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Objective: Complex regional pain syndrome (CRPS) is a debilitating chronic condition characterized by severe, nociplastic pain along with various other symptoms. Neuromodulation, particularly electrical stimulation of the dorsal root ganglion (DRG), has emerged as a promising intervention for patients with CRPS unresponsive to conventional treatments. However, little is known about the anatomical characteristics of DRGs in patients with CRPS. This study aimed to assess DRG size in patients with CRPS compared with healthy controls., Materials and Methods: A retrospective pilot study was conducted in 12 patients with unilateral lower extremity CRPS who have a history of lumbar magnetic resonance imaging, and evaluated DRG sizes bilaterally. Patients were age-, race-, and sex-matched to patients in the control group who were asymptomatic at matched spinal level. DRG sizes were evaluated by a neuroradiologist. Statistical analyses including paired t-tests were performed to compare the difference in DRG size in contralateral sides in patients with CRPS and their matched controls., Results: Patients with CRPS exhibited a statistically significant reduction in DRG size on the affected side compared with the unaffected side (4.4 mm-4.8 mm, respectively). This difference was significant when compared with the difference observed in healthy controls (4.9 mm-5.0 mm, respectively). In addition, the mean DRG size difference between the affected and unaffected side showed a greater difference in DRG size in patients with CRPS (0.6 mm difference) than in control patients (0.2 mm difference)., Conclusions: The findings suggest that CRPS is associated with a smaller DRG size in affected dermatomes, potentially indicating neuronal atrophy. Importantly, the study offers insights for DRG stimulation therapy especially among concerns for DRG compression after placement. This pilot study reveals a significant size difference in DRGs between affected and unaffected sides in patients with CRPS compared with controls, highlighting potential implications for treating CRPS. Further research is warranted to validate these findings and explore implications for clinical practice, including optimized neuromodulation strategies., Competing Interests: Conflict of Interest Johnathan H. Goree has consulting agreements with Abbott, Saluda, and Stratus Medical, and also has funded research paid to his institution from SPR Therapeutics and Mainstay Medical. The remaining authors report no conflict of interest., (Copyright © 2024 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.)

Investigators conducting human subject research have typically conveyed only clinically actionable results back to individual participants. Shifting scientific culture around viewing participants as partners in research, however, is prompting investigators to consider returning as much data or results as the participant would like, even if they are not clearly actionable. Expanding return of individual results may add value for individual participants and their communities, refine future research questions and methods, build trust, and enhance retention of participants. Yet, gaps remain in understanding the implications of these changes for groups of 'vulnerable' participants, including pregnant and pediatric participants. We present the findings of a National Institutes of Health workshop on returning individual research results, particularly as applicable to pregnant and pediatric participants. Research participants who were panelists at the workshop agreed that they desire to receive their results. Workshop findings and current literature indicate that participants have differing preferences for what results they receive. One way to address the limits of current practice is to develop flexible digital platforms that convey individual results along with researchers' availability to answer questions, and to provide as much information as possible about actionable steps to control environmental exposures associated with disease risk., (Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health 2024.)

Esophageal carcinoma (ESCA) is a leading cause of cancer-related death worldwide, and certain oral and intestinal pathogens have been associated with cancer development and progression. We asked if esophageal microbiomes had shared alterations that could provide novel biomarkers for ESCA risk. We extracted DNA from tumor and non-tumor tissue of 212 patients in the NCI-MD case control study and sequenced the 16S rRNA gene (V3-4), with TCGA ESCA RNA-seq (n = 172) and WGS (n = 123) non-human reads used as validation. We identified four taxa, Campylobacter, Prevotella, Streptococcus, and Fusobacterium as highly enriched in esophageal cancer across all cohorts. Using SparCC, we discovered that Fusobacterium and Prevotella were also co-enriched across all cohorts. We then analyzed immune cell infiltration to determine if these dysbiotic taxa were associated with immune signatures. Using xCell to obtain predicted immune infiltrates, we identified a depletion of megakaryocyte-erythroid progenitor (MEP) cells in tumors with presence of any of the four taxa, along with enrichment of platelets in tumors with Campylobactor or Fusobacterium. Taken together, our results suggest that intratumoral presence of these co-occurring bacterial genera may confer tumor promoting immune alterations that allow disease progression in esophageal cancer., (© 2023. The Author(s).)

2-Halo-3-tosyl-oxanorbornadienes are able to accept two thiol molecules through an initial nucleophilic substitution, giving isolable oxabicyclic thiovinyl sulfones that, subsequently, can react with a second thiol molecule via thio-Michael addition. The resulting oxanorbornenic thioketals undergo retro-Diels-Alder (rDA) fragmentation to release a furan derivative and a ketene S , S -acetal. The substitution pattern of the oxanorbornadienic skeleton influences the rate of the rDA through electronic and steric factors examined by quantum mechanical calculations.

The use of 7-oxa/azanorbornadienes as synthetic intermediates for the preparation of 3/4-substituted (β-substituted) furans/pyrroles is presented. The method lies in the inverse electron demand Diels-Alder (iEDDA) cycloaddition between a substituted heteronorbornadiene and an electron-poor tetrazine followed by spontaneous fragmentation of the resulting cycloadduct via two retro-Diels-Alder (rDA) reactions affording a β-substituted furan/pyrrole. The scope of this tandem iEDDA/rDA/rDA reaction was explored in the preparation of 29 heterocycles. A one-pot procedure starting directly from the alkyne precursors of the heteronorbornadiene intermediates is also described.

Carcinomatosis of the bone marrow is a rare clinical condition characterized by diffuse tumor infiltration of the bone marrow accompanied by hematological abnormalities, including thrombotic microangiopathy (TMA) and disseminated intravascular coagulation (DIC). In patients with gastric carcinoma, this association is infrequent. Below we present a case of a 19-year-old female patient with no known pathological history who presented with upper digestive tract bleeding. Upon examination, anemia and thrombocytopenia were documented, with schistocytes in the peripheral blood smear and prolonged coagulation times. Endoscopic studies indicated a lesion in the Borrmann IV gastric body, and the bone marrow biopsy showed the presence of signet ring cells. Because there was no possibility of systemic therapy, the patient died during hospitalization. This case contributes to the medical literature by describing an unusual presentation of a very frequent pathology., (© 2023 Gabriel Suarez-Reyes et al., published by Sciendo.)

Background: Assessment of individual and population-level dietary intake is critical for public health surveillance, epidemiology, and dietary intervention research. In recognition of that need, the National Insitutes of Health (NIH) has a history of funding research projects designed to support the development, implementation, and refinement of tools to assess dietary intake in humans., Objectives: This report provides data and information on NIH-funded dietary intake assessment methodological research over the period of 2012-2021., Methods: Data were extracted from an internal NIH data system using the Research, Condition, and Disease Categorization (RCDC) spending category for Nutrition. Data were then examined to identify research focused on dietary assessment tools or methods to capture or analyze dietary intake., Results: Over the decade of 2012-2021, NIH supported 46 grants and 2 large contracts specific to dietary assessment methods development. The top 6 Institutes and Offices funding dietary assessment methods research were identified. Most projects were limited to adults. Projects ranged from novel methods to capture dietary intake, and refinement of analytical methods, to biomarkers of dietary intake. One key contract supported the automated self-administered 24-h dietary assessment tool (ASA24), a widely used, free tool available to the research community for assessing dietary intake., Conclusions: NIH's support for dietary assessment methods development over this 10-y period was small but grew over time with an expanding number and variety of methods, data sources, and technological advancements in the assessment of dietary intake. NIH remains committed to supporting research seeking to advance the field of dietary assessment methods research., (Published by Elsevier Inc.)

Cancer cells are highly dependent on Nicotinamide phosphoribosyltransferase (NAMPT) activity for proliferation, therefore NAMPT represents an interesting target for the development of anti-cancer drugs. Several compounds, such as FK866 and CHS828, were identified as potent NAMPT inhibitors with strong anti-cancer activity, although none of them reached the late stages of clinical trials. We present herein the preparation of three libraries of new inhibitors containing (pyridin-3-yl)triazole, (pyridin-3-yl)thiourea and (pyridin-3/4-yl)cyanoguanidine as cap/connecting unit and a furyl group at the tail position of the compound. Antiproliferative activity in vitro was evaluated on a panel of solid and haematological cancer cell lines and most of the synthesized compounds showed nanomolar or sub-nanomolar cytotoxic activity in MiaPaCa-2 (pancreatic cancer), ML2 (acute myeloid leukemia), JRKT (acute lymphobalistic leukemia), NMLW (Burkitt lymphoma), RPMI8226 (multiple myeloma) and NB4 (acute myeloid leukemia), with lower IC 50 values than those reported for FK866. Notably, compounds 35a, 39a and 47 showed cytotoxic activity against ML2 with IC 50  = 18, 46 and 49 pM, and IC 50 towards MiaPaCa-2 of 0.005, 0.455 and 2.81 nM, respectively. Moreover, their role on the NAD + synthetic pathway was demonstrated by the NAMPT inhibition assay. Finally, the intracellular NAD +  depletion was confirmed in vitro to induced ROS accumulation that cause a time-dependent mitochondrial membrane depolarization, leading to ATP loss and cell death., 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 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

National health and nutrition monitoring is an important federal effort in the United States and Canada, and the basis for many of their nutrition and health policies. Understanding of child exposures through human milk (HM) remains out of reach due to lack of current and representative data on HM's composition and intake volume. This article provides an overview of the current national health and nutrition monitoring activities for HM-fed children, HM composition (HMC) and volume data used for exposure assessment, categories of potential measures in HM, and associated variability factors. In this Perspective, we advocate for a framework for collection and reporting of HMC data for national health and nutrition monitoring and programmatic needs, including a shared vision for a publicly available Human Milk Composition Data Repository (HMCD-R) to include essential metadata associated with HMC. HMCD-R can provide a central, integrated platform for researchers and public health officials for compiling, evaluating, and sharing HMC data. The compiled compositional and metadata in HMCD-R would provide pertinent measures of central tendency and variability and allow use of modeling techniques to approximate compositional profiles for subgroups, providing more accurate exposure assessments for purposes of monitoring and surveillance. HMC and related metadata could facilitate understanding the complexity and variability of HM composition, provide crucial data for assessment of infant and maternal nutritional needs, and inform public health policies, food and nutrition programs, and clinical practice guidelines., (Published by Oxford University Press on behalf of the American Society for Nutrition 2022.)

Aminyl radicals are nitrogen-centered radicals of interest in synthetic strategies involving C-N bond formation due to their high reactivity. These intermediate radicals are generated by the reaction of an organic azide with tributyltin hydride (Bu 3 SnH) in the presence of substoichiometric amounts of azobisisobutyronitrile (AIBN). In this work, we report the regioselective rearrangement of azanorbornanic ([2.2.1]azabicyclic) aminyl radicals into 2,8-diazabicyclo[3.2.1]oct-2-ene systems. With the aim to establish the structural requirements for this ring expansion, we have studied the effect of different bridgehead atoms of the [2.2.1]bicyclic system and the presence of an alkyl substituent at C4. Attempts to perform this ring expansion on a monocyclic analogue have been also explored to evaluate the influence of the bicyclic skeleton on the rearrangement. A detailed mechanistic proposal supported by computational studies is reported.

The Dietary Guidelines for Americans, 2020-2025, included guidelines for pregnancy, lactation, and children from birth to age 24 mo (B-24) to reflect the growing body of evidence about appropriate nutrition during the earliest stages of life. Guidelines were based on a thorough review of the existing scientific evidence by the 2020 Dietary Guidelines Advisory Committee (DGAC). This study's objective was to enumerate early-life (pregnancy, lactation, and B-24) nutrition research needs that are already being addressed by the scientific community and to identify remaining research gaps. The Scientific Report of the 2020 Dietary Guidelines Advisory Committee was reviewed, and 138 research gaps relevant to early life were identified. Research gaps were consolidated into 13 topic areas. A total of 1632 nutrition- and early-life-focused research projects funded by the NIH between 2018 and 2020 were manually coded using title, abstract, and public health relevance statement available on NIH RePORTER. Projects were coded as affirmative if they addressed a research gap within 1 of the 13 research gap topic areas. Of coded projects, 235 (14.4%) addressed any early-life nutrition research gap. Between fiscal years 2018 to 2020, total costs of projects addressing any gap represented only 15% of total costs for all projects reviewed. Complementary foods, breastfeeding (never vs. ever), and frequency of eating were research gap areas most frequently coded as being addressed by a funded project. Iron supplementation, seafood consumption, and maternal diet food allergens were research gap areas least frequently coded as being potentially addressed by a funded project. This analysis highlights opportunities for changes in the federal government investment in maternal and child nutrition research to support development of effective, evidence-based dietary guidelines for improvement in early-life nutrition practices and overall public health., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Concerned by the urgent need to explore new approaches for the treatment of Alzheimer's disease, we herein describe the synthesis and evaluation of new multitarget molecules. In particular, we have focused our attention on modulating the activity of cholinesterases (AChE, BuChE) in order to restore the levels of the neurotransmitter acetylcholine, and of O-GlcNAcase (OGA), which is associated with hyperphosphorylation of tau protein, in turn related to the formation of neurofibrillary tangles in the brain. Specifically, we considered the possibility of using carbohydrate-fused 1,3-selenazolines, decorated with a 2-alkylamino or 2-alkoxy moieties. On the one hand, the presence of a selenium atom might be useful in modulating the intrinsic oxidative stress in AD. On the other hand, such bicyclic structure might behave as a transition state analogue of OGA hydrolysis. Moreover, upon protonation, it could mimic the ammonium cation of acetylcholine. The lead compound, bearing a propylamino moiety on C-2 position of the selenazoline motif, proved to be a good candidate against AD; it turned out to be a strong inhibitor of BuChE (IC 50  = 0.46 µM), the most prevalent cholinesterase in advanced disease stages, with a roughly 4.8 selectivity index in connection to AChE (IC 50  = 2.2 µM). This compound exhibited a roughly 12-fold increase in activity compared to galantamine, one of the currently marketed drugs against AD, and a selective AChE inhibitor, and virtually the same activity as rivastigmine, a selective BuChE inhibitor. Furthermore, it was also endowed with a strong inhibitory activity against human OGA, within the nanomolar range (IC 50  = 0.053 µM for hOGA, >100 µM for hHexB), and, thus, with an outstanding selectivity (IC 50 (hHexB)/IC 50 (hOGA) > 1887). The title compounds also exhibited an excellent selectivity against a panel of glycosidases and a negligible cytotoxicity against tumor and non-tumor cell lines. Docking simulations performed on the three target enzymes (AChE, BuChE, and OGA) revealed the key interactions to rationalize the biological data., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The first 1000 days begins with pregnancy and ends at the child's second birthday. Nutrition throughout the life course, and especially during the first 1000 days, supports maternal health and optimal growth and development for children. We give a high-level summary of the state of nutrition in the first 1000 days in the United States. We provide examples where continued efforts are needed. We then discuss select opportunities to strengthen federal research and surveillance, programs, and communication and dissemination efforts aimed at improving nutrition and positively, and equitably, influencing the health and well-being of mothers and children. ( Am J Public Health . 2022;112(S8):S817-S825. https://doi.org/10.2105/AJPH.2022.307028).

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal diseases for which chemotherapy has not been very successful yet. FK866 ((E)-N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide) is a well-known NAMPT (nicotinamide phosphoribosyltransferase) inhibitor with anti-cancer activities, but it failed in phase II clinical trials. We found that FK866 shows anti-proliferative activity in three PDAC cell lines, as well as in Jurkat T-cell leukemia cells. More than 50 FK866 analogues were synthesized that introduce substituents on the phenyl ring of the piperidine benzamide group of FK866 and exchange its buta-1,4-diyl tether for 1-oxyprop-3-yl, (E)-but-2-en-1,4-diyl and 2- and 3-carbon tethers. The pyridin-3-yl moiety of FK866 was exchanged for chlorinated and fluorinated analogues and for pyrazin-2-yl and pyridazin-4-yl groups. Several compounds showed low nanomolar or sub-nanomolar cell growth inhibitory activity. Our best cell anti-proliferative compounds were the 2,4,6-trimethoxybenzamide analogue of FK866 ((E)-N-(4-(1-(2,4,6-trimethoxybenzoyl)piperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide) (9), the 2,6-dimethoxybenzamide (8) and 2-methoxybenzamide (4), which exhibited an IC 50 of 0.16 nM, 0.004 nM and 0.08 nM toward PDAC cells, respectively., (Copyright © 2022. Published by Elsevier Masson SAS.)

Objective . Reports of heterotopic tissue in the placenta are few and mainly include liver and adrenal cells. We report on adipose tissue found in the placenta. Case report . We present the case of a microscopic finding in a 25-year-old's placenta who suffered from hypertensive disorder in pregnancy. During routine microscopic study, we observed a heterotopic, benign, circumscribed and intervillous nodule of adipose tissue. Conclusion . To our knowledge, there is no other reported case of adipocytes among chorionic villi. Why foreign tissues show up in the placenta remains unknown; however, several new theories offer explanations.

Two libraries of mono- and dimeric pyrrolidine iminosugars were synthesized by CuAAC and (thio)urea-bond-forming reactions from the respective azido/aminohexylpyrrolidine iminosugar precursors. The resulting monomeric and dimeric compounds were screened for inhibition of β-N-acetylglucosaminidase from Jack beans, the plant ortholog of human lysosomal hexosaminidases. A selection of the best inhibitors of these libraries was then evaluated against human lysosomal β-N-acetylhexosaminidase B (hHexB) and human nucleocytoplasmic β-N-acetylglucosaminidase (hOGA). This evaluation identified a potent (nM) and selective monomeric inhibitor of hOGA (compound 7A) that showed a 6770-fold higher affinity for this enzyme than for hHexB. The corresponding dimeric derivative (compound 9D) further remarkably improved the selectivity in the inhibition of hOGA (2.7 × 10 4 times more selective for hOGA over hHexB) and the inhibition potency (by one order of magnitude). Docking studies were performed to explain the selectivity of inhibition observed in compound 7A., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: The objective of the present study is to describe the clinical, diagnostic, radiological and therapeutic aspects of osteoarticular tuberculosis (OATB) in patients in a tertiary pediatric hospital, to know if the diagnosis of OATB in pediatrics is a challenge due to its insidious clinical presentation., Methods: A retrospective, descriptive study of the cases of Tuberculosis (TB) in children was carried out. A total of 159 cases met the condition for the analysis., Results: The most frequent TB modality was extrapulmonary in 85%. Out of this, only 29% was OATB. The mean age was 4.9 years (range 8 months-16 years). Eighty-six per cent of cases received Bacille Calmette-Guérin (BCG) vaccination at birth. Median time of symptoms prior to diagnosis was 8 months. Microbiological confirmation was achieved only in five cases, with a high sensitivity to the antimicrobial treatment. Mycobacterium bovis BCG strain Tokio 172 was confirmed in three cases. Mortality rate was 0% during the time of study CONCLUSION: Our study describes the epidemiological characteristics of OATB cases in Mexican children. This data revealed a high prevalence of bone and joint TB infection. Pediatric OATB should be considered in cases with lytic bone lesions, fever and local pain. In countries with BCG immunization program, M. bovis should not be forgotten as an etiological agent. The low detection rate with one technique approach highlights the urgent need for more sensitive test to diagnose OATB in children., (© 2021. The Author(s).)

Background & Aims: Public interest in pre-, pro-, and synbiotic products is increasing because of interactions between gut microbiota and human health. Our aim was to describe nonfood (from dietary supplements or medication) pre-, pro-, and synbiotic use by US adults and children and reported reasons., Methods: Using data from the National Health and Nutrition Examination Survey (NHANES), we text-mined dietary supplement and prescription medication labels and ingredients to identify pre-, pro-, and synbiotic products used in the past 30 days. We describe trends in use from 1999 to 2018 (n = 101,199) and prevalence in 2015-2016 and 2017-2018 (n = 19,215) by age groups, sex, ethnicity/race, education, income, self-reported diet and health quality, and prescription gastrointestinal medication use stratified by children (<19 years) and adults (19+ years)., Results: Nonfood pre-, pro-, and synbiotic use increased up to 3-fold in recent cycles. Prevalence of use for all ages for prebiotics was 2.4% (95% confidence interval [CI], 2.0-2.9), for probiotics was 4.5% (95% CI, 3.5-5.6), and for synbiotics was 1.1% (95% CI, 0.8-1.5). Use was highest among older adults (8.8% [95% CI, 5.4-13.3] among those aged 60-69 years for probiotics), non-Hispanic Whites, those with higher educational attainment and income, those with more favorable self-reported diet or health quality, and those with concurrent prescription gastrointestinal medication use. The top reasons for use were for digestive health and to promote/maintain general health. Less than 30% reported using these products based on a health care provider's recommendation., Conclusions: One in 20 US adults or children use nonfood pre-, pro-, or synbiotic products, and use has sharply increased in recent years. Most individuals voluntarily take these products for general digestive or overall health reasons., (Published by Elsevier Inc.)

Introduction: This manuscript characterizes primary and secondary prevention research in humans and related methods research funded by NIH in 2012‒2019., Methods: The NIH Office of Disease Prevention updated its prevention research taxonomy in 2019‒2020 and applied it to a sample of 14,523 new extramural projects awarded in 2012-2019. All projects were coded manually for rationale, exposures, outcomes, population focus, study design, and type of prevention research. All results are based on that manual coding., Results: Taxonomy updates resulted in a slight increase, from an average of 16.7% to 17.6%, in the proportion of prevention research awards for 2012‒2017; there was a further increase to 20.7% in 2019. Most of the leading risk factors for death and disability in the U.S. were observed as an exposure or outcome in <5% of prevention research projects in 2019 (e.g., diet, 3.7%; tobacco, 3.9%; blood pressure, 2.8%; obesity, 4.4%). Analysis of existing data became more common (from 36% to 46.5%), whereas randomized interventions became less common (from 20.5% to 12.3%). Randomized interventions addressing a leading risk factor in a minority health or health disparities population were uncommon., Conclusions: The number of new NIH awards classified as prevention research increased to 20.7% in 2019. New projects continued to focus on observational studies and secondary data analysis in 2018 and 2019. Additional research is needed to develop and test new interventions or develop methods for the dissemination of existing interventions, which address the leading risk factors, particularly in minority health and health disparities populations., (Published by Elsevier Inc.)

Critical advancement is needed in the study of human milk as a biological system that intersects and interacts with myriad internal (maternal biology) and external (diet, environment, infections) factors and its plethora of influences on the developing infant. Human-milk composition and its resulting biological function is more than the sum of its parts. Our failure to fully understand this biology in a large part contributes to why the duration of exclusive breastfeeding remains an unsettled science (if not policy). Our current understanding of human-milk composition and its individual components and their functions fails to fully recognize the importance of the chronobiology and systems biology of human milk in the context of milk synthesis, optimal timing and duration of feeding, and period of lactation. The overly simplistic, but common, approach to analyzing single, mostly nutritive components of human milk is insufficient to understand the contribution of either individual components or the matrix within which they exist to both maternal and child health. There is a need for a shift in the conceptual approach to studying human milk to improve strategies and interventions to support better lactation, breastfeeding, and the full range of infant feeding practices, particularly for women and infants living in undernourished and infectious environments. Recent technological advances have led to a rising movement towards advancing the science of human-milk biology. Herein, we describe the rationale and critical need for unveiling the multifunctionality of the various nutritional, nonnutritional, immune, and biological signaling pathways of the components in human milk that drive system development and maturation, growth, and development in the very early postnatal period of life. We provide a vision and conceptual framework for a research strategy and agenda to change the field of human-milk biology with implications for global policy, innovation, and interventions., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

In recent years, literature examining implementation of nutritional genomics into clinical practice has increased, including publication of several randomized controlled trials (RCTs). This systematic review addressed the following question: In children and adults, what is the effect of incorporating results of genetic testing into nutrition counseling and care compared with an alternative intervention or control group, on nutrition-related health outcomes? A literature search of MEDLINE, Embase, PsycINFO, CINAHL, and other databases was conducted for peer-reviewed RCTs published from January 2008 until December 2018. An international workgroup consisting of registered dietitian nutritionists, systematic review methodologists, and evidence analysts screened and reviewed articles, summarized data, conducted meta-analyses, and graded conclusion statements. The second in a two-part series, this article specifically summarizes evidence from RCTs that examined health outcomes (ie, quality of life, disease incidence and prevention of disease progression, or mortality), intermediate health outcomes (ie, anthropometric measures, body composition, or relevant laboratory measures routinely collected in practice), and adverse events as reported by study authors. Analysis of 11 articles from nine RCTs resulted in 16 graded conclusion statements. Among participants with nonalcoholic fatty liver disease, a diet tailored to genotype resulted in a greater reduction of percent body fat compared with a customary diet for nonalcoholic fatty liver disease. However, meta-analyses for the outcomes of total cholesterol, low-density lipoprotein cholesterol, body mass index, and weight yielded null results. Heterogeneity between studies and low certainty of evidence precluded development of strong conclusions about the incorporation of genetic information into nutrition practice. Although there are still relatively few well-designed RCTs to inform integration of genetic information into the Nutrition Care Process, the field of nutritional genomics is evolving rapidly, and gaps in the literature identified by this systematic review can inform future studies., (Copyright © 2021 Academy of Nutrition and Dietetics. Published by Elsevier Inc. All rights reserved.)

Consumer interest in personalized nutrition based on nutrigenetic testing is growing. Recently, multiple, randomized controlled trials have sought to understand whether incorporating genetic information into dietary counseling alters dietary outcomes. The objective of this systematic review was to examine how incorporating genetic information into nutrition counseling and care, compared to an alternative intervention or control group, impacts dietary outcomes. This is the first of a 2-part systematic review series. Part II reports anthropometric, biochemical, and disease-specific outcomes. Peer-reviewed randomized controlled trials were identified through a systematic literature search of multiple databases, screened for eligibility, and critically reviewed and synthesized. Conclusion statements were graded to determine quality of evidence for each dietary outcome reported. Reported outcomes include intake of total energy and macronutrients, micronutrients, foods, food groups, food components (added sugar, caffeine, and alcohol), and composite diet scores. Ten articles representing 8 unique randomized controlled trials met inclusion criteria. Of 15 conclusion statements (evidence grades: Weak to Moderate), 13 concluded there was no significant effect of incorporating genetic information into nutrition counseling/care on dietary outcomes. Limited data suggested that carriers of higher-risk gene variants were more likely than carriers of low-risk gene variants to significantly reduce intake of sodium and alcohol in response to nutrition counseling that incorporated genetic results. Included studies differed in quality, selected genetic variants, timing and intensity of intervention, sample size, dietary assessment tools, and population characteristics. Therefore, strong conclusions could not be drawn. Collaboration between the Academy of Nutrition and Dietetics and professional nutrigenetic societies would likely prove valuable in prioritizing which genetic variants and targeted nutrition messages have the most potential to alter dietary outcomes in a given patient subpopulation and, thus, should be the targets of future research., (Copyright © 2021 Academy of Nutrition and Dietetics. Published by Elsevier Inc. All rights reserved.)

An efficient procedure for the preparation of β-substituted furans/pyrroles is presented. The methodology is based on the use of 7-oxa/azanorbornadienes as dipolarophiles in 1,3-dipolar cycloaddition with benzyl azide. The triazoline cycloadduct thus formed spontaneously decomposes via a retro-Diels-Alder (rDA) reaction to afford a β-substituted furan/pyrrole derivative and a stable triazole. The scope of this tandem 1,3-dipolar cycloaddition/rDA reaction was studied with thirteen 7-heteronorbornadienes. This study allowed a deep knowledge of the regioselectivity of the reaction, which can be tuned through the substituents of the heteronorbornadienic systems.

The synthesis of a chemical library of multimeric pyrrolidine-based iminosugars by incorporation of three pairs of epimeric pyrrolidine-azides into different alkyne scaffolds via CuAAC is presented. The new multimers were evaluated as inhibitors of two important therapeutic enzymes, human α-galactosidase A (α-Gal A) and lysosomal β-glucocerebrosidase (GCase). Structure-activity relationships were established focusing on the iminosugar inhitope, the valency of the dendron and the linker between the inhitope and the central scaffold. Remarkable is the result obtained in the inhibition of α-Gal A, where one of the nonavalent compounds showed potent inhibition (0.20 μM, competitive inhibition), being a 375-fold more potent inhibitor than the monovalent reference. The potential of the best α-Gal A inhibitors to act as pharmacological chaperones was analyzed by evaluating their ability to increase the activity of this enzyme in R301G fibroblasts from patients with Fabry disease, a genetic disorder related with a reduced activity of α-Gal A. The best enzyme activity enhancement was obtained for the same nonavalent compound, which increased 5.2-fold the activity of the misfolded enzyme at 2.5 μM, what constitutes the first example of a multivalent α-Gal A activity enhancer of potential interest in the treatment of Fabry disease., 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 © 2020 Elsevier Masson SAS. All rights reserved.)

An azanorbornadiene bromovinyl sulfone reagent for cysteine-selective bioconjugation has been developed. Subsequent reaction with dipyridyl tetrazine leads to bond cleavage and formation of a pyrrole-linked conjugate. The latter involves ligation of the tetrazine to the azanorbornadiene-tagged protein through inverse electron demand Diels-Alder cycloaddition with subsequent double retro-Diels-Alder reactions to form a stable pyrrole linkage. The sequence of site-selective bioconjugation followed by bioorthogonal bond cleavage was efficiently employed for the labelling of three different proteins. This method benefits from easy preparation of these reagents, selectivity for cysteine, and stability after reaction with a commercial tetrazine, which has potential for the routine preparation of protein conjugates for chemical biology studies., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Substance use is a leading preventable cause of death in the U.S. The National Institutes of Health (NIH) provides public funding to advance understanding on the causes of substance use disorders and apply that knowledge to improve public health through research that develops new and improved strategies to prevent substance use. The purpose of this study was to characterize substance use prevention research funded by the NIH., Methods: Leveraging a dataset of NIH-funded prevention research, we identified grants studying substance use during 2012-2017. We coded the substances and types of prevention research studied in these grants. We generated descriptive statistics and estimated trends using weighted data representing the entire NIH substance use prevention research portfolio., Results: Approximately 2.4% of all NIH research awards focused on substance use prevention during 2012-2017, with most focused on Epidemiologic Research. Alcohol and Nicotine were the top two substance categories studied. Marijuana prevention research showed a significant upward trend in funding over time (p = 0.002). Among studies of College Students and Military/Veterans, over three-quarters focused on Alcohol. Studies of Pregnant/Port-partum Women mostly focused on Nicotine., Conclusions: While substance use is a leading cause for morbidity and mortality, substance use prevention grants comprised a small portion of NIH's research portfolio during 2012-2017. These grants demonstrated breadth in the substances studied and the types of prevention research. Opportunities for further study are discussed., (Published by Elsevier B.V.)

Introduction: Poor diet and inadequate physical activity are common contributors to preventable death in the U.S. This paper provides a summary of the NIH-sponsored research on disease prevention that underlies public health and clinical recommendations to improve diet and physical activity., Methods: A representative sample (n=11,082) of research grants and cooperative agreements (research projects) representing the NIH prevention research portfolio between 2012 and 2017 were hand coded by trained analysts in 2017-2018. This manuscript describes the rationale(s), exposure(s), outcome(s), population(s), and study design(s) in prevention research focused on diet and physical activity and compares this research to identified research gaps in the field., Results: A relatively stable 7.8% (95% CI=7.0%, 8.8%) and 5.0% (95% CI=4.4%, 5.7%) of the NIH prevention research projects were focused on diet and physical activity, respectively, during 2012-2017. These projects often explored diet and physical activity together in the context of obesity, included observational studies, and focused on a general adult population. Few of these projects focused on development of improved assessment methods. Approximately 50% of these studies were related to research gaps identified by the 2015 Dietary or 2018 Physical Activity Guidelines Advisory Committee Scientific Reports., Conclusions: Opportunities exist for more engagement by NIH and scientific investigators in diet- and physical activity-focused prevention research, particularly around assessment and known research gaps., (Published by Elsevier Inc.)

Primary rib cage tuberculosis (TB) is an infrequent form of presentation and represents 1% of all cases of osteoarticular TB. We report three cases of children who were previously healthy and who began with swelling of the anterior surface of the rib as initial manifestation of TB. The most important clinical presentations in this series were swelling and pain, with lytic lesions and a soft tissue mass in image studies simulating oncologic pathologies. Because none of the cases had positive epidemiological contact, TB was initially not considered, so the delay in diagnosis from the onset of symptoms was 4, 1, and 2 months, respectively. The diagnosis was made through histomorphological analyses. Treatment was administered during 12, 10, and 9 months. Posttreatment studies did not show any evidence of extrapulmonary TB and until date, the patients remained without relapse or active disease. The findings in our cases illustrate that the diagnosis of chest wall TB should be suspected in all patients from endemic areas who present rib injury.

Importance: No studies to date have examined support by the National Institutes of Health (NIH) for primary and secondary prevention research in humans and related methods research that measures the leading risk factors or causes of death or disability as outcomes or exposures., Objective: To characterize NIH support for such research., Design and Setting: This serial cross-sectional study randomly sampled NIH grants and cooperative agreements funded during fiscal years 2012 through 2017. For awards with multiple subprojects, each was treated as a separate project. Study characteristics, outcomes, and exposures were coded from October 2015 through February 2019. Analyses weighted to reflect the sampling scheme were completed in March through June 2019. Using 2017 data from the Centers for Disease Control and Prevention and 2016 data from the Global Burden of Disease project, the leading risk factors and causes of death and disability in the United States were identified., Main Outcomes and Measures: The main outcome was the percentage of the NIH prevention research portfolio measuring a leading risk factor or cause of death or disability as an outcome or exposure., Results: A total of 11 082 research projects were coded. Only 25.9% (95% CI, 24.0%-27.8%) of prevention research projects measured a leading cause of death as an outcome or exposure, although these leading causes were associated with 74.0% of US mortality. Only 34.0% (95% CI, 32.2%-35.9%) measured a leading risk factor for death, although these risk factors were associated with 57.3% of mortality. Only 31.4% (95% CI, 29.6%-33.3%) measured a leading risk factor for disability-adjusted life-years lost, although these risk factors were associated with 42.1% of disability-adjusted life-years lost. Relatively few projects included a randomized clinical trial (24.6%; 95% CI, 22.5%-26.9%) or involved more than 1 leading cause (3.3%; 95% CI, 2.6%-4.1%) or risk factor (8.8%; 95% CI, 7.9%-9.8%)., Conclusions and Relevance: In this cross-sectional study, the leading risk factors and causes of death and disability were underrepresented in the NIH prevention research portfolio relative to their burden. Because so much is already known about these risk factors and causes, and because randomized interventions play such a vital role in the development of clinical and public health guidelines, it appears that greater attention should be given to develop and test interventions that address these risk factors and causes, addressing multiple risk factors or causes when possible.

Objective: Emergency Department Observation Units (Obs Units) provide a setting and a mechanism for further care of Emergency Department (ED) patients. Our hospital has a protocol-driven, type 1, complex 20 bed Obs Unit with 36 different protocols. We wanted to understand how the different protocols performed and what types of care were provided., Methods: This was an IRB-approved, retrospective chart review study. A random 10% of ED patient charts with a "transfer to observation" order were selected monthly from October 2015 through June 2017. This database was designed to identify high and low functioning protocols based on length of stays (LOS) and admission rates., Results: Over 20 months, a total of 984 patients qualified for the study. The average age was 49.5 ± 17.2 years, 57.3% were women, and 32.3% were non-Caucasian. The admission rate was 23.5% with an average LOS in observation of 13.7 h [95% CI 13.3-14.1]. Thirty day return rate was 16.8% with 5.3% of the patients returning to the ED within the first 72 h. Thirty six different protocols were used, with the most common being chest pain (13.9%) and general (13.2%). Almost 70% received a consultation from another service, and 7.2% required a procedure while in observation. Procedures included fluoroscopic-guided lumbar punctures, endoscopies, dental extractions, and catheter replacements (nephrostomy, gastrostomy, and biliary tubes)., Conclusions: An Obs Unit can care for a wide variety of patients who require multiple consultations, procedures, and care coordination while maintaining an acceptable length of stay and admission rate., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The synthesis of multivalent pyrrolidine iminosugars via CuAAC click reaction between different pyrrolidine-azide derivatives and tri- or hexavalent alkynyl scaffolds is reported. The new multimeric compounds, together with the monomeric reference, were evaluated as inhibitors against two homologous GH1 β-glucosidases (BglA and BglB from Paenibacillus polymyxa). The multivalent inhibitors containing an aromatic moiety in the linker between the pyrrolidine and the scaffold inhibited the octameric BglA (µM range) but did not show affinity against the monomeric BglB, despite the similarity between the active site of both enzymes. A modest multivalent effect (rp/n = 12) was detected for the hexavalent inhibitor 12. Structural analysis of the complexes between the monomeric and the trimeric iminosugar inhibitors (4 and 10) and BglA showed the insertion of the inhibitors at the active site of BglA, confirming a competitive mode of inhibition as indicated by enzyme kinetics. Additionally, structural comparison of the BglA/4 complex with the reported BglB/2F-glucose complex illustrates the key determinants responsible for the inhibitory effect and explains the reasons of the inhibition of BglA and the no inhibition of BglB. Potential inhibition of other β-glucosidases with therapeutic relevance is discussed under the light of these observations., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The diffusion of type 2 diabetes (T2D) throughout the world represents one of the most important health problems of this century. Patients suffering from this disease can currently be treated with numerous oral anti-hyperglycaemic drugs, but none is capable of reproducing the physiological action of insulin and, in several cases, they induce severe side effects. Developing new anti-diabetic drugs remains one of the most urgent challenges of the pharmaceutical industry. Multi-target drugs could offer new therapeutic opportunities for the treatment of T2D, and the reported data on type 2 diabetic mice models indicate that these drugs could be more effective and have fewer side effects than mono-target drugs. α-Glucosidases and Protein Tyrosine Phosphatase 1B (PTP1B) are considered important targets for the treatment of T2D: the first digest oligo- and disaccharides in the gut, while the latter regulates the insulin-signaling pathway. With the aim of generating new drugs able to target both enzymes, we synthesized a series of bifunctional compounds bearing both a nitro aromatic group and an iminosugar moiety. The results of tests carried out both in vitro and in a cell-based model, show that these bifunctional compounds maintain activity on both target enzymes and, more importantly, show a good insulin-mimetic activity, increasing phosphorylation levels of Akt in the absence of insulin stimulation. These compounds could be used to develop a new generation of anti-hyperglycemic drugs useful for the treatment of patients affected by T2D., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The synthesis of a library of pyrrolidine-aryltriazole hybrids through CuAAC between two epimeric dihydroxylated azidomethylpyrrolidines and differently substituted phenylacetylenes is reported. The evaluation of the new compounds as inhibitors of lysosomal β-glucocerebrosidase showed the importance of the substitution pattern of the phenyl moiety in the inhibition. Crystallization and docking studies revealed key interactions of the pyrrolidine motif with aminoacid residues of the catalytic site while the aryltriazole moiety extended along a hydrophobic surface groove. Some of these compounds were able to increase the enzyme activity in Gaucher patient fibroblasts, acting as a new type of chemical chaperone for Gaucher disease., (Copyright © 2019 Elsevier Inc. All rights reserved.)

We have developed [2.2.1]azabicyclic vinyl sulfone reagents that simultaneously enable cysteine-selective protein modification and introduce a handle for further bioorthogonal ligation. The reaction is fast and selective for cysteine relative to other amino acids that have nucleophilic side-chains, and the formed products are stable in human plasma and are moderately resistant to retro Diels-Alder degradation reactions. A model biotinylated [2.2.1]azabicyclic vinyl sulfone reagent was shown to efficiently label two cysteine-tagged proteins, ubiquitin and C2Am, under mild conditions (1-5 equiv. of reagent in NaP i pH 7.0, room temperature, 30 min). The resulting thioether-linked conjugates were stable and retained the native activity of the proteins. Finally, the dienophile present in the azabicyclic moiety on a functionalised C2Am protein could be fluorescently labelled through an inverse electron demand Diels-Alder reaction in cells to allow selective apoptosis imaging. The combined advantages of directness, site-specificity and easy preparation mean [2.2.1]azabicyclic vinyl sulfones can be used for residue-specific dual protein labelling/construction strategies with minimal perturbation of native function based simply on the attachment of an [2.2.1]azabicyclic moiety to cysteine.

Introduction: To fulfill its mission, the NIH Office of Disease Prevention systematically monitors NIH investments in applied prevention research. Specifically, the Office focuses on research in humans involving primary and secondary prevention, and prevention-related methods. Currently, the NIH uses the Research, Condition, and Disease Categorization system to report agency funding in prevention research. However, this system defines prevention research broadly to include primary and secondary prevention, studies on prevention methods, and basic and preclinical studies for prevention. A new methodology was needed to quantify NIH funding in applied prevention research., Methods: A novel machine learning approach was developed and evaluated for its ability to characterize NIH-funded applied prevention research during fiscal years 2012-2015. The sensitivity, specificity, positive predictive value, accuracy, and F1 score of the machine learning method; the Research, Condition, and Disease Categorization system; and a combined approach were estimated. Analyses were completed during June-August 2017., Results: Because the machine learning method was trained to recognize applied prevention research, it more accurately identified applied prevention grants (F1 = 72.7%) than the Research, Condition, and Disease Categorization system (F1 = 54.4%) and a combined approach (F1 = 63.5%) with p<0.001., Conclusions: This analysis demonstrated the use of machine learning as an efficient method to classify NIH-funded research grants in disease prevention., (Published by Elsevier Inc.)

Introduction: This paper provides the first detailed analysis of the NIH prevention research portfolio for primary and secondary prevention research in humans and related methods research., Methods: The Office of Disease Prevention developed a taxonomy of 128 topics and applied it to 11,082 projects representing 91.7% of all new projects and 84.1% of all dollars used for new projects awarded using grant and cooperative agreement activity codes that supported research in fiscal years 2012-2017. Projects were coded in 2016-2018 and analyzed in 2018., Results: Only 16.7% of projects and 22.6% of dollars were used for primary and secondary prevention research in humans or related methods research. Most of the leading risk factors for death and disability in the U.S. were selected as an outcome in <5% of the projects. Many more projects included an observational study, or an analysis of existing data, than a randomized intervention. These patterns were consistent over time., Conclusions: The appropriate level of support for primary and secondary prevention research in humans from NIH will differ by field and stage of research. The estimates reported here may be overestimates, as credit was given for a project even if only a portion of that project addressed prevention research. Given that 74% of the variability in county-level life expectancy across the U.S. is explained by established risk factors, it seems appropriate to devote additional resources to developing and testing interventions to address those risk factors., (Published by Elsevier Inc.)

Background: Lung cancer is the leading cancer diagnosis worldwide and the number one cause of cancer deaths. Exposure to cigarette smoke, the primary risk factor in lung cancer, reduces epithelial barrier integrity and increases susceptibility to infections. Herein, we hypothesize that somatic mutations together with cigarette smoke generate a dysbiotic microbiota that is associated with lung carcinogenesis. Using lung tissue from 33 controls and 143 cancer cases, we conduct 16S ribosomal RNA (rRNA) bacterial gene sequencing, with RNA-sequencing data from lung cancer cases in The Cancer Genome Atlas serving as the validation cohort., Results: Overall, we demonstrate a lower alpha diversity in normal lung as compared to non-tumor adjacent or tumor tissue. In squamous cell carcinoma specifically, a separate group of taxa are identified, in which Acidovorax is enriched in smokers. Acidovorax temporans is identified within tumor sections by fluorescent in situ hybridization and confirmed by two separate 16S rRNA strategies. Further, these taxa, including Acidovorax, exhibit higher abundance among the subset of squamous cell carcinoma cases with TP53 mutations, an association not seen in adenocarcinomas., Conclusions: The results of this comprehensive study show both microbiome-gene and microbiome-exposure interactions in squamous cell carcinoma lung cancer tissue. Specifically, tumors harboring TP53 mutations, which can impair epithelial function, have a unique bacterial consortium that is higher in relative abundance in smoking-associated tumors of this type. Given the significant need for clinical diagnostic tools in lung cancer, this study may provide novel biomarkers for early detection.

The parallel synthesis of a 26-membered-library of aromatic/aliphatic-(thio)urea-linked pyrrolizidines followed by in situ biological evaluation toward α-galactosidases has been carried out. The combination of the (thio)urea-forming click reaction and the in situ screening is pioneer in the search for glycosidase inhibitors and has allowed the discovery of a potent coffee bean α-galactosidase inhibitor (IC 50 = 0.37 μM, K i = 0.12 μM) that has also showed inhibition against human lysosomal α-galactosidase (α-Gal A, IC 50 = 5.3 μM, K i = 4.2 μM).

The synthesis of three libraries (1a-l, 1a'-l' and 2a-l) of dimeric iminosugars through CuAAC reaction between three different alkynyl pyrrolidines and a set of diazides was carried out. The resulting crude dimers were screened in situ against two α-fucosidases (libraries 1a-l and 1a'-l') and one β-galactosidase (2a-l). This method is pioneer in the search of divalent glycosidase inhibitors. It has allowed the rapid identification of dimer 1i as the best inhibitor of α-fucosidases from bovine kidney (K i  = 0.15 nM) and Homo sapiens (K i  = 60 nM), and dimer 2e as the best inhibitor of β-galactosidase from bovine liver (K i  = 5.8 μM). In order to evaluate a possible divalent effect in the inhibition, the synthesis and biological analysis of the reference monomers were also performed. Divalent effect was only detected in the inhibition of bovine liver β-galactosidase by dimer 2e., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)