Influence of Cooling duration on Efficacy in Cardiac Arrest Patients (ICECAP): study protocol for a multicenter, randomized, adaptive allocation clinical trial to identify the optimal duration of induced hypothermia for neuroprotection in comatose, adult survivors of after out-of-hospital cardiac arrest.

Background: Cardiac arrest is a common and devastating emergency of both the heart and brain. More than 380,000 patients suffer out-of-hospital cardiac arrest annually in the United States. Induced cooling of comatose patients markedly improved neurological and functional outcomes in pivotal randomized clinical trials, but the optimal duration of therapeutic hypothermia has not yet been established. Methods: This study is a multi-center randomized, response-adaptive, duration (dose) finding, comparative effectiveness clinical trial with blinded outcome assessment. We investigate two populations of adult comatose survivors of cardiac arrest to ascertain the shortest duration of cooling that provides the maximum treatment effect. The design is based on a statistical model of response as defined by the primary endpoint, a weighted 90-day mRS (modified Rankin Scale, a measure of neurologic disability), across the treatment arms. Subjects will initially be equally randomized between 12, 24, and 48 hours of therapeutic cooling. After the first 200 subjects have been randomized, additional treatment arms between 12 and 48 hours will be opened and patients will be allocated, within each initial cardiac rhythm type (shockable or non-shockable), by response adaptive randomization. As the trial continues, shorter and longer duration arms may be opened. A maximum sample size of 1800 subjects is proposed. Secondary objectives are to characterize: the overall safety and adverse events associated with duration of cooling, the effect on neuropsychological outcomes, and the effect on patient reported quality of life measures. Discussion: In-vitro and in-vivo studies have shown the neuroprotective effects of therapeutic hypothermia for cardiac arrest. We hypothesize that longer durations of cooling may improve either the proportion of patients that attain a good neurological recovery or may result in better recovery among the proportion already categorized as having a good outcome. If the treatment effect of cooling is increasing across duration, for at least some set of durations, then this provides evidence of the efficacy of cooling itself versus normothermia, even in the absence of a normothermia control arm, confirming previous RCTs for OHCA survivors of shockable rhythms and provides the first prospective controlled evidence of efficacy in those without initial shockable rhythms. Trial registration: ClinicalTrials.gov (NCT04217551, 2019-12-30).

Long-term impact of COVID-19 hospitalisation among individuals with pre-existing airway diseases in the UK: a multicentre, longitudinal cohort study - PHOSP-COVID.

Background: The long-term outcomes of COVID-19 hospitalisation in individuals with pre-existing airway diseases are unknown. Methods: Adult participants hospitalised for confirmed or clinically suspected COVID-19 and discharged between 5 March 2020 and 31 March 2021 were recruited to the Post-hospitalisation COVID-19 (PHOSP-COVID) study. Participants attended research visits at 5 months and 1 year post discharge. Clinical characteristics, perceived recovery, burden of symptoms and health-related quality of life (HRQoL) of individuals with pre-existing airway disease (i.e., asthma, COPD or bronchiectasis) were compared to the non-airways group. Results: A total of 615 out of 2697 (22.8%) participants had a history of pre-existing airway diseases (72.0% diagnosed with asthma, 22.9% COPD and 5.1% bronchiectasis). At 1 year, the airways group participants were less likely to feel fully recovered (20.4% versus 33.2%, p<0.001), had higher burden of anxiety (29.1% versus 22.0%, p=0.002), depression (31.2% versus 24.7%, p=0.006), higher percentage of impaired mobility using short physical performance battery ≤10 (57.4% versus 45.2%, p<0.001) and 27% had a new disability (assessed by the Washington Group Short Set on Functioning) versus 16.6%, p=0.014. HRQoL assessed using EQ-5D-5L Utility Index was lower in the airways group (mean±SD 0.64±0.27 versus 0.73±0.25, p<0.001). Burden of breathlessness, fatigue and cough measured using a study-specific tool was higher in the airways group. Conclusion: Individuals with pre-existing airway diseases hospitalised due to COVID-19 were less likely to feel fully recovered, had lower physiological performance measurements, more burden of symptoms and reduced HRQoL up to 1 year post-hospital discharge.

Overcoming Time-Varying Confounding in Self-Controlled Case Series with Active Comparators: Application and Recommendations.

Confounding by indication is a key challenge for pharmacoepidemiologists. Although self-controlled study designs address time-invariant confounding, indications sometimes vary over time. For example, infection might act as a time-varying confounder in a study of antibiotics and uveitis, because it is time-limited and a direct cause both of receiving antibiotics and uveitis. Methods for incorporating active comparators in self-controlled studies to address such time-varying confounding by indication have only recently been developed. In this paper we formalize these methods, and provide a detailed description for how the active comparator rate ratio can be derived in a self-controlled case series (SCCS): either by explicitly comparing the regression coefficients for a drug of interest and an active comparator under certain circumstances using a simple ratio approach, or through the use of a nested regression model. The approaches are compared in two case studies, one examining the association between thiazolidinediones and fractures, and one examining the association between fluoroquinolones and uveitis using the UK Clinical Practice Research DataLink. Finally, we provide recommendations for the use of these methods, which we hope will support the design, execution and interpretation of SCCS using active comparators and thereby increase the robustness of pharmacoepidemiological studies.

Use of Real-World Data and Machine Learning to Screen for Maternal and Paternal Characteristics Associated with Cardiac Malformations.

Effective prevention of cardiac malformations, a leading cause of infant morbidity, is constrained by limited understanding of etiology. The study objective was to screen for associations between maternal and paternal characteristics and cardiac malformations. We selected 720,381 pregnancies linked to live-born infants (n=9,076 cardiac malformations) in 2011-2021 MarketScan US insurance claims data. Odds ratios were estimated with clinical diagnostic and medication codes using logistic regression. Screening of 2,000 associations selected 81 associated codes at the 5% false discovery rate. Grouping of selected codes, using latent semantic analysis and the Apriori-SD algorithm, identified elevated risk with known risk factors, including maternal diabetes and chronic hypertension. Less recognized potential signals included maternal fingolimod or azathioprine use. Signals identified might be explained by confounding, measurement error, and selection bias and warrant further investigation. The screening methods employed identified known risk factors, suggesting potential utility for identifying novel risk factors for other pregnancy outcomes.

Investigating Haptic Feedback in Vision-Deficient Millirobot Telemanipulation.

The evolution of magnetically actuated millirobots gives rise to unique teleoperation challenges due to their non-traditional kinematic and dynamic architectures, as well as their frequent use of suboptimal imaging modalities. Recent investigations into haptic interfaces for millirobots have shown promise but lack the clinically motivated task scenarios necessary to justify future development. In this work, we investigate the utility of haptic feedback on bilateral teleoperation of a magnetically actuated millirobot in visually deficient conditions. We conducted an N=23 user study in an aneurysm coiling inspired procedure, which required participants to navigate the robot through a maze in near total darkness to manipulate beads to a target under simulated fluoroscopy. We hypothesized that users will be better able to complete the telemanipulation task with haptic feedback while reducing excess forces on their surroundings compared to the no feedback conditions. Our results showed an over 40% improvement in participants' bead scoring, a nearly 10% reduction in mean force, and 13% reduction in maximum force with haptic feedback, as well as significant improvements in other metrics. Results highlight that benefits of haptic feedback are retained when haptic feedback is removed. These findings suggest that haptic feedback has the potential to significantly improve millirobot telemanipulation and control in traditionally vision deficient tasks.

Review of chemical models and applications in Geant4-DNA: Report from the ESA BioRad III Project.

A chemistry module has been implemented in Geant4-DNA since Geant4 version 10.1 to simulate the radiolysis of water after irradiation. It has been used in a number of applications, including the calculation of G-values and early DNA damage, allowing the comparison with experimental data. Since the first version, numerous modifications have been made to the module to improve the computational efficiency and extend the simulation to homogeneous kinetics in bulk solution. With these new developments, new applications have been proposed and released as Geant4 examples, showing how to use chemical processes and models. This work reviews the models implemented and application developments for modeling water radiolysis in Geant4-DNA as reported in the ESA BioRad III Project.

Single-cell analysis of bronchoalveolar cells in inflammatory and fibrotic post-COVID lung disease.

Background: Persistent radiological lung abnormalities are evident in many survivors of acute coronavirus disease 2019 (COVID-19). Consolidation and ground glass opacities are interpreted to indicate subacute inflammation whereas reticulation is thought to reflect fibrosis. We sought to identify differences at molecular and cellular level, in the local immunopathology of post-COVID inflammation and fibrosis. Methods: We compared single-cell transcriptomic profiles and T cell receptor (TCR) repertoires of bronchoalveolar cells obtained from convalescent individuals with each radiological pattern, targeting lung segments affected by the predominant abnormality. Results: CD4 central memory T cells and CD8 effector memory T cells were significantly more abundant in those with inflammatory radiology. Clustering of similar TCRs from multiple donors was a striking feature of both phenotypes, consistent with tissue localised antigen-specific immune responses. There was no enrichment for known SARS-CoV-2-reactive TCRs, raising the possibility of T cell-mediated immunopathology driven by failure in immune self-tolerance. Conclusions: Post-COVID radiological inflammation and fibrosis show evidence of shared antigen-specific T cell responses, suggesting a role for therapies targeting T cells in limiting post-COVID lung damage.

Systemic Fluoroquinolone Use and Risk of Uveitis or Retinal Detachment.

Importance: Fluoroquinolone use has been associated with increased risk of uveitis and retinal detachment in noninterventional studies, but the findings have been conflicting and causality is unclear. Objective: To estimate the association of systemic fluoroquinolone use with acute uveitis or retinal detachment, using multiple analyses and multiple databases to increase the robustness of results. Design, Setting, and Participants: This cohort study used data from the Clinical Practice Research Datalink Aurum and GOLD UK primary care records databases, which were linked to hospital admissions data. Adults prescribed a fluoroquinolone or a comparator antibiotic, cephalosporin, between April 1997 and December 2019 were included. Adults with uveitis or retinal detachment were analyzed in a separate self-controlled case series. Data analysis was performed from May 2022 to May 2023. Exposures: Systemic fluoroquinolone or comparator antibiotic. Main Outcomes and Measures: The primary outcome was a diagnosis of acute uveitis or retinal detachment. Hazard ratios (HRs) were estimated in the cohort study for the association of fluoroquinolone prescription with either uveitis or retinal detachment, using stabilized inverse probability of treatment weighted Cox regression. Rate ratios (RRs) were estimated in the self-controlled case series, using conditional Poisson regression. Estimates were pooled across databases using fixed-effects meta-analysis. Results: In total, 3 001 256 individuals in Aurum (1 893 561 women [63.1%]; median [IQR] age, 51 [35-68] years) and 434 754 in GOLD (276 259 women [63.5%]; median [IQR] age, 53 [37-70] years) were included in the cohort study. For uveitis, the pooled adjusted HRs (aHRs) for use of fluoroquinolone vs cephalosporin were 0.91 (95% CI, 0.72-1.14) at first treatment episode and 1.07 (95% CI, 0.92-1.25) over all treatment episodes. For retinal detachment, the pooled aHRs were 1.37 (95% CI, 0.80-2.36) at first treatment episode and 1.18 (95% CI, 0.84-1.65) over all treatment episodes. In the self-controlled case series, for uveitis, the pooled adjusted RRs (aRRs) for fluoroquinolone use vs nonuse were 1.13 (95% CI, 0.97-1.31) for 1 to 29 days of exposure, 1.16 (95% CI, 1.00-1.34) for 30 to 59 days, and 0.98 (95% CI, 0.74-1.31) for 60 days for longer. For retinal detachment, pooled aRRs for fluoroquinolone use vs nonuse were 1.15 (95% CI, 0.86-1.54) for 1 to 29 days of exposure, 0.94 (95% CI, 0.69-1.30) for 30 to 59 days, and 1.03 (95% CI, 0.59-1.78) for 60 days or longer. Conclusions and Relevance: These findings do not support an association of systemic fluoroquinolone use with substantively increased risk of uveitis or retinal detachment. Although an association cannot be completely ruled out, these findings indicate that any absolute increase in risk would be small and, hence, of limited clinical importance.

Post-resolution macrophages shape long-term tissue immunity and integrity in a mouse model of pneumococcal pneumonia.

Resolving inflammation is thought to return the affected tissue back to homoeostasis but recent evidence supports a non-linear model of resolution involving a phase of prolonged immune activity. Here we show that within days following resolution of Streptococcus pneumoniae-triggered lung inflammation, there is an influx of antigen specific lymphocytes with a memory and tissue-resident phenotype as well as macrophages bearing alveolar or interstitial phenotype. The transcriptome of these macrophages shows enrichment of genes associated with prostaglandin biosynthesis and genes that drive T cell chemotaxis and differentiation. Therapeutic depletion of post-resolution macrophages, inhibition of prostaglandin E2 (PGE2) synthesis or treatment with an EP4 antagonist, MF498, reduce numbers of lung CD4+/CD44+/CD62L+ and CD4+/CD44+/CD62L-/CD27+ T cells as well as their expression of the α-integrin, CD103. The T cells fail to reappear and reactivate upon secondary challenge for up to six weeks following primary infection. Concomitantly, EP4 antagonism through MF498 causes accumulation of lung macrophages and marked tissue fibrosis. Our study thus shows that PGE2 signalling, predominantly via EP4, plays an important role during the second wave of immune activity following resolution of inflammation. This secondary immune activation drives local tissue-resident T cell development while limiting tissue injury.

The Value of Master's Degree Programmes in Health Professions Education: A Scoping Review.

INTRODUCTION: There are increasing numbers of Master's Degree Programmes in Health Professions Education (MHPE), and the value to their students and graduates is not well understood. We conducted a scoping review to explore what is known about the value of MHPE programmes to their students and graduates. METHODS: A scoping review was conducted using Arksey and O'Malley's five-stage framework. PubMed, CINAHL, Cochrane, BEI, ERIC and EThOs databases were searched in addition to cited reference searching. Original research with an evaluation and published in the English language were included. RESULTS: Nineteen studies were included. Studies were based in a variety of locations on five continents, and included in-person, distance and blended learning. Students and graduates of MHPE programmes self-reported development of their pedagogical knowledge, confidence and credibility in their role as an educator, and educational scholarship. Enhanced career opportunities and opportunities for collegial interactions and networks were also reported. Important barriers included struggling with the time and financial commitments required for studying on a MHPE programme. CONCLUSIONS: There are a variety of dimensions of value of MHPE programmes to their students and graduates. Important practical recommendations for MHPE programme providers and employers include providing opportunities for the development of networks and supporting the time and financial commitments required for studying.

Ultrasound imaging guided precision histotripsy: Effects of pulse settings on ablation properties in rat brain.

A high-frequency 6 MHz miniature handheld histotripsy device with an endoscopic form factor and co-registered high-resolution ultrasound imaging was developed. This device could allow precision histotripsy ablation during minimally invasive brain tumor surgeries with real-time image guidance. This study characterized the outcome of acute histotripsy in the normal in vivo rat brain using the device with a range of histotripsy pulse settings, including number of cycles, pulse repetition frequency, and pressure, as well as other experimental factors. The stability and shape of the bubble cloud were measured during ablations, as well as the post-histotripsy ablation shape in ultrasound B-mode and histology. The results were compared between histological images and the ultrasound imaging data to determine how well ultrasound data reflected observable damage in histology. The results indicated that while pulse settings can have some influence on ablation shape, sample-to-sample variation had a larger influence on ablation shape. This suggests that real-time ablation monitoring is essential for accurate knowledge of outcomes. Ultrasound imaging provided an accurate real-time indication of ablation shape both during ablation and post-ablation.

Bacterial surface lipoproteins mediate epithelial microinvasion by Streptococcus pneumoniae.

Streptococcus pneumoniae, a common colonizer of the upper respiratory tract, invades nasopharyngeal epithelial cells without causing disease in healthy participants of controlled human infection studies. We hypothesized that surface expression of pneumococcal lipoproteins, recognized by the innate immune receptor TLR2, mediates epithelial microinvasion. Mutation of lgt in serotype 4 (TIGR4) and serotype 6B (BHN418) pneumococcal strains abolishes the ability of the mutants to activate TLR2 signaling. Loss of lgt also led to the concomitant decrease in interferon signaling triggered by the bacterium. However, only BHN418 lgt::cm but not TIGR4 lgt::cm was significantly attenuated in epithelial adherence and microinvasion compared to their respective wild-type strains. To test the hypothesis that differential lipoprotein repertoires in TIGR4 and BHN418 lead to the intraspecies variation in epithelial microinvasion, we employed a motif-based genome analysis and identified an additional 525 a.a. lipoprotein (pneumococcal accessory lipoprotein A; palA) encoded by BHN418 that is absent in TIGR4. The gene encoding palA sits within a putative genetic island present in ~10% of global pneumococcal isolates. While palA was enriched in the carriage and otitis media pneumococcal strains, neither mutation nor overexpression of the gene encoding this lipoprotein significantly changed microinvasion patterns. In conclusion, mutation of lgt attenuates epithelial inflammatory responses during pneumococcal-epithelial interactions, with intraspecies variation in the effect on microinvasion. Differential lipoprotein repertoires encoded by the different strains do not explain these differences in microinvasion. Rather, we postulate that post-translational modifications of lipoproteins may account for the differences in microinvasion.IMPORTANCEStreptococcus pneumoniae (pneumococcus) is an important mucosal pathogen, estimated to cause over 500,000 deaths annually. Nasopharyngeal colonization is considered a necessary prerequisite for disease, yet many people are transiently and asymptomatically colonized by pneumococci without becoming unwell. It is therefore important to better understand how the colonization process is controlled at the epithelial surface. Controlled human infection studies revealed the presence of pneumococci within the epithelium of healthy volunteers (microinvasion). In this study, we focused on the regulation of epithelial microinvasion by pneumococcal lipoproteins. We found that pneumococcal lipoproteins induce epithelial inflammation but that differing lipoprotein repertoires do not significantly impact the magnitude of microinvasion. Targeting mucosal innate immunity and epithelial microinvasion alongside the induction of an adaptive immune response may be effective in preventing pneumococcal colonization and disease.

The Influence of the COVID-19 Pandemic on Baseline Concussion Symptom Assessments Among Adolescents.

Introduction The COVID-19 pandemic resulted in the cancellation of high school sports in spring 2020, a modified resumption of sports in the 2020-2021 academic year, and a return to pre-pandemic sports in 2021-2022. This cancellation had a major impact on the quality of life of adolescent athletes, but it is unknown exactly how these pandemic-driven sports disruptions on athlete baseline (preseason) symptoms affected quality of life. Therefore, the current study retrospectively evaluated symptom inventories from Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) assessments to determine whether the cancellation of sports during the COVID-19 pandemic affected baseline (preseason) self-reported symptoms among adolescent athletes. Methods Our study used a retrospective cohort design to evaluate high school athletes with complete ImPACT assessments in the academic years before (2018-2019 and 2019-2020), during (2020-2021), and after (2021-2022) the pandemic. Specifically, data from a 22-item symptom report called the Post-Concussion Symptom Scale (PCSS) assessed during ImPACT was collected and analyzed using generalized linear models with a Tweedie exponential dispersion model and post hoc Tukey's honestly significant difference tests. The main outcomes were the total symptom severity score and the affective cluster score. Secondary outcomes were the analysis of the vestibular-somatic, cognitive-sensory, and sleep-arousal symptom clusters. Results Of the 104,274 ImPACT assessments, the total symptom severity score on the PCSS was different across years (p<0.001). There were lower symptom scores in 2020-2021 (5.33, 95% CI = 5.13-5.54) than in 2018-2019 (6.82, 95% CI = 6.63-7.01), 2019-2020 (6.94, 95% CI = 6.75-7.14), and 2021-2022 (6.44, 95% CI = 6.25-6.64). The cluster scores on the PCSS for affective, cognitive-sensory, sleep-arousal, and vestibular-somatic were also lower (p<0.001) in 2020-2021 than in 2018-2019, 2019-2020, and 2021-2022. Conclusion Contrary to our expectations, total symptom severity and cluster scores on the PCSS during the pandemic (2020-2021) were significantly lower than during the years before and after the pandemic-driven sports disruptions, suggesting the pandemic did not negatively affect these athletes as expected. These results also suggested that self-reported symptoms utilized in the PCSS component of ImPACT may not be as sensitive to sports disruption among adolescent athletes as other quality-of-life measures, especially during the COVID-19 pandemic.

Twelve tips for using rapid research methods in health professions education.

Information may be required within a short time-frame for making decisions about programmes and interventions in health professions education. Rapid research methods have been increasingly used in healthcare, especially for qualitative research studies and literature reviews. An essential aspect of using rapid research methods is pragmatism, in which there is a balance between the constraints of the short time frame (typically less than 3 months), the available resources, and the rigour for an appropriate standard of quality. Achieving this balance requires careful attention to the design of the research, including clarification of the decision-maker's information needs and the use of rapid methods for literature review, selection of participants, and data collection and analysis. The intention of the article is to provide a practical guide for how rapid research methods for qualitative research studies and literature reviews can be adapted for health professions education.

The Expected Behaviors of Posterior Predictive Tests and Their Unexpected Interpretation.

Poor fit between models of sequence or trait evolution and empirical data is known to cause biases and lead to spurious conclusions about evolutionary patterns and processes. Bayesian posterior prediction is a flexible and intuitive approach for detecting such cases of poor fit. However, the expected behavior of posterior predictive tests has never been characterized for evolutionary models, which is critical for their proper interpretation. Here, we show that the expected distribution of posterior predictive P-values is generally not uniform, in contrast to frequentist P-values used for hypothesis testing, and extreme posterior predictive P-values often provide more evidence of poor fit than typically appreciated. Posterior prediction assesses model adequacy under highly favorable circumstances, because the model is fitted to the data, which leads to expected distributions that are often concentrated around intermediate values. Nonuniform expected distributions of P-values do not pose a problem for the application of these tests, however, and posterior predictive P-values can be interpreted as the posterior probability that the fitted model would predict a dataset with a test statistic value as extreme as the value calculated from the observed data.

An 8 mm endoscopic histotripsy array with integrated high-resolution ultrasound imaging.

An 8 mm diameter, image-guided, annular array histotripsy transducer was fabricated and characterized. The array was laser etched on a 5 MHz, 1-3 dice and fill, PZT-5H/epoxy composite with a 45 % volume fraction. Flexible PCBs were used to electrically connect to the array elements using wirebonds. The array was backed with a low acoustic impedance epoxy mixture. A 3.6 by 3.8 mm, 64-element, 30 MHz phased array imaging probe was positioned in the center hole, to co-align the imaging plane with the bubble cloud produced by the therapy array. A custom 16-channel high voltage pulse generator was used to test the annular array for focal lengths ranging from 3- to 8-mm. An aluminum lens-focussed transducer with a 7 mm focal length was fabricated using the same piezocomposite and backing material and tested along with the histotripsy array. Simulated results from COMSOL FEM models were compared to measured results for low voltage characterization of the array and lens-focussed transducer. The measured transmit sensitivity of the array ranged from 0.113 to 0.167 MPa/V, while the lens-focussed transducer was 0.192 MPa/V. Simulated values were 0.160 to 0.174 MPa/V and 0.169 MPa/V, respectively. The measured acoustic fields showed a significantly increased depth-of-field compared the lens-focussed transducer, while the beamwidths of the array focus were comparable to the lens. The measured cavitation voltage in water was between 254 V and 498 V depending on the focal length, and 336 V for the lens-focussed transducer. The array had a lower cavitation voltage than the lens-focussed transducer for a comparable operating depth. The histotripsy array was tested in a tissue phantom and an in vivo rat brain. It was used to produce an elongated lesion in the brain by electronically steering the focal length from 3- to 8-mm axially. Real time ultrasound imaging with a Doppler overlay was used to target the tissue and monitor ablation progress, and histology confirmed the targeted tissue was fully homogenized.

Accounting for Twins and Other Multiple Births in Perinatal Studies Conducted Using Healthcare Administration Data.

The analysis of perinatal studies is complicated by twins and other multiple births even when they are not the exposure, outcome, or a confounder of interest. Common approaches to handling multiples in studies of infant outcomes include restriction to singletons, counting outcomes at the pregnancy-level (i.e., by counting if at least one twin experienced a binary outcome), or infant-level analysis including all infants and, typically, accounting for clustering of outcomes by using generalised estimating equations or mixed effects models. Several healthcare administration databases only support restriction to singletons or pregnancy-level approaches. For example, in MarketScan insurance claims data, diagnoses in twins are often assigned to a single infant identifier, thereby preventing ascertainment of infant-level outcomes among multiples. Different approaches correspond to different causal questions, produce different estimands, and often rely on different assumptions. We demonstrate the differences that can arise from these different approaches using Monte Carlo simulations, algebraic formulas, and an applied example. Furthermore, we provide guidance on the handling of multiples in perinatal studies when using healthcare administration data.