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Background: Patient-reported outcome measures (PROMs) describe health status from the perspective of the patient. There is growing interest in the use of PROMs in clinical trials and there have been major efforts to develop PROMs for neurological conditions (e.g., Neuro-QOL, PROMIS). However, the extent to which such measures are used in stroke trials is uncertain. We sought to determine how often contemporary acute stroke trials included PROMs as primary or secondary outcome measures. Methods: We searched MEDLINE for completed RCTs published in one of nine major journals between 2010 and 2020. Eligible studies were phase 2 or 3 trials undertaken to test therapeutic interventions within one month of stroke onset. For each trial we accessed the primary publication as well as the published protocol and supplement when available. We abstracted key trial characteristics including all primary and secondary efficacy outcome measures. We defined PROMs using online databases (qolid.org) with the focus on self-reported measures of quality of life, symptoms, and function collected without interpretation of an external party. Results: 115 trials met eligibility criteria. Only one trial used a PROM for its primary outcome measure (visual analogue pain scale), but 40 trials (35%) listed at least one PROM as a secondary outcome measure in its primary publication. An additional 15 trials (13%) listed at least one PROM in their protocol. Among the 55 trials that defined at least one PROM as a secondary outcome measure, the most commonly used measure was Euro-QOL (n=42, 76%) followed by SIS-16 (n=9, 16%), SF-36 (n=7, 13%), and the stroke-specific QOL scale (n=5, 9%). Other PROMs included various measures of anxiety and depression (n=9, 16%). Only one study used a Neuro-QOL based measure. Of the 41 trials that listed a PROM as a primary or secondary outcome in the primary publication, 39 (95%) provided PROM results, but of these only 7 (18%) found statistically significant treatment differences. Conclusions: While about half of acute stroke trials listed at least one PROM as a secondary outcome, they played a minor role in the presentation of trial results. Inclusion of PROMs in acute stroke trials requires greater attention during both the design and reporting phases of the trial.

Background: We performed a systematic review of acute stroke trials to determine features associated with premature termination of trial enrollment. Methods: MEDLINE was searched for stroke RCTs between 1/1/2013-6/11/2020. Included studies were Phase 2 or 3, had a preplanned sample size ≥100, had time to treatment within 24 hours of onset for TIA, ischemic stroke, or ICH, and were published in a major clinical journal (BMJ, Circulation, Stroke, Neurology, JAMA, JAMA Neurology, Lancet, Lancet Neurology, NEJM). Studies were deemed prematurely terminated if authors reported early termination. Study variables and inclusion criteria are listed in Table 1. Complex trials required specialized training and expertise, high degree of monitoring, or procedural intervention. Univariate Chi-square tests/Fisher’s exact test were used to determine characteristics associated with early termination, and multivariable lasso logistic regression was used to select the most important predictors. Results: Of 1,219 studies assessed, 69 trials met eligibility criteria for inclusion (Table 1); 34 (49%) were prematurely terminated. In univariate analysis, variables associated with premature termination were complexity of treatment, industry involvement, exclusion of older patients, and presence of a futility stopping rule. In lasso regression, complex treatment trials (OR 3.77, 95% CI 1.30-10.97, versus moderate or simple trials combined), presence of a futility rule (OR 3.56, 95% CI 1.02-12.40 versus no rule), and geographic region (North America OR 1.97, 95% CI 0.57-6.81 versus all other regions combined) were selected as important factors. Conclusion: Half of acute stroke trials were terminated prematurely. Broadening inclusion/exclusion criteria and simplifying the complexity of trials may decrease the likelihood of unplanned premature termination, whereas planned futility analyses may appropriately terminate trials early, saving money and resources.

Background: Termination of a clinical trial before the maximum planned sample size is accrued can occur for multiple valid reasons but has implications for the interpretation of results. We undertook a systematic review of contemporary acute stroke trials to document the prevalence of and reasons for early termination. Methods: We searched MEDLINE for randomized controlled trials of acute stroke therapies published between 2013 and 2020 in 9 major clinical journals. Manuscripts describing the primary results of phase 2 and phase 3 trials of acute stroke care were included. Data on study characteristics and adherence to CONSORT reporting guidelines were abstracted and summarized using descriptive statistics. Where feasible, we compared treatment effect sizes between trials terminated early and those not terminated early. Results: Of 96 randomized controlled trials, 39 (41%) were terminated early, 84 (88%) had a data and safety monitoring board, and 57 (59%) reported a prespecified statistical stopping rule. Among the 39 trials terminated early, 10 were discontinued for benefit, 10 due to logistical issues, 8 for futility, 6 because of newly available evidence, 1 for harm, and 4 for other or a combination of reasons. The median percentage of the maximum planned sample size accrued among trials terminated early was 63% (range, 8%–89%). Only 55% of trials (53 of 96) reported whether interim efficacy analyses were conducted, as recommended by the CONSORT guidelines. When 10 endovascular therapy trials were compared according to early termination status, the effect sizes of trials terminated early for benefit were only modestly larger than those not terminated early. Conclusions: The high prevalence of early termination in combination with the wide variety of reasons underscores the necessity of meticulous trial planning and adherence to methodological and reporting guidelines for early termination. Registration: URL: https://www.crd.york.ac.uk/prospero/ ; Unique identifier: CRD42019128727.

Background and Purpose: When reporting primary results from randomized controlled trials, recommendations include reporting results by sex. We reviewed the reporting of results by sex in contemporary acute stroke randomized controlled trials. Methods: We searched MEDLINE for articles reporting the primary results of phase 2 or 3 stroke randomized controlled trials published between 2010 and June 2020 in one of nine major clinical journals. Eligible trials were restricted to those with a therapeutic intervention initiated within one month of stroke onset. Of primary interest was the reporting of results by sex for the primary outcome. We performed bivariate analyses using Fisher exact tests to identify study-level factors associated with reporting by sex and investigated temporal trends using an exact test for trend. Results: Of the 115 studies identified, primary results were reported by sex in 37% (n=42). Reporting varied significantly by journal, with the New England Journal of Medicine (61%) and Lancet journals (40%) having the highest rates ( P =0.03). Reporting also differed significantly by geographic region (21% Europe versus 48% Americas, P =0.03), trial phase (13% phase 2 versus 40% phase 3, P =0.05), and sample size (24% 750 participants, P P =0.11), there was a temporal trend in favor of greater reporting among later publications (25% 2010–2012 versus 48% 2019–2020). Conclusions: Although reporting of primary trial results by sex improved from 2010 to 2020, the prevalence of reporting in major journals is still low. Further efforts are required to encourage journals and authors to comply with current reporting recommendations.

Background: Dual antiplatelet therapy (DAPT) after ischemic stroke or transient ischemic attack may reduce recurrent stroke but also increase severe bleeding compared with single antiplatelet therapy (SAPT). The American Heart Association/American Stroke Association convened an evidence review committee to perform a systematic review and meta-analysis of the benefits and risks of DAPT compared with SAPT for secondary ischemic stroke prevention. Methods: The Medline, Embase, and Cochrane databases were searched on December 5, 2019, to identify phase III or IV randomized controlled trials (n≥100) from December 1999 to December 2019. We calculated unadjusted relative risks (RRs) and performed meta-analyses of studies based on the duration of treatment (short [≤90 days] versus long [>90 days]). Results: Three short-duration randomized controlled trials were identified that enrolled mostly patients with minor stroke or high risk transient ischemic attack. In these trials, DAPT, compared with SAPT, was associated with a lower 90-day risk of recurrent ischemic stroke (pooled RR, 0.68 [95% CI, 0.55–0.83], I 2 =37.1%). There was no significant increase in major bleeding with DAPT in short-duration trials (pooled RR, 1.88 [95% CI, 0.93–3.83], I 2 =8.9%). In 2 long-duration treatment randomized controlled trials (mean treatment duration, 18-40 months), DAPT was not associated with a significant reduction in recurrent ischemic stroke (pooled RR, 0.89 [95% CI, 0.79–1.02], I 2 =1.4%), but was associated with a higher risk of major bleeding (pooled RR, 2.42 [95% CI, 1.37–4.30], I 2 =75.5%). Conclusions: DAPT was more effective than SAPT for prevention of secondary ischemic stroke when initiated early after the onset of minor stroke/high-risk transient ischemic attack and treatment duration was

The underenrollment of women in randomized clinical trials represents a threat to the validity of the evidence supporting clinical guidelines and potential disparities in access to novel treatments.To determine whether women were underenrolled in contemporary randomized clinical trials of acute stroke therapies published in 9 major journals after accounting for their representation in underlying stroke populations.MEDLINE was searched for acute stroke therapeutic trials published between January 1, 2010, and June 11, 2020.Eligible articles reported the results of a phase 2 or 3 randomized clinical trial that enrolled patients with stroke and/or transient ischemic attack and examined a therapeutic intervention initiated within 1 month of onset.Data extraction was performed by 2 independent authors in duplicate. Individual trials were matched to estimates of the proportion of women in underlying stroke populations using the Global Burden of Disease database.The primary outcome was the enrollment disparity difference (EDD), the absolute difference between the proportion of trial participants who were women and the proportion of strokes in the underlying disease populations that occurred in women. Random-effects meta-analyses of the EDD were performed, and multivariable metaregression was used to explore the associations of trial eligibility criteria with disparity estimates.The search returned 1529 results, and 115 trials (7.5%) met inclusion criteria. Of 121 105 randomized patients for whom sex was reported, 52 522 (43.4%) were women. The random-effects summary EDD was -0.053 (95% CI, -0.065 to -0.040), indicating that women were underenrolled by 5.3 percentage points. This disparity persisted across virtually all geographic regions, intervention types, and stroke types, apart from subarachnoid hemorrhage (0.117 [95% CI, 0.084 to 0.150]). When subarachnoid hemorrhage trials were excluded, the summary EDD was -0.067 (95% CI, -0.078 to -0.057). In the multivariable metaregression analysis, an upper age limit of 80 years as an eligibility criterion was associated with a 6-percentage point decrease in the enrollment of women.Further research is needed to understand the causes of the underenrollment of women in acute stroke trials. However, to maximize representation, investigators should avoid imposing age limits on enrollment.

Introduction: Predictors of changes in depression in the early transitional period following an acute stroke are not well understood. We conducted a secondary analysis of patients enrolled in the Michigan Stroke Transitions Trial (MISTT) to characterize factors associated with changes in depressive symptoms from 7 to 90 days after returning home. Methods: MISTT was an open, parallel, randomized clinical trial testing the efficacy of social worker case management alone or in conjunction with a website to improve outcomes following acute stroke. Patient-reported outcomes including PHQ-9 were collected via telephone interviews conducted 7 and 90 days after patients returned home. PHQ-9 score ranges from 0-27 with higher scores indicating more severe symptoms. Key demographic variables were extracted from medical records. Multivariable linear regression was used to identify independent predictors of change in PHQ-9 score from 7 to 90 days using the GLM procedure in SAS. All analyses were adjusted for baseline (7-day) PHQ-9 score and pre-specified confounders (Table). We accounted for missing data using inverse probability weighting. Results: Of 265 patients enrolled in MISTT, 164 had PHQ-9 scores available at both 7 and 90 days and were included in the analysis. The mean PHQ-9 score was 5.4 at 7 days and 4.9 at 90 days. The mean within person change from 7 to 90 days was -0.5. In the final model, being unmarried (versus married), and moderate or severe stroke severity (versus mild) were associated with an increase in depressive symptoms (Table). As expected, 7-day PHQ-9 score was a strong predictor of 90-day score. Accounting for missing data did not meaningfully change model results. Conclusions: Increases in PHQ-9 scores following stroke hospitalization were seen in unmarried patients and those with greater stroke severity. Identifying factors associated with worsening symptoms over time may help guide clinical management during the early transition period.

Introduction: When reporting primary results, it is recommended that RCTs report sex-specific outcomes. We reviewed the reporting of sex-specific outcomes in contemporary acute stroke RCTs. Methods: We searched MEDLINE for manuscripts published between 2010 and June 2020 in one of nine major clinical journals reporting the primary results of phase 2 or 3 stroke RCTs. Eligible trials tested a therapeutic intervention initiated within one month of stroke onset. Reporting of sex-specific primary results was the outcome of interest. We also investigated whether the trial formally tested for an interaction between sex and treatment and if that interaction test was statistically significant. We performed bivariate analyses using Fisher’s exact tests to identify study-level factors associated with sex-specific reporting including journal, geographic region, trial phase, sample size, stroke type, trial type (e.g. thrombolytic, EVT, secondary prevention), and industry funding. Temporal trends using two-year time periods were also explored. Results: Of the 115 studies identified, sex-specific primary outcome data were reported in 37% (n=42). Reporting varied significantly by journal, with NEJM (61%) and Lancet journals (40%) having the highest rates (p=0.03) (Table). Reporting also differed by geographic region (p=0.03), trial phase (p=0.05), and sample size (p Conclusions: Although reporting of sex-specific outcomes improved from 2010 to 2020, the prevalence of reporting in major journals is still low. Further efforts are required to ensure that journals and authors comply with reporting guidelines.

Introduction: The inadequate enrollment of women in RCTs represents a threat to trial generalizability and potential inequities in access to novel treatments. We sought to determine whether women were under-enrolled in contemporary acute stroke trials. Methods: We searched MEDLINE for completed RCTs published in one of nine major journals between 2010 and 2020. Eligible studies were phase 2 or 3 trials undertaken to test therapeutic interventions within one month of stroke onset. For each trial we calculated the proportion of trial participants that were women (PPW). We used Global Burden of Disease (GBD) data to estimate the expected proportion of strokes occurring in women in the underlying stroke populations (PSW). We matched individual estimates from the GBD data to each trial based on geographic location, year, and stroke type. To quantify disparities, we calculated the enrollment disparity difference (EDD), defined as EDD = PSW - PPW. A positive EDD indicates that women were under-represented in the trial. We used random effects meta-analysis to pool individual EDDs and conducted subgroup analyses. Results: We identified 115 trials that met eligibility criteria. The random effects summary EDD was 0.053 (95% CI = 0.040, 0.053), indicating that women were under-enrolled in acute stroke trials by 5% relative to their representation in the underlying stroke population. However, there was substantial between-trial variability in the EDD (I 2 =84.4%). In subgroup analyses, the EDD was similar across subgroups except for stroke type (figure); trials that only included subarachnoid hemorrhages enrolled women in excess of their representation in the underlying population (summary EDD = -0.117 [95% CI = -0.150, -0.084]). Conclusions: Overall, women were modestly under-represented in contemporary acute stroke trials compared to their representation among all strokes. Further study is needed to elucidate factors driving sex differences in enrollment between RCTs.

Introduction Post-stroke depression is a disabling condition that occurs in approximately one-third of stroke survivors. There is limited information on changes in depressive symptoms shortly after stroke survivors return home. To identify factors associated with changes in post-stroke depressive symptoms during the early recovery period, we conducted a secondary analysis of patients enrolled in a clinical trial conducted during the transition period shortly after patients returned home (MISTT). Methods The Michigan Stroke Transitions Trial (MISTT) tested the efficacy of social worker case management and access to online information to improve patient-reported outcomes following an acute stroke. Patient Health Questionnaire-9 (PHQ-9) scores were collected via telephone interviews conducted at 7 and 90 days post-discharge; higher scores indicate more depressive symptoms. Generalized estimating equations were used to identify independent predictors of baseline PHQ-9 score at 7 days and of changes over time to 90 days. Results Of 265 patients, 193 and 185 completed the PHQ-9 survey at 7 and 90 days, respectively. The mean PHQ-9 score was 5.9 at 7 days and 5.1 at 90 days. Older age, being unmarried, and having moderate stroke severity (versus mild) were significantly associated with lower 7-day PHQ-9 scores (indicating fewer depressive symptoms). However, at 90 days, both unmarried patients and those with moderate or high stroke severity had significant increases in depressive symptoms over time. Conclusions In stroke patients who recently returned home, both marital status and stroke severity were associated with depressive symptom scores; however, the relationships were complex. Being unmarried and having higher stroke severity was associated with fewer depressive symptoms at baseline, but both factors were associated with worsening depressive symptoms over time. Identifying risk factors for changes in depressive symptoms may help guide effective management strategies during the early recovery period.

Introduction: A priori sample size determination is an essential step in designing randomized controlled trials (RCTs). Failure to reach pre-planned sample size introduces risk of both falsely negative and spuriously positive findings. We undertook a systematic review of contemporary acute stroke trials to document the prevalence and reasons for termination of trials prior to completion of enrollment. Methods: We searched MEDLINE for RCTs of acute stroke therapy published between 2013 and 2018 in 9 major journals. Manuscripts describing the final primary results of phase 3 and large phase 2 trials of any therapeutic intervention were eligible for inclusion. Study characteristics, including the presence of a data monitoring committee (DMC) and stopping rules, risk-of-bias assessment, funding sources and conflicts of interest, were abstracted from published manuscripts and trial protocols by two independent reviewers. The prevalence of and reasons for early termination were quantified. Multivariable logistic regression was used to identify study-level predictors of early termination. Results: Of 756 hits, 60 were eligible for inclusion, 21 (35%) of which were terminated early. Among the trials stopped early, 10 (48%) reported stopping for benefit or newly available evidence while 11 (52%) were terminated for futility; 20 (95%) reported a DMC and 17 (81%) reported the use of a pre-specified statistical stopping rule. Factors associated with early termination included study location in North America, larger planned sample size, and industry funding (Table). Study location in North America and larger planned sample size retained statistical significance in a multivariable model. Conclusions: One in three contemporary stroke trials were terminated prior to completion of enrollment. Reasons for termination were evenly split between benefit and futility. Further study is needed to understand the reasons for and impact of early termination on study results.

Introduction: Women have historically been underrepresented in RCTs of cardiovascular disease. We undertook a review of acute stroke RCTs to determine whether women were equitably represented and whether any sex disparity varied across geographic region. Methods: We searched for papers describing primary results of acute stroke RCTs published 2013-2018 in 9 major journals and abstracted the proportion of trial participants that were women (PPW). We then searched for incidence studies from the geographic regions in which trial enrollment took place and estimated the proportion of incident strokes occurring in women (PSW) in each region (i.e., North America, Europe, Asia Pacific, Multiple Regions). We quantified the representation of women using the enrollment disparity difference (EDD) calculated as the absolute difference between the two proportions (i.e., PSW - PPW). An EDD greater than 0 indicated a disparity in favor of men. We pooled EDDs from individual RCTs using random effects meta-analysis to estimate overall and region-specific disparities. Results: Among 60 trials the PPW ranged from 33.8% to 56.9% (median 44.7%). The overall pooled EDD was 0.07 (95% CI=0.06-0.08, Q p2 =85.8%) (Figure), indicating that 7% more men were included in the trials, relative to the underlying incidence. A statistically significant EDD existed in all regions; the magnitude was largest for RCTs with enrollment from Asia Pacific (EDD=0.11, 95% CI=0.10-0.13) and Multiple Regions (EDD=0.10, 95% CI=0.08-0.12) and smallest among North American and European trials (EDD 0.04 and 0.06, respectively). All region-specific summary estimates showed significant between study heterogeneity apart from Asia (Q p=0.102, I 2 =38.4%). Conclusions: Women were underrepresented globally in contemporary acute stroke RCTs; the magnitude of the disparity differed between regions. Future research should focus on trial eligibility criteria that may contribute to this disparity.

ObjectiveA prior meta-analysis of reports published between 2000 and 2008 found that women were 30% less likely to receive IV recombinant tissue plasminogen activator (rtPA) treatment for stroke than men; we updated this meta-analysis to determine if this sex difference persisted.MethodsWe identified studies that reported sex-specific IV rtPA treatment rates for acute ischemic stroke published between 2008 and 2018. Eligible studies included representative populations of patients with ischemic stroke from hospital-based, registry-based, or administrative data. Random effects odds ratios (ORs) were generated to quantify sex differences.ResultsTwenty-four eligible studies were identified during this 10-year period. The summary unadjusted OR based on 17 studies with data on all ischemic stroke patients was 0.87 (95% confidence interval [CI], 0.82–0.93), indicating that women had 13% lower odds of receiving IV rtPA treatment than men. However, substantial between-study variability existed. Lower treatment odds in women were also observed in 7 studies that provided data on the subgroup of patients eligible for IV rtPA treatment, although the summary OR of 0.95 (95% CI, 0.88–1.02) was not statistically significant. Examination of time trends across 33 studies published between 2000 and 2018 found evidence that the sex difference had narrowed in more recent years.ConclusionsAlthough there is considerable variability in the findings of individual studies, pooled data from recent studies show that women with acute stroke are less likely to be treated with IV thrombolysis compared with men. However, the size of this difference has narrowed compared to studies published before 2008.

In a large general education class where students demonstrate their personal creativity, a self-grading system was used during one semester and a conventional teacher-evaluation system was used during the second semester. The purpose was to gauge whether the self-grading system was appropriate. Students adapted well to the procedures used, and they reported feeling more motivated to learn and took more responsibility for their learning. A disadvantage was a tendency for grade inflation to occur.

Most polymeric thermoset materials change (cure) slowly as they lie in storage; a prime example of this is composite prepreg materials. These changes are generally vitrification, and are not readily observable using some of the standard cure-monitoring methods, such as DSC and FTIR, which sense mainly the gelation process. Evidence of this observation is presented, along with the successful results of an effort to monitor this shelf-cure process using a simplified resistivity meter.

Adhesion between organic fibers and thermoplastics in a composite material is usually weak because of the lack of chemical and mechanical bonding. This study investigated the influence of plasma gas species in a novel technique to improve interfacial adhesion of Kevlar 49 fibers to polycarbonate. Single Kevlar fibers were exposed to radio-frequency plasma discharge in atmospheres of argon, oxygen, and ammonia. Plasma treatment has been shown to generate reactive free radicals on polymer surfaces. The fibers that were coated immediately with a polycarbonate melt while still in the vacuum environment of a plasma reactor showed an increase in interfacial shear strength that was maximum at 4.1 s exposure and decreased at longer exposure times. At 4.1 s exposure, Ar and O2 plasma treatment increased shear strength by 20 and 18%, respectively. NH3 plasma treatment produced only a statistically insignificant increase at 4.1 s of exposure and a significant decrease in adhesion at 8.3 s of exposure. Fibers that were exposed to air for 1 h before coating showed no statistically significant increase or decrease in adhesion. The increase in adhesion of the directly coated fibers was attributed to free radical-initiated formation of covalent bonds between the Kevlar and the polycarbonate. © 1993 John Wiley & Sons, Inc.

A novel technique has been developed to increase interfacial adhesion be tween organic fibers and thermoplastics. The technique consists of exposing the fiber to a radio frequency plasma discharge and then immediately coating the fiber with thermo plastic while still in the vacuum environment of the plasma reactor. Increased adhesion has been shown using a polyaramid fiber (Kevlar 49) and a polycarbonate resin (Lexan 121). An oxygen plasma exposure of 4.1 seconds at 24 Watts increased interfacial shear strength by 18 % as evaluated using the critical filament length technique. The plasma ex posure had no measurable effect on the filament tensile strength or the surface roughness. It is thought that the enhanced adhesion is due to the presence of covalent bonds formed at the interface when free radicals on the fiber are quenched by the thermoplastic.

The use of composite materials for structural members has been restricted by the lack of data on the use of these composites, by the inherent brittleness of many of these materials, and by the expensive manufacturing methods associated with their fabri cation. This study examines a new process to postform a constant cross section structural section (I-beam) from a straight section to a bent or contoured section. The structural pieces were tested for stiffness and compared with finite element analysis to determine the net change, if any, due to the bending. Statistical analysis of these results indicated that the bending procedure had little or no significant effect on the stiffness of the samples. This process may, therefore, result in a method of using preformed, standard shaped composite structural members and postforming those members for specific applications.

Incremental forming is a new manufacturing method designed to create large thermoplastic composite laminate structures. These large laminates can be made utilizing small to medium sized equipment. The equipment and the operating parameters for successful incremental forming were developed. Thermoplastic laminate parts were made utilizing the incremental forming method and the properties were compared to parts of the same shape made using matched die molding. The areas of comparison were mechanical properties, physical qualities (surface quality), and uniformity of manufac ture The results revealed that the incremental forming process created parts of high mechanical integrity, excellent physical quality and good uniformity.

The experimental carbon-13 chemical shifts of acetylene, dimethyl acetylene, and allene are reported and compared with existing values for methane, ethane, ethylene, methylacetylene, and benzene. The relative importance of first-, second-, and third-order perturbation terms in the shift calculation is considered. It is concluded that second-order terms dominate the shielding but significant third- and possibly fourth-order terms indicate that overly refined second-order calculations are not warranted when higher-order terms are neglected. A comparison of the average energy method for calculating chemical shifts with the sum-over-states or coupled Hartree-Fock perturbation method is made, and the two methods are found to be similar in many details. The effects of symmetry and of electron radial character as specified by the Slater orbital exponent were examined and found to affect significantly the shielding expression. The methods presented are applicable to larger molecules where both INDO and MINDO, widely used MO programs may be employed. While the dominant structural features are revealed in chemical shielding calculations, this work indicates that excessive refinement is not warranted so long as one neglects higher-order effects, variations in orbital radial character, and details of admixtures of higher electronic states by the magnetic field into the electronic description of the molecule.