Association of prior treatment with nitrogen-containing bisphosphonates on outcomes of COVID-19 positive patients.

COVID-19 infection has resulted in significant morbidity and mortality globally, especially among older adults. Repurposed drugs have demonstrated activity in respiratory illnesses, including nitrogen-containing bisphosphonates. In this retrospective longitudinal study at 4 academic medical centers, we show no benefit of nitrogen-containing bisphosphonates regarding ICU admission, ventilator use, and mortality among older adults with COVID-19 infection. We specifically evaluated the intravenous bisphosphonate zoledronic acid and found no difference compared to oral bisphosphonates. BACKGROUND: Widely used in osteoporosis treatment, nitrogen-containing bisphosphonates (N-BP) have been associated with reduced mortality and morbidity among older adults. Based on prior studies, we hypothesized that prior treatment with N-BP might reduce intensive care unit (ICU) admission, ventilator use, and death among older adults diagnosed with COVID-19. METHODS: This retrospective analysis of the PCORnet Common Data Model across 4 academic medical centers through 1 September 2021 identified individuals age >50 years with a diagnosis of COVID-19. The composite outcome included ICU admission, ventilator use, or death within 15, 30, and 180 days of COVID-19 diagnosis. Use of N-BP was defined as a prescription within 3 years prior. ICU admission and ventilator use were determined using administrative codes. Death included both in-hospital and out-of-hospital events. Patients treated with N-BP were matched 1:1 by propensity score to patients without prior N-BP use. Secondary analysis compared outcomes among those prescribed zoledronic acid (ZOL) to those prescribed oral N-BPs. RESULTS: Of 76,223 COVID-19 patients identified, 1,853 were previously prescribed N-BP, among whom 559 were prescribed ZOL. After propensity score matching, there were no significant differences in the composite outcome at 15 days (HR 1.22, 95% CI: 0.89-1.67), 30 days (HR 1.24, 95% CI: 0.93-1.66), or 180 days (HR 1.17, 95% CI: 0.93-1.48), comparing those prescribed and not prescribed N-BP. Compared to those prescribed oral N-BP, there were no significant differences in outcomes among those prescribed ZOL. CONCLUSION: Among older COVID-19 patients, prior exposure to N-BP including ZOL was not associated with a reduction in ICU admission, ventilator use, or death.

Bepridil is potent against SARS-CoV-2 in vitro.

Guided by a computational docking analysis, about 30 Food and Drug Administration/European Medicines Agency (FDA/EMA)-approved small-molecule medicines were characterized on their inhibition of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro). Of these small molecules tested, six displayed a concentration that inhibits response by 50% (IC50) value below 100 µM in inhibiting Mpro, and, importantly, three, that is, pimozide, ebastine, and bepridil, are basic molecules that potentiate dual functions by both raising endosomal pH to interfere with SARS-CoV-2 entry into the human cell host and inhibiting Mpro in infected cells. A live virus-based modified microneutralization assay revealed that bepridil possesses significant anti-SARS-CoV-2 activity in both Vero E6 and A459/ACE2 cells in a dose-dependent manner with low micromolar effective concentration, 50% (EC50) values. Therefore, the current study urges serious considerations of using bepridil in COVID-19 clinical tests.

Consumer perception of Cheddar cheese color.

The color of Cheddar cheese in the US is influenced by many factors, primarily the amount of annatto added as a colorant. The US FDA is currently reviewing its definition of the term "natural" on food labels, which may result in the use of colorants being restricted in natural cheeses. The objective of this study was to evaluate how consumers perceive Cheddar cheese color to better understand how changes to legislation surrounding colorants in natural Cheddar cheese may affect consumption. We were also interested in determining if a relationship exists between color and other perceived characteristics of Cheddar cheese. Two online surveys on Cheddar cheese color and flavor attributes (n = 1226 and n = 1183, respectively) were conducted, followed by a consumer acceptance test on 6 commercially available Cheddar cheeses (n = 196). Overall, consumers preferred light orange color in Cheddar cheese over dark orange or white Cheddar cheese, but segmentation was observed for Cheddar color preference. Light orange Cheddar and white Cheddar were perceived as approximately equal in terms of "naturalness." White and light orange Cheddars were perceived as more natural than dark orange Cheddars conceptually and in consumer acceptance testing. White Cheddar was considered most natural by 50.3% of n = 1283 survey participants and 43.4% of n = 196 consumer acceptance test participants, while light orange Cheddar was perceived as most natural by 40.6% and 45.9% of these groups respectively. A bimodal distribution was observed in both the online survey and in consumer acceptance testing for "naturalness" of Cheddar cheese color, with a subset of consumers (31.4% of n = 1183 survey participants and 30.6% of n = 196 consumer testing participants) indicating that white Cheddar was the least natural option. Consumers associated orange color in Cheddar cheese with more "sharp" flavor both in an online survey format and consumer acceptance testing.

Milk beverage base with lactose removed with ultrafiltration: Effect of fat and protein concentration on sensory and physical properties.

Our objectives were to determine the effect of fat (skim to whole milk) and protein (3.4%-10.5%) concentration on the sensory and physical properties of milk beverage base that had lactose and other low molecular components removed by ultrafiltration (UF). In experiment 1, a matrix of 16 treatments was produced to achieve 4 levels of lactose removal (0%, 30%, 70%, and 97%) at each of 4 fat levels (skim, 1%, 2%, and whole milk). In experiment 2, a matrix of 12 treatments was produced to achieve 4 levels of lactose removal (0%, 30%, 70%, and 97%) at each of 3 protein concentrations (3.4%, 6.5%, and 10.5% protein). Physical and sensory properties of these products were determined. Removal of >95% of milk lactose by UF required a diafiltration volume of approximately 3 times the milk volume. Lactose and low molecular weight solute removal increased whiteness across the range from skim to whole milk while decreasing viscosity and making milk flavor blander. In addition, lactose (and other low molecular weight solute) removal by UF decreased titratable acidity by more than 50% and increased milk pH at 20°C to >7.0. Future work on milk and milk-based beverages with lactose removed by UF needs to focus on interaction of the remaining milk solids with added flavorings, changing casein to whey protein ratio before removal of lactose by UF, and the effect of lactose and low molecular weight solute removal on heat stability, particularly for neutral-pH, shelf-stable milk-based beverages.

Predicting and influencing PrEP use: the role of motivational and attitudinal factors.

This study examined PrEP attitude and HIV risk factors associated with PrEP motivation and evaluated the efficacy of a mock public health video that addresses both motivational and stigma issues for improving PrEP uptake over a standard educational video. Gay, bisexual, and other men who have sex with men (GBMSM; N = 604) were enrolled. One-way between subject analysis of variance (ANOVA) and post-hoc comparisons revealed that GBMSM in later stages of change had significantly higher endorsement of positive PrEP attitudes, PrEP stigma, objective and perceived HIV risk, HIV worry, and valued health benefits of PrEP more. Stepwise multiple regression revealed five significant predictors of PrEP motivation: HIV worry, objective HIV risk, anticipated PrEP stigma, positive PrEP attitudes, and perceived social consequences of PrEP use. Video conditions did not differ in their impact on PrEP attitudes or motivation; however, regardless of video condition, participants experienced a pre- to post-video increase in positive PrEP attitudes and motivation. Findings suggest HIV worry, objective HIV risk, positive PrEP attitudes, and perceived PrEP health benefits are important factors to optimize PrEP motivation, which can inform secondary prevention efforts. Further study is needed on promotional PrEP campaigns that disconfirm stigmatizing PrEP misconceptions.

Parental perception of children's school lunch milk.

School lunch programs are mandated by the US Code of Federal Regulations to serve pasteurized milk that is skim or 1% fat and fortified with vitamins A and D. In recent years, proposals have been made to alter nutritional requirements for school lunches and school lunch milk, including changes to the milk fat and flavor options available. The objective of this study was to evaluate parental understanding and perception of school lunch milk to better understand how changes to school lunch milk are perceived by parents. Four focus groups (n = 34) were conducted with parents of school-aged children (5-13 yr) who purchased milk as part of a lunch at school. Participants were asked about school lunch milk, including nutritional content, packaging, and flavoring. Focus groups included a build-your-own milk activity and discussion of children's milk products currently available on the market. Two subsequent online surveys were conducted with parents of school-aged children (survey 1, n = 216; survey 2, n = 133). Maximum difference scaling was used to evaluate what beverages parents would prefer their child to drink at school (survey 1) and which attributes of chocolate milk for children were most important to parents (survey 2). An adaptive choice-based conjoint activity (survey 1) included flavor, milk fat, heat treatment, label claims, and packaging type. Both surveys included questions to evaluate knowledge of milk nutrition and attitudes regarding milk and flavored milk. Agree/disagree questions were used in both surveys to assess parental opinions of school lunch milk. Survey 2 also included semantic differential (sliding scale) questions to assess parental opinions of chocolate milk and their acceptance of sugar alternatives in chocolate milk served in schools. Parents were familiar with the flavor options and packaging of school lunch milk, but expressed limited familiarity with school lunch milk fat content. Parents perceived milk to be healthy and a good source of vitamin D and calcium. From survey results, parents placed the highest importance on school lunch milk packaging, followed by milk fat percentage and flavoring over label claims and heat treatment. The ideal school lunch milk for parents was unflavored (white milk) or chocolate, 2% fat, and packaged in a cardboard gabletop carton. For school lunch chocolate milk, 3 distinct clusters of parents with differing opinions for children's chocolate milk were identified. Parents are largely unfamiliar with the specific attributes and nutritional profile of milk served in schools but believe that schools should offer milk to their children as part of breakfast and lunch. Parents in both surveys also displayed a preference for 2% fat milk over low-fat options, which provides actionable insight for both governmental bodies determining educational and nutritional policies for school meals and fluid milk producers seeking to optimize their products intended for schools.

The role of packaging on the flavor of fluid milk.

Few studies have addressed the effects of package material in the absence of light on contributions to fluid milk flavor. The objective of this study was to compare the sensory and chemical properties of fluid milk packaged in paperboard cartons, low-density polyethylene, high-density polyethylene (HDPE), polyethylene terephthalate (PET), linear low-density polyethylene (LLDPE), and glass. Pasteurized (high temperature short time, 77°C for 25 s) skim and whole milk were filled (280 mL ± 10 mL) into paperboard cartons, low-density polyethylene, HDPE, PET, LLDPE, and glass (control). Milks were stored at 4°C in the dark and sampled at d 0, 5, 10, and 15. Descriptive analysis was applied to document sensory profiles at each time point, and volatile compounds were extracted and identified by solid-phase microextraction with gas chromatography mass spectrometry and gas chromatography-olfactometry. Tetrad tests with consumers were conducted at d 10. Both skim and whole milks packaged in cartons had noticeable paperboard flavor by d 5 and higher levels of hexanal than skim and whole milks in other package types at d 5. Skim milks packaged in paperboard cartons and LLDPE had distinct refrigerator/stale flavor compared with milks in the other package types, concurrent with increased levels of refrigerator/package-related compounds including styrene, acetophenone and 2-ethyl-1-hexanol. Milks packaged in glass, PET and HDPE were not distinguished by consumers at d 10 post-processing. Package type influences fluid milk flavor, and these effects are greater in skim milk compared with whole milk. Paperboard cartons do not preserve milk freshness, as well as PET, HDPE, or glass, due to flavor migration and scalping. Glass remains an ideal barrier to preserve fluid milk flavor, but in the absence of light, HDPE and PET provide additional benefits while also maintaining fluid milk flavor.

Consumer perception of natural hot-pepper cheeses.

Hot-pepper cheese (HPC) is a growing category of flavored natural cheese. The objective of this study was to evaluate consumer perception of HPC using a combination of quantitative survey methods and consumer evaluation of HPC. An online survey (n = 510) was conducted to understand drivers of purchase for the HPC category. Consumers of HPC answered maximum difference exercises and an adaptive choice-based conjoint activity focused on HPC attributes. Subsequently, natural HPC were manufactured in duplicate with 5 different hot-pepper blends with a range of heat intensities and distinct color differences. Trained panel profiling and consumer-acceptance testing (n = 194 consumers) were conducted on the cheeses. Three clusters of consumers were identified from the online survey. Cluster 1 (n = 175) were traditional HPC consumers, and cluster 2 (n = 152) preferred milder HPC. Cluster 3 (n = 183) showed preference for spicier HPC as well as novel HPC, such as those made with habanero peppers or white Cheddar cheese. Conceptually, the overall ideal HPC was a Monterey Jack with medium-sized, multicolored pieces of jalapeno peppers and a medium heat and spiciness. Heat and spiciness intensity and type of cheese were the most important attributes. The 5 HPC used in consumer testing had a distinct range (low to high) of hot-pepper burn and heat intensity by trained panel profiling. Consumer overall liking increased as hot-pepper burn and heat intensity increased to a certain point, indicating HPC consumers may have an optimal point for heat and spiciness in HPC. Consumers also preferred HPC with multicolored pepper pieces over those with a single pepper color, consistent with survey results. Consumers who self-reported that they prefer mild- or medium-spicy foods (mild consumers) preferred HPC that were less intense in hot-pepper burn than consumers who self-reported preference for hot or spicy foods (hot consumers). Most HPC consumers preferred HPC with higher heat intensity and were also motivated by visual characteristics of HPC.

Parents' implicit perceptions of dairy milk and plant-based milk alternatives.

Dairy product consumption is motivated by both familiarity and habit. Milk consumption decreases with age, but milk consumption during childhood and adolescence increases the chances of lifetime milk consumption. Understanding how parents perceive dairy milk and other dairy foods further enables development of dairy-positive messaging that aligns with their perceptions. The objective of this research was to understand parent belief systems around fluid dairy milk and plant-based alternatives (PBA). This goal was accomplished by assessing parents' implicit attitudes toward dairy milk and PBA with an implicit bias exercise (n = 331), followed by qualitative interviews to understand explicitly stated purchase motivations and guided recall of information heard about dairy milk and PBA to better understand external influences on milk perception (n = 88). The majority of parents (73.4%) implicitly associated dairy milk with positive attributes compared with those with a positive association with PBA (13.8%) or with a neutral bias (12.7%). The stronger a parent's implicit bias toward PBA, the more likely they were to purchase these products either alongside or as a replacement for dairy milk. Eighty-five percent of parents in our study could recall drinking milk at home as a child, and 58% remembered encouragement from their parents to drink milk. However, only 38% encouraged their own children to drink milk (the majority, 55%, were neutral toward their children's milk consumption). Generally negative media messaging toward dairy milk and positive messaging toward PBA may contribute to this trend, even if consumers are not explicitly aware of their perception changes. Seventy-seven percent of parents felt generally confident in choosing dairy milk or PBA for their children. However, only 26% of parents felt that nothing about dairy milk or PBA information or messaging was confusing. Sources of uncertainty about dairy milk included hormones and antibiotics, animal welfare, ecological sustainability, potential contamination, and intolerances or allergies. By addressing the most commonly encountered and recalled concerns about milk from parents, dairy producers may be able to increase trust and implicit bias toward dairy milk compared with PBA.

Consumer perception of ice cream and frozen desserts in the "better-for-you" category.

The consumption of ice cream and frozen desserts in the "better-for-you" (BFY) category has grown rapidly over the past few years, even as traditional ice cream sales remain stagnant. To better understand consumer preferences within the BFY category, an online survey (n = 1,051) was conducted with ice cream and frozen dessert consumers, followed by consumer acceptance testing of commercial BFY frozen dairy desserts. Consumers of BFY frozen desserts (n = 578) completed an adaptive choice-based conjoint survey and MaxDiff exercise to identify the attributes that drive purchase of BFY frozen desserts. MaxDiff exercises were also used to determine which attributes all frozen dessert consumers (n = 1,051) perceived to make a frozen dessert BFY and which stabilizers or emulsifiers were most attractive on an ice cream or frozen dessert label. Subsequently, a consumer acceptance test (n = 186) was conducted using 4 commercial vanilla-flavored frozen dairy desserts made with different sweetening systems (sugar, sucralose + acesulfame K, monk fruit + allulose, and stevia + erythritol). Half of consumers were primed or informed with the sweeteners and basic nutritional information for the frozen desserts before tasting, and the other half of consumers evaluated samples blinded, where they were only informed that they were tasting a vanilla-flavored frozen dessert. Sweetener type and base (dairy vs. plant) were the most important attributes to BFY consumers when selecting a BFY frozen dessert (n = 578). For all ice cream and BFY dessert consumers (n = 1,051), sweetener-related claims (naturally sweetened, reduced sugar, no added sugar), along with "all natural" and a short ingredient list, were the top attributes that contributed to perception of a "healthier" frozen dessert. When BFY frozen desserts were tasted by consumers, purchase intent decreased after tasting, suggesting that frozen desserts made with natural non-nutritive sweeteners did not meet consumer expectations. Flavor of BFY frozen desserts remains more important than perceived healthiness. Consumers perceive frozen desserts, even those in the BFY category, as an indulgence. Frozen dessert manufacturers should focus on naturally sweetened, dairy-based desserts with minimal sweetener-related flavor defects when designing products for the BFY category.

Identification of aroma-active compounds in Cheddar cheese imparted by wood smoke.

Cheddar cheese is the most popular cheese in the United States, and the demand for specialty categories of cheese, such as smoked cheese, are rising. The objective of this study was to characterize the flavor differences among Cheddar cheeses smoked with hickory, cherry, or apple woods, and to identify important aroma-active compounds contributing to these differences. First, the aroma-active compound profiles of hickory, cherry, and apple wood smokes were analyzed by solid-phase microextraction (SPME) gas chromatography-olfactometry (GCO) and gas chromatography-mass spectrometry (GC-MS). Subsequently, commercial Cheddar cheeses smoked with hickory, cherry, or apple woods, as well as an unsmoked control, were evaluated by a trained sensory panel and by SPME GCO and GC-MS to identify aroma-active compounds. Selected compounds were quantified with external standard curves. Seventy-eight aroma-active compounds were identified in wood smokes. Compounds included phenolics, carbonyls, and furans. The trained panel identified distinct sensory attributes and intensities among the 3 cheeses exposed to different wood smokes (P < 0.05). Hickory smoked cheeses had the highest intensities of flavors associated with characteristic "smokiness" including smoke aroma, overall smoke flavor intensity, and meaty, smoky flavor. Cherry wood smoked cheeses were distinguished by the presence of a fruity flavor. Apple wood smoked cheeses were characterized by the presence of a waxy, green flavor. Ninety-nine aroma-active compounds were identified in smoked cheeses. Phenol, guaiacol, 4-methylguaiacol, and syringol were identified as the most important compounds contributing to characteristic "smokiness." Benzyl alcohol contributed to the fruity flavor in cherry wood smoked cheeses, and 2-methyl-2-butenal and 2-ethylfuran were responsible for the waxy, green flavor identified in apple wood smoked cheeses. These smoke flavor compounds, in addition to diacetyl and acetoin, were deemed important to the flavor of cheeses in this study. Results from this study identified volatile aroma-active compounds contributing to differences in sensory perception among Cheddar cheeses smoked with different wood sources.

Effects of micellar casein concentrate purity and milk fat on sulfur/eggy flavor in ultrapasteurized milk-based beverages.

Our objectives were to determine the level of milk-derived whey protein (MDWP) removal necessary to achieve no detectable sulfur/eggy flavor in ultrapasteurized fat-free micellar casein concentrate (MCC) beverages (6.5% protein) and in the same beverages containing 1 and 2% milk fat. Micellar casein concentrate with 95% MDWP removal was produced from skim milk (50°C) with a 3×, 3-stage ceramic microfiltration (MF) process using 0.1-µm pore size graded permeability membranes (n = 3). In experiment 1, MCC-based beverages at about 6.5% (wt/wt) true protein were formulated at a fat content of 0.15% fat (wt/wt) at 4 different levels of MDWP removal percentages (95.2%, 91.0%, 83.2%, and 69.3%). In experiment 2, a similar series of beverages at 3 MDWP removal percentages (95.2%, 83.2%, and 69.3%) with 0.1, 1, and 2% fat content were produced. The purity (or completeness of removal of whey protein by MF) of MCC was determined by the Kjeldahl method and sodium dodecyl sulfate (SDS)-PAGE. Sensory properties of beverages were documented by descriptive sensory analysis, and volatile sulfur compounds were evaluated using solid-phase microextraction followed by gas chromatography-triple quadrupole mass spectrometry. The purity of MCC measured by the Kjeldahl method (casein as a percentage of true protein) was higher after thermal treatment than before, whereas MCC purity evaluated by SDS-PAGE was unchanged by heat treatment. The purity of MCC had an effect on the flavor profile of thermally processed beverages at 6.5% protein made with fresh liquid MCC. No sulfur/eggy flavor was detected in MCC beverages when 95% of the MDWP was removed (MCC purity about 93 to 94%) from skim milk by microfiltration at 0.1, 1, and 2% fat. As the fat content of 6.5% protein beverages produced with MCC increased, sulfur/eggy flavor intensity and hydrogen sulfide concentration decreased. However, the effect of increasing milk fat on reducing sulfur/eggy flavor in MCC-based beverages at 6.5% protein was less than that of increasing MDWP removal from MCC. Sulfur off-flavors in neutral-pH dairy protein beverages can be mitigated by use of high-purity MCC or by incorporation of fat in the beverage, or both.

Children's perceptions of fluid milk with varying levels of milkfat.

Schools participating in federal meal programs are limited to serving skim or low-fat (≤1%) flavored and unflavored milk. Few studies have directly addressed child perceptions and preferences for milk containing different amounts of milkfat. The objective of this study was to determine whether children can differentiate between flavored and unflavored fluid milk containing varying levels of milkfat and whether preferences for certain levels of milkfat exist. Flavored and unflavored milks containing 4 different percentages of milkfat (≤0.5, 1, 2, and 3.25%) were high-temperature, short-time processed, filled into half-gallon light-shielded milk jugs, and stored at 4°C in the dark. Milks were evaluated by children (ages 8-13 yr) following 7 d at 4°C. Acceptance testing and tetrad difference testing were conducted on flavored and unflavored milks with and without visual cues to determine if differences were driven by visual or flavor or mouthfeel cues. Child acceptance testing (n = 138 unflavored; n = 123 flavored) was conducted to evaluate liking and perception of selected attributes. Tetrad testing (n = 127 unflavored; n = 129 flavored) was conducted to determine if children could differentiate between different fat levels even in the absence of a difference in acceptance. The experiment was replicated twice. When visual cues were present, children had higher overall liking for 1% and 2% milks than skim for unflavored milk and higher liking for chocolate milks containing at least 1% milk fat than for skim. Differences in liking were driven by appearance, viscosity, and flavor. In the absence of visual cues, no differences were observed in liking or flavor or mouthfeel attributes for unflavored milk but higher liking for at least 1% milk fat in chocolate milk compared with skim was consistent with the presence of visual cues. From tetrad testing, children could visually tell a difference between all unflavored pairs except 2% versus whole milk and could not detect consistent differences between milkfat pairs in the absence of visual cues. For chocolate milk, children could tell a difference between all milk fat pairs with visual cues and could tell a difference between skim versus 2% and skim versus whole milk without visual cues. These results demonstrate that in the absence of package-related flavors, school-age children like unflavored skim milk as well as milk with higher fat content in the absence of visual cues. In contrast, appearance as well as flavor and mouthfeel attributes play a role in children's liking as well as their ability to discriminate between chocolate milks containing different amounts of fat, with chocolate milk containing at least 1% fat preferred. The sensory quality of school lunch milk is vital to child preference, and processing efforts are needed to maximize school milk sensory quality.

Migraine-Associated Common Genetic Variants Confer Greater Risk of Posterior vs. Anterior Circulation Ischemic Stroke☆.

OBJECTIVE: To examine potential genetic relationships between migraine and the two distinct phenotypes posterior circulation ischemic stroke (PCiS) and anterior circulation ischemic stroke (ACiS), we generated migraine polygenic risk scores (PRSs) and compared these between PCiS and ACiS, and separately vs. non-stroke control subjects. METHODS: Acute ischemic stroke cases were classified as PCiS or ACiS based on lesion location on diffusion-weighted MRI. Exclusion criteria were lesions in both vascular territories or uncertain territory; supratentorial PCiS with ipsilateral fetal posterior cerebral artery; and cases with atrial fibrillation. We generated migraine PRS for three migraine phenotypes (any migraine; migraine without aura; migraine with aura) using publicly available GWAS data and compared mean PRSs separately for PCiS and ACiS vs. non-stroke control subjects, and between each stroke phenotype. RESULTS: Our primary analyses included 464 PCiS and 1079 ACiS patients with genetic European ancestry. Compared to non-stroke control subjects (n=15396), PRSs of any migraine were associated with increased risk of PCiS (p=0.01-0.03) and decreased risk of ACiS (p=0.010-0.039). Migraine without aura PRSs were significantly associated with PCiS (p=0.008-0.028), but not with ACiS. When comparing PCiS vs. ACiS directly, migraine PRSs were higher in PCiS vs. ACiS for any migraine (p=0.001-0.010) and migraine without aura (p=0.032-0.048). Migraine with aura PRS did not show a differential association in our analyses. CONCLUSIONS: Our results suggest a stronger genetic overlap between unspecified migraine and migraine without aura with PCiS compared to ACiS. Possible shared mechanisms include dysregulation of cerebral vessel endothelial function.

Mechanism-Based Inactivation of Mycobacterium tuberculosis Isocitrate Lyase 1 by (2R,3S)-2-Hydroxy-3-(nitromethyl)succinic acid.

The isocitrate lyase paralogs of Mycobacterium tuberculosis (ICL1 and 2) are essential for mycobacterial persistence and constitute targets for the development of antituberculosis agents. We report that (2R,3S)-2-hydroxy-3-(nitromethyl)succinic acid (5-NIC) undergoes apparent retro-aldol cleavage as catalyzed by ICL1 to produce glyoxylate and 3-nitropropionic acid (3-NP), the latter of which is a covalent-inactivating agent of ICL1. Kinetic analysis of this reaction identified that 5-NIC serves as a robust and efficient mechanism-based inactivator of ICL1 (kinact/KI = (1.3 ± 0.1) × 103 M-1 s-1) with a partition ratio <1. Using enzyme kinetics, mass spectrometry, and X-ray crystallography, we identified that the reaction of the 5-NIC-derived 3-NP with the Cys191 thiolate of ICL1 results in formation of an ICL1-thiohydroxamate adduct as predicted. One aspect of the design of 5-NIC was to lower its overall charge compared to isocitrate to assist with cell permeability. Accordingly, the absence of the third carboxylate group will simplify the synthesis of pro-drug forms of 5-NIC for characterization in cell-infection models of M. tuberculosis.

Introduction of a standardised maternity early warning system: indicative data from a before-and-after study at a large pilot site before national rollout in Aotearoa New Zealand.

Strong evidence now demonstrates that recognition and response systems using standardised early warning scores can help prevent harm associated with in-hospital clinical deterioration in non-pregnant adult patients. However, a standardised maternity-specific early warning system has not yet been agreed in the UK. In Aotearoa New Zealand, following the nationwide implementation of the standardised New Zealand Early Warning Score (NZEWS) for adult inpatients, a modified maternity-specific variation (NZMEWS) was piloted in a major tertiary hospital in Auckland, before national rollout. Following implementation in July 2018, we observed a significant and sustained reduction in severe maternal morbidity as measured by emergency response calls to women who were very unwell (emergency response team call), and a non-significant reduction in cardiorespiratory arrest team calls. Emergency response team calls to maternity wards fell from a median of 0.8 per 100 births at baseline (January 2017-May 2018) to 0.6 per 100 births monthly (from March 2019 to December 2020) (p < 0.0001). Cardiorespiratory arrest team calls to maternity wards fell from 0.14 per 100 births per quarter (quarter 1 2017-quarter 2 2018) to 0.09 calls per 100 births per quarter after NZMEWS was introduced (quarter 3 2018-quarter 4 2020) (p = 0.2593). These early results provide evidence that NZMEWS can detect and prevent deterioration of pregnant women, although there are multiple factors that may have contributed to the reduction in emergency response calls noted.

Consumer understanding of fluid milk and cheese processing and composition.

Ultrafiltration and microfiltration are 2 types of membrane filtration commonly used by the dairy industry. Filtered milk products are becoming increasingly common, but there is concern that consumers unfamiliar with these processing methods may form negative uninformed perceptions of cheeses made with these milks. There are many studies that address the chemical and physical properties of cheeses made with filtered milk, but, to our knowledge, there are none that address consumer perception of these products. Similarly, ultrapasteurization is becoming more common for US dairy products. Although previous work has characterized consumer liking of ultrapasteurized milks, few have investigated understanding and perception of this process. The objective of this study was to explore consumer understanding of milk processing and constituents, particularly as it relates to milk used as an ingredient in cheese. To achieve this goal, we investigated the following 4 questions: (1) Does the average dairy product consumer understand the basic ingredients and nutrients in fluid milk and cultured dairy products? (2) Does the average dairy product consumer understand the basic processes for fluid milk and cultured dairy products? (3) Do different processes affect consumer perception or purchase intent? (4) Does explaining a process change consumer understanding of, beliefs about, and purchase intent for dairy products? Qualitative interviews (n = 54) and an online survey (n = 1,210) were conducted with dairy product consumers. Survey responses paralleled those from one-on-one interviews. The average dairy product consumer could recall key words related to dairy processing, composition, nutrients, and ingredients, but was largely unfamiliar with these subjects. Highly educated and older consumers were more likely to have a better understanding of dairy composition and nutrition, particularly lactose content of milk and Cheddar cheese and the source of fluid whey and whey protein. Processing-related descriptors (e.g., ultrapasteurized or ultrafiltered) in ingredient statements were likely to be overlooked on labels (especially for familiar products), as just 34% of dairy product consumers read the labels on dairy products often or always before purchase. The majority (>80%) of dairy product consumers were unfamiliar with ultrafiltered or microfiltered milk, but uninformed perceptions were generally positive. Consumers unfamiliar with processing methods were likely to assume those methods increase the price of a dairy product. For the majority of consumers, purchase intent for fluid milk and cultured dairy products was not affected when nonconventional processing terms such as ultrafiltered or microfiltered were included in the ingredients statement. This effect was consistent for fluid milk and Cheddar cheeses but not for cottage cheese, suggesting the possibility of product-specific effects. Providing respondents with a definition of filtration increased consumer understanding of, positive beliefs about, and purchase intent for fluid filtered milk and cheese made with filtered milk. Educating consumers through on-package labeling and other marketing messaging should be investigated for dairy products that incorporate processes such as ultrapasteurization or filtration.

Invited review: Sustainability: Different perspectives, inherent conflict.

Consumer definitions of sustainability are largely uninformed by scientific research and may not align with industry definitions. Furthermore, consumers themselves have varied perceptions, definitions, and opinions of sustainability that vary between categories and products within the dairy category. Understanding these differences and developing marketing messaging aligned with consumer sustainability definitions offer an advantage to dairy product producers when strategically positioning their products in a changing marketplace. This review outlines the factors that may affect consumer sustainability perceptions to provide a basis for future marketing and scientific work. Consumer trends and desires for sustainability are explored, including how they are reflected in the rapid growth of plant-based alternatives. Factors that may influence consumer perception of dairy as sustainable are covered in detail, including packaging, labeling, animal welfare, organic status, grass-fed or pasture-raised feeding systems, and local and clean label perceptions. Finally, a discussion of the challenges of marketing dairy foods with sustainability messages is addressed.

Consumer perception of dried dairy ingredients: Healthy, natural, and sustainable?

Conscious consumerism is growing, along with consumer demand for socially conscious dairy products or dairy alternatives. To successfully position dairy products (especially conventional dairy) in this changing marketplace, dairy producers and processors must understand how to strategically use both on- and off-package messaging aligned with consumer perceptions. However, consumer perception of attributes such as sustainable, natural, and healthy is complex, and varies between product categories as well as among products within a category. The objective of this study was to characterize consumer definitions of the terms "sustainable," "natural," and "healthy" as they pertain to dried dairy ingredients. To meet this objective, we conducted an online survey with 3 maximum difference scaling exercises to determine the importance of 63 label claims to consumer definitions of the terms sustainable, natural, and healthy. The role of priming with dried ingredient processing information on consumer perception of these terms was also explored. Within the dried dairy ingredients category, there is extensive cognitive overlap between the terms sustainable, natural, and healthy. Priming did not affect consumer definitions of any of these terms. Certification-related claims were considered among the least important claims for consumer definitions of sustainable, natural, and healthy, whereas claims that were simple to read and visualize were considered among the most important. Claims related to animal welfare and happiness or simple, minimal ingredients and processing were considered by consumers to be important for all 3 terms. For each of these terms, there was a cluster of consumers who defined the term primarily by simple ingredients and minimal processing, and another cluster who defined the term primarily by happy cows and conscious farming practices. The terms sustainable and healthy each had a third, unique consumer cluster. This third definition cluster defined sustainability primarily by environmental effects, whereas this cluster defined healthy primarily in fitness and nutrition terms. Age and to a lesser extent, gender, affected importance placed on these 3 terms and also affected definition of the term. Understanding these consumer definitions provides insight on how to formulate marketing and educational messaging to speak to each consumer segment.

Child preferences and perceptions of fluid milk in school meal programs.

School meal programs in the United States feed approximately 30 million children each day and account for the majority of child milk intake. Dairy consumption during childhood and adolescence has lasting effects on lifelong health status, so it is important for schools to ensure adequate consumption in this life stage by offering an appealing product. This study identified the intrinsic and extrinsic attributes that influence children's perceptions, attitudes, and consumption of fluid milk at school, especially as they relate to fluid milk packaging. An online choice-based conjoint survey (n = 211) and four 1-h focus groups (n = 31) were conducted with child milk consumers ages 8 to 13 yr to evaluate extrinsic attributes. The survey evaluated milk package attributes including packaging type, front-of-package graphics, package color, and labeled milk fat content. Focus group topics included preferences, usability, health, taste of fluid milk, and milk consumption habits. To evaluate intrinsic properties related to packaging, 3 varieties of milk (unflavored fat-free, unflavored low-fat, and chocolate-flavored fat-free) were produced and packaged in polyethylene-coated paperboard cartons, polyethylene terephthalate (PET) bottles, and high-density polyethylene (HDPE) bottles (all 250 mL). After 10 to 13 d of storage at 4°C under dark conditions, milks were evaluated by descriptive analysis and child acceptance testing (ages 8-13 yr; n = 126, 122, and 126 for each variety, respectively). Extrinsically, package type was the most important attribute to children, but graphics, nutritional labeling, branding, package size, and overall familiarity also drove preferences. The ideal milk packaging build from the conjoint survey was an HDPE bottle with blue-colored packaging and a cow graphic, labeled as low-fat milk. Intrinsically, all varieties of milks packaged in paperboard cartons developed package-specific flavors, including refrigerator/stale and paperboard, after 10 d of storage. These off-flavors were not detected in HDPE- or PET-packaged milks. For unflavored milks, child consumers preferred the flavor of PET- or HDPE-packaged milks over cartons, regardless of milk fat content, but preferences were not distinct for chocolate-flavored milk. The results of this study demonstrate that children's liking and preference for milk are driven by both intrinsic and extrinsic factors and suggest that improvements are needed to increase acceptance of milk currently served in school meal programs.