Variability In Response Rates Research Articles

Abstract 5552: Uncovering clinically significant tumor microenvironment interaction programs across diverse cancers

Abstract Background: Cell-cell interactions (CCI) within the tumor microenvironment (TME) play pivotal roles in various tumor behaviors, including cancer growth, metastasis, immune evasion, and resistance to therapy. Compared to front-line treatments, targeting specific CCIs marks a paradigm shift in cancer therapy, aiming for enhanced response rates with reduced side effects. Although current approaches targeting immune regulation pathways exhibit effective anti-tumor responses, substantial variability in response rates across patients and cancer types persists. Consequently, a critical imperative emerges to discover novel interaction programs (IPs) across diverse TMEs, demonstrating clear clinical impact across a broad spectrum of patients. Methods: Characterization of pan cancer IPs. We compiled a pan cancer single-cell RNA-seq (scRNA-seq) atlas, including 4 million cells from 890 tumors across 14 cancer types. In each sample, CCIs were inferred using a ligand-receptor (LR) analysis framework, generating ranked CCI scores based on consensus from various LR inference methods. To find IPs enriched across TMEs, we applied an unsupervised factorization approach. The outcome represents CCIs as factors, where sample loading indicates factors’ strength, and feature loading highlights the cells and LR pairs constituting each IP. Evaluating IPs in clinical RNA-seq cohorts. Given the more immediate translational potential of bulk cancer sequencing for patient stratification, we devised an approach to predict IPs' strengths in bulk RNA-seq. Random Forest regression models using pseudo-bulk expression of cancer genes were trained to predict the loading (strength) of factors (IPs) in each sample in the scRNA-seq pan-cancer atlas. These models were subsequently applied to cancer samples in The Cancer Genome Atlas (TCGA) cohort to assess the clinical impact of various IPs on patient mortality. Results: We assessed the impact of IPs on 5-year overall survival using Cox proportional hazard models. We identified multiple factors significantly associated with survival in at least 4 cancer types. Notably, a robust prognostic factor linked to the inclusion of anti-tumor natural killer cell interactions and exclusion of pro-tumor macrophage interactions was found in MESO, LGG, ACC, and UVM (HR 1.6-6.6, p < 0.05). The validation of IPs using spatial transcriptomics and evaluation of IP prediction's utility in targeted treatment cohorts are currently underway. Conclusion: We highlight a potent method for detecting clinically significant IPs involving cells in TME communicating through LR pairs. The ability to assess these scRNA-seq-derived IPs in clinical bulk RNA-seq cohorts signifies a valuable advancement. Our approach holds promise for expanding the repertoire of cell therapies, identifying new treatment targets, and improving our predictive capabilities for responses to existing therapies. Citation Format: Ido Nofech-Mozes, Vivian Wang, Philip Awadalla, Sagi Abelson. Uncovering clinically significant tumor microenvironment interaction programs across diverse cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5552.

Taking Our Pulse: Examining 5 Years of Data from the Association of Pediatric Program Directors Research and Scholarship Learning Community

BackgroundThe Association of Pediatric Program Directors Research and Scholarship Learning Community (RSLC) prioritizes and comprehensively reviews medical education surveys directed to residency program leadership. Each survey is reviewed by two members of RSLC and the Chair and Vice Chair using a standardized scoring rubric and a limited number of surveys are accepted per cycle. MethodsInternal review data from 2015 to 2020 were analyzed to determine factors associated with survey acceptance, and for surveys accepted for distribution, determine factors associated with response rates or dissemination status. One-Way analysis of variance (ANOVA) assessed differences in evaluation scores by initial determination status. T-tests and Pearson Product Correlation assessed associations between evaluation scores and response rates by dissemination status. ResultsThe majority (47/81; 58%) of surveys submitted to RSLC are eventually accepted for distribution. Response rates for distributed surveys varied between 14% and 73%. Most (35/47; 74%) surveys distributed through RSLC are presented (62%) and/or published (60%). Higher review scores were associated with acceptance for distribution but not with response rates or dissemination status. ConclusionMost surveys are eventually accepted by RSLC for distribution and those distributed often get published or presented despite variability in response rates.

Combined Assessment of the Tumor-Stroma Ratio and Tumor Immune Cell Infiltrate for Immune Checkpoint Inhibitor Therapy Response Prediction in Colon Cancer.

The best current biomarker strategies for predicting response to immune checkpoint inhibitor (ICI) therapy fail to account for interpatient variability in response rates. The histologic tumor–stroma ratio (TSR) quantifies intratumoral stromal content and was recently found to be predictive of response to neoadjuvant therapy in multiple cancer types. In the current work, we predicted the likelihood of ICI therapy responsivity of 335 therapy-naive colon adenocarcinoma tumors from The Cancer Genome Atlas, using bioinformatics approaches. The TSR was scored on diagnostic tissue slides, and tumor-infiltrating immune cells (TIICs) were inferred from transcriptomic data. Tumors with high stromal content demonstrated increased T regulatory cell infiltration (p = 0.014) but failed to predict ICI therapy response. Consequently, we devised a hybrid tumor microenvironment classification of four stromal categories, based on histological stromal content and transcriptomic-deconvoluted immune cell infiltration, which was associated with previously established transcriptomic and genomic biomarkers for ICI therapy response. By integrating these biomarkers, stroma-low/immune-high tumors were predicted to be most responsive to ICI therapy. The framework described here provides evidence for expansion of current histological TIIC quantification to include the TSR as a novel, easy-to-use biomarker for the prediction of ICI therapy response.

Impact of vascular risk factors on clinical outcome in elderly patients with depression receiving electroconvulsive therapy

BackgroundAlthough electroconvulsive therapy (ECT) is a highly effective, safe, and well-tolerated antidepressant treatment for late-life depression (LLD), there is large variability in response rates across individuals. We hypothesized that these variations would be in part explained by the level of vascular risk in this population. We therefore compared response rates to ECT in patients with LLD presenting with or without vascular risk factors (VRF). Methods52 patients with LLD (age > 55) who received a course of ECT were separated into 2 groups according to the presence of VRF (n = 20) or not (n = 32). Framingham score (10-year risk for developing a coronary heart disease) was calculated for each patient. Our primary outcome was the number of responders to ECT in each group (defined as at least 50% decrease of the Montgomery–Åsberg Depression Rating Scale score following ECT course). Scores at the self-rated Beck Depression Inventory are also reported. ResultsPatients with VRF presented significant lower response rates to ECT (12 out of 20; 60%) than patients without VRF (30 out of 32; 94%; p = 0.004). A negative correlation was found between Framingham score and changes in depression scores pre/post ECT (r = -0.42; p = 0.0039). LimitationsOur study was limited by sample size and retrospective design. ConclusionPatients with LLD and VRF showed lower response rates to ECT than those without VRF. The more the VRF increased, the less the antidepressant effect of ECT was observed. Results are discussed in light of the role of apathy in clinical response to ECT.

What Factors Are Associated With Response Rates for Long-term Follow-up Questionnaire Studies in Hand Surgery?

Long-term follow-up studies are an important tool in the evaluation of orthopaedic illness and its treatment options. However, a patient's participation in a follow-up study may be affected by several factors, leading to variability in response rates and the risk of selection bias. (1) What is the average response rate in hand surgery questionnaire studies? (2) What factors are associated with higher and lower response rates to research questionnaires? (3) What factors are associated with higher and lower contact, initial participation, and completion rates? We included 798 adult patients who were enrolled in one of 12 questionnaire follow-up studies in the hand and upper extremity service of our institution. All included studies evaluated patient-reported outcomes for the surgical treatment of upper extremity conditions using questionnaires and all used the same enrollment design. Patients were invited by letter to ask if they would be willing to participate, and we informed them that they would be contacted by telephone at least three times if they did not respond to the letter. Patients were contacted at a median of 6.6 years (interquartile range [IQR] 3.7 to 11) after surgery. The successful response rate was 49% (390 of 798 patients). We manually reviewed records to collect data on patient characteristics, and we performed bivariate analysis and multivariable logistic regression analysis to identify factors associated with the contact rate (percentage of patients reached by either mail, phone, or email), initial response rate (percentage of reached patients who initiated participation), completion rate (percentage of patients who initiated participation and completed the entire follow-up questionnaire), and our primary outcome successful response rate (percentage of patients who were contacted and who completed the entire questionnaire). The average response rate in hand surgery questionnaire studies was 49% (390 of 798 patients). In the multivariable analysis, enrollment of women (odds ratio 1.43 [95% confidence interval 1.03 to 1.97]; p = 0.031) was independently associated with higher response rates. On the contrary, a longer follow-up time from surgery (OR 0.95; 95% CI 0.92 to 0.99]; p = 0.015) and multiple researchers contacting patients (OR 0.51 [95% CI 0.37 to 0.71]; p < 0.001) were independently associated with lower response rates. The contact rate was higher for women (OR 1.46 [95% CI 1.03 to 2.06]; p = 0.034) and patients with higher income (OR 1.000007 [95% CI 1.000001 to 1.000013]; p = 0.019). The contact rate was lower in patients with a longer follow-up time from surgery (OR 0.93 [95% CI 0.90 to 0.97]; p = 0.001). The initial participation rate was lower when patients were contacted by multiple researchers (OR: 0.34 [95% CI 0.23 to 0.52]; p < 0.001). Studies with a lower number of questions (36; IQR 22 to 46) were completed more frequently than studies with a higher number of questions (51; IQR 39 to 67; p = 0.044). Studies assessing long-term outcomes that have a large proportion of men and longer follow-up time tend to have lower response rates. When performing a follow-up study, it seems beneficial to have one researcher contact the patients and use a shorter questionnaire. Results of this study can help clarify the response rates in hand surgery follow-up questionnaire studies and help with the planning of future follow-up studies. Level II, prognostic study.

Transcranial focused ultrasound stimulation of motor cortical areas in freely-moving awake rats

BackgroundLow-intensity transcranial focused ultrasound (tFUS) has emerged as a new non-invasive modality of brain stimulation with the potential for high spatial selectivity and penetration depth. Anesthesia is typically applied in animal-based tFUS brain stimulation models; however, the type and depth of anesthesia are known to introduce variability in responsiveness to the stimulation. Therefore, the ability to conduct sonication experiments on awake small animals, such as rats, is warranted to avoid confounding effects of anesthesia.ResultsWe developed a miniature tFUS headgear, operating at 600 kHz, which can be attached to the skull of Sprague–Dawley rats through an implanted pedestal, allowing the ultrasound to be transcranially delivered to motor cortical areas of unanesthetized freely-moving rats. Video recordings were obtained to monitor physical responses from the rat during acoustic brain stimulation. The stimulation elicited body movements from various areas, such as the tail, limbs, and whiskers. Movement of the head, including chewing behavior, was also observed. When compared to the light ketamine/xylazine and isoflurane anesthetic conditions, the response rate increased while the latency to stimulation decreased in the awake condition. The individual variability in response rates was smaller during the awake condition compared to the anesthetic conditions. Our analysis of latency distribution of responses also suggested possible presence of acoustic startle responses mixed with stimulation-related physical movement. Post-tFUS monitoring of animal behaviors and histological analysis performed on the brain did not reveal any abnormalities after the repeated tFUS sessions.ConclusionsThe wearable miniature tFUS configuration allowed for the stimulation of motor cortical areas in rats and elicited sonication-related movements under both awake and anesthetized conditions. The awake condition yielded diverse physical responses compared to those reported in existing literatures. The ability to conduct an experiment in freely-moving awake animals can be gainfully used to investigate the effects of acoustic neuromodulation free from the confounding effects of anesthesia, thus, may serve as a translational platform to large animals and humans.

Avoiding non-responders to cardiac resynchronization therapy: a practical guide.

Over two decades after the introduction of cardiac resynchronization therapy (CRT) into clinical practice, ∼30% of candidates continue to fail to respond to this highly effective treatment of drug-refractory heart failure (HF). Since the causes of this non-response (NR) are multifactorial, it will require multidisciplinary efforts to overcome. Progress has, thus far, been slowed by several factors, ranging from a lack of consensus regarding the definition of NR and technological limitations to the delivery of therapy. We critically review the various endpoints that have been used in landmark clinical trials of CRT, and the variability in response rates that has been observed as a result of these different investigational designs, different sample populations enrolled and different means of therapy delivered, including new means of multisite and left ventricular endocardial simulation. Precise recommendations are offered regarding the optimal device programming, use of telemonitoring and optimization of management of HF. Potentially reversible causes of NR to CRT are reviewed, with emphasis on loss of biventricular stimulation due to competing arrhythmias. The prevention of NR to CRT is essential to improve the overall performance of this treatment and lower its risk-benefit ratio. These objectives require collaborative efforts by the HF team, the electrophysiologists and the cardiac imaging experts.

Immunology of Diabetes Society T‐Cell Workshop: HLA class II tetramer‐directed epitope validation initiative

Islet-antigen-specific CD4+ T cells are known to promote auto-immune destruction in T1D. Measuring T-cell number and function provides an important biomarker. In response to this need, we evaluated responses to proinsulin and GAD epitopes in a multicentre study. A tetramer-based assay was used in five participating centres to measure T-cell reactivities to DR0401-restricted epitopes. Three participating centres concurrently performed ELISPOT or immunoblot assays. Each centre used blind-coded, centrally distributed peptide and tetramer reagents. All participating centres detected responses to auto-antigens and the positive control antigen, and in some cases cloned the corresponding T cells. However, response rates varied among centres. In total, 74% of patients were positive for at least one islet epitope. The most commonly recognized epitope was GAD270-285. Only a minority of the patients tested by tetramer and ELISPOT were concordant for both assays. This study successfully detected GAD and proinsulin responses using centrally distributed blind-coded reagents. Centres with little previous experience using class II tetramer reagents implemented the assay. The variability in response rates observed for different centres suggests technical difficulties and/or heterogeneity within the local patient populations tested. Dual analysis by tetramer and ELISPOT or immunoblot assays was frequently discordant, suggesting that these assays detect distinct cell populations. Future efforts should investigate shared blood samples to evaluate assay reproducibility and longitudinal samples to identify changes in T-cell phenotype that correlate with changes in disease course.

Disease Modification in Migraine: Study Design and Sample Size Implications

Describe a clinical trial design that is capable of detecting disease modifying effects (DME) of anti-migraine drugs, and to explore the effect on study size of the likely variability in initial active- and placebo-response rates. An orthodox power calculation and typical response rates in studies of prophylactic drugs for migraine were used to construct the initial model. The interactions between variability in response rates for active and placebo treatments (ARR and PRR, respectively), as well as required sample size, was then analyzed as a 3-dimensional problem. Overall, the putative study design requires 4 times as many patients as in each analyzable treatment group, all with allowances for loss to follow up, when both positive and negative control groups are available for comparison with the group being tested for DME. For an example prophylactic agent with ARR = 50% and PRR = 25%, the model suggests that the study might need 260-270 patients. Sample sizes increase in quasi-exponential manner as placebo-response rates rise, and active-response rates fall, and these are plotted for the reported variability of ARR and PRR in migraine prophylaxis. Variations on the study design can be modeled for the likely variability in outcome using a straightforward technique. Investigating DME activity for drugs with the efficacy that is typical of approved prophylactic agents might not require impractically large numbers of patients. Such models can be used not only in study design, but also in assessing the overall feasibility of whether or not to pursue DME detection within a given development program.

Exploring the Impact of E-mail and Postcard Prenotification on Response Rates to a Mail Survey in an Academic Setting

What techniques effectively and consistently impact response rates to a mail survey? No clear answer to this question exists, largely because variability in response rates occurs depending on the population of interest, questionnaire type, and procedures used by researchers. This article examines the impact of e-mail and postcard prenotification on response rates to a mail survey by using a population of university full-time faculty and staff. Comparisons were made among respondents who received a postcard prenotification, those who received an e-mail prenotification, and those who received no prenotification prior to the initial mailing of a questionnaire. Data show that e-mail prenotification had the largest impact on response rate, while postcard prenotification had the least impact. In addition, the use of e-mail prenotification reduced overall project costs (both time and money). We suggest that the uses and applicability of e-mail prenotification be further explored to examine both its initial and overall impact on response rate in populations utilizing an electronic environment.

Role of Chemotherapy and Rituximab for Treatment of Posttransplant Lymphoproliferative Disorder in Solid Organ Transplantation

To evaluate the role of chemotherapy and/or rituximab for treatment of posttransplant lymphoproliferative disorder (PTLD) in solid organ transplantation. A MEDLINE search (1966-May 2007) was conducted using the key words posttransplant lymphoproliferative disorder, solid organ transplantation, chemotherapy, and rituximab. References of relevant articles and abstracts from recent hematology, oncology, and transplantation scientific meetings (2004-May 2007) were also reviewed. Prospective and retrospective studies identified from the data sources were evaluated, and all information deemed relevant was included for this review. Overall response rates ranged from 53% to 68%, 25% to 83%, and 74% to 100% for rituximab monotherapy, chemotherapy, and chemotherapy plus rituximab, respectively. Positive response to treatment was influenced by prognostic factors, including presence of Epstein-Barr virus in tumor cells, normal lactate dehydrogenase levels, good performance status, early disease onset after transplantation, and early disease stages. These factors in study patients likely contribute to the variability in response rates seen between treatment options. Severe adverse effects, ranging from grade 3 neutropenia to infection resulting in death, occurred more frequently in patients receiving chemotherapy than in patients receiving only rituximab. Although reduction in immunosuppressive medications remains the first-line therapy for PTLD treatment, many cases do not respond to this treatment alone, especially monomorphic or more aggressive cases of lymphoma. Therefore, it is reasonable to begin active treatment including rituximab and/or chemotherapy initially, along with reduction in immunosuppression in many cases. Further prospective, comparative studies are urgently needed to confirm the efficacy of these treatment strategies as well as to clarify which subset of patients may benefit most from them.

A Comparison of Two Distribution Methods on Response Rates to a Patient Safety Questionnaire in Nursing Homes

Survey research focusing on patient safety issues in the nursing home sector poses challenges owing to nursing staff turnover rates, and the adversarial and punitive nature of US nursing home regulation which may promote a negative culture of distrust. Using a patient safety questionnaire, we compared two methods of survey distribution on response rates, respondent sample characteristics, and resident safety ratings. We hypothesized that employees may provide overly positive perceptions when the surveys are distributed on-site as opposed to distribution to employees' homes, as has been reported by studies evaluating patient satisfaction in other settings. In August 2003, 26 nursing homes indicated their distribution method preference (mail directly to staff members' homes vs. distributed at work) for a survey determining perceptions of resident safety. Facilities provided lists of currently employed nurses (n=721) and nursing assistants (n=1,233). The survey process included an initial mailing of the survey packet, a reminder postcard, a re-mail of the survey packet to non-respondents to the initial survey, and a final reminder postcard. Return envelopes were addressed to the research team. In nursing facilities where surveys were distributed at work, a greater proportion of respondents were identified as no longer currently employed. Response rates were similar regardless of distribution method, but with greater variability in the facility-specific response rate in surveys distributed at work. Regardless of staffing type, yield of the first mailing was lower and yield of the second mailing higher in homes with surveys distributed at work than those mailed directly to respondents' homes. While characteristics of nurses were similar regardless of wave, nursing assistant responders to second mailing were more likely to be black relative to responders to the first wave. Distributing surveys at the workplace may not result in a reduction of response rate, but may provide overly positive perceptions of patient safety issues. Mailing directly to homes may result in less facility-level variability in response rates. Multiple mailings may increase the diversity of the respondent pool.

Suture Location Impacts Clinical Outcome for Endoscopic Treatment of Gastroesophageal Reflux Disease

Purpose: Endoscopic treatments for gastroesophageal reflux disease (GERD) have variable long-term success rates, however the reason for such variability in response rates is unclear. The aim of this study was to determine the effects of location and number of sutures on clinical outcome in patients undergoing endoscopic treatment for GERD. Methods: Patients with persistent GERD symptoms despite medical therapy and undergoing endoscopic anti-reflux treatment with more than one year follow up were included. Endoscopic suturing of the gastroesophageal junction (GEJ) was done using commercially available endoscopic suturing devices. Sutures were placed within 2 cm distal to the squamo-columnar junction in a circumferential fashion. The number of sutures was recorded and the locations of the sutures were documented according to the face clock position at the GEJ. Greater curve sutures were at the 6 o'clock position and lesser curve sutures were at the 12 o'clock position. Complete symptom resolution was defined as absence of heartburn and regurgitation symptoms at the longest available follow up. The association between number of sutures, suture location (combination of lesser and greater curve, or lesser curvature or greater curvature) and symptom resolution was examined using Fisher's exact test. Results: Forty-two patients (26F/16M) with a mean follow up of 20 months were included in the analysis. Thirteen patients (31%) achieved complete symptom resolution. Sixteen patients had placement of three sutures, 24 patients had placement of two sutures, and 2 patients had placement of one suture. The number of sutures did not correlate with clinical outcome. Patients with a combination of greater and lesser curve sutures achieved the best clinical outcome (p = 0.014) during follow up. Conclusions: A combination of greater and lesser curve sutures at the gastroesophageal junction was associated with the best long-term clinical outcome of endoscopic treatment for gastroesophageal reflux disease. Future larger studies will be needed to confirm this finding and to determine the optimal suture placement configuration.

Major Histocompatibility Complex Susceptibility Genes and Immune Thrombocytopenic Purpura in Caucasian Adults

Immune thrombocytopenic purpura (ITP) is a heterogeneous disorder with wide variability in response rates to treatments including corticosteroids, splenectomy and intravenous immune globulins. The nature of the underlying predisposing causes for this autoimmune disorder are not known. We have HLA typed 71 adult Caucasian patients with chronic primary ITP, and compared the data with 750 control samples. In this association study, we were not able to identify a significant immunogenetic susceptibility factor for ITP with HLA class I and class II alleles. However, it appeared that there might be an association between HLA-A2 and ITP, particularly in female patients, who are the predominantly affected group; and HLA-A2 was also present at increased frequency in patients with chronic ITP progressing to splenectomy. These findings are reviewed in the context of other similar reported HLA studies in ITP. Further studies based on larger groups of patients will be necessary to identify genetic susceptibility factors for this disease.

Opioids in non-cancer pain: a life-time sentence?

There is continuing reluctance to prescribe strong opioids for the management of chronic non-cancer pain due to concerns about side-effects, physical tolerance, withdrawal and addiction. Randomized controlled trials have now provided evidence for the efficacy of opioids against both nociceptive and neuropathic pain. However, there is considerable variability in response rates, possibly depending on the type of pain, the type of opioid and its route of administration, the time to follow-up, compliance and the development of tolerance.Five patients were selected with nociceptive or neuropathic pain in whom other pharmacological or physical therapies had failed to provide satisfactory pain relief. They received transdermal fentanyl (starting dose 25μg/h) for at least 6 weeks. Transdermal fentanyl dosage was titrated upwards as required. Transdermal fentanyl provided adequate pain relief in patients with nociceptive pain (diabetic ulcer, osteoporotic vertebral fracture, ankylosing spondylitis) or neuropathic pain with a nociceptive component (radicular pain due to disc protrusion, herpetic neuralgia). The duration of treatment ranged from 6 weeks to 6 months for four cases. In the case of ankylosing spondylitis, treatment was carried out for 2 years, stopped and then restarted successfully. There were no withdrawal effects or addictive behaviour on treatment cessation, regardless of duration of the treatment. In conclusion, strong opioids may provide prolonged effective pain relief in selected patients with nociceptive and neuropathic non-cancer pain. Transdermal fentanyl treatment can often be temporary and can easily be stopped following adequate pain relief without withdrawal effects or any evidence of addictive behaviour.

Mass Mailing and Staff Experience in a Total Recruitment Program for a Clinical Trial: The SHEP Experience

The Systolic Hypertension in the Elderly Program (SHEP) staff contacted 447,921 screenees, of whom 11,919 (2.7%) were originally eligible and 4,736 (1.1%) maintained eligibility and were randomized. The total number of participants enrolled at the 16 clinical centers ranged from 133 to 559. The low yield of screenees to randomizations resulted from the study design, not from low levels of agreement to participate, and required the employment of a variety of recruitment strategies in a prudent overall plan. SHEP was one of the first clinical trials to use mass mailing as a primary strategy of recruitment. The study used mailing lists from seven generic sources. More than 3.4 million letters of invitation were mailed; they yielded an overall response rate of 4.3%. Motor vehicle and voter registration lists provided the greatest numbers of names. Mailings to members of health maintenance organizations (HMOs) and registrants of the Health Care Finance Administration (HCFA) provided the greatest response rates. Considerable variability in response rates existed among clinical centers using generically similar mailing lists. Generally, the number of hours spent on recruitment showed a positive, but not statistically significant, association with randomization yields. The recruitment yield was statistically significantly higher in clinics with experienced recruitment coordinators than in clinics with inexperienced ones ( p = 0.0008). From these findings we conclude that mass mailing is an important strategy in an overall recruitment program, that the involvement of experienced recruitment staff is important, and that although the total time spent by staff on recruitment may also improve results, it matters less than the staff’s level of recruiting experience.

Yaw direction neurons in the cat inferior olive.

1. Single units that responded to yaw rotation were recorded extracellularly in the caudal inferior olive (IO) of barbiturate-anesthetized cats. Of 276 neurons, 55 responded reliably to yaw, and extensive quantitative data were recorded from 25. 2. No yaw-sensitive IO neuron responded to somatosensory or auditory stimuli but two responded, though unreliably, to flash. 3. Yaw-sensitive IO cells fired at low (1-4 spikes/s), irregular rates during one direction of rotation. Though cells responded reliably during yaw, firing rates varied considerably from cycle to cycle. Rotation speed and acceleration were not represented in any cell's firing rate. 4. Eighty five percent (47/55) of yaw-sensitive cells fired during contralateral rotation, 9% (5/55) during ipsilateral rotation, and 6% (3/55) fired from late in the ipsilateral phase of a sinusoidal oscillation to the middle of the contralateral phase. 5. Responses were tested to 0.1-Hz sinusoidal yaw oscillations with a range of peak angular velocities (1-200 degrees/s). Thresholds were not sharp because of the cycle to cycle variability in response rates but were estimated using averaged responses. The peak rate of the most sensitive cell was driven to criterion (2 SD above spontaneous rate) by an oscillation with a peak velocity of 1 degrees/s. Other cells reached criterion between 5 and 50 degrees/s. 6. Sinusoidal oscillation at all frequencies tested (0.01-0.5 Hz) elicited approximately the same firing rates. Even at 0.01 Hz cells responded well. Responses lagged acceleration by approximately 25 degrees at 0.01 Hz and shifted to later parts of the cycle as frequency increased so that firing lagged acceleration by approximately 200 degrees at 0.5 Hz. 7. Histological reconstruction showed that yaw-sensitive neurons were recorded in olivary subnucleus beta (N beta), the dorsal cap of Kooy (DC), the posterior medial region of the medial accessory division of the inferior olive (MAO), and in the medial-lateral center of the caudal MAO. 8. Yaw-sensitive neurons in the inferior olive provide a signal to the cerebellum that indicates the direction of passive rotation over a wide range of velocity and acceleration. The signal from individual neurons does not reliably encode either rotation velocity or acceleration. Yaw-sensitive IO neurons are therefore unlike other central vestibular neurons but are similar to somatosensory IO cells which signal the presence, but not the intensity of a stimulus.

Learning takes place in rats with deafferentation of the medial basal hypothalamus

The present experiments were designed primarily to determine whether or not the neural connections of the hypophysiotrophic region of the hypothalamus are essential for learning (habituation, acquisition, retention, and extinction) in the male rat. The paradigms employed measured learning of a food-related habit, inhibitory and passive shock avoidance, and swim escape. In addition, measurements were made of body weights throughout the entire experimental period, of open field activity, of deposition of fecal boli, and of male sexual behavior. The results showed that learning took place approximately to the same extent in rats whether or not the hypophysiotrophic region was isolated from the rest of the brain. Thus, if the operation of the hypophysiotrophic region is essential at all for learning, humoral communication to and from the isolated region may be sufficient to maintain the required processes at a normal level. When placed on an ad libitum food intake, the hypothalamic island animals became obese. Impairment in male sexual function also was noted. In the feeding paradigm and five of seven measurements made in the other behavioral studies, the variabilities (standard deviations) were less among the animals with hypothalamic islands than in the operated controls. In measurements of the feeding habit, the variability in response rates among individual rats in the hypothalamic island group was significantly lower than among sham-operated animals during the times when high response rates were observed. One of the roles of the hypothalamus is to help maintain homeostatic constancy. It is suggested that another role, largely mediated by the activities of the hypophysiotrophic region, might be to emit neural and humoral signals that increase the number of behavioral options available to an individual organism, concomitantly increasing the variability among individuals, viz., the hypophysiotrophic region may be viewed as a variability generator. Increases in behavioral variability among members of a particular species in response to increasing environmental exigencies may enhance the ability of that species to survive.