Slp1-Emp65: A Guardian Factor that Protects Folding Polypeptides from Promiscuous Degradation.

Newly synthesized proteins engage molecular chaperones that assist folding. Their progress is monitored by quality control systems that target folding errors for degradation. Paradoxically, chaperones that promote folding also direct unfolded polypeptides for degradation. Hence, a mechanism was previously hypothesized that prevents the degradation of actively folding polypeptides. In this study, we show that a conserved endoplasmic reticulum (ER) membrane protein complex, consisting of Slp1 and Emp65 proteins, performs this function in the ER lumen. The complex binds unfolded proteins and protects them from degradation during folding. In its absence, approximately 20%-30% of newly synthesized proteins that could otherwise fold are degraded. Although the Slp1-Emp65 complex hosts a broad range of clients, it is specific for soluble proteins. Taken together, these studies demonstrate the vulnerability of newly translated, actively folding polypeptides and the discovery of a new proteostasis functional class we term "guardian" that protects them from degradation.

Glycosylation-directed quality control of protein folding.

Membrane-bound and soluble proteins of the secretory pathway are commonly glycosylated in the endoplasmic reticulum. These adducts have many biological functions, including, notably, their contribution to the maturation of glycoproteins. N-linked glycans are of oligomeric structure, forming configurations that provide blueprints to precisely instruct the folding of protein substrates and the quality control systems that scrutinize it. O-linked mannoses are simpler in structure and were recently found to have distinct functions in protein quality control that do not require the complex structure of N-linked glycans. Together, recent studies reveal the breadth and sophistication of the roles of these glycan-directed modifications in protein biogenesis.

Reinforcement learning informs optimal treatment strategies to limit antibiotic resistance.

Antimicrobial resistance was estimated to be associated with 4.95 million deaths worldwide in 2019. It is possible to frame the antimicrobial resistance problem as a feedback-control problem. If we could optimize this feedback-control problem and translate our findings to the clinic, we could slow, prevent, or reverse the development of high-level drug resistance. Prior work on this topic has relied on systems where the exact dynamics and parameters were known a priori. In this study, we extend this work using a reinforcement learning (RL) approach capable of learning effective drug cycling policies in a system defined by empirically measured fitness landscapes. Crucially, we show that it is possible to learn effective drug cycling policies despite the problems of noisy, limited, or delayed measurement. Given access to a panel of 15 [Formula: see text]-lactam antibiotics with which to treat the simulated Escherichia coli population, we demonstrate that RL agents outperform two naive treatment paradigms at minimizing the population fitness over time. We also show that RL agents approach the performance of the optimal drug cycling policy. Even when stochastic noise is introduced to the measurements of population fitness, we show that RL agents are capable of maintaining evolving populations at lower growth rates compared to controls. We further tested our approach in arbitrary fitness landscapes of up to 1,024 genotypes. We show that minimization of population fitness using drug cycles is not limited by increasing genome size. Our work represents a proof-of-concept for using AI to control complex evolutionary processes.

Range and Pasture Plants Likely to Poison Horses.

Range and pasture toxic plants can poison horses. Many of these plants are noxious weeds that can dominate plant populations and replace healthy forages. Poisoning is often difficult to diagnose as the resulting plant-induced disease is similar to other infectious, toxic, and nutritional diseases. Identifying potentially problem plants, and observing what plants horses are eating, is essential in determining the risk of poisoning. If the risk is significant, it can drive management to invest in strategies to avoid exposure, animal disease, and suffering.

Modelling structural colour from helicoidal multi-layer thin films with natural disorder.

A coupled mode theory based on Takagi-Taupin equations describing electromagnetic scattering from distorted periodic arrays is applied to the problem of light scattering from beetles. We extend the method to include perturbations in the permittivity tensor to helicoidal arrays seen in many species of scarab beetle and optically anisotropic layered materials more generally. This extension permits analysis of typical dislocations arising from the biological assembly process and the presence of other structures in the elytra. We show that by extracting structural information from transmission electron microscopy data, including characteristic disorder parameters, good agreement with spectral specular and non-specular reflectance measurements is obtained.

Small molecule targeting of the p38/Mk2 stress signaling pathways to improve cancer treatment.

PURPOSE: Although a long-term goal of cancer therapy always has been the development of agents that selectively destroy cancer cells, more recent trends have been to seek secondary agents that sensitize cancer cells to existing treatment regimens. In this regard, the present study explored the possibility of using small molecule inhibitors of p38MAPK/MK2 stress signaling pathways as potential agents to enhance the sensitivity of cancer cells with abrogated G1 checkpoint to the DNA damaging agent etoposide by specifically targeting the DNA damage-induced G2 cell cycle checkpoint. METHODS: We have applied CCK8 and FACS-based viability assays and cell cycle analysis to investigate the effect of small molecules SB203580 and MK2.III on the sensitivity of small cell lung cancer cells (SCLC) that lack the G1 checkpoint to the DNA damaging agent Etoposide when used in combination. We have also assessed the effectiveness of combination chemotherapy on tumor xenograft suppression with etoposide and MK2.III in immunosuppressed mice. In addition, additional CCK8 cell viability analysis of the MDA-MB-231 breast cancer cell line, and SW620, and SW480 colorectal cancer cell lines was performed. RESULTS: Results suggest that etoposide produces a profound effect on the cell cycle profile of cells in a manner that is consistent with the degree of cell viability that is seen using the viable cell assay. Results of the co-treatment experiments revealed that the p38/MK2 kinase inhibitors SB203580 and MK2.III both enhanced the DNA-damaging effects of etoposide on NCI-H69 cell viability in vitro. Results revealed that in vivo MK2.III was able to act as a chemosensitizer when used in combination with etoposide making NCI-H69 lung cancer cells sensitive to chemotherapeutic drug by 45% compared to single usage of the drug. We also report that MK2.III sensitizes metastatic cell lines SW-620 and MDA-MB-231 to etoposide but does not increase the sensitivity of non-metastasizing SW-480 colorectal cells to DNA damaging agent in vitro. CONCLUSION: Findings reported in this study provide evidence that specific inhibitors of MK2 may indeed improve overall cancer therapy; however, their effectiveness depends on cell types.

Chronic ethanol induces a pro-inflammatory switch in interleukin-1ß regulation of GABAergic signaling in the medial prefrontal cortex of male mice.

Neuroimmune pathways regulate brain function to influence complex behavior and play a role in several neuropsychiatric diseases, including alcohol use disorder (AUD). In particular, the interleukin-1 (IL-1) system has emerged as a key regulator of the brain's response to ethanol (alcohol). Here we investigated the mechanisms underlying ethanol-induced neuroadaptation of IL-1ß signaling at GABAergic synapses in the prelimbic region of the medial prefrontal cortex (mPFC), an area responsible for integrating contextual information to mediate conflicting motivational drives. We exposed C57BL/6J male mice to the chronic intermittent ethanol vapor-2 bottle choice paradigm (CIE-2BC) to induce ethanol dependence, and conducted ex vivo electrophysiology and molecular analyses. We found that the IL-1 system regulates basal mPFC function through its actions at inhibitory synapses on prelimbic layer 2/3 pyramidal neurons. IL-1ß can selectively recruit either neuroprotective (PI3K/Akt) or pro-inflammatory (MyD88/p38 MAPK) mechanisms to produce opposing synaptic effects. In ethanol naïve conditions, there was a strong PI3K/Akt bias leading to a disinhibition of pyramidal neurons. Ethanol dependence produced opposite IL-1 effects - enhanced local inhibition via a switch in IL-1ß signaling to the canonical pro-inflammatory MyD88 pathway. Ethanol dependence also increased cellular IL-1ß in the mPFC, while decreasing expression of downstream effectors (Akt, p38 MAPK). Thus, IL-1ß may represent a key neural substrate in ethanol-induced cortical dysfunction. As the IL-1 receptor antagonist (kineret) is already FDA-approved for other diseases, this work underscores the high therapeutic potential of IL-1 signaling/neuroimmune-based treatments for AUD.

Evolution-Informed Strategies for Combating Drug Resistance in Cancer.

The ever-changing nature of cancer poses the most difficult challenge oncologists face today. Cancer's remarkable adaptability has inspired many to work toward understanding the evolutionary dynamics that underlie this disease in hopes of learning new ways to fight it. Eco-evolutionary dynamics of a tumor are not accounted for in most standard treatment regimens, but exploiting them would help us combat treatment-resistant effectively. Here, we outline several notable efforts to exploit these dynamics and circumvent drug resistance in cancer.

Plants that Contaminate Feed and Forage and Poison Horses: Equine Ttxicology.

Many toxic plants are unpalatable to horses and are not eaten when alternative forage is available. However, when such plants contaminate prepared or baled feed and forage, herd competition and improved palatability can alter acceptance and thereby cause equine plant poisonings. Dehydropyrrolizidine alkaloid-containing plants; cocklebur; Salvia reflexa; kleingrass, switchgrass, and other saponin-containing grasses; jimson weed, black henbane, and other tropane alkaloid-containing plants; lantana; Cassia spp and other myotoxic plants; castor bean; cyanogenic glycoside-containing plants; thiaminase-containing plants; and hoary alyssum are among those that most commonly poison horses in North America via contaminated feed or forage.

Network potential identifies therapeutic miRNA cocktails in Ewing sarcoma.

MicroRNA (miRNA)-based therapies are an emerging class of targeted therapeutics with many potential applications. Ewing Sarcoma patients could benefit dramatically from personalized miRNA therapy due to inter-patient heterogeneity and a lack of druggable (to this point) targets. However, because of the broad effects miRNAs may have on different cells and tissues, trials of miRNA therapies have struggled due to severe toxicity and unanticipated immune response. In order to overcome this hurdle, a network science-based approach is well-equipped to evaluate and identify miRNA candidates and combinations of candidates for the repression of key oncogenic targets while avoiding repression of essential housekeeping genes. We first characterized 6 Ewing sarcoma cell lines using mRNA sequencing. We then estimated a measure of tumor state, which we term network potential, based on both the mRNA gene expression and the underlying protein-protein interaction network in the tumor. Next, we ranked mRNA targets based on their contribution to network potential. We then identified miRNAs and combinations of miRNAs that preferentially act to repress mRNA targets with the greatest influence on network potential. Our analysis identified TRIM25, APP, ELAV1, RNF4, and HNRNPL as ideal mRNA targets for Ewing sarcoma therapy. Using predicted miRNA-mRNA target mappings, we identified miR-3613-3p, let-7a-3p, miR-300, miR-424-5p, and let-7b-3p as candidate optimal miRNAs for preferential repression of these targets. Ultimately, our work, as exemplified in the case of Ewing sarcoma, describes a novel pipeline by which personalized miRNA cocktails can be designed to maximally perturb gene networks contributing to cancer progression.

A proposed methodology for uncertainty extraction and verification in priority setting partnerships with the James Lind Alliance: an example from the Common Conditions Affecting the Hand and Wrist Priority Setting Partnership.

BACKGROUND: To report our recommended methodology for extracting and then confirming research uncertainties - areas where research has failed to answer a research question - derived from previously published literature during a broad scope Priority Setting Partnership (PSP) with the James Lind Alliance (JLA). METHODS: This process was completed in the UK as part of the PSP for "Common Conditions Affecting the Hand and Wrist", comprising of health professionals, patients and carers and reports the data (uncertainty) extraction phase of this. The PSP followed the robust methodology dictated by the JLA and sought to identify knowledge gaps, termed "uncertainties" by the JLA. Published Cochrane Systematic Reviews, Guidelines and Protocols, NICE (National Institute for Health and Care Excellence) Guidelines, and SIGN (Scottish Intercollegiate Guidelines Network) Guidelines were screened for documented "uncertainties". A robust method of screening, internally verifying and then checking uncertainties was adopted. This included independent screening and data extraction by multiple researchers and use of a PRISMA flowchart, alongside steering group consensus processes. Selection of research uncertainties was guided by the scope of the Common Conditions Affecting the Hand and Wrist PSP which focused on "common" hand conditions routinely treated by hand specialists, including hand surgeons and hand therapists limited to identifying questions concerning the results of intervention, and not the basic science or epidemiology behind disease. RESULTS: Of the 2358 records identified (after removal of duplicates) which entered the screening process, 186 records were presented to the PSP steering group for eligibility assessment; 79 were deemed within scope and included for the purpose of research uncertainty extraction (45 full Cochrane Reviews, 18 Cochrane Review protocols, 16 Guidelines). These yielded 89 research uncertainties, which were compared to the stakeholder survey, and added to the longlist where necessary; before derived uncertainties were checked against non-Cochrane published systematic reviews. CONCLUSIONS: In carrying out this work, beyond reporting on output of the Common Conditions Affecting the Hand and Wrist PSP, we detail the methodology and processes we hope can inform and facilitate the work of future PSPs and other evidence reviews, especially those with a broader scope beyond a single disease or condition.

Algorithm development for individualized precision feeding of supplemental top dresses to influence feed efficiency of dairy cattle.

Individualized, precision feeding of dairy cattle may contribute to profitable and sustainable dairy production. Feeding strategies targeted at optimizing efficiency of individual cows, rather than groups of animals with similar characteristics, is a logical goal of individualized precision feeding. However, algorithms designed to make feeding recommendations for specific animals are scarce. The objective of this study was to develop and test 2 algorithms designed to improve feed efficiency of individual cows by supplementing total mixed rations (TMR) with varying types and amounts of top-dressed feedstuffs. Twenty-four Holstein dairy cows were assigned to 1 of 3 treatment groups as follows: a control group fed a common TMR ad libitum, a group fed individually according to algorithm 1, and a group fed individually according to algorithm 2. Algorithm 1 used a mixed-model approach with feed efficiency as the response variable and automated measurements of production parameters and top-dress type as dependent variables. Cow was treated as a random effect, and cow by top-dress interactions were included if significant. Algorithm 2 grouped cows based on top-dress response efficiency structure using a principal components and k-means clustering. Both algorithms were trained over a 36-d experimental period immediately before testing, and were updated weekly during the 35-d testing period. Production performance responses for dry matter intake (DMI), milk yield, milk fat percentage and yield, milk protein percentage and yield, and feed efficiency were analyzed using a mixed-effects model with fixed effects for feeding algorithm, top dress, week, and the 2- and 3-way interactions among these variables. Milk protein percentage and feed efficiency were significantly affected by the 3-way interaction of top dress, algorithm, and week, and DMI tended to be affected by this 3-way interaction. Feeding algorithm did not affect milk yield, milk fat yield, or milk protein yield. However, feeding costs were reduced, and hence milk revenue increased on the algorithm-fed cows. The efficacy of feeding algorithms differed by top dress and time, and largely relied on DMI shifts to modulate feed efficiency. The net result, for the cumulative feeding groups, was that cows in the algorithm 1 and 2 groups earned over $0.45 and $0.70 more per head per day in comparison to cows on the TMR control, respectively. This study yielded 2 candidate approaches for efficiency-focused, individualized feeding recommendations. Refinement of algorithm selection, development, and training approaches are needed to maximize production parameters through individualized feeding.

Combining bio-telemetry and underwater imagery to elucidate the reproductive behaviour of a large, long-lived Australian freshwater teleost.

Murray cod Maccullochella peelii (Mitchell) have a key ecological role in ensuring the health of Australia's largest inland waterway, but many aspects surrounding its reproductive strategies in the wild are unknown. From 2015 to 2019 within the Northern Murray-Darling Basin, Australia, we used a combination of bio-telemetry and underwater imagery to quantify the behaviour of Murray cod across their breeding cycle in a natural riverine environment. In most years, breeding behaviour including nest site selection was observed from early-August and spawning from late-August through to late-October, which is considerably earlier than previously reported. There was a positive correlation between the onset of breeding behaviour and week-of-year, and spawning was correlated with moon-phase. Whilst some nesting sites were amongst woody debris and in hollow logs, the majority were located in shallow water on hard substrate underneath undercuts along the riverbank edge. Nests were frequently established in isolated and disconnected pools with little or no measurable flow, suggesting that river hydraulics is not a key component driving spawning of Murray cod across at least some areas of its range. Larvae were observed actively swimming and controlling their position within and near nests and used a scatter tactic when dispersing. We also established that disturbing nesting Murray cod had a negative impact on egg and larval survival. We suggest a review of current regulations to safeguard the long-term conservation of the species across all sections of its range.

The biosynthesis of the anti-microbial diterpenoid leubethanol in Leucophyllum frutescens proceeds via an all-cis prenyl intermediate.

Serrulatane diterpenoids are natural products found in plants from a subset of genera within the figwort family (Scrophulariaceae). Many of these compounds have been characterized as having anti-microbial properties and share a common diterpene backbone. One example, leubethanol from Texas sage (Leucophyllum frutescens) has demonstrated activity against multi-drug-resistant tuberculosis. Leubethanol is the only serrulatane diterpenoid identified from this genus; however, a range of such compounds have been found throughout the closely related Eremophila genus. Despite their potential therapeutic relevance, the biosynthesis of serrulatane diterpenoids has not been previously reported. Here we leverage the simple product profile and high accumulation of leubethanol in the roots of L. frutescens and compare tissue-specific transcriptomes with existing data from Eremophila serrulata to decipher the biosynthesis of leubethanol. A short-chain cis-prenyl transferase (LfCPT1) first produces the rare diterpene precursor nerylneryl diphosphate, which is cyclized by an unusual plastidial terpene synthase (LfTPS1) into the characteristic serrulatane diterpene backbone. Final conversion to leubethanol is catalyzed by a cytochrome P450 (CYP71D616) of the CYP71 clan. This pathway documents the presence of a short-chain cis-prenyl diphosphate synthase, previously only found in Solanaceae, which is likely involved in the biosynthesis of other known diterpene backbones in Eremophila. LfTPS1 represents neofunctionalization of a compartment-switching terpene synthase accepting a novel substrate in the plastid. Biosynthetic access to leubethanol will enable pathway discovery to more complex serrulatane diterpenoids which share this common starting structure and provide a platform for the production and diversification of this class of promising anti-microbial therapeutics in heterologous systems.

The association between carotid disease, arterial stiffness and diabetic retinopathy in type 2 diabetes: the Fremantle Diabetes Study Phase II.

AIM: To determine whether macrovascular disease assessed by carotid ultrasonography and arterial stiffness by pulse wave velocity are independently associated with diabetic retinopathy in type 2 diabetes. METHODS: A random subgroup of surviving participants with type 2 diabetes from the Fremantle Diabetes Study Phase II were invited to take part in this sub-study in 2018-2019. In addition to standardized questionnaires, a physical examination and fasting biochemical tests, each underwent dilated colour fundus photography, carotid arterial ultrasonography with measurement of the intima-media thickness (IMT) and quantification of the degree of stenosis, and pulse wave analysis calculation of the carotid-femoral pulse wave velocity (cfPWV). The cross-sectional association between arterial disease parameters and diabetic retinopathy was assessed using generalized estimating equation models which enabled both eyes to be included in the analysis. RESULTS: Some 270 participants [mean ± sd age 72 ± 9 years, 153 (57%) men and median (IQR) diabetes duration 15 (11-22) years] were included in analysis. Of 524 assessable eyes, 82 (16%) had diabetic retinopathy. In multivariable analysis, significant independent associates of diabetic retinopathy were age at diabetes diagnosis (inversely), HbA1c , insulin treatment and urinary albumin to creatinine ratio (all P ≤ 0.022), as well as cfPWV [odds ratio (OR) 1.13, 95% confidence interval (CI) 1.03, 1.23 per 1 m/s increase; P = 0.008] and common carotid artery (CCA) IMT ≥1 mm (OR 2.95, 95% CI 1.21, 7.23; P = 0.018). CONCLUSIONS: The association between diabetic retinopathy and CCA IMT suggests that carotid disease may share cardiovascular risk factors with diabetic retinopathy. The association between diabetic retinopathy and cfPWV may reflect the consequences of altered intravascular haemodynamics.

Aneuploidy-induced proteotoxic stress can be effectively tolerated without dosage compensation, genetic mutations, or stress responses.

BACKGROUND: The protein homeostasis (proteostasis) network maintains balanced protein synthesis, folding, transport, and degradation within a cell. Failure to maintain proteostasis is associated with aging and disease, leading to concerted efforts to study how the network responds to various proteotoxic stresses. This is often accomplished using ectopic overexpression of well-characterized, model misfolded protein substrates. However, how cells tolerate large-scale, diverse burden to the proteostasis network is not understood. Aneuploidy, the state of imbalanced chromosome content, adversely affects the proteostasis network by dysregulating the expression of hundreds of proteins simultaneously. Using aneuploid haploid yeast cells as a model, we address whether cells can tolerate large-scale, diverse challenges to the proteostasis network. RESULTS: Here we characterize several aneuploid Saccharomyces cerevisiae strains isolated from a collection of stable, randomly generated yeast aneuploid cells. These strains exhibit robust growth and resistance to multiple drugs which induce various forms of proteotoxic stress. Whole genome re-sequencing of the strains revealed this was not the result of genetic mutations, and transcriptome profiling combined with ribosome footprinting showed that genes are expressed and translated in accordance to chromosome copy number. In some strains, various facets of the proteostasis network are mildly upregulated without chronic activation of environmental stress response or heat shock response pathways. No severe defects were observed in the degradation of misfolded proteins, using model misfolded substrates of endoplasmic reticulum-associated degradation or cytosolic quality control pathways, and protein biosynthesis capacity was not impaired. CONCLUSIONS: We show that yeast strains of some karyotypes in the genetic background studied here can tolerate the large aneuploidy-associated burden to the proteostasis machinery without genetic changes, dosage compensation, or activation of canonical stress response pathways. We suggest that proteotoxic stress, while common, is not always an obligate consequence of aneuploidy, but rather certain karyotypes and genetic backgrounds may be able to tolerate the excess protein burden placed on the protein homeostasis machinery. This may help clarify how cancer cells are paradoxically both highly aneuploid and highly proliferative at the same time.

Risk factors and outcomes of anxiety symptom trajectories in type 2 diabetes: the Fremantle Diabetes Study Phase II.

AIM: To identify determinants and outcomes of 4-year trajectories of anxiety symptoms in a community-based cohort with type 2 diabetes. METHODS: Some 1091 participants in the Fremantle Diabetes Study-Phase II with type 2 diabetes completed the Generalized Anxiety Disorder Scale at baseline and biennially for 4 years, in addition to psychological, biomedical and self-management measures. Latent growth mixture modelling identified trajectories of anxiety symptom severity, and regression models determined predictors of trajectory membership and associated outcomes. RESULTS: Two distinct groups of participants were identified: those with continuously low-no anxiety symptoms (87%) and those with improving but consistently high anxiety symptoms (elevated anxiety; 13%). Higher HbA1c and BMI, macrovascular complications and a history of generalized anxiety and/or major depressive disorder increased the risk of elevated anxiety. Elevated anxiety did not predict change in health-related outcomes over time. Elevated anxiety and depression symptoms were highly comorbid and those with both displayed the most persistent anxiety symptoms. CONCLUSIONS: A subgroup of individuals with type 2 diabetes are at risk of persistently elevated anxiety symptoms. Routine monitoring of the severity of psychological symptoms over time in this population should facilitate earlier and more intensive mood management.

The membrane stress response buffers lethal effects of lipid disequilibrium by reprogramming the protein homeostasis network.

Lipid composition can differ widely among organelles and even between leaflets of a membrane. Lipid homeostasis is critical because disequilibrium can have disease outcomes. Despite their importance, mechanisms maintaining lipid homeostasis remain poorly understood. Here, we establish a model system to study the global effects of lipid imbalance. Quantitative lipid profiling was integral to monitor changes to lipid composition and for system validation. Applying global transcriptional and proteomic analyses, a dramatically altered biochemical landscape was revealed from adaptive cells. The resulting composite regulation we term the "membrane stress response" (MSR) confers compensation, not through restoration of lipid composition, but by remodeling the protein homeostasis network. To validate its physiological significance, we analyzed the unfolded protein response (UPR), one facet of the MSR and a key regulator of protein homeostasis. We demonstrate that the UPR maintains protein biogenesis, quality control, and membrane integrity-functions otherwise lethally compromised in lipid dysregulated cells.

Health-related quality of life in glomerular disease.

There is scant literature describing the effect of glomerular disease on health-related quality of life (HRQOL). The Cure Glomerulonephropathy study (CureGN) is an international longitudinal cohort study of children and adults with four primary glomerular diseases (minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and IgA nephropathy). HRQOL is systematically assessed using items from the Patient-Reported Outcomes Measurement Informative System (PROMIS). We assessed the relationship between HRQOL and demographic and clinical variables in 478 children and 1115 adults at the time of enrollment into CureGN. Domains measured by PROMIS items included global assessments of health, mobility, anxiety, fatigue, and sleep impairment, as well as a derived composite measure incorporating all measured domains. Multivariable models were created that explained 7 to 32% of variance in HRQOL. Patient-reported edema consistently had the strongest and most robust association with each measured domain of HRQOL in multivariable analysis (adjusted ß [95% CI] for composite PROMIS score in children, -5.2 [-7.1 to -3.4]; for composite PROMIS score in adults, -6.1 [-7.4 to -4.9]). Female sex, weight (particularly obesity), and estimated glomerular filtration rate were also associated with some, but not all, domains of HRQOL. Primary diagnosis, disease duration, and exposure to immunosuppression were not associated with HRQOL after adjustment. Sensitivity analyses and interaction testing demonstrated no significant association between disease duration or immunosuppression and any measured domain of HRQOL. Thus, patient-reported edema has a consistent negative association with HRQOL in patients with primary glomerular diseases, with substantially greater impact than other demographic and clinical variables.

Multicenter Evaluation of NeuMoDx Group B Streptococcus Assay on the NeuMoDx 288 Molecular System.

Group B Streptococcus (GBS) is the leading cause of neonatal sepsis and meningitis in developed countries. Recommendations for antepartum GBS detection include enriched culture with several options for identifying GBS, some of which are time-consuming. To reduce the time for identification and determination of the maternal GBS colonization status, rapid nucleic acid amplification technologies have been developed and commercialized. For rapid detection of GBS, a three-site clinical study was conducted to evaluate the NeuMoDx GBS assay, a real-time PCR test performed for vaginal/rectal swab specimens in Lim broth enrichment culture on the NeuMoDx 288 molecular system (NeuMoDx system); these data were used to a support 510(k) submission. A total of 1,250 eligible remnant samples were prospectively enrolled and tested during the study. The results of the PCR assay were compared to the results of the Centers for Disease Control and Prevention (CDC)-recommended enriched-culture method, which served as the gold standard reference method for the study. The NeuMoDx GBS assay results yielded a sensitivity of 96.9% (95% confidence interval [CI] = 94.1 to 98.4), specificity of 96.0% (95% CI = 94.6 to 97.1), and a total agreement with the reference method of 96.2% (95% CI = 93.8 to 98.3). NeuMoDx GBS assay results were also compared to results obtained using the BD MAX GBS assay on the BD MAX system. The two systems demonstrated a total percent agreement of 98.0% (95% CI = 95.5 to 100.0). The performance of the NeuMoDx GBS assay implemented on the NeuMoDx system compared favorably to the CDC enriched-culture method and to the BD MAX GBS assay.