Identifying molecular phenotypes in sepsis: an analysis of two prospective observational cohorts and secondary analysis of two randomised controlled trials.

BACKGROUND: In sepsis and acute respiratory distress syndrome (ARDS), heterogeneity has contributed to difficulty identifying effective pharmacotherapies. In ARDS, two molecular phenotypes (hypoinflammatory and hyperinflammatory) have consistently been identified, with divergent outcomes and treatment responses. In this study, we sought to derive molecular phenotypes in critically ill adults with sepsis, determine their overlap with previous ARDS phenotypes, and evaluate whether they respond differently to treatment in completed sepsis trials. METHODS: We used clinical data and plasma biomarkers from two prospective sepsis cohorts, the Validating Acute Lung Injury biomarkers for Diagnosis (VALID) study (N=1140) and the Early Assessment of Renal and Lung Injury (EARLI) study (N=818), in latent class analysis (LCA) to identify the optimal number of classes in each cohort independently. We used validated models trained to classify ARDS phenotypes to evaluate concordance of sepsis and ARDS phenotypes. We applied these models retrospectively to the previously published Prospective Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis and Septic Shock (PROWESS-SHOCK) trial and Vasopressin and Septic Shock Trial (VASST) to assign phenotypes and evaluate heterogeneity of treatment effect. FINDINGS: A two-class model best fit both VALID and EARLI (p<0·0001). In VALID, 804 (70·5%) of the 1140 patients were classified as hypoinflammatory and 336 (29·5%) as hyperinflammatory; in EARLI, 530 (64·8%) of 818 were hypoinflammatory and 288 (35·2%) hyperinflammatory. We observed higher plasma pro-inflammatory cytokines, more vasopressor use, more bacteraemia, lower protein C, and higher mortality in the hyperinflammatory than in the hypoinflammatory phenotype (p<0·0001 for all). Classifier models indicated strong concordance between sepsis phenotypes and previously identified ARDS phenotypes (area under the curve 0·87-0·96, depending on the model). Findings were similar excluding participants with both sepsis and ARDS. In PROWESS-SHOCK, 1142 (68·0%) of 1680 patients had the hypoinflammatory phenotype and 538 (32·0%) had the hyperinflammatory phenotype, and response to activated protein C differed by phenotype (p=0·0043). In VASST, phenotype proportions were similar to other cohorts; however, no treatment interaction with the type of vasopressor was observed (p=0·72). INTERPRETATION: Molecular phenotypes previously identified in ARDS are also identifiable in multiple sepsis cohorts and respond differently to activated protein C. Molecular phenotypes could represent a treatable trait in critical illness beyond the patient's syndromic diagnosis. FUNDING: US National Institutes of Health.

Perceptions of Safety of Daily Cannabis vs Tobacco Smoking and Secondhand Smoke Exposure, 2017-2021.

Importance: While rates of cigarette use are declining, more US adults are using cannabis. Perceptions of safety are important drivers of substance use and public policy; however, little is known about the comparative views of US adults on tobacco and cannabis safety. Objective: To compare public perceptions of safety of cannabis vs tobacco smoke and evaluate how perceptions may be changing over time. Design, Setting, and Participants: This longitudinal survey study was conducted using a web-based survey administered in 2017, 2020, and 2021. US adults participating in Ipsos KnowledgePanel, a nationally representative, population-based survey panel, were included. Data were analyzed from March 2021 through June 2023. Main Outcomes and Measures: Two questions directly compared the perception of safety of cannabis vs tobacco in terms of daily smoking and secondhand smoke exposure. Additional questions assessed perceptions of safety of secondhand tobacco smoke for adults, children, and pregnant women, with an analogous set of questions for secondhand cannabis smoke. Results: A total of 5035 participants (mean [SD] age, 53.4 [16.2] years; 2551 males [50.7%]) completed all 3 surveys and provided responses for tobacco and cannabis risk questions. More than one-third of participants felt that daily smoking of cannabis was safer than tobacco, and their views increasingly favored safety of cannabis vs tobacco over time (1742 participants [36.7%] in 2017 vs 2107 participants [44.3%] in 2021; P < .001). The pattern was similar for secondhand cannabis smoke, with 1668 participants (35.1%) responding that cannabis was safer than tobacco in 2017 vs 1908 participants (40.2%) in 2021 (P < .001). Participants who were younger (adjusted odds ratio [aOR] for ages 18-29 years vs ≥60 years, 1.4 [95% CI, 1.1-1.8]; P = .01) or not married (aOR, 1.2 [95% CI, 1.0-1.4]; P = .01) were more likely to move toward safer views of cannabis use over time, while those who were retired (aOR vs working, 0.8 [95% CI, 0.7-0.9]; P = .01) were less likely to move toward a safer view of cannabis. Participants were also more likely to rate secondhand smoke exposure to cannabis vs tobacco as completely or somewhat safe in adults (629 participants [12.6%] vs. 119 participants [2.4%]; P < .001), children (238 participants [4.8%] vs. 90 participants [1.8%]; P < .001), and pregnant women (264 participants [5.3%] vs. 69 participants [1.4%]; P < .001). Conclusions and Relevance: This study found that US adults increasingly perceived daily smoking and secondhand exposure to cannabis smoke as safer than tobacco smoke from 2017 to 2021. Given that these views do not reflect the existing science on cannabis and tobacco smoke, the findings may have important implications for public health and policy as the legalization and use of cannabis increase.

Diagnostics of new species of Neotropical Tischeriidae (Lepidoptera), with the first record of Coptotriche Walshingham from South America.

We describe seven new Neotropical species of Tischeriidae: Astrotischeria dondavisi Stonis Diskus, sp. nov., A. bacchariphaga Diskus Stonis, sp. nov., A. guatemalica Diskus Stonis, sp. nov., A. sanjosei Stonis Diskus, sp. nov., A. truncata Diskus Stonis, sp. nov., Coptotriche parvisacculata Diskus Stonis, sp. nov. and C. carmencita Stonis Diskus, sp. nov. We report the discovery of Coptotriche Walsingham in South America and provide the following new host-plant records for the Neotropical Tischeriidae: Terminalia australis Cambess. (Combretaceae), Baccharis latifolia (Ruiz Pav.) Pers., and B. emarginata (Ruiz Pav.) Pers. (Asteraceae). We update the biology of Astrotischeria ochrimaculosa Diskus, Stonis Vargas with the discovery that Wissadula (Malvaceae) is a new, verified host plant. The new species are illustrated with photographs of the adults, male and, if available, female genitalia, and the leaf mines. We expect broader distributions of tisheriid species in South America inferred from known host-plant distributions.

Diet and Exercise in Pediatric Liver Transplant Recipients: Behaviors and Association With Metabolic Syndrome.

OBJECTIVE: The aim of the study is to analyze the impact of physical activity and eating behaviors on precursors of cardiovascular disease-including overweight/obesity, hypertension, low high-density lipoprotein, and impaired glucose tolerance-in pediatric liver transplant (LT) recipients and matched controls. METHOD: Cross-sectional study of pediatric LT recipients 8 to 30 years, matched to controls from the National Health and Nutrition Examination Survey. Dietary intake assessed with 24-hour recall. Physical activity assessed by standardized questionnaires. LT recipients ≥12 years completed a confidential survey on alcohol consumption. RESULTS: LT recipients (n = 90) were 0.9 to 24.7 years post-transplant. LT recipients and controls were equally likely to consume excess carbohydrates (32% vs 34%) and sugar, per age- and gender-specific recommended dietary intake guidelines. LT recipients spent more hours sedentary or on the computer daily and fewer days each week physically active for >60 minutes than controls. More overweight/obese LT recipients spent 3+ hours at the computer than non-overweight LT recipients (49% vs 27%; P = 0.02). Normal weight LT recipients spent more days doing vigorous activity each week (median 5 days, interquartile range 2-6) than did the overweight/obese LT recipients (median 3 days, interquartile range 2-4; P = 0.01). Among LT recipients, neither dietary intake nor physical activity were consistently associated with measures of hypertension, glucose intolerance, or dyslipidemia. Among LT adolescents and young adults (n = 38), 36% reported ever consuming alcohol; 38% of these reported significant alcohol consumption by frequency or quantity. CONCLUSIONS: Additional counseling during routine post-LT care on the importance of physical activity and healthy diet may be useful. However, it is unlikely that these factors alone explain the increased prevalence of metabolic syndrome components in pediatric LT recipients.

Performance of Leishmania PFR1 recombinant antigen in serological diagnosis of asymptomatic canine leishmaniosis by ELISA.

BACKGROUND: Leishmania infantum is a protozoan parasite transmitted by phlebotomine sand flies that causes life-threatening disease in humans and dogs. The dog is the primary reservoir of the parasite and early diagnosis of canine leishmaniosis is crucial at the clinical and epidemiological level. The currently available serological tests for CanL diagnostic show limitations therefore the aim of the present study was to investigate the diagnostic performance of an indirect antibody ELISA based on the Leishmania infantum recombinant antigen PFR1 in asymptomatically infected dogs. One hundred fifty-six dogs including Leishmania-free experimental Beagles and pet dogs from England, Scotland and Leishmania-endemic Murcia in Spain, were tested with the assay. The later were also tested with two commercial L. infantum crude antigen ELISAs (INgezim and Civtest, respectively) and a real-time kinetoplast PCR test. RESULTS: Anti-PFR1 antibodies were detected in the four groups of dogs, and the mean log-transformed optical density (OD) values were lowest in Beagles and in dogs from England and highest among dogs from Murcia (p < 0.05). Using the highest OD in beagles as the PFR1 ELISA cut-off point, the estimated seroprevalence was 27% (14-40%) in dogs from Murcia, 4% (0-9%) in dogs from Scotland and 3% (0-8%) in dogs from England (p < 0.05). Seroprevalence in dogs from Murcia according to the INgezim and Civtest ELISAs were 24% (12-37%) and 31% (18-45%), respectively, whilst the prevalence of infection based on PCR in these dogs was 73% (60-86). The percentages of PFR1-positive dogs that tested negative on the INgezim and Civtest ELISAs were 30% and 35%, respectively, and all of them tested positive on the PCR test. Relative to the PCR, the specificity, sensitivity and area under the ROC curve of the PFR1 ELISA were 100%, 36% and 0.74 (0.63-0.86), respectively. CONCLUSIONS: The ability shown by the PFR1 ELISA to detect infected dogs that go undetected by the crude antigen ELISAs is clinically and epidemiologically useful and PFR1 could be considered a candidate for a multi-antigen-based immunoassay for early detection of L. infantum infected dogs.

Fertility preservation with ovarian stimulation and time to treatment in women with stage II-III breast cancer receiving neoadjuvant therapy.

PURPOSE: To determine whether fertility preservation with ovarian stimulation (OS) results in treatment delay in breast cancer (BC) patients receiving neoadjuvant therapy (NAT). METHODS: This is a retrospective study of women screened for the prospective neoadjuvant ISPY2 trial at the University of California San Francisco. All patients were <43, had stage II-III BC, and received neoadjuvant therapy. Time to initiation of NAT was compared between women who underwent OS (STIM) and women who did not (control). Patient and tumor characteristics, as well as oncologic outcomes, were compared between STIM and control groups. RESULTS: 82 patients were included (34 STIM and 48 control). STIM patients were overall younger (mean = 35 vs. 36.9 years old, p = 0.06), and more likely to be childless (79.4 vs 31.2%, p < 0.0001) than controls. Mean time from diagnosis to initiation of NAT was 40 days, with no significant difference between STIM and control groups (mean 39.8 days vs 40.9 days, p = 0.75). Mean time from diagnosis to fertility consultation was 16.3 days. With median follow-up of 79 months, 16 (19.5%) patients have recurred or died from BC. Rates of pCR, recurrence, and death were similar in both groups. Six of 34 STIM patients have undergone embryo transfer, resulting in one patient with two live births. CONCLUSION: Fertility preservation with OS can be performed in the neoadjuvant setting without delay in initiation of systemic therapy and should be discussed with all early-stage BC patients of reproductive age.

Wild deer as a source of infection for livestock and humans in the UK.

Wild deer can feature in the epidemiology of a wide range of livestock and human diseases in the United Kingdom by representing a source of disease via various transmission routes. This review highlights current and possible future infections of deer in the UK which may have an impact on livestock and/or human health. Increases in deer abundance as well as range expansion are likely to exacerbate the potential for disease persistence due to the formation of multi-species deer assemblages, which may act as disease reservoirs. Climatic changes are likely to have a direct impact on the presence and abundance of various pathogens and their vectors, so that with a warming climate exotic diseases may play a role in future UK livestock and wildlife disease management. This paper highlights the need for a monitoring strategy for wildlife diseases, in particular infections in wild deer, in the UK.