notable change in faculty account registration during COVID-19 (2019–2020). In 2022, oncology represented the highest total number of registered Twitter users (225), with the highest number of total tweets (24622), followers (138541), and tweets per user per day (0.32). However, andrology (50%) and reconstruction (51.3%) were 2 of the highest proportionally represented subspecialties within academic urology. Within the context of conversation surrounding a specified topic (#aua21), female pelvic medicine and reconstructive surgery (FPMRS) and endourology demonstrated the total highest number of intersubspecialty conversations. ConclusionsThere is a steady increase in Twitter representation among academic urologists, largely unaffected by COVID-19. While urologic oncology represents the largest group, andrology and reconstructive urology represent the highest proportion of their respective subspecialties. Interaction analysis highlights the variant interaction among subspecialties based on topic, with strong direct ties between endourology, FPMRS, and oncology.

Pharmacists are well-positioned to help increase pediatric immunization rates. This study assessed the types of pediatric vaccines offered in community pharmacies, compared participant/pharmacy characteristics and participants’ perceptions of barriers and pharmacists’ role in providing pediatric immunizations between pharmacy-based providers and non-providers, and assessed factors associated with pharmacy-based pediatric immunization provision. A cross-sectional survey was sent to Alabama community pharmacies from February to April 2023, of which 240 responded (20.5% response rate). Measures included whether they offered childhood vaccines in 2022 and the types of vaccines administered, participants’ perceptions of pharmacists’ role in pediatric immunization, and perceived barriers to providing pharmacy-based pediatric immunizations. Roughly half of pharmacies (50.8%) provided pediatric immunization services with influenza vaccines (91.0%) the most commonly provided vaccines and poliovirus-inactivated vaccines (4.9%) the least. Pharmacies providing pediatric immunization services significantly differed from non-providers. That is, the majority of providers practiced within a grocery or retail store; they were younger and practiced in a pharmacy with higher average daily prescription volume and a higher average pharmacy practice full-time equivalent; and they perceived lower implementation logistics barriers and a lower role of pharmacists regarding pediatric immunization. Multivariable logistic regression analysis indicated that implementation logistics is significantly associated with pharmacies offering pediatric immunization services after controlling for pharmacy/participant characteristics (p = 0.01). Therefore, ameliorating implementation logistics barriers should be considered when devising strategies to promote pediatric immunization services in community pharmacies.

Kratom (Mitragyna speciosa) is a botanical substance whose leaves produce stimulant- and opioid-like effects. Kratom use has increased precipitously in the United States (U.S.) over the last decade, yet, in our experience, many pharmacists are unfamiliar with this herb. The purpose of this study was to assess pharmacists’ awareness and knowledge of kratom. This cross-sectional study used an online questionnaire to preferentially solicit community pharmacists’ knowledge of kratom and collect demographic information. The survey was sent via email to approximately 10,000 pharmacists, targeting those in the state of Alabama, U.S. Data were analyzed using descriptive statistics, and the Chi Square test was used to compare nominal data. A total of 257 participants responded to the survey. Almost 50% of participants had heard of kratom, and 50% had not. Compared to females, males were more likely to have heard of kratom (64% vs. 42%; p = 0.0015), as were pharmacists who worked for an independent pharmacy vs. a chain (61% vs. 41%; p = 0.025). Of the participants who had heard of kratom, only 14% considered themselves knowledgeable or very knowledgeable about the herb, and only 44% knew it was illegal in Alabama. These data indicate a need to further kratom education among community pharmacists in Alabama.

Abstract This study assesses attitudes towards COVID-19 vaccination and the predictive value of COVID-VAC, a novel scale, among adults in the four largest US metropolitan areas and nationally. A 36-item survey of 6037 Americans was conducted in mid-April 2021. The study reports factors for COVID-19 vaccine acceptance among: (1) already vaccinated; (2) unvaccinated but willing to accept a vaccine; and (3) unvaccinated and unwilling to vaccinate. More than 20% were unwilling to vaccinate, expressing concerns about vaccine efficacy and safety and questioning the disease’s severity. Poverty, working outside of the home and conservative political views are predictors of unwillingness. Conversely, those who either personally tested positive for COVID-19, or had a family member who did so, were more likely to accept vaccination. Majorities of all respondents supported vaccination mandates for employees and university students. Respondents preferred to receive vaccines in their doctor´s office. Lower income and conservative ideology, but not race, were strongly associated with vaccine unwillingness. The predictive value of COVID-VAC was demonstrated. While vaccination mandates are likely to be accepted, additional effective, targeted interventions to increase vaccine uptake are needed urgently.

One of the possible options for spent-fuel management in Korea is pyroprocessing, which is a process for electrochemical recycling of spent nuclear fuel. Nuclear material accountancy is considered to be a safeguards measure of fundamental importance, for the purposes of which, the amount of nuclear material in the input and output materials should be measured as accurately as possible by means of chemical analysis and/or non-destructive assay. In the present study, a neutron measurement system based on the fast-neutron energy multiplication (FNEM) and passive neutron albedo reactivity (PNAR) techniques was designed for nuclear material accountancy of a spent-fuel assembly (i.e., the input accountancy of a pyroprocessing facility). Various parameters including inter-detector distance, source-to-detector distance, neutron-reflector material, the structure of a cadmium sleeve around the close detectors, and an air cavity in the moderator were investigated by MCNP6 Monte Carlo simulations in order to maximize its performance. Then, the detector responses with the optimized geometry were estimated for the fresh-fuel assemblies with different 235U enrichments and a spent-fuel assembly. It was found that the measurement technique investigated here has the potential to measure changes in neutron multiplication and, in turn, amount of fissile material. Keywords: Nondestructive assay, Nuclear safeguards, Nuclear material accountancy, Spent-fuel assembly

Clostridioides difficile infections (CDIs), and particularly recurrent infections, cause a significant burden on the health-care system. Bezlotoxumab is a new agent for the prevention of recurrent CDIs that has shown strong efficacy and high tolerability in clinical trials. The purpose of this review is to evaluate the published literature for bezlotoxumab, with a focus on literature published since the release of the 2021 focused update to the CDI treatment guidelines. A Medline/PubMed search for “bezlotoxumab” was conducted, resulting in 152 articles. Seventeen studies are included in this review, after excluding non-English-language papers, phase I and II trials, and review articles. Studies published since the 2021 focused update support the recommendations in those guidelines. Furthermore, real-world studies have shown similar results to larger clinical trials. Those with more risk factors for recurrent CDI appear to benefit most from bezlotoxumab. Currently, there are no data to support the use of bezlotoxumab outside current guideline recommendations, but future trials may build on the data seen in real-world studies to further elucidate the place in therapy for bezlotoxumab.

Inexpensive, simple, rapid diagnostics are necessary for efficient detection, treatment, and mitigation of COVID-19. Assays for SARS-CoV2 using reverse transcription polymerase chain reaction (RT-PCR) offer good sensitivity and excellent specificity, but are expensive, slowed by transport to centralized testing laboratories, and often unavailable. Antigen-based assays are inexpensive and can be rapidly mass-produced and deployed at point-of-care, with lateral flow assays (LFAs) being the most common format. While various manufacturers have produced commercially available SARS-Cov2 antigen LFAs, access to validated tests remains difficult or cost prohibitive in low-and middle-income countries. Herein, we present a visually read open-access LFA (OA-LFA) using commercially-available antibodies and materials for the detection of SARS-CoV-2. The LFA yielded a Limit of Detection (LOD) of 4 TCID50/swab of gamma irradiated SARS-CoV-2 virus, meeting the acceptable analytical sensitivity outlined by in World Health Organization target product profile. The open-source architecture presented in this manuscript provides a template for manufacturers around the globe to rapidly design a SARS-CoV2 antigen test.

Category: Hindfoot; Ankle Introduction/Purpose: Achilles Tendon (AT) rupture is the most common tendon rupture in the lower extremity with an incidence of 2.1 AT ruptures per 100,000 person years. Due to the non-emergent nature of this injury, a delay in presentation may occur leading to delays in diagnosis and treatment; which may alter both nonoperative and operative management. Health insurance status may directly impact time to presentation for many patients. To our knowledge, no study has evaluated the effect of insurance status on delay in diagnosis and treatment of AT rupture. Methods: From December 2013 to December 2018, 89 patients with AT ruptures who underwent surgical management were identified by CPT code in a dual-institution retrospective chart analysis. Demographic and injury-specific data were obtained with attention to the date of injury, date of diagnosis, location of initial presentation (clinic vs. emergency room), and number of medical visits. A univariate two tail t test was used to compare various groups. Statistical significance was set at p < 0.05 to determine the effects of insurance type on the time to diagnosis and treatment of acute AT ruptures. Results: When compared to adequately insured patients (private and Medicare), underinsured patients (uninsured and Medicaid) experienced a significantly greater time from the date of: injury to first clinic visit (14.5 days versus 5.2 days, p < 0.001), first clinic visit to surgery (34.6 days versus 4.8 days, p < 0.002), injury to surgery date (48.9 days versus 9.8 days, p < 0.001), initial presentation to when magnetic resonance imaging (MRI) was obtained (48.1 days versus 1.9 days, p < 0.002), and initial presentation to diagnosis (22.8 days versus 1.71 days, p < 0.029). Conclusion: Disparities in access to care are intimately related to insurance status. Uninsured and medicaid patients are subject to institutional delays and decreased access to care when compared to patients with private insurance. Under and uninsured patients are significantly more likely to present to the emergency department for their initial visit, potentially resulting in increased healthcare costs. Emergency department visits as well as difficulty in obtaining an appointment with an orthopedic surgeon may directly contribute to delay in diagnosis.

QBMMlib is an open source package of quadrature-based moment methods and their algorithms. Such methods are commonly used to solve fully-coupled disperse flow and combustion problems, though formulating and closing the corresponding governing equations can be complex. QBMMlib aims to make analyzing these techniques simple and more accessible. Its routines use symbolic manipulation to formulate the moment transport equations for a population balance equation and a prescribed dynamical system. The resulting moment transport equations are closed by first trading the moments for a set of quadrature points and weights via an inversion algorithm, of which several are available. Quadratures then compute the moments required for closure. Embedded code snippets show how to use QBMMlib, with the algorithm initialization and solution spanning just 13 total lines of code. Examples are shown and analyzed for a linear harmonic oscillator and a bubble dynamics problem.

The conservation and management of subterranean biodiversity is hindered by a lack of knowledge on the true distributions for many species, e.g., the Wallacean shortfall. In recent years, several studies have demonstrated the potential of environmental DNA (eDNA) as an effective approach to detect and monitor biodiversity, including rare, threatened, and endangered taxa. However, there are few eDNA studies of groundwater fauna. Here we report the results of the development and implementation of an eDNA assay targeting a short fragment of the mitochondrial CO1 locus of a critically imperiled cave crayfish, the Sweet Home Alabama Cave Crayfish (Cambarus speleocoopi), known from just four cave systems in the Interior Plateau karst region of northern Alabama. We detected C. speleocoopi DNA from water samples collected at 5 of 16 sites sampled (caves and springs), including two historical sites as well as three additional and potentially new sites in Marshall County, Alabama. All three of these sites were within 2 km of historical sites. Our study is the first to detect a groundwater crustacean in the Interior Plateau karst region. Additionally, our study contributes to the growing literature that eDNA is a viable complementary tool for detection and monitoring of a fauna that is difficult to survey and study using traditional approaches.

Abstract Geologic mapping, a magnetotelluric survey, well data, and earlier reports are integrated to guide further development of the Fang geothermal system. The Fang Hot Springs originally flowed ~ 20 l s−1 of 90–99 °C water from a 10-hectare area of crystalline rocks presumed to be of Triassic age. Four wells 92–500 m deep now flow ~ 20 l s−1 of 110–115 °C water and generate 115–250 kWe from the 1989 Ormat binary power plant. Wells are not pumped nor is the spent water re-injected. Temperatures of 130 °C occur in some wells and water chemistry indicates reservoir temperatures of 150 °C. The springs now flow ~ 10 l s−1. The Fang geothermal area is at the west end of the active left-lateral strike-slip Mae Chan fault (MCF). MCF transitions to extensional faulting along the western boundary of the Cenozoic Fang basin. The hot waters emanate from crystalline rocks 0.7 km north of the MCF. Permeable fractures may be tensile fractures at the right-stepping fault tip. The less permeable MCF fault core and Cenozoic sediments of the Fang basin to the SW are not considered to be drilling targets. Unrelated to the fracture system is the Doi Kia detachment fault which places Paleozoic sediments over crystalline rock with a low-angle contact. Electrical resistivity surveys detect low resistivity ( 100 Ωm. Low resistivity is caused mostly by conductive minerals of hydrothermal alteration, and not by the geothermal water of resistivity 5.6 Ωm. No deep resistivity anomaly is detected beneath the seeps or producing wells, although resolution of past surveys would not have imaged narrow zones of alteration. High-resolution resistivity surveys focused on detecting the deeper fracture system are recommended over the hot well area and south over the area underlain by crystalline rocks. Future development should focus on drilling wells (≤ 500 m) with diameters large enough to install submersible pumps to increase flows. Development of several MWe may be possible and should include a designed re-injection well system to sustain pump levels.

Studying the correlation between temperature-driven molecular structure and nuclear spin dynamics is essential to understanding fundamental design principles for thermometric nuclear magnetic resonance spin-based probes. Herein, we study the impact of progressively encapsulating ligands on temperature-dependent 59Co T1 (spin–lattice) and T2 (spin–spin) relaxation times in a set of Co(III) complexes: K3[Co(CN)6] (1); [Co(NH3)6]Cl3 (2); [Co(en)3]Cl3 (3), en = ethylenediamine); [Co(tn)3]Cl3 (4), tn = trimethylenediamine); [Co(tame)2]Cl3 (5), tame = triaminomethylethane); and [Co(dinosar)]Cl3 (6), dinosar = dinitrosarcophagine). Measurements indicate that 59Co T1 and T2 increase with temperature for 1–6 between 10 and 60 °C, with the greatest ΔT1/ΔT and ΔT2/ΔT temperature sensitivities found for 4 and 3, 5.3(3)%T1/°C and 6(1)%T2/°C, respectively. Temperature-dependent T2* (dephasing time) analyses were also made, revealing the highest ΔT2*/ΔT sensitivities in structures of greatest encapsulation, as high as 4.64%T2*/°C for 6. Calculations of the temperature-dependent quadrupolar coupling parameter, Δe2qQ/ΔT, enable insight into the origins of the relative ΔT1/ΔT values. These results suggest tunable quadrupolar coupling interactions as novel design principles for enhancing temperature sensitivity in nuclear spin-based probes.

Urinary tract infections (UTIs) are a commonly diagnosed problem in long-term care facilities (LTCFs), but antimicrobial treatment is often incorrectly prescribed. Although bacterial resistance to antimicrobials commonly used for UTIs, such as trimethoprim/sulfamethoxazole and fluoroquinolones, has been dramatically increasing, they are still commonly prescribed. The purpose of this project was to determine if implementation of a standard treatment protocol for UTIs, which emphasized correct UTI diagnosis and use of nitrofurantoin and cefpodoxime/ceftriaxone as empiric therapy per the institutional antibiogram, changed clinician prescribing practices. This quasi-experimental model utilized two years of pre-intervention and two years of post-intervention data. Three hundred patient encounters were included. Antibiotics prescribed in the pre-intervention period included: trimethoprim/sulfamethoxazole (32%), ciprofloxacin (14%), amoxicillin (13%), levofloxacin (9%), cefpodoxime (9%), ceftriaxone (8%), amoxicillin/clavulanate (5%), nitrofurantoin (4%), and other (6%). By contrast, antibiotics prescribed in the post-intervention period included: cefpodoxime (46%), nitrofurantoin (30%), ceftriaxone (10%), trimethoprim/sulfamethoxazole (8%), amoxicillin/clavulanate (1%), and other (5%). These differences in prescribed drug between the pre-intervention and post-intervention encounters were statistically significant (p < 0.001). Overall, appropriate empiric treatment was prescribed in only 48/217 encounters (22%) during the pre-intervention period, but this increased to 73/83 encounters (88%) in the post-intervention period (p < 0.001). The results indicate that the treatment protocol was successful in changing prescribing practices and decreasing the use of inappropriate antimicrobials at the LTCF.

Clinical trials that led to ibrutinib’s approval for the treatment of chronic lymphocytic leukemia showed that its side effects differ from those of traditional chemotherapy. Reasons for discontinuation in clinical practice have not been adequately studied. We conducted a retrospective analysis of chronic lymphocytic leukemia patients treated with ibrutinib either commercially or on clinical trials. We aimed to compare the type and frequency of toxicities reported in either setting, assess discontinuation rates, and evaluate outcomes. This multicenter, retrospective analysis included ibrutinib-treated chronic lymphocytic leukemia patients at nine United States cancer centers or from the Connect® Chronic Lymphocytic Leukemia Registry. We examined demographics, dosing, discontinuation rates and reasons, toxicities, and outcomes. The primary endpoint was progression-free survival. Six hundred sixteen ibrutinib-treated patients were identified. A total of 546 (88%) patients were treated with the commercial drug. Clinical trial patients were younger (mean age 58 versus 61 years, P=0.01) and had a similar time from diagnosis to treatment with ibrutinib (mean 85 versus 87 months, P=0.8). With a median follow-up of 17 months, an estimated 41% of patients discontinued ibrutinib (median time to ibrutinib discontinuation was 7 months). Notably, ibrutinib toxicity was the most common reason for discontinuation in all settings. The median progression-free survival and overall survival for the entire cohort were 35 months and not reached (median follow-up 17 months), respectively. In the largest reported series on ibrutinib- treated chronic lymphocytic leukemia patients, we show that 41% of patients discontinued ibrutinib. Intolerance as opposed to chronic lymphocytic leukemia progression was the most common reason for discontinuation. Outcomes remain excellent and were not affected by line of therapy or whether patients were treated on clinical studies or commercially. These data strongly argue in favor of finding strategies to minimize ibrutinib intolerance so that efficacy can be further maximized. Future clinical trials should consider time-limited therapy approaches, particularly in patients achieving a complete response, in order to minimize ibrutinib exposure.

Parasitic helminth infections can be associated with lifelong morbidity such as immune-mediated organ failure. A better understanding of the host immune response to helminths could provide new avenues to promote parasite clearance and/or alleviate infection-associated morbidity. Murine resistin-like molecules (RELM) exhibit pleiotropic functions following helminth infection including modulating the host immune response; however, the relevance of human RELM proteins in helminth infection is unknown. To examine the function of human resistin (hResistin), we utilized transgenic mice expressing the human resistin gene (hRetnTg+). Following infection with the helminth Nippostrongylus brasiliensis (Nb), hResistin expression was significantly upregulated in infected tissue. Compared to control hRetnTg- mice, hRetnTg+ mice suffered from exacerbated Nb-induced inflammation characterized by weight loss and increased infiltration of inflammatory monocytes in the lung, along with elevated Nb egg burdens and delayed parasite expulsion. Genome-wide transcriptional profiling of the infected tissue revealed that hResistin promoted expression of proinflammatory cytokines and genes downstream of toll-like receptor signaling. Moreover, hResistin preferentially bound lung monocytes, and exogenous treatment of mice with recombinant hResistin promoted monocyte recruitment and proinflammatory cytokine expression. In human studies, increased serum resistin was associated with higher parasite load in individuals infected with soil-transmitted helminths or filarial nematode Wuchereria bancrofti, and was positively correlated with proinflammatory cytokines. Together, these studies identify human resistin as a detrimental factor induced by multiple helminth infections, where it promotes proinflammatory cytokines and impedes parasite clearance. Targeting the resistin/proinflammatory cytokine immune axis may provide new diagnostic or treatment strategies for helminth infection and associated immune-mediated pathology.

Abstract Background Molecular switch systems that activate gene expression by a small molecule are effective technologies that are widely used in applied biological research. Nuclear receptors are valuable candidates for these regulation systems due to their functional role as ligand activated transcription factors. Previously, our group engineered a variant of the retinoid × receptor to be responsive to the synthetic compound, LG335, but not responsive to its natural ligand, 9-cis-retinoic acid. Results This work focuses on characterizing a molecular switch system that quantitatively controls transgene expression. This system is composed of an orthogonal ligand/nuclear receptor pair, LG335 and GRQCIMFI, along with an artificial promoter controlling expression of a target transgene. GRQCIMFI is composed of the fusion of the DNA binding domain of the yeast transcription factor, Gal4, and a retinoid × receptor variant. The variant consists of the following mutations: Q275C, I310M, and F313I in the ligand binding domain. When introduced into mammalian cell culture, the switch shows luciferase activity at concentrations as low as 100 nM of LG335 with a 6.3 ± 1.7-fold induction ratio. The developed one-component system activates transgene expression when introduced transiently or virally. Conclusions We have successfully shown that this system can induce tightly controlled transgene expression and can be used for transient transfections or retroviral transductions in mammalian cell culture. Further characterization is needed for gene therapy applications.

Abstract Background The successful interaction of bacterial pathogens with host tissues requires the sensing of specific chemical and physical cues. The human gut contains a huge number of neurons involved in the secretion and sensing of a class of neuroendocrine hormones called catecholamines. Recently, in Escherichia coli O157:H7, the catecholamines adrenaline and noradrenaline were shown to act synergistically with a bacterial quorum sensing molecule, autoinducer 3 (AI-3), to affect bacterial virulence and motility. We wished to investigate the impact of adrenaline on the biology of Salmonella spp. Results We have determined the effect of adrenaline on the transcriptome of the gut pathogen Salmonella enterica serovar Typhimurium. Addition of adrenaline led to an induction of key metal transport systems within 30 minutes of treatment. The oxidative stress responses employing manganese internalisation were also elicited. Cells lacking the key oxidative stress regulator OxyR showed reduced survival in the presence of adrenaline and complete restoration of growth upon addition of manganese. A significant reduction in the expression of the pmrHFIJKLM antimicrobial peptide resistance operon reduced the ability of Salmonella to survive polymyxin B following addition of adrenaline. Notably, both phenotypes were reversed by the addition of the β-adrenergic blocker propranolol. Our data suggest that the BasSR two component signal transduction system is the likely adrenaline sensor mediating the antimicrobial peptide response. Conclusion Salmonella are able to sense adrenaline and downregulate the antimicrobial peptide resistance pmr locus through the BasSR two component signalling system. Through iron transport, adrenaline may affect the oxidative stress balance of the cell requiring OxyR for normal growth. Both adrenaline effects can be inhibited by the addition of the β-adrenergic blocker propranolol. Adrenaline sensing may provide an environmental cue for the induction of the Salmonella stress response in anticipation of imminent host-derived oxidative stress. However, adrenaline may also serve in favour of the host defences by lowering antimicrobial peptide resistance and hence documenting for the first time such a function for a hormone.

Working with a prominent mentor can offer many benefits to one's career: mentors provide skills, resources, and values that leave a lasting imprint. Yet, these promising starting points also present a puzzle as people make sense of their careers further on: they must acknowledge their association with their prominent mentor, without being overshadowed by them. We refer to this tension as the paradox of promise. Through a qualitative study of former employees at the Eames Office, we examine how individuals navigate the paradox of promise as they construct retrospective career narratives. We find that individuals narrate their formative experience as imprints, but with two distinct emphases—values-dominant imprints versus skills-dominant imprints. Individuals then narrate their later career experiences by reprinting, reinforcing the existing meaning or finding new meaning in relation to their imprint; we induced three reprinting practices: (a) embracing values, (b) contrasting values, and (c) supplanting values. Using imprints and reprinting, former Eames employees crafted overarching sources of career meaningfulness: belongingness narratives, emphasizing collaboration and contribution with others; self-expression narratives, emphasizing authenticity and freedom; and achievement narratives, emphasizing expertise and accomplishment. Our study contributes to interpretive perspectives of career success and mentor relationships, and how meaningfulness is constructed over the career. [ABSTRACT FROM AUTHOR]

Hexavalent chromium (Cr[VI]) is a widespread environmental pollutant in air and water that is primarily attributed to industrial pollution. The current maximum contaminant levels (MCLs) for drinking water from the World Health Organization and the U.S. Environmental Protection Agency (0.05 and 0.1 mg/L, respectively) were set based on contact dermatitis and warrant further toxicological investigation. While Cr(VI) is neurotoxic and accumulates in the brain, most animal studies only report whole-brain Cr, leaving large knowledge gaps. Few studies consider differences between ages or sexes, and fewer consider essential metal dyshomeostasis. We sought to investigate where Cr accumulates in the brain, considering sex and age differences, following a 90-day drinking water exposure to current MCLs. Here, we report Cr levels in six brain regions of rats exposed to drinking water Cr(VI). We observed Cr only accumulated in the hippocampus, and only in older females. We further assessed changes to essential metals in the hippocampus, observing opposite effects across sexes and between young rats compared to older rats. In sum, our data indicate drinking water Cr(VI) selectively targeted the hippocampus, with geriatric females accumulating the most Cr, and induced significant essential metal dyshomeostasis even in tissues lacking evident Cr accumulation. [ABSTRACT FROM AUTHOR]

Fluid flow simulations marshal our most powerful computational resources. In many cases, even this is not enough. Quantum computers provide an opportunity to speed up traditional algorithms for flow simulations. We show that lattice-based mesoscale numerical methods can be executed as efficient quantum algorithms due to their statistical features. This approach revises a quantum algorithm for lattice gas automata to reduce classical computations and state preparation at every time step. For this, the algorithm approximates the qubit relative phases and subtracts them at the end of each time step. Phases are evaluated using the iterative phase estimation algorithm and subtracted using single-qubit rotation phase gates. This method optimizes the quantum resource required and makes it more appropriate for near-term quantum hardware. We also demonstrate how the checkerboard deficiency that the D1Q2 scheme presents can be resolved using the D1Q3 scheme. The algorithm is validated by simulating two canonical partial differential equations: the diffusion and Burgers' equations on different quantum simulators. We find good agreement between quantum simulations and classical solutions for the presented algorithm. [ABSTRACT FROM AUTHOR]