Efficacy of long-term risankizumab treatment for moderate-to-severe plaque psoriasis: Subgroup analyses by baseline characteristics and psoriatic disease manifestations through 256 weeks (LIMMitless trial).

BACKGROUND: Psoriasis is an inflammatory skin disease that impacts a heterogeneous group of patients and can have multiple clinical manifestations. Risankizumab is approved for the treatment of moderate-to-severe plaque psoriasis. OBJECTIVES: To evaluate the long-term efficacy of risankizumab according to baseline patient characteristics, and for the treatment of high-impact disease manifestations (nail, scalp and palmoplantar psoriasis), through 256 weeks of continuous treatment in the phase 3 LIMMitless study. METHODS: This subgroup analysis evaluated pooled data from patients with moderate-to-severe plaque psoriasis who were randomized to risankizumab 150 mg during two double-blind, phase 3, 52-week base studies (UltIMMa-1/2; NCT02684370/NCT02684357) and were enrolled in the phase 3 LIMMitless open-label extension study (NCT03047395). Subgroup assessments included the proportion of patients who achieved ≥90%/100% improvement in Psoriasis Area and Severity Index (PASI 90/100). Among patients with nail, scalp and/or palmoplantar psoriasis in addition to skin psoriasis, assessments included changes from baseline in and resolution of these three psoriatic manifestations. RESULTS: Overall, a numerically similar proportion of patients (N = 525) achieved PASI 90/100 through Week 256, regardless of their baseline age, sex, body mass index, weight, PASI or psoriatic arthritis status. Patients with nail, scalp and/or palmoplantar psoriasis experienced substantial improvements in manifestation-specific indices (mean improvement from baseline to Week 256 of >81%, >94% and >97%, respectively); in patients with all three manifestations (N = 121), 44.6% achieved complete clearance of these manifestations at Week 256. CONCLUSIONS: Risankizumab demonstrated generally consistent efficacy through 256 weeks across patient subgroups and showed durable long-term efficacy for psoriatic disease manifestations.

Long-term safety and efficacy of risankizumab for the treatment of moderate-to-severe plaque psoriasis: Interim analysis of the LIMMitless open-label extension trial up to 5 years of follow-up.

BACKGROUND: Psoriasis is a chronic, inflammatory skin disease often requiring long-term therapy. OBJECTIVE: To evaluate the long-term safety and efficacy of risankizumab in patients with psoriasis. METHODS: LIMMitless is an ongoing phase 3, open-label extension study evaluating the long-term safety and efficacy of continuous risankizumab 150 mg every 12 weeks for adults with moderate-to-severe plaque psoriasis following multiple phase 2/3 base studies. This interim analysis assessed safety (ie, monitored treatment-emergent adverse events [TEAEs]) through 304 weeks. Efficacy assessments included determining the proportion of patients who achieved ≥90% or 100% improvement in Psoriasis Area and Severity Index (PASI 90/100), static Physician's Global Assessment of clear/almost clear (sPGA 0/1), and Dermatology Life Quality Index of no effect on patient's life (DLQI 0/1) through 256 weeks. RESULTS: Among 897 patients randomized to risankizumab in the base studies, 706 were still ongoing at data cutoff. Rates of TEAEs, TEAEs leading to discontinuation, and TEAEs of safety interest were low. At week 256, 85.1%/52.3% of patients achieved PASI 90/100, respectively, 85.8% achieved sPGA 0/1, and 76.4% achieved DLQI 0/1. LIMITATIONS: Open-label study with no placebo or active-comparator group. CONCLUSIONS: Long-term continuous risankizumab treatment for up to 5 years was well tolerated and demonstrated high and durable efficacy.

COVID-19 vaccine-related presumed allergic reactions and second dose administration by using a two-step graded protocol.

Background: Acute allergic reactions to messenger RNA (mRNA) vaccines are rare but may limit public health immunization efforts. Objectives: To characterize suspected allergic reactions to the first dose of coronavirus disease 2019 (COVID-19) mRNA vaccine and to assess the safety and utility of a two-step graded-dose protocol for the second dose of the Pfizer-BioNTech vaccine in patients with a history of low suspicion of anaphylaxis to their first dose. Methods: This was a retrospective evaluation of referrals to the allergy and immunology clinic for a presumed allergic reaction to the first dose of the COVID-19 mRNA vaccine (Pfizer-BioNTech or Moderna) between December 17, 2020, and February 28, 2021. Recommendations for the second dose and outcomes were evaluated by trained board-certified allergists. Results: Seventy-seven patients presented with a Pfizer-BioNTech reaction (56 [72.7%]) or with a Moderna reaction (21 [27.3%]). Most patients (69.7%) had symptom onset within 4 hours. Most commonly reported symptoms were cutaneous (51.9%), cardiovascular (48.1%), and respiratory (33.8%) symptoms. Recommendations included to proceed with the single dose (70.1%), two-step graded dose (19.5%), or deferral (10.4%). Twelve of 15 patients completed the second dose with a graded-dose protocol. Of these patients, five reported at least one or more similar symptoms as experienced with their first dose. Conclusion: Of the patients with presumed allergic reactions to their first dose of COVID-19 mRNA vaccine, most were able to safely receive the second dose. For those with a low suspicion of anaphylaxis, the two-step graded protocol with the Pfizer-BioNTech vaccine was well tolerated. A graded-dose protocol could be an effective strategy for second-dose vaccination in those who may otherwise defer the second dose.

Prevalence and characterization of asthma in hospitalized and nonhospitalized patients with COVID-19.

BACKGROUND: The Centers for Disease Control and Prevention advises that patients with moderate to severe asthma belong to a high-risk group that is susceptible to severe coronavirus disease 2019 (COVID-19). However, the association between asthma and COVID-19 has not been well-established. OBJECTIVE: The primary objective was to determine the prevalence of asthma among patients with COVID-19 in a major US health system. We assessed the clinical characteristics and comorbidities in asthmatic and nonasthmatic patients with COVID-19. We also determined the risk of hospitalization associated with asthma and/or inhaled corticosteroid use. METHODS: Medical records of patients with COVID-19 were searched by a computer algorithm (March 1 to April 15, 2020), and chart review was used to validate the diagnosis of asthma and medications prescribed for asthma. All patients had PCR-confirmed COVID-19. Demographic and clinical features were characterized. Regression models were used to assess the associations between asthma and corticosteroid use and the risk of COVID-19-related hospitalization. RESULTS: Of 1526 patients identified with COVID-19, 220 (14%) were classified as having asthma. Asthma was not associated with an increased risk of hospitalization (relative risk, 0.96; 95% CI, 0.77-1.19) after adjusting for age, sex, and comorbidities. The ongoing use of inhaled corticosteroids did not increase the risk of hospitalization in a similar adjusted model (relative risk, 1.39; 95% CI, 0.90-2.15). CONCLUSIONS: Despite a substantial prevalence of asthma in our COVID-19 cohort, asthma was not associated with an increased risk of hospitalization. Similarly, the use of inhaled corticosteroids with or without systemic corticosteroids was not associated with COVID-19-related hospitalization.

Moyamoya Presenting after Whole Body Cryotherapy.

BACKGROUND PURPOSE: Moyamoya syndrome is the progressive stenosis of intracranial carotids with secondary collateralization. Whole body cryotherapy (WBC) involves external cooling and is used in holistic and sports medicine, its neurologic effects are unknown. CASE REPORT: We report a first case of symptoms of moyamoya syndrome presenting following WBC and diagnosed with classic MRI ( "Brush Sign", "Ivy sign") and digital subtracted angiography. CONCLUSION: WBC may provoke symptoms of moyamoya syndrome possibly through hyperventilation or vasoconstriction. Practitioners should be aware of possible consequences of WBC in patients with poor cerebrovascular reserve.

Kupffer Cell p38 Mitogen-Activated Protein Kinase Signaling Drives Postburn Hepatic Damage and Pulmonary Inflammation When Alcohol Intoxication Precedes Burn Injury.

OBJECTIVES: Clinical and animal studies demonstrate that alcohol intoxication at the time of injury worsens postburn outcome. The purpose of this study was to determine the role and mechanism of Kupffer cell derangement in exacerbating postburn end organ damage in alcohol-exposed mice. DESIGN: Interventional study. SETTING: Research Institute. SUBJECTS: Male C57BL/6 mice. INTERVENTIONS: Alcohol administered 30 minutes before a 15% scald burn injury. Antecedent Kupffer cell depletion with clodronate liposomes (0.5 mg/kg). p38 mitogen-activated protein kinase inhibition via SB203580 (10 mg/kg). MEASUREMENTS AND MAIN RESULTS: Kupffer cells were isolated 24 hours after injury and analyzed for p38 activity and interleukin-6 production. Intoxicated burned mice demonstrated a two-fold (p < 0.05) elevation of Kupffer cell p38 activation relative to either insult alone, and this corresponded to a 43% (p < 0.05) increase in interleukin-6 production. Depletion of Kupffer cells attenuated hepatic damage as seen by decreases of 53% (p < 0.05) in serum alanine aminotransferase and 74% (p < 0.05) in hepatic triglycerides, as well as a 77% reduction (p < 0.05) in serum interleukin-6 levels compared to matched controls. This mitigation of hepatic damage was associated with a 54% decrease (p < 0.05) in pulmonary neutrophil infiltration and reduced alveolar wall thickening by 45% (p < 0.05). In vivo p38 inhibition conferred nearly identical hepatic and pulmonary protection after the combined injury as mice depleted of Kupffer cells. CONCLUSIONS: Intoxication exacerbates postburn hepatic damage through p38-dependent interleukin-6 production in Kupffer cells.

An alteration of the gut-liver axis drives pulmonary inflammation after intoxication and burn injury in mice.

Approximately half of all adult burn patients are intoxicated at the time of their injury and have worse clinical outcomes than those without prior alcohol exposure. This study tested the hypothesis that intoxication alters the gut-liver axis, leading to increased pulmonary inflammation mediated by burn-induced IL-6 in the liver. C57BL/6 mice were given 1.2 g/kg ethanol 30 min prior to a 15% total body surface area burn. To restore gut barrier function, the specific myosin light chain kinase inhibitor membrane-permeant inhibitor of kinase (PIK), which we have demonstrated to reduce bacterial translocation from the gut, was administered 30 min after injury. Limiting bacterial translocation with PIK attenuated hepatic damage as measured by a 47% reduction in serum alanine aminotransferase (P < 0.05), as well as a 33% reduction in hepatic IL-6 mRNA expression (P < 0.05), compared with intoxicated and burn-injured mice without PIK. This mitigation of hepatic damage was associated with a 49% decline in pulmonary neutrophil infiltration (P < 0.05) and decreased alveolar wall thickening compared with matched controls. These results were reproduced by prophylactic reduction of the bacterial load in the intestines with oral antibiotics before intoxication and burn injury. Overall, these data suggest that the gut-liver axis is deranged when intoxication precedes burn injury and that limiting bacterial translocation in this setting attenuates hepatic damage and pulmonary inflammation.

Tirasemtiv amplifies skeletal muscle response to nerve activation in humans.

INTRODUCTION: In this study we tested the hypothesis that tirasemtiv, a selective fast skeletal muscle troponin activator that sensitizes the sarcomere to calcium, could amplify the response of muscle to neuromuscular input in humans. METHODS: Healthy men received tirasemtiv and placebo in a randomized, double-blind, 4-period, crossover design. The deep fibular nerve was stimulated transcutaneously to activate the tibialis anterior muscle and produce dorsiflexion of the foot. The force-frequency relationship of tibialis anterior dorsiflexion was assessed after dosing. RESULTS: Tirasemtiv increased force produced by the tibialis anterior in a dose-, concentration-, and frequency-dependent manner with the largest increases [up to 24.5% (SE 3.1), P < 0.0001] produced at subtetanic nerve stimulation frequencies (10 Hz). CONCLUSIONS: The data confirm that tirasemtiv amplifies the response of skeletal muscle to nerve input in humans. This outcome provides support for further studies of tirasemtiv as a potential therapy in conditions marked by diminished neuromuscular input.

Adipose inflammation and macrophage infiltration after binge ethanol and burn injury.

BACKGROUND: Ethanol (EtOH) exposure prior to traumatic injury, such as a burn, elevates systemic and local inflammatory responses and increases morbidity and mortality. Adipose is a large tissue mass that is often inflamed during obesity or other stresses, which disturbs metabolic homeostasis. To date, there has been little investigation into the inflammatory response of adipose tissue after combined EtOH exposure and burn injury. METHODS: Two EtOH exposure regimens were utilized to examine the role of inflammation in adipose tissue after EtOH and burn injury. Mice were either given a single or episodic binge exposure to EtOH or saline followed by scald (burn) or sham injury 30 minutes later. Twenty-four hours post injury, serum and adipose tissue were collected for assessment of inflammatory mediators. RESULTS: Single binge EtOH alone induced no inflammation in adipose when compared with sham vehicle-treated mice. However, single binge EtOH followed by burn injury induced significant elevations in mRNA and protein concentrations of pro-inflammatory mediators interleukin-6 (IL-6), KC, and monocyte chemoattractant protein 1 compared with either insult alone or sham vehicle group. Additionally, EtOH exposure and burn injury significantly blunted inducible nitric oxide synthase (iNOS), indicating a complex inflammatory response. Episodic binge EtOH exposure followed by burn injury exacerbated the postburn adipose inflammatory response. The magnitude of the episodic binge-induced inflammatory parameters postburn were 2- to 5-fold greater than the response detected after a single exposure of EtOH, indicating EtOH-induced potentiation of burn-induced inflammatory response. Finally, inflammatory loci and crown-like structures in adipose were significantly increased by episodic binge EtOH and burn injury. CONCLUSIONS: This is the first report of binge and burn-induced crown-like structure formation. Evidence presented herein suggests an important role for alcohol and burn as an additional mediator of adipose inflammation in postburn injury, a common complication in burn patients.

Efficacy and Safety of Risankizumab for Active Psoriatic Arthritis: 100-Week Results from the KEEPsAKE 2 Randomized Clinical Trial.

INTRODUCTION: Long-term therapeutic options providing durable response and tolerability are needed for psoriatic arthritis (PsA). The ongoing KEEPsAKE 2 trial is evaluating risankizumab treatment in patients with active PsA who previously had inadequate response/intolerance to ≥ 1 conventional synthetic disease-modifying antirheumatic drug (csDMARD-IR) and/or 1-2 biologic DMARDs (bDMARD-IR). Herein, we report results through 100 weeks of treatment. METHODS: KEEPsAKE 2 is a global phase 3 trial. Patients with active PsA were randomized 1:1 to double-blind subcutaneous risankizumab 150 mg or placebo (weeks 0, 4, and 16). At week 24, all patients received open-label risankizumab every 12 weeks until end of study. Efficacy endpoints included achieving ≥ 20% improvement in PsA symptoms using American College of Rheumatology criteria (ACR20), attaining minimal disease activity (MDA; meeting ≥ 5/7 criteria of low disease activity and extent), and improving in other measures. RESULTS: At the cutoff date, 345/443 (77.9%) patients were ongoing in the study. ACR20 was achieved in 57.1% and 52.5% of the continuous risankizumab and placebo/risankizumab cohorts, respectively, at week 100 and in 60.0% and 55.8%, respectively, at week 52. In week 52 responders, maintenance of ACR20 at week 100 was achieved in 74.8% (continuous risankizumab) and 78.7% (placebo/risankizumab) of patients. In the continuous risankizumab and placebo/risankizumab cohorts, respectively, MDA was achieved by 33.0% and 33.3% of patients at week 100 and by 27.2% and 33.8% at week 52. Among MDA responders at week 52, maintenance of MDA response was achieved by 83.6% and 73.0% of the continuous risankizumab and placebo/risankizumab cohorts, respectively. Risankizumab was well tolerated through week 100. CONCLUSIONS: Risankizumab demonstrated durable efficacy and tolerability through 100 weeks; most patients who achieved ACR20 and MDA responses at week 52 maintained this achievement through week 100. There were no new safety signals in patients who had csDMARD-IR and bDMARD-IR. TRIAL REGISTRATION: ClinicalTrials.gov NCT03671148.

Risankizumab, a biologic disease-modifying antirheumatic drug, helps control the body's immune system to reduce symptoms of psoriatic arthritis (a disease that inflames the joints of people who have the skin condition psoriasis). The ongoing KEEPsAKE 2 study is evaluating how well risankizumab works and how safe it is for treating adult patients with active psoriatic arthritis who previously experienced inadequate response to one or more specific types of disease-modifying anti-arthritis drugs. Patients were randomly assigned to receive either risankizumab or an inactive drug; after 24 weeks, all patients received risankizumab. At study week 100, 57% of patients who were assigned to receive continuous risankizumab since the start of the study experienced a 20% or more improvement in a measure of psoriatic arthritis symptoms using criteria established by the American College of Rheumatology (ACR20); a similar proportion of patients achieved a 20% improvement at both weeks 24 and 52. Similarly, 56% and 53% of patients who switched from inactive drug to risankizumab achieved ACR20 at weeks 52 and 100 (more than before switching to risankizumab at week 24). Minimal disease activity (MDA) was evaluated by assessing joint and skin symptoms, affected body surface area, pain, and physical function. At week 100, 33% of patients achieved MDA (both groups), which was similar to week 52. Most patients who achieved ACR20 or MDA at week 52 maintained responses at week 100. Improvements with risankizumab were seen in several other measures of treatment outcomes through week 100. Risankizumab was generally safe through 100 weeks.

Intoxication by intraperitoneal injection or oral gavage equally potentiates postburn organ damage and inflammation.

The increasing prevalence of binge drinking and its association with trauma necessitate accurate animal models to examine the impact of intoxication on the response and outcome to injuries such as burn. While much research has focused on the effect of alcohol dose and duration on the subsequent inflammatory parameters following burn, little evidence exists on the effect of the route of alcohol administration. We examined the degree to which intoxication before burn injury causes systemic inflammation when ethanol is given by intraperitoneal (i.p.) injection or oral gavage. We found that intoxication potentiates postburn damage in the ileum, liver, and lungs of mice to an equivalent extent when either ethanol administration route is used. We also found a similar hematologic response and levels of circulating interleukin-6 (IL-6) when either ethanol paradigm achieved intoxication before burn. Furthermore, both i.p. and gavage resulted in similar blood alcohol concentrations at all time points tested. Overall, our data show an equal inflammatory response to burn injury when intoxication is achieved by either i.p. injection or oral gavage, suggesting that findings from studies using either ethanol paradigm are directly comparable.

Dose-dependent augmentation of cardiac systolic function with the selective cardiac myosin activator, omecamtiv mecarbil: a first-in-man study.

BACKGROUND: Decreased systolic function is central to the pathogenesis of heart failure in millions of patients worldwide, but mechanism-related adverse effects restrict existing inotropic treatments. This study tested the hypothesis that omecamtiv mecarbil, a selective cardiac myosin activator, will augment cardiac function in human beings. METHODS: In this dose-escalating, crossover study, 34 healthy men received a 6-h double-blind intravenous infusion of omecamtiv mecarbil or placebo once a week for 4 weeks. Each sequence consisted of three ascending omecamtiv mecarbil doses (ranging from 0·005 to 1·0 mg/kg per h) with a placebo infusion randomised into the sequence. Vital signs, blood samples, electrocardiographs (ECGs), and echocardiograms were obtained before, during, and after each infusion. The primary aim was to establish maximum tolerated dose (the highest infusion rate tolerated by at least eight participants) and plasma concentrations of omecamtiv mecarbil; secondary aims were evaluation of pharmacodynamic and pharmacokinetic characteristics, safety, and tolerability. This study is registered at ClinicalTrials.gov, number NCT01380223. FINDINGS: The maximum tolerated dose of omecamtiv mecarbil was 0·5 mg/kg per h. Omecamtiv mecarbil infusion resulted in dose-related and concentration-related increases in systolic ejection time (mean increase from baseline at maximum tolerated dose, 85 [SD 5] ms), the most sensitive indicator of drug effect (r(2)=0·99 by dose), associated with increases in stroke volume (15 [2] mL), fractional shortening (8% [1]), and ejection fraction (7% [1]; all p<0·0001). Omecamtiv mecarbil increased atrial contractile function, and there were no clinically relevant changes in diastolic function. There were no clinically significant dose-related adverse effects on vital signs, serum chemistries, ECGs, or adverse events up to a dose of 0·625 mg/kg per h. The dose-limiting toxic effect was myocardial ischaemia due to excessive prolongation of systolic ejection time. INTERPRETATION: These first-in-man data show highly dose-dependent augmentation of left ventricular systolic function in response to omecamtiv mecarbil and support potential clinical use of the drug in patients with heart failure. FUNDING: Cytokinetics Inc.

Phase I dose-escalation and pharmacokinetic study of ispinesib, a kinesin spindle protein inhibitor, administered on days 1 and 15 of a 28-day schedule in patients with no prior treatment for advanced breast cancer.

The objective of the study was to evaluate the safety, pharmacokinetics, and antitumor activity of ispinesib, a kinesin spindle protein inhibitor. Patients with locally advanced or metastatic breast cancer who had received only prior neoadjuvant or adjuvant chemotherapy were treated with escalating doses of ispinesib administered as a 1-h infusion on days 1 and 15 every 28 days until toxicity or progression of disease. Doses were escalated until dose-limiting toxicity was observed in two out of six patients during cycle 1. A total of 16 patients were treated at three dose levels: 10 mg/m (n=3), 12 mg/m (n=6), and 14 mg/m (n=7). Forty-four percent of the patients had locally advanced disease and 56% had metastatic disease; 50% were estrogen receptor positive, 44% were progesterone receptor positive, 25% human epidermal growth factor 2 were positive, and 31% triple (estrogen receptor, progesterone receptor, human epidermal growth factor 2) negative. Sixty-nine percent of patients were chemo-naive. The maximum tolerated dose was 12 mg/m and dose-limiting toxicity was grade 3 increased aspartate aminotransferase and alanine aminotransferase. The most common toxicities included neutropenia (88%; 38% grade 3 and 44% grade 4), increased alanine aminotransferase (56%), anemia (38%), increased aspartate aminotransferase (31%), and diarrhea (31%). No neuropathy, mucositis, or alopecia was reported. Among the 15 patients evaluable for antitumor activity, there were three partial responses, one confirmed by the response evaluation criteria in solid tumors (7% response rate). Nine patients (60%) had stable disease lasting at least 42 days, with four (27%) lasting for at least 90 days. Disease stabilization (partial responses+stable disease) was observed in 11 (73.3%) patients. In conclusion, ispinesib was well tolerated when administered on days 1 and 15 every 28 days. Limited activity was observed with this schedule in patients with previously untreated advanced breast cancer.

An International, Retrospective Study of Off-Label Biologic Use in the Treatment of Hypereosinophilic Syndromes.

BACKGROUND: Treatment of hypereosinophilic syndrome (HES) often requires the use of immunomodulators with substantial side effect profiles. The emergence of biologics offers an alternative treatment modality. OBJECTIVE: To examine real-world practice data to describe the safety and consequences of various biologics suspected to directly or indirectly affect eosinophilic inflammation for the treatment of HES. METHODS: Retrospective data from 13 centers were collected via an online Research Electronic Data Capture repository. Inclusion criteria included (1) peripheral eosinophil count of 1,500/mm3 or greater without a secondary cause; (2) clinical manifestations attributable to the eosinophilia; and (3) having received mepolizumab (anti-IL-5), benralizumab (afucosylated anti-IL-5 receptor α), omalizumab (anti-IgE), alemtuzumab (anti-CD52), dupilumab (anti-IL-4 receptor α), or reslizumab (anti-IL-5) outside a placebo-controlled clinical trial. RESULTS: Of the 151 courses of biologics prescribed for 121 patients with HES, 59% resulted in improved HES symptoms and 77% enabled tapering of other HES medications. Overall, 105 patients were receiving daily systemic glucocorticoids at the time of a biologic initiation and were able to reduce the glucocorticoid dose by a median reduction of 10 mg of daily prednisone equivalents. Biologics were generally safe and well-tolerated other than infusion reactions with alemtuzumab. Thirteen of 24 patients had clinical improvement after switching biologics and nine patients responded to increasing the dose of mepolizumab after a lack of response to a lower dose. CONCLUSIONS: Biologics may offer a safer treatment alternative to existing therapies for HES, although the optimal dosing and choice for each subtype of HES remain to be determined. Limitations of this study include its retrospective nature and intersite differences in data collection and availability of each biologic.

A panel of cytochrome P450 BM3 variants to produce drug metabolites and diversify lead compounds.

Herein we demonstrate that a small panel of variants of cytochrome P450 BM3 from Bacillus megaterium covers the breadth of reactivity of human P450s by producing 12 of 13 mammalian metabolites for two marketed drugs, verapamil and astemizole, and one research compound. The most active enzymes support preparation of individual metabolites for preclinical bioactivity and toxicology evaluations. Underscoring their potential utility in drug lead diversification, engineered P450 BM3 variants also produce novel metabolites by catalyzing reactions at carbon centers beyond those targeted by animal and human P450s. Production of a specific metabolite can be improved by directed evolution of the enzyme catalyst. Some variants are more active on the more hydrophobic parent drug than on its metabolites, which limits production of multiply-hydroxylated species, a preference that appears to depend on the evolutionary history of the P450 variant.

Alcohol Intoxication and the Postburn Gastrointestinal Hormonal Response.

Gastrointestinal hormones are essential in postburn metabolism. Since near 50% of burn victims test positive for blood alcohol levels at hospital admission and have inferior outcomes compared to nonintoxicated burn patients; we hypothesized that the gastrointestinal hormone secretion is compromised in intoxicated burn victims. To test our theory, we quantified gastrointestinal hormones serum levels in a combine ethanol intoxication and burn injury mouse model. Thus, mice received a daily dose of ethanol for 3 days, rested 4 days, and were given ethanol 3 additional days. Mice underwent 15% TBSA scald burn 30 minutes after their last ethanol dose. Serum samples were collected 24 hours after burn injury. Nonintoxicated burned mice exhibited an increase in glucose, insulin, ghrelin, plasminogen activator inhibitor-1, leptin, and resistin by 1.4-, 3-, 13.5-, 6.2-, 9.4-, and 2.4-fold, respectively, compared to sham vehicle mice (P < .05). Burn injury also reduced serum gastric inhibitory polypeptide (GIP) by 32% compared to sham-injured, vehicle-treated mice. Leptin, resistin, glucagon-like peptide-1, as well as insulin, were not different from sham groups when intoxication preceded burn injury. Nevertheless, in burned mice treated with ethanol, gastric inhibitory polypeptide and glucagon serum levels exhibited a significant fold increase of 3.5 and 4.7, respectively. With these results, we conclude that 24 hours after burn injury, mice developed significant changes in gastrointestinal hormones, along with hyperglycemia. Moreover, the combined insult of burn and ethanol intoxication led to additional hormonal changes that may be attributed to a potential pancreatic dysfunction. Further multiday studies are required to investigate the etiology, behavior, and clinical significance of these hormonal changes.

Mapping a Reliable Stroke Onset Time Course Using Signal Intensity on DWI Scans.

BACKGROUND AND PURPOSE: Identifying a last known well (LKW) time surrogate for acute stroke is vital to increase stroke treatment. Diffusion-weighted imaging (DWI) signal intensity initially increases from onset of stroke but mapping a reliable time course to the signal intensity has not been demonstrated. METHODS: We retrospectively reviewed stroke code patients between 1/2016 and 6/2017 from the prospective; Institutional review board (IRB) approved University of California San Diego Stroke Registry. Patients who had magnetic resonance imaging of brain from onset, with or without intervention, are included. All ischemic strokes were confirmed and timing from onset to imaging was calculated. Raw DWI intensity is measured using IMPAX software and compared to contralateral side for control for a relative DWI intensity (rDWI). LKW and magnetic resonance imaging (MRI) time were collected by chart review. Correlation is assessed using Pearson correlation coefficient between DWI intensity, rDWI, and time to MRI imaging. 1.5T, 3T, and combined modalities were examined. RESULTS: Seventy-eight patients were included in this analysis. Overall, there was statistically significant positive correlation (.53, P < .001) between DWI intensity and LKW time irrespective of scanner strength. Using 1.5T analyses, there was good correlation (.46, P < .001). 3T MRI analysis further showed comparatively stronger positive correlation (.66, P < .001). CONCLUSIONS: There is good correlation between DWI intensity and minutes from onset to MRI. This suggests a time-dependent DWI intensity response and supports the potential use of DWI intensity measurements to extrapolate an LKW time. Further studies are being pursued to increase both experience and generalizability.

Influence of Functional Capacity Evaluation on Physician's Assessment of Physical Capacity of Veterans With Chronic Pain: A Retrospective Analysis.

BACKGROUND: Physicians have difficulty predicting patients' occupational limitations, abilities, and success from clinical evaluation (CE) of pathology and impairments, especially in the presence of chronic pain. Additional information from a functional capacity evaluation (FCE) may improve the accuracy of their physical capacity assessments. It is not known whether FCE information will change these assessments. No such study has been published using Veterans or non-Veterans. OBJECTIVE: To determine the influence of FCE data on the physician's assessment of the US Department of Labor's Dictionary of Occupational Titles (DOT) work capacity levels of Veterans with chronic moderate-intensity pain. DESIGN: Retrospective analysis. SETTING: Tertiary care medical center. PARTICIPANTS: Veterans aged 18-60 years with moderate chronic musculoskeletal pain who were seeking employment. METHODS: Two kinesiotherapists performed FCEs on all participants, namely, the lumbar protocol of the EvalTech Functional Testing System (BTE, Inc, Hanover, MD). One physiatrist performed CEs in all participants. Two other physiatrists assessed DOT physical capacity levels using CE data alone and later using combined CE and FCE data. MAIN OUTCOME MEASUREMENTS: DOT physical capacity level (sedentary = 1, light = 2, medium = 3, heavy = 4, very heavy = 5). RESULTS: Of 55 charts reviewed, 27 met inclusion/exclusion criteria. The mean age was 38 years, and there were 25 male and 2 female participants. The predominant pain location was the lower back. DOT scores for 2 physicians were averaged. The mean ± SD DOT scores for CE only and CE+FCE conditions were 2.04 ± 0.33 and 2.40 ± 0.90, respectively. In all, 65% of DOT scores changed (17% decreased and 48% increased at least 1 level) after FCE data were considered. A 1-sample t test revealed that the mean CE+FCE DOT score was significantly greater than the mean CE-only score (by 20%, P = .02). Interrater agreement (weighted κ) for CE+FCE-based DOT scores was much higher than for CE alone (0.715 versus 0.182). CONCLUSION: The addition of FCE data to CE changed the majority of physician-assigned DOT levels. FCE significantly increased the mean DOT physical work capacity level provided by the physician to Veterans with chronic moderate-intensity pain, especially if the initial assessment was designated as "light." FCE may facilitate a more objective and accurate determination of Veterans' work capacity. LEVEL OF EVIDENCE: III.