Evaluating Vitamin C in Septic Shock: A Randomized Controlled Trial of Vitamin C Monotherapy.

OBJECTIVES: To determine whether IV vitamin C therapy reduces 28-day mortality in patients with septic shock. DESIGN: Multicenter, double-blinded, randomized controlled trial. SETTING: One academic medical ICU and four community ICUs. PATIENTS: Of 167 adult patients within 24 hours of vasopressor initiation for septic shock, 126 consented to participation, and 124 received study drug and were included in analysis. INTERVENTIONS: IV vitamin C (10 mg/mL in normal saline) administered as a 1,000-mg bolus over 30 minutes followed by continuous infusion of 250 mg/hr for 96 hours or placebo of equal volumes of normal saline. MEASUREMENTS AND MAIN RESULTS: Of 124 subjects receiving study drug and included in analysis, 60 received vitamin C and 64 placebo. The primary outcome of all-cause 28-day mortality (vitamin C, 26.7%; placebo, 40.6%; p = 0.10) was lower in the vitamin C arm but did not reach statistical significance. Initiation of renal replacement therapy was higher in the vitamin C arm (vitamin C, 16.7%; placebo, 3.3%; p = 0.015), as was volume of fluid administration within 6 hours of study drug initiation (vitamin C, 1.07 L; placebo, 0.76 L; p = 0.03). There were no statistically significant differences in other secondary outcomes. In post hoc subgroup analysis, there was a decrease in 28-day mortality in the vitamin C arm among patients requiring positive-pressure ventilation at the time of enrollment (vitamin C, 36.3%; placebo, 60.0%; p = 0.05). This trial is registered at clinicaltrials.gov under identifier NCT03338569. CONCLUSIONS: Vitamin C monotherapy failed to significantly reduce mortality in septic shock patients as hypothesized. Our findings do not support its routine clinical use for this purpose.

Delivering Interventions Via Telehealth: Functional Communication Training with a Child with Autism as a Case Example.

In this article, we provide a case example of how telehealth can be used by care providers in their homes to access empirically validated procedures such as functional communication training. As shown in the case example, complex assessment and intervention procedures were implemented successfully by care providers in their homes while receiving real-time coaching by behavior analysts who were located in a hospital in a different city. This case example is representative of the results we obtained thus far; substantial improvements in challenging and adaptive behavior occurred. Given these results obtained to date with telehealth, in terms of both outcomes of interventions and rated acceptability of the procedures by care providers, further and more widespread application of telehealth is warranted.

The Long-Term Effects of Functional Communication Training Conducted in Young Children's Home Settings.

This article describes the results of a series of studies that involved functional communication training (FCT) conducted in children's homes by their parents. The 103 children who participated were six years old or younger, had developmental delays, and engaged in destructive behaviors such as self-injury. The core procedures used in each study were functional analyses (FA) and FCT conducted by parents with coaching by the investigators. The overall results of the projects showed that the FA plus FCT intervention package produced substantial reductions in destructive behavior (M = 90%), which were often maintained following treatment. In terms of behavioral momentum theory, these results suggest that analyses of behavioral persistence provide an explicit technology of maintenance.

A comparative effectiveness trial of functional behavioral assessment methods.

Clinicians report primarily using functional behavioral assessment (FBA) methods that do not include functional analyses. However, studies examining the correspondence between functional analyses and other types of FBAs have produced inconsistent results. In addition, although functional analyses are considered the gold standard, their contribution toward successful treatment compared with other FBA methods remains unclear. This comparative effectiveness study, conducted with 57 young children with autism spectrum disorder, evaluated the results of FBAs that did (n = 26) and did not (n = 31) include a functional analysis. Results of FBAs with and without functional analyses showed modest correspondence. All participants who completed functional communication training achieved successful outcomes regardless of the type of FBA conducted.

AN EVALUATION OF RESURGENCE DURING FUNCTIONAL COMMUNICATION TRAINING.

Three children who displayed destructive behavior maintained by negative reinforcement received functional communication training (FCT). During FCT, the children were required to complete a demand and then to mand (touch a card attached to a microswitch, sign, or vocalize) to receive brief play breaks. Prior to and 1 to 3 times following the initiation of FCT, extinction probes were conducted to evaluate the resurgence of destructive behavior when the microswitch without the mand card was present or the microswitch and the mand card were absent to determine if different patterns of resurgence occurred when the microswitch was present or absent and, for 2 of the children, if changes in resurgence occurred at different points in treatment. Results showed that FCT led to relatively rapid reductions in destructive behavior. During all extinction sessions, resurgence of destructive behavior occurred with only minimal differences across the switch/no card and no-switch conditions.

Patient Outcomes and Unit Composition With Transition to a High-Intensity ICU Staffing Model: A Before-and-After Study.

Provider staffing models for ICUs are generally based on pragmatic necessities and historical norms at individual institutions. A better understanding of the role that provider staffing models play in determining patient outcomes and optimizing use of ICU resources is needed. OBJECTIVES: To explore the impact of transitioning from a low- to high-intensity intensivist staffing model on patient outcomes and unit composition. DESIGN SETTING AND PARTICIPANTS: This was a prospective observational before-and-after study of adult ICU patients admitted to a single community hospital ICU before (October 2016-May 2017) and after (June 2017-November 2017) the transition to a high-intensity ICU staffing model. MAIN OUTCOMES AND MEASURES: The primary outcome was 30-day all-cause mortality. Secondary outcomes included in-hospital mortality, ICU length of stay (LOS), and unit composition characteristics including type (e.g., medical, surgical) and purpose (ICU-specific intervention vs close monitoring only) of admission. RESULTS: For the primary outcome, 1,219 subjects were included (779 low-intensity, 440 high-intensity). In multivariable analysis, the transition to a high-intensity staffing model was not associated with a decrease in 30-day (odds ratio [OR], 0.90; 95% CI, 0.61-1.34; p = 0.62) or in-hospital (OR, 0.89; 95% CI, 0.57-1.38; p = 0.60) mortality, nor ICU LOS. However, the proportion of patients admitted to the ICU without an ICU-specific need did decrease under the high-intensity staffing model (27.2% low-intensity to 17.5% high-intensity; p < 0.001). CONCLUSIONS AND RELEVANCE: Multivariable analysis showed no association between transition to a high-intensity ICU staffing model and mortality or LOS outcomes; however, the proportion of patients admitted without an ICU-specific need decreased under the high-intensity model. Further research is needed to determine whether a high-intensity staffing model may lead to more efficient ICU bed usage.

Development of a proteomic signature associated with severe disease for patients with COVID-19 using data from 5 multicenter, randomized, controlled, and prospective studies.

Significant progress has been made in preventing severe COVID-19 disease through the development of vaccines. However, we still lack a validated baseline predictive biologic signature for the development of more severe disease in both outpatients and inpatients infected with SARS-CoV-2. The objective of this study was to develop and externally validate, via 5 international outpatient and inpatient trials and/or prospective cohort studies, a novel baseline proteomic signature, which predicts the development of moderate or severe (vs mild) disease in patients with COVID-19 from a proteomic analysis of 7000 + proteins. The secondary objective was exploratory, to identify (1) individual baseline protein levels and/or (2) protein level changes within the first 2 weeks of acute infection that are associated with the development of moderate/severe (vs mild) disease. For model development, samples collected from 2 randomized controlled trials were used. Plasma was isolated and the SomaLogic SomaScan platform was used to characterize protein levels for 7301 proteins of interest for all studies. We dichotomized 113 patients as having mild or moderate/severe COVID-19 disease. An elastic net approach was used to develop a predictive proteomic signature. For validation, we applied our signature to data from three independent prospective biomarker studies. We found 4110 proteins measured at baseline that significantly differed between patients with mild COVID-19 and those with moderate/severe COVID-19 after adjusting for multiple hypothesis testing. Baseline protein expression was associated with predicted disease severity with an error rate of 4.7% (AUC = 0.964). We also found that five proteins (Afamin, I-309, NKG2A, PRS57, LIPK) and patient age serve as a signature that separates patients with mild COVID-19 and patients with moderate/severe COVID-19 with an error rate of 1.77% (AUC = 0.9804). This panel was validated using data from 3 external studies with AUCs of 0.764 (Harvard University), 0.696 (University of Colorado), and 0.893 (Karolinska Institutet). In this study we developed and externally validated a baseline COVID-19 proteomic signature associated with disease severity for potential use in both outpatients and inpatients with COVID-19.

Cinematic virtual reality for anxiety management in mechanically ventilated patients: a feasibility and pilot study.

BACKGROUND: Mechanically ventilated patients experience anxiety for many reasons. Pharmacological treatments such as benzodiazepines are commonly employed to manage anxiety; however, these therapies often cause undesired side effects. Additional therapies for anxiety management are needed. We sought to determine whether cell phone-based virtual reality therapy could feasibly be used for anxiety management in mechanically ventilated patients. METHODS: Mechanically ventilated subjects underwent at least one session of virtual reality therapy in which they were shown a cinematic video of an outdoor green space or blue space with 360° visual range of motion. Goal session duration was 5 minutes. The primary outcome was incidence of predefined patient safety events, including self-extubation and accidental removal of tubes or lines. RESULTS: Ten subjects underwent a total of 18 virtual reality sessions. Fifteen sessions lasted the planned 5 minutes, one session was extended at participant request, and two sessions were terminated early at participant request. There were no occurrences of the predefined safety events, and no occurrences of cybersickness. Use of a visual analog scale to measure anxiety level was feasible for this pilot study, demonstrating feasibility of this scale for future, larger scale studies. CONCLUSIONS: Virtual reality therapy shows potential as a means of managing anxiety in patients undergoing mechanical ventilation, and further rigorous exploration with this protocol is feasible.

Parent Ratings of Generalized and Indirect Effects of Functional Communication Training for Children with Autism Spectrum Disorder.

Functional communication training (FCT) is a behavioral treatment that has been shown to reduce problem behavior and increase appropriate communication in young children with autism spectrum disorder (ASD). In this study, we assessed the effects of FCT on targeted and nontargeted problem behaviors outside of the training context, as well as parent stress, for 30 young children with ASD and their parents. Indirect measures of generalization treatment effects were administered prior to and following FCT treatment delivered via telehealth. Children demonstrated significant improvement on both targeted (measured via observation) and nontargeted (measured via checklist) problem behaviors, both within and outside of the training context, and parent stress was significantly reduced following treatment. These results suggest that the impact of FCT may extend beyond the training context for both the children being treated and the parents delivering treatment, even when generalization is not specifically programmed for during treatment.

Efficacy of Losartan in Hospitalized Patients With COVID-19-Induced Lung Injury: A Randomized Clinical Trial.

Importance: SARS-CoV-2 viral entry may disrupt angiotensin II (AII) homeostasis, contributing to COVID-19 induced lung injury. AII type 1 receptor blockade mitigates lung injury in preclinical models, although data in humans with COVID-19 remain mixed. Objective: To test the efficacy of losartan to reduce lung injury in hospitalized patients with COVID-19. Design, Setting, and Participants: This blinded, placebo-controlled randomized clinical trial was conducted in 13 hospitals in the United States from April 2020 to February 2021. Hospitalized patients with COVID-19 and a respiratory sequential organ failure assessment score of at least 1 and not already using a renin-angiotensin-aldosterone system (RAAS) inhibitor were eligible for participation. Data were analyzed from April 19 to August 24, 2021. Interventions: Losartan 50 mg orally twice daily vs equivalent placebo for 10 days or until hospital discharge. Main Outcomes and Measures: The primary outcome was the imputed arterial partial pressure of oxygen to fraction of inspired oxygen (Pao2:Fio2) ratio at 7 days. Secondary outcomes included ordinal COVID-19 severity; days without supplemental o2, ventilation, or vasopressors; and mortality. Losartan pharmacokinetics and RAAS components (AII, angiotensin-[1-7] and angiotensin-converting enzymes 1 and 2)] were measured in a subgroup of participants. Results: A total of 205 participants (mean [SD] age, 55.2 [15.7] years; 123 [60.0%] men) were randomized, with 101 participants assigned to losartan and 104 participants assigned to placebo. Compared with placebo, losartan did not significantly affect Pao2:Fio2 ratio at 7 days (difference, -24.8 [95%, -55.6 to 6.1]; P = .12). Compared with placebo, losartan did not improve any secondary clinical outcomes and led to fewer vasopressor-free days than placebo (median [IQR], 9.4 [9.1-9.8] vasopressor-free days vs 8.7 [8.2-9.3] vasopressor-free days). Conclusions and Relevance: This randomized clinical trial found that initiation of orally administered losartan to hospitalized patients with COVID-19 and acute lung injury did not improve Pao2:Fio2 ratio at 7 days. These data may have implications for ongoing clinical trials. Trial Registration: ClinicalTrials.gov Identifier: NCT04312009.

Indirect Effects of Functional Communication Training on Non-Targeted Disruptive Behavior.

The purpose of this study was to evaluate the effects of functional communication training (FCT) on the occurrence of non-targeted disruptive behavior. The 10 participants were preschool-aged children with developmental disabilities who engaged in both destructive (property destruction, aggression, self-injury) and disruptive (hand flapping, spinning in circles, shrill laughter, screaming, crying) behaviors. Only destructive behavior was targeted for the functional analyses and FCT, but data were also collected on disruptive behaviors. All procedures were conducted in the participants' homes by their mothers with investigator coaching. Phase 1 consisted of conducting a functional analysis within a multielement design. Phase 2 consisted of conducting FCT with demand fading and repeated extinction baselines within a reversal design. Single-case data are provided for 3 participants, and summary data are provided for all 10 participants. Results of phase 1 showed that all participants' destructive and disruptive behavior was maintained, at least in part, by negative reinforcement. Results of phase 2 showed that both destructive behavior and non-targeted disruptive behavior occurred at lower levels during FCT when compared to the functional analysis demand condition and baseline conditions, suggesting that FCT was effective in decreasing both target destructive behavior and non-targeted disruptive behaviors.

A Preliminary Evaluation of Functional Communication Training Effectiveness and Language Preference When Spanish and English are Manipulated.

We evaluated whether differences in treatment effectiveness or preference between languages emerged across Spanish and English during functional communication training (FCT) for young children with developmental disabilities exposed to Spanish and English in the home environment. Participants were 2 young children with developmental disabilities who displayed destructive behavior maintained by social contingencies and whose families spoke Spanish and English at home. All procedures were conducted in the participants' homes by their mothers with coaching from the investigator. The effectiveness of FCT was evaluated within a reversal design across baseline, FCT, and extinction conditions. A multielement design across language type (Spanish and English) was embedded within the reversal design during the extinction and FCT conditions to evaluate differences in treatment effectiveness across type of language. Finally, during all FCT sessions, a concurrent schedules design was used to evaluate participant preference for type of language. Results suggested that FCT was effective in reducing destructive behavior, increasing manding, and/or increasing task completion for these 2 participants across Spanish and English treatment conditions. Preference for the type of language did not emerge for either participant during FCT. Results are discussed in terms of the merits of systematically evaluating language variables when working with culturally and linguistically diverse families and children.

A multi-center phase II randomized clinical trial of losartan on symptomatic outpatients with COVID-19.

BACKGROUND: The SARS-CoV-2 virus enters cells via Angiotensin-converting enzyme 2 (ACE2), disrupting the renin-angiotensin-aldosterone axis, potentially contributing to lung injury. Treatment with angiotensin receptor blockers (ARBs), such as losartan, may mitigate these effects, though induction of ACE2 could increase viral entry, replication, and worsen disease. METHODS: This study represents a placebo-controlled blinded randomized clinical trial (RCT) to test the efficacy of losartan on outpatients with COVID-19 across three hospital systems with numerous community sites in Minnesota, U.S. Participants included symptomatic outpatients with COVID-19 not already taking ACE-inhibitors or ARBs, enrolled within 7 days of symptom onset. Patients were randomized to 1:1 losartan (25 mg orally twice daily unless estimated glomerular filtration rate, eGFR, was reduced, when dosing was reduced to once daily) versus placebo for 10 days, and all patients and outcome assesors were blinded. The primary outcome was all-cause hospitalization within 15 days. Secondary outcomes included functional status, dyspnea, temperature, and viral load. (clinicatrials.gov, NCT04311177, closed to new participants). FINDINGS: From April to November 2020, 117 participants were randomized 58 to losartan and 59 to placebo, and all were analyzed under intent to treat principles. The primary outcome did not differ significantly between the two arms based on Barnard's test [losartan arm: 3 events (5.2% 95% CI 1.1, 14.4%) versus placebo arm: 1 event (1.7%; 95% CI 0.0, 9.1%)]; proportion difference -3.5% (95% CI -13.2, 4.8%); p = 0.32]. Viral loads were not statistically different between treatment groups at any time point. Adverse events per 10 patient days did not differ signifcantly [0.33 (95% CI 0.22-0.49) for losartan vs. 0.37 (95% CI 0.25-0.55) for placebo]. Due to a lower than expected hospitalization rate and low likelihood of a clinically important treatment effect, the trial was terminated early. INTERPRETATION: In this multicenter blinded RCT for outpatients with mild symptomatic COVID-19 disease, losartan did not reduce hospitalizations, though assessment was limited by low event rate. Importantly, viral load was not statistically affected by treatment. This study does not support initiation of losartan for low-risk outpatients.

The DNA binding and catalytic domains of poly(ADP-ribose) polymerase 1 cooperate in the regulation of chromatin structure and transcription.

We explored the mechanisms of chromatin compaction and transcriptional regulation by poly(ADP-ribose) polymerase 1 (PARP-1), a nucleosome-binding protein with an NAD(+)-dependent enzymatic activity. By using atomic force microscopy and a complementary set of biochemical assays with reconstituted chromatin, we showed that PARP-1 promotes the localized compaction of chromatin into supranucleosomal structures in a manner independent of the amino-terminal tails of core histones. In addition, we defined the domains of PARP-1 required for nucleosome binding, chromatin compaction, and transcriptional repression. Our results indicate that the DNA binding domain (DBD) of PARP-1 is necessary and sufficient for binding to nucleosomes, yet the DBD alone is unable to promote chromatin compaction and only partially represses RNA polymerase II-dependent transcription in an in vitro assay with chromatin templates (approximately 50% of the repression observed with wild-type PARP-1). Furthermore, our results show that the catalytic domain of PARP-1, which does not bind nucleosomes on its own, cooperates with the DBD to promote chromatin compaction and efficient transcriptional repression in a manner independent of its enzymatic activity. Collectively, our results have revealed a novel function for the catalytic domain in chromatin compaction. In addition, they show that the DBD and catalytic domain cooperate to regulate chromatin structure and chromatin-dependent transcription, providing mechanistic insights into how these domains contribute to the chromatin-dependent functions of PARP-1.

Analysis of Mand Selection across Different Stimulus Conditions.

We conducted a three-phase study to evaluate the use of mands and the occurrence of problem behavior for 2 children with developmental disabilities. During Phase 1, a functional analysis identified the variables maintaining problem behavior. During Phase 2, functional communication training was implemented within a concurrent schedules design. The children were reinforced for using either a novel mand (communication card) or other existing mands (vocal speech, manual signs) that were not specifically trained but were observed to be part of the children's existing repertoire. We then conducted an assessment of mands and problem behavior across different stimulus conditions (card absent, card present) within an ABAB design (Phase 3). Results showed that during Phase 2, problem behavior decreased and participants used the card more frequently than they used other existing mands. Phase 3 showed that problem behavior remained low across both stimulus conditions. When the card was absent, the children used other existing mands; when the card was present, they primarily used the card. These results suggested that the presence of a communication card may function as a discriminative stimulus for a specific topography of manding, but that training with the card did not inhibit the use of other mands when the card was absent.

Functional assessment and function-based treatment delivered via telehealth: A brief summary.

As the world navigates the COVID-19 health crisis, behavior analysts are considering how best to support families while maintaining services and ensuring the health and safety of everyone involved. Telehealth is one service delivery option that provides families with access to care in their own communities and homes. In this article, we provide a brief summary of the telehealth literature in applied behavior analysis that provided coaching and training to families for individuals who displayed challenging behavior. These studies targeted functional assessment and function-based treatment for challenging behavior. We briefly summarize what is known relative to the assessment and treatment of challenging behavior via telehealth, place these results within a descriptive context of the decisions made by the research team at the University of Iowa, and discuss what we, as behavior analysts, should consider next to advance our understanding and practice of telehealth.

An evaluation of resurgence following functional communication training conducted in alternative antecedent contexts via telehealth.

Treatments based on differential reinforcement may inadvertently increase the recurrence of problem behavior in the face of challenges because reinforcers for appropriate behavior occur in the same context as problem behavior. The current study evaluated one potential approach to mitigating these problems with differential reinforcement treatments based on behavioral momentum theory. Specifically, appropriate behavior was trained in contexts without a history of reinforcement prior to intervening with problem behavior. Participants were 4 children with autism spectrum disorder. Treatment used telehealth to implement functional communication training (FCT) in three alternative contexts with minimal or no history of reinforcement for problem behavior before initiating FCT in the treatment context. Evaluations of the effects of treatment and tests of resurgence were conducted intermittently during treatment to evaluate maintenance. When FCT treatment was initiated in alternative contexts, initial results were comparable to more typical implementations of FCT. Resurgence was reduced to similar levels during tests of resurgence for all participants when compared to more typical previously published implementations of FCT, but clinically significant reductions in resurgence occurred more quickly in the present study. These findings support training appropriate behavior in an alternative context to mitigate the resurgence of problem behavior during differential reinforcement treatments.

A Randomized Controlled Trial of Functional Communication Training via Telehealth for Young Children with Autism Spectrum Disorder.

Many children with autism spectrum disorder (ASD) have problem behaviors that interfere with learning and social interaction. This randomized controlled trial compared treatment with functional communication training (FCT) to "treatment as usual" for young children with ASD (n = 38, ages 21-84 months). FCT was conducted by parents with training and real-time coaching provided by behavioral consultants using telehealth. FCT treatment via telehealth achieved a mean reduction in problem behavior of 98% compared to limited behavioral improvement in children receiving "treatment as usual" during a 12-week period. Social communication and task completion also improved. For children with ASD and moderate to severe behavior problems, parent-implemented FCT using telehealth significantly reduced problem behavior while ongoing interventions typically did not.

From sextant to GPS: twenty-five years of mapping the genome with ChIP.

Since its inception, ChIP technology has evolved immensely. Technological advances have improved its specificity and sensitivity, its scale has expanded to a genome-wide level, and its relative ease of use has made it a virtually ubiquitous tool. This year marks the 25th anniversary of the development of ChIP. In honor of this milestone, we briefly revisit its history, offer a review of recent articles employing ChIP on a genome-wide scale, and lay out our views for the future of ChIP.