Plasma neurofilament light chain (NfL)'s link to dementia may be mediated through white matter integrity (WMI). In this study, we examined plasma NfL's relationships with diffusion tensor magnetic resonance imaging markers: global and cortical white matter fractional anisotropy (FA) and trace (TR). Plasma NfL measurements at 2 times (v1: 2004-2009 and v2: 2009-2013) and ancillary dMRI (vscan: 2011-2015) were considered (n = 163, mean time v1 to vscan = 5.4 years and v2 to vscan: 1.1 years). Multivariable-adjusted regression models, correcting for multiple-testing revealed that, overall, higher NfLv1 was associated with greater global TR (β ± SE: +0.0000560 ± 0.0000186, b = 0.27, p = 0.003, q = 0.012), left frontal WM TR (β ± SE: + 0.0000706 ± 0.0000201, b ± 0.30, p = 0.001, q = 0.0093) and right frontal WM TR (β ± SE: + 0.0000767 ± 0.000021, b ± 0.31, p < 0.001, q = 0.0093). These associations were mainly among males and White adults. Among African American adults only, NfLv2 was associated with greater left temporal lobe TR. "Tracking high" in NfL was associated with reduced left frontal FA (Model 2, body mass index-adjusted: β ± SE:-0.01084 ± 0.00408, p = 0.009). Plasma NfL is a promising biomarker predicting future brain white matter integrity (WMI) in middle-aged adults.

Micronuclei (MN) are fragments of damaged nucleic acids which budded from a cell's nuclei as a repair mechanism for chromosomal instabilities, which within circulating white blood cells (cWBCs) signifies increased cancer risk, and in tumor cells indicates aggressive subtypes. MN form overtime and with therapy induction, which requires sequential monitoring of rarer cell subpopulations. We evaluated the peripheral blood (7.5 mL) for MN in Circulating Stromal Cells (CStCs) in a prospective pilot study of advanced colorectal cancer patients (n = 25), identifying MN by DAPI+ structures (&lt;3 µm) within the cellular cytoplasm. MN+ was compared to genotoxic induction, progression free survival (PFS) or overall survival (OS) hazard ratios (HR) over three years. MN were identified in 44% (n = 11/25) of CStCs, but were not associated with genotoxic therapies (p = 0.110) nor stage (p = 0.137). However, presence of MN in CStCs was independently prognostic for PFS (HR = 17.2, 95% CI 3.6-80.9, p = 0.001) and OS (HR = 70.3, 95% CI 6.6-752.8, p = 0.002), indicating a non-interventional mechanism in their formation. Additionally, MN formation did not appear associated with chemotherapy induction, but was correlated with tumor response. MN formation in colorectal cancer is an underlying biological mechanism that appears independent of chemotherapeutic genotoxins, changes during treatment, and predicts for poor clinical outcomes.

Background: A dominance of non-iners Lactobacillus species in the vaginal microbiome is optimal and strongly associated with gynecological and obstetric health, while the presence of diverse obligate or facultative anaerobic bacteria and a paucity in Lactobacillus species, similar to communities found in bacterial vaginosis (BV), is considered non-optimal and associated with adverse health outcomes. Various therapeutic strategies are being explored to modulate the composition of the vaginal microbiome; however, there is no human model that faithfully reproduces the vaginal epithelial microenvironment for preclinical validation of potential therapeutics or testing hypotheses about vaginal epithelium-microbiome interactions. Results: Here, we describe an organ-on-a-chip (organ chip) microfluidic culture model of the human vaginal mucosa (vagina chip) that is lined by hormone-sensitive, primary vaginal epithelium interfaced with underlying stromal fibroblasts, which sustains a low physiological oxygen concentration in the epithelial lumen. We show that the Vagina Chip can be used to assess colonization by optimal L. crispatus consortia as well as non-optimal Gardnerella vaginalis-containing consortia, and to measure associated host innate immune responses. Co-culture and growth of the L. crispatus consortia on-chip was accompanied by maintenance of epithelial cell viability, accumulation of D- and L-lactic acid, maintenance of a physiologically relevant low pH, and down regulation of proinflammatory cytokines. In contrast, co-culture of G. vaginalis-containing consortia in the vagina chip resulted in epithelial cell injury, a rise in pH, and upregulation of proinflammatory cytokines. Conclusion: This study demonstrates the potential of applying human organ chip technology to create a preclinical model of the human vaginal mucosa that can be used to better understand interactions between the vaginal microbiome and host tissues, as well as to evaluate the safety and efficacy of live biotherapeutics products.

Background: Influenza virus infection is associated with incident ischemic heart disease (IHD) events. Here, we estimate the global, regional, and national IHD mortality burden attributable to influenza. Methods: We used vital registration data from deaths in adults ≥50 years (13.2 million IHD deaths as underlying cause) to assess the relationship between influenza activity and IHD mortality in a non-linear meta-regression framework from 2010 to 2019. This derived relationship was then used to estimate the global influenza attributable IHD mortality. We estimated the population attributable fraction (PAF) of influenza for IHD deaths based on the relative risk associated with a given level of weekly influenza test positivity rate and multiplied PAFs by IHD mortality from the Global Burden of Disease study. Findings: Influenza activity was associated with increased risk of IHD mortality across all countries analyzed. The mean PAF of influenza for IHD mortality was 3.9% (95% uncertainty interval [UI] 2.5-5.3%), ranging from <1% to 10%, depending on country and year. Globally, 299,858 IHD deaths (95% UI 191,216-406,809) in adults ≥50 years could be attributed to influenza, with the highest rates per 100,000 population in the Central Europe, Eastern Europe and Central Asia Region (32.3; 95% UI 20.6-43.8), and in the North Africa and Middle East Region (26.7; 95% UI 17-36.2). Interpretation: Influenza may contribute substantially to the burden of IHD. Our results suggest that if there were no influenza, an average of 4% of IHD deaths globally would not occur.

Objective: To quantify patient preferences towards time to return to driving relative to compromised reaction time and potential complication risks. Design: Cross-sectional discrete choice experiment. Setting: Academic trauma center. Patients: Ninety-six adult patients with an operative lower extremity fracture from December 2019 through December 2020. Intervention: None. Main outcome measurement: Patient completed a discrete choice experiment survey consisting of 12 hypothetical return to driving scenarios with varied attributes: time to return to driving (range: 1 to 6 months), risk of implant failure (range: 1% to 12%), pain upon driving return (range: none to severe), and driving safety measured by braking distance (range: 0 to 40 feet at 60 mph). The relative importance of each attribute is reported on a scale of 0% to 100%. Results: Patients most valued a reduced pain level when resuming driving (62%), followed by the risk of implant failure (17%), time to return to driving (13%), and braking safety (8%). Patients were indifferent to returning to driving at 1 month (median utility: 28, interquartile range [IQR] -31 to 80) or 2 months (median utility: 59, IQR: 41 to 91) postinjury. Conclusion: Patients with lower extremity injuries demonstrated a willingness to forego earlier return to driving if it might mean a decrease in their pain level. Patients are least concerned about their driving safety, instead placing higher value on their own pain level and chance of implant failure. The findings of this study are the first to rigorously quantify patient preferences toward a return to driving and heterogeneity in patient preferences.

Background: There is a critical need for a diverse pool of academic leaders to increase the number and diversity of the medical workforce. Physician Assistant/Associate (PA) is a growing medical profession. Although the master's degree is the terminal degree for PAs, a growing number of PAs obtain a variety of doctoral degrees. However, there is no standardized training for academic PA leaders. The purpose of this study was to identify factors associated with PA academic leadership. Specifically, this study explored the following factors: doctoral degree credentials, gender and underrepresented minority status. Methods: Using the 2019 Physician Assistant Education Association Faculty and Directors survey, we assessed the relationship between academic leadership groups [Program Director (PD), Academic Director (AD), and Clinical Director (CD)] doctoral degree, gender, and underrepresented minority in medicine (URIM) status. Multivariable logistic regression models were used to determine the predictors of being in a leadership role. Results with p < 0.05 were considered statistically significant. Results: Of the 956 participants, 71% were female, 4% Hispanic, 86% White, 4% Black, 2% Asian, and 1% Native Hawaiian/Pacific Islander/American Indian/Alaska Native. Overall, 9% were URIM. Mean age was 45.6 (SD = 10.2) years. Average time in PA education was 2.9 years (SD = 1.4). Approximately 50% (n = 472) had a leadership role (PD-24%, AD-10%, CD-16%). Of all leaders, 68% were female, 9% were URIM, and 19% had a doctoral degree. Having a doctoral degree increased the odds of being a PD [AOR 2.38, CI [1.57-3.59], p = < 0.0001, AD and CD = non-significant]. More time in PA education increased the odds of being a PD [AOR 1.10, CI [1.07-1.12, p = < 0.0001] and AD [AOR 1.06, CI [1.03-1.09], p = < 0.0001], but not a CD. Gender and URIM status were not significantly associated with leadership roles. URIMs had doctorate degrees at higher rates than non-URIMs. Conclusion: PA academic leaders differ by doctoral degree attainment but not by gender and URIM status. URIM faculty are grossly underrepresented in the PA professorate, but disproportionately have doctoral degrees. Academic training opportunities for all PA academic leaders and strategies to increase URIM faculty are needed.

Dengue virus (DENV) infection is one of the major public health concerns around the globe, especially in the tropical regions of the world that contribute to 75% percent of dengue cases. While the majority of DENV infections are mild or asymptomatic, approximately 5% of the cases develop a severe form of the disease that is mainly attributed to sequential infection with different DENV serotypes. The severity of dengue depends on many immunopathogenic mechanisms involving both viral and host factors. Emerging evidence implicates an impaired immune response as contributing to disease progression and severity by restricting viral clearance and inducing severe inflammation, subsequently leading to dengue hemorrhagic fever and dengue shock syndrome. Moreover, the ability of DENV to infect a wide variety of immune cells, including monocytes, macrophages, dendritic cells, mast cells, and T and B cells, further dysregulates the antiviral functions of these cells, resulting in viral dissemination. Although several risk factors associated with disease progression have been proposed, gaps persist in the understanding of the disease pathogenesis and further investigations are warranted. In this review, we discuss known mechanisms of DENV-mediated immunopathogenesis and its association with disease progression and severity.

Objective: Delirium and agitation can be devastating and prolong the length of hospitalization. As part of our continuous improvement efforts, we implemented the use of intermittent chlorpromazine therapy to target refractory agitation associated with hyperactive or mixed delirium (RAA-D). The purpose of this study was to evaluate the effectiveness of chlorpromazine on RAA-D and delirium symptoms as well as any adverse effects in critically ill children. Methods: Retrospective chart review was conducted for children admitted to the pediatric intensive care unit who were treated with chlorpromazine for RAA-D from March 2017 to January 2019. The primary end point was to determine differences in Cornell Assessment for Pediatric Delirium (CAPD) and State Behavioral Scale (SBS) scores 24 hours before and after chlorpromazine administration. The secondary end points were the 24-hour cumulative dosing of narcotic and sedative agents before and after chlorpromazine administration and adverse events associated with chlorpromazine use. Results: Twenty-six patients were treated with chlorpromazine for RAA-D; 16 (61.5%) were male with a median age of 14.5 months (IQR, 6-48). The mean CAPD (n = 24) and median SBS (n = 23) scores were significantly lower 24 hours after chlorpromazine use when compared to baseline scores, 12 vs 8.9 (p = 0.0021) and 1 vs -1, (p = 0.0005) respectively. No significant adverse effects were observed. Conclusions: Chlorpromazine use in critically ill children with RAA-D was helpful for managing symptoms without adverse events. Further investigation is needed to evaluate the use of chlorpromazine to treat RAA-D to avoid long-term use of an antipsychotic.

Background: Although some emergency department risk stratification tools consider non-specific ECG findings as an aid in disposition decisions, their clinical value in patients with an initially low high-sensitivity cardiac troponin I (hsTnI) is unclear. Objective: Our purpose was to determine if non-specific ECG (ns-ECG) findings are associated with 30-day major adverse cardiac events (MACE) in ED patients presenting with suspected acute coronary syndromes (ACS) who have a low initial hsTnI. Methods: Using the prospective Siemens Atellica hsTnI Food and Drug Administration submission observational database, we conducted a retrospective cohort study of the association between ns-ECG findings (defined as left bundle branch block [LBBB], ST depression [STD], or T-wave inversions [TWI]) and 30-day MACE (death, myocardial infarction, heart failure hospitalization, or coronary revascularization). Eligible patients presented with suspected ACS to one of 29 US EDs from April 2015 to April 2016, had stable vital signs, a blood sample for hsTnI (Siemen's Atellica, Siemens Healthineers, Inc, Malvern, PA) obtained at 1, 3, and 6 hours after ED presentation, and were followed for 30 days. The relationship between 30-day outcome, initial hsTnI, and ns-ECG was evaluated using chi-square testing. Results: Of 2676 enrolled, 1313 patients met the inclusion criteria and are included in the analysis. Median (interquartile range) age was 62 years (54, 72), 54% were male, with 56% white, and 39% African American. Median (interquartile range) times from symptom onset to presentation and presentation to specimen collection were 92 (0, 216) and 146 (117, 177) minutes, respectively. The most common presenting symptoms were chest pain (84%), followed by dyspnea (9%). ECG findings were categorized as T-wave inversion or non-specific T wave changes (42%), ST depression ns-ECG ST changes (16%), or LBBB (2%). Thirty-day MACE occurred in 72 (5.5%) patients, with coronary revascularization (35 patients, 2.7%) and heart failure (25 patients, 1.9%) being the most frequent outcomes. In patients with an initial hsTnI below the limit of quantitation (LOQ) of 2.5 ng/L (n = 449), there was no association between ns-ECG changes and 30-day MACE (P = 0.42). If the hsTnI was ≥LOQ (2.5 ng/L), there were increased rates of 30-day MACE and ns-ECG findings (P = 0.01). Conclusion: In ED suspected ACS patients without unstable vital signs, and an initial hsTnI less than the LOQ (2.5 ng/L), ns-ECG findings are not associated with 30-day major adverse cardiac events. The use of ns-ECG findings in ACS disposition should be considered in the context of hsTnI levels.

Background: HIV transmission can occur with a viral load of at least 200 copies per mL of blood and low-level viraemia can lead to virological failure; the threshold level at which risk for virological failure is conferred is uncertain. To better understand low-level viraemia prevalence and outcomes, we analysed retrospective longitudinal data from a large cohort of people living with HIV on antiretroviral therapy (ART) in Nigeria. Methods: In this retrospective cohort study using previously collected longitudinal patient data, we estimated rates of virological suppression (≤50 copies per mL), low-level viraemia (51-999 copies per mL), virological non-suppression (≥1000 copies per mL), and virological failure (≥2 consecutive virological non-suppression results) among people living with HIV aged 18 years and older who initiated and received at least 24 weeks of ART at 1005 facilities in 18 Nigerian states. We analysed risk for low-level viraemia, virological non-suppression, and virological failure using log-binomial regression and mixed-effects logistic regression. Findings: At first viral load for 402 668 patients during 2016-21, low-level viraemia was present in 64 480 (16·0%) individuals and virological non-suppression occurred in 46 051 (11·4%) individuals. Patients with low-level viraemia had increased risk of virological failure (adjusted relative risk 2·20, 95% CI 1·98-2·43; p<0·0001). Compared with patients with virological suppression, patients with low-level viraemia, even at 51-199 copies per mL, had increased odds of low-level viraemia and virological non-suppression at next viral load; patients on optimised ART (ie, integrase strand transfer inhibitors) had lower odds than those on non-integrase strand transfer inhibitors for the same low-level viraemia range (eg, viral load ≥1000 copies per mL following viral load 400-999 copies per mL, integrase strand transfer inhibitor: odds ratio 1·96, 95% CI 1·79-2·13; p<0·0001; non-integrase strand transfer inhibitor: 3·21, 2·90-3·55; p<0·0001). Interpretation: Patients with low-level viraemia had increased risk of virological non-suppression and failure. Programmes should revise monitoring benchmarks and targets from less than 1000 copies per mL to less than 50 copies per mL to strengthen clinical outcomes and track progress to epidemic control.