Selective Cytopheretic Device Use in Continuous Kidney Replacement Therapy in Children: A Cohort Study With a Historical Comparator.

Rationale and Objective: Critically ill children with acute kidney injury (AKI) requiring continuous renal replacement therapy (CRRT) are at increased risk of death. The selective cytopheretic device (SCD) promotes an immunomodulatory effect at circuit-ionized calcium of <0.40 mmol/L. In an adult CRRT patient study, SCD-treated patients reported improved survival or dialysis independence. We reported safety data from children who received CRRT-SCD therapy and compared outcomes with a historic pediatric CRRT cohort. Study Design: We performed 2 prospective multicenter studies to evaluate the safety and feasibility of SCD in critically ill children. Setting and Participants: Four pediatric institutions enrolled children weighing 10 kg or more with AKI and multi-organ dysfunction receiving CRRT as the standard of care with the SCD-integrated post-CRRT membrane. Exposure: Patients received CRRT-SCD with regional citrate anticoagulation for up to 7-10 days, or CRRT discontinuation, whichever came first. Analytical Approach: We reported serious adverse events among patients and CRRT-SCD-related process and outcome variables. We compared survival to intensive care unit (ICU) discharge rates between the CRRT-SCD cohort and a matched cohort from the prospective pediatric CRRT registry, using odds ratios in multivariable analysis for factors associated with prospective pediatric CRRT patient ICU mortality. To validate these crude analyses, Bayesian logistic regression was performed to assess for attributable benefit-risk assessment of the SCD. Results: Twenty-two patients received CRRT-SCD treatments. Fifteen serious adverse events were recorded; none were SCD-related. Seventeen patients survived till ICU discharge or day 60. Both multivariable and Bayesian analyses revealed a probable benefit of the addition of SCD. Fourteen of the 16 patients surviving ICU discharge reported a normal estimated glomerular filtration rate and no patient was dialysis dependent at 60 days. Limitations: The study had a few limitations, such as (1) a small sample size in the SCD-PED cohort group; (2) unchanging historic control group; and (3) adverse events were not recorded in the control group. Conclusions: The SCD therapy is feasible, safe, and demonstrates probable benefit for critically ill children who require CRRT for AKI.

Only 50% of critically ill children with kidney failure who require the most advanced forms of dialysis survive. One cause of this poor survival is the increased activation of the immune system, which leads to inflammation and organ failure. Reducing the effects of inflammation could improve the survival rate in this very sick population. We studied a device, the selective cytopheretic device (SCD) that lessens the activity of cells in the body that cause inflammation. Twenty-two children received treatment with the SCD put in line with a standard dialysis machine, of which 17 (77%) survived (compared to the expected 11). There were no adverse effects noted with the SCD. Hence, we suggest that the SCD offers an option to improve outcomes in critically ill children with kidney failure.

Restricted access and advanced disease in post-pandemic testicular cancer.

INTRODUCTION: Urologists observed reduced cancer consultations and surgeries during the SARS-CoV-2 pandemic, raising concern about treatment delays. Testicular cancer serves as a particularly sensitive marker of this phenomenon, as the clinical stage of testicular cancer at presentation is predictive of cancer-specific survival. We aimed to investigate whether COVID-related restrictions to primary care access resulted in increased incidence of metastatic germ cell testis cancer. METHODS: A retrospective chart review was conducted on all cases of testicular cancer managed surgically at our center from March 1, 2018, to February 28, 2023. Patients were categorized into temporal cohorts, representing before, during, and following the implementation of COVID-19 public health restrictions in the province of Newfoundland and Labrador. RESULTS: Forty-one cases of testicular germ cell tumors were identified during the study period. The mean age at diagnosis was 40.8 years (standard deviation ±13.7). Demographics did not vary across the cohorts. Clinical stage 3 disease remained stable before and during the pandemic at 10.5% and 9.1% of cases, respectively. In the post-pandemic period, there was an increase to 27.3% (p=0.617). Surgical wait times remained stable across the pandemic (p=0.151). CONCLUSIONS: There was a 16.8% rise in clinical stage III disease from the pre-pandemic to post-pandemic period. Our study failed to identify a statistically significant increase in metastatic testis cancer incidence upon lifting of pandemic restrictions. Further study is necessary to confirm suspicions that pandemic restrictions contributed to increased incidence of metastatic testis cancer.

Effect of an Arsenic Mitigation Program on Arsenic Exposure in American Indian Communities: A Cluster Randomized Controlled Trial of the Community-Led Strong Heart Water Study Program.

BACKGROUND: Chronic arsenic exposure has been associated with an increased risk of cardiovascular disease; diabetes; cancers of the lung, pancreas and prostate; and all-cause mortality in American Indian communities in the Strong Heart Study. OBJECTIVE: The Strong Heart Water Study (SHWS) designed and evaluated a multilevel, community-led arsenic mitigation program to reduce arsenic exposure among private well users in partnership with Northern Great Plains American Indian Nations. METHODS: A cluster randomized controlled trial (cRCT) was conducted to evaluate the effectiveness of the SHWS arsenic mitigation program over a 2-y period on a) urinary arsenic, and b) reported use of arsenic-safe water for drinking and cooking. The cRCT compared the installation of a point-of-use arsenic filter and a mobile Health (mHealth) program (3 phone calls; SHWS mHealth and Filter arm) to a more intensive program, which included this same program plus three home visits (3 phone calls and 3 home visits; SHWS Intensive arm). RESULTS: A 47% reduction in urinary arsenic [geometric mean (GM)=13.2 to 7.0µg/g creatinine] was observed from baseline to the final follow-up when both study arms were combined. By treatment arm, the reduction in urinary arsenic from baseline to the final follow-up visit was 55% in the mHealth and Filter arm (GM=14.6 to 6.55µg/g creatinine) and 30% in the Intensive arm (GM=11.2 to 7.82µg/g creatinine). There was no significant difference in urinary arsenic levels by treatment arm at the final follow-up visit comparing the Intensive vs. mHealth and Filter arms: GM ratio of 1.21 (95% confidence interval: 0.77, 1.90). In both arms combined, exclusive use of arsenic-safe water from baseline to the final follow-up visit significantly increased for water used for cooking (17% to 53%) and drinking (12% to 46%). DISCUSSION: Delivery of the interventions for the community-led SHWS arsenic mitigation program, including the installation of a point-of-use arsenic filter and a mHealth program on the use of arsenic-safe water (calls only, no home visits), resulted in a significant reduction in urinary arsenic and increases in reported use of arsenic-safe water for drinking and cooking during the 2-y study period. These results demonstrate that the installation of an arsenic filter and phone calls from a mHealth program presents a promising approach to reduce water arsenic exposure among private well users. https://doi.org/10.1289/EHP12548.

Impact of the COVID-19 pandemic on diagnosis of renal cell carcinoma and disease stage at presentation.

INTRODUCTION: Renal cell carcinoma (RCC) is often associated with significant morbidity and mortality, with overall survival contingent on multiple factors - most importantly, disease stage at diagnosis. Disruptions in healthcare delivery during the COVID-19 pandemic have resulted in various reported diagnostic and treatment delays, which have had detrimental impacts on malignancies such as RCC. METHODS: Surgically managed cases of RCC at our center were identified using a retrospective chart review of all nephrectomies conducted from March 1, 2018, to February 28, 2023. Examination of disease characteristics in three time period cohorts (before, during, and following the COVID-19 pandemic) was undertaken. Timeframes were consistent with implementation and abolition of public health restrictions in the province of Newfoundland and Labrador. RESULTS: A total of 483 surgically managed RCC cases were identified during the study period. The median age was 65 years (interquartile range [IQR] 56-71), and 62.3% of patients were male. Demographics did not vary across timeframes. Before and during the pandemic, pathologic stage 3 (pT3) disease was reported in 38.9% and 35.4% of cases, respectively, whereas the post-pandemic period saw this presentation in 50.0% of patients. Surgical wait times increased significantly across study timeframes (p=0.003). CONCLUSIONS: The first year following the COVID-19 pandemic saw an 11.1% increase in patients presenting with pT3 RCC. These findings are suggestive of a clinically significant stage migration, which paired with prolonged wait times for surgery, provide critical consideration in the urgency of diagnostic and treatment decisions for RCC in the immediate future.

Vortex fluidic regulated phospholipid equilibria involving liposomes down to sub-micelle size assemblies.

Conventional channel-based microfluidic platforms have gained prominence in controlling the bottom-up formation of phospholipid based nanostructures including liposomes. However, there are challenges in the production of liposomes from rapidly scalable processes. These have been overcome using a vortex fluidic device (VFD), which is a thin film microfluidic platform rather than channel-based, affording ∼110 nm diameter liposomes. The high yielding and high throughput continuous flow process has a 45° tilted rapidly rotating glass tube with an inner hydrophobic surface. Processing is also possible in the confined mode of operation which is effective for labelling pre-VFD-prepared liposomes with fluorophore tags for subsequent mechanistic studies on the fate of liposomes under shear stress in the VFD. In situ small-angle neutron scattering (SANS) established the co-existence of liposomes ∼110 nm with small rafts, micelles, distorted micelles, or sub-micelle size assemblies of phospholipid, for increasing rotation speeds. The equilibria between these smaller entities and ∼110 nm liposomes for a specific rotational speed of the tube is consistent with the spatial arrangement and dimensionality of topological fluid flow regimes in the VFD. The prevalence for the formation of ∼110 nm diameter liposomes establishes that this is typically the most stable structure from the bottom-up self-assembly of the phospholipid and is in accord with dimensions of exosomes.

Behavioral determinants of arsenic-safe water use among Great Plains Indian Nation private well users: results from the Community-Led Strong Heart Water Study Arsenic Mitigation Program.

BACKGROUND: The objective of this study was to evaluate the behavioral determinants associated with exclusive use of arsenic-safe water in the community-led Strong Heart Water Study (SHWS) arsenic mitigation program. METHODS: The SHWS is a randomized controlled trial of a community-led arsenic mitigation program designed to reduce arsenic exposure among private well users in American Indian Great Plains communities. All households received point-of-use (POU) arsenic filters installed at baseline and were followed for 2 years. Behavioral determinants selected were those targeted during the development of the SHWS program, and were assessed at baseline and follow-up. RESULTS: Among participants, exclusive use of arsenic-safe water for drinking and cooking at follow-up was associated with higher self-efficacy for accessing local resources to learn about arsenic (OR: 5.19, 95% CI: 1.48-18.21) and higher self-efficacy to resolve challenges related to arsenic in water using local resources (OR: 3.11, 95% CI: 1.11-8.71). Higher commitment to use the POU arsenic filter faucet at baseline was also a significant predictor of exclusive arsenic-safe water use for drinking (OR: 32.57, 95% CI: 1.42-746.70) and cooking (OR: 15.90, 95% CI: 1.33-189.52) at follow-up. From baseline to follow-up, the SHWS program significantly increased perceived vulnerability to arsenic exposure, self-efficacy, descriptive norms, and injunctive norms. Changing one's arsenic filter cartridge after installation was associated with higher self-efficacy to obtain arsenic-safe water for drinking (OR: 6.22, 95% CI: 1.33-29.07) and cooking (OR: 10.65, 95% CI: 2.48-45.68) and higher perceived vulnerability of personal health effects (OR: 7.79, 95% CI: 1.17-51.98) from drinking arsenic-unsafe water. CONCLUSIONS: The community-led SHWS program conducted a theory-driven approach for intervention development and evaluation that allowed for behavioral determinants to be identified that were associated with the use of arsenic safe water and changing one's arsenic filter cartridge. These results demonstrate that theory-driven, context-specific formative research can influence behavior change interventions to reduce water arsenic exposure. The SHWS can serve as a model for the design of theory-driven intervention approaches that engage communities to reduce arsenic exposure. TRIAL REGISTRATION: The SHWS is registered with ClinicalTrials.gov (Identifier: NCT03725592).

Reuse of the paramedian forehead flap pedicle: A case report.

The paramedian forehead flap is an axial flap which utilizes vascular support from the supratrochlear artery to repair extensive nasal defects. Adverse outcomes including flap necrosis, infection, alar rim pull, and poor cosmesis can be seen with this flap. We report an 85-year-old woman with chronic obstructive pulmonary disease who underwent a staged paramedian forehead flap repair with a cartilage inlay complicated by moderate left alar rim necrosis and pedicle notching. In this patient, we were able to salvage the original pedicle and reposition it to achieve a satisfactory functional and cosmetic outcome.

Implementing a Community-Led Arsenic Mitigation Intervention for Private Well Users in American Indian Communities: A Qualitative Evaluation of the Strong Heart Water Study Program.

Arsenic is a naturally occurring toxicant in groundwater, which increases cancer and cardiovascular disease risk. American Indian populations are disproportionately exposed to arsenic in drinking water. The Strong Heart Water Study (SHWS), through a community-centered approach for intervention development and implementation, delivered an arsenic mitigation program for private well users in American Indian communities. The SHWS program comprised community-led water arsenic testing, point-of-use arsenic filter installation, and a mobile health program to promote sustained filter use and maintenance (i.e., changing the filter cartridge). Half of enrolled households received additional in-person behavior change communication and videos. Our objectives for this study were to assess successes, barriers, and facilitators in the implementation, use, and maintenance of the program among implementers and recipients. We conducted 45 semi-structured interviews with implementers and SHWS program recipients. We analyzed barriers and facilitators using the Consolidated Framework for Implementation Research and the Risks, Attitudes, Norms, Abilities, and Self-regulation model. At the implementer level, facilitators included building rapport and trust between implementers and participating households. Barriers included the remoteness of households, coordinating with community plumbers for arsenic filter installation, and difficulty securing a local supplier for replacement filter cartridges. At the recipient level, facilitators included knowledge of the arsenic health risks, perceived effectiveness of the filter, and visual cues to promote habit formation. Barriers included attitudes towards water taste and temperature and inability to procure or install replacement filter cartridges. This study offers insights into the successes and challenges of implementing an arsenic mitigation program tailored to American Indian households, which can inform future programs in partnership with these and potentially similar affected communities. Our study suggests that building credibility and trust between implementers and participants is important for the success of arsenic mitigation programs.

"I'm still the queen and I'm still on my throne ": Women's reflections on gender and living with dementia.

People with dementia have long been defined by the label of dementia, rather than by other aspects of their identities including gender. As a result, little research has focused on gender and dementia, particularly through the perspectives of those living with dementia. The purpose of this study was to explore the experiences and perspectives of women living with dementia. Specifically, we sought to understand how gender structured their experiences of receiving and coping with a diagnosis, services, and important relationships and supports. Utilizing a qualitative research approach, twenty-one women living with dementia participated in individual or group interviews. Women discussed the following aspects of gender and dementia: caregiver roles, perceptions of gender differences, the impact of dementia on families, and women's strength and resilience. The findings of this study indicate a clear need for further research to explore diversity and gendered experiences for those diagnosed with dementia.

Analysis of carbohydrates and glycoconjugates by matrix-assisted laser desorption/ionization mass spectrometry: An update for 2017-2018.

This review is the tenth update of the original article published in 1999 on the application of matrix-assisted laser desorption/ionization mass spectrometry (MALDI) mass spectrometry to the analysis of carbohydrates and glycoconjugates and brings coverage of the literature to the end of 2018. Also included are papers that describe methods appropriate to glycan and glycoprotein analysis by MALDI, such as sample preparation techniques, even though the ionization method is not MALDI. Topics covered in the first part of the review include general aspects such as theory of the MALDI process, new methods, matrices, derivatization, MALDI imaging, fragmentation and the use of arrays. The second part of the review is devoted to applications to various structural types such as oligo- and poly-saccharides, glycoproteins, glycolipids, glycosides, and biopharmaceuticals. Most of the applications are presented in tabular form. The third part of the review covers medical and industrial applications of the technique, studies of enzyme reactions, and applications to chemical synthesis. The reported work shows increasing use of combined new techniques such as ion mobility and highlights the impact that MALDI imaging is having across a range of diciplines. MALDI is still an ideal technique for carbohydrate analysis and advancements in the technique and the range of applications continue steady progress.

On the equivalence between Generalized Proportional Integral Observer and Disturbance Observer.

This paper presents the equivalence between generalized proportional integral observer (GPIO) and disturbance observer (DOB), which is applicable to reduced-order GPIO (ROGPIO), full-order GPIO (FOGPIO), and extended state observer (ESO). From this equivalence, established in frequency-domain, comprehensive analyses are performed regarding the influence of the system order, the number of extended states, the uncertain control gain, and the tuning method on the robustness and performance of GPIO. In addition, the equivalence allows a detailed comparison between ROGPIO and FOGPIO in the active disturbance rejection control (ADRC) framework. Finally, experimental validation of the main results is presented for the study case of a synchronous buck converter.

Antibiotic review kit for hospitals (ARK-Hospital): a stepped-wedge cluster-randomised controlled trial.

BACKGROUND: Strategies to reduce antibiotic overuse in hospitals depend on prescribers taking decisions to stop unnecessary antibiotic use. There is scarce evidence for how to support these decisions. We evaluated a multifaceted behaviour change intervention (ie, the antibiotic review kit) designed to reduce antibiotic use among adult acute general medical inpatients by increasing appropriate decisions to stop antibiotics at clinical review. METHODS: We performed a stepped-wedge, cluster (hospital)-randomised controlled trial using computer-generated sequence randomisation of eligible hospitals in seven calendar-time blocks in the UK. Hospitals were eligible for inclusion if they admitted adult non-elective general or medical inpatients, had a local representative to champion the intervention, and could provide the required study data. Hospital clusters were randomised to an implementation date occurring at 1-2 week intervals, and the date was concealed until 12 weeks before implementation, when local preparations were designed to start. The intervention effect was assessed using data from pseudonymised routine electronic health records, ward-level antibiotic dispensing, Clostridioides difficile tests, prescription audits, and an implementation process evaluation. Co-primary outcomes were monthly antibiotic defined daily doses per adult acute general medical admission (hospital-level, superiority) and all-cause mortality within 30 days of admission (patient level, non-inferiority margin of 5%). Outcomes were assessed in the modified intention-to-treat population (ie, excluding sites that withdrew before implementation). Intervention effects were assessed by use of interrupted time series analyses within each site, estimating overall effects through random-effects meta-analysis, with heterogeneity across prespecified potential modifiers assessed by use of meta-regression. This trial is completed and is registered with ISRCTN, ISRCTN12674243. FINDINGS: 58 hospital organisations expressed an interest in participating. Three pilot sites implemented the intervention between Sept 25 and Nov 20, 2017. 43 further sites were randomised to implement the intervention between Feb 12, 2018, and July 1, 2019, and seven sites withdrew before implementation. 39 sites were followed up for at least 14 months. Adjusted estimates showed reductions in total antibiotic defined daily doses per acute general medical admission (-4·8% per year, 95% CI -9·1 to -0·2) following the intervention. Among 7 160 421 acute general medical admissions, the ARK intervention was associated with an immediate change of -2·7% (95% CI -5·7 to 0·3) and sustained change of 3·0% (-0·1 to 6·2) in adjusted 30-day mortality. INTERPRETATION: The antibiotic review kit intervention resulted in sustained reductions in antibiotic use among adult acute general medical inpatients. The weak, inconsistent intervention effects on mortality are probably explained by the onset of the COVID-19 pandemic. Hospitals should use the antibiotic review kit to reduce antibiotic overuse. FUNDING: UK National Institute for Health and Care Research.

Evaluation of a water arsenic filter in a participatory intervention to reduce arsenic exposure in American Indian communities: The Strong Heart Water Study.

Many rural populations, including American Indian communities, that use private wells from groundwater for their source of drinking and cooking water are disproportionately exposed to elevated levels of arsenic. However, programs aimed at reducing arsenic in American Indian communities are limited. The Strong Heart Water Study (SHWS) is a randomized controlled trial aimed at reducing arsenic exposure among private well users in American Indian Northern Great Plains communities. The community-led SHWS program installed point-of-use (POU) arsenic filters in the kitchen sink of households, and health promoters delivered arsenic health communication programs. In this study we evaluated the efficacy of these POU arsenic filters in removing arsenic during the two-year installation period. Participants were randomized into two arms. In the first arm households received a POU arsenic filter, and 3 calls promoting filter use (SHWS mobile health (mHealth) & filter arm). The second arm received the same filter and phone calls, and 3 in-person home visits and 3 Facebook messages (SHWS intensive arm) for program delivery. Temporal variability in water arsenic concentrations from the main kitchen faucet was also evaluated. A total of 283 water samples were collected from 50 households with private wells from groundwater (139 filter and 144 kitchen faucet samples). Ninety-three percent of households followed after baseline had filter faucet water arsenic concentrations below the arsenic maximum contaminant level of 10 µg/L at the final visit during our 2 year study period with no difference between study arms (98 % in the intensive arm vs. 94 % in the mHealth & filter arm). No significant temporal variation in kitchen arsenic concentration was observed over the study period (intraclass correlation coefficient = 0.99). This study demonstrates that POU arsenic filters installed for the community participatory SHWS program were effective in reducing water arsenic concentration in study households in both arms, even with delivery of the POU arsenic filter and mHealth program only. Furthermore, we observed limited temporal variability of water arsenic concentrations from kitchen faucet samples collected over time from private wells in our study setting.

Analysis of carbohydrates and glycoconjugates by matrix-assisted laser desorption/ionization mass spectrometry: An update for 2019-2020.

This review is the tenth update of the original article published in 1999 on the application of matrix-assisted laser desorption/ionization (MALDI) mass spectrometry to the analysis of carbohydrates and glycoconjugates and brings coverage of the literature to the end of 2020. Also included are papers that describe methods appropriate to analysis by MALDI, such as sample preparation techniques, even though the ionization method is not MALDI. The review is basically divided into three sections: (1) general aspects such as theory of the MALDI process, matrices, derivatization, MALDI imaging, fragmentation, quantification and the use of arrays. (2) Applications to various structural types such as oligo- and polysaccharides, glycoproteins, glycolipids, glycosides and biopharmaceuticals, and (3) other areas such as medicine, industrial processes and glycan synthesis where MALDI is extensively used. Much of the material relating to applications is presented in tabular form. The reported work shows increasing use of incorporation of new techniques such as ion mobility and the enormous impact that MALDI imaging is having. MALDI, although invented nearly 40 years ago is still an ideal technique for carbohydrate analysis and advancements in the technique and range of applications show little sign of diminishing.

An Aggressively Enlarging Benign Mixed Epithelial Stromal Tumor (MEST) of the Kidney.

Renal neoplasms represent a diverse spectrum of tumors with varying degrees of solid and cystic components that often dictate the potential for malignancy. Mixed epithelial stromal tumors (MEST) of the kidney represent an uncommon and heterogenous subset of these tumors, for which there remains a lack of extant literature and a poor degree of relative understanding. Our case represents a typical presentation of this uncommon neoplasm that contains several important differences regarding immunohistochemical staining and familial interplay that contribute to the literature surrounding these tumors.

Human FSH Glycoform α-Subunit Asparagine52 Glycans: Major Glycan Structural Consistency, Minor Glycan Variation in Abundance.

Follicle-stimulating hormone (FSH), an α/ß heterodimeric glycoprotein hormone, consists of functionally significant variants resulting from the presence or absence of either one of two FSHß subunit N-glycans. The two most abundant variants are fully-glycosylated FSH24 (based on 24 kDa FSHß band in Western blots) and hypo-glycosylated FSH21 (21 kDa band, lacks ßAsn24 glycans). Due to its ability to bind more rapidly to the FSH receptor and occupy more FSH binding sites than FSH24, hypo-glycosylated FSH21 exhibits greater biological activity. Endoglycosidase F1-deglycosylated FSH bound to the complete extracellular domain of the FSH receptor crystallized as a trimeric complex. It was noted that a single biantennary glycan attached to FSHα Asn52 might preemptively fill the central pocket in this complex and prevent the other two FSH ligands from binding the remaining ligand-binding sites. As the most active FSH21 preparations possessed more rapidly migrating α-subunit bands in Western blots, we hypothesized that Asn52 glycans in these preparations were small enough to enable greater FSH21 receptor occupancy in the putative FSHR trimer model. Highly purified hFSH oligosaccharides derived from each FSH subunit, were characterized by electrospray ionization-ion mobility-collision-induced dissociation (ESI-IM-CID) mass spectrometry. FSHß glycans typically possessed core-linked fucose and were roughly one third bi-antennary, one third tri-antennary and one third tetra-antennary. FSHα oligosaccharides largely lacked core fucose and were bi- or tri-antennary. Those αAsn52 glycans exhibiting tetra-antennary glycan m/z values were found to be tri-antennary, with lactosamine repeats accounting for the additional mass. Selective αAsn52 deglycosylation of representative pituitary hFSH glycoform Superdex 75 gel filtration fractions followed by ESI-IM-CID mass spectrometry revealed tri-antennary glycans predominated even in the lowest molecular weight FSH glycoforms. Accordingly, the differences in binding capacity of the same receptor preparation to different FSH glycoforms are likely the organization of the FSH receptor in cell membranes, rather than the αAsn52 oligosaccharide.

Tapwater Exposures, Effects Potential, and Residential Risk Management in Northern Plains Nations.

In the United States (US), private-supply tapwater (TW) is rarely monitored. This data gap undermines individual/community risk-management decision-making, leading to an increased probability of unrecognized contaminant exposures in rural and remote locations that rely on private wells. We assessed point-of-use (POU) TW in three northern plains Tribal Nations, where ongoing TW arsenic (As) interventions include expansion of small community water systems and POU adsorptive-media treatment for Strong Heart Water Study participants. Samples from 34 private-well and 22 public-supply sites were analyzed for 476 organics, 34 inorganics, and 3 in vitro bioactivities. 63 organics and 30 inorganics were detected. Arsenic, uranium (U), and lead (Pb) were detected in 54%, 43%, and 20% of samples, respectively. Concentrations equivalent to public-supply maximum contaminant level(s) (MCL) were exceeded only in untreated private-well samples (As 47%, U 3%). Precautionary health-based screening levels were exceeded frequently, due to inorganics in private supplies and chlorine-based disinfection byproducts in public supplies. The results indicate that simultaneous exposures to co-occurring TW contaminants are common, warranting consideration of expanded source, point-of-entry, or POU treatment(s). This study illustrates the importance of increased monitoring of private-well TW, employing a broad, environmentally informative analytical scope, to reduce the risks of unrecognized contaminant exposures.

Artemisia annua L. plants lacking Bornyl diPhosphate Synthase reallocate carbon from monoterpenes to sesquiterpenes except artemisinin.

The monoterpene camphor is produced in glandular secretory trichomes of the medicinal plant Artemisia annua, which also produces the antimalarial drug artemisinin. We have found that, depending on growth conditions, camphor can accumulate at levels ranging from 1- 10% leaf dry weight (LDW) in the Artemis F1 hybrid, which has been developed for commercial production of artemisinin at up to 1% LDW. We discovered that a camphor null (camphor-0) phenotype segregates in the progeny of self-pollinated Artemis material. Camphor-0 plants also show reduced levels of other less abundant monoterpenes and increased levels of the sesquiterpene precursor farnesyl pyrophosphate plus sesquiterpenes, including enzymatically derived artemisinin pathway intermediates but not artemisinin. One possible explanation for this is that high camphor concentrations in the glandular secretory trichomes play an important role in generating the hydrophobic conditions required for the non-enzymatic conversion of dihydroartemisinic acid tertiary hydroperoxide to artemisinin. We established that the camphor-0 phenotype associates with a genomic deletion that results in loss of a Bornyl diPhosphate Synthase (AaBPS) gene candidate. Functional characterization of the corresponding enzyme in vitro confirmed it can catalyze the first committed step in not only camphor biosynthesis but also in a number of other monoterpenes, accounting for over 60% of total volatiles in A. annua leaves. This in vitro analysis is consistent with loss of monoterpenes in camphor-0 plants. The AaBPS promoter drives high reporter gene expression in A. annua glandular secretory trichomes of juvenile leaves with expression shifting to non-glandular trichomes in mature leaves, which is consistent with AaBPS transcript abundance.

Clinical management of community-acquired meningitis in adults in the UK and Ireland in 2017: a retrospective cohort study on behalf of the National Infection Trainees Collaborative for Audit and Research (NITCAR).

OBJECTIVES: To assess practice in the care of adults with suspected community-acquired bacterial meningitis in the UK and Ireland. DESIGN: Retrospective cohort study. SETTING: 64 UK and Irish hospitals. PARTICIPANTS: 1471 adults with community-acquired meningitis of any aetiology in 2017. RESULTS: None of the audit standards, from the 2016 UK Joint Specialists Societies guideline on diagnosis and management of meningitis, were met in all cases. With respect to 20 of 30 assessed standards, clinical management provided for patients was in line with recommendations in less than 50% of cases. 45% of patients had blood cultures taken within an hour of admission, 0.5% had a lumbar puncture within 1 hour, 26% within 8 hours. 28% had bacterial molecular diagnostic tests on cerebrospinal fluid. Median time to first dose of antibiotics was 3.2 hours (IQR 1.3-9.2). 80% received empirical parenteral cephalosporins. 55% ≥60 years and 31% of immunocompromised patients received anti-Listeria antibiotics. 21% received steroids. Of the 1471 patients, 20% had confirmed bacterial meningitis. Among those with bacterial meningitis, pneumococcal aetiology, admission to intensive care and initial Glasgow Coma Scale Score less than 14 were associated with in-hospital mortality (adjusted OR (aOR) 2.08, 95% CI 0.96 to 4.48; aOR 4.28, 95% CI 1.81 to 10.1; aOR 2.90, 95% CI 1.26 to 6.71, respectively). Dexamethasone therapy was weakly associated with a reduction in mortality in both those with proven bacterial meningitis (aOR 0.57, 95% CI 0.28 to 1.17) and with pneumococcal meningitis (aOR 0.47, 95% CI 0.20 to 1.10). CONCLUSION: This study demonstrates that clinical care for patients with meningitis in the UK is not in line with current evidence-based national guidelines. Diagnostics and therapeutics should be targeted for quality improvement strategies. Work should be done to improve the impact of guidelines, understand why they are not followed and, once published, ensure they translate into changed practice.

Implementation of a Nationwide Knowledge-Based COVID-19 Contact Tracing Training Program, 2020.

In the United States, the public health response to control COVID-19 required rapid expansion of the contact tracing workforce from approximately 2200 personnel prepandemic to more than 100 000 during the pandemic. We describe the development and implementation of a free nationwide training course for COVID-19 contact tracers that launched April 28, 2020, and summarize participant characteristics and evaluation findings through December 31, 2020. Uptake of the online asynchronous training was substantial: 90 643 registrants completed the course during the first 8 months. In an analysis of a subset of course participants (n = 13 697), 7724 (56.4%) reported having no prepandemic public health experience and 7178 (52.4%) reported currently serving as case investigators, contact tracers, or both. Most participants who completed a course evaluation reported satisfaction with course utility (94.8%; 59 497 of 62 753) and improved understanding of contact tracing practice (93.0%; 66 107 of 71 048). These findings suggest that the course successfully reached the intended audience of new public health practitioners. Lessons learned from this implementation indicate that an introductory course level is appropriate for a national knowledge-based training that aims to complement jurisdiction-specific training. In addition, offering a range of implementation options can promote course uptake among public health agency staff. This course supported the emerging needs of the public health practice community by training a workforce to fill an important gap during the COVID-19 pandemic and could serve as a feasible model for enhancing workforce knowledge for future and ongoing public health threats.