Public health infection prevention: An analysis of existing training during the COVID-19 pandemic.

OBJECTIVES: In response to the COVID-19 pandemic, agencies and organizations required trainings to support the needs of the public health workforce. To better understand the training resources available, this study identified, organized, and classified infection prevention and control (IPC) training and educational opportunities. STUDY DESIGN: Environmental scan. METHODS: A total of 306 IPC training resources were compiled between January and April 2021. Key themes and topics were identified and compared to the Healthcare Infection Control Practices Advisory Committee's (HICPAC) core IPC practices. RESULTS: Three hundred and six training resources, including webinars, fact sheets, module-based learning activities, infographics, and professional practice guidance materials, were identified. Common themes included proper use of personal protective equipment (e.g., masks, gloves), community reopening guidance, and mass vaccination resources. A large proportion (74.9%) of trainings were under 60 min. Using the HICPAC framework, the most frequently addressed content included standard precautions (40%), leadership support (31.6%), and transmission-based precautions (25.8%). Few trainings addressed performance monitoring and feedback (17.1%). CONCLUSIONS: A wide range of organizations developed IPC-specific content during the pandemic. However, these resources did not address the breadth of knowledge required to implement IPC concepts effectively. The creation of universally applicable IPC core competencies and the development of high-quality IPC education and trainings for public health and the overall responder workforces should be prioritized. Accessible high-quality online and just-in-time trainings are critical for future pandemic and disaster preparedness.

Edoxaban vs. warfarin in patients with atrial fibrillation on amiodarone: a subgroup analysis of the ENGAGE AF-TIMI 48 trial.

BACKGROUND: In the ENGAGE AF-TIMI 48 trial, the higher-dose edoxaban (HDE) regimen had a similar incidence of ischaemic stroke compared with warfarin, whereas a higher incidence was observed with the lower-dose regimen (LDE). Amiodarone increases edoxaban plasma levels via P-glycoprotein inhibition. The current pre-specified exploratory analysis was performed to determine the effect of amiodarone on the relative efficacy and safety profile of edoxaban. METHODS AND RESULTS: At randomization, 2492 patients (11.8%) were receiving amiodarone. The primary efficacy endpoint of stroke or systemic embolic event was significantly lower with LDE compared with warfarin in amiodarone treated patients vs. patients not on amiodarone (hazard ratio [HR] 0.60, 95% confidence intervals [CIs] 0.36-0.99 and HR 1.20, 95% CI 1.03-1.40, respectively; P interaction <0.01). In patients randomized to HDE, no such interaction for efficacy was observed (HR 0.73, 95% CI 0.46-1.17 vs. HR 0.89, 95% CI 0.75-1.05, P interaction = 0.446). Major bleeding was similar in patients on LDE (HR 0.35, 95% CI 0.21-0.59 vs. HR 0.53, 95% CI 0.46-0.61, P interaction = 0.131) and HDE (HR 0.94, 95% CI 0.65-1.38 vs. HR 0.79, 95% CI 0.69-0.90, P interaction = 0.392) when compared with warfarin, independent of amiodarone use. CONCLUSIONS: Patients randomized to the LDE treated with amiodarone at the time of randomization demonstrated a significant reduction in ischaemic events vs. warfarin when compared with those not on amiodarone, while preserving a favourable bleeding profile. In contrast, amiodarone had no effect on the relative efficacy and safety of HDE.

A "SMART" design for building individualized treatment sequences.

Interventions often involve a sequence of decisions. For example, clinicians frequently adapt the intervention to an individual's outcomes. Altering the intensity and type of intervention over time is crucial for many reasons, such as to obtain improvement if the individual is not responding or to reduce costs and burden when intensive treatment is no longer necessary. Adaptive interventions utilize individual variables (severity, preferences) to adapt the intervention and then dynamically utilize individual outcomes (response to treatment, adherence) to readapt the intervention. The Sequential Multiple Assignment Randomized Trial (SMART) provides high-quality data that can be used to construct adaptive interventions. We review the SMART and highlight its advantages in constructing and revising adaptive interventions as compared to alternative experimental designs. Selected examples of SMART studies are described and compared. A data analysis method is provided and illustrated using data from the Extending Treatment Effectiveness of Naltrexone SMART study.

Variable Selection for Qualitative Interactions.

In this article we discuss variable selection for decision making with focus on decisions regarding when to provide treatment and which treatment to provide. Current variable selection techniques were developed for use in a supervised learning setting where the goal is prediction of the response. These techniques often downplay the importance of interaction variables that have small predictive ability but that are critical when the ultimate goal is decision making rather than prediction. We propose two new techniques designed specifically to find variables that aid in decision making. Simulation results are given along with an application of the methods on data from a randomized controlled trial for the treatment of depression.

Filtered Diffusion-Weighted MRI of the Human Cervical Spinal Cord: Feasibility and Application to Traumatic Spinal Cord Injury.

BACKGROUND AND PURPOSE: In traumatic spinal cord injury, DTI is sensitive to injury but is unable to differentiate multiple pathologies. Axonal damage is a central feature of the underlying cord injury, but prominent edema confounds its detection. The purpose of this study was to examine a filtered DWI technique in patients with acute spinal cord injury. MATERIALS AND METHODS: The MR imaging protocol was first evaluated in a cohort of healthy subjects at 3T (n = 3). Subsequently, patients with acute cervical spinal cord injury (n = 8) underwent filtered DWI concurrent with their acute clinical MR imaging examination <24 hours postinjury at 1.5T. DTI was obtained with 25 directions at a b-value of 800 s/mm2. Filtered DWI used spinal cord-optimized diffusion-weighting along 26 directions with a "filter" b-value of 2000 s/mm2 and a "probe" maximum b-value of 1000 s/mm2. Parallel diffusivity metrics obtained from DTI and filtered DWI were compared. RESULTS: The high-strength diffusion-weighting perpendicular to the cord suppressed signals from tissues outside of the spinal cord, including muscle and CSF. The parallel ADC acquired from filtered DWI at the level of injury relative to the most cranial region showed a greater decrease (38.71%) compared with the decrease in axial diffusivity acquired by DTI (17.68%). CONCLUSIONS: The results demonstrated that filtered DWI is feasible in the acute setting of spinal cord injury and reveals spinal cord diffusion characteristics not evident with conventional DTI.

Association between white blood cell count, epicardial blood flow, myocardial perfusion, and clinical outcomes in the setting of acute myocardial infarction: a thrombolysis in myocardial infarction 10 substudy.

BACKGROUND: Elevation of the white blood cell (WBC) count during acute myocardial infarction (AMI) is associated with adverse outcomes. We examined the relationship between the WBC count and angiographic findings to gain insight into this relationship. Results and Methods-We evaluated data from 975 patients in the Thrombolysis In Myocardial Infarction (TIMI) 10A and 10B trials. Patients with a closed artery at 60 and 90 minutes had higher a WBC count than patients with an open artery (P:=0.02). Likewise, the presence of angiographically apparent thrombus was associated with a higher WBC count (11.5+/-5.2x10(9)/L, n=290, versus 10.7+/-3. 5x10(9)/L, n=648; P=0.008). In addition, a higher WBC count was associated with poorer TIMI myocardial perfusion grades (4-way P=0.04). Mortality rates were higher in patients with a higher WBC count (0% for WBC count 0 to 5x10(9)/L, 4.9% for WBC count 5 to 10x10(9)/L, 3.8% for WBC count 10 to 15x10(9)/L, 10.4% for WBC count >15x10(9)/L; P=0.03). The development of new congestive heart failure or shock was also associated with a higher WBC count (0% for WBC count 0 to 5x10(9)/L, 5.2% for WBC count 5 to 10x10(9)/L, 6.1% for WBC count 10 to 15x10(9)/L, 17.1% for WBC count >15x10(9)/L; P<0.001), an observation that remained significant in a multivariable model that adjusted for potential confounding variables (odds ratio 1.21, P=0.002). CONCLUSIONS: Elevation in WBC count was associated with reduced epicardial blood flow and myocardial perfusion, thromboresistance (arteries open later and have a greater thrombus burden), and a higher incidence of new congestive heart failure and death. These observations provide a potential explanation for the higher mortality rate observed among AMI patients with elevated WBC counts and helps explain the growing body of literature that links inflammation and cardiovascular disease.

Relationship between TIMI frame count and clinical outcomes after thrombolytic administration. Thrombolysis In Myocardial Infarction (TIMI) Study Group.

BACKGROUND: The corrected TIMI frame count (CTFC) is the number of cine frames required for dye to first reach standardized distal coronary landmarks, and it is an objective and quantitative index of coronary blood flow. METHODS AND RESULTS: The CTFC was measured in 1248 patients in the TIMI 4, 10A, and 10B trials, and its relationship to clinical outcomes was examined. Patients who died in the hospital had a higher CTFC (ie, slower flow) than survivors (69. 6+/-35.4 [n=53] versus 49.5+/-32.3 [n=1195]; P=0.0003). Likewise, patients who died by 30 to 42 days had higher CTFCs than survivors (66.2+/-36.4 [n=57] versus 49.9+/-32.1 [n=1059]; P=0.006). In a multivariate model that excluded TIMI flow grades, the 90-minute CTFC was an independent predictor of in-hospital mortality (OR=1.21 per 10-frame rise [95% CI, 1.1 to 1.3], an approximately 0.7% increase in absolute mortality for every 10-frame rise; P<0.001) even when other significant correlates of mortality (age, heart rate, anterior myocardial infarction, and female sex) were adjusted for in the model. The CTFC identified a subgroup of patients with TIMI grade 3 flow who were at a particularly low risk of adverse outcomes. The risk of in-hospital mortality increased in a stepwise fashion from 0.0% (n=41) in patients with a 90-minute CTFC that was faster than the 95% CI for normal flow (0 to 13 frames, hyperemia, TIMI grade 4 flow), to 2.7% (n=18 of 658 patients) in patients with a CTFC of 14 to 40 (a CTFC of 40 has previously been identified as the cutpoint for distinguishing TIMI grade 3 flow), to 6.4% (35/549) in patients with a CTFC >40 (P=0.003). Although the risk of death, recurrent myocardial infarction, shock, congestive heart failure, or left ventricular ejection fraction 20 to

Relationship of TIMI myocardial perfusion grade to mortality after administration of thrombolytic drugs.

BACKGROUND: Although improved epicardial blood flow (as assessed with either TIMI flow grades or TIMI frame count) has been related to reduced mortality after administration of thrombolytic drugs, the relationship of myocardial perfusion (as assessed on the coronary arteriogram) to mortality has not been examined. METHODS AND RESULTS: A new, simple angiographic method, the TIMI myocardial perfusion (TMP) grade, was used to assess the filling and clearance of contrast in the myocardium in 762 patients in the TIMI (Thrombolysis In Myocardial Infarction) 10B trial, and its relationship to mortality was examined. TMP grade 0 was defined as no apparent tissue-level perfusion (no ground-glass appearance of blush or opacification of the myocardium) in the distribution of the culprit artery; TMP grade 1 indicates presence of myocardial blush but no clearance from the microvasculature (blush or a stain was present on the next injection); TMP grade 2 blush clears slowly (blush is strongly persistent and diminishes minimally or not at all during 3 cardiac cycles of the washout phase); and TMP grade 3 indicates that blush begins to clear during washout (blush is minimally persistent after 3 cardiac cycles of washout). There was a mortality gradient across the TMP grades, with mortality lowest in those patients with TMP grade 3 (2.0%), intermediate in TMP grade 2 (4.4%), and highest in TMP grades 0 and 1 (6.0%; 3-way P=0.05). Even among patients with TIMI grade 3 flow in the epicardial artery, the TMP grades allowed further risk stratification of 30-day mortality: 0.73% for TMP grade 3; 2.9% for TMP grade 2; 5.0% for TMP grade 0 or 1 (P=0.03 for TMP grade 3 versus grades 0, 1, and 2; 3-way P=0.066). TMP grade 3 flow was a multivariate correlate of 30-day mortality (OR 0.35, 95% CI 0.12 to 1.02, P=0.054) in a multivariate model that adjusted for the presence of TIMI 3 flow (P=NS), the corrected TIMI frame count (OR 1.02, P=0.06), the presence of an anterior myocardial infarction (OR 2.3, P=0.03), pulse rate on admission (P=NS), female sex (P=NS), and age (OR 1.1, P<0.001). CONCLUSIONS: Impaired perfusion of the myocardium on coronary arteriography by use of the TMP grade is related to a higher risk of mortality after administration of thrombolytic drugs that is independent of flow in the epicardial artery. Patients with both normal epicardial flow (TIMI grade 3 flow) and normal tissue level perfusion (TMP grade 3) have an extremely low risk of mortality.

Combination therapy with abciximab reduces angiographically evident thrombus in acute myocardial infarction: a TIMI 14 substudy.

BACKGROUND: Use of abciximab in combination with administration of thrombolytics has been shown to improve epicardial and microvascular coronary blood flow in acute myocardial infarction (AMI). As a potential mechanism, we hypothesized that combination therapy would reduce angiographically evident thrombus (AET) and would increase lumen diameter compared with thrombolytic monotherapy. METHODS AND RESULTS: Patients who received combination therapy in TIMI 14 (low-dose thrombolytic plus abciximab, n=732) were compared with patients who received thrombolytic monotherapy without abciximab in the TIMI 4, 10A, 10B, and 14 trials (n=1662). Thrombus burden was assessed 90 minutes after treatment, and quantitative angiography was performed in an angiographic core laboratory by investigators blinded to treatment assignment. The frequency of AET was reduced in patients who received abciximab combination therapy compared with thrombolytic monotherapy (26.6% versus 35.4%, P<0.001). Similar findings were observed when the analysis was restricted to patients with patent arteries (14.7% versus 20.8%, P=0.001). Residual percent diameter stenosis at 90 minutes was also improved in the abciximab therapy group both in patent arteries (64.6+/-16.6 versus 68.3+/-14.8, P<0.001) and between patent and occluded arteries (69.3+/-19.5 versus 73.8+/-17.9, P<0.001). The absence of AET was associated with an increased frequency of >70% ST-segment resolution by 90 minutes (37.2%, 110/296 versus 18.9%, 54/286, P<0.001). CONCLUSIONS: Compared with thrombolytic monotherapy, combination therapy with abciximab reduces AET, which in turn is associated with reduced residual stenosis and improved ST-segment resolution in AMI. These data provide a pathophysiological link between platelet inhibition, reduced thrombus, and improvements in both epicardial and microvascular perfusion in AMI.

TIMI risk score for ST-elevation myocardial infarction: A convenient, bedside, clinical score for risk assessment at presentation: An intravenous nPA for treatment of infarcting myocardium early II trial substudy.

BACKGROUND: Considerable variability in mortality risk exists among patients with ST-elevation myocardial infarction (STEMI). Complex multivariable models identify independent predictors and quantify their relative contribution to mortality risk but are too cumbersome to be readily applied in clinical practice. METHODS AND RESULTS: We developed and evaluated a convenient bedside clinical risk score for predicting 30-day mortality at presentation of fibrinolytic-eligible patients with STEMI. The Thrombolysis in Myocardial Infarction (TIMI) risk score for STEMI was created as the simple arithmetic sum of independent predictors of mortality weighted according to the adjusted odds ratios from logistic regression analysis in the Intravenous nPA for Treatment of Infarcting Myocardium Early II trial (n=14 114). Mean 30-day mortality was 6.7%. Ten baseline variables, accounting for 97% of the predictive capacity of the multivariate model, constituted the TIMI risk score. The risk score showed a >40-fold graded increase in mortality, with scores ranging from 0 to >8 (P:<0.0001); mortality was <1% among patients with a score of 0. The prognostic discriminatory capacity of the TIMI risk score was comparable to the full multivariable model (c statistic 0. 779 versus 0.784). The prognostic performance of the risk score was stable over multiple time points (1 to 365 days). External validation in the TIMI 9 trial showed similar prognostic capacity (c statistic 0.746). CONCLUSIONS: The TIMI risk score for STEMI captures the majority of prognostic information offered by a full logistic regression model but is more readily used at the bedside. This risk assessment tool is likely to be clinically useful in the triage and management of fibrinolytic-eligible patients with STEMI.

Abciximab improves both epicardial flow and myocardial reperfusion in ST-elevation myocardial infarction. Observations from the TIMI 14 trial.

BACKGROUND: In the presence of ST-elevation myocardial infarction, patients with successful epicardial reperfusion (TIMI 3 flow) but persistent ST elevation on a 12-lead ECG are at high risk for subsequent death and left ventricular dysfunction. In the TIMI 14 trial, a dose-ranging angiographic study, combined therapy with abciximab plus reduced-dose tPA enhanced the speed and efficacy of epicardial reperfusion. We determined whether the combination of abciximab plus reduced-dose tPA provided additional benefit in terms of myocardial reperfusion, as evidenced by greater resolution of ST elevation. METHODS AND RESULTS: All 346 patients with interpretable baseline and 90-minute ECGs, treated with either tPA alone or abciximab plus reduced-dose tPA (combination therapy), were included. Patients receiving combination therapy (n=221) had a 59% rate of complete (>/=70%) ST resolution at 90 minutes versus 37% in those treated with tPA alone (n=125) (P<0.0001). When the analysis was limited to patients with TIMI 3 flow, patients treated with combination therapy (n=151) remained significantly more likely to achieve complete ST resolution than those receiving tPA alone (n=80) (69% versus 44%; P=0.0002). CONCLUSIONS: Combination therapy with abciximab and reduced-dose tPA improves myocardial (microvascular) reperfusion, as reflected in greater ST-segment resolution, in addition to epicardial flow. This finding may translate into improved clinical outcomes by enhancing myocardial salvage.

Impaired coronary blood flow in nonculprit arteries in the setting of acute myocardial infarction. The TIMI Study Group. Thrombolysis in myocardial infarction.

OBJECTIVES AND BACKGROUND: While attention has focused on coronary blood flow in the culprit artery in acute myocardia infarction (MI), flow in the nonculprit artery has not been studied widely, in part because it has been assumed to be normal. We hypothesized that slower flow in culprit arteries, larger territories infarcted and hemodynamic perturbations may be associated with slow flow in nonculprit arteries. METHODS: The number of frames for dye to first reach distal landmarks (corrected TIMI [Thrombolysis in Acute Myocardial Infarction] frame count [CTFC]) were counted in 1,817 nonculprit arteries from the TIMI 4, 10A, 10B and 14 thrombolytic trials. RESULTS: Nonculprit artery flow was slowed to 30.9 +/- 15.0 frames at 90 min after thrombolytic administration, which is 45% slower than normal flow in the absence of acute MI (21 +/- 3.1, p < 0.0001). Patients with TIMI grade 3 flow in the culprit artery had faster nonculprit artery CTFCs than those patients with TIMI grades 0, 1 or 2 flow (29.1 +/- 13.7, n = 1,050 vs. 33.3 +/- 16.1, n = 752, p < 0.0001). The nonculprit artery CTFC improved between 60 and 90 min (3.3 +/- 17.9 frames, n = 432, p = 0.0001), and improvements were related to improved culprit artery flow (p = 0.0005). Correlates of slower nonculprit artery flow included a pulsatile flow pattern (i.e., systolic flow reversal) in the nonculprit artery (p < 0.0001) and in the culprit artery (p = 0.01), a left anterior descending artery culprit artery location (p < 0.0001), a decreased systolic blood pressure (p = 0.01), a decreased ventriculographic cardiac output (p = 0.02), a decreased double product (p = 0.0002), a greater percent diameter stenosis of the nonculprit artery (p = 0.01) and a greater percent of the culprit artery bed lying distal to the stenosis (p = 0.04). Adjunctive percutaneous transluminal coronary angioplasty (PTCA) of the culprit artery restored a culprit artery CTFC (30.4 +/- 22.2) that was similar to that in the nonculprit artery at 90 min (30.2 +/- 13.5), but both were slower than normal CTFCs (21 +/- 3.1, p < 0.0005 for both). If flow in the nonculprit artery was abnormal (CTFC > or = 28 frames) then the CTFC after PTCA in the culprit artery was 17% slower (p = 0.01). Patients who died had slower global CTFCs (mean CTFC for the three arteries) than patients who survived (46.8 +/- 21.3, n = 47 vs. 39.4 +/- 16.7, n = 1,055, p = 0.02). CONCLUSIONS: Acute MI slows flow globally, and slower global flow is associated with adverse outcomes. Relief of the culprit artery stenosis by PTCA restored culprit artery flow to that in the nonculprit artery, but both were 45% slower than normal flow.

Hand dominance and performance in a laparoscopic skills curriculum.

BACKGROUND: This study evaluated the influence of hand dominance on skill acquisition during a basic laparoscopic skills curriculum. METHODS: A total of 27 surgical residents (5 postgraduate year 3 [PGY-3] and 22 PGY-2 residents) participated in a 4-week laparoscopic skills curriculum. The residents were pre- and posttested on six laparoscopic tasks during weeks 1 and 4. During weeks 2 and 3, the residents attended a proctored practice session. The results were compared using analysis of variance (ANOVA), (with significance determined by a p value less than 0.05. RESULTS: The posttest scores were significantly higher than the pretest scores. On the pretest, lefthand-dominant (LHD) surgeons (n = 4) performed significantly better than righthand-dominant (RHD) surgeons (n = 23). In the analysis of individual task pretest scores, LHD surgeons performed significantly better on pattern cutting and vessel loop application. Posttest analysis of overall performance did not show significant differences between the RHD and LHD surgeons. CONCLUSIONS: Participation in a laparoscopic skills curriculum improved overall performance. The LHD surgeons demonstrated better initial performance, but posttest comparison showed no difference between the two groups.

Marrow antioxidant enzyme activity in tumor-bearing and non-tumor-bearing mice following vincristine treatment.

Pretreatment or "priming" with vincristine (VcR) has been documented to radioprotect animals from whole body irradiation by accelerating recovery of hematopoietic marrow. The mechanisms underlying this phenomenon are unclear, but the marked similarities between priming with VcR and with immune stimulants such as endotoxin and glucan have led to speculation that VcR may be inducing such radioprotective immunoregulators as interleukin 1 (IL-1) and tumor necrosis factor (TNF). The radioprotective ability of these cytokines, in turn, has been linked to an induction of the antioxidant enzyme manganese superoxide dismutase (Mn SOD). To establish whether priming with VcR is associated with induction of antioxidant enzymes, the activities of Mn SOD, copper-zinc (Cu-Zn) SOD, catalase (CAT), and glutathione peroxidase (GPX) were measured in the marrow of both LLca tumor-bearing and non-tumor-bearing mice given a priming dose of VcR. Results in non-tumor-bearing mice indicate that, similar to IL-1 and TNF administration, VcR treatment increases Mn-SOD activity, but not Cu-Zn SOD, CAT, or GPX activity. Furthermore, this increase occurs at the time VcR priming has been demonstrated previously to exhibit maximal radioprotection, suggesting that it may be contributing factor. However, VcR priming has been demonstrated to radioprotect both tumor-bearing and non-tumor-bearing animals, and no increase in Mn SOD activity (or the other enzymes monitored) was found in the tumor-bearing group. Rather, the presence of tumor significantly suppressed antioxidant enzyme activity. Collectively, the present data suggest that it is unlikely that increased antioxidant enzyme activity is directly involved in the VcR priming response.

Effect of phorbol esters on rat lacrimal gland protein secretion.

To identify a role for protein kinase C in lacrimal gland protein secretion, we incubated rat exorbital lacrimal gland acini in the ester 4-beta-phorbol 12, 13 dibutyrate (beta-phorbol dibutyrate), its inactive isomer 4-alpha-phorbol 12, 13 dibutyrate (alpha-phorbol dibutyrate), and the diacylglycerol analog 1,2-oleoyl acetylglycerol (OAG). We determined protein secretion by measuring the activity of peroxidase, a protein secreted by lacrimal gland acini. beta-phorbol dibutyrate, but not alpha-phorbol dibutyrate, stimulated peroxidase secretion in a concentration-dependent manner with 3 X 10(-8) M producing maximal secretion. OAG (10(-6) M) also stimulated peroxidase secretion. To determine whether muscarinic and alpha 1-adrenergic agonists activate protein kinase C, we added beta-phorbol dibutyrate (10(-7) M) simultaneously with carbachol (10(-5) M) or phenylephrine (10(-4) M); under both conditions, secretion was less than additive. Protein secretion in the presence of beta-phorbol dibutyrate (10(-7) M) and vasoactive intestinal peptide (VIP) (10(-8) M), the latter that acts through cAMP, was additive, and when the beta-phorbol dibutyrate but not the VIP concentration was decreased to 10(-8) M, secretion was potentiated. We conclude that muscarinic and alpha 1-adrenergic agonists, but not VIP, stimulated lacrimal gland protein secretion by activating protein kinase C.

Role of cyclic AMP and Ca2+ in potentiation of rat lacrimal gland protein secretion.

Addition of a cholinergic agonist carbachol and vasoactive intestinal peptide (VIP) to dispersed rat exorbital lacrimal gland acini produces protein secretion, measured by secretion of the enzyme peroxidase, that was statistically significantly greater than additive (potentiated). To determine where in stimulus-secretion coupling these secretagogues interact to potentiate secretion, rat exorbital gland acini were incubated simultaneously with cyclic AMP- and Ca2+-dependent agonists and protein secretion, cyclic AMP level, or Ca2+ concentration measured. As a measure of protein secretion, the supernatant obtained after centrifugation of acini was analyzed for peroxidase, a protein secreted by rat lacrimal glands. Interaction did not occur at the receptor level, because peroxidase secretion also was potentiated by simultaneous addition of carbachol and forskolin, which activates the catalytic subunit of adenyl cyclase. A potentiated increase in the cyclic AMP level did not potentiate protein secretion, because the level was the same with VIP as with carbachol and VIP added together at concentrations that potentiated peroxidase secretion. A potentiated increase in free intracellular [Ca2+] did not potentiate protein secretion, because [Ca2+] was greater with carbachol than with carbachol and VIP added together at concentrations that potentiated peroxidase secretion. We conclude that cholinergic- and VIP-dependent pathways interact to potentiate lacrimal gland protein secretion after the rise of intracellular cyclic AMP or Ca2+.

Can we replace the 90-minute thrombolysis in myocardial infarction (TIMI) flow grades with those at 60 minutes as a primary end point in thrombolytic trials? TIMI Study Group.

The establishment of patency (Thrombolysis In Myocardial Infarction [TIMI] grade 2 or 3 flow) and/or TIMI grade 3 flow at 60 minutes after thrombolytic administration is both a univariate and multivariate predictor of in-hospital and 30-day mortality, and the odds ratios for mortality are nearly identical for TIMI grade 3 flow at 60 and 90 minutes. Thus, the 60-minute angiographic end point appears to be a valid alternative to that at 90 minutes and may permit earlier decisions regarding post-thrombolytic intervention.

Global impairment of coronary blood flow in the setting of acute coronary syndromes (a RESTORE substudy). Randomized Efficacy Study of Tirofiban for Outcomes and Restenosis.

Acute coronary syndromes result in a global impairment of coronary blood flow with nonculprit artery blood flow being associated with culprit artery flow and vice versa. Improvements in nonculprit artery flow are related to improvements in culprit artery flow after percutaneous intervention; nonculprit arteries with abnormal flow sustain greater improvements in their flow after culprit artery intervention.

ST-segment resolution and infarct-related artery patency and flow after thrombolytic therapy. Thrombolysis in Myocardial Infarction (TIMI) 14 investigators.

Because patients who fail to achieve reperfusion after thrombolytic therapy remain at high risk for morbidity and mortality, noninvasive measures of infarct-related artery (IRA) patency are needed to identify candidates for rescue interventions. We prospectively studied 444 patients from the Thrombolysis In Myocardial Infarction (TIMI) 14 trial with interpretable baseline and 90 minute 12-lead electrocardiograms. The percent resolution of ST-segment deviation from baseline to 90 minutes was compared with 90-minute IRA TIMI flow grade, as determined in an angiographic core laboratory. Patients with complete (> or = 70%) ST resolution (n = 208; 47%) had a patency (TIMI 2 or 3 flow) rate of 94%, a TIMI 3 flow rate of 79%, and a 30-day mortality rate of 1.0%. Patients with partial (30% to 70%) or no (< or = 30%) ST resolution had significantly lower rates of patency (72% and 68%; p < 0.0001 vs complete ST resolution) and TIMI 3 flow (50% and 44%; p < 0.0001 vs complete ST resolution), and higher 30-day mortality (4.2% and 5.9%; p = 0.01 vs complete ST resolution). With use of electrocardiographic criteria alone, approximately 50% of patients can be classified as having a high (94%) probability of IRA patency and a very low risk for mortality. Angiography to determine patency of the IRA may be unnecessary in these patients. In patients without complete (> or = 70%) ST resolution, the IRA is still likely to be patent, and additional information from clinical variables or serum markers may help to identify candidates for coronary angiography. Patients with persistent ST elevation despite a patent IRA are at increased risk for mortality, likely due to extensive microvascular and tissue injury.

Early coronary intervention following pharmacologic therapy for acute myocardial infarction (the combined TIMI 10B-TIMI 14 experience).

Earlier studies have suggested that immediate percutaneous coronary intervention (PCI) following thrombolytic therapy for acute myocardial infarction (AMI) is associated with an increase in adverse events and that routine PCI in this setting has offered no advantage over a conservative strategy. To reassess this issue in a more recent era, we evaluated 1,938 patients from the Thrombolysis in Myocardial Infarction (TIMI) 10B and 14 trials of AMI. Patients in TIMI 10B were randomized to receive tissue plasminogen activator or TNK tissue plasminogen activator, whereas patients in TIMI 14B trial were randomized to receive thrombolytic therapy with or without abciximab. All patients underwent angiography 90 minutes after receiving pharmacologic therapy. Patients who underwent PCI were classified as having undergone a rescue procedure (TIMI 0 or 1 flow at 90 minutes), an adjunctive procedure (TIMI 2 or 3 flow at 90 minutes), or a delayed procedure (performed >150 minutes after symptom onset, median of 2.75 days). Among patients with TIMI 0 or 1 flow, there was a trend for lower 30-day mortality among patients who underwent rescue PCI than among those who did not (6% vs 17%, p = 0.01, adjusted p = 0.28). Patients who underwent adjunctive PCI had similar 30-day mortality and/or reinfarction as those who underwent delayed PCI. In a multivariate model both had lower 30-day mortality and/or reinfarction than patients with "successful thrombolysis" (i.e., TIMI 3 flow at 90 minutes) who did not undergo revascularization (p = 0.02). Thus, early PCI following AMI is associated with excellent outcomes. Randomized trials of an early invasive strategy following thrombolysis are warranted.