Cerebral blood flow, arterial pulsation, and vasomotion play important roles in the transport of waste metabolites out of the brain. Impaired vasomotion results in reduced driving force for the ...perivascular/glymphatic clearance of beta-amyloid. Noninvasive cerebrovascular characteristic features that potentially assess these transport mechanisms are mean blood flow (MBF) and pulsatility index (PI). In this study, 4D flow MRI was used to measure intra-cranial flow features, particularly MBF, PI, resistive index (RI) and cross-sectional area in patients with Alzheimer’s disease (AD), mild cognitive impairment and in age matched and younger cognitively healthy controls. Three-hundred fourteen subjects participated in this study. Volumetric, time-resolved phase contrast (PC) MRI data were used to quantify hemodynamic parameters from 11 vessel segments. Anatomical variants of the Circle of Willis were also cataloged. The AD population reported a statistically significant decrease in MBF and cross-sectional area, and also an increase in PI and RI compared to age matched cognitively healthy control subjects. The 4D flow MRI technique used in this study provides quantitative measurements of intracranial vessel geometry and the velocity of flow. Cerebrovascular characteristics features of vascular health such as pulsatility index can be extracted from the 4D flow MRI data.
Urbanization contributes to the formation of novel elemental combinations and signatures in terrestrial and aquatic watersheds, also known as ‘chemical cocktails.’ The composition of chemical ...cocktails evolves across space and time due to: (1) elevated concentrations from anthropogenic sources, (2) accelerated weathering and corrosion of the built environment, (3) increased drainage density and intensification of urban water conveyance systems, and (4) enhanced rates of geochemical transformations due to changes in temperature, ionic strength, pH, and redox potentials. Characterizing chemical cocktails and underlying geochemical processes is necessary for: (1) tracking pollution sources using complex chemical mixtures instead of individual elements or compounds; (2) developing new strategies for co-managing groups of contaminants; (3) identifying proxies for predicting transport of chemical mixtures using continuous sensor data; and (4) determining whether interactive effects of chemical cocktails produce ecosystem-scale impacts greater than the sum of individual chemical stressors. First, we discuss some unique urban geochemical processes which form chemical cocktails, such as urban soil formation, human-accelerated weathering, urban acidification-alkalinization, and Freshwater Salinization Syndrome. Second, we review and synthesize global patterns in concentrations of major ions, carbon and nutrients, and trace elements in urban streams across different world regions and make comparisons with reference conditions. In addition to our global analysis, we highlight examples from watersheds in the Baltimore-Washington DC area, USA, which show increased transport of major ions, trace metals, and nutrients across streams draining a well-defined land-use gradient. Urbanization increased the concentrations of multiple major and trace elements in streams draining human-dominated watersheds compared to reference conditions. Chemical cocktails of major and trace elements were formed over diurnal cycles coinciding with changes in streamflow, dissolved oxygen, pH, and other variables measured by high-frequency sensors. Some chemical cocktails of major and trace elements were also significantly related to specific conductance (p < 0.05), which can be measured by sensors. Concentrations of major and trace elements increased, peaked, or decreased longitudinally along streams as watershed urbanization increased, which is consistent with distinct shifts in chemical mixtures upstream and downstream of other major cities in the world. Our global analysis of urban streams shows that concentrations of multiple elements along the periodic table significantly increase when compared with reference conditions. Furthermore, similar biogeochemical patterns and processes can be grouped among distinct mixtures of elements of major ions, dissolved organic matter, nutrients, and trace elements as chemical cocktails. Chemical cocktails form in urban waters over diurnal cycles, decades, and throughout drainage basins. We conclude our global review and synthesis by proposing strategies for monitoring and managing chemical cocktails using source control, ecosystem restoration, and green infrastructure. We discuss future research directions applying the watershed chemical cocktail approach to diagnose and manage environmental problems. Ultimately, a chemical cocktail approach targeting sources, transport, and transformations of different and distinct elemental combinations is beneficial to more holistically monitor and manage the emerging impacts of chemical mixtures in the world's fresh waters.
•Urbanization has altered global elemental concentrations in streams compared to baseline reference conditions.•The chemical composition of global freshwaters can be classified as distinct elemental mixtures or ‘chemical cocktails’.•Chemical cocktails can be applied to track pollution sources, co-manage contaminants, and identify Anthropocene signatures.•There is a growing need to holistically monitor and manage the emerging impacts of chemical cocktails in global freshwaters.
Opioids are frequently overprescribed after surgery. The 2018 AUA position statement on opioid use suggests using the lowest dose and potency to achieve pain control but the lack of procedure ...specific prescribing guidelines contributes to wide variation in prescribing patterns. To address this gap we aimed to develop opioid prescribing recommendations through an expert panel consensus.
The 15-member multidisciplinary expert panel included representatives from 5 stakeholder groups. A 3-step modified Delphi method was used to develop recommendations for postoperative opioid prescribing. Recommendations were made for opioid naïve patients without chronic pain conditions. The panel used oxycodone 5 mg equivalents to define the number of prescribed tablets.
Procedure specific recommendations were developed for 16 endourological and minimally invasive urological procedures. The panel agreed that not all patients desire or require opioids and, thus, the minimum recommended number of opioid tablets for all procedures was 0. Consensus ranges were identified to allow prescribed quantities to be aligned with expected needs. The maximum recommended quantity varied by procedure from 0 tablets (3 procedures) to 15 tablets (6 procedures) with a median of 10 tablets. Attending urologists typically voted for higher opioid quantities than nonattending panel members. The panel identified 8 overarching strategies for opioid stewardship, including contextualizing postoperative pain management with patient goals and preferences, and maximizing nonopioid therapies.
Procedure specific guidelines for postoperative opioid prescribing may help align individual urologist prescribing habits with consensus recommendations. These guidelines can aid quality improvement efforts to reduce overprescribing in urology.
To evaluate outcomes for patients with local recurrence (LR) of clinically localized renal cell carcinoma (RCC) without concurrent systemic metastasis from our institution, an event that occurs ...rarely (1%-3%) after surgery. LR may be a harbinger of poor outcomes, and the best management of these patients is unclear.
We retrospectively reviewed patients surgically treated for clinically localized RCC (cT1-2N0M0) with subsequent LR (in the partial or radical nephrectomy bed) and/or regional recurrence (RR; in the abdomen distant from the direct site of surgery) without concurrent metastasis from our institutional database (2004-2018). Comparative and survival analyses were performed.
Out of 3038 total patients, 1895 had clinically localized RCC, with 30 patients (1.6%) having isolated LR/RR. Median time to recurrence was 26.5 months (IQR:16-35). Of 26 patients treated with local therapy, 14 (53.8%) recurred over a median follow-up time of 29.5 months (IQR:12-45). The 1-year and 2-year secondary recurrence-free survival rates are 60.7% and 49.7%, respectively. Two or more sites of locoregional recurrence significantly predicted secondary recurrence/metastasis after local therapy for local recurrence (hazard ratio: 2.22, P= .04).
Our results suggest local therapy is appropriate for select patients with LR/RR, with almost 50% of patients undergoing a second local therapy remaining alive with “local cure” and no secondary recurrence. The number of sites of recurrence can be used to better select patients that will benefit from local therapy or systemic/combination therapy. This work provides a framework onto which further studies regarding local therapy and locoregional recurrence of RCC can be performed.
The recent report of the existence of meningeal lymphatic vessels (MLVs) in human and nonhuman primates used both histology and magnetic resonance imaging (MRI). Many questions about the physiology ...and function of these lymphatic vessels remain unanswered. Through the combination of appropriately positioned saturation bands and time-of-flight angiography sequences, MRI can resolve direction of flow within vessels without the use of exogenous contrast agent. Six healthy volunteers underwent high-resolution MRI of the MLVs running alongside the superior sagittal sinus to determine the direction of the lymphatic flow. In all subjects, the lymphatic flow was posterior to anterior, countercurrent to the direction of venous flow in the superior sagittal sinus and alongside the superior sagittal sinus. This flow strongly supports that a large proportion of the CNS lymphatic flow in humans is directed to the cribriform plate. The countercurrent direction of flow in the MLVs relative to venous flow in the superior sagittal sinus has implications for modeling flow of fluid and solutes across the various compartments of the CNS. A hypothetical compartmental model incorporating countercurrent flow is presented here.
ABSTRACT We report the detection of two new long-period giant planets orbiting the stars HD 95872 and HD 162004 ( Dra B) by the McDonald Observatory planet search. The planet HD 95872b has a minimum ...mass of 4.6 and an orbital semimajor axis of 5.2 AU. The giant planet Dra Bb has a minimum mass of 1.5 and an orbital semimajor axis of 4.4 AU. Both of these planets qualify as Jupiter analogs. These results are based on over one and a half decades of precise radial velocity (RV) measurements collected by our program using the McDonald Observatory Tull Coude spectrograph at the 2.7 m Harlan J. Smith Telescope. In the case of Dra B we also detect a long-term nonlinear trend in our data that indicates the presence of an additional giant planet, similar to the Jupiter-Saturn pair. The primary of the binary star system, Dra A, exhibits a very large amplitude RV variation due to another stellar companion. We detect this additional member using speckle imaging. We also report two cases-HD 10086 and HD 102870 (β Virginis)-of significant RV variation consistent with the presence of a planet, but that are probably caused by stellar activity, rather than reflexive Keplerian motion. These two cases stress the importance of monitoring the magnetic activity level of a target star, as long-term activity cycles can mimic the presence of a Jupiter-analog planet.
Levels of plasma SARS-CoV-2 nucleocapsid (N) antigen may be an important biomarker in patients with COVID-19 and enhance our understanding of the pathogenesis of COVID-19.
To evaluate whether levels ...of plasma antigen can predict short-term clinical outcomes and identify clinical and viral factors associated with plasma antigen levels in hospitalized patients with SARS-CoV-2.
Cross-sectional study of baseline plasma antigen level from 2540 participants enrolled in the TICO (Therapeutics for Inpatients With COVID-19) platform trial from August 2020 to November 2021, with additional data on day 5 outcome and time to discharge.
114 centers in 10 countries.
Adults hospitalized for acute SARS-CoV-2 infection with 12 days or less of symptoms.
Baseline plasma viral N antigen level was measured at a central laboratory. Delta variant status was determined from baseline nasal swabs using reverse transcriptase polymerase chain reaction. Associations between baseline patient characteristics and viral factors and baseline plasma antigen levels were assessed using both unadjusted and multivariable modeling. Association between elevated baseline antigen level of 1000 ng/L or greater and outcomes, including worsening of ordinal pulmonary scale at day 5 and time to hospital discharge, were evaluated using logistic regression and Fine-Gray regression models, respectively.
Plasma antigen was below the level of quantification in 5% of participants at enrollment, and 1000 ng/L or greater in 57%. Baseline pulmonary severity of illness was strongly associated with plasma antigen level, with mean plasma antigen level 3.10-fold higher among those requiring noninvasive ventilation or high-flow nasal cannula compared with room air (95% CI, 2.22 to 4.34). Plasma antigen level was higher in those who lacked antispike antibodies (6.42 fold; CI, 5.37 to 7.66) and in those with the Delta variant (1.73 fold; CI, 1.41 to 2.13). Additional factors associated with higher baseline antigen level included male sex, shorter time since hospital admission, decreased days of remdesivir, and renal impairment. In contrast, race, ethnicity, body mass index, and immunocompromising conditions were not associated with plasma antigen levels. Plasma antigen level of 1000 ng/L or greater was associated with a markedly higher odds of worsened pulmonary status at day 5 (odds ratio, 5.06 CI, 3.41 to 7.50) and longer time to hospital discharge (median, 7 vs. 4 days; subhazard ratio, 0.51 CI, 0.45 to 0.57), with subhazard ratios similar across all levels of baseline pulmonary severity.
Plasma samples were drawn at enrollment, not hospital presentation. No point-of-care test to measure plasma antigen is currently available.
Elevated plasma antigen is highly associated with both severity of pulmonary illness and clinically important patient outcomes. Multiple clinical and viral factors are associated with plasma antigen level at presentation. These data support a potential role of ongoing viral replication in the pathogenesis of SARS-CoV-2 in hospitalized patients.
U.S. government Operation Warp Speed and National Institute of Allergy and Infectious Diseases.
IMPORTANCE: The effect of continued treatment with tirzepatide on maintaining initial weight reduction is unknown. OBJECTIVE: To assess the effect of tirzepatide, with diet and physical activity, on ...the maintenance of weight reduction. DESIGN, SETTING, AND PARTICIPANTS: This phase 3, randomized withdrawal clinical trial conducted at 70 sites in 4 countries with a 36-week, open-label tirzepatide lead-in period followed by a 52-week, double-blind, placebo-controlled period included adults with a body mass index greater than or equal to 30 or greater than or equal to 27 and a weight-related complication, excluding diabetes. INTERVENTIONS: Participants (n = 783) enrolled in an open-label lead-in period received once-weekly subcutaneous maximum tolerated dose (10 or 15 mg) of tirzepatide for 36 weeks. At week 36, a total of 670 participants were randomized (1:1) to continue receiving tirzepatide (n = 335) or switch to placebo (n = 335) for 52 weeks. MAIN OUTCOMES AND MEASURES: The primary end point was the mean percent change in weight from week 36 (randomization) to week 88. Key secondary end points included the proportion of participants at week 88 who maintained at least 80% of the weight loss during the lead-in period. RESULTS: Participants (n = 670; mean age, 48 years; 473 71% women; mean weight, 107.3 kg) who completed the 36-week lead-in period experienced a mean weight reduction of 20.9%. The mean percent weight change from week 36 to week 88 was −5.5% with tirzepatide vs 14.0% with placebo (difference, −19.4% 95% CI, −21.2% to −17.7%; P < .001). Overall, 300 participants (89.5%) receiving tirzepatide at 88 weeks maintained at least 80% of the weight loss during the lead-in period compared with 16.6% receiving placebo (P < .001). The overall mean weight reduction from week 0 to 88 was 25.3% for tirzepatide and 9.9% for placebo. The most common adverse events were mostly mild to moderate gastrointestinal events, which occurred more commonly with tirzepatide vs placebo. CONCLUSIONS AND RELEVANCE: In participants with obesity or overweight, withdrawing tirzepatide led to substantial regain of lost weight, whereas continued treatment maintained and augmented initial weight reduction. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04660643
Microvascular abnormalities and impaired gas transfer have been observed in patients with COVID-19. The progression of pulmonary changes in these patients remains unclear.
Do patients hospitalized ...with COVID-19 without evidence of architectural distortion on structural imaging exhibit longitudinal improvements in lung function measured by using 1H and 129Xe MRI between 6 and 52 weeks following hospitalization?
Patients who were hospitalized with COVID-19 pneumonia underwent a pulmonary 1H and 129Xe MRI protocol at 6, 12, 25, and 51 weeks following hospital admission in a prospective cohort study between November 2020 and February 2022. The imaging protocol was as follows: 1H ultra-short echo time, contrast-enhanced lung perfusion, 129Xe ventilation, 129Xe diffusion-weighted, and 129Xe spectroscopic imaging of gas exchange.
Nine patients were recruited (age 57 ± 14 median ± interquartile range years; six of nine patients were male). Patients underwent MRI at 6 (n = 9), 12 (n = 9), 25 (n = 6), and 51 (n = 8) weeks following hospital admission. Patients with signs of interstitial lung damage were excluded. At 6 weeks, patients exhibited impaired 129Xe gas transfer (RBC to membrane fraction), but lung microstructure was not increased (apparent diffusion coefficient and mean acinar airway dimensions). Minor ventilation abnormalities present in four patients were largely resolved in the 6- to 25-week period. At 12 weeks, all patients with lung perfusion data (n = 6) showed an increase in both pulmonary blood volume and flow compared with 6 weeks, although this was not statistically significant. At 12 weeks, significant improvements in 129Xe gas transfer were observed compared with 6-week examinations; however, 129Xe gas transfer remained abnormally low at weeks 12, 25, and 51.
129Xe gas transfer was impaired up to 1 year following hospitalization in patients who were hospitalized with COVID-19 pneumonia, without evidence of architectural distortion on structural imaging, whereas lung ventilation was normal at 52 weeks.
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