High-efficiency fungal pathogen intervention for seed protection: new utility of long-chain alkyl gallates as heat-sensitizing agents.

Control of food-contaminating fungi, especially pathogens that produce mycotoxins, is problematic since effective method for intervening fungal infection on food crops is often limited. Generally Regarded As Safe (GRAS) chemicals, such as natural compounds or their structural derivatives, can be developed as antimicrobial agents for sustainable food/crop production. This study identified that long-chain alkyl gallates, i.e., octyl-, nonyl-, and decyl gallates (OG (octyl 3,4,5-trihydroxybenzoic acid), NG, DG), can function as heat-sensitizing agents that effectively prevent fungal contamination. Out of twenty-eight candidate compounds and six conventional antifungal agents examined, the heat-sensitizing capacity was unique to the long-chain alkyl gallates, where OG exhibited the highest activity, followed by DG and NG. Since OG is a GRAS compound classified by the United States Food and Drug Administration (FDA), further in vitro antifungal studies were performed using OG. When OG and mild heat (57.5°C) were co-administered for 90 seconds, the treatment achieved > 99.999% fungal death (> 5 log reduction). Application of either treatment alone was significantly less effective at reducing fungal survival. Of note, co-application of OG (3 mM) and mild heat (50°C) for 20 minutes completely prevented the survival of aflatoxigenic Aspergillus flavus contaminating crop seeds (Brassica rapa Pekinensis), while seed germination rate was unaffected. Heat-sensitization was also determined in selected bacterial strains (Escherichia coli, Agrobacterium tumefaciens). Altogether, OG is an effective heat-sensitizing agent for control of microbial pathogens. OG-mediated heat sensitization will improve the efficacy of antimicrobial practices, achieving safe, rapid, and cost-effective pathogen control in agriculture/food industry settings.

Information Technology-Enhanced Telehealth Consultations Reduce Preoperative Evaluation Center Visits in a Bariatric Surgery Population.

Background: Preoperative patient evaluation and optimization in a preoperative evaluation center (PEC) has been shown to improve operating room (OR) efficiency and patient care. However, performing preoperative evaluation on all patients scheduled for surgery or procedure would be time- and resource-consuming. Therefore, appropriate patient selection for evaluation at PECs is one aspect of improving PEC efficiency. In this study, we evaluate the effect of an enhanced preoperative evaluation process (PEP), utilizing a nursing triage phone call and information technology (IT) optimizations, on PEC efficiency and the quality of care in bariatric surgery patients. We hypothesized that, compared to a traditional PEP, the enhanced PEP would improve PEC efficiency without a negative impact on quality. Methods: The study was a retrospective cohort analysis of 1550 patients from January 2014 to March 2017 at a large, tertiary care academic health system. The study was a before/after comparison that compared the enhanced PEP model to the traditional PEP model. The primary outcome was the efficiency of the PEC, which was measured by the reduction of in-person patient visits at the PEC. The secondary outcome was the quality of care, which was measured by delays, cancellations, and the need for additional testing on the day of surgery (DOS). Results: The enhanced PEP improved the primary outcome of efficiency, as evident by an 80% decrease in in-person patient visits to the PEC. There was no reduction in the secondary outcome of the quality of care as measured by delays, cancellations, or the need for additional testing on the DOS. The implementation of the enhanced PEP did not result in increased costs or resource utilization. Conclusions: The enhanced PEP in a multi-disciplinary preoperative process can improve the efficiency of PEC for bariatric surgery patients without any decrease in the quality of care. The enhanced PEP process can be implemented without an increase in resource utilization and can be particularly useful during the COVID-19 pandemic.

Breastfeeding in Canada: predictors of initiation, exclusivity, and continuation from the 2017-2018 Canadian Community Health Survey.

Human milk is the ideal source of nutrition for infants; however, adherence to breastfeeding recommendations is suboptimal and availability of Canadian breastfeeding data are limited. Using the 2017-2018 Canadian Community Health Survey Public Use Microdata File (Maternal Experiences Module, n = 5558, weighted n = 1 669 462) we computed breastfeeding indicators and explored sociodemographic, health, and geographical predictors of breastfeeding with univariate logistic regression models. Nationally, of all participants who gave birth in the preceding 5 years, 91% initiated breastfeeding, 43% exclusively breastfed to ≥5 months and 35% to ≥6 months, 56% reported any breastfeeding at ≥6 months, and 31% reported breastfeeding at ≥12 months. Breastfeeding cessation was most commonly attributed to insufficient milk supply (25%), but reasons differed significantly by breastfeeding duration. Breastfeeding initiation, exclusivity for ≥5 months, and extended breastfeeding ≥12 months all differed by geographic region, and by most sociodemographic and health characteristics. Positive breastfeeding outcomes were highest in British Columbia, and lowest in Quebec and the Atlantic region, and generally higher if caregivers had recently immigrated to Canada, were married, were >30 years of age, were not White, were nonsmoking, had completed postsecondary education, and had an annual household income >$40 000. These disparities indicate the need for tailored, equitable approaches to breastfeeding support, and continued regional monitoring of breastfeeding outcomes.

Valorizing Tree-Nutshell Particles as Delivery Vehicles for a Natural Herbicide.

The United States is a principal producer of tree nuts (almonds, pistachios, and walnuts), resulting in the generation of excess of tree-nutshell by-products each year, with few market outlets. A nutshell is an essential, lignocellulosic layer that protects a kernel (seed) from the environment during cultivation. The objective of this study was to develop nutshell by-products as herbicide delivery systems, which would not only enable sustainable weed control in fields but also increases nutshell value and reduce the cost of waste disposal. We recently identified a natural salicylaldehyde (SA) that emits volatiles with both herbicidal and antifungal properties. In this study, walnut shell particles saturated with 0.8 to 1.6 M SA were developed as delivery vehicles for SA to soil, which allowed for the controlled release of an SA fumigant for weed control. The pre- and post-emergent herbicidal efficacy of SA was investigated using model monocot (Lolium arundinaceum (Schreb.) Darbysh; turfgrass) and dicot (Brassica rapa var. pekinensis; Chinese cabbage) plants. We compared (1) the effects of different types of solvents for dissolving SA (dimethyl sulfoxide (DMSO) and ethanol (60%, v/v)), and (2) the effect of covering soil with plastic layers (i.e., soil pasteurization) or not covering soil during SA fumigation using nutshells. Results: In the pre-emergent herbicidal testing with the soil covered, the dicot plants exhibited levels of higher susceptibility to SA in DMSO emitted from nutshells when compared to the monocot plants. The seed germination frequencies in the dicots were 15% and 1% with 0.8 and 1.6 M SA, respectively, while those in the monocots were 32% and 18%, respectively, under the same test conditions. In the post-emergent herbicidal testing with the soil covered, the growth of both the monocot and dicot plants was completely prevented after 5 to 7 days of SA fumigation, resulting in the deaths of entire plants. It was noteworthy that in the post-emergent herbicidal testing, SA dissolved in ethanol (60%, v/v) completely disrupted the growth of the monocot and dicot plants as early as 3 days after SA emission from the nutshells, even without the soil being covered. Tree-nutshell particles could serve as effective SA delivery vehicles with controlled release capabilities for SA. The SA exhibited pre- and post-emergent herbicidal activities against the monocot and dicot plants at most growth stages. SA (0.8 and 1.6 M) dissolved in ethanol (60%, v/v) might exert a synergism for higher herbicidal activity after emission from nutshells. Since tree nuts capture/store a substantial amount of carbon over their life-cycles, the new and sustainable utility of using nutshells not only reduces carbon emissions but also valorizes tree-nut by-products, thus benefitting the tree-nut industry.

Article: "Too Old" and "Too Cold": Discomfort Towards Photographs of Breastfeeding Beyond Infancy and Public Breastfeeding in Nova Scotia, Canada.

BACKGROUND: Social norms and public perception of breastfeeding are well-established predictors of breastfeeding outcomes; however, little is known about perceptions of breastfeeding beyond infancy or public breastfeeding among the public in Nova Scotia, Canada. RESEARCH AIM: To explore public opinion about breastfeeding beyond infancy and public breastfeeding. METHODS: In this cross-sectional study participants were recruited from public spaces in Nova Scotia, Canada. Using photo elicitation methods, participants (N = 229) viewed six photographs of breastfeeding children aged 2 weeks, 13 months, and 2.5 years, one photograph captured at home, and the other in a public space (a café, a store, or outdoors). Participants were asked to score their self-rated comfort with each photograph on a 10.0 cm visual analog scale and asked to share their feelings about each photograph (open-ended responses). RESULTS: Mean (SD) visual analog scale comfort scores for photographs differed by location (private, 7.9 [2.2]; public, 7.3 [2.6]; p < .05) and child age (2 weeks, 8.5 [2.0]; 13 months, 7.5 [2.6]; 2.5 years, 6.9 [3.0]; p < .05). Participants who identified as women and parents self-reported significantly higher comfort with all photographs, while younger participants and urban dwellers were generally less comfortable. Open-ended responses varied considerably, but a higher proportion of negative comments were reported for older children feeding in public spaces (e.g., 2.5-year-old in public: "Inappropriate. Indecent. Abnormal."). CONCLUSION: Given the importance of social norms in supporting breastfeeding, future public health campaigns should strive to normalize breastfeeding beyond infancy, and in public spaces.

Antifungal Efficacy of Redox-Active Natamycin against Some Foodborne Fungi-Comparison with Aspergillus fumigatus.

The fungal antioxidant system is one of the targets of the redox-active polyene antifungal drugs, including amphotericin B (AMB), nystatin (NYS), and natamycin (NAT). Besides medical applications, NAT has been used in industry for preserving foods and crops. In this study, we investigated two parameters (pH and food ingredients) affecting NAT efficacy. In the human pathogen, Aspergillus fumigatus, NAT (2 to 16 µg mL-1) exerted higher activity at pH 5.6 than at pH 3.5 on a defined medium. In contrast, NAT exhibited higher activity at pH 3.5 than at pH 5.6 against foodborne fungal contaminants, Aspergillus flavus, Aspergillus parasiticus, and Penicillium expansum, with P. expansum being the most sensitive. In commercial food matrices (10 organic fruit juices), food ingredients differentially affected NAT antifungal efficacy. Noteworthily, NAT overcame tolerance of the A. fumigatus signaling mutants to the fungicide fludioxonil and exerted antifungal synergism with the secondary metabolite, kojic acid (KA). Altogether, NAT exhibited better antifungal activity at acidic pH against foodborne fungi; however, the ingredients from commercial food matrices presented greater impact on NAT efficacy compared to pH values. Comprehensive determination of parameters affecting NAT efficacy and improved food formulation will promote sustainable food/crop production, food safety, and public health.

Thiamine supplementation holds neurocognitive benefits for breastfed infants during the first year of life.

Women reliant on mostly rice-based diets can have inadequate thiamine intake, placing breastfed infants at risk of thiamine deficiency and, in turn, physical and cognitive impairments. We investigated the impact of maternal thiamine supplementation doses on infants' cognitive, motor, and language development across the first year. In this double-blind, four-parallel-arm, randomized controlled trial, healthy mothers of exclusively breastfed newborn infants were recruited in Kampong Thom, Cambodia. At 2 weeks postnatal, women (n = 335) were randomized to one of four treatment groups to consume one capsule/day with varying amounts of thiamine for 22 weeks: 0, 1.2, 2.4, and 10 mg. At 2, 12, 24, and 52 weeks of age, infants were assessed with the Mullen Scales of Early Learning (MSEL) and the Caregiver Reported Early Development Instrument (CREDI). Multiple regression and mixed effects modeling suggest that by 6 months of age, the highest maternal thiamine dose (10 mg/day) held significant benefits for infants' language development, but generally not for motor or visual reception development. Despite having achieved standardized scores on the MSEL that approximated U.S. norms by 6 months, infants showed a significant drop relative to these norms in both language domains following trial completion, indicating that nutritional interventions beyond 6 months may be necessary.

Low-dose thiamine supplementation of lactating Cambodian mothers improves human milk thiamine concentrations: a randomized controlled trial.

BACKGROUND: Infantile beriberi-related mortality is still common in South and Southeast Asia. Interventions to increase maternal thiamine intakes, and thus human milk thiamine, are warranted; however, the required dose remains unknown. OBJECTIVES: We sought to estimate the dose at which additional maternal intake of oral thiamine no longer meaningfully increased milk thiamine concentrations in infants at 24 wk postpartum, and to investigate the impact of 4 thiamine supplementation doses on milk and blood thiamine status biomarkers. METHODS: In this double-blind, 4-parallel arm randomized controlled dose-response trial, healthy mothers were recruited in Kampong Thom, Cambodia. At 2 wk postpartum, women were randomly assigned to consume 1 capsule, containing 0, 1.2 (estimated average requirement), 2.4, or 10 mg of thiamine daily from 2 through 24 weeks postpartum. Human milk total thiamine concentrations were measured using HPLC. An Emax curve was plotted, which was estimated using a nonlinear least squares model in an intention-to-treat analysis. Linear mixed-effects models were used to test for differences between treatment groups. Maternal and infant blood thiamine biomarkers were also assessed. RESULTS: In total, each of 335 women was randomly assigned to1 of the following thiamine-dose groups: placebo (n = 83), 1.2 mg (n = 86), 2.4 mg (n = 81), and 10 mg (n = 85). The estimated dose required to reach 90% of the maximum average total thiamine concentration in human milk (191 µg/L) is 2.35 (95% CI: 0.58, 7.01) mg/d. The mean ± SD milk thiamine concentrations were significantly higher in all intervention groups (183 ± 91, 190 ± 105, and 206 ± 89 µg/L for 1.2, 2.4, and 10 mg, respectively) compared with the placebo group (153 ± 85 µg/L; P < 0.0001) and did not significantly differ from each other. CONCLUSIONS: A supplemental thiamine dose of 2.35 mg/d was required to achieve a milk total thiamine concentration of 191 µg/L. However, 1.2 mg/d for 22 wk was sufficient to increase milk thiamine concentrations to similar levels achieved by higher supplementation doses (2.4 and 10 mg/d), and comparable to those of healthy mothers in regions without beriberi. This trial was registered at clinicaltrials.gov as NCT03616288.

Infant feeding experiences and concerns among caregivers early in the COVID-19 State of Emergency in Nova Scotia, Canada.

The global emergency caused by the novel coronavirus (COVID-19) pandemic has impacted access to goods and services such as health care and social supports, but the impact on infant feeding remains unclear. Thus, the objective of this study was to explore how caregivers of infants under 6 months of age perceived changes to infant feeding and other food and health-related matters during the COVID-19 State of Emergency in Nova Scotia, Canada. Four weeks after the State of Emergency began, between 17 April and 15 May 2020, caregivers completed this online survey, including the Perceived Stress Scale. Participants (n = 335) were 99% female and mostly White (87%). Over half (60%) were breastfeeding, and 71% had a household income over CAD$60,000. Most participants (77%) received governmental parental benefits before the emergency, and 59% experienced no COVID-19-related economic changes. Over three quarters of participants (77%) scored moderate levels of perceived stress. Common themes of concern included social isolation, COVID-19 infection (both caregiver and infant), and a lack of access to goods, namely, human milk substitutes ('infant formula'), and services, including health care, lactation support, and social supports. Most COVID-19-related information was sought from the internet and social media, so for broad reach, future evidence-based information should be shared via online platforms. Although participants were experiencing moderate self-perceived stress and shared numerous concerns, very few COVID-19-related changes to infant feeding were reported, and there were few differences by socio-economic status, likely due to a strong economic safety net in this Canadian setting.

Assessment of salt intake to consider salt as a fortification vehicle for thiamine in Cambodia.

Thiamine deficiency is a public health issue in Cambodia. Thiamine fortification of salt has been proposed; however, the salt intake of lactating women, the target population, is currently unknown. We estimated salt intakes among lactating women (<6 months postpartum) using three methods: repeat observed-weighed intake records and 24-h urinary sodium excretions (n = 104), and household salt disappearance (n = 331). Usual salt intake was estimated by adjusting for intraindividual intakes using the National Cancer Institute method, and a thiamine salt fortification scenario was modeled using a modified estimated average requirement (EAR) cut-point method. Unadjusted salt intake from observed intakes was 9.3 (8.3-10.3) g/day, which was not different from estimated salt intake from urinary sodium excretions, 9.0 (8.4-9.7) g/day (P = 0.3). Estimated salt use from household salt disappearance was 11.3 (10.7-11.9) g/person/day. Usual (adjusted) salt intake from all sources was 7.7 (7.4-8.0) g/day. Assuming no stability losses, a modeled fortification dose of 275 mg thiamine/kg salt could increase thiamine intakes from fortified salt to 2.1 (2.0-2.2) mg/day, with even low salt consumers reaching the EAR of 1.2 mg/day from fortified salt alone. These findings, in conjunction with future sensory and stability research, can inform a potential salt fortification program in Cambodia.

Antifungal Drug Repurposing.

Control of fungal pathogens is increasingly problematic due to the limited number of effective drugs available for antifungal therapy. Conventional antifungal drugs could also trigger human cytotoxicity associated with the kidneys and liver, including the generation of reactive oxygen species. Moreover, increased incidences of fungal resistance to the classes of azoles, such as fluconazole, itraconazole, voriconazole, or posaconazole, or echinocandins, including caspofungin, anidulafungin, or micafungin, have been documented. Of note, certain azole fungicides such as propiconazole or tebuconazole that are applied to agricultural fields have the same mechanism of antifungal action as clinical azole drugs. Such long-term application of azole fungicides to crop fields provides environmental selection pressure for the emergence of pan-azole-resistant fungal strains such as Aspergillus fumigatus having TR34/L98H mutations, specifically, a 34 bp insertion into the cytochrome P450 51A (CYP51A) gene promoter region and a leucine-to-histidine substitution at codon 98 of CYP51A. Altogether, the emerging resistance of pathogens to currently available antifungal drugs and insufficiency in the discovery of new therapeutics engender the urgent need for the development of new antifungals and/or alternative therapies for effective control of fungal pathogens. We discuss the current needs for the discovery of new clinical antifungal drugs and the recent drug repurposing endeavors as alternative methods for fungal pathogen control.

Specific ablation of CD4+ T-cells promotes heart regeneration in juvenile mice.

Unlike adult cardiomyocytes, neonatal cardiomyocytes can readily proliferate that contributes to a transient regenerative potential after myocardial injury in mice. We have recently reported that CD4+ regulatory T-cells promote this process; however, the role of other CD4+ T-cell subsets as well as CD8+ T-cells in postnatal heart regeneration has been less studied. Methods: by comparing the regenerating postnatal day (P) 3 and the non-regenerating P8 heart after injury, we revealed the heterogeneity of CD4+ and CD8+ T-cells in the myocardium through single cell analysis. We also specifically ablated CD4+ and CD8+ T-cells using the lytic anti-CD4 and -CD8 monoclonal antibodies, respectively, in juvenile mice at P8 after myocardial injury. Results: we observe significantly more CD4+FOXP3- conventional T-cells in the P8 heart when compared to that of the P3 heart within a week after injury. Surprisingly, such a difference is not seen in CD8+ T-cells that appear to have no function as their depletion does not reactivate heart regeneration. On the other hand, specific ablation of CD4+ T-cells contributes to mitigated cardiac fibrosis and increased cardiomyocyte proliferation after injury in juvenile mice. Single-cell transcriptomic profiling reveals a pro-fibrotic CD4+ T-cell subset in the P8 but not P3 heart. Moreover, there are likely more Th1 and Th17 cells in the P8 than P3 heart. We further demonstrate that cytokines of Th1 and Th17 cells can directly reduce the proliferation and increase the apoptosis of neonatal cardiomyocytes. Moreover, ablation of CD4+ T-cells can directly or indirectly facilitate the polarization of macrophages away from the pro-fibrotic M2-like signature in the juvenile heart. Nevertheless, ablation of CD4+ T-cells alone does not offer the same protection in the adult heart after myocardial infarction, suggesting a developmental change of immune cells including CD4+ T-cells in the regulation of age-related mammalian heart repair. Conclusions: our results demonstrate that ablation of CD4+ but not CD8+ T-cells promotes heart regeneration in juvenile mice; and CD4+ T-cells play a distinct role in the regulation of heart regeneration and repair during development.

Rapid elimination of foodborne and environmental fungal contaminants by benzo analogs.

BACKGROUND: Contamination of food or the environment by fungi, especially those resistant to conventional fungicides or drugs, represents a hazard to human health. The objective of this study is to identify safe, natural antifungal agents that can remove fungal pathogens or contaminants rapidly from food and / or environmental sources. RESULTS: Fifteen antifungal compounds (nine benzo derivatives as candidates; six conventional fungicides as references) were investigated. Three benzo analogs, namely octyl gallate (OG), trans-cinnamaldehyde (CA), and 2-hydroxy-5-methoxybenzaldehyde (2H5M), at 1 g L-1 (3.54 mmol), 1 mL L-1 (7.21 mmol), 1 mL L-1 (5.39 mmol), respectively, achieved ≥99.9% fungal death after 0.5, 2.5 or 24 h of treatments, respectively, in in vitro phosphate-buffered saline (PBS) bioassay. However, when OG, CA, and 2H5M were examined in commercial food matrices, organic apple, or grape juices, only CA maintained a similar level of antifungal activity, compared with a PBS bioassay. trans-Cinnamaldehyde showed higher antifungal activity at pH 3.5, equivalent to that of commercial fruit juices, than at pH 5.6. In soil sample tests, the application of 1 mL L-1 (7.21 mmol) CA to conventional maize / tomato soil samples (pH 6.8) for 2.5 h resulted in ≥99.9% fungal death, indicating CA could also eliminate fungal contaminants in soil. While the conventional fungicide thiabendazole exerted antifungal activity comparable to CA, thiabendazole enhanced the production of carcinogenic aflatoxins by Aspergillus flavus, an undesirable side effect. CONCLUSION: trans-Cinnamaldehyde could be developed as a potent antifungal agent in food processing or soil sanitation by reducing the time / cost necessary for fungal removal. Published 2020. This article is a U.S. Government work and is in the public domain in the USA.

Exploring Breastfeeding Knowledge and Attitudes among Noncaregivers: A Narrative Review.

Exclusive breastfeeding to 6 months with continued breastfeeding up to 2 years and beyond are well-established infant feeding recommendations based on evidence that breastfeeding has unparalleled maternal and infant health benefits as well as environmental and economic benefits. As with many high-income countries, breastfeeding rates remain suboptimal with only a quarter of Canadian and European infants receiving breast milk exclusively for the first 6 months. Breastfeeding promotion efforts have largely targeted caregivers in the prenatal and postnatal period; however, breastfeeding outcomes have been shown to be associated with broader sociocultural factors. Noncaregivers play an influential role in infant feeding at both an individual level (e.g., cues and input from health care practitioners and caregivers' social networks; as future parents) as well as a broader population level (sociocultural norms and policy decisions). This paper outlines recent research on breastfeeding knowledge and attitudes of noncaregivers by population subgroup. Positive correlations have been identified between breastfeeding attitudes, infant feeding knowledge, breastfeeding exposure, and breastfeeding intention among different subgroups; however, key knowledge gaps, lack of exposure to breastfeeding, and negative public perceptions of breastfeeding persist. Dietitians can advocate for breastfeeding promotion strategies that consider the role of noncaregivers to address sociocultural norms around breastfeeding.

High confidence, yet poor knowledge of infant feeding recommendations among adults in Nova Scotia, Canada.

In Canada, adherence to the national 'Nutrition for Healthy Term Infants' recommendations of infant and young child feeding (IYCF; 0-24 months) is suboptimal. While maternal knowledge of IYCF is commonly assessed, that of the general public has rarely been explored. Our objective was to assess the knowledge of, and confidence in answers to, Canadian IYCF recommendations among a diverse sample of adults in Nova Scotia, Canada. Between March and May 2018, a self-administered questionnaire examining IYCF knowledge, self-rated confidence, and sociodemographic information was conducted among Nova Scotians (≥19 years) in public locations. We surveyed 229 adults; 60% (n=134) were women. Mean (95% CI) age was 44 (41,46) years, 73% self-identified as white, 77% were born in Canada, and 69% were parents. Knowledge deficits were: age to terminate breastfeeding (18.3 (16.7,19.9) months; recommendation: ≥24 months), age to introduce solids (9.2 (8.2,10.2) months; recommendation: 6 months), vitamin D supplementation (10% correct), and optimal complementary foods (only 37% indicated iron-rich foods). Correct IYCF knowledge was lower among men, non-parents, young adults (19-29 years) and low-income adults (<$50,000/year). Mean self-rated confidence (out of 10) was high (7.2 (6.9,7.5)), and not different (p>0.05) between correct and incorrect responses for: best food for a newborn, age to terminate any breastfeeding, and age to start family meal foods. We found low knowledge of IYCF guidelines, yet high confidence in responses regardless of accuracy, among adults in Nova Scotia. General public knowledge deficits may contribute to an unsupportive culture around IYCF practices and low adherence to current recommendations.

Thiamine dose response in human milk with supplementation among lactating women in Cambodia: study protocol for a double-blind, four-parallel arm randomised controlled trial.

INTRODUCTION: Thiamine (vitamin B1) deficiency remains a concern in Cambodia where women with low thiamine intake produce thiamine-poor milk, putting their breastfed infants at risk of impaired cognitive development and potentially fatal infantile beriberi. Thiamine fortification of salt is a potentially low-cost, passive means of combating thiamine deficiency; however, both the dose of thiamine required to optimise milk thiamine concentrations as well as usual salt intake of lactating women are unknown. METHODS AND ANALYSIS: In this community-based randomised controlled trial, 320 lactating women from Kampong Thom, Cambodia will be randomised to one of four groups to consume one capsule daily containing 0, 1.2, 2.4 or 10 mg thiamine as thiamine hydrochloride, between 2 and 24 weeks postnatal. The primary objective is to estimate the dose where additional maternal intake of thiamine no longer meaningfully increases infant thiamine diphosphate concentrations 24 weeks postnatally. At 2, 12 and 24 weeks, we will collect sociodemographic, nutrition and health information, a battery of cognitive assessments, maternal (2 and 24 weeks) and infant (24 weeks only) venous blood samples (biomarkers: ThDP and transketolase activity) and human milk samples (also at 4 weeks; biomarker: milk thiamine concentrations). All participants and their families will consume study-provided salt ad libitum throughout the trial, and we will measure salt disappearance each fortnight. Repeat weighed salt intakes and urinary sodium concentrations will be measured among a subset of 100 participants. Parameters of Emax dose-response curves will be estimated using non-linear least squares models with both 'intention to treat' and a secondary 'per-protocol' (capsule compliance ≥80%) analyses. ETHICS AND DISSEMINATION: Ethical approval was obtained in Cambodia (National Ethics Committee for Health Research 112/250NECHR), Canada (Mount Saint Vincent University Research Ethics Board 2017-141) and the USA (University of Oregon Institutional Review Board 07052018.008). Results will be shared with participants' communities, as well as relevant government and scientific stakeholders via presentations, academic manuscripts and consultations. TRIAL REGISTRATION NUMBER: NCT03616288.

High Efficiency Drug Repurposing Design for New Antifungal Agents.

Current antifungal interventions have often limited efficiency in treating fungal pathogens, particularly those resistant to commercial drugs or fungicides. Antifungal drug repurposing is an alternative intervention strategy, whereby new utility of various marketed, non-antifungal drugs could be repositioned as novel antifungal agents. In this study, we investigated "chemosensitization" as a method to improve the efficiency of antifungal drug repurposing, wherein combined application of a second compound (viz., chemosensitizer) with a conventional, non-antifungal drug could greatly enhance the antifungal activity of the co-applied drug. Redox-active natural compounds or structural derivatives, such as thymol (2-isopropyl-5-methylphenol), 4-isopropyl-3-methylphenol, or 3,5-dimethoxybenzaldehyde, could serve as potent chemosensitizers to enhance antifungal activity of the repurposed drug bithionol. Of note, inclusion of fungal mutants, such as antioxidant mutants, could also facilitate drug repurposing efficiency, which is reflected in the enhancement of antifungal efficacy of bithionol. Bithionol overcame antifungal (viz., fludioxonil) tolerance of the antioxidant mutants of the human/animal pathogen Aspergillus fumigatus. Altogether, our strategy can lead to the development of a high efficiency drug repurposing design, which enhances the susceptibility of pathogens to drugs, reduces time and costs for new antifungal development, and abates drug or fungicide resistance.

Current characterization methods for cellulose nanomaterials.

A new family of materials comprised of cellulose, cellulose nanomaterials (CNMs), having properties and functionalities distinct from molecular cellulose and wood pulp, is being developed for applications that were once thought impossible for cellulosic materials. Commercialization, paralleled by research in this field, is fueled by the unique combination of characteristics, such as high on-axis stiffness, sustainability, scalability, and mechanical reinforcement of a wide variety of materials, leading to their utility across a broad spectrum of high-performance material applications. However, with this exponential growth in interest/activity, the development of measurement protocols necessary for consistent, reliable and accurate materials characterization has been outpaced. These protocols, developed in the broader research community, are critical for the advancement in understanding, process optimization, and utilization of CNMs in materials development. This review establishes detailed best practices, methods and techniques for characterizing CNM particle morphology, surface chemistry, surface charge, purity, crystallinity, rheological properties, mechanical properties, and toxicity for two distinct forms of CNMs: cellulose nanocrystals and cellulose nanofibrils.

Cinnamic Acid Analogs as Intervention Catalysts for Overcoming Antifungal Tolerance.

Disruption of fungal cell wall should be an effective intervention strategy. However, the cell wall-disrupting echinocandin drugs, such as caspofungin (CAS), cannot exterminate filamentous fungal pathogens during treatment. For potency improvement of cell wall-disrupting agents (CAS, octyl gallate (OG)), antifungal efficacy of thirty-three cinnamic acid derivatives was investigated against Saccharomyces cerevisiaeslt2Δ, bck1Δ, mutants of the mitogen-activated protein kinase (MAPK), and MAPK kinase kinase, respectively, in cell wall integrity system, and glr1Δ, mutant of CAS-responsive glutathione reductase. Cell wall mutants were highly susceptible to four cinnamic acids (4-chloro-α-methyl-, 4-methoxy-, 4-methyl-, 3-methylcinnamic acids), where 4-chloro-α-methyl- and 4-methylcinnamic acids possessed the highest activity. Structure-activity relationship revealed that 4-methylcinnamic acid, the deoxygenated structure of 4-methoxycinnamic acid, overcame tolerance of glr1Δ to 4-methoxycinnamic acid, indicating the significance of para substitution of methyl moiety for effective fungal control. The potential of compounds as chemosensitizers (intervention catalysts) to cell wall disruptants (viz., 4-chloro-α-methyl- or 4-methylcinnamic acids + CAS or OG) was assessed according to Clinical Laboratory Standards Institute M38-A. Synergistic chemosensitization greatly lowers minimum inhibitory concentrations of the co-administered drug/agents. 4-Chloro-α-methylcinnamic acid further overcame fludioxonil tolerance of Aspergillus fumigatus antioxidant MAPK mutants (sakAΔ, mpkCΔ). Collectively, 4-chloro-α-methyl- and 4-methylcinnamic acids possess chemosensitizing capability to augment antifungal efficacy of conventional drug/agents, thus could be developed as target-based (i.e., cell wall disruption) intervention catalysts.

Augmenting the Activity of Monoterpenoid Phenols against Fungal Pathogens Using 2-Hydroxy-4-methoxybenzaldehyde that Target Cell Wall Integrity.

Disruption of cell wall integrity system should be an effective strategy for control of fungal pathogens. To augment the cell wall disruption efficacy of monoterpenoid phenols (carvacrol, thymol), antimycotic potency of benzaldehyde derivatives that can serve as chemosensitizing agents were evaluated against strains of Saccharomyces cerevisiae wild type (WT), slt2Δ and bck1Δ (mutants of the mitogen-activated protein kinase (MAPK) and MAPK kinase kinase, respectively, in the cell wall integrity pathway). Among fourteen compounds investigated, slt2Δ and bck1Δ showed higher susceptibility to nine benzaldehydes, compared to WT. Differential antimycotic activity of screened compounds indicated "structure-activity relationship" for targeting the cell wall integrity, where 2-hydroxy-4-methoxybenzaldehyde (2H4M) exhibited the highest antimycotic potency. The efficacy of 2H4M as an effective chemosensitizer to monoterpenoid phenols (viz., 2H4M + carvacrol or thymol) was assessed in yeasts or filamentous fungi (Aspergillus, Penicillium) according to European Committee on Antimicrobial Susceptibility Testing or Clinical Laboratory Standards Institute M38-A protocols, respectively. Synergistic chemosensitization greatly lowers minimum inhibitory or fungicidal concentrations of the co-administered compounds. 2H4M also overcame the tolerance of two MAPK mutants (sakAΔ, mpkCΔ) of Aspergillus fumigatus to fludioxonil (phenylpyrrole fungicide). Collectively, 2H4M possesses chemosensitizing capability to magnify the efficacy of monoterpenoid phenols, which improves target-based (viz., cell wall disruption) antifungal intervention.