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1.
Am J Bot ; 111(7): e16361, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38924532

ABSTRACT

PREMISE: The huge diversity of Salix subgenus Chamaetia/Vetrix clade in North America and the lack of phylogenetic resolution within this clade has presented a difficult but fascinating challenge for taxonomists to resolve. Here we tested the existing taxonomic classification with molecular tools. METHODS: In this study, 132 samples representing 46 species from 22 described sections of shrub willows from the United States and Canada were analyzed and combined with 67 samples from Eurasia. The ploidy levels of the samples were determined using flow cytometry and nQuire. Sequences were produced using a RAD sequencing approach and subsequently analyzed with ipyrad, then used for phylogenetic reconstructions (RAxML, SplitsTree), dating analyses (BEAST, SNAPPER), and character evolution analyses of 14 selected morphological traits (Mesquite). RESULTS: The RAD sequencing approach allowed the production of a well-resolved phylogeny of shrub willows. The resulting tree showed an exclusively North American (NA) clade in sister position to a Eurasian clade, which included some North American endemics. The NA clade began to diversify in the Miocene. Polyploid species appeared in each observed clade. Character evolution analyses revealed that adaptive traits such as habit and adaxial nectaries evolved multiple times independently. CONCLUSIONS: The diversity in shrub willows was shaped by an evolutionary radiation in North America. Most species were monophyletic, but the existing sectional classification could not be supported by molecular data. Nevertheless, monophyletic lineages share several morphological characters, which might be useful in the revision of the taxonomic classification of shrub willows.


Subject(s)
Phylogeny , Salix , Salix/anatomy & histology , Salix/classification , Salix/genetics , Biological Evolution , North America , Canada , United States
2.
J Med Internet Res ; 26: e55676, 2024 May 28.
Article in English | MEDLINE | ID: mdl-38805692

ABSTRACT

BACKGROUND: Clinical natural language processing (NLP) researchers need access to directly comparable evaluation results for applications such as text deidentification across a range of corpus types and the means to easily test new systems or corpora within the same framework. Current systems, reported metrics, and the personally identifiable information (PII) categories evaluated are not easily comparable. OBJECTIVE: This study presents an open-source and extensible end-to-end framework for comparing clinical NLP system performance across corpora even when the annotation categories do not align. METHODS: As a use case for this framework, we use 6 off-the-shelf text deidentification systems (ie, CliniDeID, deid from PhysioNet, MITRE Identity Scrubber Toolkit [MIST], NeuroNER, National Library of Medicine [NLM] Scrubber, and Philter) across 3 standard clinical text corpora for the task (2 of which are publicly available) and 1 private corpus (all in English), with annotation categories that are not directly analogous. The framework is built on shell scripts that can be extended to include new systems, corpora, and performance metrics. We present this open tool, multiple means for aligning PII categories during evaluation, and our initial timing and performance metric findings. Code for running this framework with all settings needed to run all pairs are available via Codeberg and GitHub. RESULTS: From this case study, we found large differences in processing speed between systems. The fastest system (ie, MIST) processed an average of 24.57 (SD 26.23) notes per second, while the slowest (ie, CliniDeID) processed an average of 1.00 notes per second. No system uniformly outperformed the others at identifying PII across corpora and categories. Instead, a rich tapestry of performance trade-offs emerged for PII categories. CliniDeID and Philter prioritize recall over precision (with an average recall 6.9 and 11.2 points higher, respectively, for partially matching spans of text matching any PII category), while the other 4 systems consistently have higher precision (with MIST's precision scoring 20.2 points higher, NLM Scrubber scoring 4.4 points higher, NeuroNER scoring 7.2 points higher, and deid scoring 17.1 points higher). The macroaverage recall across corpora for identifying names, one of the more sensitive PII categories, included deid (48.8%) and MIST (66.9%) at the low end and NeuroNER (84.1%), NLM Scrubber (88.1%), and CliniDeID (95.9%) at the high end. A variety of metrics across categories and corpora are reported with a wider variety (eg, F2-score) available via the tool. CONCLUSIONS: NLP systems in general and deidentification systems and corpora in our use case tend to be evaluated in stand-alone research articles that only include a limited set of comparators. We hold that a single evaluation pipeline across multiple systems and corpora allows for more nuanced comparisons. Our open pipeline should reduce barriers to evaluation and system advancement.


Subject(s)
Natural Language Processing
3.
Psychiatr Psychol Law ; 31(2): 189-215, 2024.
Article in English | MEDLINE | ID: mdl-38628247

ABSTRACT

Risk assessment instruments are used to estimate risk of recidivism and aid in decision-making and treatment planning. However, many of these instruments, including the Level of Service/Risk, Need, Responsivity (LS/RNR), are validated on predominantly Western populations, and research has questioned whether the factors included in the LS/RNR adequately capture the experiences and needs of non-Western communities, including Aboriginal and Torres Strait Islanders. The current study aimed to canvas the opinions of Aboriginal and Torres Strait Islander community justice workers as to the suitability of the LS/RNR for use with this population. A general qualitative methodology was adopted to gain in-depth information through the facilitation of a focus group, and data were analysed thematically. Whilst participants agreed that the LS/RNR risk factors are relevant to Aboriginal and Torres Strait Islander offenders, they reported that the instrument did not adequately capture relevant culturally specific considerations and made suggestions to improve the LS/RNR.

4.
Lancet HIV ; 11(4): e245-e254, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38467135

ABSTRACT

BACKGROUND: In 2014, UNAIDS set a goal to end the AIDS epidemic by achieving targets for the percentage of people living with HIV who were aware of their status, on antiretroviral therapy (ART), and virally suppressed. In 2020, these targets were revised to 95% for each measure (known as 95-95-95), to be reached among people living with HIV by 2025. We used data from the Fifth Botswana AIDS Impact Survey (BAIS V) to measure progress towards these testing and treatment targets in Botswana. METHODS: BAIS V used a two-stage cluster design to obtain a nationally representative sample of people aged 15-64 years in Botswana. During March-August, 2021, 14 763 consenting participants were interviewed and tested for HIV in their households by survey teams. HIV-positive specimens were tested for viral load, presence of antiretroviral drugs, and recency of infection using the HIV-1 limiting antigen avidity enzyme immunoassay. Estimates of HIV-positive status and use of ART were based on self-report and the analysis of blood specimens for antiretroviral drugs. Viral load suppression was defined as an HIV RNA concentration of less than 1000 copies per mL. HIV incidence was calculated using the recent infection testing algorithm. Data were weighted to account for the complex survey design. FINDINGS: The national HIV prevalence in Botswana among people aged 15-64 years was 20·8% and the annual incidence of HIV infection was 0·2%. 95·1% (men 93·0%, women 96·4%) of people living with HIV aged 15-64 years were aware of their status, 98·0% (men 97·2%, women 98·4%) of those aware were on ART, and 97·9% (men 96·6%, women 98·6%) of those on ART had viral load suppression. Among young people (aged 15-24 years) living with HIV, 84·5% were aware of their status, 98·5% of those aware were on ART, and 91·6% of those on ART had viral load suppression. The prevalance of viral load suppression among all people living with HIV was 91·8%, and varied by district-ranging from 85·3% in Gaborone to 100·0% in Selibe Phikwe. INTERPRETATION: BAIS V is the first population-based survey worldwide to report the achievement of the UNAIDS 95-95-95 goals, both overall and among women. Strategies to reach undiagnosed men and young people, including young women, are needed. FUNDING: US President's Emergency Plan for AIDS Relief.


Subject(s)
Acquired Immunodeficiency Syndrome , HIV Infections , Male , Humans , Female , Adolescent , Acquired Immunodeficiency Syndrome/drug therapy , Acquired Immunodeficiency Syndrome/epidemiology , HIV Infections/drug therapy , HIV Infections/epidemiology , Botswana/epidemiology , Anti-Retroviral Agents/therapeutic use , Surveys and Questionnaires , Viral Load , Prevalence
5.
Clin Nutr ; 43(3): 674-691, 2024 03.
Article in English | MEDLINE | ID: mdl-38309229

ABSTRACT

BACKGROUND: Disease-related malnutrition in polymorbid medical inpatients is a highly prevalent syndrome associated with significantly increased morbidity, disability, short- and long-term mortality, impaired recovery from illness, and healthcare costs. AIM: As there are uncertainties in applying disease-specific guidelines to patients with multiple conditions, our aim was to provide evidence-based recommendations on nutritional support for the polymorbid patient population hospitalized in medical wards. METHODS: The 2023 update adheres to the standard operating procedures for ESPEN guidelines. We undertook a systematic literature search for 15 clinical questions in three different databases (Medline, Embase and the Cochrane Library), as well as in secondary sources (e.g., published guidelines), until July 12th, 2022. Retrieved abstracts were screened to identify relevant studies that were used to develop recommendations (including SIGN grading), which was followed by submission to Delphi voting. Here, the practical version of the guideline is presented which has been shortened and equipped with flow charts for patients care. RESULTS: 32 recommendations (7× A, 11× B, 10× O and 4× GPP), which encompass different aspects of nutritional support were included from the scientific guideline including indication, route of feeding, energy and protein requirements, micronutrient requirements, disease-specific nutrients, timing, monitoring and procedure of intervention. Here, the practical version of the guideline is presented which has been shortened and equipped with flow charts for patients care. CONCLUSIONS: Recent high-quality trials have provided increasing evidence that nutritional support can reduce morbidity and other complications associated with malnutrition in polymorbid patients. The timely screening of patients for risk of malnutrition at hospital admission followed by individualized nutritional support interventions for at-risk patients should be part of routine clinical care and multimodal treatment in hospitals worldwide. Use of this updated practical guideline offers an evidence-based nutritional approach to polymorbid medical inpatients and may improve their outcomes.


Subject(s)
Inpatients , Malnutrition , Humans , Hospitalization , Hospitals , Malnutrition/diagnosis , Nutritional Support/methods
7.
Science ; 382(6674): 1073-1079, 2023 12.
Article in English | MEDLINE | ID: mdl-38033053

ABSTRACT

Skin-resident CD8+ T cells include distinct interferon-γ-producing [tissue-resident memory T type 1 (TRM1)] and interleukin-17 (IL-17)-producing (TRM17) subsets that differentially contribute to immune responses. However, whether these populations use common mechanisms to establish tissue residence is unknown. In this work, we show that TRM1 and TRM17 cells navigate divergent trajectories to acquire tissue residency in the skin. TRM1 cells depend on a T-bet-Hobit-IL-15 axis, whereas TRM17 cells develop independently of these factors. Instead, c-Maf commands a tissue-resident program in TRM17 cells parallel to that induced by Hobit in TRM1 cells, with an ICOS-c-Maf-IL-7 axis pivotal to TRM17 cell commitment. Accordingly, by targeting this pathway, skin TRM17 cells can be ablated without compromising their TRM1 counterparts. Thus, skin-resident T cells rely on distinct molecular circuitries, which can be exploited to strategically modulate local immunity.


Subject(s)
CD8-Positive T-Lymphocytes , Immunologic Memory , Memory T Cells , Skin , CD8-Positive T-Lymphocytes/immunology , Memory T Cells/immunology , Skin/immunology , Humans , Th17 Cells/immunology , Inducible T-Cell Co-Stimulator Ligand/metabolism , Proto-Oncogene Proteins c-maf/metabolism , Interleukin-7/metabolism
8.
Emerg Infect Dis ; 29(11): 2325-2334, 2023 11.
Article in English | MEDLINE | ID: mdl-37877591

ABSTRACT

Identifying persons who have newly acquired HIV infections is critical for characterizing the HIV epidemic direction. We analyzed pooled data from nationally representative Population-Based HIV Impact Assessment surveys conducted across 14 countries in Africa for recent infection risk factors. We included adults 15-49 years of age who had sex during the previous year and used a recent infection testing algorithm to distinguish recent from long-term infections. We collected risk factor information via participant interviews and assessed correlates of recent infection using multinomial logistic regression, incorporating each survey's complex sampling design. Compared with HIV-negative persons, persons with higher odds of recent HIV infection were women, were divorced/separated/widowed, had multiple recent sex partners, had a recent HIV-positive sex partner or one with unknown status, and lived in communities with higher HIV viremia prevalence. Prevention programs focusing on persons at higher risk for HIV and their sexual partners will contribute to reducing HIV incidence.


Subject(s)
HIV Infections , Humans , Adult , Female , Male , HIV Infections/diagnosis , HIV Infections/epidemiology , Africa/epidemiology , Risk Factors , Sexual Partners , Data Collection
9.
J Immunol ; 211(10): 1506-1515, 2023 11 15.
Article in English | MEDLINE | ID: mdl-37756528

ABSTRACT

Affinity maturation, the progressive increase in serum Ab affinity after vaccination, is an essential process that contributes to an effective humoral response against vaccines and infections. Germinal centers are key for affinity maturation, because they are where B cells undergo somatic hypermutation of their Ig genes in the dark zone before going through positive selection in the light zone via interactions with T follicular helper cells and follicular dendritic cells. In aged mice, affinity maturation has been shown to be impaired after immunization, but whether B cell-intrinsic factors contribute to this defect remains unclear. In this study, we show that B cells from aged BCR transgenic mice are able to become germinal center B cells, which are capable of receiving positive selection signals to a similar extent as B cells from young adult mice. Consistent with this, aging also does not impact the ability of B cells to undergo somatic hypermutation and acquire affinity-enhancing mutations. By contrast, transfer of B cells from young adult BCR mice into aged recipients resulted in the impaired acquisition of affinity-enhancing mutations, demonstrating that the aged microenvironment causes altered affinity maturation.


Subject(s)
B-Lymphocytes , Germinal Center , Mice , Animals , Immunization , Vaccination , Mice, Transgenic
10.
Nutr. hosp ; 40(4): 858-885, Juli-Agos. 2023. ilus
Article in Spanish | IBECS | ID: ibc-224211

ABSTRACT

Esta guía práctica de la European Society for Clinical Nutrition and Metabolism (ESPEN) proporciona información a médicos, enfermeras, dietistas, farmacéuticos, cuidadores y otros proveedores de nutrición enteral domiciliaria (NED) de forma concisa, sobre las indicaciones y contraindicaciones de la NED, así como sobre su administración y seguimiento. Esta guía también ofrece información a los pacientes interesados que necesiten NED. La nutrición parenteral domiciliaria no está incluida, pero se abordará en otra guía de la ESPEN. La guía se basa en la guía científica de la ESPEN publicada anteriormente, que consta de 61 recomendaciones (que se han reproducido y renumerado), junto con los comentarios asociados (que se han resumido en relación a la guía científica). Se indican los grados de evidencia y los niveles de consenso. La ESPEN encargó y financió la guía y seleccionó también a los miembros del grupo.(AU)


This ESPEN practical guideline will inform physicians, nurses, dieticians, pharmacists, caregivers and other home enteral nutrition (HEN) providersin a concise way about the indications and contraindications for HEN, as well as its implementation and monitoring. This guideline will also informinterested patients requiring HEN. Home parenteral nutrition is not included but will be addressed in a separate ESPEN guideline. The guideline isbased on the ESPEN scientific guideline published before, which consists of 61 recommendations that have been reproduced and renumbered,along with the associated commentaries that have been shorted compared to the scientific guideline. Evidence grades and consensus levels areindicated. The guideline was commissioned and financially supported by ESPEN and the members of the guideline group were selected by ESPEN.(AU)


Subject(s)
Humans , Enteral Nutrition/standards , Parenteral Nutrition, Home , Malnutrition , 52503 , 35170 , Enteral Nutrition/methods
11.
Cell Rep ; 42(8): 112991, 2023 08 29.
Article in English | MEDLINE | ID: mdl-37590132

ABSTRACT

Suboptimal responses to a primary vaccination course have been reported in the elderly, but there is little information regarding the impact of age on responses to booster third doses. Here, we show that individuals 70 years or older (median age 73, range 70-75) who received a primary two-dose schedule with AZD1222 and booster third dose with mRNA vaccine achieve significantly lower neutralizing antibody responses against SARS-CoV-2 spike pseudotyped virus compared with those younger than 70 (median age 66, range 54-69) at 1 month post booster. Impaired neutralization potency and breadth post third dose in the elderly is associated with circulating "atypical" spike-specific B cells expressing CD11c and FCRL5. However, when considering individuals who received three doses of mRNA vaccine, we did not observe differences in neutralization or enrichment in atypical B cells. This work highlights the finding that AdV and mRNA COVID-19 vaccine formats differentially instruct the memory B cell response.


Subject(s)
COVID-19 , Aged , Humans , COVID-19/prevention & control , COVID-19 Vaccines , ChAdOx1 nCoV-19 , SARS-CoV-2 , Vaccination
12.
Nat Commun ; 14(1): 4622, 2023 08 01.
Article in English | MEDLINE | ID: mdl-37528097

ABSTRACT

Caspase recruitment-domain containing protein 9 (CARD9) is a key signaling pathway in macrophages but its role in atherosclerosis is still poorly understood. Global deletion of Card9 in Apoe-/- mice as well as hematopoietic deletion in Ldlr-/- mice increases atherosclerosis. The acceleration of atherosclerosis is also observed in Apoe-/-Rag2-/-Card9-/- mice, ruling out a role for the adaptive immune system in the vascular phenotype of Card9 deficient mice. Card9 deficiency alters macrophage phenotype through CD36 overexpression with increased IL-1ß production, increased lipid uptake, higher cell death susceptibility and defective autophagy. Rapamycin or metformin, two autophagy inducers, abolish intracellular lipid overload, restore macrophage survival and autophagy flux in vitro and finally abolish the pro-atherogenic effects of Card9 deficiency in vivo. Transcriptomic analysis of human CARD9-deficient monocytes confirms the pathogenic signature identified in murine models. In summary, CARD9 is a key protective pathway in atherosclerosis, modulating macrophage CD36-dependent inflammatory responses, lipid uptake and autophagy.


Subject(s)
Atherosclerosis , Humans , Animals , Mice , Atherosclerosis/metabolism , Autophagy/genetics , Apolipoproteins E/genetics , Lipids , CARD Signaling Adaptor Proteins/metabolism , Mice, Knockout , Mice, Inbred C57BL
13.
Clin Nutr ; 42(9): 1545-1568, 2023 09.
Article in English | MEDLINE | ID: mdl-37478809

ABSTRACT

BACKGROUND: Disease-related malnutrition in polymorbid medical inpatients is a highly prevalent syndrome associated with significantly increased morbidity, disability, short- and long-term mortality, impaired recovery from illness, and cost of care. AIM: As there are uncertainties in applying disease-specific guidelines to patients with multiple conditions, our aim was to provide evidence-based recommendations on nutritional support for the polymorbid patient population hospitalized in medical wards. METHODS: This update adheres to the standard operating procedures for ESPEN guidelines. We did a systematic literature search for 15 clinical questions in three different databases (Medline, Embase and the Cochrane Library), as well as in secondary sources (e.g. published guidelines), until July 12th. Retrieved abstracts were screened to identify relevant studies that were used to develop recommendations (incl. SIGN grading), which was followed by submission to Delphi voting. RESULTS: From a total of 3527 retrieved abstracts, 60 new relevant studies were analyzed and used to generate a guideline draft that proposed 32 recommendations (7x A, 11x B, 10x O and 4x GPP), which encompass different aspects of nutritional support including indication, route of feeding, energy and protein requirements, micronutrient requirements, disease-specific nutrients, timing, monitoring and procedure of intervention. The results of the first online voting showed a strong consensus (agreement of >90%) on 100% of the recommendations. Therefore, no final consensus conference was needed. CONCLUSIONS: Recent high-quality trials have provided increasing evidence that nutritional support can reduce morbidity and other complications associated with malnutrition in polymorbid patients. The timely screening of patients for risk of malnutrition at hospital admission followed by individualized nutritional support interventions for at-risk patients should be part of routine clinical care and multimodal treatment in hospitals worldwide. Use of this updated guideline offers an evidence-based nutritional approach to the polymorbid medical inpatients and may improve their outcomes.


Subject(s)
Inpatients , Malnutrition , Humans , Hospitalization , Hospitals , Malnutrition/therapy , Malnutrition/diagnosis , Nutritional Support , Practice Guidelines as Topic
14.
Nutr Hosp ; 40(4): 858-885, 2023 Aug 28.
Article in Spanish | MEDLINE | ID: mdl-37409729

ABSTRACT

Introduction: This ESPEN practical guideline will inform physicians, nurses, dieticians, pharmacists, caregivers and other home enteral nutrition (HEN) providers in a concise way about the indications and contraindications for HEN, as well as its implementation and monitoring. This guideline will also inform interested patients requiring HEN. Home parenteral nutrition is not included but will be addressed in a separate ESPEN guideline. The guideline is based on the ESPEN scientific guideline published before, which consists of 61 recommendations that have been reproduced and renumbered, along with the associated commentaries that have been shorted compared to the scientific guideline. Evidence grades and consensus levels are indicated. The guideline was commissioned and financially supported by ESPEN and the members of the guideline group were selected by ESPEN.


Introducción: Esta guía práctica de la European Society for Clinical Nutrition and Metabolism (ESPEN) proporciona información a médicos, enfermeras, dietistas, farmacéuticos, cuidadores y otros proveedores de nutrición enteral domiciliaria (NED) de forma concisa, sobre las indicaciones y contraindicaciones de la NED, así como sobre su administración y seguimiento. Esta guía también ofrece información a los pacientes interesados que necesiten NED. La nutrición parenteral domiciliaria no está incluida, pero se abordará en otra guía de la ESPEN. La guía se basa en la guía científica de la ESPEN publicada anteriormente, que consta de 61 recomendaciones (que se han reproducido y renumerado), junto con los comentarios asociados (que se han resumido en relación a la guía científica). Se indican los grados de evidencia y los niveles de consenso. La ESPEN encargó y financió la guía y seleccionó también a los miembros del grupo.


Subject(s)
Enteral Nutrition , Parenteral Nutrition, Home , Humans , Societies, Scientific , Consensus
15.
J Anim Sci ; 1012023 Jan 03.
Article in English | MEDLINE | ID: mdl-37402612

ABSTRACT

Our objective was to evaluate the effects of feeding 3-nitrooxypropanol (3-NOP; Bovaer, DSM Nutritional Products) at two levels on methane emissions, nitrogen balance, and performance by feedlot cattle. In experiment 1, a total of 138 Nellore bulls (initial body weight, 360 ± 37.3 kg) were housed in pens (27 pens with either 4 or 5 bulls per pen) and fed a high-concentrate diet for 96 d, containing 1) no addition of 3-NOP (control), 2) inclusion of 3-NOP at 100 mg/kg dry matter (DM), and 3) inclusion of 3-NOP at 150 mg/kg DM. No adverse effects of 3-NOP were observed on DM intake (DMI), animal performance, and gain:feed (P > 0.05). In addition, there was no effect (P > 0.05) of 3-NOP on carcass characteristics (subcutaneous fat thickness and rib eye area). In experiment 2, 24 bulls (initial BW, 366 ± 39.6 kg) housed in 12 pens (2 bulls/pen) from experiment 1 were used for CH4 measurements and nitrogen balance. Irrespective of the level, 3-NOP consistently decreased (P < 0.001) animals' CH4 emissions (g/d; ~49.3%), CH4 yield (CH4/DMI; ~40.7%) and CH4 intensity (CH4/average daily gain; ~38.6%). Moreover, 3-NOP significantly reduced the gross energy intake lost as CH4 by 42.5% (P < 0.001). The N retention: N intake ratio was not affected by 3-NOP (P = 0.19). We conclude that feeding 3-NOP is an effective strategy to reduce methane emissions, with no impairment on feedlot cattle performance.


During fiber digestion in the rumen, enteric methane is produced. Methane is a potent greenhouse gas. Recently several studies have focused on developing synthetic compounds and their utilization as specific inhibitors of methanogenesis. 3-Nitrooxypropanol is a structural compound that can help to mitigate CH4 emissions. The objective of this study was to evaluate the effects of feeding 3-nitrooxypropanol (3-NOP; Bovaer, DSM Nutritional Products) at two levels on methane emissions, nitrogen balance, and performance by feedlot cattle. No effect of 3-NOP on animal performance and N balance was found. However, regarding CH4 production 3-NOP consistently decreased (P < 0.001) animals' CH4 emissions (g/d; ~49.3%), methane yield (CH4/dry matter intake; ~40.7%), and CH4 intensity (CH4/average daily gain; ~38.6%). This study provides information on the potential role of 3-NOP on reducing CH4 emissions from feedlot cattle without reducing animal performance.


Subject(s)
Dietary Supplements , Methane , Cattle , Animals , Male , Dietary Supplements/analysis , Tropical Climate , Animal Feed/analysis , Diet/veterinary , Nitrogen/pharmacology , Rumen
16.
Cancer Res ; 83(17): 2952-2969, 2023 09 01.
Article in English | MEDLINE | ID: mdl-37335139

ABSTRACT

Immune checkpoint inhibitors (ICI) represent the cornerstone for the treatment of patients with metastatic clear cell renal cell carcinoma (ccRCC). Despite a favorable response for a subset of patients, others experience primary progressive disease, highlighting the need to precisely understand the plasticity of cancer cells and their cross-talk with the microenvironment to better predict therapeutic response and personalize treatment. Single-cell RNA sequencing of ccRCC at different disease stages and normal adjacent tissue (NAT) from patients identified 46 cell populations, including 5 tumor subpopulations, characterized by distinct transcriptional signatures representing an epithelial-to-mesenchymal transition gradient and a novel inflamed state. Deconvolution of the tumor and microenvironment signatures in public data sets and data from the BIONIKK clinical trial (NCT02960906) revealed a strong correlation between mesenchymal-like ccRCC cells and myofibroblastic cancer-associated fibroblasts (myCAF), which are both enriched in metastases and correlate with poor patient survival. Spatial transcriptomics and multiplex immune staining uncovered the spatial proximity of mesenchymal-like ccRCC cells and myCAFs at the tumor-NAT interface. Moreover, enrichment in myCAFs was associated with primary resistance to ICI therapy in the BIONIKK clinical trial. These data highlight the epithelial-mesenchymal plasticity of ccRCC cancer cells and their relationship with myCAFs, a critical component of the microenvironment associated with poor outcome and ICI resistance. SIGNIFICANCE: Single-cell and spatial transcriptomics reveal the proximity of mesenchymal tumor cells to myofibroblastic cancer-associated fibroblasts and their association with disease outcome and immune checkpoint inhibitor response in clear cell renal cell carcinoma.


Subject(s)
Cancer-Associated Fibroblasts , Carcinoma, Renal Cell , Kidney Neoplasms , Humans , Cancer-Associated Fibroblasts/pathology , Carcinoma, Renal Cell/drug therapy , Carcinoma, Renal Cell/genetics , Gene Expression Profiling , Immunotherapy , Kidney Neoplasms/drug therapy , Kidney Neoplasms/genetics , Prognosis , Tumor Microenvironment , Clinical Trials as Topic
17.
Nat Med ; 29(5): 1146-1154, 2023 05.
Article in English | MEDLINE | ID: mdl-37169862

ABSTRACT

Obesity is associated with an increased risk of severe Coronavirus Disease 2019 (COVID-19) infection and mortality. COVID-19 vaccines reduce the risk of serious COVID-19 outcomes; however, their effectiveness in people with obesity is incompletely understood. We studied the relationship among body mass index (BMI), hospitalization and mortality due to COVID-19 among 3.6 million people in Scotland using the Early Pandemic Evaluation and Enhanced Surveillance of COVID-19 (EAVE II) surveillance platform. We found that vaccinated individuals with severe obesity (BMI > 40 kg/m2) were 76% more likely to experience hospitalization or death from COVID-19 (adjusted rate ratio of 1.76 (95% confidence interval (CI), 1.60-1.94). We also conducted a prospective longitudinal study of a cohort of 28 individuals with severe obesity compared to 41 control individuals with normal BMI (BMI 18.5-24.9 kg/m2). We found that 55% of individuals with severe obesity had unquantifiable titers of neutralizing antibody against authentic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus compared to 12% of individuals with normal BMI (P = 0.0003) 6 months after their second vaccine dose. Furthermore, we observed that, for individuals with severe obesity, at any given anti-spike and anti-receptor-binding domain (RBD) antibody level, neutralizing capacity was lower than that of individuals with a normal BMI. Neutralizing capacity was restored by a third dose of vaccine but again declined more rapidly in people with severe obesity. We demonstrate that waning of COVID-19 vaccine-induced humoral immunity is accelerated in individuals with severe obesity. As obesity is associated with increased hospitalization and mortality from breakthrough infections, our findings have implications for vaccine prioritization policies.


Subject(s)
COVID-19 , Obesity, Morbid , Humans , COVID-19 Vaccines , Longitudinal Studies , Prospective Studies , COVID-19/epidemiology , COVID-19/prevention & control , SARS-CoV-2 , Obesity/epidemiology , Antibodies, Neutralizing , Antibodies, Viral , Vaccination
18.
Clin Nutr ESPEN ; 55: 212-220, 2023 06.
Article in English | MEDLINE | ID: mdl-37202049

ABSTRACT

BACKGROUND AND AIMS: To investigate the incidence and the severity of COVID-19 infection in patients enrolled in the database for home parenteral nutrition (HPN) for chronic intestinal failure (CIF) of the European Society for Clinical Nutrition and Metabolism (ESPEN). METHODS: Period of observation: March 1st, 2020 March 1st, 2021. INCLUSION CRITERIA: patients included in the database since 2015 and still receiving HPN on March 1st, 2020 as well as new patients included in the database during the period of observation. Data related to the previous 12 months and recorded on March 1st 2021: 1) occurrence of COVID-19 infection since the beginning of the pandemic (yes, no, unknown); 2) infection severity (asymptomatic; mild, no-hospitalization; moderate, hospitalization no-ICU; severe, hospitalization in ICU); 3) vaccinated against COVID-19 (yes, no, unknown); 4) patient outcome on March 1st 2021: still on HPN, weaned off HPN, deceased, lost to follow up. RESULTS: Sixty-eight centres from 23 countries included 4680 patients. Data on COVID-19 were available for 55.1% of patients. The cumulative incidence of infection was 9.6% in the total group and ranged from 0% to 21.9% in the cohorts of individual countries. Infection severity was reported as: asymptomatic 26.7%, mild 32.0%, moderate 36.0%, severe 5.3%. Vaccination status was unknown in 62.0% of patients, non-vaccinated 25.2%, vaccinated 12.8%. Patient outcome was reported as: still on HPN 78.6%, weaned off HPN 10.6%, deceased 9.7%, lost to follow up 1.1%. A higher incidence of infection (p = 0.04), greater severity of infection (p < 0.001) and a lower vaccination percentage (p = 0.01) were observed in deceased patients. In COVID-19 infected patients, deaths due to infection accounted for 42.8% of total deaths. CONCLUSIONS: In patients on HPN for CIF, the incidence of COVID-19 infection differed greatly among countries. Although the majority of cases were reported to be asymptomatic or have mild symptoms only, COVID-19 was reported to be fatal in a significant proportion of infected patients. Lack of vaccination was associated with a higher risk of death.


Subject(s)
COVID-19 , Intestinal Diseases , Intestinal Failure , Parenteral Nutrition, Home , Humans , COVID-19/epidemiology , Intestinal Diseases/epidemiology , Intestinal Diseases/therapy , Parenteral Nutrition, Home/adverse effects
19.
BMC Med Res Methodol ; 23(1): 88, 2023 04 11.
Article in English | MEDLINE | ID: mdl-37041475

ABSTRACT

BACKGROUND: To advance new therapies into clinical care, clinical trials must recruit enough participants. Yet, many trials fail to do so, leading to delays, early trial termination, and wasted resources. Under-enrolling trials make it impossible to draw conclusions about the efficacy of new therapies. An oft-cited reason for insufficient enrollment is lack of study team and provider awareness about patient eligibility. Automating clinical trial eligibility surveillance and study team and provider notification could offer a solution. METHODS: To address this need for an automated solution, we conducted an observational pilot study of our TAES (TriAl Eligibility Surveillance) system. We tested the hypothesis that an automated system based on natural language processing and machine learning algorithms could detect patients eligible for specific clinical trials by linking the information extracted from trial descriptions to the corresponding clinical information in the electronic health record (EHR). To evaluate the TAES information extraction and matching prototype (i.e., TAES prototype), we selected five open cardiovascular and cancer trials at the Medical University of South Carolina and created a new reference standard of 21,974 clinical text notes from a random selection of 400 patients (including at least 100 enrolled in the selected trials), with a small subset of 20 notes annotated in detail. We also developed a simple web interface for a new database that stores all trial eligibility criteria, corresponding clinical information, and trial-patient match characteristics using the Observational Medical Outcomes Partnership (OMOP) common data model. Finally, we investigated options for integrating an automated clinical trial eligibility system into the EHR and for notifying health care providers promptly of potential patient eligibility without interrupting their clinical workflow. RESULTS: Although the rapidly implemented TAES prototype achieved only moderate accuracy (recall up to 0.778; precision up to 1.000), it enabled us to assess options for integrating an automated system successfully into the clinical workflow at a healthcare system. CONCLUSIONS: Once optimized, the TAES system could exponentially enhance identification of patients potentially eligible for clinical trials, while simultaneously decreasing the burden on research teams of manual EHR review. Through timely notifications, it could also raise physician awareness of patient eligibility for clinical trials.


Subject(s)
Artificial Intelligence , Natural Language Processing , Humans , Pilot Projects , Patient Selection , Machine Learning
20.
Law Hum Behav ; 47(1): 1-11, 2023 02.
Article in English | MEDLINE | ID: mdl-36931845

ABSTRACT

Police killings of Black civilians have brought unprecedented attention to racial and ethnic discrimination in the criminal justice and legal systems. However, these topics have been underexamined in the field of law-psychology, both in research and forensic-clinical practice. We discuss how a racial justice framework can provide guidance for advancing psycholegal research and forensic-clinical practice related to race, ethnicity, culture, and their intersections. A racial justice framework centers the goal of increasing fair and responsive treatment and just outcomes for the most vulnerable populations involved with the criminal justice, legal, and carceral systems and ending existing disparities. We argue that the framework should include the use of transparent nonobjectivity, in which racial justice is an explicit and acknowledged goal of research and practice that exists alongside a commitment to open and rigorous science and evidence-based practice. We then use the racial justice framework as a backdrop for discussing the articles and broader themes that appear in the special issue, which include racial biases in policing, public views of the police and use of force, expanding research on racial bias in lay judgments, understanding disparities in sentencing and corrections, and improving forensic practice. Finally, we look to the future, discussing practices and perspectives that can facilitate a racial justice approach in psycholegal research and forensic-clinical practice. Our recommendations include engaging in reflexivity and addressing positionality; expanding research questions and methods, especially qualitative and community-based participatory action research; centering and engaging with communities of color; greater emphasis on intersectionality; shifting toward structural and adaptive interventions; and greater integration of work from other fields. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


Subject(s)
Forensic Psychology , Law Enforcement , Humans , Criminal Law , Police , Ethnicity , Social Justice
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