Automatic Population of the Case Report Forms for an International Multifactorial Adaptive Platform Trial Amid the COVID-19 Pandemic.

OBJECTIVES: To automatically populate the case report forms (CRFs) for an international, pragmatic, multifactorial, response-adaptive, Bayesian COVID-19 platform trial. METHODS: The locations of focus included 27 hospitals and 2 large electronic health record (EHR) instances (1 Cerner Millennium and 1 Epic) that are part of the same health system in the United States. This paper describes our efforts to use EHR data to automatically populate four of the trial's forms: baseline, daily, discharge, and response-adaptive randomization. RESULTS: Between April 2020 and May 2022, 417 patients from the UPMC health system were enrolled in the trial. A MySQL-based extract, transform, and load pipeline automatically populated 499 of 526 CRF variables. The populated forms were statistically and manually reviewed and then reported to the trial's international data coordinating center. CONCLUSIONS: We accomplished automatic population of CRFs in a large platform trial and made recommendations for improving this process for future trials.

Skin care advice to patients with multiple sclerosis on Fingolimod treatment at increased risk of skin malignancy-room for improvement?

Fingolimod is used to treat relapsing-remitting multiple sclerosis. It has an immunosuppressive effect that predisposes to skin malignancies. The Summary of Product Characteristics recommends that persons receiving Fingolimod be educated regarding photoprotection and vigilance of skin lesions and should undergo a dermatological evaluation at initiation of treatment and 6-12 monthly thereafter. The incidence of keratinocytic carcinomas in those on long-term immunosuppression following solid organ transplantation is declining. This trend coincided with temporal changes in immunosuppressive protocols and the introduction of skin cancer prevention programmes suggesting that the risk of developing these malignancies may be mitigated by the provision of education to patients amongst other measures. The aim of our study was to assess if health care professionals are explaining skin advice and documenting the discussion when prescribing Fingolimod in a University Hospital outpatient setting. Clinical records of consecutive patients on Fingolimod were reviewed. Data on demographics, documented provision of advice on skin protection and who provided the advice was collected. Fifty patients with multiple sclerosis were identified. Median age was 40.5 years (range 25-63). Forty-two were female (42/50, 84%). Provision of advice regarding skin protection was documented in 20% (10/50). This was provided by nurse specialists in 14% (7/50), doctors in 10% (5/50) and both in 4% (2/50). The risk of developing skin cancers can be reduced by the adoption of simple preventative measures; patients on Fingolimod are at an increased risk of developing these cancers. This study demonstrates a need for improvement in the documentation of advice around skin protection.

Decline in vaccine-type human papillomavirus prevalence in young men from a Midwest metropolitan area of the United States over the six years after vaccine introduction.

PURPOSE: The aim of this study was to determine changes in human papillomavirus (HPV) prevalence among young men from a Midwest metropolitan area over the six years after vaccine introduction, including HPV prevalence in men overall, in vaccinated men to examine vaccine impact and in unvaccinated men to examine herd protection. An exploratory aim was to examine associations between number of vaccine doses and HPV prevalence. METHODS: Men aged 14-26 years reporting male-female and/or male-male sexual contact were recruited from a primary care clinic, sexually transmitted disease clinic, and community setting during two waves of data collection: 2013-2014 (N = 400) and 2016-2017 (N = 347). Participants completed a questionnaire and were tested for penile, scrotal and anal HPV. Changes in prevalence of any (≥1 type) and vaccine-type HPV (HPV6, 11, 16, and/or 18) were examined using propensity score weighted logistic regression. Associations between number of doses and HPV infection were determined using chi-square tests and logistic regression. RESULTS: The proportion of men with a history of ≥1 HPV vaccine doses increased from 23% to 44% (p < 0.001) from waves 1 to 2. After propensity score weighting, infection with ≥1 vaccine-type HPV significantly decreased among all men (29% to 20%; 31% decrease; odds ratio [OR] = 0.62, 95% confidence interval [CI] = 0.44-0.88) and unvaccinated men (32% to 21%; 36% decrease; OR = 0.56, 95%CI = 0.34-0.86); there was a non-significant decrease (21%) among vaccinated men. Associations between number of doses and HPV prevalence were not statistically significant. CONCLUSIONS: Prevalence of vaccine-type HPV decreased among all, vaccinated, and unvaccinated men six years after HPV vaccine recommendation, supporting vaccine impact and herd protection. Decreases in vaccine-type HPV in all men appear to be due to decreases in unvaccinated men, suggesting that the full impact of vaccination has yet to be realized. Continued monitoring and efforts to vaccinate men prior to sexual initiation are warranted.

Factors Associated With HPV Vaccine Initiation, Vaccine Completion, and Accuracy of Self-Reported Vaccination Status Among 13- to 26-Year-Old Men.

Human papillomavirus (HPV) vaccination coverage in young men is suboptimal. The aims of this study were (a) to examine HPV vaccination and factors associated with HPV vaccination in men 13 to 26 years of age and (b) to examine and determine factors associated with accurate self-report of vaccination. Young men ( n = 400) recruited from a teen health center and a sexually transmitted disease (STD) clinic completed a survey. Accuracy was defined as correct report of at least one dose and number of doses. Mean age was 21.5 years, 104 (26.0%) received at least one vaccine dose and 49 (12.3%) received all three doses. Factors significantly associated with receipt of at least one dose in multivariable models included recruitment site (teen health center vs. STD clinic, adjusted odds ratio [AOR] = 2.75), public versus other insurance (AOR = 2.12), and age (AOR = 0.68). Most young men accurately reported their vaccination status but accuracy of report differed by age: 50.6% of 14- to 18-year-olds, 75.9% of 19- to 21-year-olds, and 93.2% of 22- to 26-year-olds. Most (293, 73.3%) accurately reported number of doses received. Age was associated with accuracy of self-report of at least one vaccine dose (AOR = 1.42), while recruitment site (STD vs. teen health center, AOR = 2.56) and age (AOR = 1.44) were associated with accuracy of self-report of number of vaccine doses. In conclusion, HPV initiation and completion in this study sample were low. Teen health center attendance, public insurance, and younger age were associated with vaccine initiation; older age and STD clinic setting were associated with accurate vaccination self-report.

Non-endoscopic biopsy techniques: a review.

INTRODUCTION: Diseases of the stomach and small intestine account for approximately 20% of all gastrointestinal (GI)-related mortality. Biopsy of the stomach and small intestine remains a key diagnostic tool for most of the major diseases that affect the GI tract. While endoscopic means for obtaining biopsy is generally the standard of care, it has several limitations that make it less ideal for pediatric patients and in low resource areas of the world. Therefore, non-endoscopic means for obtaining biopsy samples is of interest in these settings. Areas covered: We review non-endoscopic biopsy techniques reported thus far, and critically examine their merits and demerits regarding their suitability for obtaining biopsy samples in non-sedated subjects. Expert commentary: Esophagogastroduodenoscopy (EGD) is the current standard for acquiring biopsy from the GI tract, however, its limitations include subject sedation, expensive endoscopy infrastructure, expert personnel, and a small but significant risk of complications. A less costly, minimally-invasive and non-endoscopic means for obtaining biopsy samples is therefore of interest for addressing these issues. Such a technology would be of significant impact in low- and middle-income countries where conducting endoscopy is challenging.

Adolescents' intention and self-efficacy to follow Pap testing recommendations after receiving the HPV vaccine.

Human papillomavirus (HPV) vaccines are recommended in the US for girls and women 11-26 y of age. Because these vaccines do not prevent all cervical cancers, Papanicolaou (Pap) screening is still recommended after vaccination. Young women who have been vaccinated may perceive themselves at lower risk for HPV infection and cervical cancer, which could lead to lower intention and self-efficacy to follow cervical cancer screening guidelines, and subsequent nonadherence to Pap testing. The aim of this study was to examine whether perceived risk of human papillomavirus (HPV) after vaccination and other factors are associated with adolescents' intention and self-efficacy to get Pap testing after HPV vaccination. Women 13-21 y of age (N = 339) receiving their first HPV vaccine dose completed a survey. Multivariable logistic regression examined associations between perceived risk of HPV and intention/self-efficacy to get a Pap test while adjusting for other factors. Approximately half of participants reported high intention and half reported high self-efficacy to get a Pap test. Factors significantly associated with high intention were Pap testing history and knowledge about HPV/HPV vaccines; factors significantly associated with high self-efficacy included insurance plan, Pap testing history, communication with clinician about needing a Pap test after vaccination, lifetime number of male sexual partners, and recent smoking. In conclusion, educating adolescents about HPV/HPV vaccines and the need for Pap testing may increase self-efficacy/intention to get a Pap test after vaccination.

Multidisciplinary meetings as an effective clinical intervention.

When used well, multidisciplinary meetings can function in the same way as other clinical interventions to improve communication, efficiency and outcomes. They help break down barriers, manage difficult emotions, and benefit service users and staff. But it is imperative that they are well prepared, well attended, and that the purpose and agenda are agreed. It is also vital to have an efficient chair and that meetings take place in an environment where feelings can be shared openly and respected. Services should recognise and address relevant training and support requirements.

Measuring slope to improve energy expenditure estimates during field-based activities.

This technical note describes methods to improve activity energy expenditure estimates by using a multi-sensor board (MSB) to measure slope. Ten adults walked over a 4-km (2.5-mile) course wearing an MSB and mobile calorimeter. Energy expenditure was estimated using accelerometry alone (base) and 4 methods to measure slope. The barometer and global positioning system methods improved accuracy by 11% from the base (p < 0.05) to 86% overall. Measuring slope using the MSB improves energy expenditure estimates during field-based activities.

Community pharmacy and pharmacist staff call center: assessment of medication safety and effectiveness.

OBJECTIVE: To determine proof of concept for use of a network of pharmacists to evaluate the safety of medications. DESIGN: Pilot, comparative, prospective evaluation. SETTING: Community pharmacies and a pharmacist-staffed call center in Arizona during January through August 2006. PATIENTS: Patients filling prescriptions for ipratropium or tiotropium bromide at 1 of 55 Arizona pharmacies were encouraged to call a pharmacist-staffed call center. A total of 67 patients contacted the center and 41 participated. INTERVENTION: A network of community pharmacies and a call center were used to collect data on patients receiving one of two medications for the treatment of chronic obstructive pulmonary disease. Pharmacists in the community pharmacies recruited patients who presented with a prescription or requested a refill for one of the medications. The call center was used to collect patient data. Patients provided data on medication use, completed the chronic respiratory questionnaire (CRQ), and were encouraged to call the center to report health problems. After 30 days, patients were called to determine whether they experienced any adverse events while taking their medication and the CRQ was readministered. MAIN OUTCOME MEASURE: Knowledge gained on the feasibility of the model using pharmacists to assess drug safety. RESULTS: A total of 67 (6.7%) of a possible 995 patients contacted the call center about participating in the study. Approximately one-half (n = 28) of the 55 pharmacies had one or more patients contact the center about the study. A total of 41 patients met inclusion/exclusion criteria and were enrolled. Six (15%) patients reported an adverse effect, including one serious adverse event (acute glaucoma). CONCLUSION: This study provides limited evidence that community pharmacies and a pharmacist-staffed call center can be used to assess medication safety; however, a number of issues need to be examined to determine whether the approaches can be sufficiently effective.

Accuracy of a novel multi-sensor board for measuring physical activity and energy expenditure.

The ability to relate physical activity to health depends on accurate measurement. Yet, none of the available methods are fully satisfactory due to several factors. This study examined the accuracy of a multi-sensor board (MSB) that infers activity types (sitting, standing, walking, stair climbing, and running) and estimates energy expenditure in 57 adults (32 females) 39.2 ± 13.5 years. In the laboratory, subjects walked and ran on a treadmill over a select range of speeds and grades for 3 min each (six stages in random order) while connected to a stationary calorimeter, preceded and followed by brief sitting and standing. On a different day, subjects completed scripted activities in the field connected to a portable calorimeter. The MSB was attached to a strap at the right hip. Subjects repeated one condition (randomly selected) on the third day. Accuracy of inferred activities compared with recorded activities (correctly identified activities/total activities × 100) was 97 and 84% in the laboratory and field, respectively. Absolute accuracy of energy expenditure [100 - absolute value (kilocalories MSB - kilocalories calorimeter/kilocalories calorimeter) × 100] was 89 and 76% in the laboratory and field, the later being different (P < 0.05) from the calorimeter. Test-retest reliability for energy expenditure was significant in both settings (P < 0.0001; r = 0.97). In general, the MSB provides accurate measures of activity type in laboratory and field settings and energy expenditure during treadmill walking and running although the device underestimates energy expenditure in the field.

Adolescent changes in homeostatic regulation of EEG activity in the delta and theta frequency bands during NREM sleep.

STUDY OBJECTIVES: Slow wave EEG activity in NREM sleep decreases by more than 60% between ages 10 and 20 years. Slow wave EEG activity also declines across NREM periods (NREMPs) within a night, and this decline is thought to represent the dynamics of sleep homeostasis. We used longitudinal data to determine whether these homeostatic dynamics change across adolescence. DESIGN: All-night sleep EEG was recorded semiannually for 6 years. SETTING: EEG was recorded with ambulatory recorders in the subjects' homes. PARTICIPANTS: Sixty-seven subjects in 2 cohorts, one starting at age 9 and one starting at age 12 years. MEASUREMENTS AND RESULTS: For NREM delta (1-4 Hz) and theta (4-8 Hz) EEG, we tested whether the proportion of spectral energy contained in the first NREMP changes with age. We also tested for age changes in the parameters of the process S exponential decline. For both delta and theta, the proportion of energy in the first NREMP declined significantly across ages 9 to 18 years. Process S parameters SWA(0) and TWA(0), respectively, represent slow wave (delta) activity and theta wave activity at the beginning of the night. SWA(0) and TWA(0) declined significantly (P < 0.0001) across ages 9 to 18. CONCLUSIONS: These declines indicate that the intensity of the homeostatic or restorative processes at the beginning of sleep diminished across adolescence. We propose that this change in sleep regulation is caused by the synaptic pruning that occurs during adolescent brain maturation.

The increase in longitudinally measured sleepiness across adolescence is related to the maturational decline in low-frequency EEG power.

OBJECTIVES: A changing sleep schedule that reduces sleep duration is thought to produce the increasing daytime sleepiness of adolescents. We tested the hypothesis that adolescent daytime sleepiness also results from adolescent brain maturational processes indexed by declining delta electroencephalographic (EEG) activity. DESIGN: Data are from the first 3 years of a semilongitudinal study of EEG changes in adolescence. All-night EEG was recorded semiannually. SETTING: EEG was recorded with ambulatory recorders in the subjects' homes. PARTICIPANTS: Thirty-one subjects were 9 years old (cohort C9), and 38 subjects were 12 years old (cohort C12) at the start of the study. MEASUREMENTS: EEG power density (power/minute) was calculated for the first 5 hours of non-rapid eye movement sleep. Subjects rated sleepiness on a modified Epworth Sleepiness Scale. Habitual sleep schedules were assessed with self-reports and actigraphy. RESULTS: In C9 subjects, sleepiness increased slightly and was related only to age. In C12 subjects, the increase in subjective sleepiness was related to changes in age, bedtime, time in bed, and a wide frequency range of EEG power density. Sleepiness was not related to rise time, non-rapid eye movement sleep duration, rapid eye movement sleep duration, or total sleep time. With sleep schedule measures statistically controlled, the increase in sleepiness in the C12 group was strongly related to declining delta power density and, unexpectedly, even more strongly related to declining theta power density. CONCLUSIONS: The data support our hypothesis that, independent of sleep schedule changes, increasing adolescent daytime sleepiness is related to brain maturational changes indexed by declining EEG power. Our working hypothesis is that the declines in delta and theta power are correlates of an adolescent synaptic pruning that reduces waking arousal levels.

The adolescent decline of NREM delta, an indicator of brain maturation, is linked to age and sex but not to pubertal stage.

Two dramatic phenomena of human adolescence are sexual maturation and a steep decline in the delta EEG of non-rapid eye movement (NREM) sleep. It has long been speculated that these developmental changes are causally related. Here, we present the first longitudinal data on this issue. Cohorts of 9- and 12-year-old children (n = 31, 38) were studied with in-home sleep EEG recordings at 6-mo intervals over 2 years. Pubertal (Tanner) stage, height, and weight were obtained at each time point. NREM delta power density (DPD) did not change significantly over ages 9-11 years, and its level did not differ in boys and girls. DPD declined by 25% between ages 12 and 14 years. This decline was parallel in the two sexes, but levels were lower in girls, suggesting that their DPD decline began earlier. Mixed effect analyses demonstrated that DPD was strongly related to age with Tanner stage, height, weight and body mass index controlled but that none of these measures of physical and sexual development was related to DPD with age controlled. NREM delta is the sleep EEG component homeostatically related to prior waking duration and the intensity of waking brain activity. We hypothesize that the DPD decline is caused by age-programmed synaptic pruning that decreases waking brain metabolic rate. This reduced rate would decrease the "substrate" for delta homeostasis. Whether or not this interpretation proves correct, these longitudinal data demonstrate that the delta decline in adolescence reflects brain processes that are not predicted by physical growth or sexual maturation.

Sleep EEG evidence of sex differences in adolescent brain maturation.

STUDY OBJECTIVES: The steep decline in slow-wave (delta) electroencephalogram (EEG) intensity across adolescence is a prominent feature of late brain maturation. As a first step in determining whether the adolescent delta decline is similar in both sexes, we compared cross-sectional sleep EEG data from 9- and 12-year-old boys and girls. DESIGN: All-night EEG recordings, 6 months apart, were conducted on each subject. SETTING: EEG was recorded in the subjects' homes. PARTICIPANTS: Thirty-two 9-year-olds and 38 12-year-olds are enrolled in a 4-year longitudinal study of adolescent sleep. There are equal numbers of each sex in both age cohorts. INTERVENTIONS: N/A. MEASUREMENTS: Using ambulatory recorders, EEG was recorded in the subjects' homes on their normal sleep schedule. For each of the 2 semi-annual recording periods, data from the 10 subjects from each age-sex group with the cleanest (fewest artifacts) signals were selected for crosssectional comparisons of visual scoring and EEG variables. All artifact-free 20-second non-rapid eye movement epochs were analyzed with power spectral and period-amplitude analysis. RESULTS: In the 12-year-old cohort, delta power per minute was 37% higher in boys than girls. The 9-year-old cohort showed no sex difference. A second recording 6 months later produced similar results. CONCLUSION: These cross-sectional data indicate that girls begin the steep adolescent decline in slow-wave EEG earlier than boys. We hypothesize that this reflects an earlier onset of adolescent synaptic pruning in females.

In vivo phage display to identify M cell-targeting ligands.

PURPOSE: The purpose of this study was to use in vivo phage display screening technology to identify novel lead peptides that target delivery to M cells and to follicle-associated epithelium (FAE) of the intestine. METHODS: Phage display libraries were screened in vivo within the gastrointestinal tract of a rat model by successive screenings across four cycles of selection. RESULTS: Following four cycles of in vivo screening, we identified 30 unique peptide sequences that bound to Peyer's patch tissue, human Caco-2, and rat IEC-6 epithelial cells. Two of the lead targeting peptides, peptides P8 (LETTCASLCYPS) and P25 (VPPHPMTYSCQY), were shown to bind to receptors on the surface of human intestinal tissue. The L-form, D-form, retro-inverted D-form, and selective Cys-to-Ala site-directed mutants of peptides P8 and P25 were also shown to retain binding to Caco-2 cell membranes when immobilized on the surface of a model particulate. Finally, the D-peptide analog of peptide P8 (yqcsytmphppv) enhanced the delivery of polystyrene particles to M cells in vivo in a mouse model, and these particles were delivered into Peyer's patch tissue, as determined by confocal microscopy. CONCLUSIONS: In summary, we have identified novel ligands that target M cells and Peyer's patch tissue, and thus may have utility in the targeted oral delivery of vaccines and vaccine carrier systems to the mucosal immune system within the gastrointestinal tract.

Cell culture modeling of specialized tissue: identification of genes expressed specifically by follicle-associated epithelium of Peyer's patch by expression profiling of Caco-2/Raji co-cultures.

Peyer's patch follicle-associated epithelium (FAE) regulates intestinal antigen access to the immune system in part through the action of microfold (M) cells which mediate transcytosis of antigens and microorganisms. Studies on M cells have been limited by the difficulties in isolating purified cells, so we applied TOGA mRNA expression profiling to identify genes associated with the in vitro induction of M cell-like features in Caco-2 cells and tested them against normal Peyer's patch tissue for their expression in FAE. Among the genes identified by this method, laminin beta3, a matrix metalloproteinase and a tetraspan family member, showed enriched expression in FAE of mouse Peyer's patches. Moreover, the C. perfringens enterotoxin receptor (CPE-R) appeared to be expressed more strongly by UEA-1(+) M cells relative to neighboring FAE. Expression of the tetraspan TM4SF3 gene and CPE-R was also confirmed in human Peyer's patch FAE. Our results suggest that while the Caco-2 differentiation model is associated with some functional features of M cells, the genes induced may instead reflect the acquisition of a more general FAE phenotype, sharing only select features with the M cell subset.

Peptidoglycan recognition protein expression in mouse Peyer's Patch follicle associated epithelium suggests functional specialization.

Mammalian Peyer's Patches possess specialized epithelium, the follicle associated epithelium (FAE), and specialized cells called M cells which mediate transcytosis of antigens to underlying lymphoid tissue. To identify FAE specific genes, we used TOGA gene expression profiling of microdissected mouse Peyer's Patch tissue. We found expression of laminin beta3 across the FAE, and scattered expression of peptidoglycan recognition protein (PGRP)-S. Using the M cell specific lectin Ulex europaeus agglutinin 1 (UEA-1), PGRP-S expression was nearly exclusively co-localized with UEA-1+ M cells. By contrast, the related gene PGRP-L was expressed among a subset of UEA-1 negative FAE cells. Expression of these proteins in transfected cells demonstrated distinct subcellular localization. PGRP-S showed a vesicular pattern and extracellular secretion, while PGRP-L showed localization to both the cytoplasm and the cell surface. The potential function of these PGRP proteins as pattern recognition receptors and their distinctive cellular distribution suggests a complex coordination among specialized cells of the FAE in triggering mucosal immunity and innate immune responses.