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Objective: Whereas studies have documented racial differences in attitudes toward police between White and Black Americans, relatively little is known about the intragroup, gender-based variations among urban Black residents involved in criminal activity (i.e., street-identified men and women)., Hypotheses: We hypothesized Black women would be more likely to believe in police legitimacy and positive intent than men (Hypothesis 1), especially among the younger segment of the sample (Hypothesis 2). We also expected this relationship to be moderated by contact with police (Hypothesis 3) and experiences with victimization (Hypothesis 4)., Method: Using survey data, this Street Participatory Action Research project examined the direct and interactional relationships between gender, age, involuntary police contact, personal victimization, and participants' perceptions of police legitimacy and positive intent. Participants included 515 street-identified Black men (40.4%; n = 208) and women (59.6%; n = 307), ages 18-35 years, from two high-crime neighborhoods in Wilmington, Delaware., Results: Women had significantly higher perceptions of police legitimacy than did men (Hypothesis 1). While older participants tended to have lower perceptions that the police behave with positive intent, age did not moderate the relationship between gender and perceptions of police (Hypothesis 2). The relationship between gender and perceptions of positive police intent was moderated by involuntary police contact (Hypothesis 3) and experiences of victimization (Hypothesis 4)., Conclusions: Contrary to existing literature, prior involuntary police contact mattered more for street-identified Black women than men in predicting perceptions of police. Experiences of victimization were also more impactful for these perceptions for street-identified Black women than men. Men's perceptions of positive police intent were consistent, regardless of the frequency of police contact, whereas women's favorable perceptions declined with more police contact and victimization experiences, and they eventually became more critical of the police than their male counterparts. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Buprenorphine has become an important medication in the context of the ongoing opioid epidemic. However, complex pharmacologic properties and varying government regulations create barriers to its use. This narrative review is intended to facilitate buprenorphine use-including non-traditional initiation methods-by providers ranging from primary care providers to addiction specialists. This article briefly discusses the opioid epidemic and the diagnosis and treatment of opioid use disorder (OUD). We then describe the basic and complex pharmacologic properties of buprenorphine, linking these properties to their clinical implications. We guide readers through the process of initiating buprenorphine in patients using full agonist opioids. As there is no single recommended approach for buprenorphine initiation, we discuss the details, advantages, and disadvantages of the standard, low-dose, bridging-strategy, and naloxone-facilitated initiation techniques. We consider the pharmacology of, and evidence base for, buprenorphine in the treatment of pain, in both OUD and non-OUD patients. Throughout, we address the use of buprenorphine in children and adolescent patients, and we finish with considerations related to the settings of pregnancy and breastfeeding., (© 2023. The Author(s).)

Lyme disease, caused by vector-borne Borrelia bacteria, can present with diverse multi-system symptoms that resemble other conditions. The objective of this study was to evaluate disease presentations and Borrelia seroreactivity in individuals experiencing a spectrum of chronic and complex illnesses. We recruited 157 participants from Eastern Canada who reported one or more diagnoses of Lyme disease, neurological, rheumatic, autoimmune, inflammatory, gastrointestinal, or cardiovascular illnesses, or were asymptomatic and presumed healthy. Intake categories were used to classify participants based on their perceived proximity to Lyme disease, distinguishing between those with a disclosed history of Borrelia infection, those with lookalike conditions (e.g. fibromyalgia syndrome), and those with unrelated ailments (e.g. intestinal polyps). Participants completed three questionnaires, the SF-36 v1, SIQR, and HMQ, to capture symptoms and functional burden, and provided blood serum for analysis at an accredited diagnostic lab. Two-tiered IgG and IgM serological assessments (whole cell ELISA and Western blot) were performed in a blinded fashion on all samples. The pattern of symptoms and functional burden were similarly profound in the presumptive Lyme and Lyme-like disease categories. Borrelia seroprevalence across the study cohort was 10% for each of IgG and IgM, and occurred within and beyond the Lyme disease intake category. Western blot positivity in the absence of reactive ELISA was also substantial. Fibromyalgia was the most common individual diagnostic tag disclosed by two-tier IgG-positive participants who did not report a history of Lyme disease. Within the IgG seropositive cohort, the presence of antibodies against the 31 kDa Outer Surface Protein A (OspA) was associated with significantly better health outcomes. Previously, this marker has been linked to treatment-refractory Lyme arthritis. Overall, our findings support prior observations of phenotypic overlap between Lyme and other diseases. Seropositivity associated with non-specific symptoms and functional impairment warrants further mechanistic investigation and therapeutic optimization., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Sanderson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Substance use disorders (SUDs) are highly prevalent among adults with persistent pain. Yet, standard competencies for integrating pain and SUD content are lacking across health science student curricula. Additionally, pharmacotherapies to treat SUDs are underutilized., Aim: To address these gaps, a team of health science faculty created an interprofessional simulation activity using a standardized patient and evaluated learner outcomes related to assessment and treatment of comorbid persistent pain and substance use., Methods: A total of 304 health science students representing nursing, medicine, pharmacy, and social work programs attended virtual learning sessions. Interprofessional student teams developed a team-based care plan for an adult with musculoskeletal pain who takes prescribed opioids while using alcohol. Pre- and post-activity surveys assessing knowledge and confidence were matched for 198 students. Descriptive statistics summarized survey data with inferential analysis of paired data., Results: The largest significant improvements between pre- and post-activity knowledge were observed in items specific to pharmacotherapy options for alcohol and opioid use disorders. Similar gains were noted in students' confidence regarding pharmacotherapies. No significant differences were noted on pre-post-activity knowledge scores between the three main profession groups (medicine, nursing, and pharmacy)., Conclusions: Students attending this interprofessional simulation demonstrated improved knowledge and confidence, particularly in pharmacotherapies for alcohol and opioid use disorders. Replication of such programs can be used to provide consistent content across health science disciplines to heighten awareness and receptivity to medications available to treat SUDs in people treated for persistent pain. The curriculum is freely available from the corresponding author., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 American Society for Pain Management Nursing. Published by Elsevier Inc. All rights reserved.)

Terpene indole alkaloids (TIAs) are plant-derived natural products synthesized in low levels in medicinal plants such as Catharanthus roseus and Camptotheca acuminata . TIA pathways species utilize several CYP72A subfamily members to form loganic acid from 7-deoxyloganic acid (a simple hydroxylation) as well as secologanin and secologanic acid from loganin and loganic acid (a C-C bond scission). Divergences in the specificities of these P450s have allowed Camptotheca secologanic acid synthases (SLASs) to become bifunctional enzymes capable of performing both reactions. In contrast, Catharanthus 7-deoxyloganic acid hydroxylase (7DLH) and secologanin synthase (SLS) have remained monofunctional enzymes capable either of monooxygenation or C-C bond scission. Our in vitro reconstitutions have now demonstrated that Camptotheca also contains a monofunctional 7DLH capable only of hydroxylating 7-deoxyloganic acid. Mutageneses aimed at evaluating residues important for the tight specificity of Camptotheca 7DLH (CYP72A729) and the broad specificity of SLAS (CYP72A564) have identified several residues where reciprocal switches substantially affect their activities: Lys128His in 7DLH increases hydroxylation of 7-deoxyloganic acid, and His132Lys in SLAS decreases this hydroxylation and C-C bond scissions of loganic acid and loganin; Gly321Ser in 7DLH does not affect hydroxylation of 7-deoxyloganic acid, whereas Ser324Gly in SLAS significantly increases C-C bond scission of loganic acid; Asp332Glu in the acid-alcohol pair of 7DLH increases hydroxylation of 7-deoxyloganic acid, whereas Glu335Asp in SLAS completely eliminates both of its activities. These mutations that enhance or eliminate these respective activities have significant potential to aid engineering efforts aimed at increasing TIA production in cell cultures, microbial systems, and/or other plants.

Since the emergence of SARS-CoV-2 in 2019 through to mid-2021, much of the Australian population lived in a COVID-19-free environment. This followed the broadly successful implementation of a strong suppression strategy, including international border closures. With the availability of COVID-19 vaccines in early 2021, the national government sought to transition from a state of minimal incidence and strong suppression activities to one of high vaccine coverage and reduced restrictions but with still-manageable transmission. This transition is articulated in the national 're-opening' plan released in July 2021. Here, we report on the dynamic modelling study that directly informed policies within the national re-opening plan including the identification of priority age groups for vaccination, target vaccine coverage thresholds and the anticipated requirements for continued public health measures-assuming circulation of the Delta SARS-CoV-2 variant. Our findings demonstrated that adult vaccine coverage needed to be at least 60% to minimize public health and clinical impacts following the establishment of community transmission. They also supported the need for continued application of test-trace-isolate-quarantine and social measures during the vaccine roll-out phase and beyond.

Several recent emerging diseases have exhibited both sexual and nonsexual transmission modes (Ebola, Zika, and mpox). In the recent mpox outbreaks, transmission through sexual contacts appears to be the dominant mode of transmission. Motivated by this, we use an SIR-like model to argue that an initially dominant sexual transmission mode can be overtaken by casual transmission at later stages, even if the basic casual reproduction number is less than one. Our results highlight the risk of intervention designs which are informed only by the early dynamics of the disease., (© The Author(s) 2023. Published by Oxford University Press on behalf of National Academy of Sciences.)

Information on fortifiable food consumption is essential to design, monitor and evaluate fortification programmes, yet detailed methods like 24-h recalls (24HRs) that provide such data are rarely conducted. Simplified questionnaire-based methods exist but their validity compared with 24HRs has not been shown. We compared two simplified methods (i.e., a household food acquisition and purchase questionnaire [FAPQ] and a 7-day semiquantitative food frequency questionnaire [SQ-FFQ]) against 24HRs for estimating fortifiable food consumption. We assessed the consumption of fortifiable wheat flour and oil using a FAPQ and, for wheat flour only, a 7-day SQ-FFQ and compared the results against 24HRs. The participants included children 12-18 months (n = 123) and their mothers 18-49 years selected for a study assessing child vitamin A intake and status in Mandaluyong City, Philippines. For fortifiable wheat flour, the FAPQ estimated considerably lower mean intakes compared to 24HRs for children and mothers (2.2 vs. 14.1 g/day and 5.1 vs. 42.3 g/day, respectively), while the SQ-FFQ estimated slightly higher mean intakes (15.7 vs. 14.1 g/day and 51.5 vs. 42.3 g/day, respectively). For fortifiable oil, the FAPQ estimated considerably higher mean intakes compared to 24HRs for children and mothers (4.6 vs. 1.8 g/day and 12.5 vs. 6.1 g/day, respectively). The SQ-FFQ, but not the FAPQ, generated useful information on fortifiable food consumption that can inform fortification programme design and monitoring decisions in the absence of more detailed individual-level data. Potential adaptations to improve the FAPQ, such as additional questions on foods prepared away from home and usage patterns, merit further research., (© 2023 The Authors. Maternal & Child Nutrition published by John Wiley & Sons Ltd.)

Infectious disease control measures often require collective compliance of large numbers of individuals to benefit public health. This raises ethical questions regarding the value of the public health benefit created by individual and collective compliance. Answering these requires estimating the extent to which individual actions prevent infection of others. We develop mathematical techniques enabling quantification of the impacts of individuals or groups complying with three public health measures: border quarantine, isolation of infected individuals, and prevention via vaccination/prophylaxis. The results suggest that (i) these interventions exhibit synergy: They become more effective on a per-individual basis as compliance increases, and (ii) there is often substantial "overdetermination" of transmission. If a susceptible person contacts multiple infectious individuals, an intervention preventing one transmission may not change the ultimate outcome (thus, risk imposed by some individuals may erode the benefits of others' compliance). These results have implications for public health policy during epidemics.

The cytochrome P450 (CYP) superfamily of heme monooxygenases has demonstrated ability to facilitate hydroxylation, desaturation, sulfoxidation, epoxidation, heteroatom dealkylation, and carbon-carbon bond formation and cleavage (lyase) reactions. Seeking to study the carbon-carbon cleavage reaction of α-hydroxy ketones in mechanistic detail using a microbial P450, we synthesized α-hydroxy ketone probes based on the physiological substrate for a well-characterized benzoic acid metabolizing P450, CYP199A4. After observing low activity with wild-type CYP199A4, subsequent assays with an F182L mutant demonstrated enzyme-dependent C-C bond cleavage toward one of the α-hydroxy ketones. This C-C cleavage reaction was subject to an inverse kinetic solvent isotope effect analogous to that observed in the lyase activity of the human P450 CYP17A1, suggesting the involvement of a species earlier than Compound I in the catalytic cycle. Co-crystallization of F182L-CYP199A4 with this α-hydroxy ketone showed that the substrate bound in the active site with a preference for the (S)-enantiomer in a position which could mimic the topology of the lyase reaction in CYP17A1. Molecular dynamics simulations with an oxy-ferrous model of CYP199A4 revealed a displacement of the substrate to allow for oxygen binding and the formation of the lyase transition state proposed for CYP17A1. This demonstration that a correctly positioned α-hydroxy ketone substrate can realize lyase activity with an unusual inverse solvent isotope effect in an engineered microbial system opens the door for further detailed biophysical and structural characterization of CYP catalytic intermediates.

Objective. Children with heart failure have higher rates of emergency department utilization, health care expenditure, and hospitalization. Therefore, a need exists for a simple, non-invasive, and inexpensive method of screening for left ventricular (LV) dysfunction. We recently demonstrated the practicality and reliability of a wireless smartphone-based handheld device in capturing carotid pressure waveforms and deriving cardiovascular intrinsic frequencies (IFs) in children with normal LV function. Our goal in this study was to demonstrate that an IF-based machine learning method (IF-ML) applied to noninvasive carotid pressure waveforms can distinguish between normal and abnormal LV ejection fraction (LVEF) in pediatric patients. Approach . Fifty patients ages 0 to 21 years underwent LVEF measurement by echocardiogram or cardiac magnetic resonance imaging. On the same day, patients had carotid waveforms recorded using Vivio. The exclusion criterion was known vascular disease that would interfere with obtaining a carotid artery pulse. We adopted a hybrid IF- Machine Learning (IF-ML) method by applying physiologically relevant IF parameters as inputs to Decision Tree classifiers. The threshold for low LVEF was chosen as <50%. Main results. The proposed IF-ML method was able to detect an abnormal LVEF with an accuracy of 92% (sensitivity = 100%, specificity = 89%, area under the curve (AUC) = 0.95). Consistent with previous clinical studies, the IF parameterω1was elevated among patients with reduced LVEF. Significance. A hybrid IF-ML method applied on a carotid waveform recorded by a hand-held smartphone-based device can differentiate between normal and abnormal LV systolic function in children with normal cardiac anatomy., (Creative Commons Attribution license.)

Introduction: Kombucha is a complex probiotic beverage made from fermented tea, yet despite extensive historical, anecdotal, and in-vivo evidence for its health benefits, no controlled trials have been published on its effect on humans., Methods: We conducted a randomised placebo-controlled, cross-over study that examined the Glycemic Index (GI) and Insulin Index (II) responses after a standardised high-GI meal consumed with three different test beverages (soda water, diet lemonade soft drink and an unpasteurised kombucha) in 11 healthy adults. The study was prospectively registered with the Australian New Zealand Clinical Trials Registry (anzctr.org.au: 12620000460909). Soda water was used as the control beverage. GI or II values were calculated by expressing the 2-h blood glucose or insulin response as a percentage of the response produced by 50 g of glucose dissolved in water., Results: There was no statistically significant difference in GI or II between the standard meal consumed with soda water (GI: 86 and II: 85) or diet soft drink (GI: 84 and II: 81, ( p = 0.929 for GI and p = 0.374 for II). In contrast, when kombucha was consumed there was a clinically significant reduction in GI and II (GI: 68, p = 0.041 and II: 70, p = 0.041) compared to the meal consumed with soda water., Discussion: These results suggest live kombucha can produce reductions in acute postprandial hyperglycemia. Further studies examining the mechanisms and potential therapeutic benefits of kombucha are warranted., Competing Interests: FA and JB-M manage The University of Sydney’s glycemic index testing service and are directors of the Glycemic Index Foundation, a not-for-profit health promotion charity. FA and JB-M are authors of books in The New Glucose Revolution series (De Capo, Cambridge, MA). MC is a consultant to The Good Brew Company and co-owner of Extremely Alive Pty Ltd., which produces wellness tonics based on Good Brew Kombucha. He was involved in the design of the study, writing the manuscript and decision to publish the results. He was not involved in the collection, analyses, or interpretation of data. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Atkinson, Cohen, Lau and Brand-Miller.)

Purpose: The current study examined experienced weight stigma (EWS), internalized weight bias (IWB), and maladaptive eating patterns (ME) among sexual minority (SM) and heterosexual individuals., Methods: The sample consisted of cisgender heterosexual and SM men and women. Participants were drawn from introductory psychology classes and a variety of supplemental recruitment methods (Facebook, Instagram, MTURK, etc.)., Results: SM individuals reported higher levels of EWS, IWB, and maladaptive eating patterns than heterosexual individuals. Heterosexual men reported the lowest levels of EWS, IWB, and ME compared to all other groups. Additionally, there was a significant association between greater EWS and IWB and greater ME. Gender identity and sexual orientation impacted the strength of the relationship between IWB and ME and, to a lesser extent, EWS and ME., Conclusion: This investigation contributes to knowledge of the impact of gender identity and sexual orientation on EWS and IWB, and demonstrates that IWB and EWS are significant concerns for the SM community, especially in relation to ME., Level of Evidence: Level IV, cross-sectional study., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Scope: Metabolic syndrome (MetS) alters the gut microbial ecology and increases the risk of cardiovascular disease. This study investigates whether strawberry consumption reduces vascular complications in an animal model of MetS and identifies whether this effect is associated with changes in the composition of gut microbes., Methods and Results: Seven-week-old male mice consume diets with 10% (C) or 60% kcal from fat (high-fat diet fed mice; HF) for 12 weeks and subgroups are fed a 2.35% freeze-dried strawberry supplemented diet (C+SB or HF+SB). This nutritional dose is equivalent to ≈160 g of strawberry. After 12 weeks treatment, vascular inflammation is enhanced in HF versus C mice as shown by an increased monocyte binding to vasculature, elevated serum chemokines, and increased mRNA expression of inflammatory molecules. However, strawberry supplementation suppresses vascular inflammation in HF+SB versus HF mice. Metabolic variables, blood pressure, and indices of vascular function were similar among the groups. Further, the abundance of opportunistic microbe is decreased in HF+SB. Importantly, circulating chemokines are positively associated with opportunistic microbes and negatively associated with the commensal microbes (Bifidobacterium and Facalibaculum)., Conclusion: Dietary strawberry decreases the abundance of opportunistic microbe and this is associated with a decrease in vascular inflammation resulting from MetS., (© 2022 Wiley-VCH GmbH.)

Thrombosis, especially thrombosis of the pulmonary artery, is a large contributor to morbidity and mortality following comprehensive stage 2 procedure for single ventricle cardiac physiology. A peri-operative management protocol was implemented at our institution in March 2010. It includes 6 weeks of therapeutic anticoagulation post-operatively to mitigate the thrombotic risks in this patient population. This is a retrospective study of hospitalized children who received post-operative anticoagulation following a comprehensive stage 2 procedure for single ventricle cardiac physiology at a free-standing children's hospital. The primary objectives are to describe our institution's anticoagulation strategy and report on the number of thromboses and major bleeding episodes in the 6 weeks post-operatively. Secondary objectives include the dose of enoxaparin required to obtain a therapeutic low-molecular weight anti-factor-Xa (AFXaLMWH) level, and the number of patients outside of the therapeutic range. A total of 71 infants were included in the final analysis. Four patients experienced a thrombosis episode and three patients experienced clinically significant bleeding. The mean dose of enoxaparin required to obtain a therapeutic AFXaLMWH level between 0.5-1 unit/mL was 1.23 mg/kg SQ every 12 h and 37% of patients achieved goal AFXaLMWH levels with the initial starting dose of enoxaparin 1 mg/kg SQ every 12 h. We describe a 9-year experience of anticoagulation after single ventricle palliation. Anticoagulation with therapeutic AFXaLMWH goals of 0.5-1 unit/mL may reduce the rates of clinically significant thrombosis post-operatively in this population and appears safe without increase in significant bleeding episodes when compared to a historical cohort. Further studies comparing this population to those who do not receive post-operative anticoagulation are warranted., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Terpene indole alkaloids (TIAs) are plant-derived specialized metabolites with widespread use in medicine. Species-specific pathways derive various TIAs from common intermediates, strictosidine or strictosidinic acid, produced by coupling tryptamine with secologanin or secologanic acid. The penultimate reaction in this pathway is catalyzed by either secologanin synthase (SLS) or secologanic acid synthase (SLAS) according to whether plants produce secologanin from loganin or secologanic acid from loganic acid. Previous work has identified SLSs and SLASs from different species, but the determinants of selectivity remain unclear. Here, combining molecular modeling, ancestral sequence reconstruction, and biochemical methodologies, we identified key residues that toggle SLS and SLAS selectivity in two CYP72A (cytochrome P450) subfamily enzymes from Camptotheca acuminata. We found that the positions of foremost importance are in substrate recognition sequence 1 (SRS1), where mutations to either of two adjacent histidine residues switched selectivity; His131Phe selects for and increases secologanin production whereas His132Asp selects for secologanic acid production. Furthermore, a change in SRS3 in the predicted substrate entry channel (Arg/Lys270Thr) and another in SRS4 at the start of the I-helix (Ser324Glu) decreased enzyme activity toward either substrate. We propose that the Camptotheca SLASs have maintained the broadened activities found in a common asterid ancestor, even as the Camptotheca lineage lost its ability to produce loganin while the campanulid and lamiid lineages specialized to produce secologanin by acquiring mutations in SRS1. The identification here of the residues essential for the broad substrate scope of SLASs presents opportunities for more tailored heterologous production of TIAs., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Little is known about Se intakes and status in very young New Zealand children. However, Se intakes below recommendations and lower Se status compared with international studies have been reported in New Zealand (particularly South Island) adults. The Baby-Led Introduction to SolidS (BLISS) randomised controlled trial compared a modified version of baby-led weaning (infants feed themselves rather than being spoon-fed), with traditional spoon-feeding (Control). Weighed 3-d diet records were collected and plasma Se concentration measured using inductively coupled plasma mass spectrometry (ICP-MS). In total, 101 (BLISS n 50, Control n 51) 12-month-old toddlers provided complete data. The OR of Se intakes below the estimated average requirement (EAR) was no different between BLISS and Control (OR: 0·89; 95 % CI 0·39, 2·03), and there was no difference in mean plasma Se concentration between groups (0·04 μmol/l; 95 % CI -0·03, 0·11). In an adjusted model, consuming breast milk was associated with lower plasma Se concentrations (-0·12 μmol/l; 95 % CI -0·19, -0·04). Of the food groups other than infant milk (breast milk or infant formula), 'breads and cereals' contributed the most to Se intakes (12 % of intake). In conclusion, Se intakes and plasma Se concentrations of 12-month-old New Zealand toddlers were no different between those who had followed a baby-led approach to complementary feeding and those who followed traditional spoon-feeding. However, more than half of toddlers had Se intakes below the EAR.

Background: Young children exposed to high-dose vitamin A supplements (VAS) and vitamin A (VA)-fortified foods may be at risk of high VA intake and high VA total body stores (TBS)., Objectives: TBS and estimated liver VA concentration were compared among children with adequate or high VA intake and different timing of exposure to VAS, and associations between estimated liver VA concentrations and biomarkers of VA toxicity were examined., Methods: Children 12-18 mo of age ( n  = 123) were selected for 3 groups: 1 ) retinol intake >600 µg/d and VAS within the past mo, 2 ) retinol intake >600 µg/d and VAS in the past 3-6 mo, and 3 ) VA intake 200-500 µg retinol activity equivalents (RAE)/d and VAS in the past 3-6 mo. Dietary intake data were collected to measure VA intakes from complementary foods, breast milk, and low-dose, over-the-counter supplements. TBS were assessed by retinol isotope dilution, and VA toxicity biomarkers were measured. Main outcomes were compared by group., Results: Mean (95% CI) VA intakes excluding VAS were 1184 (942, 1426), 980 (772, 1187), and 627 (530, 724) µg RAE/d, in groups 1-3, respectively; mean VA intake was higher in groups 1 and 2 compared with group 3 ( P  < 0.05). Geometric mean (GM) (95% CI) TBS were 589 (525, 661), 493 (435, 559), and 466 (411, 528) µmol, respectively. GM TBS and GM liver VA concentrations were higher in group 1 compared with group 3 (liver VA concentration: 1.62 vs. 1.33 µmol/g; P  < 0.05). Plasma retinyl ester and 4-oxo-retinoic acid concentrations and serum markers of bone turnover and liver damage did not indicate VA toxicity., Conclusions: In this sample, most children had retinol intakes above the Tolerable Upper Intake Level (UL) and liver VA concentrations above the proposed cutoff for "hypervitaminosis A" (>1 µmol/g liver). There was no evidence of chronic VA toxicity, suggesting that the liver VA cutoff value should be re-evaluated. This trial was registered at www.clinicaltrials.gov as NCT03030339., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Purpose: To examine (1) whether a wife's BMI interacts with either her husband's weight stigma or (2) her perceived weight criticisms from her husband predict husbands' and wives' psychological and relational outcomes., Methods: The study sample consisted of 209 currently married men and women in a heterosexual relationship. Participants were drawn from an online survey platform (Qualtrics, Inc. Provo, UT) designed to approximate the US population on age, race, and region of the country. Online measures assessed husbands' weight stigma, wives' perceived weight criticisms from husband, and husbands' and wives': (1) relationship satisfaction, (2) sexual intimacy, (3) self-esteem, (4) depressive symptoms, and (5) perceptions of a desirable or ideal mate., Results: Wives' BMI interacted with husbands' weight stigma to predict (1) mate value for husbands and wives and (2) marital satisfaction for husbands. The same pattern was noted with interaction of wives' BMI and perceptions of husbands' weight related criticisms. The interaction reflected that higher wife BMI and higher husband weight stigma or wife perceived weight-related criticism predicted lower marital satisfaction, greater depression, and lower perceptions of a desirable or an ideal mate. Lower BMI was not associated with outcomes regardless of the husbands' weight stigma or wives' perceived weight-related criticisms., Conclusion: To understand the impact of weight stigma and weight related criticisms on perceptions of a desirable or ideal mate and marital outcomes, it is important to examine the interaction with partner's BMI., Level of Evidence: III: Evidence obtained from cohort or case-control analytic studies., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objective: In this review article, we discuss the role of chemotherapy, surgery, and radiation therapy in the treatment of brain metastases from germ cell tumors (GCT)., Background: GCT rarely metastasize to the brain and there is limited data to guide management. Most instances of brain metastases occur in patients with non-seminomatous germ cell tumors (NSGCT)., Methods: We searched PubMed using the terms 'central nervous system (CNS) metastases' or 'brain metastases' and 'germ cell' from 2011 through August 2021. Review articles and prospective trials related to the treatment of brain metastases in GCT were included in addition to articles obtained by hand search of the references and clinical practice guidelines., Conclusions: We highlight the importance of using chemotherapy as first-line therapy in most situations. We discuss the very minimal data regarding surgery and its primary role when there is significant mass effect or brain shift. We also compare whole brain radiation therapy (WBRT) with the use of radiosurgery. We then provide overall recommendations based on the reviewed data and our experience as a referral center for GCT.

Background and Purpose: To describe the implementation of a pediatric vaccination training for student pharmacists and to assess student confidence in providing pediatric vaccinations after taking part in a mixed media, traditional lecture, and active learning, formatted training course., Educational Activity and Setting: Student pharmacists were trained with a two-hour pediatric immunization training module which consisted of materials to detail administration techniques. Students were assessed using a live skills assessment and a multiple-choice knowledge examination. To assess student confidence in these skills, the students were given a pre- and post-instruction survey which was analyzed using the Mann-Whitney U test., Findings: All 170 students enrolled successfully completed the knowledge assessment with an average score of 87% (SD 10%). The skills assessment items most commonly needing remediation were verifying that caregivers received the Vaccine Information Sheet (24%) and reviewing comfort measures and after care instructions with the caregiver (24%). The pre-course survey was completed by 169 out of 170 student pharmacists (99.4%) while the post-course survey was completed by 164 student pharmacists (96.4%) with each item showing a statistically significant increase in perceived confidence in vaccine administration., Summary: Pediatric vaccination training was integrated into a doctor of pharmacy curriculum with the goals of increasing student knowledge and confidence in giving pediatric immunizations. Upon course completion, there was a statistically significant increase in student-perceived knowledge and confidence when administering pediatric immunizations. By expanding access to pediatric immunizers, pharmacists can aid in increasing immunization rates improving public health in their communities., (Copyright © 2021. Published by Elsevier Inc.)

Block design stimulus variables (perceptual cohesiveness, response uncertainty, partial components) have been previously shown to impact test performance. However, relevant studies suggest designs that "look" different should elicit similar performance, where these stimulus parameters are identical. The current study sought to explore other, previously unidentified parameters. To control for known parameters, designs with no perceptual cohesiveness and maximum uncertainty were presented-rotated in increments of 90° and with block edges either cued or uncued-to 65 university undergraduates. Even with cohesiveness and uncertainty constant, performance differences between designs that "look" different were elicited. Post hoc, we hypothesized two possible contributory parameters and coded the designs accordingly. Regression analysis suggested redundancy of adjacent blocks (i.e., coherent regions within the design) appeared to reduce the actual uncertainty of some designs. On the other hand, local and global symmetry, as defined by Palmer (1991, The Perception of Structure, pp. 23-39, The American Psychological Association), did not seem to predict block design performance above and beyond the effects of coherent regions. The advantages of a more complete understanding of stimulus contributions to test performance are discussed., (© 2022. The Psychonomic Society, Inc.)

Deterministic approximations to stochastic Susceptible-Infectious-Susceptible models typically predict a stable endemic steady-state when above threshold. This can be hard to relate to the underlying stochastic dynamics, which has no endemic steady-state but can exhibit approximately stable behaviour. Here, we relate the approximate models to the stochastic dynamics via the definition of the quasi-stationary distribution (QSD), which captures this approximately stable behaviour. We develop a system of ordinary differential equations that approximate the number of infected individuals in the QSD for arbitrary contact networks and parameter values. When the epidemic level is high, these QSD approximations coincide with the existing approximation methods. However, as we approach the epidemic threshold, the models deviate, with these models following the QSD and the existing methods approaching the all susceptible state. Through consistently approximating the QSD, the proposed methods provide a more robust link to the stochastic models., (© 2021. The Author(s), under exclusive licence to Society for Mathematical Biology.)

We describe the development, optimization, and validation of a multiplex droplet digital PCR (ddPCR) assay for the simultaneous detection of Babesia , Bartonella , and Borrelia spp. DNA from several sample matrices, including clinical blood samples from animals and humans, vectors, in-vitro infected human and animal cell lines, and tissues obtained from animal models (infected with Bartonella and/or B. burgdorferi ). The multiplex ddPCR assay was able to detect 31 Bartonella , 13 Borrelia , and 24 Babesia species, including Theileria equi , T. cervi , and Cytauxzoon felis . No amplification of Treponema or Leptospira spp. was observed. Sensitivity of 0.2-5 genome equivalent DNA copies per microliter was achieved for different members of the Bartonella and Borrelia genus, depending on the species or matrix type (water or spiked blood DNA) tested. The ddPCR assay facilitated the simultaneous detection of co-infections with two and three vector-borne pathogens comprising four different genera ( Babesia , Bartonella , Borrelia , and Theileria ) from clinical and other sample sources.

Background: Reliable tables of glycemic indexes (GIs) and glycemic loads (GLs) are critical to research examining the relationship between glycemic qualities of carbohydrate in foods, diets, and health. In the 12 years since the last edition of the tables, a large amount of new data has become available., Objectives: To systematically review and tabulate published and unpublished sources of reliable GI values, including an assessment of the reliability of the data., Methods: This edition of the tables lists over 4000 items, a 61% increase in the number of entries compared to the 2008 edition. The data have been separated into 2 lists. The first represents more precise values derived using the methodology recommended by the International Standards Organization (∼2100 items). The second list contains values determined using less robust methods, including using limited numbers of healthy subjects or with a large SEM (∼1900 food items)., Results: Dairy products, legumes, pasta, and fruits were usually low-GI foods (≤55 on the 100-point glucose scale) and had consistent values around the world. Cereals and cereal products, however, including whole-grain or whole-meal versions, showed wide variation in GI values, presumably arising from variations in manufacturing methods. Breads, breakfast cereals, rice, savory snack products, and regional foods were available in high-, medium-, and low-GI versions. Most varieties of potato were high-GI foods, but specific low-GI varieties have now been identified., Conclusions: The availability of new data on the GIs of foods will facilitate wider research and application of the twin concepts of GI and GL. Although the 2021 edition of the tables improves the quality and quantity of GI data available for research and clinical practice, GI testing of regional foods remains a priority. This systematic review was registered in PROSPERO as #171204., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background: Individuals with pre-diabetes are commonly overweight and benefit from dietary and physical activity strategies aimed at decreasing body weight and hyperglycemia. Early insulin resistance can be estimated via the triglyceride glucose index {TyG = Ln [TG (mg/dl) × fasting plasma glucose (FPG) (mg/dl)/2]} and the hypertriglyceridemic-high waist phenotype (TyG-waist), based on TyG x waist circumference (WC) measurements. Both indices may be useful for implementing personalized metabolic management. In this secondary analysis of a randomized controlled trial (RCT), we aimed to determine whether the differences in baseline TyG values and TyG-waist phenotype predicted individual responses to type-2 diabetes (T2D) prevention programs. Methods: The present post-hoc analyses were conducted within the Prevention of Diabetes through Lifestyle intervention and population studies in Europe and around the world (PREVIEW) study completers ( n = 899), a multi-center RCT conducted in eight countries (NCT01777893). The study aimed to reduce the incidence of T2D in a population with pre-diabetes during a 3-year randomized intervention with two sequential phases. The first phase was a 2-month weight loss intervention to achieve ≥8% weight loss. The second phase was a 34-month weight loss maintenance intervention with two diets providing different amounts of protein and different glycemic indices, and two physical activity programs with different exercise intensities in a 2 x 2 factorial design. On investigation days, we assessed anthropometrics, glucose/lipid metabolism markers, and diet and exercise questionnaires under standardized procedures. Results: Diabetes-related markers improved during all four lifestyle interventions. Higher baseline TyG index ( p < 0.001) was associated with greater reductions in body weight, fasting glucose, and triglyceride (TG), while a high TyG-waist phenotype predicted better TG responses, particularly in those randomized to physical activity (PA) of moderate intensity. Conclusions: Two novel indices of insulin resistance (TyG and TyG-waist) may allow for a more personalized approach to avoiding progression to T2D. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT01777893 reference, identifier: NCT01777893., Competing Interests: TL was employed by company NetUnion Sarl. PS has received travel grants from the Cambridge Weight Plan, UK. JB-M is the President and Director of the Glycemic Index Foundation, oversees a glycemic index GI testing service at the University of Sydney and is a co-author of books about diet and diabetes. IM is a member of the UK Government Scientific Advisory Committee on Nutrition, Treasurer of the Federation of European Nutrition Societies, Treasurer of the World Obesity Federation, member of the Mars Scientific Advisory Council, member of the Mars Europe Nutrition Advisory Board, and Scientific Adviser to the Waltham Centre for Pet Nutrition. He is also a member of the Nestle Research Scientific Advisory Board and of the Novozymes Scientific Advisory Board. SP was the Fonterra Chair in Human Nutrition and Principle Investigator for NZ National Science Challenge High Value Nutrition during the PREVIEW intervention. TML is an advisor for the “Sense” diet program. AR has received honorariums from Novo Nordisk A/S, the International Sweeteners Association, Nordic Sugar and Unilever. JM is the President of IUNS. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Navas-Carretero, San-Cristobal, Siig Vestentoft, Brand-Miller, Jalo, Westerterp-Plantenga, Simpson, Handjieva-Darlenska, Stratton, Huttunen-Lenz, Lam, Muirhead, Poppitt, Pietiläinen, Adam, Taylor, Handjiev, McNarry, Hansen, Brodie, Silvestre, Macdonald, Boyadjieva, Mackintosh, Schlicht, Liu, Larsen, Fogelholm, Raben and Martinez.)

The contact structure of a population plays an important role in transmission of infection. Many 'structured models' capture aspects of the contact pattern through an underlying network or a mixing matrix. An important observation in unstructured models of a disease that confers immunity is that once a fraction [Formula: see text] has been infected, the residual susceptible population can no longer sustain an epidemic. A recent observation of some structured models is that this threshold can be crossed with a smaller fraction of infected individuals, because the disease acts like a targeted vaccine, preferentially immunising higher-risk individuals who play a greater role in transmission. Therefore, a limited 'first wave' may leave behind a residual population that cannot support a second wave once interventions are lifted. In this paper, we set out to investigate this more systematically. While networks offer a flexible framework to model contact patterns explicitly, they suffer from several shortcomings: (i) high-fidelity network models require a large amount of data which can be difficult to harvest, and (ii) very few, if any, theoretical contact network models offer the flexibility to tune different contact network properties within the same framework. Therefore, we opt to systematically analyse a number of well-known mean-field models. These are computationally efficient and provide good flexibility in varying contact network properties such as heterogeneity in the number contacts, clustering and household structure or differentiating between local and global contacts. In particular, we consider the question of herd immunity under several scenarios. When modelling interventions as changes in transmission rates, we confirm that in networks with significant degree heterogeneity, the first wave of the epidemic confers herd immunity with significantly fewer infections than equivalent models with less or no degree heterogeneity. However, if modelling the intervention as a change in the contact network, then this effect may become much more subtle. Indeed, modifying the structure disproportionately can shield highly connected nodes from becoming infected during the first wave and therefore make the second wave more substantial. We strengthen this finding by using an age-structured compartmental model parameterised with real data and comparing lockdown periods implemented either as a global scaling of the mixing matrix or age-specific structural changes. Overall, we find that results regarding (disease-induced) herd immunity levels are strongly dependent on the model, the duration of the lockdown and how the lockdown is implemented in the model., (© 2021. The Author(s).)

The glycaemic index (GI) is a food metric that ranks the acute impact of available (digestible) carbohydrates on blood glucose. At present, few countries regulate the inclusion of GI on food labels even though the information may assist consumers to manage blood glucose levels. Australia and New Zealand regulate GI claims as nutrition content claims and also recognize the GI Foundation's certified Low GI trademark as an endorsement. The GI Foundation of South Africa endorses foods with low, medium and high GI symbols. In Asia, Singapore's Healthier Choice Symbol has specific provisions for low GI claims. Low GI claims are also permitted on food labels in India. In China, there are no national regulations specific to GI; however, voluntary claims are permitted. In the USA, GI claims are not specifically regulated but are permitted, as they are deemed to fall under general food-labelling provisions. In Canada and the European Union, GI claims are not legal under current food law. Inconsistences in food regulation around the world undermine consumer and health professional confidence and call for harmonization. Global provisions for GI claims/endorsements in food standard codes would be in the best interests of people with diabetes and those at risk.

Sugary carbohydrate foods have long been associated with increased risk of dental caries formation, but the dental health impact of starchy carbohydrates, particularly those with a high glycemic index (GI), has not been well examined., Aim: To investigate the effect of different starchy foods varying in their GI, on acute changes in dental plaque pH., Methods: In a series of sub-studies in healthy adults, common starchy carbohydrate foods, including white bread, instant mashed potatoes, canned chickpeas, pasta, breakfast cereals, white rice, and an oral glucose solution were consumed in fixed 25 g available carbohydrate portions. The change in dental plaque pH was assessed postprandially over 1 h and capillary plasma glucose was measured at regular intervals over 2 h., Results: Higher GI starchy foods produced greater acute plaque pH decreases and larger overall postprandial glucose responses compared to lower GI starchy foods (white bread compared with canned chickpeas: -1.5 vs. -0.7 pH units, p = 0.001, and 99 ± 8 mmol/L min vs. 47 ± 7 mmol/L min, p = 0.026). Controlling for other food factors (food form and nutritional composition), lower GI versions of matched food pairs produced smaller plaque pH excursions compared to higher GI versions of the same food. Using linear regression analysis, the GI value of starchy carbohydrate foods explained 60% of the variation in maximum plaque pH nadir and 64% of the variation in overall acute dental plaque pH excursion ( p < 0.01)., Conclusion: The findings imply that starchy foods, in particular those with a higher GI, may play a role in increasing the risk of dental caries.

Recent declines in adult HIV-1 incidence have followed the large-scale expansion of antiretroviral therapy and primary HIV prevention across high-burden communities of sub-Saharan Africa. Mathematical modeling suggests that HIV risk will decline disproportionately in younger adult age-groups as interventions scale, concentrating new HIV infections in those >age 25 over time. Yet, no empirical data exist to support these projections. We conducted a population-based cohort study over a 16-y period (2004 to 2019), spanning the early scale-up of antiretroviral therapy and voluntary medical male circumcision, to estimate changes in the age distribution of HIV incidence in a hyperepidemic region of KwaZulu-Natal, South Africa, where adult HIV incidence has recently declined. Median age of HIV seroconversion increased by 5.5 y in men and 3.0 y in women, and the age of peak HIV incidence increased by 5.0 y in men and 2.0 y in women. Incidence declined disproportionately among young men (64% in men 15 to 19, 68% in men 20 to 24, and 46% in men 25 to 29) and young women (44% in women 15 to 19, 24% in women 20 to 24) comparing periods pre- versus post-universal test and treat. Incidence was stable (<20% change) in women aged 30 to 39 and men aged 30 to 34. Age shifts in incidence occurred after 2012 and were observed earlier in men than in women. These results provide direct epidemiological evidence of the changing demographics of HIV risk in sub-Saharan Africa in the era of large-scale treatment and prevention. More attention is needed to address lagging incidence decline among older individuals., Competing Interests: The authors declare no competing interest., (Copyright © 2021 the Author(s). Published by PNAS.)

Background: During endovascular treatment of pararenal aortic aneurysms (PAA) and thoracoabdominal aortic aneurysms (TAAA), our antegrade vascular access of choice is a lateral axillary exposure (LAE). We directly access the axillary artery with multiple sheaths followed by primary closure of the axillary artery at case completion. The aim of this study is to describe our technique and to report our results with this approach., Methods: This study is a single-institution, retrospective review of 53 patients who were treated with parallel grafts for endovascular repair of PAA and TAAA from 2006 to 2018. The aortic repairs requiring LAE included: 9 cases of endo-leaks from prior endovascular repair, 20 TAAAs, and 24 PAAs. The axillary artery was exposed with a vertical axillary skin incision followed by retraction of the lateral border of the pectoralis major to expose the axillary artery distal to the pectoralis minor. A 5-French (F) through 12F sheaths were used to directly access the axillary artery for delivery of endovascular devices., Results: Two hundred and sixty reno-visceral stents were delivered through 125 axillary sheaths in an antegrade fashion to 114 arteries without intraoperative complications or technical failures. Two postoperative complications included an access-site hematoma managed conservatively (1.9%) and a left brachial vein thrombosis treated with anticoagulation (1.9%). There were no cases of cerebrovascular or peripheral neurologic events, upper extremity ischemia, or reoperation related to LAE., Conclusions: LAE is a valid approach for upper extremity access during the endovascular repair of complex aortic aneurysms requiring simultaneous delivery of multiple reno-visceral devices. It does not require the use of a prosthetic conduit. There were no neurologic events or upper extremity ischemia in our series., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Diseases spread over temporal networks of interaction events between individuals. Structures of these temporal networks hold the keys to understanding epidemic propagation. One early concept of the literature to aid in discussing these structures is concurrency-quantifying individuals' tendency to form time-overlapping 'partnerships'. Although conflicting evaluations and an overabundance of operational definitions have marred the history of concurrency, it remains important, especially in the area of sexually transmitted infections. Today, much of theoretical epidemiology uses more direct models of contact patterns, and there is an emerging body of literature trying to connect methods to the concurrency literature. In this review, we will cover the development of the concept of concurrency and these new approaches.

Background: The retinol isotope dilution (RID) method has been used to evaluate vitamin A (VA) status in healthy adults and children in low- and middle-income countries (LMIC) and to assess the efficacy of various VA interventions., Objective: The study was designed to examine whether dried serum spots (DSS) can be applied to RID when conducting VA total body store (TBS) assessments in community settings., Methods: Four days after an oral dose of 0.4 mg [13C10]retinyl acetate was administered to Filipino children (12-18 mo), a single blood draw was divided to isolate both serum and plasma. Serum (40 μL) was spotted and dried on Whatman 903 cards and shipped at ambient temperature whereas liquid plasma (LP) was frozen at -80°C and shipped on dry ice. The VA tracer to tracee ratio from DSS and LP was quantified by LC-MS/MS. Comparisons between DSS and LP paired samples (n = 72) were made for [13C10]retinol specific activity (SAp) by Pearson's correlation and for VA TBS by Bland-Altman analysis., Results: The sum of 3 coextracted DSS were required to consistently detect [13C10]retinol above the LC-MS/MS limit of quantitation (LOQ). [13C10]retinol SAp from DSS was highly correlated with SAp from LP (r = 0.945; P < 0.01). A comparison of methods for TBS determination using Bland-Altman analysis indicated agreement with an intraindividual difference of 24.7 μmol (4.6%). Mean total liver reserve (TLR) values from DSS and LP were 1.7 μmol/g (± 0.6 SD) and 1.6 μmol/g (± 0.6 SD), respectively., Conclusions: VA TBS can be determined from DSS thereby reducing the logistics and cost of maintaining a cold chain by shipping samples at ambient temperature and, thus, making the RID technique more feasible in LMIC community settings. This trial was registered at https://clinicaltrials.gov as NCT03030339., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Knowledge regarding genetic diversity and population structure of breeding materials is essential for crop improvement. The Texas A&M University Potato Breeding Program has a collection of advanced clones selected and maintained in-vitro over a 40-year period. Little is known about its genetic makeup and usefulness for the current breeding program. In this study, 214 potato clones were genotyped with the Infinium Illumina 22 K V3 Potato Array. After filtering, a total of 10,106 single nucleotide polymorphic (SNP) markers were used for analysis. Heterozygosity varied by SNP, with an overall average of 0.59. Three groups of tetraploid clones primarily based on potato market classes, were detected using STRUCTURE software and confirmed by discriminant analysis of principal components. The highest coefficient of differentiation observed between the groups was 0.14. Signatures of selection were uncovered in genes controlling potato flesh and skin color, length of plant cycle and tuberization, and carbohydrate metabolism. A core set of 43 clones was obtained using Core Hunter 3 to develop a sub-collection that retains similar genetic diversity as the whole population, minimize redundancies, and facilitates long-term conservation of genetic resources. The comprehensive molecular characterization of our breeding clone bank collection contributes to understanding the genetic diversity of existing potato resources. This analysis could be applied to other breeding programs and assist in the selection of parents, fingerprinting, protection, and management of the breeding collections.

Anemia is a significant comorbidity for older adults not fully attributable to iron deficiency. Low-grade inflammation and other micronutrient deficiencies also contribute. This cross-sectional study examined the relationships between nutrient and non-nutrient factors with hemoglobin and anemia in 285 residents (>65 years) of 16 New Zealand aged-care facilities. Blood samples were analyzed for hemoglobin, ferritin, sTfR, hepcidin, zinc, selenium, and interleukin-6 (IL-6), (with ferritin, sTfR, zinc and selenium adjusted for inflammation). Linear regression models examined the relationships between micronutrient biomarkers (iron, zinc, selenium, vitamin B-12 and D), age, sex, and health factors with hemoglobin. Thirty-two percent of participants exhibited anemia, although <2% had either depleted iron stores or iron deficiency. Plasma zinc and selenium deficiencies were present in 72% and 38% of participants, respectively. Plasma zinc and total body iron (TBI) were positively associated ( p < 0.05) with hemoglobin, while gastric acid suppressing medications, hepcidin, and interleukin-6 were inversely associated. These relationships were maintained after the application of anemia cut-offs. These findings emphasize the importance of considering multiple micronutrient deficiencies as risk factors for anemia.

Background: Previous research showed that weight-reducing diets increase appetite sensations and/or circulating ghrelin concentrations for up to 36 months, with transient or enduring perturbations in circulating concentrations of the satiety hormone peptide YY. Objective: This study assessed whether a diet that is higher in protein and low in glycemic index (GI) may attenuate these changes. Methods: 136 adults with pre-diabetes and a body mass index of ≥25 kg/m 2 underwent a 2-month weight-reducing total meal replacement diet. Participants who lost ≥8% body weight were randomized to one of two 34-month weight-maintenance diets: a higher-protein and moderate-carbohydrate (CHO) diet with low GI, or a moderate-protein and higher-CHO diet with moderate GI. Both arms involved recommendations to increase physical activity. Fasting plasma concentrations of total ghrelin and total peptide YY, and appetite sensations, were measured at 0 months (pre-weight loss), at 2 months (immediately post-weight loss), and at 6, 12, 24, and 36 months. Results: There was a decrease in plasma peptide YY concentrations and an increase in ghrelin after the 2-month weight-reducing diet, and these values approached pre-weight-loss values by 6 and 24 months, respectively ( P = 0.32 and P = 0.08, respectively, vs. 0 months). However, there were no differences between the two weight-maintenance diets. Subjective appetite sensations were not affected by the weight-reducing diet nor the weight-maintenance diets. While participants regained an average of ~50% of the weight they had lost by 36 months, the changes in ghrelin and peptide YY during the weight-reducing phase did not correlate with weight regain. Conclusion: A higher-protein, low-GI diet for weight maintenance does not attenuate changes in ghrelin or peptide YY compared with a moderate-protein, moderate-GI diet. Clinical Trial Registry: ClinicalTrials.gov registry ID NCT01777893 (PREVIEW) and ID NCT02030249 (Sub-study)., Competing Interests: RS serves on the Nestlé Health Science Optifast® VLCDTM™ Advisory Board. JB-M is the President of the Glycemic Index Foundation (a non-profit food endorsement program), oversees a glycemic index testing service at the University of Sydney and is the author of books about the glycemic index, food and healthy eating. AS owns 50% of the shares in Zuman International, a company which receives royalties for books she has written about weight management and payments for presentations at industry conferences. She has also received presentation fees and travel reimbursements from Eli Lilly and Co, the Pharmacy Guild of Australia, Novo Nordisk, the Dietitians Association of Australia, Shoalhaven Family Medical Centres, the Pharmaceutical Society of Australia, and Metagenics, and served on the Nestlé Health Science Optifast VLCD advisory board from 2016 to 2018. FA is a director of the Glycemic Index Foundation (a non-profit food endorsement program), manages a glycemic index testing service at the University of Sydney, and is a co-author of books about the glycemic index. Finally, Cambridge Weight Plan©, Ltd, UK provided all meal replacement products used at all sites of the PREVIEW Study. The commercial and funding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, nor in the decision to publish the results. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Buso, Seimon, McClintock, Muirhead, Atkinson, Brodie, Dodds, Zibellini, Das, Wild-Taylor, Burk, Fogelholm, Raben, Brand-Miller and Sainsbury.)

Neuronal tau reduction confers resilience against β-amyloid and tau-related neurotoxicity in vitro and in vivo. Here, we introduce a novel translational approach to lower expression of the tau gene MAPT at the transcriptional level using gene-silencing zinc finger protein transcription factors (ZFP-TFs). Following a single administration of adeno-associated virus (AAV), either locally into the hippocampus or intravenously to enable whole-brain transduction, we selectively reduced tau messenger RNA and protein by 50 to 80% out to 11 months, the longest time point studied. Sustained tau lowering was achieved without detectable off-target effects, overt histopathological changes, or molecular alterations. Tau reduction with AAV ZFP-TFs was able to rescue neuronal damage around amyloid plaques in a mouse model of Alzheimer's disease (APP/PS1 line). The highly specific, durable, and controlled knockdown of endogenous tau makes AAV-delivered ZFP-TFs a promising approach for the treatment of tau-related human brain diseases., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

The interventions and outcomes in the ongoing COVID-19 pandemic are highly varied. The disease and the interventions both impose costs and harm on society. Some interventions with particularly high costs may only be implemented briefly. The design of optimal policy requires consideration of many intervention scenarios. In this paper we investigate the optimal timing of interventions that are not sustainable for a long period. Specifically, we look at at the impact of a single short-term non-repeated intervention (a "one-shot intervention") on an epidemic and consider the impact of the intervention's timing. To minimize the total number infected, the intervention should start close to the peak so that there is minimal rebound once the intervention is stopped. To minimise the peak prevalence, it should start earlier, leading to initial reduction and then having a rebound to the same prevalence as the pre-intervention peak rather than one very large peak. To delay infections as much as possible (as might be appropriate if we expect improved interventions or treatments to be developed), earlier interventions have clear benefit. In populations with distinct subgroups, synchronized interventions are less effective than targeting the interventions in each subcommunity separately., Competing Interests: The authors have declared that no competing interests exist.

Bartonella bacilliformis (B. bacilliformis) , Bartonella henselae (B. henselae) , and Bartonella quintana (B. quintana) are bacteria known to cause verruga peruana or bacillary angiomatosis, vascular endothelial growth factor (VEGF)-dependent cutaneous lesions in humans. Given the bacteria's association with the dermal niche and clinical suspicion of occult infection by a dermatologist, we determined if patients with melanoma had evidence of Bartonella spp. infection. Within a one-month period, eight patients previously diagnosed with melanoma volunteered to be tested for evidence of Bartonella spp. exposure/infection. Subsequently, confocal immunohistochemistry and PCR for Bartonella spp. were used to study melanoma tissues from two patients. Blood from seven of the eight patients was either seroreactive, PCR positive, or positive by both modalities for Bartonella spp. exposure. Subsequently, Bartonella organisms that co-localized with VEGFC immunoreactivity were visualized using multi-immunostaining confocal microscopy of thick skin sections from two patients. Using a co-culture model, B. henselae was observed to enter melanoma cell cytoplasm and resulted in increased vascular endothelial growth factor C (VEGFC) and interleukin 8 (IL-8) production. Findings from this small number of patients support the need for future investigations to determine the extent to which Bartonella spp. are a component of the melanoma pathobiome.

Introduction: Since its onset, the COVID-19 pandemic has caused significant morbidity and mortality worldwide, with particularly severe outcomes in healthcare institutions and congregate settings. To mitigate spread, healthcare systems have been cohorting patients to limit contacts between uninfected patients and potentially infected patients or healthcare workers (HCWs). A major challenge in managing the pandemic is the presence of currently asymptomatic/presymptomatic individuals capable of transmitting the virus, who could introduce COVID-19 into uninfected cohorts. The optimal combination of personal protective equipment (PPE), testing and other approaches to prevent these events is unclear, especially in light of ongoing limited resources., Methods: Using stochastic simulations with a susceptible-exposed-infected-recovered dynamic model, we quantified and compared the impacts of PPE use, patient and HCWs surveillance testing and subcohorting strategies., Results: In the base case without testing or PPE, the healthcare system was rapidly overwhelmed, and became a net contributor to the force of infection. We found that effective use of PPE by both HCWs and patients could prevent this scenario, while random testing of apparently asymptomatic/presymptomatic individuals on a weekly basis was less effective. We also found that even imperfect use of PPE could provide substantial protection by decreasing the force of infection. Importantly, we found that creating smaller patient/HCW-interaction subcohorts can provide additional resilience to outbreak development with limited resources., Conclusion: These findings reinforce the importance of ensuring adequate PPE supplies even in the absence of testing and provide support for strict subcohorting regimens to reduce outbreak potential in healthcare institutions., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Divergent terpene indole alkaloid (TIA) pathways in Catharanthus roseus and Camptotheca acuminata generate vinblastine and vincristine, and camptothecin, respectively. In contrast to Catharanthus which feeds secologanin (from methylated loganin) into its species-specific late pathway, Camptotheca feeds secologanic acid (from unmethylated loganic acid) into its late pathway. Having identified putative Camptotheca secologanic acid synthases (SLASs) and cytochrome P450 reductases (CPRs) in transcriptome databases, we have demonstrated that two P450s, CYP72A564 and CYP72A565, are capable of utilizing both loganic acid and loganin to generate secologanic acid and secologanin. We have extended the previous report of these activities by CYP72A565 and CYP72A610 (Yang et al., 2019) by demonstrating that both Arabidopsis CPRs (ATR1, ATR2) couple with these CYP72A proteins in yeast microsomal assays and that purified Camptotheca CPR1 couples with them in in vitro reconstitution assays. Kinetic analyses of purified full-length Camptotheca SLASs have indicated that both process loganic acid with nearly identical catalytic rates and efficiencies as measured by their k cat and k cat /K M . In contrast, CYP72A564 processes loganin with two-fold greater efficiency than CYP72A565 correlating with the former's 3-fold greater affinity for loganin. The closely-related CYP72A730 does not bind or process either compound. Molecular modeling of these three proteins and comparisons with Catharanthus secologanin synthase (SLS) have identified key differences that likely determine their SLAS versus SLS selectivities. Our ability to reconstitute these SLAS/SLS activities provides valuable tools for further examinations of the residues involved in substrate recognition and determinations of their unusual mechanism of C-C bond scission., (Copyright © 2020. Published by Elsevier Ltd.)

There is an emerging consensus that achieving global tuberculosis control targets will require more proactive case finding approaches than are currently used in high-incidence settings. Household contact tracing (HHCT), for which households of newly diagnosed cases are actively screened for additional infected individuals is a potentially efficient approach to finding new cases of tuberculosis, however randomized trials assessing the population-level effects of such interventions in settings with sustained community transmission have shown mixed results. One potential explanation for this is that household transmission is responsible for a variable proportion of population-level tuberculosis burden between settings. For example, transmission is more likely to occur in households in settings with a lower tuberculosis burden and where individuals mix preferentially in local areas, compared with settings with higher disease burden and more dispersed mixing. To better understand the relationship between endemic incidence levels, social mixing, and the impact of HHCT, we developed a spatially explicit model of coupled household and community transmission. We found that the impact of HHCT was robust across settings of varied incidence and community contact patterns. In contrast, we found that the effects of community contact tracing interventions were sensitive to community contact patterns. Our results suggest that the protective benefits of HHCT are robust and the benefits of this intervention are likely to be maintained across epidemiological settings., Competing Interests: The authors have declared that no competing interests exist.

Background: Rugby is the fastest growing team sport in the United States for male and female athletes. It is a contact/collision sport with an injury risk profile that includes concussions., Purpose: To examine the prevalence of concussions in male and female rugby players in the United States and to characterize behaviors around reporting concussions that could be a target for prevention and treatment efforts., Study Design: Cross-sectional study; Level of evidence, 3., Methods: An online survey distributed to active members on the USA Rugby membership list was used to examine self-reported concussions in male and female athletes. Concussion-reporting behaviors and return to play after a concussion were also explored. Statistical analysis was used to compare male with female athletes and report differences, with years of experience as a dependent variable., Results: The proportion of athletes with a history of at least 1 concussion was 61.9% in all respondents. Of those who reported a concussion, 50.8% reported the concussion during the game or practice in which it occurred, and 57.6% reported at least 1 concussion to a qualified medical provider. Overall, 27.7% of participants who reported ≥1 rugby-related concussion in our survey noted that at least 1 of these concussions was not formally reported. The most commonly cited reasons for not reporting a concussion included not thinking that it was a serious injury, not knowing that it was a concussion at the time, and not wanting to be pulled out of the game or practice. Additionally, 61.0% of athletes did not engage in recommended return-to-play protocols after their most recent rugby-related concussion., Conclusion: US rugby union athletes may not report concussions to medical personnel or follow return-to-play protocols guided by medical advice. This could result from a lack of education on concussion recognition and the risks associated with continued play after a concussion as well as limited access to health care. Further education efforts focusing on the identification of concussions, removal from play, and return-to-play protocols are necessary in the US rugby union population., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: D.P.T. has received grant support from Arthrex and educational support from Peerless Surgical and Smith & Nephew. T.B. has received educational support from Arthrex and honoraria from Fidia Pharma. C.S.A. has received research support from Arthrex, Major League Baseball, and Stryker; has received consulting fees from Arthrex; has received royalties from Arthrex and Lead Player; and has stock/stock options in At Peak Sports. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto., (© The Author(s) 2021.)