Stimulation of otolith irregular fibers produces a rostro-caudal gradient in activity in the vestibular nuclear complex (VNC), but not the vestibulocerebellum (VeCb).

The vestibular system is important for posture, balance, motor control, and spatial orientation. Each of the vestibular end organs have specialized neuroepithelia with both regular and irregular afferents. In otolith organs, the utricle and saccule, afferents most responsive to linear jerk (jerk - derivative of acceleration) are located in the striola and project centrally to the vestibular nuclear complex (VNC) as well as the uvula and nodulus of the vestibulocerebellum (VeCb). The pattern of central neuronal activation attributed to otolith irregular afferents is relatively unknown. To address this gap, c-Fos was used as a marker of neuronal activity to map the distribution of active neurons throughout the rostro-caudal extent of the VNC and VeCb. Immunohistochemistry for c-Fos was performed to assess activation of VNC and VeCb neurons in response to a linear jerk stimulus delivered in the naso-occipital plane. Activated neurons were distributed throughout the VNC, including the lateral vestibular nucleus (LVe), magnocellular medial vestibular nucleus (MVeMC), parvocellular medial vestibular nucleus (MVePC), spinal vestibular nucleus (SpVe), and superior vestibular nucleus (SuVe). Notably, after stimulation, the MVePC exhibited the greatest number of c-Fos labeled nuclei. Significant increases in c-Fos labeling were found in mid-rostrocaudal and caudal regions of the VNC in the LVe, MVe, and SpVe. Additionally, c-Fos labeling was observed across all regions of the VeCb after jerk stimulation. Significant increases in the number of labeled nuclei were found throughout the rostro-caudal extent of the nodulus and uvula. However, jerk stimulated increases in activity for the paraflocculus were restricted to the caudal VeCb. The distribution of neuronal activity suggests that regions receiving the greatest direct otolith input exhibit the most substantial changes in response to otolith derived, irregular fiber stimulation. Highlights: Nuclei with descending projections (LVe, MVePC, and SpVe) demonstrated the greatest change in activity after naso-occipital jerk stimulation.Naso-occipital jerk stimulation preferentially activates caudal VNC neuronsNaso-occipital jerk stimulation activates neurons throughout the VeCbJerk stimulation in the naso-occipital plane has the greatest effects on activity in VNC and VeCb regions with the greatest inputs from afferents originating in gravity receptors.

Getting to the root of root-microbe interactions.

Microbial relationships with roots influence many ecosystem functions and nutrient fluxes, including their sometimes-profound effects on plant health and productivity. Fine roots were often classified with a diameter less than 2 mm, but fine roots under that size perform distinct functional roles in the environment. Importantly, two broad functional categories of fine roots are absorptive and transportive, with absorptive fine roots acting as metabolic hotspots for root activity. In two of our recent studies, we have shown that several microbial community characteristics differ between absorptive and transportive fine roots, including composition, abundance, and function, as well as the root metabolome. This highlights a growing recognition within microbial ecology that we must consider fine-scale environmental variability, such as root physiology and morphology, when interpreting microbial patterns. In this commentary, we summarize the findings of our latest article, further speculate on some of these patterns, and suggest future studies for examining decomposition and applying cutting-edge single-cell sequencing techniques.

Esophageal Per-Oral Endoscopic Myotomy (E-POEM): Future Directions and Perspectives.

PURPOSE OF REVIEW: POEM is a mature procedure endorsed by societal guidelines as a first line therapy for achalasia and spastic esophageal disorders. Nonetheless, several questions remain, including expanding indications for POEM, periprocedural evaluation and management, and the optimal POEM technique to enhance clinical success while mitigating risk for reflux. RECENT FINDINGS: There is uncertainty regarding several technical aspects of the POEM myotomy; though aggregating evidence supports the use of real-time impedance planimetry to guide the myotomy. While post-POEM reflux remains a concerning long term sequela, there is an increasing focus on the potential role of endoscopic anti-reflux interventions. Lastly, with the widespread adoption of POEM, we continue to witness ongoing efforts to standardize post-procedural care and training in this procedure. POEM is no longer a novel but rather established procedure. Yet, this technique has continued to evolve, with the aim of optimizing treatment success while reducing adverse events and risk for post-procedural reflux.

Point-of-Care Multiplex Detection of Respiratory Viruses.

The COVID-19 pandemic, in addition to the co-occurrence of influenza virus and respiratory syncytial virus (RSV), has emphasized the requirement for efficient and reliable multiplex diagnostic methods for respiratory infections. While existing multiplex detection techniques are based on reverse transcription quantitative polymerase chain reaction (RT-qPCR) and extraction and purification kits, the need for complex instrumentation and elevated cost limit their scalability and availability. In this study, we have developed a point-of-care (POC) device based on reverse transcription loop-mediated isothermal amplification (RT-LAMP) that can simultaneously detect four respiratory viruses (SARS-CoV-2, Influenza A, Influenza B, and RSV) and perform two controls in less than 30 min, while avoiding the use of the RNA extraction kit. The system includes a disposable microfluidic cartridge with mechanical components that automate sample processing, with a low-cost and portable optical reader and a smartphone app to record and analyze fluorescent images. The application as a real point-of-care platform was validated using swabs spiked with virus particles in nasal fluid. Our portable diagnostic system accurately detects viral RNA specific to respiratory pathogens, enabling deconvolution of coinfection information. The detection limits for each virus were determined using virus particles spiked in chemical lysis buffer. Our POC device has the potential to be adapted for the detection of new pathogens and a wide range of viruses by modifying the primer sequences. This work highlights an alternative approach for multiple respiratory virus diagnostics that is well-suited for healthcare systems in resource-limited settings or at home.

Candida albicans' inorganic phosphate transport and evolutionary adaptation to phosphate scarcity.

Phosphorus is essential in all cells' structural, metabolic and regulatory functions. For fungal cells that import inorganic phosphate (Pi) up a steep concentration gradient, surface Pi transporters are critical capacitators of growth. Fungi must deploy Pi transporters that enable optimal Pi uptake in pH and Pi concentration ranges prevalent in their environments. Single, triple and quadruple mutants were used to characterize the four Pi transporters we identified for the human fungal pathogen Candida albicans, which must adapt to alkaline conditions during invasion of the host bloodstream and deep organs. A high-affinity Pi transporter, Pho84, was most efficient across the widest pH range while another, Pho89, showed high-affinity characteristics only within one pH unit of neutral. Two low-affinity Pi transporters, Pho87 and Fgr2, were active only in acidic conditions. Only Pho84 among the Pi transporters was clearly required in previously identified Pi-related functions including Target of Rapamycin Complex 1 signaling, oxidative stress resistance and hyphal growth. We used in vitro evolution and whole genome sequencing as an unbiased forward genetic approach to probe adaptation to prolonged Pi scarcity of two quadruple mutant lineages lacking all 4 Pi transporters. Lineage-specific genomic changes corresponded to divergent success of the two lineages in fitness recovery during Pi limitation. Initial, large-scale genomic alterations like aneuploidies and loss of heterozygosity eventually resolved, as populations gained small-scale mutations. Severity of some phenotypes linked to Pi starvation, like cell wall stress hypersensitivity, decreased in parallel to evolving populations' fitness recovery in Pi scarcity, while severity of others like membrane stress responses diverged from Pi scarcity fitness. Among preliminary candidate genes for contributors to fitness recovery, those with links to TORC1 were overrepresented. Since Pi homeostasis differs substantially between fungi and humans, adaptive processes to Pi deprivation may harbor small-molecule targets that impact fungal growth, stress resistance and virulence.

Edge-Passivated Monolayer WSe2 Nanoribbon Transistors.

The ongoing reduction in transistor sizes drives advancements in information technology. However, as transistors shrink to the nanometer scale, surface and edge states begin to constrain their performance. 2D semiconductors like transition metal dichalcogenides (TMDs) have dangling-bond-free surfaces, hence achieving minimal surface states. Nonetheless, edge state disorder still limits the performance of width-scaled 2D transistors. This work demonstrates a facile edge passivation method to enhance the electrical properties of monolayer WSe2 nanoribbons, by combining scanning transmission electron microscopy, optical spectroscopy, and field-effect transistor (FET) transport measurements. Monolayer WSe2 nanoribbons are passivated with amorphous WOxSey at the edges, which is achieved using nanolithography and a controlled remote O2 plasma process. The same nanoribbons, with and without edge passivation are sequentially fabricated and measured. The passivated-edge nanoribbon FETs exhibit 10 ± 6 times higher field-effect mobility than the open-edge nanoribbon FETs, which are characterized with dangling bonds at the edges. WOxSey edge passivation minimizes edge disorder and enhances the material quality of WSe2 nanoribbons. Owing to its simplicity and effectiveness, oxidation-based edge passivation could become a turnkey manufacturing solution for TMD nanoribbons in beyond-silicon electronics and optoelectronics.

Heart rate characteristics predict risk of mortality in preterm infants in low and high target oxygen saturation ranges.

Background: The Neonatal Oxygenation Prospective Meta-analysis found that in infants <28 weeks gestational age, targeting an oxygen saturation (S pO2 ) range of 85-89% versus 91-95% resulted in lower rates of retinopathy of prematurity but increased mortality. We aimed to evaluate the accuracy of the heart rate characteristics index (HRCi) in assessing the dynamic risk of mortality among infants managed with low and high target S pO2 ranges. Methods: We linked the SUPPORT and HRCi datasets from one centre in which the randomised controlled trials overlapped. We examined the maximum daily HRCi (MaxHRCi24) to predict mortality among patients randomised to the lower and higher target S pO2 groups by generating predictiveness curves and calculating model performance metrics, including area under the receiver operating characteristics curve (AUROC) at prediction windows from 1-60 days. Cox proportional hazards models tested whether MaxHRCi24 was an independent predictor of mortality. We also conducted a moderation analysis. Results: There were 84 infants in the merged dataset. MaxHRCi24 predicted mortality in infants randomised to the lower target S pO2 (AUROC of 0.79-0.89 depending upon the prediction window) and higher target S pO2 (AUROC 0.82-0.91). MaxHRCi24 was an important additional predictor of mortality in multivariable modelling. In moderation analysis, in a model that also included demographic predictor variables, the individual terms and the interaction term between MaxHRCi24 and target S pO2 range all predicted mortality. Conclusions: Associations between HRCi and mortality, at low and high S pO2 target ranges, suggest that future research may find HRCi metrics helpful to individually optimise target oxygen saturation ranges for hospitalised preterm infants.

Esophagitis Dissecans Superficialis After Thermal Injury.

Esophagitis dissecans superficialis (EDS) is a rare esophageal condition characterized by sloughing of the esophageal mucosal epithelium, typically associated with a desquamating dermatologic disorder or mucosal irritants. We present a case of a 49-year-old man who presented for thermal burns sustained from an outdoor heater explosion. On body trauma imaging, he was incidentally found to have a midcervical esophageal prominence causing asymptomatic posterior tracheal compression. Endoscopy with esophageal biopsy were performed and consistent with EDS. He never exhibited symptoms associated with this diagnosis. To our knowledge, thermal injury has been a purported, albeit without case reference, etiology of EDS.

Autoclaving is at least as effective as gamma irradiation for biotic clearing and intentional microbial recolonization of soil.

Sterilization is commonly used to remove or reduce the biotic constraints of a soil to allow recolonization by soil-dwelling organisms, with autoclaving and gamma irradiation being the most frequently used approaches. Many studies have characterized sterilization impacts on soil physicochemical properties, with gamma irradiation often described as the preferred approach, despite the lower cost and higher scalability of autoclaving. However, few studies have compared how sterilization techniques impact soil recolonization by microorganisms. Here, we compared how two sterilization approaches (autoclaving; gamma irradiation) and soil washing impacted microbial recolonization of soil from a diverse soil inoculum. Sterilization method had little impact on microbial alpha diversity across recolonized soils. For sterile soil regrowth microcosms, species richness and diversity were significantly reduced by autoclaving relative to gamma irradiation, particularly for fungi. There was no impact of sterilization method on bacterial composition in recolonized soils and minimal impact on fungal composition (P = 0.05). Washing soils had a greater impact on microbial composition than sterilization method, and sterile soil regrowth had negligible impacts on microbial recolonization. These data suggest that sterilization method has no clear impact on microbial recolonization, at least across the soils tested, indicating that soil autoclaving is an appropriate and economical approach for biotically clearing soils.IMPORTANCESterilized soils represent soil-like environments that act as a medium to study microbial colonization dynamics in more "natural" settings relative to artificial culturing environments. Soil sterilization is often carried out by gamma irradiation or autoclaving, which both alter soil properties, but gamma irradiation is thought to be the gentler technique. Gamma irradiation can be cost prohibitive and does not scale well for larger experiments. We sought to examine how soil sterilization technique can impact microbial colonization, and additionally looked at the impact of soil washing which is believed to remove soil toxins that inhibit soil recolonization. We found that both gamma-irradiated and autoclaved soils showed similar colonization patterns when reintroducing microorganisms. Soil washing, relative to sterilization technique, had a greater impact on which microorganisms were able to recolonize the soil. When allowing sterilized soils to regrow (i.e., persisting microorganisms), gamma irradiation performed worse, suggesting that gamma irradiation does not biotically clear soils as well as autoclaving. These data suggest that both sterilization techniques are comparable, and that autoclaving may be more effective at biotically clearing soil.

Safety of cold resection of non-ampullary duodenal polyps: Systematic review and meta-analysis.

Background and study aims Endoscopic resection has traditionally involved electrosurgical cautery (hot snare) to resect premalignant polyps. Recent data have suggested superior safety of cold resection. We aimed to assess the safety of cold compared with traditional (hot) resection for non-ampullary duodenal polyps. Methods We performed a systematic review ending in September 2022. The primary outcome of interest was the adverse event (AE) rate for cold compared with hot polyp resection. We reported odds ratios with 95% confidence intervals (CIs). Secondary outcomes included rates of polyp recurrence and post-polypectomy syndrome. We assessed publication bias with the classic fail-safe test and used forest plots to report pooled effect estimates. We assessed heterogeneity using I 2 index. Results Our systematic review identified 1,215 unique citations. Eight of these met inclusion criteria, seven of which were published manuscripts and one of which was a recent meeting abstract. On random effect modeling, cold resection was associated with significantly lower odds of delayed bleeding compared with hot resection. The difference in the odds of perforation (odds ratio [OR] 0.31 [95% confidence interval [CI] 0.05-2.87], P =0.2, I 2 =0) and polyp recurrence (OR 0.75 [95% CI 0.15-3.73], P =0.72, I 2 =0) between hot and cold resection was not statistically significant. There were no cases of post-polypectomy syndrome reported with either hot or cold techniques. Conclusions Cold resection is associated with lower odds of delayed bleeding compared with hot resection for duodenal tumors. There was a trend toward higher odds of perforation and recurrence following hot resection, but this trend was not statistically significant.

Temperate trees locally engineer decomposition and litter-bound microbiomes through differential litter deposits and species-specific soil conditioning.

Leaf decomposition varies widely across temperate forests, shaped by factors like litter quality, climate, soil properties, and decomposers, but forest heterogeneity may mask local tree influences on decomposition and litter-associated microbiomes. We used a 24-yr-old common garden forest to quantify local soil conditioning impacts on decomposition and litter microbiology. We introduced leaf litter bags from 10 tree species (5 arbuscular mycorrhizal; 5 ectomycorrhizal) to soil plots conditioned by all 10 species in a full-factorial design. After 6 months, we assessed litter mass loss, C/N content, and bacterial and fungal composition. We hypothesized that (1) decomposition and litter-associated microbiome composition would be primarily shaped by the mycorrhizal type of litter-producing trees, but (2) modified significantly by underlying soil, based on mycorrhizal type of the conditioning trees. Decomposition and, to a lesser extent, litter-associated microbiome composition, were primarily influenced by the mycorrhizal type of litter-producing trees. Interestingly, however, underlying soils had a significant secondary influence, driven mainly by tree species, not mycorrhizal type. This secondary influence was strongest under trees from the Pinaceae. Temperate trees can locally influence underlying soil to alter decomposition and litter-associated microbiology. Understanding the strength of this effect will help predict biogeochemical responses to forest compositional change.

Do the blood anti-Müllerian hormone concentrations in young females correlate with the ovarian follicular population later in life in water buffalo?

In this longitudinal study, the anti-Müllerian hormone (AMH) levels in blood were determined in 32 Murrah buffalo females at 8, 10, 12, 16 and 19 months of age when females were synchronized and the antral follicular population (AFP) was estimated. Correlations of AFP to the AMH level at 19 months of age and retrospectively to younger ages were investigated. Then females were split into high and low AFP, and their AMH levels were compared for all ages and tested as predictors of AFP categories. The highest AMH level (p < .05) was detected at 8 months, reducing but not differing (p > .05) at 10, 12 and 16 months then reducing again (p < .05) at 19 months of age. The mean AFP was 17.6 ± 6.3 follicles, and it was positively correlated with AMH in all ages tested. High AFP females had approximately two times more antral follicles than low AFP (p < .05) and their AMH levels were higher (p < .01) than in low AFP ones in all ages. Only at 8 months, AMH levels can be used to precociously detect high AFP heifers (a cut-off point of 464.7 pg/mL; p < .05), while low AFP heifers could be detected by AMH measurements at 8, 10, 12 and 16 months of age (p < .05). We conclude that AMH of buffalo calves correlates with AFP of heifers later in life and depending on the age, its levels could be used to identify future females with low or high AFP.

Cost-effectiveness of methenamine hippurate compared with antibiotic prophylaxis for the management of recurrent urinary tract infections in secondary care: a multicentre, open-label, randomised, non-inferiority trial.

OBJECTIVES: To estimate the cost-effectiveness of methenamine hippurate compared with antibiotic prophylaxis in the management of recurrent urinary tract infections. DESIGN: Multicentre, open-label, randomised, non-inferiority trial. SETTING: Eight centres in the UK, recruiting from June 2016 to June 2018. PARTICIPANTS: Women aged ≥18 years with recurrent urinary tract infections, requiring prophylactic treatment. INTERVENTIONS: Women were randomised to receive once-daily antibiotic prophylaxis or twice-daily methenamine hippurate for 12 months. Treatment allocation was not masked and crossover between arms was allowed. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary economic outcome was the incremental cost per quality-adjusted life year (QALY) gained at 18 months. All costs were collected from a UK National Health Service perspective. QALYs were estimated based on responses to the EQ-5D-5L administered at baseline, 3, 6, 9, 12 and 18 months. Incremental costs and QALYs were estimated using an adjusted analysis which controlled for observed and unobserved characteristics. Stochastic sensitivity analysis was used to illustrate uncertainty on a cost-effectiveness plane and a cost-effectiveness acceptability curve. A sensitivity analysis, not specified in the protocol, considered the costs associated with antibiotic resistance. RESULTS: Data on 205 participants were included in the economic analysis. On average, methenamine hippurate was less costly (-£40; 95% CI: -684 to 603) and more effective (0.014 QALYs; 95% CI: -0.05 to 0.07) than antibiotic prophylaxis. Over the range of values considered for an additional QALY, the probability of methenamine hippurate being considered cost-effective ranged from 51% to 67%. CONCLUSIONS: On average, methenamine hippurate was less costly and more effective than antibiotic prophylaxis but these results are subject to uncertainty. Methenamine hippurate is more likely to be considered cost-effective when the benefits of reduced antibiotic use were included in the analysis. TRIAL REGISTRATION NUMBER: ISRCTN70219762.

Natural antibodies drive type 2 immunity in response to damage-associated molecular patterns.

Allergic airway disease (AAD) is an example of type 2 inflammation that leads to chronic airway eosinophilia controlled by CD4 Th2 cells. Inflammation is reinforced by mast cells and basophils armed with allergen-specific IgE made by allergen-specific B2 B cells of the adaptive immune system. Little is known about how AAD is affected by innate B1 cells, which produce natural antibodies (NAbs) that facilitate apoptotic cell clearance and detect damage- and pathogen-associated molecular patterns (DAMPS and PAMPS). We used transgenic mice lacking either B cells or NAbs in distinct mouse models of AAD that require either DAMPS or PAMPS as the initial trigger for type 2 immunity. In a DAMP-induced allergic model, driven by alum and uric acid, mouse strains lacking B cells (CD19DTA), NAbs (IgHEL MD4), or all secreted antibodies (sIgm-/-Aid-/-) displayed a significant reduction in both eosinophilia and Th2 priming compared with WT or Aid-/- mice lacking only germinal center-dependent high-affinity class-switched antibodies. Replenishing B cell-deficient mice with either unimmunized B1 B cells or NAbs during sensitization restored eosinophilia, suggesting that NAbs are required for licensing antigen-presenting cells to prime type 2 immunity. Conversely, PAMP-dependent type 2 priming to house dust mite or Aspergillus was not dependent on NAbs. This study reveals an underappreciated role of B1 B cell-generated NAbs in selectively driving DAMP-induced type 2 immunity.

Leveraging aquatic-terrestrial interfaces to capture putative habitat generalists.

Habitat type is a strong determinant of microbial composition. Habitat interfaces, such as the boundary between aquatic and terrestrial systems, present unique combinations of abiotic factors for microorganisms to contend with. Aside from the spillover of certain harmful microorganisms from agricultural soils into water (e.g. fecal coliform bacteria), we know little about the extent of soil-water habitat switching across microbial taxa. In this study, we developed a proof-of-concept system to facilitate the capture of putatively generalist microorganisms that can colonize and persist in both soil and river water. We aimed to examine the phylogenetic breadth of putative habitat switchers and how this varies across different source environments. Microbial composition was primarily driven by recipient environment type, with the strongest phylogenetic signal seen at the order level for river water colonizers. We also identified more microorganisms colonizing river water when soil was collected from a habitat interface (i.e. soil at the side of an intermittently flooded river, compared to soil collected further from water sources), suggesting that environmental interfaces could be important reservoirs of microbial habitat generalists. Continued development of experimental systems that actively capture microorganisms that thrive in divergent habitats could serve as a powerful tool for identifying and assessing the ecological distribution of microbial generalists.

Candida albicans' inorganic phosphate transport and evolutionary adaptation to phosphate scarcity.

Phosphorus is essential in all cells' structural, metabolic and regulatory functions. For fungal cells that import inorganic phosphate (Pi) up a steep concentration gradient, surface Pi transporters are critical capacitators of growth. Fungi must deploy Pi transporters that enable optimal Pi uptake in pH and Pi concentration ranges prevalent in their environments. Single, triple and quadruple mutants were used to characterize the four Pi transporters we identified for the human fungal pathogen Candida albicans, which must adapt to alkaline conditions during invasion of the host bloodstream and deep organs. A high-affinity Pi transporter, Pho84, was most efficient across the widest pH range while another, Pho89, showed high-affinity characteristics only within one pH unit of neutral. Two low-affinity Pi transporters, Pho87 and Fgr2, were active only in acidic conditions. Only Pho84 among the Pi transporters was clearly required in previously identified Pi-related functions including Target of Rapamycin Complex 1 signaling and hyphal growth. We used in vitro evolution and whole genome sequencing as an unbiased forward genetic approach to probe adaptation to prolonged Pi scarcity of two quadruple mutant lineages lacking all 4 Pi transporters. Lineage-specific genomic changes corresponded to divergent success of the two lineages in fitness recovery during Pi limitation. In this process, initial, large-scale genomic alterations like aneuploidies and loss of heterozygosity were eventually lost as populations presumably gained small-scale mutations. Severity of some phenotypes linked to Pi starvation, like cell wall stress hypersensitivity, decreased in parallel to evolving populations' fitness recovery in Pi scarcity, while that of others like membrane stress responses diverged from these fitness phenotypes. C. albicans therefore has diverse options to reconfigure Pi management during prolonged scarcity. Since Pi homeostasis differs substantially between fungi and humans, adaptive processes to Pi deprivation may harbor small-molecule targets that impact fungal growth and virulence.

Valuing selected WAItE health states using the Time Trade-Off methodology: findings from an online interviewer-assisted remote survey.

PURPOSE: The Weight-Specific Adolescent Instrument for Economic Evaluation (WAItE) is a physical weight-specific patient reported outcome measure for use in adolescence. The purpose of this study was to use the Time Trade-Off (TTO) methodology, administered using an online interviewer-assisted remote survey, to obtain utility values for several health states from the WAItE descriptive system from a sample of the UK adult general population. METHODS: The adult sample was gathered using a market research company and a sample of local residents. All participants completed the same interviewer-assisted remote survey, which included rating WAItE states of varying impairment using the TTO. RESULTS: 42 adults completed the survey. Utility values were gathered for four health states, ranging from low impairment to the most severe health from the WAItE descriptive system (the Pits state). Consistent orderings of the WAItE health states were observed; the health state with the lowest level of impairment was valued highest and the Pits state was valued lowest. Several respondents (n = 7, 17%) considered the Pits state to be worse than death; however, the mean value of this health state was 0.23. CONCLUSIONS: The utility value of the Pits state relative to death generated from this study will be used to anchor latent values for WAItE health states generated from a Discrete Choice Experiment onto the 0 = death, 1 = full health Quality Adjusted Life Year (QALY) scale as part of a valuation study for the WAItE in the UK population. This study also provides further evidence that interviewer-assisted digital studies are feasible for collecting TTO data.

The glycerophosphocholine acyltransferase Gpc1 contributes to phosphatidylcholine biosynthesis, long-term viability, and embedded hyphal growth in Candida albicans.

Candida albicans is a commensal fungus, opportunistic pathogen, and the most common cause of fungal infection in humans. The biosynthesis of phosphatidylcholine (PC), a major eukaryotic glycerophospholipid, occurs through two primary pathways. In Saccharomyces cerevisiae and some plants, a third PC synthesis pathway, the PC deacylation/reacylation pathway (PC-DRP), has been characterized. PC-DRP begins with the acylation of the lipid turnover product, glycerophosphocholine (GPC), by the GPC acyltransferase, Gpc1, to form Lyso-PC. Lyso-PC is then acylated by lysolipid acyltransferase, Lpt1, to produce PC. Importantly, GPC, the substrate for Gpc1, is a ubiquitous metabolite available within the host. GPC is imported by C. albicans, and deletion of the major GPC transporter, Git3, leads to decreased virulence in a murine model. Here we report that GPC can be directly acylated in C. albicans by the protein product of orf19.988, a homolog of ScGpc1. Through lipidomic studies, we show loss of Gpc1 leads to a decrease in PC levels. This decrease occurs in the absence of exogenous GPC, indicating that the impact on PC levels may be greater in the human host where GPC is available. A gpc1Δ/Δ strain exhibits several sensitivities to antifungals that target lipid metabolism. Furthermore, loss of Gpc1 results in both a hyphal growth defect in embedded conditions and a decrease in long-term cell viability. These results demonstrate for the first time the importance of Gpc1 and this alternative PC biosynthesis route (PC-DRP) to the physiology of a pathogenic fungus.

Impact of Visit Volume on the Effectiveness of Electronic Tools to Improve Heart Failure Care.

BACKGROUND: Electronic health record (EHR) tools can improve prescribing of guideline-recommended therapies for heart failure with reduced ejection fraction (HFrEF), but their effectiveness may vary by physician workload. OBJECTIVES: This paper aims to assess whether physician workload modifies the effectiveness of EHR tools for HFrEF. METHODS: This was a prespecified subgroup analysis of the BETTER CARE-HF (Building Electronic Tools to Enhance and Reinforce Cardiovascular Recommendations for Heart Failure) cluster-randomized trial, which compared effectiveness of an alert vs message vs usual care on prescribing of mineralocorticoid antagonists (MRAs). The trial included adults with HFrEF seen in cardiology offices who were eligible for and not prescribed MRAs. Visit volume was defined at the cardiologist-level as number of visits per 6-month study period (high = upper tertile vs non-high = remaining). Analysis at the patient-level used likelihood ratio test for interaction with log-binomial models. RESULTS: Among 2,211 patients seen by 174 cardiologists, 932 (42.2%) were seen by high-volume cardiologists (median: 1,853; Q1-Q3: 1,637-2,225 visits/6 mo; and median: 10; Q1-Q3: 9-12 visits/half-day). MRA was prescribed to 5.5% in the high-volume vs 14.8% in the non-high-volume groups in the usual care arm, 10.3% vs 19.6% in the message arm, and 31.2% vs 28.2% in the alert arm, respectively. Visit volume modified treatment effect (P for interaction = 0.02) such that the alert was more effective in the high-volume group (relative risk: 5.16; 95% CI: 2.57-10.4) than the non-high-volume group (relative risk: 1.93; 95% CI: 1.29-2.90). CONCLUSIONS: An EHR-embedded alert increased prescribing by >5-fold among patients seen by high-volume cardiologists. Our findings support use of EHR alerts, especially in busy practice settings. (Building Electronic Tools to Enhance and Reinforce Cardiovascular Recommendations for Heart Failure [BETTER CARE-HF]; NCT05275920).