Design and methods of the Apple Women's Health Study: a digital longitudinal cohort study.

BACKGROUND: Prospective longitudinal cohorts assessing women's health and gynecologic conditions have historically been limited. OBJECTIVE: The Apple Women's Health Study was designed to gain a deeper understanding of the relationship among menstrual cycles, health, and behavior. This paper describes the design and methods of the ongoing Apple Women's Health Study and provides the demographic characteristics of the first 10,000 participants. STUDY DESIGN: This was a mobile-application-based longitudinal cohort study involving survey and sensor-based data. We collected the data from 10,000 participants who responded to the demographics survey on enrollment between November 14, 2019 and May 20, 2020. The participants were asked to complete a monthly follow-up through November 2020. The eligibility included installed Apple Research app on their iPhone with iOS version 13.2 or later, were living in the United States, being of age greater than 18 years (19 in Alabama and Nebraska, 21 years old in Puerto Rico), were comfortable in communicating in written and spoken English, were the sole user of an iCloud account or iPhone, and were willing to provide consent to participate in the study. RESULTS: The mean age at enrollment was 33.6 years old (±standard deviation, 10.3). The race and ethnicity was representative of the US population (69% White and Non-Hispanic [6910/10,000]), whereas 51% (5089/10,000) had a college education or above. The participant geographic distribution included all the US states and Puerto Rico. Seventy-two percent (7223/10,000) reported the use of an Apple Watch, and 24.4% (2438/10,000) consented to sensor-based data collection. For this cohort, 38% (3490/9238) did not respond to the Monthly Survey: Menstrual Update after enrollment. At the 6-month follow-up, there was a 35% (3099/8972) response rate to the Monthly Survey: Menstrual Update. 82.7% (8266/10,000) of the initial cohort and 95.1% (2948/3099) of the participants who responded to month 6 of the Monthly Survey: Menstrual Update tracked at least 1 menstrual cycle via HealthKit. The participants tracked their menstrual bleeding days for an average of 4.44 (25%-75%; range, 3-6) calendar months during the study period. Non-White participants were slightly more likely to drop out than White participants; those remaining at 6 months were otherwise similar in demographic characteristics to the original enrollment group. CONCLUSION: The first 10,000 participants of the Apple Women's Health Study were recruited via the Research app and were diverse in race and ethnicity, educational attainment, and economic status, despite all using an Apple iPhone. Future studies within this cohort incorporating this high-dimensional data may facilitate discovery in women's health in exposure outcome relationships and population-level trends among iPhone users. Retention efforts centered around education, communication, and engagement will be utilized to improve the survey response rates, such as the study update feature.

A Randomized Controlled Trial Comparison of NeuroSENSE and Bispectral Brain Monitors During Propofol-Based Versus Sevoflurane-Based General Anesthesia.

BACKGROUND: NeuroSENSE is a depth of anesthesia monitor that uses automated electroencephalogram quantification. The Wavelet-based Anesthetic Value for Central Nervous System (WAVCNS) index calculated by this monitor is based on wavelet analysis of a normalized electroencephalogram signal in the γ-frequency band. The aim of this study was to determine the extent of disagreement between the Bispectral Index (BIS) and the WAVCNS index during propofol-based and sevoflurane-based maintenance of general anesthesia in a routine surgical population. METHODS: Patients undergoing elective surgery were enrolled in the study and randomly assigned to receive either propofol or sevoflurane for the maintenance of anesthesia and remifentanil in both groups. Anesthesiologists were blinded to monitors in both groups. Discordance between the 2 monitors was assessed by the count of discrepancy in recommendation (DR) (type 1 defined as one parameter <40 and the other >60, or type 2 defined as BIS and WAVCNS values on different sides of a threshold [40 or 60]) and also by the proportion of agreement (P0) between WAVCNS and BIS, obtained every 5 seconds, in 3 categories of index (<40, 40-60, and >60). RESULTS: The analyzed data set consisted of 22 patients (36,872 data pairs) in the propofol group and 24 patients (32,826 data pairs) in the sevoflurane group. The type 1 DR rarely occurred in both the groups (<1%); however, the median (interquartile range) type 2 DR was significantly more frequent in the propofol group (20.6% [7.0-36.9] vs 4.5% [2.3-12.4]; P = 0.0005). The median difference in P0 was 11.53% (95% confidence interval, 0.57-21.32). Major disagreement between WAVCNS index and BIS was related to the weight of burst suppression pattern for the index calculation. CONCLUSIONS: Disagreement between BIS and NeuroSENSE during the maintenance of general anesthesia was worse in the propofol group than that in the sevoflurane groups. The disagreement increases during deep anesthesia or in the occurrence of burst suppression.

NREM sleep staging using WAV(CNS) index.

OBJECTIVE: Visual scoring of 30-s epochs of sleep data is not always adequate to show the dynamic structure of sleep in sufficient details. It is also prone to considerable inter- and intra-rater variability. Moreover, it involves considerable training and experience, and is very tedious, time-consuming, labor-intensive and costly. Hence, automatic sleep staging is needed to overcome these limitations. Since naturally occurring NREM sleep and anesthesia have been reported to possess various underlying neurophysiological similarities, EEG-based depth-of-anesthesia monitors have started to penetrate into sleep research. This study investigates the ability of WAV(CNS) index (as implemented in NeuroSENSE depth-of-anesthesia monitor) to detect NREM sleep stages and wake state for full overnight PSG data. METHODS: Full overnight PSG sleep data, obtained from 24 adolescents, was scored by a registered PSG technologist for different sleep stages. Retrospective analysis was performed on a single frontal channel using the WAV(CNS) algorithm. Non-parametric descriptive statistics were used to examine the relationship between WAV(CNS) index and sleep stages. RESULTS: A strong correlation (ρ = 0.9458) was found between the WAV(CNS) index and NREM sleep stages, with WAV(CNS) index values decreasing with increasing sleep stages. Moreover, there was no significant overlap between different NREM sleep stages as classified by the WAV(CNS) index, which was able to significantly differentiate (P < 0.001) between all pairs of Awake and different NREM stages. CONCLUSIONS: This study demonstrates that changes in the depth of natural NREM sleep are reflected sensitively by changes in the WAV(CNS) index. Hence, WAV(CNS) index may serve as an automatic real-time indicator of depth of natural sleep with high temporal resolution, and can possibly be of great use for automated sleep staging in routine/postoperative somnographic studies.

Human glial-restricted progenitors survive, proliferate, and preserve electrophysiological function in rats with focal inflammatory spinal cord demyelination.

Transplantation of glial progenitor cells results in transplant-derived myelination and improved function in rodents with genetic dysmyelination or chemical demyelination. However, glial cell transplantation in adult CNS inflammatory demyelinating models has not been well studied. Here we transplanted human glial-restricted progenitor (hGRP) cells into the spinal cord of adult rats with inflammatory demyelination, and monitored cell fate in chemically immunosuppressed animals. We found that hGRPs migrate extensively, expand within inflammatory spinal cord lesions, do not form tumors, and adopt a mature glial phenotype, albeit at a low rate. Human GRP-transplanted rats, but not controls, exhibited preserved electrophysiological conduction across the spinal cord, though no differences in behavioral improvement were noted between the two groups. Although these hGRPs myelinated extensively after implantation into neonatal shiverer mouse brain, only marginal remyelination was observed in the inflammatory spinal cord demyelination model. The low rate of transplant-derived myelination in adult rat spinal cord may reflect host age, species, transplant environment/location, and/or immune suppression regime differences. We conclude that hGRPs have the capacity to myelinate dysmyelinated neonatal rodent brain and preserve conduction in the inflammatory demyelinated adult rodent spinal cord. The latter benefit is likely dependent on trophic support and suggests further exploration of potential of glial progenitors in animal models of chronic inflammatory demyelination.

Slope analysis of somatosensory evoked potentials in spinal cord injury for detecting contusion injury and focal demyelination.

In spinal cord injury (SCI) research there is a need for reliable measures to determine the extent of injury and assess progress due to natural recovery, drug therapy, surgical intervention or rehabilitation. Somatosensory evoked potentials (SEP) can be used to quantitatively examine the functionality of the ascending sensory pathways in the spinal cord. A reduction of more than 50% in peak amplitude or an increase of more than 10% in latency are threshold indicators of injury. However, in the context of injury, SEP peaks are often obscured by noise. We have developed a new technique to investigate the morphology of the SEP waveform, rather than focusing on a small number of peaks. In this study, we compare SEP signals before and after SCI using two rat models: a contusion injury model and a focal experimental autoimmune encephalomyelitis model. Based on mean slope changes over the signal, we were able to effectively differentiate pre-injury and post-injury SEP values with high levels of sensitivity (83.3%) and specificity (79.2%).

Evoked potential and behavioral outcomes for experimental autoimmune encephalomyelitis in Lewis rats.

A reliable outcome measurement is needed to assess the effects of experimental lesions in the rat spinal cord as well as to assess the benefits of therapies designed to modulate them. The Basso, Beattie, and Bresnahan (BBB) behavioral scores can be indicative of the functionality in motor pathways. However, since lesions are often induced in the more accessible dorsal parts associated with the sensory pathways, the BBB scores may not be ideal measure of the disability. We propose somatosensory evoked potential (SEP) as a complementary measure to assess the integrity of sensory pathways. We used the focal experimental autoimmune encephalomyelitis (EAE) model, in which focal demyelinating lesions were induced by injecting cytokine-ethidium bromide into dorsal white matter after MOG-IFA immunization. Both the SEP and BBB measures reflected injury; however, the SEP was uniformly and consistently altered after the injury whereas the BBB varied widely. The results suggest that the SEP measures are more sensitive and reliable markers of focal spinal cord demyelination compared to the behavioral measures like the BBB score.

Characterization of graded multicenter animal spinal cord injury study contusion spinal cord injury using somatosensory-evoked potentials.

STUDY DESIGN: Electrophysiological analysis using somatosensory-evoked potentials (SEPs) and behavioral assessment using Basso, Beattie, Bresnahan (BBB) scale were compared over time for graded Multicenter Animal Spinal Cord Injury Study (MASCIS) contusion spinal cord injury (SCI). OBJECTIVE: To study the SEP responses across different contusion injury severities and to compare them with BBB scores. SUMMARY OF BACKGROUND DATA: For any SCI therapy evaluation, it is important to accurately and objectively standardize the injury model. The graded MASCIS contusion injuries on dorsal spine have been standardized using BBB, which is subjective and prone to human errors. Furthermore, dorsal pathway disruption does not always produce locomotor deficits. SEP monitoring provides an advantage of providing a reliable and objective assessment of the functional integrity of dorsal sensory pathways. METHODS: Four groups of Fischer rats received contusion at T8 using New York University (NYU)-MASCIS impactor from impact heights of 6.25 mm (mild), 12.5 mm (moderate), 25 mm (severe), or 50 mm (very severe). The control group underwent laminectomy only. SEP and BBB recordings were performed once before injury, and then weekly for up to 7 weeks. RESULTS: Graded levels of injury produced concomitant attenuations in hindlimb SEP amplitudes. Following injury, 25 and 50 mm groups together differed significantly from 12.5 and 6.25 mm groups (P < 0.01). From week 5, differences between 12.5 and 6.25 mm groups also became apparent (P < 0.01), which showed significant electrophysiological improvement. However, no significant differences were observed between 25 and 50 mm groups, which showed negligible electrophysiological recovery. Although comparable differences between different groups were also detected by BBB after injury (P < 0.001), BBB was less sensitive in detecting any improvement in 6.25 and 12.5 mm groups. CONCLUSION: SEP amplitudes and BBB scores decrease corresponding to increase in injury severity, however, these show different temporal patterns of recovery. These results demonstrate the utility of SEPs in conjunction with BBB, to monitor therapeutic interventions in SCI research.

Efficient differentiation of human embryonic stem cells into oligodendrocyte progenitors for application in a rat contusion model of spinal cord injury.

This study utilized a contusion model of spinal cord injury (SCI) in rats using the standardized NYU-MASCIS impactor, after which oligodendrocyte progenitor cells (OPCs) derived from human embryonic stem cell (ESC) were transplanted into the spinal cord to study their survival and migration route toward the areas of injury. One critical aspect of successful cell-based SCI therapy is the time of injection following injury. OPCs were injected at two clinically relevant times when most damage occurs to the surrounding tissue, 3 and 24 hours following injury. Migration and survivability after eight days was measured postmortem. In-vitro immunofluorescence revealed that most ESC-derived OPCs expressed oligodendrocyte markers, including CNPase, GalC, Olig1, O4, and O1. Results showed that OPCs survived when injected at the center of injury and migrated away from the injection sites after one week. Histological sections revealed integration of ESC-derived OPCs into the spinal cord with contusion injury without disruption to the parenchyma. Cells survived for a minimum of eight days after injury, without tumor or cyst formation. The extent of injury and effect of early cell transplant was measured using behavioral and electrophysiological assessments which demonstrated increased neurological responses in rats transplanted with OPCs compared to controls.

A comparative study of recording procedures for motor evoked potential signals.

Motor evoked potential (MEP) signals serve as an objective measure of the functional integrity of motor pathways in the spinal cord. Hence, they provide a reliable assessment of the extent of spinal cord injury (SCI). There are two methods currently being used for serial MEP recordings in rats: a low-frequency and a high-frequency method. In this paper, we compared the two methods and determined the better method for MEP recordings. We also compared the effect of two anesthetic agents - inhalational isoflurane and intraperitoneal ketamine - on the MEP signals. We found that under ketamine anesthesia, low-frequency stimulation led to more consistent results, while high-frequency stimulation required greater stimulation intensity and was prone to unwanted side-effects including excessive head twitches. We further found that isoflurane anesthesia severely depressed the MEP response for both low-frequency and high-frequency stimulation which rendered the resulting signal unusable.

Evoked potential versus behavior to detect minor insult to the spinal cord in a rat model.

Reliable outcome measurement is needed for spinal cord injury research to critically evaluate the severity of injury and recovery thereafter. However, such measurements can sometimes be affected by minor, injury to the spinal cord during surgical procedures, including laminectomy. The open-field Basso, Beattie and Bresnahan (BBB) behavior motor scores are subjective and prone to human error. We investigated somatosensory evoked potential (SEP) as an electrophysiological measure to assess the integrity of the spinal cord after injury. In our experiment, control rats with a minor unintentional spinal cord insult during laminectomy showed a decrease in SEP amplitude by 16% to 18%, which recovered in around 7 days. However, there was no change in the BBB scores for the same animals over the same period. This highlights the sensitivity of SEP to minor insult as compared to BBB. These differences may be beneficial in accurate evaluation of the severity and progression of spinal cord injury, and subsequent recovery.

Effect of MOG sensitization on somatosensory evoked potential in Lewis rats.

Myelin oligodendrocyte glycoprotein (MOG) is commonly used as an immunogen to induce an immune response against endogenous myelin, thereby modeling multiple sclerosis in rodents. When MOG is combined with complete Freund's adjuvant (CFA), multifocal, multiphasic disease ensues; whereas when MOG is combined with incomplete Freund's adjuvant (IFA), clinical disease is usually absent. MOG-IFA immunized animals can be induced to have neurological disease after intraspinal injections of cytokines and ethidium bromide (EtBr). In this study, we investigated whether MOG-IFA immunized rats exhibited subclinical injury as defined by somatosensory evoked potential (SEP) recordings. The titration of anti-MOG-125 antibodies showed robust peripheral mounting of immune response against myelin in MOG-immunized rats. However the SEP measures showed no significant change over time. Upon injecting cytokine-EtBr in the spinal cord after MOG sensitization, the SEP recordings showed reduced amplitude and prolonged latency, suggestive of axonal injury and demyelination in the dorsal column, respectively. These findings were later confirmed using T2-weighted MRI and histological hematoxylin-eosin stain of the spinal cord. This report establishes that MOG-IFA immunization alone does not alter neuronal conduction in SEP-related neural-pathways and that longitudinal in-vivo SEP recordings provide a sensitive read-out for focal myelitis (MOG-IFA and intraspinal cytokine-EtBr) in rats.

Spinal cord injury detection and monitoring using spectral coherence.

In this paper, spectral coherence (SC) is used to study the somatosensory evoked potential (SEP) signals in rodent model before and after spinal cord injury (SCI). The SC technique is complemented with the Basso, Beattie, and Bresnahan (BBB) behavior analysis method to help us assess the status of the motor recovery. SC can be used to follow the effects of SCI without any preinjury baseline information. In this study, adult female Fischer rats received contusion injury at T8 level with varying impact heights using the standard New York University impactor. The results show that the average SC between forelimb and hindlimb SEP signals before injury was relatively high ( > or =0.7). Following injury, the SC between the forelimb and hindlimb SEP signals dropped to various levels ( < or =0.7) corresponding to the severity of SCI. The SC analysis gave normalized quantifiable results for the evaluation of SCI and recovery thereafter using the forelimb signals as an effective control, without the need of any baseline data. This technique solves the problems associated with the commonly used time-domain analysis like the need of a trained neurophysiologist to interpret the data and the need for baseline data. We believe that both SC and BBB may provide a comprehensive and complementary picture of the health status of the spinal cord after injury. The presented method is applicable to SCIs not affecting the forelimb SEP signals.

A novel shape analysis technique for somatosensory evoked potentials.

Somatosensory evoked potentials (SEP) have been shown to be an important electrophysiological measure to assess the integrity of the spinal cord. However the peaks in the SEP waveform are often undetectable due to low signal-to-noise (SNR) ratio. Sometimes they also become indistinct during injury when the SEP flattens. Hence time-domain analysis methods are often subject to errors, and need human-expert intervention. In this paper, we propose a new technique for analyzing the shape of the evoked potentials, in which slope information is obtained for the entire signal in specific time bins. Apart from solving the problems associated with present methods, this technique has an added advantage of analyzing the SEP signal as a whole rather than simply a few peaks. The efficacy of this technique was investigated on SEP signals recorded from 12 rats before and after contusion spinal cord injury at thoracic vertebra T8. The statistical analysis results revealed significant effect of injury to hindlimbs, whereas almost none to forelimbs. Thus, the results show high potential of this technique to differentiate between normal and injured spinal cord.