Acetaminophen for Prevention and Treatment of Organ Dysfunction in Critically Ill Patients With Sepsis: The ASTER Randomized Clinical Trial.

Importance: Acetaminophen (paracetamol) has many pharmacological effects that might be beneficial in sepsis, including inhibition of cell-free hemoglobin-induced oxidation of lipids and other substrates. Objective: To determine whether acetaminophen increases days alive and free of organ dysfunction in sepsis compared with placebo. Design, Setting, and Participants: Phase 2b randomized, double-blind, clinical trial conducted from October 2021 to April 2023 with 90-day follow-up. Adults with sepsis and respiratory or circulatory organ dysfunction were enrolled in the emergency department or intensive care unit of 40 US academic hospitals within 36 hours of presentation. Intervention: Patients were randomized to 1 g of acetaminophen intravenously every 6 hours or placebo for 5 days. Main Outcome and Measures: The primary end point was days alive and free of organ support (mechanical ventilation, vasopressors, and kidney replacement therapy) to day 28. Treatment effect modification was evaluated for acetaminophen by prerandomization plasma cell-free hemoglobin level higher than 10 mg/dL. Results: Of 447 patients enrolled (mean age, 64 [SD, 15] years, 51% female, mean Sequential Organ Failure Assessment [SOFA] score, 5.4 [SD, 2.5]), 227 were randomized to acetaminophen and 220 to placebo. Acetaminophen was safe with no difference in liver enzymes, hypotension, or fluid balance between treatment arms. Days alive and free of organ support to day 28 were not meaningfully different for acetaminophen (20.2 days; 95% CI, 18.8 to 21.6) vs placebo (19.6 days; 95% CI, 18.2 to 21.0; P = .56; difference, 0.6; 95% CI, -1.4 to 2.6). Among 15 secondary outcomes, total, respiratory, and coagulation SOFA scores were significantly lower on days 2 through 4 in the acetaminophen arm as was the rate of development of acute respiratory distress syndrome within 7 days (2.2% vs 8.5% acetaminophen vs placebo; P = .01; difference, -6.3; 95% CI, -10.8 to -1.8). There was no significant interaction between cell-free hemoglobin levels and acetaminophen. Conclusions and Relevance: Intravenous acetaminophen was safe but did not significantly improve days alive and free of organ support in critically ill sepsis patients. Trial Registration: ClinicalTrials.gov Identifier: NCT04291508.

Angiotensin II in liver transplantation (AngLT-1): protocol of a randomised, double-blind, placebo-controlled trial.

INTRODUCTION: Catecholamine vasopressors such as norepinephrine are the standard drugs used to maintain mean arterial pressure during liver transplantation. At high doses, catecholamines may impair organ perfusion. Angiotensin II is a peptide vasoconstrictor that may improve renal perfusion pressure and glomerular filtration rate, a haemodynamic profile that could reduce acute kidney injury. Angiotensin II is approved for vasodilatory shock but has not been rigorously evaluated for treatment of hypotension during liver transplantation. The objective is to assess the efficacy of angiotensin II as a second-line vasopressor infusion during liver transplantation. This trial will establish the efficacy of angiotensin II in decreasing the dose of norepinephrine to maintain adequate blood pressure. Completion of this study will allow design of a follow-up, multicentre trial powered to detect a reduction of organ injury in liver transplantation. METHODS AND ANALYSIS: This is a double-blind, randomised clinical trial. Eligible subjects are adults with a Model for End-Stage Liver Disease Sodium Score ≥25 undergoing deceased donor liver transplantation. Subjects are randomised 1:1 to receive angiotensin II or saline placebo as the second-line vasopressor infusion. The study drug infusion is initiated on reaching a norepinephrine dose of 0.05 µg kg-1 min-1 and titrated per protocol. The primary outcome is the dose of norepinephrine required to maintain a mean arterial pressure ≥65 mm Hg. Secondary outcomes include vasopressin or epinephrine requirement and duration of hypotension. Safety outcomes include incidence of thromboembolism within 48 hours of the end of surgery and severe hypertension. An intention-to-treat analysis will be performed for all randomised subjects receiving the study drug. The total dose of norepinephrine will be compared between the two arms by a one-tailed Mann-Whitney U test. ETHICS AND DISSEMINATION: The trial protocol was approved by the local Institutional Review Board (#20-30948). Results will be posted on ClinicalTrials.gov and published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: ClinicalTrials.govNCT04901169.

Aquatic macrophytes show distinct spatial trends in contaminant metal and nutrient concentrations in Coeur d'Alene Lake, USA.

Coeur d'Alene Lake (the Lake) has received significant contamination from legacy mining. Aquatic macrophytes provide important ecosystem services, such as food or habitat, but also have the ability to accumulate contaminants. We examined contaminants (arsenic, cadmium, copper, lead, and zinc) and other analytes (e.g., iron, phosphorus, and total Kjeldahl nitrogen (TKN)) in macrophytes from the Lake. Macrophytes were collected in the Lake from the uncontaminated southern end to the outlet of the Coeur d'Alene River (main contaminant source) located northward and mid lake. Most analytes showed significant north to south trends (Kendall's tau p ≤ 0.015). Concentrations of cadmium (18.2 ± 12.1), copper (13.0 ± 6.6), lead (195 ± 193), and zinc (1128 ± 523) were highest in macrophytes near the Coeur d'Alene River outlet (mean ± standard deviation in mg/kg dry biomass). Conversely, aluminum, iron, phosphorus, and TKN were highest in macrophytes from the south, potentially related to the Lake's trophic gradient. Generalized additive modelling confirmed latitudinal trends, but revealed that longitude and depth were also important predictors of analyte concentration (40-95% deviance explained for contaminants). We used sediment and soil screening benchmarks to calculate toxicity quotients. Quotients were used to assess potential toxicity to macrophyte associated biota and delineate where macrophyte concentrations exceeded local background concentrations. Exceedances (toxicity quotient > one) of background levels by macrophyte concentrations were highest for zinc (86%), followed by cadmium (84%), lead (23%), and arsenic (5%).

Promoting a research culture in family medicine: Five years of scholarly works and activities group.

BACKGROUND: The professional advancement of Family Medicine faculty requires contributions in the form of clinical service, teaching, and scholarly activity. While teaching and clinical work are part of the everyday routine of faculty members, a research culture can be challenging to build. METHODS: Our department started a Scholarly Works and Activities Group (SWAG). The group's aim is to promote a collegial, collaborative research culture in the department. Meetings occur monthly, and faculty have the opportunity to discuss scholarly projects with peers, as well as promotion/tenure goals. Minutes from each meeting are sent to all faculty members in the department. The aim of this retrospective study was to determine if SWAG meetings impacted faculty scholarly activity. Data were collected on presentations, publications, and collaborations from Curriculum Vitae (CVs), and were compared between 5 years prior to the intervention and the 5 years since. RESULTS: Results indicated increased scholarly activity in the time period during the SWAG group meetings. Faculty presentations increased by 34% while faculty publications more than doubled (221% increase), with publications constituting a small Cohen's d effect size. Interestingly, faculty collaboration did not increase. Two faculty members were promoted during the 5 years study period, and the total number of faculty who published went from three to eight. CONCLUSIONS: Implementation of a monthly SWAG meeting led to an increase in faculty peer reviewed publications. Furthermore, two faculty members were promoted during the time of the intervention. A monthly faculty meeting, even when brief, can help promote and build a research culture.

How to screen for and treat teen alcohol use.

A full biopsychosocial interview is key, including use of an efficient tool such as the S2BI questionnaire to quickly stratify risk level and to guide follow-up decisions.

Contaminant metal concentrations in three species of aquatic macrophytes from the Coeur d'Alene Lake basin, USA.

The Coeur d'Alene Lake basin in Northwestern USA has extensive contamination from legacy mining waste, which overlaps with aquatic macrophyte habitat. We examined concentrations of arsenic (As), cadmium (Cd), copper (Cu), lead (Pb), and zinc (Zn) in three macrophytes: Elodea canadensis (submerged), Myriophyllum spicatum (submerged), and Sagittaria latifolia (emergent). We collected macrophyte tissues from five contaminated sites and one uncontaminated site. Tissue concentrations were compared to sediment quality guidelines to assess potential toxicity from metal(loid)s to macrophyte-associated biota. We used threshold and probable effect concentrations to screen for potential toxicity. For the submerged species, the highest site means ± SD (analyte mg/kg dry mass) were 96 ± 61 (As), 18 ± 1.7 (Cd), 24 ± 15 (Cu), 610 ± 392 (Pb), and 1425 ± 222 (Zn). For contaminated sites, the probable effect threshold was exceeded in 38% (As), 45% (Cd), 0% (Cu), 74% (Pb), and 67% (Zn) of submerged species concentrations. Metal concentrations in S. latifolia tubers were lower than the submerged species leaves and shoots. Tuber concentrations did not exceed the probable effect threshold for any metal. Spatial differences in concentrations were most distinct for the submerged species. Our work shows significant amounts of metals are accumulating in some macrophytes of the study area and that biota associated with this vegetation may experience toxicity based upon guideline exceedances. Additionally, managers of invasive plants (e.g., M. spicatum) should consider the ramifications of control efforts given the high metal content of some plants (e.g., disposal issue).

Clinical Quality Measure Exchange is Not Easy.

PURPOSE: The Trial of Aggregate Data Exchange for Maintenance of Certification and Raising Quality was a randomized controlled trial which first had to test whether quality reporting could be a by-product of clinical care. We report on the initial descriptive study of the capacity for and quality of exchange of whole-panel, standardized quality measures from health systems. METHODS: Family physicians were recruited from 4 health systems with mature quality measurement programs and agreed to submit standardized, physician-level quality measures for consenting physicians. Identified measure or transfer errors were captured and evaluated for root-cause problems. RESULTS: The health systems varied considerably by patient demographics and payer mix. From the 4 systems, 256 family physicians elected to participate. Of 19 measures negotiated for use, 5 were used by all systems. There were more than 15 types of identified errors including breaks in data delivery, changes in measures, and nonsensical measure results. Only 1 system had no identified errors. CONCLUSIONS: The secure transfer of standardized, physician-level quality measures from 4 health systems with mature measure processes proved difficult. There were many errors that required human intervention and manual repair, precluding full automation. This study reconfirms an important problem, namely, that despite widespread health information technology adoption and federal meaningful use policies, we remain far from goals to make clinical quality reporting a reliable by-product of care.

Bipolar disorder: Managing the peaks and valleys.

Bipolar disorder is a psychiatric illness that is relatively common among patients presenting for treatment in primary care clinics. Physicians in primary care often face difficult decisions about how and when to intervene when a patient is experiencing depressive, manic, or hypomanic episodes consistent with bipolar disorder. This article reviews the literature on how to assess and diagnose bipolar disorder in primary care, and how to choose from the array of treatment options that exist. The psychotherapy and pharmacotherapy evidence base provides guidance on how to help patients effectively manage this ailment. Collaboration among health and mental health practitioners is key in helping manage the "peaks and valleys" of bipolar disorder. Special considerations need to be made to routinely assess for impulsivity, suicidality, and patient progress throughout the course of treatment.

Open-Label Phase 1 Futility Studies of Salsalate and Young Plasma in Progressive Supranuclear Palsy.

BACKGROUND: Progressive supranuclear palsy (PSP) is a neurodegenerative disease without approved therapies, and therapeutics are often tried off-label in the hope of slowing disease progression. Results from these experiences are seldom shared, which limits evidence-based knowledge to guide future treatment decisions. OBJECTIVES: To describe an open-label experience, including safety/tolerability, and longitudinal changes in biomarkers of disease progression in PSP-Richardson's syndrome (PSP-RS) patients treated with either salsalate or young plasma and compare to natural history data from previous multicenter studies. METHODS: For 6 months, 10 PSP-RS patients received daily salsalate 2,250 mg, and 5 patients received monthly infusions of four units of young plasma. Every 3 months, clinical severity was assessed with the Progressive Supranuclear Palsy Rating Scale (PSPRS), and MRI was obtained for volumetric measurement of midbrain. A range of exploratory biomarkers, including cerebrospinal fluid levels of neurofilament light chain, were collected at baseline and 6 months. Interventional data were compared to historical PSP-RS patients from the davunetide clinical trial and the 4-Repeat Tauopathy Neuroimaging Initiative. RESULTS: Salsalate and young plasma were safe and well tolerated. PSPRS change from baseline (mean ± standard deviation [SD]) was similar in salsalate (+5.6 ± 9.6), young plasma (+5.0 ± 7.1), and historical controls (+5.6 ± 7.1), and change in midbrain volume (cm3 ± SD) did not differ between salsalate (-0.07 ± 0.03), young plasma (-0.06 ± 0.03), and historical controls (-0.06 ± 0.04). No differences were observed between groups on any exploratory endpoint. CONCLUSIONS: Neither salsalate nor young plasma had a detectable effect on disease progression in PSP-RS. Focused open-label clinical trials incorporating historical clinical, neuropsychological, fluid, and imaging biomarkers provide useful preliminary data about the promise of novel PSP-directed therapies.

A practical guide to the management of phobias.

When a patient reports symptoms suggestive of phobia, ask questions designed to clarify thoughts and behaviors. A 4-step exposure therapy plan can also help.

How to treat complicated grief.

Several DSM-5 criteria lasting 6 months or longer can help identify complicated grief, as can available assessment tools. Treatment has a unique focus.

Effectiveness of a Mailed Colorectal Cancer Screening Outreach Program in Community Health Clinics: The STOP CRC Cluster Randomized Clinical Trial.

Importance: Approximately 24 million US individuals receive care at federally qualified health centers, which historically have low rates of colorectal cancer screening. The US Preventive Services Task Force recommends routine colorectal cancer screening for individuals aged 50 to 75 years. Objective: To determine the effectiveness of an electronic health record (EHR)-embedded mailed fecal immunochemical test (FIT) outreach program implemented in health centers as part of standard care. Design, Setting, and Participants: This cluster randomized pragmatic clinical trial was conducted in 26 federally qualified health center clinics, representing 8 health centers in Oregon and California, randomized to intervention (n = 13) or usual care (n = 13). All participants were overdue for colorectal cancer screening during the accrual interval (February 4, 2014 to February 3, 2015). Interventions: Electronic health record-embedded tools to identify eligible adults and to facilitate implementation of a stepwise mailed intervention involving (1) an introductory letter, (2) a mailed FIT, and (3) a reminder letter; training, collaborative learning, and facilitation through a practice improvement process. Main Outcomes and Measures: Effectiveness was measured as clinic-level proportions of adults who completed a FIT, and secondarily, any colorectal cancer screening within 12 months of accrual or by August 3, 2015. Implementation was measured as clinic-level proportions of adults who were mailed an introductory letter and ordered a FIT. Results: Twenty-six clinics with 41 193 adults (mean [SD] age, 58.5 [6.3] years; 22 994 women) were randomized to receive the direct mail colorectal screening intervention (13 clinics; 21 134 patients) or usual care (13 clinics; 20 059 patients). Compared with usual care clinics, intervention clinics had significantly higher adjusted clinic-level proportion of participants who completed a FIT (13.9% vs 10.4%; difference, 3.4 percentage points; 95% CI, 0.1%-6.8%) and any colorectal cancer screening (18.3% vs 14.5%; difference, 3.8 percentage points; 95% CI, 0.6%-7.0%). We observed large variation across health centers in effectiveness (FIT completion differences range, -7.4 percentage points to 17.6 percentage points) and implementation (proportion who were mailed a FIT range, 6.5% to 68.2%). The number needed to mail to achieve a completed FIT was 4.8 overall, and 4.0 in clinics that mailed a FIT reminder. Conclusions and Relevance: An EHR-embedded mailed FIT outreach intervention significantly improved rates of FIT completion and rates of any colorectal cancer screening. Higher rates of colorectal cancer screening occurred in clinics that successfully implemented the mailed outreach program. Trial Registration: ClinicalTrials.gov identifier: NCT01742065.

Building Meaningful Patient Engagement in Research: Case Study From ADVANCE Clinical Data Research Network.

BACKGROUND: Strategies to engage patients to improve and enhance research and clinical care are increasingly being implemented in the United States, yet little is known about best practices for or the impacts of meaningful patient engagement. OBJECTIVE: We describe and reflect on our patient stakeholder groups, engagement framework, experiences, and lessons learned in engaging patients in research, from generating proposal ideas to disseminating findings. SETTING: The ADVANCE (Accelerating Data Value Across a National Community Health Center Network) clinical data research network is the nation's largest clinical dataset on the safety net, with outpatient clinical data from 122 health systems (1109 clinics) in 23 states. RESULTS: Patients stakeholders codeveloped the ADVANCE engagement framework and its implementation in partnership with network leaders. In phase I of ADVANCE, patients were involved with designing studies (input on primary outcome measures and methods) and usability testing (of the patient portal). In phase II, the network is prioritizing research training, dissemination opportunities, an "ambassador" program to pair more experienced patient stakeholders with those less experienced, and evaluation of engagement activities and impacts. DISCUSSION: The ADVANCE framework for patient engagement has successfully involved a diverse group of patients in the design, implementation, and interpretation of comparative effectiveness research. Our experience and framework can be used by other organizations and research networks to support patient engagement activities.

Inhibition of ATR acutely sensitizes acute myeloid leukemia cells to nucleoside analogs that target ribonucleotide reductase.

The ataxia telangiectasia and Rad3-related (ATR) protein kinase promotes cancer cell survival by signaling stalled replication forks generated by replication stress, a common feature of many cancers including acute myeloid leukemia (AML). Here we show that the antileukemic activity of the chemotherapeutic nucleoside analogs hydroxyurea and gemcitabine was significantly potentiated by ATR inhibition via a mechanism involving ribonucleotide reductase (RNR) abrogation and inhibition of replication fork progression. When administered in combination with gemcitabine, an inhibitor of the M1 RNR subunit, the ATR inhibitor VX-970, eradicated disseminated leukemia in an orthotopic mouse model, eliciting long-term survival and effective cure. These data identify a synergistic interaction between ATR inhibition and RNR loss that will inform the deployment of small molecule inhibitors for the treatment of AML and other hematologic malignancies.

An 8-week, open-label, dose-finding study of nimodipine for the treatment of progranulin insufficiency from GRN gene mutations.

INTRODUCTION: Frontotemporal lobar degeneration-causing mutations in the progranulin (GRN) gene reduce progranulin protein (PGRN) levels, suggesting that restoring PGRN in mutation carriers may be therapeutic. Nimodipine, a Food and Drug Administration-approved blood-brain barrier-penetrant calcium channel blocker, increased PGRN levels in PGRN-deficient murine models. We sought to assess safety and tolerability of oral nimodipine in human GRN mutation carriers. METHODS: We performed an open-label, 8-week, dose-finding, phase 1 clinical trial in eight GRN mutation carriers to assess the safety and tolerability of nimodipine and assayed fluid and radiologic markers to investigate therapeutic endpoints. RESULTS: There were no serious adverse events; however, PGRN concentrations (cerebrospinal fluid and plasma) did not change significantly following treatment (percent changes of -5.2 ± 10.9% in plasma and -10.2 ± 7.8% in cerebrospinal fluid). Measurable atrophy within the left middle frontal gyrus was observed over an 8-week period. DISCUSSION: While well tolerated, nimodipine treatment did not alter PGRN concentrations or secondary outcomes.

Adult ADHD: Addressing a unique set of challenges.

ADHD diagnostic criteria are different for adults than they are for children. Plus, prescribing psychostimulants for adults raises the risk of misuse and diversion.